Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:13](=O)[CH2:14][S:15][C:16]3[NH:17][CH2:18][CH2:19][N:20]=3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1>C(O)(=O)C>[BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:13]3[N:20]4[CH2:19][CH2:18][N:17]=[C:16]4[S:15][CH:14]=3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(CSC1=NCCN1)C1(c2ccc(Cl)cc2)CCC1
Agent: Br
Solvent: CC(=O)O
Product: Clc1ccc(C2(C3=CSC4=NCCN34)CCC2)cc1
Temperature: 25 °C

Procedure:
A suspension of 1-[1-(4-chlorophenyl)cyclobutyl]-2-(2-imidazolin-2 ylthio)ethanone hydrobromide (2.4 g—prepared in a manner similar to that described above) in acetic acid (6 ml) was heated under reflux for 16 hours, then allowed to cool to ambient temperature. The solvent was removed in vacuo, the residue was triturated with ether (50 ml), and the resulting solid was collected by filtration, washed with ether (50 ml), dried in vacuo at ambient temperature, and recrystallised from methanol. The resulting solid was collected by filtration and dried in vacuo at ambient temperature to give 3-[1-(4-chlorophenyl)cyclobutyl]-5,6-dihydroimidazo-[2,1-b]thiazole hydrobromide as a white solid (1.4 g), m.p. 258-260° C.
Reaction SMILES: C(O)C.Cl.[C:5]([C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-])=O)=[CH:15][N:14]=1)([CH3:8])([CH3:7])[CH3:6]>[Fe].O>[C:5]([C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][C:13]1[N:14]=[CH:15][C:16]([NH2:20])=[CH:17][C:18]=1[CH3:19])([CH3:8])([CH3:6])[CH3:7]
Reactant: Cc1cc([N+](=O)[O-])cnc1Oc1cccc(C(C)(C)C)c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(N)cnc1Oc1cccc(C(C)(C)C)c1
Temperature: 50 °C
Yield: 54.4 %

Procedure:
A 100 ml two-necked round-bottomed flask equipped with a KPG-stirrer, a thermometer and a reflux condenser is charged with ethanol (50 ml), water (5 ml), iron (1.43 g) and hydrochloric acid 37% (0.2 ml). The reaction mixture is heated at 50° C. 2-(3-tert-Butyl-phenoxy)-3-methyl-5-nitro-pyridine (2.26 g) was added portionwise. The mixture is heated at reflux for 3 hours. After cooling the mixture to 50° C. it is filtered through celite. The filtrate is poured into water (200 ml) and extracted with ethylacetate (2×50 ml). The combined organic layers are washed with brine (100 ml), dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification by flash chromatography over silica gel with hexane/ethyl acetate 1:1 (v:v) gives 1.10 g of the compound as a brownish solid (MP: 83-84° C.).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10](O)=O.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>>[CH:13]1([NH:16][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:15][CH2:14]1
Reactant: O=C(O)Cc1cccc(F)c1F
Reactant: NC1CC1
Product: Fc1cccc(CCNC2CC2)c1F

Procedure:
Synthesized according to typical procedures C and D from (2,3-difluorophenyl)-acetic acid and cyclopropylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[F:14].[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[F:14]
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(2,5-dichloro-phenoxy)-2-fluoro-4-nitro-benzene (0.5 g, 1.7 mmol) and tin chloride (1.57 g, 8.3 mmol) in 30 ml of anhydrous ethanol was heated to 70° C. under argon and stirred for 4 hours. The solution was allowed to cool and then poured into ice. The solution was made slightly basic (pH 7-8) by addition of saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate. The organic phase was thoroughly washed with brine and dried treated with anhydrous sodium sulfate. Evaporation of the solvent left a yellow oily product which was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[NH2:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=2)[N:3]=1
Reactant: CCC(CC)n1cnc2c(Cl)nc(Cl)nc21
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCCCO
Solvent: CC(C)O
Product: CCOC(=O)c1ccc(Nc2nc(Cl)nc3c2ncn3C(CC)CC)cc1
Reaction time: 22 h
Yield: 69.8 %

Procedure:
The operation is carried out as in Stage 2 of Example 3 starting from 200 mg of the product obtained in Stage 1 of Example 3 and 4 ml of butanol and using 158 mg of ethyl 4-amino-benzoate in place of the benzylamine. Agitation is carried out at ambient temperature then the reaction medium is taken to a temperature of 80 to 85° C. for 22 hours, left to return to ambient temperature, diluted with 4 ml of isopropanol, left for two days at a temperature of approximately 0° C., followed by separating, washing with 10 ml of isopropanol and drying at a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 209 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[C:9]([C:11]2[NH:12][C:13](=[O:24])[C:14]3[C:15](=[C:17]([CH2:21][CH2:22][CH3:23])[N:18]([CH3:20])[N:19]=3)[N:16]=2)[CH:10]=1)=[NH:4].[C:30](O)(=[O:32])[CH3:31].Cl.CN(C)CCCN=C=NCC>O1CCOCC1>[C:30]([O:1][N:2]=[C:3]([NH2:4])[C:5]1[CH:10]=[C:9]([C:11]2[NH:12][C:13](=[O:24])[C:14]3[C:15](=[C:17]([CH2:21][CH2:22][CH3:23])[N:18]([CH3:20])[N:19]=3)[N:16]=2)[C:8]([O:25][CH2:26][CH:27]([CH3:28])[CH3:29])=[N:7][CH:6]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)O
Reactant: CCCc1c2nc(-c3cc(C(=N)NO)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCc1c2nc(-c3cc(C(N)=NOC(C)=O)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Yield: 82.1 %

Procedure:
N-Hydroxy-6-isobutoxy-5-(2-methyl-7-oxo-3-propyl-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-5-yl)-3-pyridinecarboximidamide (Example 39) (65 mg, 0.16 mmol), N,N-dimethylaminopyridine (24 mg, 0.20 mmol), acetic acid (9.7 mg, 0.16 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (37.5 mg, 0.20 mmol) were stirred in dioxan (2 mL) for 14 h. The solvent was removed in vacuo and the product purified by flash column chromatography (eluting with 90% dichloromethane:methanol) to give the product (58 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.[N:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:21]=[O:22]>CN(C)C=O>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][NH:20][C:21]([NH:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[CH:10][C:11]([S:14](=[O:15])(=[O:16])[N:17]([CH3:18])[CH3:19])=[CH:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1)=[O:22])[CH3:28]
Reactant: Cc1nc(N)sc1-c1ccc(S(=O)(=O)N(C)C)cc1
Reactant: CCOC(=O)CN=C=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N(C)C)cc2)s1

Procedure:
4-(2-Amino-4-methyl-thiazol-5-yl)-N,N-dimethyl-benzenesulfonamide (Example 24a) (0.083 g, 0.28 mmol) and ethyl isocyanatoacetate (0.05 ml, 0.34 mmol) are stirred in dimethylformamide at 100° C. for 3 hours. The mixture is then partitioned between 1M aqueous hydrochloric acid and ethyl acetate. The organic extract is washed with brine, dried over MgSO4 and the solvent removed in vacuo. Purification by preparative HPLC affords the title compound. MH+ (TOF, MS, ES+): 441.4
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([F:33])[CH:25]=4)=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:35]1C=C(S(Cl)(=O)=O)C=C[C:40]=1Cl>>[CH2:35]([O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:18]2[CH:19]=[C:20]3[C:15]([CH2:14][CH2:13][N:12]3[S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])=[CH:16][CH:17]=2)=[O:22])=[CH:25][C:26]=1[F:33])[CH3:40]
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)CC2
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC3)cc1F

Procedure:
4-{[1-(3,4-Dichloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 509.15 (M+H+.), was prepared in analogy to example 9, steps 1 to 5. Step 4 was performed using 3,4-dichloro-benzenesulfonyl chloride and yielded 4-{[1-(3,4-dichloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4].Br[CH:13]([CH3:17])[C:14](Br)=[O:15].C(N(CC)CC)C>CC(C)=O>[CH3:17][CH:13]1[O:4][C:3](=[O:5])[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:1][C:14]1=[O:15]
Reactant: CCCCCCC(O)C(=O)O
Reactant: CC(Br)C(=O)Br
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCC1OC(=O)C(C)OC1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
2.5 g 2-hydroxyoctanoic acid (15.6 mmol) and 1.75 mL 2-bromopropionyl bromide (16.3 mmol) were stirred at 80° C. under nitrogen for 12 h. 150 mL acetone and 4.35 mL anhydrous triethylamine (31 mmol) were added to the mixture and the solution was stirred for 3 h at 60° C. After filtration of the triethylammonium bromide salts, acetone was distilled off and the resulting mixture was dissolved in 250 mL ethyl acetate:hexane mixture (1:2). After filtration over silica gel the solvents were distilled off, and the remaining crude product was recrystallized from hexane. 1H NMR (500 MHz, CDCl3): δ 5.00 (q, 1H), 4.89 (dd, 1H), 1.9-2.15 (br m, 2H), 1.70 (d), 1.66 (d), (3H, of 2 diastereoisomers), 1.45-1.65 (br m, 2H), 1.25-1.40 (br m, 6H), 0.90 (t, 3H). 13C NMR (500 MHz, CDCl3): δ 167.53, 166.90. 166.26, 165.87, 75.80, 72.49, 72.25, 31.92, 31.45, 31.39, 30.00, 28.73, 28.50, 24.60, 24.29, 22.48, 22.44, 17.54, 15.83, 14.00. ELEM. ANAL. Calcd. for C11H18O4: C, 61.68; H, 8.41. Found: C, 61.63; H, 8.48. Yield: 45%.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:41])[CH:12]([CH2:15][C:16]3[N:17]=[CH:18][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12.O>C(O)(=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:41])[CH:12]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)C(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]cnc1CC1CCc2c(C)c3ccccc3n2C1=O
Reaction time: 2 h

Procedure:
A solution of crude 8,9-dihydro-10-methyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]-indol-6(7H)-one in acetic acid ) 50 ml) and water (15 ml) was stirred at 45° C. for 2 hours and then at 65° C. for 2 hours. After evaporation of the solvent, the residue was diluted with water, neutralized with an aqueous sodium bicarbonate solution, and extracted three times with methylene chloride. The organic layer combined was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Purification of the residue with silica gel column chromatography (10% methanol-methylene chloride) gave 8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (1.0 g) as crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([CH3:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:44])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[C:34]([CH2:35][O:36]C3CCCCO3)=[CH:33][N:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:36][CH2:35][C:34]1[N:30]([C:26]2[CH:25]=[C:24]([C:23]3[CH2:22][C:21](=[O:44])[NH:20][C:9]4[CH:10]=[C:11]([CH3:19])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[N:31]=[N:32][CH:33]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-methyl-5-(methyl-propyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M80) (0.42 g, 0.71 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pale yellow solid (200 mg, 72%).
Reaction SMILES: [N+](=[CH:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7])=[N-].[CH3:9][C:10]1[C:15]([CH3:16])=[C:14]([CH3:17])[CH:13]=[C:12]([CH3:18])[C:11]=1[S:19]([OH:22])(=[O:21])=[O:20]>CCOCC>[O:8]=[C:4]([CH2:5][CH2:6][CH3:7])[CH2:3][O:22][S:19]([C:11]1[C:12]([CH3:18])=[CH:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=1[CH3:9])(=[O:20])=[O:21]
Reactant: Cc1cc(C)c(S(=O)(=O)O)c(C)c1C
Reactant: CCCC(=O)C=[N+]=[N-]
Solvent: CCOCC
Product: CCCC(=O)COS(=O)(=O)c1c(C)cc(C)c(C)c1C
Yield: 60 %

Procedure:
A 1.0 g quantity of 1-diazo-2-pentanone is reacted with 2.3 g of 2,3,4,6-tetramethyl-benzene-sulfonic acid in 30 ml of ether until nitrogen no longer evolves. The reaction mixture is washed with water, dried and distilled in a vacuum to remove the ether. The residue is recrystallized from ethanol/water, affording 1.6 g of 2-oxopentyl-2,3,4,6-tetramethylbenzene sulfonate (Compound 95), m.p. 49° to 50° C. Yield 60.0%.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].C1C[O:10]CC1.[CH2:12]([NH:16][C:17]([C:19]1[S:23][C:22]2[S:24][C:25]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:26][C:21]=2[CH:20]=1)=[O:18])[CH2:13][S:14][CH3:15]>O>[O:10]=[S:14]([CH3:15])[CH2:13][CH2:12][NH:16][C:17]([C:19]1[S:23][C:22]2[S:24][C:25]([S:27]([NH2:30])(=[O:28])=[O:29])=[CH:26][C:21]=2[CH:20]=1)=[O:18]
Reactant: C1CCOC1
Reactant: CSCCNC(=O)c1cc2cc(S(N)(=O)=O)sc2s1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CS(=O)CCNC(=O)c1cc2cc(S(N)(=O)=O)sc2s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium periodate (1.40 g., 6.54 mmoles) was dissolved in water (20 mL). THF (20 mL) was added followed by 5-[N-(3-thia-n-butyl)carbamoyl]thieno[2,3-b]thiophene-2-sulfonamide (1.10 g., 3.27 mmoles) were stirred at room temperature under Argon for 24 hours. The solution was filtered and then stripped of the THF and all but 2-2 mL of water. The product was then crystallized, collected and dried. Recrystallization from nitromethane gave 1.0 g. of 5-[N-(3-oxo-3-thia-n-butyl)carbamoyl]thieno[2,3-b]thiophene-5-sulfonamide, mp 242°-243° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[C:7]([C@H:9]([NH2:11])[CH3:10])[CH:8]=1.C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45](O)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([F:13])([F:14])[F:15])=[C:7]([C@H:9]([NH:11][C:45]([C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][CH:42]=2)[N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([C:24]4[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:34][CH:33]=2)[C:37]([CH3:49])=[C:38]3[CH3:48])=[O:46])[CH3:10])[CH:8]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@@H](N)c1cc(F)ccc1C(F)(F)F
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3cc(F)ccc3C(F)(F)F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(5-fluoro-2-(trifluoromethyl)phenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 589 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:14][OH:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].[O-:18][Mn](=O)(=O)=O.[K+]>CO>[C:1]([NH:8][C@H:9]([C:14]([OH:18])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.25 h
Yield: 94 %

Procedure:
BOC-leucinol (130 mg, 0.598 mmol) was treated with 3.1 ml of 0.25 N NaOH followed by KMnO4 (125 mg, 0.796 mmol) at room temperature and stirred 15 min. The reaction was treated with methanol, stirred 15 min, and the brown precipitate removed by filtration through Celite. The filtrate was acidified with solid citric acid and extracted with ether (3×). The combined ethereal extracts were washed with saturated NaCl (aq) (2×), dried over MgSO4 and filtered. Evaporation of the filtrate in vacuo gave 130 mg of BOC-leucine as an oil homogeneous by TLC (Rf, 0.34; silica GF in 5% MeOH/95% CH2Cl2).
Reaction SMILES: [IH:1].[F:2][C:3]([F:8])([F:7])[C:4]([O-:6])=[O:5].[NH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([OH:56])[CH:50]=2)([O:19][N:20]=[CH:21][C:22]([NH:24][CH:25]2[C:32](=[O:33])[N:31]3[CH:26]2[S:27][CH2:28][C:29]([CH:37]=[CH:38][CH2:39][N+:40]2[CH:45]=[CH:44][C:43]4SC=C[C:42]=4[CH:41]=2)=[C:30]3[C:34]([OH:36])=[O:35])=[O:23])[C:16]([OH:18])=[O:17])[N:14]=1.[CH3:57][C:58]1[N:59](C)[C:60]2N=CC=CC=2[N:62]=1>>[IH:1].[F:2][C:3]([F:8])([F:7])[C:4]([O-:6])=[O:5].[NH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([OH:56])[CH:50]=2)([O:19][N:20]=[CH:21][C:22]([NH:24][CH:25]2[C:32](=[O:33])[N:31]3[CH:26]2[S:27][CH2:28][C:29]([CH:37]=[CH:38][CH2:39][N:40]2[CH:45]=[CH:44][C:43]4=[NH+:62][CH:58]([CH3:57])[N:59]([CH3:60])[C:42]4=[CH:41]2)=[C:30]3[C:34]([OH:36])=[O:35])=[O:23])[C:16]([OH:18])=[O:17])[N:14]=1
Reactant: Nc1nc(C(ON=CC(=O)NC2C(=O)N3C(C(=O)O)=C(C=CC[n+]4ccc5sccc5c4)CSC23)(C(=O)O)c2ccc(O)c(O)c2)cs1
Reactant: Cc1nc2cccnc2n1C
Agent: I
Agent: O=C([O-])C(F)(F)F
Product: CC1[NH+]=C2C=CN(CC=CC3=C(C(=O)O)N4C(=O)C(NC(=O)C=NOC(C(=O)O)(c5ccc(O)c(O)c5)c5csc(N)n5)C4SC3)C=C2N1C
Yield: 45 %

Procedure:
Using the procedure of Step A of Example 20, 1.92 g of the product of Step B of Example 11 and 303 mg of 2,3-dimethyl-4-azabenzimidazole were reacted to obtain 877 mg of the expected product.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=1[N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[C:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=23)=[N:12]1)(O)=[O:2].Cl>O1CCCC1>[OH:2][CH2:1][CH2:4][C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=1[N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[C:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=23)=[N:12]1
Reactant: O=C(O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Agent: Cl
Solvent: C1CCOC1
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1C1=C(CCO)CCCC1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 56.9 %

Procedure:
To a solution of 3-[2-(2-carboxymethyl-1-cyclohexenyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (2.07 g) in tetrahydrofuran (40 ml) was added dropwise under nitrogen atmosphere a solution of borane-tetrahydrofuran complex in tetrahydrofuran (1M solution, 9.72 ml) at -10° C. over a period of 10 minutes. The reaction mixture was allowed to stir at room temperature for 5.5 hours. Then, the mixture was cooled to 10° C. in an ice bath and treated with 1N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined extracts were washed with 1N aqueous sodium hydroxide solution, water, and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (toluene:MeOH=10:1) to give colorless crystals of 3-[2-{2-(2-hydroxyethyl)-1-cyclohexenyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (1.14 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(N)cc1
Reaction time: 16 h

Procedure:
To a solution of (2R)-tert-butoxycarbonylamino-(4-nitro-phenyl)-acetic acid (350 mg, <1.18 mmol) in absolute ethanol (15 mL) was added a small amount of 10% palladium on carbon and the mixture stirred under an atmosphere of hydrogen for 16 hours. The reaction mixture was filtered through a pad of Celite and the Celite eluted with absolute ethanol. The filtrate was concentrated in vacuo then purified by chromatography over silica gel gradient eluted between 0 and 7% v/v methanol in dichloromethane. (2R)-(4-Amino-phenyl)-tert-butoxycarbonylamino-acetic acid was obtained as a yellow oil (146 mg, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:16][CH3:17].[CH2:18]1[O:29][C:28]2[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][C:20]=2[O:19]1>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:16][C:4]1[CH:5]=[C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]3[O:29][CH2:18][O:19][C:20]=3[CH:21]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc([C@H]2CCCC[C@H]2NC(=O)c2ccc3c(c2)OCO3)cc1OC
Reaction time: 8 h
Yield: 95.1 %

Procedure:
4.0 g of (−)-cis-1,2-dimethoxy-4-(2-aminocyclohexyl)benzene (compound B2) are dissolved in 100 ml of methylene chloride and 5.0 ml of triethylamine. A solution of 3.8 g of 3,4-methylenedioxybenzoyl chloride in 50 ml of methylene chloride is added dropwise at RT and the mixture is extracted with 100 ml each of water, 2N hydrochloric acid, satd. sodium hydrogencarbonate solution and water again after stirring overnight. The organic phase is dried using sodium sulfate and concentrated. 6.2 g of the title compound are obtained.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27](Cl)=O.C(N(CC)CC)C>C(#N)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(Cl)ccc2Cl)n1
Temperature: 150 °C
Yield: 42 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.05 g, 0.154 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 2,5-dichlorobenzoyl chloride (0.111 g, 0.529 mmol) and triethylamine (1.0 mL, 13.6 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.031 g (42% yield) of pure product: MS (ES) m/z 479 (M+1).