Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+].O>ClCCl>[N:5]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])=[CH:19][CH:20]=1)=[C:1]=[S:2]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(Cc1ccc(N=C=S)cc1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thiophosgene (4.1 mL, 54 mmol) was added al at once to a mixture of diethyl 4-aminobenzylphosphonate (12.04 g, 50 mmol), sodium bicarbonate (8.33 g, 99 mmol), water (100 mL), and dichloromethane (250 mL), and the mixture was stirred at room temperature for about 2 hours. The organic and aqueous layers were separated, the organic layer dried over magnesium sulfate, filtered, and concentrated to give the product isothiocyanate as a brown oil. This was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[CH3:40][O:41][C:42](=[O:47])[CH2:43][C:44](Cl)=[O:45]>CCOC(C)=O>[CH3:40][O:41][C:42](=[O:47])[CH2:43][C:44]([NH:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])=[NH:9])[S:11][C:12]=2[S:32][CH3:33])(=[O:17])=[O:16])[CH:19]=1)=[O:45]
Reactant: COC(=O)CC(=O)Cl
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CC(=O)Nc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
{[4-(2′-Amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (22 mg, 0.04 mmol, Example 25: step c) was dissolved into THF (1 mL) and to this was added chlorocarbonyl-acetic acid methyl ester (9 μL, 0.085 mmol). The reaction was heated to 50° C. for 5 hours and then allowed to stir at RT for 48 hours. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and removal of the solvents in vacuo was followed by purification by preparative TLC (SiO2) (30% EtOAc in hexanes) that yielded the title compound. ESI-MS (m/z): Calcd. for C28H31N3O7S3: 618.1 (M+1) found: 617.9.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Cl:31])[C:17]=1[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)=[O:20]>>[Cl:31][C:16]1[CH:15]=[N:14][CH:13]=[C:12]([Cl:11])[C:17]=1/[CH:18]=[C:19](\[O:20][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)/[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Reactant: O=C(Cl)Cc1ccccc1
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)Cc2ccccc2)cc1OC

Procedure:
The compound was obtained starting from phenyl-acetyl chloride and 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethanone following the procedure of Example 7.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:15]([O-])=O)[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]>CO.[Ni]>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([NH2:15])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(O)c([N+](=O)[O-])c2)CC1
Agent: [Ni]
Solvent: CO
Product: COC(=O)C1(c2ccc(O)c(N)c2)CC1
Temperature: 35 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of 1-(4-hydroxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester (8.3 g, 35 mmol) in MeOH (100 mL) was added Raney Nickel (0.8 g) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at 35° C. for 8 hours. The catalyst was filtered off through a Celite pad and the filtrate was evaporated under vacuum to give crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 1:1) to give 1-(3-amino-4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester (5.3 g, 74%). 1H NMR (CDCl3, 400 MHz) δ 6.77 (s, 1 H), 6.64 (d, J=2.0 Hz, 2 H), 3.64 (s, 3 H), 1.55-1.52 (m, 2 H), 1.15-1.12 (m, 2 H).
Reaction SMILES: [CH:1](=[CH:8][C:9](=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[NH:19])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:8]=[C:9]([CH3:10])[NH:19][C:17]=1[NH2:18])=[O:20])[CH3:13]
Reactant: CCOC(=O)CC(=N)N
Reactant: CC(=O)C=Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(C)=CC1c1ccccc1
Yield: 73 %

Procedure:
Boiling a solution of 14.6 g of benzylideneacetone and 13.0 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours yields 2-amino-6-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 150°C (ethanol). Yield: 73 percent of theory.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1[CH:22]=[CH:21][C:9]2[N:10]=[C:11]([S:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[S:12][C:8]=2[CH:7]=1>N1C=CC=CC=1>[Cl:5][C:6]1[CH:22]=[CH:21][C:9]2[N:10]=[C:11]([S:13][C:14]3[CH:20]=[CH:19][C:17]([NH:18][C:3]([NH:2][CH3:1])=[O:4])=[CH:16][CH:15]=3)[S:12][C:8]=2[CH:7]=1
Reactant: Nc1ccc(Sc2nc3ccc(Cl)cc3s2)cc1
Reactant: CN=C=O
Solvent: c1ccncc1
Product: CNC(=O)Nc1ccc(Sc2nc3ccc(Cl)cc3s2)cc1
Yield: 62.8 %

Procedure:
Methyl isocyanate (0.41 g) was added to a solution of 4-(6-chlorobenzothiazol-2-ylthio)-aniline (2.0 g) in pyridine (20 ml), with stirring. The mixture was stirred at room temperature for 12 hours and evaporated to dryness. The residue was dissolved in a minimal volume of boiling ethanol and the solution was cooled in a refrigerator. The resulting solid substance was collected by filtration and dried to give N-[4-(6-chlorobenzothiazol-2-ylthio)phenyl]-N'-methylurea (1.5 g), which had a melting point of 289°-291° C. This urea (1.4 g) was dissolved in 1,4-dioxane (50 ml), and chlorocarbonyl isocyanate (0.47 g) was added. The mixture was heated at the boiling point for 5 hours and evaporated to dryness. The solid residue was dissolved in a minimal volume of boiling ethanol and the solution was cooled in a refrigerator. The resulting solid substance was collected by filtration and dried to give 1.3 g of 1-[4-(6-chlorobenzothiazol-2-ylthio)phenyl]-3-methyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione of melting point 232°-233° C.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33])[N:5]([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[O:15][CH3:16].O.[OH-].[Li+]>C1COCC1.O>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]([N:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[O:15][CH3:16])[CH:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:3]([OH:34])=[O:2])=[O:26])=[CH:23][CH:22]=1
Reactant: COC(=O)C(c1ccccc1Cl)N(Cc1ccc(OC)cc1OC)C(=O)c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)N(Cc2ccc(OC)cc2OC)C(C(=O)O)c2ccccc2Cl)cc1
Yield: 94.7 %

Procedure:
To a solution of N-(4-methoxybenzoyl)-N-(2,4-dimethoxybenzyl)-(2-chlorophenyl)glycine methyl ester (30 g) in THF (350 ml) is added a solution of lithium hydroxide monohydrate (4.2 g) in water (85 ml) and the mixture is refluxed for 2 h before cooling and evaporation of excess THF in vacuo. The aqueous solution is extracted with ether to remove neutral compounds and the aqueous solution adjusted to pH2 with conc. hydrochloric acid. The acidic solution is extracted with dichloromethane (×3), washed with water, dried (MgSO4) and evaporated in vacuo to give the title compound (27.6 g) as a solid foam.
Reaction SMILES: C([N:8]1[C@H:12]([C:13]#[CH:14])[C@@H:11]([CH3:15])[O:10]C1(C)C)(OC(C)(C)C)=O.[F:18][C:19]1[C:20](I)=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])/[C:22]/2=[CH:29]\[C:30]1[NH:31][CH:32]=[CH:33][C:34]=1[O:35][CH3:36].FC(F)(F)C(O)=O.C(Cl)Cl>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.CN(C=O)C.CCN(CC)CC.C(Cl)Cl.O>[NH2:8][C@@H:12]([C@H:11]([OH:10])[CH3:15])[C:13]#[C:14][C:20]1[C:19]([F:18])=[CH:27][CH:26]=[C:25]2[C:21]=1/[C:22](=[CH:29]/[C:30]1[NH:31][CH:32]=[CH:33][C:34]=1[O:35][CH3:36])/[C:23](=[O:28])[NH:24]2
Reactant: C#C[C@@H]1[C@@H](C)OC(C)(C)N1C(=O)OC(C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H](N)[C@@H](C)O)c21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Using Method C above, (4R,5R)-N-Boc-2,2,5-trimethyl-4-ethynyl-oxazolidine (0.18 g, 0.65 mmol) (Example 102B) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0.1 g, 0.26 mmol) (Starting Material 6) using (Ph3P)4Pd (30 mg) and Cul (6 mg) as catalyst in DMF (6 mL) and Et3N (6 mL) as solvent at 85° C. for 1 day. To the resulting compound in CH2Cl2 (6 mL) was added a 1:1 mixture of trifluoroacetic acid/CH2Cl2 (6 mL) and 3 drops of water at 0° C. and the mixture was stirred at 0° C. for 1.5 h. The mixture was then quenched with conc. NH4OH (6 mL) and diluted with EtOAc. The organic layer was washed with brine and dried with MgSO4. (Z)-4-[(3R,4R)-3-Amino-4-hydroxy-1-pentynyl]-1,3-dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was purified via flash column chromatography (10% MeOH in CH2Cl2). (Yield 44 mg, 48%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH3:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:26][C:25]3[CH:27]=[CH:28][C:22]([CH3:21])=[CH:23][CH:24]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: Cc1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 95.5 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.44 mmol) and p-methylaniline (107 mg, 1 mmol) to give 180 mg of the title compound (95%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.06 (s, 1H), 9.91 (s, 1H), 7.44 (d, 2H, J=8.6 Hz), 7.23 (bs, 1H), 7.17 (bs, 1H), 7.10 (d, 2H, J=8.6 Hz), 5.16~5.26 (m, 1H), 3.07 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.55~2.66 (m, 2H), 2.26 (s, 3H), 2.09 (dm, 1H, J=13.5 Hz), 1.80~1.94 (m, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([CH2:7][C:8]#[N:9])=[O:6].[C:13]1([N:19](C2C=CC=CC=2)[CH:20]=N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.CCOCC>[I:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([C:7](=[CH:20][NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]#[N:9])=[O:6]
Reactant: N#CCC(=O)c1cccc(I)c1
Reactant: N=CN(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: N#CC(=CNc1ccccc1)C(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A mixture of 2-(3-iodobenzoyl)acetonitrile (36.2 g, 133.5 mmol) and N,N-diphenylformamidine (26.2 g, 133.5 mmol) in toluene (200 ml) was heated at reflux under a nitrogen atmosphere. After 8 h, the reaction mixture was cooled to room temperature and diluted with ether (200 ml) to give 2-(3-iodobenzoyl)-3-phenylaminoacrylonitrile (31.2 g) as a solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:21]2[CH2:26][CH2:25][CH2:24]/[C:23](=[CH:27]\[C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]4)=[C:30]([O:40][CH3:41])[CH:29]=3)/[C:22]2=[O:42])[CH2:19][OH:20])=[CH:14][CH:13]=1.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(N(CC)CC)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:21]2[CH2:26][CH2:25][CH2:24]/[C:23](=[CH:27]\[C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]4)=[C:30]([O:40][CH3:41])[CH:29]=3)/[C:22]2=[O:42])[CH:19]=[O:20])=[CH:14][CH:13]=1
Reactant: COc1cc(/C=C2\CCCN(C(CO)c3ccc(F)cc3)C2=O)ccc1-n1cnc(C)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(/C=C2\CCCN(C(C=O)c3ccc(F)cc3)C2=O)ccc1-n1cnc(C)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of dimethyl sulfoxide (0.19 mL) in methylene chloride (1 mL) was added dropwise to a solution of oxalyl chloride (167 mg) in methylene chloride (2 mL) at −78° C. The reaction solution was stirred at −78° C. for 5 minutes, and then a solution of (E)-1-(1-(4-fluorophenyl)-2-hydroxyethyl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidin-2-one synthesized by the method described in Example 629 (260 mg) in methylene chloride (3 mL) was added dropwise to the reaction solution. The reaction solution was stirred at −78° C. for 1 hour, and then triethylamine (0.42 mL) was added to the reaction solution. The reaction solution was stirred at −78° C. for 15 minutes, and further stirred at room temperature for 45 minutes. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to obtain 250 mg of crude (E)-(4-fluorophenyl)-(3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-2-oxopiperidin-1-yl)acetaldehyde. p-Toluenesulfonic acid (107 mg) and ethylene glycol (0.29 mL) were added to a solution of the resulting crude (E)-(4-fluorophenyl)-(3-(3-methoxy-4-(4-methyl-1H)benzylidene)-2-oxopiperidin-1-yl)acetaldehyde (225 mg) in toluene (5 mL), and the reaction solution was heated to reflux for 1 hour and 20 minutes. After allowing the reaction solution to be cooled to room temperature, saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain 7 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: BrCc1ccccc1
Reactant: CC(Oc1cc(-c2cn(C3CCNCC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1cc(-c2cn(C3CCN(Cc4ccccc4)CC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 90 °C

Procedure:
The product of the above mentioned Example 2 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-2-aminopyridine (451 mg, 1 mmol) was added to N,N-dimethyl formamide (10 mL), and to which were added potassium carbonate (276 mg, 2 mmol) and benzyl bromide (342 mg, 2 mmol). The reaction mixture was warmed to 90° C. for 5 h. After the reaction mixture was cooled to room temperature, to which was added water. The reaction mixture was extracted with dichloromethane, the organic layer was washed with water for several times, dried over anhydrous sodium sulfate, and then filtered, the filtrate was rotatedly concentrated to dryness to yield a solid, which was purified via silica gel column chromatography (dichloromethane:methanol=10:1) to yield the title compound as gray solid powder.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[CH2:27]([O:34][C:35]1[C:40]([CH2:41][CH2:42]O)=[C:39]([F:44])[C:38]([F:45])=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([F:45])=[C:39]([F:44])[C:40]=1[CH2:41][CH2:42][I:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: II
Reactant: OCCc1c(OCc2ccccc2)ccc(F)c1F
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(OCc2ccccc2)c(CCI)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
A solution of Ph3P (697 mg, 2.66 mmol) and imidazole (181 mg, 2.66 mmol) in DCM (15 mL) was cooled to 0° C. Added to this was iodine (674 mg, 2.66 mmol) and the resulting mixture was stirred at 0° C. for 30 min. 2-(6-(benzyloxy)-2,3-difluorophenyl)ethanol (585 mg, 2.214 mmol) was added portionwise over several minutes and the resulting mixture was stirred at room temp. After 5 h, the mixture was filtered washing the solids with DCM. The filtrate was washed with aq Na2S2O3 and the organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane) to give 1-(benzyloxy)-3,4-difluoro-2-(2-iodoethyl)benzene (720 mg, 1.924 mmol, 87% yield) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.52-7.35 (m, 5H), 7.03 (q, J=9.3 Hz, 1H), 6.69-6.52 (m, 1H), 5.10 (s, 2H), 3.37-3.29 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2([NH:32]C(=O)C)[CH2:29][O:28]C(C)(C)[O:26][CH2:25]2)=[CH:18][CH:17]=1.[ClH:36]>CO>[ClH:36].[NH2:32][C:24]([CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:3]2[CH:4]=[CH:5][C:6]([S:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)=[CH:7][C:2]=2[F:1])=[CH:21][CH:20]=1)([CH2:29][OH:28])[CH2:25][OH:26]
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Sc4cccc(C)c4)cc3F)cc2)COC(C)(C)OC1
Agent: Cl
Solvent: CO
Product: Cc1cccc(Sc2ccc(-c3ccc(CCC(N)(CO)CO)cc3)c(F)c2)c1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
N-[5-{2-[2′-Fluoro-4′-(3-methylphenylthio)biphenyl-4-yl]ethyl}-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (187 mg) was dissolved in methanol (4 mL), concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 70° C. for 7 hr. The reaction mixture was concentrated, and the residual crude crystals were suspended in ethyl acetate and collected by filtration to give the title compound (52 mg) as white crystals.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[N:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.[OH:12][C@H:13]([C:21]1[CH:30]=[CH:29][C:24]2[C:25](=[O:28])[O:26][CH2:27][C:23]=2[C:22]=1[CH3:31])[CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CCO>[OH:1][CH:2]([C:4]1[N:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1)[CH2:3][N:18]1[CH2:19][CH2:20][N:15]([CH2:14][C@H:13]([OH:12])[C:21]2[CH:30]=[CH:29][C:24]3[C:25](=[O:28])[O:26][CH2:27][C:23]=3[C:22]=2[CH3:31])[CH2:16][CH2:17]1
Reactant: N#Cc1ccc(C2CO2)nc1
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(CC(O)c3ccc(C#N)cn3)CC2)ccc2c1COC2=O
Temperature: 140 °C

Procedure:
To a microwave tube were added isomer B of 6-(oxiran-2-yl)pyridine-3-carbonitrile (330 mg, 2.26 mmol), 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one (686 mg, 2.48 mmol, as a free base), and EtOH (7.0 mL). The mixture was heated in the microwave for 60 min at 140° C. The solvent was evaporated and the crude product was purified by silica gel MPLC (0->10% CH2CH2:MeOH) to provide 6-(1-Hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)pyridine-3-carbonitrile as a single isomer. Further, the product was treated with 1 M HCl in diethyl ether to give the final product as an HCl salt. 1H NMR (500 MHz, DMSO-d6), δ 8.92 (s, 1H), 8.28 (dd, J=1.9 Hz, J=2.0 Hz, 1H), 7.68-7.63 (m, 3H), 5.48 (d, J=4.8 Hz, 1H), 5.37 (d, J=2.2 Hz, 2H), 5.20 (d, J=3.9 Hz, 1H), 5.03 (m, 1H), 4.78 (m, 1H), 2.64 (dd, J=4.1, 1H), 2.55-2.41 (m, 8H), 2.33 (dd, J=3.7 Hz, 1H), 2.24 (s, 3H); LC/MS: (IE, m/z) [(M+1)]+=423.04 (57A). The isomer corresponding to inversion of the benzylic hydroxyl stereocenter was also prepared in a similar fashion starting with isomer A of 6-(oxiran-2-yl)pyridine-3-carbonitrile (57B):
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:28]([C:29](=[O:32])[NH:30][CH3:31])=[C:27]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)[O:26][C:5]2=[N:6][C:7]=1[N:8]([CH2:13][CH2:14][CH2:15][C:16]([CH3:25])([CH3:24])[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[S:9]([CH3:12])(=[O:11])=[O:10].[CH:40]1([B-](F)(F)F)[CH2:42][CH2:41]1.[K+].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:40]1([C:2]2[CH:3]=[C:4]3[C:28]([C:29](=[O:32])[NH:30][CH3:31])=[C:27]([C:33]4[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=4)[O:26][C:5]3=[N:6][C:7]=2[N:8]([CH2:13][CH2:14][CH2:15][C:16]([CH3:24])([CH3:25])[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[S:9]([CH3:12])(=[O:11])=[O:10])[CH2:42][CH2:41]1
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCC(C)(C)C(=O)OCC(C)C)S(C)(=O)=O)c(I)cc12
Reactant: F[B-](F)(F)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCC(C)(C)C(=O)OCC(C)C)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 116 °C
Yield: 99.6 %

Procedure:
Isobutyl 5-(N-(5-iodo-3-(methylcarbamoyl)-2-p-tolylfuro[2,3-b]pyridin-6-yl)methylsulfonamido)-2,2-dimethylpentanoate (70 mg, 0.086 mmol) is dissolved in toluene (6 mL) and a premixed solution of potassium cyclopropyltrifluoroborate (155 mg, 1.045 mmol) and potassium carbonate (2M, 0.62 mL, 1.255 mmol) is added followed by Pd(Ph3)4 (3.6 mg, 3.14 umol). The mixture is degassed for 10 min then heated at 116° C. for 20 min in the microwave. The reaction mixture is then filtered through celite and aqueous extracted with EtOAc (3×15 mL). The organic is then washed with Brine (10 mL) and dried over Na2SO4 and concentrated. HPLC purification gives 50 mg (82% yield) of isobutyl 5-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-p-tolylfuro[2,3-b]pyridin-6-yl)methylsulfonamido)-2,2-dimethylpentanoate. MS-ES [M+H]+=584.3. This compound is used directly in the next step.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:23](=[O:29])[NH:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:11][N:10]=1)(C)(C)C.Cl.C(OCC)C>O1CCOCC1>[CH3:28][O:27][CH2:26][CH2:25][NH:24][C:23]([C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:9]([CH2:8][NH2:7])=[N:10][CH:11]=1)=[O:29]
Reactant: COCCNC(=O)c1cnc(CNC(=O)OC(C)(C)C)c2cc(OC)c(OC)cc12
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COCCNC(=O)c1cnc(CN)c2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of [6,7-dimethoxy-4-(2-methoxy-ethylcarbamoyl)-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester (45 mg, 0.11 mmol) in dioxane (2 ml) was treated with 4M HCl in dioxane (2 ml) and the mixture was stirred overnight at room temperature. Diethyl ether was added and the HCl salt was collected by suction filtration (38 mg, quant.): 1H NMR (DMSO-d6) δ 3.28 (s, 3H), 3.47-3.53 (m, 4H), 3.89 (s, 3H), 3.99 (s, 3H), 4.72 (m, 2H), 7.46 (s, 1H), 7.70 (s, 1H), 8.42 (s, 1H), 8.65 (br s, 3H), 8.82 (m, 1H); MS (APCI) m/z 320.1 [M+1]+.