Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[N:11]=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:9]=[C:8]3[N:22]([CH3:24])[CH3:23])[CH2:3][CH2:2]1.[C:25](O)(=[O:27])[CH3:26].C(Cl)(=O)C.[OH-].[Na+]>C(OCC)(=O)C>[CH:1]1([N:4]([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[N:11]=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:9]=[C:8]3[N:22]([CH3:24])[CH3:23])[C:25](=[O:27])[CH3:26])[CH2:3][CH2:2]1
Reactant: CN(C)c1cc(-c2cccc(F)c2)nc2ccc(NC3CC3)cc12
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: CC(=O)N(c1ccc2nc(-c3cccc(F)c3)cc(N(C)C)c2c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound was prepared by acetylation at the 6-nitrogen as follows. Into a 50 mL round-bottom flask equipped with a magnetic stirrer, condenser silicone oil bath and nitrogen inlet, was placed 750 mg (2.33 mmoles) of N6-cyclopropyl-N4,N4-dimethyl-2-[3-fluorophenyl]-4,6-quinolinediamine. To this was added 5 mL of glacial acetic acid. After the material dissolved, 202 mg (2.57 mmoles, 1.1 equiv.) of acetyl chloride was added. The mixture was stirred at room temperature for 1 hr, then heated to 60° C. for 2 hr. At the end of this time the reaction was cooled and poured into a 1 L separatory funnel containing 300 mL ethyl acetate and 500 mL of 1 N NaOH solution. The organic layer was separated, washed with NaOH solution, dried over Na2SO4, filtered and concentrated. The residue was then crystallised from methylene chloride and hexane to give 550 mg (65%) of product.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:22]([OH:24])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.Cl>[OH-].[Na+]>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:1][C@H:2]([C:10]([NH:12][C@H:13]([C:22]([OH:24])=[O:23])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[O:11])[CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)cc1
Reaction time: 2 h
Yield: 56.4 %

Procedure:
In 20 ml of 1N sodium hydroxide solution, 3.28 g of phenylalanyltyrosine was dissolved and the solution was cooled with ice. To the cold solution were added dropwise 1.7 g of 4-methoxybenzoylchloride and 10 ml of 1N sodium hydroxide solution. After stirring for 2 hours, the mixture was neutralized with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate to give 2.6 g of N-(4-methoxybenzoyl)-phenylalanyltyrosine in a yield of 56%.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[CH3:16][O:15][N:13]1[CH:14]=[C:10]2[CH:9]=[N:8][C:7]3[CH:2]=[C:3]([CH3:20])[CH2:4][N:5]([CH2:17][CH2:18][CH3:19])[C:6]=3[N:11]2[CH2:12]1
Reactant: [H][H]
Reactant: CCCN1CC(C)=C(Cl)C2=C1N1CN(OC)C=C1C=N2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCN1CC(C)=CC2=C1N1CN(OC)C=C1C=N2
Temperature: 30 °C
Reaction time: 4 h

Procedure:
2 g of intermediate A1 are suspended in 50 ml ethanol. 1 ml triethylamine and 1 g palladium catalyst are added. An autoclave is used as reaction vessel. Hydrogen is pressed in up to 20 bar pressure. Now, the mixture is stirred at 30° C. for 4 hours. After filtration the solvent is removed. The crude product is dissolved in 100 ml dichloromethane. This solution is washed with 50 ml water. The solvent is removed to isolate pure product.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[CH3:13][O:14][C:15]1[CH:32]=[CH:31][C:18]2[CH2:19][NH:20][CH2:21][CH2:22][C@@:23]34[C@@H:28]([O:29][C:16]=1[C:17]=23)[CH2:27][C@@H:26]([OH:30])[CH:25]=[CH:24]4>>[Cl:1][CH2:2][C:3]([N:20]1[CH2:21][CH2:22][C:23]23[CH:24]=[CH:25][C@H:26]([OH:30])[CH2:27][CH:28]2[O:29][C:16]2=[C:15]([O:14][CH3:13])[CH:32]=[CH:31][C:18](=[C:17]32)[CH2:19]1)=[O:4]
Reactant: COc1ccc2c3c1O[C@H]1C[C@@H](O)C=C[C@@]31CCNC2
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Product: COc1ccc2c3c1OC1C[C@@H](O)C=CC31CCN(C(=O)CCl)C2
Yield: 7.7 %

Procedure:
0.82 g of chloroacetyl chloride (7.3 mmol) and 0.81 g (8.0 mmol) of triethylamine were added to a solution of (+/−)-norgalanthamine (2.0 g, 7.3 mmol) in dry TRF (100 ml). The reaction mixture was refluxed for 3 hours and concentrated by evaporation. The residue was diluted with 2N hydrochloric acid (100 ml) and extracted with EtOAc (3×75 ml). The aqueous phase was set at pH>8.5 with concentrated ammonia and extracted with 3×75 ml of CH2Cl2. The combined, organic phases were washed with common salt solution, dried on sodium sulfate and concentrated by evaporation. Flash chromatography yielded 0.20 g (7.7% of compound 4j): 1H-NMR (CDCl3) δ 6.78 (b, 1H), 6.12 (m, 2H), 5.30 (d, J=11.0 Hz, 1H), 4.65 (m, 2H), 4.32–4.01 (m, 3H), 3.78 (s, 3H), 3.59 (m, 1H), 3.06 (m, 1H), 2.61 (d, J=16.0 Hz, 1H), 1.90 (m, 3H), 13C-NMR (CDCl3) δ 166.0 (s) 146.2 (s), 144.9 (s), 132.3 (d), 128.3 (s), 127.3 (s), 126.0 (d), 120.2 (d), 111.2 (d), 88.2 (d), 61.7 (d), 55.8 (q), 52.8 (t), 48.1 (s), 45.5 (t), 41.4 (t), 35.4 (t), 29.6 (t).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][C:14]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]([OH:25])[CH2:17]3)[CH2:13]2)=[CH:4][CH:3]=1.[CH3:27][N:28]=[C:29]=[O:30]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:26])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][C:14]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]([O:25][C:29](=[O:30])[NH:28][CH3:27])[CH2:17]3)[CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(CCCN1CCC2(CC(O)c3ccccc32)C1)c1ccc(F)cc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)OC1CC2(CCN(CCCC(=O)c3ccc(F)cc3)C2)c2ccccc21
Reaction time: 20 h

Procedure:
9.0 g of p-fluoro-4-(3-hydroxyspiro[indan-1,3'-pyrrolidin]-1'-yl) butyrophenone and 2.0 g of methyl isocyanate are dissolved in 50 cc of methylene chloride. After allowing the reaction solution to stand at room temperature for 20 hours, it is concentrated by evaporation, and the resulting oil is converted into the hydrogen fumarate. After recrystallization from ethanol/ether, the hydrogen fumarate of the title compound has a M.P. of 167°-169°.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH:16]1[CH:21]=[C:20]2[C:22]([N-:24][S:25](=[O:27])(=[O:26])[C:19]2=[CH:18][CH:17]=1)=[O:23].[Na+]>CN(C)C=O>[C:9]([C:8]1[CH:14]=[CH:15][C:5]([C:3]([CH2:2][N:24]2[C:22](=[O:23])[C:20]3[C:19](=[CH:18][CH:17]=[CH:16][CH:21]=3)[S:25]2(=[O:27])=[O:26])=[O:4])=[CH:6][CH:7]=1)([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: O=C1[N-]S(=O)(=O)c2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C(=O)CN2C(=O)c3ccccc3S2(=O)=O)cc1

Procedure:
45 mmol of ethyl 4-bromoacetylbenzoate in 120 ml of dimethylformamide and 48 mmol of sodium saccharinate are maintained at 100° C. for 180 minutes. After evaporation of the solvent, taking up in 200 ml of water, extraction with dichloromethane, drying and evaporation, the residue is taken up in isopropyl ether, then filtered and taken to the expected product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:35][CH2:36][CH3:37])[C:7]2[N:8]([C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23]C(=O)OCC)[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[N:12]=2)[N:9]=1)[CH3:2].[OH-].[K+].[CH2:40](O)[CH2:41]CC>>[CH2:36]([O:35][C:6]1[C:7]2[N:8]([C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4([NH2:23])[CH2:20][CH2:21][CH2:22]4)=[CH:17][CH:18]=3)[N:12]=2)[N:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH2:37][CH2:40][CH3:41]
Reactant: CCCCO
Reactant: CCOC(=O)NC1(c2ccc(-c3nc4c(OCC)cc(OCC)nn4c3-c3ccccc3)cc2)CCC1
Agent: [K+]
Agent: [OH-]
Product: CCCCOc1cc(OCC)nn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc12
Temperature: 25 °C
Yield: 9 %

Procedure:
A mixture of ethyl {1-[4-(6,8-diethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.12 g, 0.24 mmol) and potassium hydroxide (powder, 0.077 g, 1.17 mmol, 5.0 equiv) in n-butanol (2.5 mL) was heated at the reflux temperature for 24 h. The resulting mixture was cooled to room temperature and separated between a 4:1 DCM/isopropanol solution (50 mL) and water 50 mL). The organic phase was washed with a saturated aqueous NaCl solution (25 mL), dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; SNAP 10 g cartridge: 100% DCM 4.0 min., gradient to 95% DCM/5% MeOH 1 min., 95% DCM/5% MeOH 3.5 min., gradient to 90% DCM/10% MeOH 1 min., 90% DCM/10% MeOH 3.5 min., gradient to 80% DCM/20% MeOH 6 min., 80% DCM/20% MeOH 4.7 min.) to give 1-[4-(8-butoxy-6-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (0.013 g, 9%):
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(OCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
4-Benzyloxyphenol (39 g, 0.19 mole) and tert-butyldimethylsilyl chloride (32.31 g, 0.21 mole) were dissolved in dimethylformamide (200 ml). Imidazole (14.59 g, 0.21 mole) was added in portions and after the addition the reaction mixture was stirred overnight. Water was added and the mixture was extracted with ether. The combined organic layers were washed with water and dried over anhydrous calcium chloride. The solvent was evaporated to yield crystallized product (60.2 g, 0.19 mole, 98%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][Si](C=[N+]=[N-])(C)C>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)O
Product: COC(=O)c1c(C)cccc1[N+](=O)[O-]

Procedure:
2-Methyl-6-nitrobenzoic acid is reacted with trimethylsilyldiazomethane to yield methyl 2-methyl-6-nitrobenzoate with m.p. 44-45° (Chem. Pharm. Bull., Vol. 29, 1475 (1981)). Methyl 2-methyl-6-nitrobenzoate is hydrogenated in methanol in the presence of palladium, 10% on carbon powder, at room temperature and atmospheric pressure to give methyl 2-methyl 6-aminobenzoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:11]([OH:13])[OH:12])[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].O[C:15]([C:18](O)([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1.CCO>[F:1][C:2]1[CH:3]=[C:4]([B:11]2[O:13][C:18]([CH3:20])([CH3:19])[C:15]([CH3:17])([CH3:16])[O:12]2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Reactant: CC(C)(O)C(C)(C)O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2ccc(C(=O)O)c(F)c2)OC1(C)C

Procedure:
3-Fluoro-4-carboxy-phenylboronic acid (CAS 120153-08-4) (1.0 g, 5.4 mmol) and pinacol (0.645 g, 5.4 mmol) were stirred in Toluene/EtOH (1:1) (30 ml) with heating to give a thick white slurry. The mixture was concentrated under reduced pressure, toluene (30 ml) was added and the mixture was again concentrated under reduced pressure to a white solid. LCMS (−ve ion mode) showed a single peak trace with 265 (M−H RP). The material was dried under high vacuum overnight to give 1.42 g.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[C:23]([CH3:35])=[N:22]1>>[NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5]([C:24]2[C:23]([CH3:35])=[N:22][N:21]([CH3:20])[CH:25]=2)=[CH:4][N:3]=1
Reactant: Cc1nn(C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc(-c2cc(Br)cnc2N)cc1F
Product: Cc1nn(C)cc1-c1cnc(N)c(-c2ccc(C(=O)O)c(F)c2)c1

Procedure:
Following Steps 2 and 3 in Scheme 97, using methyl 4-(2-amino-5-bromopyridin-3-yl)-2-fluorobenzoate and 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 4-(2-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-fluorobenzoic acid was obtained. LCMS (m/z): 327.2 (MH+), 0.47 min.
Reaction SMILES: O[C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14]>N1C=CC=CC=1>[SH:14][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2nc1O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: Cc1nc2ccccc2nc1S

Procedure:
2-Hydroxy-3-methylquinoxaline (2 g) and phosphorus pentasulphide (3.05 g) were stirred together in 40 ml of pyridine and the reaction mixture heated to reflux.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[CH:11]([CH:13]=O)=O>C1COCC1.O>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]2[C:4]([N:5]=1)=[N:9][CH:11]=[CH:13][N:10]=2
Reactant: O=CC=O
Reactant: Nc1nc(Cl)cc(Cl)c1N
Solvent: O
Solvent: C1CCOC1
Product: Clc1cc(Cl)c2nccnc2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4.81 g (27 mmol) 4,6-dichloro-pyridine-2,3-diamine (synthesis described in J. E. Schelling, C. A. Salemink, Rec. Tray. Chim. Pays-Bas 91, 650 [1972]) in 50 ml THF was treated with 5.22 g (27 mmol) of a 30% solution of glyoxal in water and the mixture was stirred for 3 days at room temperature. The reaction mixture was evaporated and the residue was partitioned between dichloromethane and diluted sodium carbonate solution. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent yielding 6,8-dichloro-pyrido[2,3-b]pyrazine as off-white fine needles; HPLC/MS (B): 1.93 min, [M+H] 200.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[Cl:18][C:19]1[C:20]([O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[N:21][CH:22]=[CH:23][CH:24]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][C:20]3[C:19]([Cl:18])=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:27][CH:28]=2)(=[O:34])=[O:33])[C:4]1=[O:17])#[N:13]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ncccc2Cl)cc1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc(Oc4ncccc4Cl)cc3)C2=O)c1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using 4-(3-chloropyridin-2-yloxy)benzene sulfonyl chloride in place of 6-methoxynaphthalene-2-sulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17](=[O:33])[C:18]4[C:23]([F:24])=[CH:22][CH:21]=[C:20]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[C:19]=4[F:32])=[CH:15][N:14]([CH2:34][O:35][C:36](=[O:50])[CH:37]([NH:42]C(OC(C)(C)C)=O)[CH2:38][CH:39]([CH3:41])[CH3:40])[C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[ClH:1].[NH2:42][C@@H:37]([CH2:38][CH:39]([CH3:40])[CH3:41])[C:36]([O:35][CH2:34][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:33])[C:18]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[C:19]=2[F:32])=[CH:15]1)=[O:50]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)C(CC(C)C)NC(=O)OC(C)(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)[C@@H](N)CC(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 0 °C
Reaction time: 10 h
Yield: 156.2 %

Procedure:
A solution of (5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl2-((tert-butoxycarbonyl)amino)-4-methylpentanoate (284 mg, 0.39 mmol) was added in a saturated solution of HCl in EtOAc (3 mL). The reaction mixture was stirred at 0° C. for 10 h. The resulting mixture was concentrated in vacuo, and washed with PE/EtOAc (1/1) to afford the title compound as a white solid (204 mg, 78.7%).
Reaction SMILES: [NH2:1][C@@:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:6][O:5][C@H:4]([CH3:7])[C@H:3]1[CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10].[C:21]([N:29]=[C:30]=[S:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.CCOC(C)=O>[C:21]([NH:29][C:30]([NH:1][C@:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C@H:3]([CH:8]([OH:13])[C:9]([F:12])([F:10])[F:11])[C@@H:4]([CH3:7])[O:5][CH2:6]1)=[S:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H]1OC[C@@](N)(c2ccccc2F)[C@@H]1C(O)C(F)(F)F
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H]1OC[C@@](NC(=S)NC(=O)c2ccccc2)(c2ccccc2F)[C@@H]1C(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
1-[(2R,3R,4S)-4-Amino-4-(2-fluoro-phenyl)-2-methyl-tetrahydro-furan-3-yl]-2,2,2-trifluoro-ethanol (Preparation Example 30-(4)) (550 mg, 1.87 mmol) was dissolved in DCM (15 mL) was transferred into the reaction vessel. Solution was cooled to 0° C. Benzoyl isothiocyanate (1.22 g, 7.50 mmol) was added drop-wise over 20 mins as a solution in DCM (100 mL). Reaction mixture was allowed to warm up to RT and stir overnight. TLC in neat EtOAc showed the weak SM spot was gone from Rf 0.10. Product was at Rf 0.40. (EtOAc:Hex 4:6), product was concentrated. Saturated aqueous sodium bicarbonate (30 ml) was added and then extracted with DCM (3×40 ml). The combined organic phases were combined and purified via flash chromatography (Hexane/EtoAc 0-50%). 0.75 g (87% yield) title compound (85%) and its epimer at the CF3 position (15%) were isolated as a brown solid. 1H NMR (400 MHz, CDCl3) ppm 1.36 (d, J=6.06 Hz, 3H) 2.66 (d, J=7.33 Hz, 1H) 4.53-4.59 (m, 1H) 4.59-4.69 (m, 2H) 4.89 (d, J=9.73 Hz, 1H) 7.05 (ddd, J=12.54, 8.18, 1.14 Hz, 1H) 7.12-7.17 (m, 1H) 7.28-7.32 (m, 1H) 7.43 (td, J=8.12, 1.58 Hz, 1H) 7.46-7.51 (m, 2H) 7.58-7.64 (m, 1H) 7.79-7.84 (m, 2H) 9.20 (s, 1H) 11.73 (s, 1H)
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:17][CH2:18][CH2:19][OH:20])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[C:23]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[CH3:24][C:23]([C:27]1[CH:32]=[CH:31][C:30]([O:20][CH2:19][CH2:18][CH2:17][N:4]([CH2:3][C:2]([CH3:22])([CH3:21])[CH3:1])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=2)=[CH:29][CH:28]=1)([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CC(C)(C)CN(CCCO)c1ccc(C#N)c(C(F)(F)F)c1
Product: CC(C)(C)CN(CCCOc1ccc(C(C)(C)C)cc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1C from 4-[(2,2-dimethylpropyl)(3-hydroxypropyl)amino]-2-(trifluoromethyl)benzonitrile and 4-tert-butylphenol: MS (ESI) m/z 447 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]([C@@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)=[CH:16][N:17]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].CO>O>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]([C@@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)=[CH:16][N:17]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(-c2ncc([C@@H]3CCCO3)[nH]2)c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)c(-c2ncc([C@@H]3CCCO3)[nH]2)cc1C(=O)O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a round-bottom flask was added a solution of (S)-methyl 2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate (compound 257.3, 400 mg, 1.33 mmol, 1.00 equiv) and sodium hydroxide (300 mg, 7.50 mmol, 5.63 equiv) in a solvent mixture of methanol and H2O (20/10 mL). The resulting solution was stirred for 2 h at 70° C. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The residual aqueous layer was washed with 2×50 mL of ethyl acetate. The pH of the aqueous layer was adjusted to 5-6 with hydrogen chloride (aq., 6 M), then extracted with 3×50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 340 mg (90%) of (S)-methyl 2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate as a yellow solid.
Reaction SMILES: [CH2:1]1[C:6](=O)N(Br)[C:3](=[O:4])[CH2:2]1.CC1C=C[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH:11]=1.C1N2CN3CN(C2)CN1C3>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH:3]([C:2]1[CH:1]=[CH:6][C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH:11]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2sccc2c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc2sccc2c1
Reaction time: 0.25 h
Yield: 297.4 %

Procedure:
Under N2, NBS (6 g, 0.034 mol) was added to a solution of 5-methylbenzo[b]thiophene (30.8 g, 0.21 mol), benzoylperoxide (1.6 g) in CCl4 (300 ml) and was heated at reflux. After 15 minutes, the remainder of the NBS (35 g, 0.2 mol) was added over a period of 5 minutes and heated at reflux for 1.5 hours. The reaction mixture was then cooled, filtered and the filtrate washed with H2O (2x), dried, filtered and concentrated to dryness. The residue was dissolved in CHCl3 (130 ml) and added to a solution of hexamethylenetetramine (33.6 g, 0.24 mol) in CHCl3 (60 ml). After 0.5 hour, the reaction mixture was cooled, filtered and the solid washed with hexane. After drying, the solid was dissolved in acetic acid-H2O (275 ml) and heated at reflux for 2 hours. Then concentrated HCl (55 ml) was added and the mixture refluxed an additional 5 minutes. After cooling, the solution was extracted with ether (3×), and the organic extracts were backwashed with saturated Na2CO3 (2×), dried, filtered, and concentrated to dryness to yield 16.4 g (48%) of product
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:23].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:10]([C:11](=[O:23])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COC(=O)C1(CCC(C)C)C(OC)=CCc2ccccc21
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(CCC(C)C)C(OC)=CC(=O)c2ccccc21
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A mixture of Example 178A (0.3 g, 1.0 mmol) and pyridinium dichromate (0.98 g, 2.6 mmol) in chloroform (20 mL) was heated at reflux with a Dean-Stark trap for 18 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo. Column chromatography on silica (5%-15% ethyl acetate/hexane) afforded product as a white solid (0.18 g, 58%). 1H NMR (300 MHz, CDCl3) 8 ppm 0.40 (m, 1 H), 0.72 (m, 7 H), 1.37 (m, 1 H), 2.36 (m, 2 H), 3.61 (s, 3 H), 3.83 (s, 3 H), 5.96 (s, 1 H), 7.42 (m, 2 H), 7.56 (m, 1 H), 8.19 (d, J=7.72 Hz, 1 H); MS m/z 303.1 (M+H)+.