Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[N:16]=[C:10]([C:6]1[N:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=1)[CH3:11]
Reactant: Cc1cc(C)c(N)c(Cl)c1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Yield: 5.1 %

Procedure:
10 g of 2,6-diacetylpyridine (0.0613 mol), 9.54 g of 2-chloro-4,6-dimethylaniline (0.0613 mol) and 0.6 g of p-toluenesulfonic acid were heated under reflux on a water separator in 400 ml of methanol for 90 min. The solvent was distilled off completely and the residue was recrystallized twice from 50 ml of isopropanol. 0.92 g (0.0031 mol) of 1-{6-[1-(2-chloro-4,6-dimethyl-phenylimino)ethyl]pyridin-2-yl}ethanone was obtained in a yield of 5%.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[C:7]([C:9]2[S:19][C:12]3=[N:13][CH:14]=[C:15]([CH:17]=O)[CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.[NH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C(N(CC)CC)C.[BH4-].[Na+]>CO>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:8]=[C:7]([C:9]2[S:19][C:12]3=[N:13][CH:14]=[C:15]([CH2:17][NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCC(=O)O
Reactant: O=Cc1cnc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)CCNCc1cnc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 58.1 %

Procedure:
To a solution of 2-(2-trifluoromethyl-biphenyl-4-yl)-thieno[2,3-b]pyridine-5-carbaldehyde (32 mg, 0.083 mmol) in MeOH (2 mL) is added β-alanine HCl salt (37 mg, 0.42 mmol) and triethylamine (23 uL, 0.16 mmol). The mixture is stirred at 50° C. for 20 minutes. Sodium borohydride (30 mg, 0.8 mmol) is added at room temperature and it is stirred for 10 minutes. The mixture is purified with preparative LCMS to give 22 mg of 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-thieno[2,3-b]pyridin-5-ylmethyl]-amino}-propionic acid, which is converted to HCl salt: 1H NMR (400 MHz, CD3OD) δ 8.56 (d, 1H), 8.30 (d, 1H), 8.08 (d, 1H), 7.98 (dd, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 7.40-7.34 (m, 3H), 7.30-7.24 (m, 2H); MS (ES) 457.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.O>C(#N)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4,6-Dichloro-5-nitropyrimidine [CAS No. 4316-93-2] (2.0 g) was dissolved in acetonitrile (30 mL), and then piperazine-1-carboxylic acid t-butyl ester (1.92 g) and triethylamine (2.1 mL) were added to this solution. The reaction solution was stirred at room temperature for 14 hours, and then water (30 mL) was added. The reaction solution was stirred at room temperature for 30 minutes, and then the precipitate was collected by filtration. The obtained solid was washed with water and hexane to give the title compound (2.94 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12]1[C:13]2[N:14]([C:21]([CH3:25])=[C:22]([CH3:24])[N:23]=2)[CH:15]=[C:16]([C:18]([OH:20])=O)[CH:17]=1.[CH3:26][NH:27][CH3:28]>ClCCl>[OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12]1[C:13]2[N:14]([C:21]([CH3:25])=[C:22]([CH3:24])[N:23]=2)[CH:15]=[C:16]([C:18]([N:27]([CH3:28])[CH3:26])=[O:20])[CH:17]=1
Reactant: CNC
Reactant: Cc1nc2c(N[C@@H]3c4ccccc4C[C@H]3O)cc(C(=O)O)cn2c1C
Solvent: ClCCl
Product: Cc1nc2c(N[C@@H]3c4ccccc4C[C@H]3O)cc(C(=O)N(C)C)cn2c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
3.0 g (8.9 mmol)-8-(trans-2,3-dihydro-2-hydroxy-1-indenylamino)-2,3-dimethyl-imidazo[1,2-a]pyridine-6-carboxylic acid and 3.7 g (11.6 mmol) —O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) are suspended in 150 ml dichloromethane and 3.2 ml (17.8 mmol) dimethylamine (5.6 M in ethanol) are added to the reaction mixture. After stirring for 16 h at room temperature, the reaction mixture is extracted with saturated aqueous sodium hydrogencarbonate. The organic phase is separated, dried over anhydrous magnesium sulphate and evaporated. The residue is dissolved in 10 ml dichloromethane and 50 ml diethyl ether are added. After stirring for 30 min, the precipitate is collected, washed with diethyl ether and dried in vacuo to give 2.35 g (73%) of the title compound as a colourless solid (m.p. 148-149° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:3]=1[CH3:19].[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:25]([NH2:27])[CH:26]=1.Cl.O1CCOCC1>CN1C(=O)CCC1>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[C:25]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:3]=2[CH3:19])[CH:26]=1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Cl
Reactant: Nc1cc(Br)ccc1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(Br)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 2 using 4-chloro-2-(2-fluorophenyl)-3-methylquinoline (230 mg, 848 μmol), 5-bromo-2-morpholinobenzenamine (109 mg, 424 μmol) and 4N hydrochloric acid solution in dioxane (0.011 mL, 42 μmol) in NMP (0.50 mL) to afford a colorless solid upon purification by chromatography on silica gel, eluting with EtOAc gradient in hexane. Mass Spectrum (ESI) m/e=492.1 & 494.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[F:36][C:37]([F:42])([F:41])[CH2:38][CH2:39][NH2:40]>CN(C=O)C.O.C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:40][CH2:39][CH2:38][C:37]([F:42])([F:41])[F:36])[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: NCCC(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(NCCC(F)(F)F)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1

Procedure:
At 100° C., 150 mg (0.21 mmol, purity about 74%) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 93 mg (0.82 mmol) of 3,3,3-trifluoropropan-1-amine were stirred in 2.0 ml of DMF for 2 h. The reaction mixture was then diluted with about 1 ml of water and about 3 ml of THF and purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 105 mg (83% of theory) of the target compound.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C@H:36]3[CH2:41][CH2:40][C@H:39]([O:42]C4CCCCO4)[CH2:38][CH2:37]3)=[CH:30][CH:29]=2)=[CH:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][C@@:11]([CH3:26])([S:22]([CH3:25])(=[O:24])=[O:23])[C:12]([NH:14][O:15]C2CCCCO2)=[O:13])[CH:8]=1>O1CCOCC1.C(Cl)Cl.O>[F:2][C:3]1[C:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C@H:36]3[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38][CH2:37]3)=[CH:30][CH:29]=2)=[CH:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][C@@:11]([CH3:26])([S:22]([CH3:25])(=[O:23])=[O:24])[C:12]([NH:14][OH:15])=[O:13])[CH:8]=1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: C[C@@](CCn1cc(F)c(-c2ccc(OC[C@H]3CC[C@H](O)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 1 h

Procedure:
Hydrochloric acid (4.0 M in 1,4-dioxane, 1.7 mL, 6.63 mmol) was added to a solution of (2R)-4-[5-fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)-pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (450 mg, 0.66 mmol) in 1,4-dioxane:DCM:water (2:2:1, 5 mL) at room temperature. After 1 h, the reaction was concentrated under reduced pressure. The crude residue was triturated in ethanol (10 mL) overnight. The solid was collected via filtration, washed with ethanol (5 mL), and dried under reduced pressure to afford the title compound as a white solid (110 mg, 33%). MS (LCMS) m/z 511.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97-1.19 (m, 4H) 1.54 (s, 3H) 1.58-1.72 (m, 1H) 1.72-1.89 (m, 4H) 2.04-2.23 (m, 1H) 2.41 (m, 1H) 3.08 (s, 3H) 3.18-3.40 (m, 1H) 3.65-3.84 (m, 3H) 4.01 (td, J=11.61, 4.88 Hz, 1H) 4.49 (br. s., 1H) 6.45 (d, J=7.81 Hz, 1H) 6.94-7.06 (m, 2H) 7.36-7.54 (m, 2H) 7.96 (d, J=6.83 Hz, 1H) 9.21 (s, 1H) 11.07 (s, 1H) 11.12 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[C:12]([C@H:16]1[CH2:20]OS(=O)(=O)[O:17]1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(Cl)(=O)C>CN(C)C=O.CO>[Cl:11][C:10]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:20][C@@H:16]([OH:17])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[N:6][C:5]=2[CH:9]=1
Reactant: CC(C)(C)[C@H]1COS(=O)(=O)O1
Reactant: Clc1cc2nc[nH]c2cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CC(C)(C)[C@H](O)Cn1cnc2cc(Cl)c(Cl)cc21
Temperature: 60 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
A solution of 2.08 g (11.1 mmol) of 5,6-dichloro-1H-benzimidazole and 2.00 g (11.1 mmol) of (4S)-4-tert-butyl-1,3,2-dioxathiolane 2,2-dioxide in 28 mL of N,N-dimethylformamide was stirred as 1.57 g (11.4 mmol) of potassium carbonate was added. The mixture was stirred at 60° C. for 18 h, and then cooled in an ice bath. A solution of 12 mL of acetyl chloride in 120 mL of methanol was then added. The reaction mixture was stirred for one day, and concentrated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was concentrated, and the residue was slurried in ethyl acetate. The solid was isolated by filtration to yield 1.88 g of (2S)-1-(5,6-dichloro-1H-benzimidazol-1-yl)-3,3-dimethyl-2-butanol. The filtrate was concentrated, and the residue was purified by silica gel column chromatography eluting with ethyl acetate to yield an additional 0.50 g (total yield 2.38 g, 74%) of the title compound. 1H-NMR (300 MHz, DMSO-d6): δ 8.29 (d, J=8 Hz, 2H), 7.90 (s, 1H), 7.86 (s, 1H), 4.96 (d, J=6 Hz, 1H), 4.39 (dd, J=14 Hz, J=2 Hz, 1H), 3.98 (dd, J=14 Hz, J=10 Hz, 1H), 3.32 (m, overlapping H2O), 0.95 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C)C=O>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:3]1[C:4]2[C:9](=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1])[CH3:22]
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)cc2cc([N+](=O)[O-])ccc21
Reaction time: 1 h
Yield: 78.6 %

Procedure:
2-Methyl-5-nitro-1H-indole (5.3 g) was dissolved in dimethyl formamide (20 ml) and to it added sodium hydride (1.2 g) for the mixture to be stirred for 1 hour. Ethyl bromoacetate (6.8 g) was added all at once and a precipitate started to form. The mixture was quenched with 1% aqueous acetic acid and the precipitate collected by filtration and washed thoroughly with water, triturated with diethyl ether and dried under vacuum to give pure sub-title product (6.2 g).
Reaction SMILES: [K].[NH2:2][C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:10].[CH:11]1([CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=2[O:25][CH:26]([F:28])[F:27])[C:19](Cl)=[O:20])[CH2:13][CH2:12]1.Cl>CN(C=O)C.O>[CH:22]1[C:18]([C:19]([NH:2][C:3]2[C:4]([Cl:10])=[CH:5][N:6]=[CH:7][C:8]=2[Cl:9])=[O:20])=[CH:17][C:16]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13]2)=[C:24]([O:25][CH:26]([F:27])[F:28])[CH:23]=1
Reactant: Nc1c(Cl)cncc1Cl
Reactant: O=C(Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C

Procedure:
The potassium salt suspension of the anion of 4-amino-3,5-dichloropyridine in DMF (2-25 equivalents) is introduced into a reaction vessel. A solution of 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride (1 equivalent) in DMF is slowly added to this suspension while stirring vigorously at a temperature of 15 to 40° C., preferably 20 to 30° C. After the reaction is complete, water is slowly added while stirring at 15-25° C., and the pH is adjusted to 2-3 with hydrochloric acid.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[Cl-].O[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH3+:30])[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=1.C(N(CC)CC)C.Cl>ClCCl.O>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:30][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:8])[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=1)(=[O:10])=[O:11]
Reactant: COC(=O)[C@@H]([NH3+])Cc1ccc(O)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.6 %

Procedure:
A solution of triflic anhydride (0.934 g, 3.3.1 mmol) in dichloromethane (3.31 mL) was added dropwise to a solution of (2S)-3-(4-hydroxyphenyl)-1-methoxy-1-oxopropan-2-aminium chloride (0.767 g, 3.31 mmol) and triethylamine (1.005 g, 9.93 mmol) in dichloromethane (12.79 mL) at −78° C. The mixture was stirred for 24 h at room temperature. Water (5 mL) was added and the pH was adjusted to pH=5 using 32% hydrochloric acid. The aqueous layer was extracted with diethyl ether. The organics extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (diethyl ether) afforded the title compound as yellow solid (0.704 g, 49%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1nccs1
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: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2nccs2)cc1
Temperature: 95 °C
Reaction time: 5 h
Yield: 82.5 %

Procedure:
To a stirred solution of (4-fluorophenyl)boronic acid (10 g, 60.9 mmol) in toluene (70 mL) and ethanol (200 mL) was added 2-bromothiazole (12.7 g, 91.4 mmol) and Na2CO3 (2M, 100 mL, 19.39 g). The reaction mixture was purged with argon for 45 min, Pd(PPh3)4 (3.5 g, 3.04 mmol) added, and the mixture stirred at 95° C. for 5 h. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution (2×100 mL), and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with ice-cold water (2×100 mL), followed by brine solution (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (100-200 mesh silica gel; using 10% ethyl acetate in hexane) to obtain 2-(4-fluorophenyl)thiazole as white solid (9.0 g, 82% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.98 (dd, 2H), 7.88 (d, 1H); 7.91 (d, 1H), 7.88 (d, 1H), 7.31 (t, 2H); LC-MS m/z calculated for [M+H]+180.02 found 179.91.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1C=CC2N(O)N=[N:18]C=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.N.CO>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: On1nnc2ccccc21
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(F)cc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.7 %

Procedure:
To solution of 2-amino-4-fluorobenzoic acid (4.0 g, 25.8 mmol) in degassed DMF (50 mL) were added HOBt (4.19 g, 31 mmol), DIEA (5.4 mL, 31 mmol), EDCI (5.94 g, 31 mmol) and 2N NH3/MeOH (18 mL, 36.1 mmol). The solution was stirred at rt for 48 h, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford 2-amino-4-fluorobenzamide as a solid (2.89 g, 66%). 1H NMR (300 MHz, DMSO-d6) δ 6.28 (m, 1H), 6.44 (m, 1H), 6.90 (br s, 2H), 7.08 (m, 1H), 7.58 (m, 1H), 7.71 (br d, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=[O:4].[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([O:20][C:21]([C:23]1([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])[CH2:13]2.C(OCC)C>C(#N)C>[Cl-:1].[C:30]1([C:23]2([C:21]([O:20][C@@H:14]3[CH:15]4[CH2:18][CH2:19][N+:12]([CH2:2][C:3](=[O:4])[NH:5][C:6]5[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=5)([CH2:17][CH2:16]4)[CH2:13]3)=[O:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(CCl)Nc1ccncc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CCOCC
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1ccncc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.8 %

Procedure:
2-Chloro-N-pyridin-4-yl-acetamide (Example 16a) (30 mg) was added to a solution of 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (53 mg) in acetonitrile (1 mL). The reaction mixture was stirred at room temperature for 24 h. Diethyl ether (2 mL) was added and the reaction mixture was filtered to give a light brown solid. The solid was washed several times with diethyl ether and dried under vacuum at 40° C. Purification by column chromatography eluting with 0-10% MeOH/ dichloromethane gave the title compound as a white solid (20 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[C:11]([OH:25])([CH3:24])[CH2:12][S:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:5][C:4]=1[C:27]([F:30])([F:29])[F:28])#[N:2].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:36].[OH2:46]>ClCCl.[Cl-].[Na+].O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[C:11]([OH:25])([CH3:24])[CH2:12][S:13]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)(=[O:36])=[O:46])=[CH:5][C:4]=1[C:27]([F:29])([F:28])[F:30])#[N:2]
Reactant: CC(O)(CSc1cccc2ccccc12)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(O)(CS(=O)(=O)c1cccc2ccccc12)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(naphthalen-1-ylthio)propanamide (31 mg, 0.072 mmol) was dissolved in dichloromethane (0.2 mL) and cooled to −78° C. 30% hydrogen peroxide (16.7 μL, 0.58 mmol) was added followed by the slow addition of trifluoroacetic anhydride (62 μL, 0.43 mmol). The reaction was stirred at room temperature for 16 h. The reaction was diluted with dichloromethane. Cold water and brine were added and the reaction was stirred for 20 minutes. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. Purification by column chromatography (hexane:EtOAc 50:50) yielded 25 mg of desired product. Production of PLM1 was confirmed by 1-H NMR, 13-C NMR, and mass spectral analysis.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:13][C:14]([F:43])([F:42])[C:15]1[CH:41]=[CH:40][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:37]=[CH:38][CH:39]=2)[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33](=[O:36])(=[O:35])[NH2:34])=[O:25])=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[F:43][C:14]([F:13])([F:42])[C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:37]=[CH:38][CH:39]=2)[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([NH:34][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:36])=[O:35])=[O:25])=[CH:40][CH:41]=1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Reactant: CCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
In a stream of nitrogen and at 0° C., 0.24 ml (1.10 mmol) of decanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 451 mg (1.00 mmol) of 3-(4-trifluoromethylbenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 8 and 249 mg (2.00 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 512 mg (yield: 84.6%) of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH:7]([CH2:11][NH:12][C:13]([C:15]1[N:16]=[C:17]([C:33]#[N:34])[C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:19]=2)=[O:14])[CH2:8][CH2:9][CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:33]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:19]=2)[C:24]([OH:25])=[C:15]([C:13]([NH:12][CH2:11][CH:7]([CH2:8][CH2:9][CH3:10])[C:6]([OH:35])=[O:5])=[O:14])[N:16]=1)#[N:34]
Reactant: CCCC(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A mixture of 2-{[(1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-methyl}-pentanoic acid tert-butyl ester (44 mg), TFA (2 mL) and DCM (2 mL) was stirred at rt overnight; then concentrated, the residue was dissolved in water and added 2 M HCl solution, solids were collected via filtration, washed with water and air dried to give the desired product (27 mg). LC MS ESI+: 420 (M+1)+.