Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]=[C:12]([C:18]([F:21])([F:20])[F:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(OCC)C>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:18]([F:19])([F:21])[F:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=NC(=O)OCc1ccccc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(NC(=O)OCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a solution of ethyl 2-(benzyloxycarbonylimino)-3,3,3-trifluoropropanoate (45.0 g, 148.5 mmol) in diethyl ether (300 mL) was added sodium borohydride (11.3 g 297 mmol) in portions at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. The reaction was quenched with water (100 mL) carefully and the organic layer was separated. The aqueous layer was extracted with EtOAc (100 mL×3). The organic layers were combined, washed with brine (200 mL×2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/petroleum ether=1:9) to afford ethyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoropropanoate (22.0 g, 48% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][NH2:32].CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18]([NH:32][CH2:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2]
Reactant: NCc1ccccn1
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCc4ccccn4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), (pyridin-2-ylmethyl)-amine and DIEA to give 4-ethoxy-6-[4-oxo-2-[(pyridin-2-ylmethyl)-amino]-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile. LC-MS m/e 416 (MH+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1.C(N(CC)CC)C.Cl[Si](C)(C)C.[Cl:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>ClCCl>[Cl:27][CH2:28][CH2:29][CH2:30][C:31]([N:10]([C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1)[CH2:11][C:12]([OH:14])=[O:13])=[O:32]
Reactant: O=C(O)CNc1csc2ccccc12
Reactant: O=C(Cl)CCCCl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CN(C(=O)CCCCl)c1csc2ccccc12
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 621 mg (3 mM) of 3-benzothienylglycine in 15 ml of dichloromethane containing 0.92 ml (6.6 mM) of triethylamine and 717 mg of chlorotrimethylsilane was heated at 50° C. and stirred for thirty minutes and then cooled to 5° C. A solution of 0.336 ml (3 mM) of 4-chlorobutyryl chloride in 5 ml of dichloromethane was added dropwise to the reaction mixture and stirring was continued at 5° C. for one hour following the addition. The reaction mixture was warmed to 25° C. and stirred for an additional hour. The reaction mixture was next washed twice with 10 ml portions of water, dried, and the solvent was removed by evaporation to give an oil. The oil was crystallized from 0.7 ml of acetone and 2.7 ml of water, and recrystallized from ethyl acetate to afford 150 mg of N-(3-chloropropylcarbonyl)-3-benzothienylglycine. m.p. 167°-168° C.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13](Cl)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[C:20]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)#[N:21].C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Cl
Reactant: N#Cc1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ccc(Nc2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)cnc2C#N)cc1
Reaction time: 4 h
Yield: 37.9 %

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (74 mg, 0.257 mmol), 4-cyanoaniline (40 mg, 0.339 mmol), K2CO3 (80 mg, 0.579 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 4 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-cyanophenylamino)pyrazine-2-carbonitrile (36 mg).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=2)[N:4]([CH3:12])[N:3]=1.[CH3:13][S:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[N:21][CH:22]=1)(=[O:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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].CCOCC>[CH3:13][S:14]([C:17]1[CH:18]=[C:19]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=3)[N:4]([CH3:12])[N:3]=2)[CH:20]=[N:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
Reactant: Cn1nc(Br)c2cnc(N)nc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cn1nc(-c2cncc(S(C)(=O)=O)c2)c2cnc(N)nc21
Temperature: 25 °C

Procedure:
3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 3) (150 mg, 0.66 mmol) and 5-(methylsulfonyl)pyridine-3-boronic acid (200 mg, 0.99 mmol) are suspended in 1,4-dioxane (4 ml). 2M aqueous Na2CO3 (1 ml) is added and the reaction mixture is degassed by bubbling argon through for 5 minutes. Pd(dppf)Cl2 (27 mg, 0.033 mmol) is added and the reaction mixture is heated using microwave radiation at 100° C. for 30 minutes. Water (20 ml) and Et2O (50 ml) are added to the reaction mixture and the resulting grey solid is collected by filtration washing further with water. The solid is suspended in MeOH and excess TFA is added until a solution forms. The organic solvent is reduced in vacuo and the crude residue is purified by reverse phase column chromatography (Isolute™ C18, water/acetonitrile, 0.1% TFA), the appropriate fractions are combined and concentrated in vacuo. The resulting solid is refluxed in EtOH, cooled to room temperature, filtered and dried under vacuum to afford the title compound.
Reaction SMILES: [C:1]1([N:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8]([C:10]2[C:14](Br)=[CH:13][N:12]([C:16]34[CH2:25][CH:20]5[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]5)[CH2:17]3)[CH2:23]4)[N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O)=[O:33].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C.O.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:16]12([N:12]3[CH:13]=[C:14]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[CH:32]=[O:33])[C:10]([C:8]([N:7]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[O:9])=[N:11]3)[CH2:17][CH:18]3[CH2:19][CH:20]([CH2:21][CH:22]([CH2:24]3)[CH2:23]1)[CH2:25]2
Reactant: O=C(c1nn(C23CC4CC(CC(C4)C2)C3)cc1Br)N(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1B(O)O
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=Cc1ccccc1-c1cn(C23CC4CC(CC(C4)C2)C3)nc1C(=O)N(c1ccccc1)c1ccccc1
Temperature: 180 °C

Procedure:
1-Adamantan-1-yl-4-bromo-1H-pyrazole-3-carboxylic acid diphenylamide (47 mg), 2-formylphenylboronic acid (18 mg), sodium carbonate (32 mg), and tetrakis(triphenylphosphine)palladium(0) (7 mg) were combined in dimethoxyethane/ethanol/water 12/3/4 (1 mL) and heated in a CEM Discover microwave reactor at 180° C. for 5 minutes. The reaction was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration and concentration, the crude material was purified by column chromatography on silica gel using hexanes/ethyl acetate 4/1.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1Cl.[CH3:15][SH:16].[OH-].[Na+]>CS(C)=O.O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[S:16][CH3:15]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CS
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CSc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a stirred solution containing 45.1 g (0.20 mole) of 3-(trifluoromethyl)-4-chloronitrobenzene and 15 g (0.30 mole) of methyl mercaptan in 150 ml of DMSO was added dropwise at ambient temperature a solution containing 8.0 g (0.20 mole) of sodium hydroxide in 20 ml of water. This addition was exothermic to 60° C. After one hour, the reaction mixture was poured into ice water. The product was filtered and dried to give 45.0 g (95%) of yellow solid; m.p. 50° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:4][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl.[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[N:4][C:3]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:31]1[CH2:30][CH2:29][N:28]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=3[Cl:20])[CH2:33][CH2:32]1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9]2
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=CCCCOc1nc2c(cc1Br)CCC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(Br)c(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
To a solution of 4-(3-bromo-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.43 g, approx. 1.37 mmol, crude from previous reaction) in DCE (6 mL) was added 1-(2,3-dichloro-phenyl)-piperazine hydrochloride (367 mg, 1.37 mmol) followed by Et3N (0.38 mL, 2.75 mmol). The solution was stirred for 15 min and NaBH(OAc)3 (407 mg, 1.92 mmol) was added as a powder. The reaction was stirred at room temperature for 2 h and quenched with saturated NaHCO3 and H2O. The mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography (4% MeOH/CH2Cl2) afforded the title compound as a white foam (497 mg, 0.941 mmol, 69%). MS: APCI: M+1: 527.0, 529.0, 531.0 (Exact Mass: 526.05).
Reaction SMILES: [CH2:1]([C:5]1([CH2:17][CH2:18][C:19](=[O:22])[CH2:20][CH3:21])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=O)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.Cl>[CH2:1]([C:5]12[CH2:17][CH2:18][C:19](=[O:22])[C:20]([CH3:21])=[C:6]1[C:7]1[C:12](=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=1)[CH2:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCC(=O)CC)Cc2cc(OC)ccc2C1=O
Agent: Cl
Solvent: CC(=O)O
Product: CCCCC12CCC(=O)C(C)=C1c1ccc(OC)cc1C2
Temperature: 100 °C
Yield: 95.4 %

Procedure:
A solution of 2-butyl-5-methoxy-2-(3-oxo-pentyl)-1-indanone (84 mg, 0.28 mmol) in acetic acid (0.5 mL) and 6N HCl (0.5 mL) was stirred and heated in an oil bath at 100° C. for 21 hours. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL). The organic phase was washed with water (10 mL), 5% NaHCO3 (20 mL), and brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum to afford 9a-butyl-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (76 mg) as a gum.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[C:19]1([CH:25]([CH3:28])[CH2:26]O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH:25]([CH3:28])[CH2:26][O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(CO)c1ccccc1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Product: CC(COc1ccc(C(=O)NCC(=O)O)cc1)c1ccccc1
Yield: 71.7 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (247 mg, 0.983 mmol) prepared in Example 1 (1a) and 2-phenylpropan-1-ol (185 μL, 1.32 mmol) to give 221 mg of the title compound (white powder, yield: 72%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][CH:7]=1.[C:16]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][CH:32]=[C:33]([CH2:35]Cl)[N:34]=2)=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][CH:32]=[C:33]([CH2:35][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)[CH:3]=3)[N:34]=2)=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(c1ccccc1)c1ccc(-c2nc(CCl)co2)cc1
Reactant: Oc1cccc(CCCn2ccnc2)c1
Product: O=C(c1ccccc1)c1ccc(-c2nc(COc3cccc(CCCn4ccnc4)c3)co2)cc1
Yield: 85 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(4-benzoylphenyl)-4-chloromethyloxazole to gave 2-(4-benzoylphenyl)-4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 85%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 97-98° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21](Cl)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[C:26]([N:31]1[CH2:36][CH2:35][N:34]2[N:37]=[C:38]([NH:40][C:41]3[C:42](=[O:57])[N:43]([CH3:56])[CH:44]=[C:45](B4OC(C)(C)C(C)(C)O4)[CH:46]=3)[CH:39]=[C:33]2[CH2:32]1)(=[O:30])[CH:27]([CH3:29])[CH3:28].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.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>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:45]3[CH:46]=[C:41]([NH:40][C:38]4[CH:39]=[C:33]5[CH2:32][N:31]([C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH2:36][CH2:35][N:34]5[N:37]=4)[C:42](=[O:57])[N:43]([CH3:56])[CH:44]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Reactant: CC(C)C(=O)N1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)C(=O)N1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 37.3 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (150 mg, 0.42 mmol), 148d (278 mg, 0.63 mmol), Pd(dppf)Cl2 (17.1 mg, 0.021 mmol), K3PO4 (178.1 mg, 0.84 mmol), sodium acetate (68.9 mg, 0.84 mmol), acetonitrile (15 mL), and water (5 drops). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was washed with acetonitrile (0.5 mL) to afford 148e as a white solid (100 mg, 37%), which was used in the next step without further purification. MS-ESI: [M+H]+ 638.8
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C:5]1[CH:16]=[CH:15][C:8]([C:9](N(OC)C)=[O:10])=[CH:7][CH:6]=1.[CH3:21][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[C:9]([C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[OH:1])=[CH:16][CH:15]=1)(=[O:10])[CH3:21]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(Cc2ccccc2O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Cc2ccccc2O)cc1
Reaction time: 0.25 h
Yield: 53 %

Procedure:
Next, 4-(2-hydroxybenzyl)-N-methoxy-N-methylbenzamide (250 mg, 0.921 mmol) was dissolved in tetrahydrofuran (10 mL), followed by addition of methylmagnesium bromide (12% in THF, 2.8 mL) at −20° C. After 15 minutes, a second addition of methylmagnesium bromide (12% in THF, 2.5 mL) was made, followed by a third addition of methylmagnesium bromide (12% in THF, 2.0 mL). After 10 minutes, saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was concentrated, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the titled compound (110 mg, 53%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:7](F)=[C:6]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:22])[N:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:23][C:24](=[O:32])[C@:25]([OH:31])([CH3:30])[C:26]([F:29])([F:28])[F:27].[OH:33][CH2:34][CH2:35][SH:36].C[O-].[Na+]>CN1C(=O)CCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[C:7]([S:36][CH2:35][CH2:34][OH:33])=[C:6]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:22])[N:19]([CH3:20])[CH3:21])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:23][C:24](=[O:32])[C@:25]([OH:31])([CH3:30])[C:26]([F:28])([F:27])[F:29]
Reactant: OCCS
Reactant: CN(C)C(=O)c1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2F)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(C)C(=O)c1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2SCCO)cc1
Temperature: 120 °C
Yield: 12 %

Procedure:
To (R)-N-{2-chloro-3-fluoro-4-[4-(N,N-dimethylcarbamoyl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 18) (600 mg), as a solution in NMP (5 ml), was added 2-hydroxyethanethiol (0.1 ml) and sodium methoxide (0.65 g), and the reaction mixture was heated at 120° C. overnight under an argon atmosphere. The solution was diluted with saturated brine and extracted with ether (3×30 ml). The ether extracts were combined and dried. The volatile material was removed by evaporation and purified by chromatography on a Mega Bond Elut column (20 g silica) eluting with hexane/EtOAc to yield the title compound as a white solid (60 mg, 12%). NMR: 1.60 (s, 3H), 2.60-2.65 (m, 2H),), 2.85 (s, 3H), 2.95 (s, 3H), 3.10-3.20 (m, 2H), 4.75 (dd, 1H), 7.60 (d, 2H); 7.95 (d, 2N), 8.05 (s, 1H), 8.35 (d, 1H), 8.45 (d, 1H), 9.95 (s, 1H); m/z: 553.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:27])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.CN1CCCN(C)C1=O.IC>C1COCC1.O>[CH3:13][O:14][C:15](=[O:27])[CH:16]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1)[CH3:1]
Reactant: COC(=O)Cc1ccc(S(C)(=O)=O)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)c1ccc(S(C)(=O)=O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of diisopropylamide (0.46 g, 4.56 mmol) in THF (10 ml) was added n-Butyl lithium (3 ml of 1.6 M, 4.80 mmol) drop wise at −78° C. in nitrogen atmosphere and stirred for 30 minutes, to this slowly added solution of (4-Methanesulfonyl-phenyl)-acetic acid methyl ester (1.0 g, 4.38 mmol) and 1,3 dimethyl 3,4,5,6-tetrahydro-2-pyrimidone (3.17 g, 27.75 mmol), stirred for 1 hour at −78° C., followed by drop wise addition of solution of iodomethane in THF (1.14 g, 8.03 mmol in 10 ml) and stirred at the same temperature for one hour. Reaction mixture was allowed to come at RT and stirred for overnight. The reaction mixture was then poured into water (40 ml) under stirring, THF was removed under reduced pressure, and residue was extracted with ethyl acetate (2×25 ml), organic layer was washed with water (2×20 ml), dried over sodium sulfate and solvent was removed under reduced pressure to get oily residue which was purified by column chromatography over silica gel (100-200 mesh), using 50% ethyl acetate in hexanes as an eluent to afford 2-(4-Methanesulfonyl-phenyl)-propionic acid methyl ester (0.94 g, 88.5%) as white solid. 1H NMR (400 MHz, CDCl3): δ 1.54 (d, J=7.2 Hz, 3H), 3.06 (s, 3H), 3.69 (s, 3H), 3.83 (q, J=7.2 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.90 (d, J=8.4 Hz, 2H), 2-Bromo-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester (O1-III)
Reaction SMILES: OC[C@@H](N[C:11](=[O:25])[C@@:12]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])C1C=CC=CC=1.S(=O)(=O)(O)[OH:27]>O1CCOCC1>[CH3:24][C@:12]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:11]([OH:25])=[O:27]
Reactant: CC(C)CC[C@@](C)(C(=O)N[C@H](CO)c1ccccc1)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)CC[C@@](C)(C(=O)O)c1ccccc1
Yield: 97 %

Procedure:
To a solution of Example 39A (4.26 g, 12.55 mmol) in 1,4-dioxane (15 mL) was added 4M sulfuric acid (15 mL) and the reaction was stirred at reflux for 48 hours. The solution was concentrated in vacuo and partitioned between water and methylene chloride. The methylene chloride layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.70 g, 97%). 1H NMR (300 MHz, CDCl3): δ ppm 0.88 m, 6 H) 1.09 m, 2 H) 1.52 m, 4 H) 1.99 m, 2 H) 7.35 m, 5 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](Br)=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)=[O:14])=[CH:5][CH:4]=1.[CH2:31]([Sn](CCCC)(CCCC)C#CC)[CH2:32][CH2:33]C.[OH-].[Na+]>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>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:31]#[C:32][CH3:33])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)=[O:14])=[CH:5][CH:4]=1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(CNc2ccccc2C(=O)Nc2ccc(Br)c(C(F)(F)F)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC#Cc1ccc(NC(=O)c2ccccc2NCc2ccc(OC)nc2)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
A stirred solution of 2-[[6-methoxy-3-pyridinyl]methyl]amino-N-[4-bromo-3-(trifluoromethyl)-phenyl]benzamide (Reference Example 1; 3.98 g, 8.3 mmol) in dry toluene (200 mL) is purged with argon for 20 minutes at 25° C. Tributyl-1-propynylstannane (4.1 g of 80%, 9.96 mmol) and tetrakis(triphenylphosphine)palladium (0) (260 mg) are then added and the resulting mixture is heated at 100° C. for 17 hours under an argon atmosphere. The mixture is then cooled, treated with an aqueous solution of sodium hydroxide (85 mL of 0.1 M) and purged with air for 2 hours. The resulting mixture is extracted with ethyl acetate (3×100 mL). The organic phase is sequentially washed with water (2×40 mL) and saturated aqueous sodium chloride (1×40 mL), dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 33% ethyl acetate in hexane and recrystallised from diethylether-hexane to give the title compound as a pale-yellow crystalline solid; m.p. 123–124° C.