Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]([C:19]4[C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:21][O:22][C:23]=4[CH3:24])=[N:17][N:18]=3)=[CH:10][CH:9]=2)=[O:7])[CH:5]=[CH:4]N=C1.[CH:31]1(N)CC1>O1CCCC1>[CH:5]1([NH:1][C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]([C:19]4[C:20]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[N:21][O:22][C:23]=4[CH3:24])=[N:17][N:18]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:31]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(=O)n3ccnc3)cc2)o1
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(=O)NC3CC3)cc2)o1
Temperature: 80 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a suspension of imidazol-1-yl-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-methanone (200 mg, 0.50 mmol) in tetrahydrofuran (2 mL) was added cyclopropylamine (37 mg, 0.65 mmol) and the mixture was stirred for 3 h at 80° C. After cooling to ambient temperature the resulting suspension was concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20) afforded the title compound (149 mg, 77%) as a white solid. MS: m/e=387.2 [M+H]+.
Reaction SMILES: Cl[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]3[CH2:22][CH2:23][C:24]4[NH:25][C:26](=[O:29])[CH:27]=[CH:28][C:19]([C:20]=43)=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)(Cl)Cl>[C:4]1([CH2:3][CH:2]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]4[CH2:22][CH2:23][C:24]5[NH:25][C:26](=[O:29])[CH:27]=[CH:28][C:19]([C:20]=54)=[CH:18][N:17]=3)=[CH:12][CH:11]=2)[N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C1CCNC1
Reactant: O=C1C=CC2=CN=C(c3ccc(C(Cl)Cc4ccccc4)cc3)N3CCC(=C23)N1
Solvent: ClC(Cl)Cl
Product: O=C1C=CC2=CN=C(c3ccc(C(Cc4ccccc4)N4CCCC4)cc3)N3CCC(=C23)N1

Procedure:
This compound was prepared from intermediate 247b and pyrrolidine according to the procedure described in Example 245, with the exception of chloroform as solvent. Received 40 mg (11%).
Reaction SMILES: Cl[CH2:2][C:3](=[O:33])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:32])[C@@H:14]([N:24]4[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]4)[CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[C-]#N.[Na+].[CH3:37][N:38](C)C=O>CO.O>[OH:32][C@@H:13]1[C@@H:14]([N:24]2[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]2)[CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[C:19](=[O:23])[CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:33])[CH2:2][C:37]#[N:38])[CH2:12]1
Reactant: CN(C)C=O
Reactant: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(=O)CCl)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(=O)CC#N)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1

Procedure:
A stirred mixture of (2β,3α,5α)-21-chloro-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnane-11,20-dione (500 mg), sodium cyanide (500 mg), N,N-dimethylformamide (1.25 ml) in methanol (10 ml) and water (0.25 ml) was heated under reflux for 16 h. The resulting solution was cooled and poured into water (50 ml). The mixture was extracted with dichloromethane and the organic layer was washed with water to pH 7. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure and the residue (430 mg) was chromatographed on silica gel. The purified product (208 mg) was crystallised from dichloromethane-methanol to give (2β,3α,5α)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)-11,20-dioxopregnane-21-carbonitrile (96 mg). δ (CDCl3) 0.62 (s, 3H), 1.06 (s,3H), 1.22 (s,3H), 1.26 (s,3H) and 3.38 (s,2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:13](=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=2)[CH3:10])[C:5]([I:36])=[CH:4][N:3]=1.[OH-].[NH4+:38]>O1CCOCC1>[NH2:38][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:13](=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=2)[CH3:10])[C:5]([I:36])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: COc1ncc(-c2cccc3cc([C@H](C)Nc4nc(Cl)ncc4I)n(-c4ccccc4)c(=O)c23)cn1
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ncc(-c2cccc3cc([C@H](C)Nc4nc(N)ncc4I)n(-c4ccccc4)c(=O)c23)cn1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
To a solution of (S)-3-(1-((2-chloro-5-iodopyrimidin-4-yl)amino)ethyl)-8-(2-methoxypyrimidin-5-yl)-2-phenylisoquinolin-1 (2H)-one 3 (800 mg, 1.31 mmol) in anhydrous 1,4-dioxane (4 mL) in a sealed tube, ammonium hydroxide (7 mL) was added and the resulting mixture was stirred at 110° C. for 20 h. The mixture was allowed to cool to RT, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography using a silica gel cartridge and eluting with 0-8% MeOH-DCM to afford the product, (S)-3-(1-((2-amino-5-iodopyrimidin-4-yl)amino)ethyl)-8-(2-methoxypyrimidin-5-yl)-2-phenylisoquinolin-1(2H)-one 4.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=NC=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.BrC1C=C[N:28]=[C:27]([Cl:31])C=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:22]=[CH:21][N:28]=[C:27]([Cl:31])[CH:18]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: Clc1cc(Br)ccn1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2ccnc(Cl)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 4-Bromo-2-chloropyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as an off-white solid, MS (ISP): m/e=343.0, 345.0 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[CH2:2].Cl.[NH2:12][OH:13].C(=O)(O)[O-].[Na+]>CC(O)C.C(OCC)(=O)C>[OH:13][N:12]=[C:7]([NH2:8])[C:6]1[CH:9]=[CH:10][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1
Reactant: NO
Reactant: C=Cc1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C=Cc1ccc(C(N)=NO)cc1
Temperature: 80 °C
Yield: 96.7 %

Procedure:
To a mixture of 4-vinylbenzonitrile (4.36 g, 33.8 mmol) and hydroxylamine hydrochloride (4.69 g, 67.5 mmol) in 2-propanol (50 mL) was added sodium bicarbonate (11.34 g, 135 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried MgSO4, filtered, and concentrated to yield 5.3 g of N′-hydroxy-4-vinylbenzimidamide. MS (m+1)=163. HPLC Peak RT=0.53 minutes (Analytical Method B).
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[C:43]([CH3:44])=[CH:42][C:37]([C:38]([O:40]C)=O)=[CH:36][C:35]=5[CH3:45])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:46]4[CH2:49][CH:48]([F:50])[CH2:47]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:54][NH2:55]>C(O)C>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[C:35]([CH3:45])=[CH:36][C:37]([C:38]([NH:54][NH2:55])=[O:40])=[CH:42][C:43]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:46]4[CH2:49][CH:48]([F:50])[CH2:47]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:4]=[C:3]([C:2]([F:52])([F:1])[F:53])[CH:8]=1
Reactant: NN
Reactant: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Solvent: CCO
Product: COc1ncc(-c2c(C)cc(C(=O)NN)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C

Procedure:
Methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3-fluoroazetidin-1-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (EXAMPLE 32 Step A, 0.091 g, 0.122 mmol) was dissolved in ethanol (0.80 mL). Added hydrazine (0.115 mL, 3.65 mmol) and stirred at 85° C. in a screw cap vial (with a pressure relief cap) under a nitrogen blanket. The reaction was monitored by LCMS. Once complete the reaction was cooled to room temperature. The solvent was removed by rotary evaporation and the crude isolate was partitioned between ethyl acetate and water. Washed the organic twice more with water, then once with brine, dried over sodium sulfate, filtered and evaporated to give an off-white foam as the product. The compound was used without further purification. 1H NMR (CDCl3, 500 MHz): δ 8.15 (s, 1H), 8.00 (d, 1H), 7.88 (s, 1H), 7.74 (s, 2H), 7.51 (d, 2H), 7.43 (s, 1H), 7.27 (d, 1H), 5.70 (d, 1H), 5.51 (m, 0.5H), 5.40 (m, 0.5H), 4.69 (d, 1H), 4.45 (m, 3H), 4.29 (m, 2H), 3.99 (m, s, 4H), 2.14 (s, 3H), 2.13 (s, 3H), 1.65 (br, 2H), 0.74 (d, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1.[NH:23]1[CH2:34][CH2:33][CH2:32][C@H:24]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>>[CH3:31][C:28]([O:27][C:25](=[O:26])[C@@H:24]1[CH2:32][CH2:33][CH2:34][N:23]1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:13])[N:3]=1)([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1c1ccc2c(C(=O)NCC3CCCCC3)c(Cl)ccc2n1

Procedure:
Prepared according to the method of example 30, using 2,6-dichloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide Example 43(a)) (200 mg) and L-proline, 1,1-dimethylethyl ester (305 mg). Purification (SiO2, ethyl acetate:isohexane 20:80 as eluant) gave the sub-title compound as an oil (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:22]([C:21]3[CH:20]=[CH:19][C:18]([C:16]4[CH:15]=[N:14][C:10]5[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]6[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=6[C:28]([F:30])([F:29])[F:31])[C:9]=5[CH:17]=4)=[CH:26][CH:25]=3)=[O:23])[CH2:41][CH2:40]2)=[CH:37][CH:38]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=625.96 (M+H+); retention time=1.06 minutes.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
4.62 ml (0.03 mol) of ethyl piperidine-4-carboxylate were dissolved in 50 ml of dimethylformamide and treated with 4.98 ml (0.036 mol) of triethylamine. 3.9 ml (0.033 mol) of benzyl bromide were added while cooling with ice and the mixture was stirred for 10 min., warmed to 40° and stirred under an argon atmosphere for 18 hrs. The solvent was then distilled off, the residue was added to 100 ml of water, extracted three times with 100 ml of ether each time and the organic phase was dried over magnesium sulfate. 5.33 g (72%) of ethyl 1-benzyl-piperidine-4-carboxylate were obtained as a yellow oil. MS: me/e=248 (C15H22NO2+).
Reaction SMILES: [CH:1]1([N:4]=[C:5]=[O:6])[CH2:3][CH2:2]1.[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([NH2:25])[CH:23]=2)[N:18]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[N:17]=1.N1C=CC=CC=1>C(Cl)Cl>[NH:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]=[C:8]1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:6])[CH:23]=2)[N:18]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[N:17]=1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Reactant: O=C=NC1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)NC1CC1
Reaction time: 24 h
Yield: 53.4 %

Procedure:
Cyclopropylisocyanate (4 g, 0.048 mmol) was added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (15 mg, 0.045 mmol) and pyridine (0.01 mL, 0.126 mmol) in CH2Cl2 (5 mL). The mixture was stirred for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (2% CH3OH/CH2Cl2) afforded the title compound (10 mg) as a solid. 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 7.93 (d, 1H, J=8.8 Hz), 7.83 (m, 1H), 7.49 (d, 1H, J=8.8 Hz), 7.27-7.24 (m, 2H), 7.17 (s, 1H), 5.71 (dd, 1H, J=2.4 and 9.2 Hz), 4.04 (m, 1H), 3785 (m, 1H), 2.59 (m, 2H), 2.17-2.07 (m, 2H), 1.74 (m, 5H), 0.84 (q, 2H, J=5.2 Hz).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[C:15]1[N:23]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[CH:16]=1)=[NH:4].[C:34](OC(=O)C)(=O)[CH3:35]>C1(C)C=CC=CC=1>[CH3:14][N:10]1[C:11]2[C:7](=[CH:6][C:5]([C:3]3[N:4]=[C:34]([CH3:35])[O:1][N:2]=3)=[CH:13][CH:12]=2)[C:8]([C:15]2[N:23]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)(=[O:26])=[O:25])[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH:16]=2)=[CH:9]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(C(=N)NO)cc34)cc3cccnc32)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(-c5noc(C)n5)cc34)cc3cccnc32)cc1
Yield: 43.4 %

Procedure:
To a suspension of N-hydroxy-1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indole-5-carboxamidine [0.7 g, Reference Example 26] in toluene (30 mL) at ambient temperature under nitrogen was added acetic anhydride (0.467 g). The reaction mixture was heated at reflux for 4.5 hours then filtered. The filtrate was evaporated to give the title compound (0.32 g) as a dark red oil which was used immediately without further purification.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)([O-:3])=[O:2].[C:15]([O:22][CH3:23])(=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:17]([CH:16]([CH:5]([C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[C:15]([O:22][CH3:23])=[O:21])=[O:18]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])/C=C/c1ccc2c(c1)OCO2
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)C(C[N+](=O)[O-])c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 48 h

Procedure:
[(S,S)-N-(pentamethylbenzenesulfonyl)-1,2-diphenyl-ethylenediamine](hexamethylbenzene)ruthenium (13.7 mg, 0.02 mmol, S/C=50), 5-[(1E)-2-nitroethenyl]-1,3-benzodioxole (193 mg, 1.0 mmol), dimethyl malonate (137 μl, 1.2 mmol) and toluene (4 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at 0° C. for 48 hours. The reaction solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2), showing that the isolation yield of the product was 99%. The optical purity was measured by HPLC (CHIRALPACK AS-H manufactured by Daicel Co., Ltd., hexane:2-propanol=90:10, flow rate 1 m/min, detection by 210 nm), resulting to 95% ee.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[C:34]([F:46])=[CH:33][N:32]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.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>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[C:34]([F:46])=[CH:33][N:32]=[C:31]([Cl:30])[CH:36]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC1(C)OB(c2cc(Cl)ncc2F)OC1(C)C
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
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: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(Cl)ncc3F)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (104 mg, 0.21 mmol), 2-Chloro-5-fluoropyridine-4-boronic acid pinacol ester (80 mg, 0.31 mmol), then Pd(PPh3)4 (23 mg, 0.02 mmol). The vial was flushed with argon, diluted with dioxane (2.0 mL) and to this was added 2M aqueous K2CO3 (0.30 mL, 0.60 mmol). The vial was sealed, heated to 100° C. for 2 hours, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-20% EtOAc/Hex gradient) to afford the desired product. LCMS-ESI+: calc'd for C27H26Cl2FN2O3S: 547.1 (M+H+); Found: 547.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](B4OC(C)(C)C(C)(C)O4)=[CH:24][N:23]=[C:22]([N:35]4[CH2:38][CH:37]([F:39])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:44]1[CH:45]=[C:46]([C:51]2[CH:63]=[CH:62][C:54]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=[CH:53][C:52]=2[CH3:64])[CH:47]=[N:48][C:49]=1[CH3:50].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd](Cl)Cl.O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:44]4[CH:45]=[C:46]([C:51]5[CH:63]=[CH:62][C:54]([C:55]([O:57][C:58]([CH3:60])([CH3:61])[CH3:59])=[O:56])=[CH:53][C:52]=5[CH3:64])[CH:47]=[N:48][C:49]=4[CH3:50])=[CH:24][N:23]=[C:22]([N:35]4[CH2:36][CH:37]([F:39])[CH2:38]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:4]=[C:3]([C:2]([F:42])([F:41])[F:1])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)C2)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1-c1cnc(C)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1-c1cnc(C)c(-c2cnc(N3CC(F)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
To a 10 mL microwave tube was added (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2-(3-fluoroazetidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 22, 86 mg, 0.142 mmol), tert-butyl 4-(5-chloro-6-methylpyridin-3-yl)-3-methylbenzoate (INTERMEDIATE 39, 41 mg, 0.129 mmol), potassium phosphate (41 mg, 0.194 mmol), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride (XPHOS Biphenyl Precatalyst) (20.3 mg, 0.026 mmol), followed by dioxane (2 mL) and water (0.1 mL). The tube was sealed and stirred at 180° C. in the microwave reactor for 10 minutes. After cooling down, the solvent was evaporated. The residue was purified by silica gel chromatography (0 to 100% Ethyl acetate/hexane) and afforded the title compound as a white solid in 46% yield. LCMS (M+H)+: 760.2.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[O:57])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCCc4nncn4CCC)cc2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)CCc4nncn4CCC)cc2)CCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.7 g) was dissolved in dichloromethane (50 ml), and the mixture was cooled to −78° C. To the mixture, a solution of 3-chloroperbenzoic acid (0.39 g) in dichloromethane (5 ml) was added dropwise. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture, and the mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 52) (0.43 g) as pale yellow crystals.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[C:27]([NH:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[CH:12]=[C:11]([C:13]([F:14])([F:16])[F:15])[CH:10]=[C:9]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)[N:8]=3)[CH:6]=2)[CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-n3cnc(I)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)c1

Procedure:
The title compound was prepared from 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.23) (0.483 g, 1.0 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.334 g, 1.3 mmol) according to the general procedure VI. Obtained as a white solid (0.126 g, 22%). MS (ISP) 539.3 [(M+H)+].