Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:22]2[CH2:24][CH2:23]2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:7][C:8]=1[CH2:9][O:10][CH3:11].[CH2:25]([O:27][C:28](=[O:40])[C:29]([O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)([CH3:31])[CH3:30])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:25]([O:27][C:28](=[O:40])[C:29]([O:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:2][C:3]2[C:4]([CH:22]3[CH2:24][CH2:23]3)=[N:5][C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:7][C:8]=2[CH2:9][O:10][CH3:11])=[CH:37][CH:38]=1)([CH3:31])[CH3:30])[CH3:26]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(COC)nc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1
Yield: 73.1 %

Procedure:
A solution of 200 mg (0.56 mmol) 5-chloromethyl-4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 113H]), 125 mg (0.56 mmol) 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester [Newman, Melvin S.; Cella, James A. Monoalkylation of hydroquinone. Journal of Organic Chemistry (1974), 39(2), p 214–15] and 237 mg (0.73 mmol) cesium carbonate in 3 ml DMF was stirred for 3 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. After purification of the crude product by chromatography over silica gel with AcOEt/heptane 1:3, 223 mg of pure 2-{4-[4-Cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester was isolated.
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.C([O-])(=O)C=C.[CH3:64][C:65]1[CH:70]=[CH:69][C:68]([S:71]([N-:74][Cl:75])(=[O:73])=[O:72])=[CH:67][CH:66]=1.O.O.O.[Na+].S([O-])([O-])=O.[Na+].[Na+].CC1C=CC(S(N)(=O)=O)=CC=1>C(#N)C.O>[CH3:64][C:65]1[CH:70]=[CH:69][C:68]([S:71]([NH:74][Cl:75])(=[O:73])=[O:72])=[CH:67][CH:66]=1
Reactant: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: C=CC(=O)[O-]
Agent: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: Cc1ccc(S(N)(=O)=O)cc1
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)NCl)cc1

Procedure:
To a stirred solution of (DHQ)2-PHAL (0.11 g, 0.14 mmol, 5 mol %) in 20 mL of acetonitrile and 20 mL of water, in any convenient-sized glass vessel or vial, was added desired acrylate or methacrylates entries 1-10 (all commercially available from Aldrich, 2.8 mmol), Chloramine-T trihydrate (2.42 g, 8.4 mmol, 3 eq) and K2OsO2(OH)4 (41.6 mg, 0.112 mmol, 4 mol %). As the reaction proceeded to completion over the course of about one and half hours at room temperature, the color of the solution changed from yellow to pale green, then deep green and finally back to yellow. After addition of aqueous sodium sulfite (1.0 g in 15 mL H2O), the phases were separated, and the aqueous phase extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine, dried over MgSO4 and the solvent concentrated to give the crude product, which also contains the p-toluenesulfonamide by-product produced upon the reduction of the excess Chloramine-T. Purification provides compounds as shown in FIG. 16, entries 1-10 with the indicated yields and conditions. NOTE: Replacement of the 3 eq of Chloramine-T with 1.5 eq of Chloramine-T and 1.5 eq of Et4NOAc gives comparable results and reduces the amount of p-toluenesulfonamide by-product formed. This can greatly simplify product isolation, especially in cases where the product and the toluenesulfonamide have similar chromatographic mobilities.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[OH-:32].[Na+].[I-].[Na+]>O>[OH:32][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6]
Reactant: [OH-]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCO)CC3)c[nH]c12
Yield: 68 %

Procedure:
Following the general procedure of example 159, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (23.0 mg, 0.050 mmol), 50% NaOH in water (1 mL), and sodium iodide (5.0 mg) were reacted to give the title compound (15.0 mg, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([C:12]=1[Cl:13])[C:7]([O:9]CC)=[O:8].C(O)C.[OH-].[Na+].Cl>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([C:12]=1[Cl:13])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(OC)ccc(Br)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Br)c(Cl)c1C(=O)O

Procedure:
A mixture of 4A (1.7 g, 5.8 mmol), water (10 ml), ethanol (20 ml) and sodium hydroxide (0.5 g, 12.5 mmol) is heated under reflux with stirring. The reaction mixture is diluted with water (80 ml) and acidified with concentrated hydrochloric acid. The solid material is collected by filtration, washed with water and dried yielding white crystals, 1.3 g (85%), mp 186-188° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:24]=[C:15]3[CH2:16][N:17]([CH2:20][CH2:21][O:22][CH3:23])[CH2:18][CH2:19][N:14]3[N:13]=2)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[CH2:56][CH2:55][N:54]3[C:47](=[CH:48][C:49]4[CH2:50][C:51]([CH3:58])([CH3:57])[CH2:52][C:53]=43)[C:46]2=[O:59])=[N:32][CH:33]=[CH:34][C:35]=1B1OC(C)(C)C(C)(C)O1)(=[O:27])[CH3:26].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[CH2:56][CH2:55][N:54]3[C:47](=[CH:48][C:49]4[CH2:50][C:51]([CH3:58])([CH3:57])[CH2:52][C:53]=43)[C:46]2=[O:59])=[N:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:24]=[C:15]3[CH2:16][N:17]([CH2:20][CH2:21][O:22][CH3:23])[CH2:18][CH2:19][N:14]3[N:13]=2)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8])(=[O:27])[CH3:26]
Reactant: COCCN1CCn2nc(Nc3cc(Br)c(C)n(C)c3=O)cc2C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: COCCN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)c(C)n(C)c3=O)cc2C1
Temperature: 95 °C
Yield: 44.9 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 327e (158 mg, 0.40 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (159 mg, 0.40 mmol), K3PO4 (170 mg, 0.80 mmol), sodium acetate (66 mg, 0.80 mmol), Pd(dppf)Cl2 (15 mg, 0.020 mmol), and acetonitrile/water (7/0.5 mL). After three cycles of vacuum/N2 flush, the mixture was heated at 95° C. for 1 h. LCMS analysis showed complete conversion to the desired product. The reaction mixture was cooled to room temperature, and diluted with dichloromethane (50 mL) and water (30 mL). The water layer was extracted with dichloromethane (2×30 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1) to afford 327f (120 mg, 45%) as a yellow solid. MS-ESI: [M+H]+ 668.8
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[C:14](Cl)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:20][NH2:21].[ClH:22].CO>CO.C(OCC)C>[ClH:18].[ClH:22].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:21][CH3:20])[N:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CN
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(Cl)c2)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(Cl)n1
Yield: 41 %

Procedure:
0.11 g (0.00035 mol) of 4-amino-N-(2,6-dichloro-pyridin-4-yl)-benzenesulfonamide was stirred in 25 ml of liquid methylamine in an autoclave at 130° C. for 72 hours. After removal of the methylamine the residue was taken up in 5 ml of dichloro-methane/methanol 1:1, filtered and, after removal of the solvent, chromatographed on silica gel with hexane/ethyl acetate 3:1, 2:1 and finally 1:1. The product, obtained as a white, amorphous solid substance, was dissolved in 2 ml of methanol, treated with 2 ml of 2N HCl/methanol, diluted with 20 ml of diethyl ether and filtered off under suction. The material on the suction filter was washed well with diethyl ether and dried in a high vacuum. There was obtained 0.055 g (41%) of 4-amino-N-(2-chloro-6-methylamino-pyridin-4-yl)-benzenesulfonamide dihydrochloride (1:2) as white crystals; m.p.: >215° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:8]([Cl:13])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ncccc1Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ncccc1Cl
Temperature: 120 °C
Reaction time: 20 h

Procedure:
To a suspension of 3-chloropicolinic acid (1.58 g, 10 mmol) in toluene (6 mL) was added an excess of thionyl chloride (9.52 g, 5.84 mL, 80.0 mmol) at room temperature under a nitrogen atmosphere. The resulting suspension was heated to 120° C. (oil bath temperature) and stirred for 20 h. Then, the solvent and excess of thionyl chloride were removed under vacuum and the residue was dissolved one more time in toluene and the solvent was removed again. The resulting residue was dried under high vacuum and used in the next step.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].O.[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14])[CH3:17]
Reactant: CCc1ccccc1B(O)O
Reactant: COCc1cc(C(=O)OC)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccccc1-c1ccc(C(=O)OC)cc1COC
Reaction time: 12 h
Yield: 83 %

Procedure:
To a solution of methyl 4-bromo-3-(methoxymethyl)benzoate, (Intermediate 28, step 2) (12 g, 0.0463 mol) in toluene (150 mL) and water (35 mL) under N2, was added 2-ethyl benzene boronic acid (9.02 g, 0.0601 mol) followed by potassium carbonate (19 g, 0.1389 mol) and Pd(PPh3)4 (2.67 g, 0.0023 mol). The reaction mixture was degassed with N2 for 10 min before heating. After 12 hours at 100° C., the reaction mixture was diluted with EtOAc. The organic layer was washed with sodium bicarbonate sat. solution (1×100 mL), water (2×100 mL) and finally with brine (1×100 mL). It was then dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, 60-120 mesh, eluting with pet ether/EtOAc) to afford the title compound as a pale yellow liquid (12 g, 83%). 1H NMR (CDCl3, 400 MHz) δ 8.24-8.26 (1H, s), 7.99-8.01 (1H, d), 7.32-7.38 (2H, m), 7.22-7.27 (2H, m), 7.07-7.09 (1H, d), 4.12-4.21 (2H, d), 3.93-3.95 (3H, s), 3.28-3.30 (3H, s), 2.28-2.43 (2H, m), 1.01-1.05 (3H, t).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:34])[N:7]([CH2:14][CH2:15][CH2:16][C@H:17]3[O:21][C:20](=[O:22])[N:19]([C:23]4[CH:24]=[CH:25][C:26]5[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=5[CH:33]=4)[CH2:18]3)[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O1CCO[CH2:43][CH2:42]1>O>[CH3:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH:42]=[CH2:43])[CH:11]=2)[C:6](=[O:34])[N:7]([CH2:14][CH2:15][CH2:16][C@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:24]=[CH:25][C:26]4[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=4[CH:33]=3)[CH2:18]2)[C:8]1=[O:13]
Reactant: Cn1c(=O)n(CCC[C@@H]2CN(c3ccc4c(c3)NC(=O)CS4)C(=O)O2)c(=O)c2ccc(Br)cc21
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1ccc2c(=O)n(CCC[C@@H]3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)c(=O)n(C)c2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A suspension of the compound of Example 46 (0.33 mmol), tetrakis(triphenylphosphine)palladium(0) complex (0.016 mmol), vinylboronic anhydride pyridine complex (0.165 mmol) and K2CO3 (0.33 mmol) in dioxane (2.5 ml) and water (0.8 ml) was purged with argon. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was allowed cooling to rt and was diluted with water and EA. The org. layer was separated and the aq. layer was extracted with EA. The combined org. layers were washed with brine and dried over MgSO4, filtered and concentrated under reduced pressure. The resulting material was sequentially crystallized from TBME/MeOH, EA/MeOH and finally DCM, affording the title compound as colourless crystals in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[CH:13]=2)=[N+:4]([O-:29])[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: COc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cc(-c2c(Cl)cc(C(F)(F)F)c[n+]2[O-])ccc1Cl
Reaction time: 16 h

Procedure:
A solution of 4.5 g (14 mmol) of 3-chloro-2-(4-chloro-3-methoxyphenyl)-5-trifluoromethylpyridine and 9.7 g (31 mmol) of 3-chloroperbenzoic acid in 80 ml of methylene chloride was stirred at 23° C. for 4 days and then at 40° C. for 16 h. The mixture was then extracted with 100 ml of 10% strength aqueous sodium bisulfate solution, with 100 ml of a 10% strength aqueous sodium bicarbonate solution and three times with 80 ml of water each time. The organic phase was concentrated, and the residue was chromatographed on silica gel with cyclohexane/ethyl acetate (5:1). Yield: 3.6 g (76%) of colorless crystals; melting point: 156°-157° C.
Reaction SMILES: C([O:3][C:4]1[CH:13]=[C:12]([CH3:14])[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)C.Cl.N1C=CC=CC=1>>[OH:3][C:4]1[CH:13]=[C:12]([CH3:14])[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1
Reactant: CCOc1cc(C)c2[nH]c(=O)sc2c1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)cc2sc(=O)[nH]c12
Temperature: 180 °C
Reaction time: 15 h

Procedure:
1.00 g (4.78 mmol) 6-ethoxy-4-methylbenzo[d]thiazol-2(3H)-one and 7.00 g (60.57 mmol) pyridine hydrochloride were thoroughly mixed and stirred for 15 h under a nitrogen atmosphere at 180° C. The reaction mixture was poured onto water and extracted with ethyl acetate. The organic phase was washed with water and evaporated down i.vac. The residue was stirred with diisopropylether and suction filtered.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:10]1([N:1]2[C:9]3[C:4](=[N:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1cnc2cc[nH]c2c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(-n2ccc3ncccc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.5 %

Procedure:
1H-Pyrrolo[3,2-b]pyridine (0.5 g, 4.24 mmol), phenylboronic acid (1.03 g, 8.44 mmol), copper(II) acetate (1.54 g, 8.48 mmol), and 4A molecular sieves (2 g), were suspended in DCM (10 mL). Triethylamine (1.19 mL, 8.5 mmol) and pyridine (0.7 mL, 8.65 mmol) were added and the reaction stirred at r.t. for three days. The reaction mixture was diluted with further DCM, filtered and concentrated in vacuo. Chromatography (silica, EtOAc) gave the title compound (325 mg). δH (CDCl3) 7.80 (1H, d, J 8.2 Hz), 7.54–7.30 (7H, m), 7.15 (1H, brs), 6.88 (1H, brs). LCMS (ES+) RT 1.20 minutes, 195 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:21][CH:20]([O:23][CH2:24][CH3:25])[O:19][CH2:17][CH3:18])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(Cl)cc1C=O)OCC
Yield: 46.8 %

Procedure:
To a stirred suspension of 5-chloro-2-hydroxybenzaldehyde (5.0 g, 32.1 mmol) and K2CO3 (4.87 g, 35.3 mmol) in DMF (20 mL), bromoacetaldehyde diethyl acetal (5.43 mL, 35.3 mmol) was added dropwise. The mixture was refluxed for 4 h. After cooling, the precipitate was filtered off and the solvent was evaporated in vacuo. The crude residue was adsorbed on silica gel and purified by flash chromatography. The product was eluted with hexane/EtOAc (4:1) to give 33 (4.10 g, 38%) as an oil. 1H NMR (500 MHz, CDCl3): δ: 10.42 (1H, s, CHO), 7.76 (1H, d, J=2.8 Hz, ArH), 7.46 (1H, dd, J=6.15 & 2.75 Hz, ArH), 6.96 (1H, d, J=8.90 Hz, ArH), 4.87 (1H, t, J=5.25 Hz, CH), 4.10 (2H, d, J=5.25 Hz, CH2), 3.80-3.77 (2H, m, CH2CH3), 3.67-3.62 (2H, m, CH2CH3), 1.24 (6H, t, J=7.05 Hz, 2×CH3).
Reaction SMILES: Cl[Si](C)(C)C.BrCCBr.I[CH:11]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[F:18][C:19]1[C:24](I)=[N:23][CH:22]=[CH:21][N:20]=1>CC(N(C)C)=O.[Zn].[Cu]I>[F:18][C:19]1[C:24]([CH:11]2[CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:23][CH:22]=[CH:21][N:20]=1
Reactant: IC1CCCOCC1
Reactant: Fc1nccnc1I
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: CC(=O)N(C)C
Product: Fc1nccnc1C1CCCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of chlorotrimethylsilane (0.11 mL, 0.87 mmol) and 1,2 dibromoethane (0.075 mL, 0.87 mmol) was added slowly to a stirred mixture of zinc dust (0.71 g, 10.9 mmol) in DMA (2 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred for 15 min before a solution of 4-iodooxepane (1.97 g, 8.71 mmol) in DMA (5 mL) was added dropwise via syringe. The reaction mixture was stirred at room temperature for an additional 30 min before being warmed to 60° C. for 15 min. The reaction mixture was cooled to room temperature and added directly via syringe to a stirred mixture of 2-fluoro-3-iodopyrazine (1.39 g, 6.23 mmol), copper(i) iodide (0.12 g, 0.62 mmol), and dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(ii) (0.25 g, 0.31 mmol) in DMA (8 mL) under an argon atmosphere. The reaction mixture was stirred at 80° C. for 3 h. The reaction mixture was cooled to room temperature, quenched with sat. ammonium chloride, and extracted with EtOAc. The organic layer was separated, washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give 2-fluoro-3-(oxepan-4-yl)pyrazine. [M+1]=197.1.
Reaction SMILES: CS(C)=O.Cl[C:6]1[N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([C:21]1[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=1)[N:9]=2.[CH3:32][C@H:33]1[CH2:38][NH:37][CH2:36][CH2:35][NH:34]1>C(Cl)Cl.CO>[CH:29]1([CH2:28][N:7]2[C:6]([N:37]3[CH2:36][CH2:35][NH:34][C@@H:33]([CH3:32])[CH2:38]3)=[N:14][C:13]3[C:8]2=[N:9][C:10]([C:21]2[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=2)=[N:11][C:12]=3[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:31][CH2:30]1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Reactant: C[C@H]1CNCCN1
Solvent: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: C[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CCN1
Temperature: 85 °C
Reaction time: 18.5 h
Yield: 93.1 %

Procedure:
A dimethyl sulfoxide suspension (5 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (476.1 mg, 1.23 mmol) and (2S)-2-methylpiperazine (616.4 mg, 6.15 mmol) was heated at 100° C. to dissolve and the resulting mixture was stirred at 85° C. for 18.5 hours. (2S)-2-Methylpiperazine (123.3 mg, 1.23 mmol) was added and the resulting mixture was further stirred at 85° C. for 5.5 hours, left standing to cool, poured into methylene chloride-methanol (10:1), and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=32:1 to 9:1) to give the title compound (516.0 mg, 93%) as a pale yellow solid.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH:4](C)[C:5]([O:7][CH3:8])=[O:6].N[C@H:11](C)CC(O)=O>>[ClH:1].[NH2:2][C@H:3]([CH3:11])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: C[C@@H](N)CC(=O)O
Reactant: COC(=O)C(C)CN
Agent: Cl
Product: COC(=O)C[C@@H](C)N

Procedure:
Compound 57-B was prepared in analogy to compound W in Example 20 by using (R)-3-aminobutanoic acid instead of DL-3-aminoisobutyric acid.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[N:16]=[C:17]([N:25]5[CH2:30][CH2:29][N:28]([CH2:31][CH3:32])[CH2:27][CH2:26]5)[C:18]5[C:23]([CH:24]=4)=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[O:2]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[ClH:50]>CO>[ClH:50].[ClH:50].[ClH:50].[CH2:31]([N:28]1[CH2:29][CH2:30][N:25]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([N:6]4[CH2:5][CH2:4][CH:3]([OH:2])[CH2:8][CH2:7]4)=[CH:10][CH:11]=3)[N:16]=2)[CH2:26][CH2:27]1)[CH3:32]
Reactant: CCN1CCN(c2nc(-c3ccc(N4CCC5(CC4)OCCO5)cc3)cc3ccccc23)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: CO
Product: CCN1CCN(c2nc(-c3ccc(N4CCC(O)CC4)cc3)cc3ccccc23)CC1

Procedure:
3-[4-(4,4-Ethylenedioxypiperidin-1-yl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline (290 mg) obtained in Example 96 was treated with camphorsulfonic acid and methanol. Then, a 2N aqueous solution of hydrochloric acid (50 ml) was added thereto, and the mixture was reacted for 1 hr. The reaction solution was basified and extracted with ethyl acetate. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, the resulting residue was dissolved in methanol (20 ml), and then it was reacted with sodium borohydride (54 mg). The reaction solution was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 119 mg of the free compound of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:17]Br>CCOCC>[Br:17][CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:12]
Reactant: BrBr
Reactant: CCOc1cccc(C(C)=O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOc1cccc(C(=O)CBr)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
While a mixture of 3′-ethoxyacetophenone (37 g, 0.225 mol), aluminum chloride (0.27 g, 2 m mol) and ether (100 ml) was stirred under cooling with ice, bromine (11.5 ml, 0.225 m mol) was added dropwise thereto over a period of 15 minutes. After this mixture was further stirred for 10 minutes, ice water (500 ml) was added thereto and this mixture was extracted with ether (2×100 ml). After the extract was washed with water and dried, the solvent was distilled off under reduced pressure. The resulting residue was distilled under reduced pressure (150-155° C./5 mmHg) to obtain the desired compound (45.7 g). Although this product contained a small amount of dibromo-substituted compounds, it was directly used in the following step.