Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.[NH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:22]([O:21][C:20](=[O:26])[NH:19][CH2:18][CH2:17][NH:16][CH:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COc1ccccc1N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccccc1N1CCC(NCCNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 20 (186 mg, 0.906 mmol), 1 (153 mg, 0.955 mmol), and acetic acid (288 mg, 4.80 mmol) in methanol (1 mL) was treated with sodium cyanoborohydride (63 mg, 1.00 mmol) at room temperature. The resulting mixture was stirred at room temperature (2 h). The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 2 mm, 10% EtOH; 90% CHCl3) afforded the title compound (21).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:14][CH2:15][C:16]([N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:26]([NH:1][C:2]1[C:3]([NH:14][CH2:15][C:16]([N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1)(=[O:28])[CH3:27]
Reactant: CN(C(=O)CNc1nc(-c2ccccc2)ncc1N)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cnc(-c2ccccc2)nc1NCC(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(5-amino-2-phenyl-4-pyrimidinylamino)-N-methyl-N-phenylacetamide (3.6 g) obtained in Example 124, acetic anhydride (10 ml) and pyridine (7 ml) is stirred at room temperature for four hours. To the reaction mixture is added chloroform, and the mixture is washed with 1N hydrochloric acid, then washed with a saturated aqueous sodium hydrogen carbonate solution. The chloroform layer is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from ethanol to give the desired compound (4.0 g), m.p. 200-201° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CN=C1.C(O)C>CN(C)C=O>[Si:17]([O:16][C@@H:13]1[CH2:14][CH2:15][N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:12]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1csc(N2CC[C@@H](O)C2)n1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1csc(N2CC[C@@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
To a solution of (3R)-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-3-hydroxypyrrolidine (3.0 g, 12.4 mmol) (obtained as described in Reference Example 18(2)) in dimethylformamide (90 ml) were added t-butyldiphenylsilyl chloride (6.45 ml, 24.8 mmol) and imidazole (1.69 g, 24.8 mmol) in an ice bath. After stirring the mixture in an ice bath for 10 minutes, the resulting mixture was stirred at room temperature overnight. After checking the completion of the reaction, ethanol (2.59 ml) was added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1→1:1) as the eluant to afford (3R)-3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)pyrrolidine (5.85 g, yield 90%) as a pale brown solid.
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[C:5]([C:11]#[N:12])=[N:6][C:7]([I:10])=[CH:8][N:9]=1>C(O)CCC>[I:10][C:7]1[N:6]=[C:5]2[C:11]([NH2:12])=[N:2][NH:1][C:4]2=[N:9][CH:8]=1
Reactant: N#Cc1nc(I)cnc1Cl
Reactant: NN
Solvent: CCCCO
Product: Nc1n[nH]c2ncc(I)nc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
0.74 ml (9.8 mmol) of hydrazine is added to 2.6 g (9.80 mmol) of a solution of 3-chloro-6-iodopyrazine-2-carbonitrile in 15 ml of butanol. The reaction mixture is heated at 110° C. for 5 hours and then left at room temperature overnight. The suspended solid is filtered, rinsed with butanol and then dried in an oven at 50° C. to yield 2.2 g (86%) of 5-iodo-1H-pyrazolo[3,4-b]pyrazine-3-amine in the form of a brown solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:20]=[C:19]3[C:14]([C:15]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:16][C:17]([C:21]4[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[Cl:34][C:35]([Cl:42])([Cl:41])[CH2:36][O:37][C:38](Cl)=[O:39]>C(Cl)Cl>[Cl:34][C:35]([Cl:42])([Cl:41])[CH2:36][O:37][C:38](=[O:39])[NH:27][C:24]1[CH:23]=[CH:22][C:21]([C:17]2[N:16]=[C:15]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:14]3[C:19](=[CH:20][C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=4)=[CH:12][CH:13]=3)[N:18]=2)=[CH:26][N:25]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1cccc(-c2ccc3c(N4CCOCC4)nc(-c4ccc(N)nc4)nc3c2)c1
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2ccc3c(N4CCOCC4)nc(-c4ccc(NC(=O)OCC(Cl)(Cl)Cl)nc4)nc3c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57934.4 %

Procedure:
To a cooled solution (0° C.) of 5-[7-(3-methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-pyridin-2-ylamine (125 mg, 0.000271 mmol) in DCM (4 mL) was added 2,2,2-trichloroethylchloroformate (0.054 mL, 0.0004 mol) and TEA (0.056 mL, 0.0004 mol). The reaction mixture was allowed to stir at ambient temperature for 5 h. The volatiles were evaporated to get the crude product (100 mg). This material was taken to the next step without further purification.
Reaction SMILES: Cl.Cl.[NH:3]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][NH2:11])[N:5]=[CH:4]1.C(N(CC)CC)C.[CH2:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:19]([NH:26][C:27]([NH:11][CH2:10][CH2:9][CH2:8][C:6]1[N:5]=[CH:4][NH:3][CH:7]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCCc1c[nH]cn1
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCCCc1c[nH]cn1)NCc1ccccc1
Reaction time: 1 h

Procedure:
5 mmol of 3-(1H-imidazol-4-yl)propanamine dihydrochloride and 10 mmol of triethylamine are mixed in 10 ml of acetonitrile and, after addition of 5 mmol of benzyl isocyanate, the whole mixture is brought to boiling for 1 h at reflux. After evaporation under vacuum, the title compound is taken up in a small amount of water and recrystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([N:25]([CH3:27])[CH3:26])[CH:5]=2.[Cl:28][CH2:29][C:30](Cl)=[O:31]>>[Cl:28][CH2:29][C:30]([NH:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([N:25]([CH3:27])[CH3:26])[CH:5]=2)=[O:31]
Reactant: O=C(Cl)CCl
Reactant: COc1cc(C2C(C#N)=C(N)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Product: COc1cc(C2C(C#N)=C(NC(=O)CCl)Oc3cc(N(C)C)ccc32)cc(Br)c1OC

Procedure:
The title compound was prepared from 2-amino-3-cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxyphenyl)-4H-chromene and chloroacetyl chloride as a yellow solid by a procedure similar to that described for Example 80. 1H NMR (CDCl3): 8.26 (s, 1H), 6.97-6.80 (m, 3H), 6.50-6.46 (m, 1H), 6.33 (d, J=2.4, 1H), 4.73 (s, 3H), 4.23 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 2.95 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]3[C@H:19]([CH:20]4[CH2:22][CH2:21]4)[CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[C:32](O)=[O:33])[CH:25]=[CH:24]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[C:32]([N:17]2[CH2:18][C@@H:19]([CH:20]3[CH2:21][CH2:22]3)[C@H:15]([CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[CH2:16]2)=[O:33])[CH:25]=[CH:24]1
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: Fc1ccc(C2CCN(C[C@@H]3CNC[C@H]3C3CC3)CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(c1cccc2cc[nH]c12)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](C2CC2)C1
Reaction time: 1 h

Procedure:
To a solution of 0.02 g (0.067 mmol) of 3-(S)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine and 0.0012 g of (0.01 mmol) dimethylanrinopyridine (DMAP) in 2 mL of CH2Cl2 at rt was added 0.019 g (0.1 mmol) of 1,3-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 0.016 g (0.1 mmol) of 7-indolecarboxylic acid and the reaction mixture was stirred for 1 h. The reaction mixture was partitioned between ethyl acetate and sat'd NaHCO3 solution. The organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (HPLC Waters Nova-Pak 8×10 RCM 25-40% MeOH in H2O 0.5% TFA) to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4]3=[C:5]([CH2:25][CH2:26][N:3]13)[CH:6]=[C:7]([C:12]([C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][NH:21]C(=O)C)[CH2:16][CH2:15]1)=[O:13])[CH:8]=2.[ClH:27]>>[ClH:27].[NH2:21][CH2:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:12]([C:7]2[CH:8]=[C:9]3[C:4]4=[C:5]([CH2:25][CH2:26][N:3]4[C:2](=[O:1])[CH2:11][CH2:10]3)[CH:6]=2)=[O:13])[CH2:15][CH2:16]1
Reactant: CC(=O)NC[C@H]1CC[C@H](C(=O)c2cc3c4c(c2)CCN4C(=O)CC3)CC1
Agent: Cl
Product: NC[C@H]1CC[C@H](C(=O)c2cc3c4c(c2)CCN4C(=O)CC3)CC1
Temperature: 140 °C
Reaction time: 12 h

Procedure:
Concentrated hydrochloric acid (100 ml) was added to trans-N-({4-[(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)carbonyl]cyclohexyl}methyl)acetamide (12.0 g) obtained in Reference Example 77, and the mixture was stirred at 140° C. for 12 hours. Hydrochloric acid was evaporated under reduced pressure to give white powders. Further recrystallization from water-isopropyl ether afforded the title compound as colorless crystals (9.40 g) having a melting point of 255 to 257° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[N:8]=[C:7](O)[N:6]=[CH:5]2.P(Cl)(Cl)([Cl:16])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[N:8]=[C:7]([Cl:16])[N:6]=[CH:5]2
Reactant: Oc1ncc2cc(Br)cc(Cl)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncc2cc(Br)cc(Cl)c2n1

Procedure:
A solution of 6-bromo-8-chloroquinazolin-2-ol (9.0 g, 35 mmol) in phosphorus oxychloride (100 mL) was refluxed for 5 hours. Most of phosphorus oxychloride was removed under reduced pressure, and the residue was added to a stirring ice water (500 mL). The resulting precipitate was collected via filtration and then refluxed in THF. The solid was filtered off, and the filtrate was concentrated to give the title compound a yellow solid (7.0 g, 78%). MS (ES+) C8H4BrClN2 requires: 275, 277, found: 276, 278 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[CH2:10]1.[BH3-]C#N.[Na+].CC(O)=O.[O:28]=[C:29]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][CH:39]=O)=[CH:37][C:32]=2[CH2:31][O:30]1.C([O-])([O-])=O.[Na+].[Na+]>CO>[O:1]=[C:2]1[CH2:7][N:6]([CH2:39][CH2:38][C:36]2[CH:35]=[CH:34][C:33]3[C:29](=[O:28])[O:30][CH2:31][C:32]=3[CH:37]=2)[CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[CH2:10]1
Reactant: N#Cc1ccc2c(c1)CC(CN1CCNCC1=O)C2
Reactant: O=CCc1ccc2c(c1)COC2=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)CC(CN1CCN(CCc3ccc4c(c3)COC4=O)CC1=O)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-[(2-Oxopiperazin-1-yl)methyl]-2,3-dihydro-1H-indene-5-carbonitrile (170 mg, 0.70 mmol), NaBH3CN (84 mg, 1.3 mmol) and HOAc (80 mg, 1.3 mmol) in 50 mL MeOH was added (1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (235 mg, 1.3 mmol) and the mixture was stirred at RT overnight. Then saturated Na2CO3 (50 mL) was added and stirred for 30 min and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-TLC to give the title product. 1H-NMR (400 MHz, MeOD) δ ppm 7.78 (d, J=7.8 Hz, 1H), 7.46˜7.51 (m, 4H), 7.34 (d, J=7.8 Hz, 1H), 5.34 (s, 2H), 3.48 (d, J=7.0 Hz, 2H), 3.43 (t, J=5.5 Hz, 2H), 3.21 (s, 2H), 2.69˜3.09 (m, 11H).
Reaction SMILES: [C:1]1([C@@:7]2([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:9][C@H:8]2[CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:30][N:20]([CH2:19][C@:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][C@H:8]1[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(C[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of 1,1-dimethylethyl [((1R,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropyl)methyl]carbamate (7.5 g, 20.4 mmol), accessed via the method of 11B, and methyl iodide (14.4 g, 102.0 mmol, 5 eq) in 100 mL THF cooled to 0° C. was added 1M sodium bis(trimethylsilyl)amide in THF (30.6 mL, 30.6 mmol, 1.5 eq). The reaction mixture was stirred 8 h at 0° C. followed by 16 h at ambient temperature. The reaction mixture was partitioned between EtOAc and water, the phases separated, the aqueous phase extracted twice with EtOAc, the organic phases combined, washed with brine, dried over MgSO4, filtered and concentrated to an amber oil. The crude material was purified by flash chromatography (SiO2, eluted with EtOAc/hexanes (1:4)) to give the title compound (3.1 g, 8.1 mmol, 40%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.34-7.18 (m, 10H), 4.36-4.27 (m, 2H), 3.67-3.45 (m, 1H), 3.26-3.13 (m, 2H), 3.07-2.99 (m, 1H), 2.77-2.62 (m, 3H), 1.39-0.80 (m, 12H). ES-LCMS m/z 404.2 (M+Na).
Reaction SMILES: [Br:1]CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:28]1>>[Br:1][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:28]1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Reactant: O=C(OCc1ccccc1)N1CCCC(CCCCCO)C1
Product: O=C(OCc1ccccc1)N1CCCC(CCCCCBr)C1

Procedure:
Prepared similarly to Intermediate 30 from phenylmethyl 3-(5-hydroxypentyl)-1-piperidinecarboxylate.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]4)([CH3:20])[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[OH:29][NH:30][C:31](=N)[CH:32]([CH3:34])[CH3:33]>>[CH:32]([C:31]1[N:28]=[C:27]([N:24]2[CH2:25][CH2:26][CH:21]([C@@:18]3([CH3:20])[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:22][CH2:23]2)[O:29][N:30]=1)([CH3:34])[CH3:33]
Reactant: CC(C)C(=N)NO
Reactant: C[C@@]1(C2CCN(C#N)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Product: CC(C)c1noc(N2CCC([C@]3(C)Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from (S)-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile (Intermediate 42; the configuration of the stereocenter is arbitrarily assigned) and N-hydroxy-isobutyramidine following a procedure analogous to that described in Example 2. LC (method 4): tR=0.97 min; Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: [N+](=[C:3](P(=O)(OC)OC)C(=O)C)=[N-].[NH2:13][C:14]1[C:19]([F:20])=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]=O)=[C:23]([F:29])[CH:22]=2)[N:17]=[C:16]([C:30]([O:32][CH3:33])=[O:31])[C:15]=1[Cl:34].C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:13][C:14]1[C:19]([F:20])=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[CH:3])=[C:23]([F:29])[CH:22]=2)[N:17]=[C:16]([C:30]([O:32][CH3:33])=[O:31])[C:15]=1[Cl:34]
Reactant: COC(=O)c1nc(-c2ccc(C=O)c(F)c2)c(F)c(N)c1Cl
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccc(-c2nc(C(=O)OC)c(Cl)c(N)c2F)cc1F
Temperature: 23 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
Dimethyl 1-diazo-2-oxopropylphosphonate (290 mg, 1.5 mmol, 1.2 equiv) was added to a stirred mixture of methyl 4-amino-3-chloro-5-fluoro-6-(3-fluoro-4-formylphenyl)picolinate (410 mg, 1.3 mmol, 1.0 equiv) and solid potassium carbonate (350 mg, 2.5 mmol, 2.0 equiv) in methanol (12 mL) at 23° C. The resulting cloudy pale yellow mixture was stirred at 23° C. for 2 h. The reaction mixture was diluted with water (150 mL) and extracted with dichloromethane (4×60 mL). The organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (33% ethyl acetate in hexanes) to afford the title compound as a white powder (150 mg, 38%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12](=O)N(C)C)=[C:7]([Cl:17])[CH:6]=1.C[O-].[Na+].BrC[CH2:24][CH2:25][O:26][C:27]1[C:36]([CH2:37][CH2:38][CH3:39])=[C:35]2[C:30]([C:31]([CH2:41][CH3:42])=[CH:32][C:33](=[O:40])[O:34]2)=[CH:29][CH:28]=1>CO>[Cl:17][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:18])[CH:10]=[CH:9][C:8]=1[S:11][CH2:12][CH2:24][CH2:25][O:26][C:27]1[C:36]([CH2:37][CH2:38][CH3:39])=[C:35]2[C:30]([C:31]([CH2:41][CH3:42])=[CH:32][C:33](=[O:40])[O:34]2)=[CH:29][CH:28]=1
Reactant: COC(=O)Cc1ccc(SC(=O)N(C)C)c(Cl)c1
Reactant: CCCc1c(OCCCBr)ccc2c(CC)cc(=O)oc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1c(OCCCSc2ccc(CC(=O)OC)cc2Cl)ccc2c(CC)cc(=O)oc12
Temperature: 70 °C

Procedure:
To a solution of 3-chloro-4-dimethylcarbamoylthiophenylacetic acid methyl ester (129 mg, 0.3991 mmol) in 0.75 mL methanol was added a 0.5M solution of sodium methoxide in methanol. This mixture was heated to 70° C. for 90 minutes. After cooling to ambient temperature, a solution of 7-(3-bromopropoxy)-4-ethyl-8-propylcoumarin (Step D) in 1.2 mL methanol was added dropwise. The mixture was heated to 70° C. for 16 hours. The reaction mixture was concentrated in vacuo and diluted with ethyl acetate. The organic mixture was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (20% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[CH:8]=[CH:7]2.C([Li])CCC.[C:18](=[O:20])=[O:19].O>C1(C)C=CC=CC=1>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([C:18]([OH:20])=[O:19])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Clc1ccc2cccc(Br)c2n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1cccc2ccc(Cl)nc12
Reaction time: 0.33 h

Procedure:
To a solution of 8-bromo-2-chloroquinoline (14.3 g, 60 mmol) in toluene (90 mL) at −75° C. was added butyllithium in hexanes (2 mol/L, 30 mL) and the reaction mixture was kept for 20 min at −75° C. The reaction mixture was poured onto an excess of freshly crushed dry ice. Water was added (200 mL), and the aqueous layer was washed with ethyl acetate (3×100 mL), acidified to pH 1 with HCl (aq), and extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried, and concentrated to afford 2-chloroquinoline-8-carboxylic acid as a white solid. Yield 6.56 g (53.6%).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]([O:30][CH:31]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][Si](C(C)(C)C)(C)C)[CH:34]=4)[CH3:32])=[O:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Li+]>O>[OH:39][C:35]1[CH:34]=[C:33]([CH:31]([O:30][C:28]([NH:27][C:22]2[C:23]([CH3:26])=[N:24][O:25][C:21]=2[C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)=[O:29])[CH3:32])[CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)c4cccc(O[Si](C)(C)C(C)(C)C)c4)cc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC(=O)OC(C)c1cccc(O)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-[4′-(4-{1-[3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-ethoxycarbonylamino}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.400 g, 0.63 mmol) in 3:1 MeOH:H2O (10 mL) was treated with excess lithium hydroxide. The reaction was stirred overnight at 60° C., and then acidified and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C(N(CC)CC)C>C(O)C>[N:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])=[CH:3][CH:4]=1
Reactant: Sc1ccncc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 100 ml of ethanol were suspended 6.66 g of 4-mercaptopyridine and 16.9 g of N-(4-bromobutyl)phthalimide. To the suspension was added 9.09 g of triethylamine, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure. To the residue was added 300 ml of water, and the mixture was subjected to extraction twice with dichloromethane. The extract solutions were combined, washed with an aqueous saline solution, then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel (500 g) column chromatography, using as the developer a mixture of hexane and ethyl acetate (1:2), followed by elution with ethyl acetate. The eluate was concentrated under reduced pressure. To the concentrate were added ethyl acetate and hexane. Resulting powders were collected by filtration to give N-[4-(4-pyridylthio)butyl]phthalimide as a colorless powdery product, m.p. 106.5°-107.5° C.