Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:8][CH2:7]2)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:8][CH2:7]2
Reactant: O=C(CN1CCc2cc([N+](=O)[O-])ccc21)OCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CCN2CC(=O)OCc1ccccc1
Yield: 98.9 %

Procedure:
To a suspension of benzyl 2-(5-nitroindolin-1-yl)acetate (0.700 g, 2.241 mmol) in a mixture of ethanol (20 ml) and water (10 ml), iron powder (0.751 g, 13.45 mmol) and ammonium chloride (0.084 g, 1.569 mmol) were added, and the resulting mixture was heated to reflux for 1 hour and 15 minutes. The insoluble was filtered off, and the filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and evaporated to dryness to give benzyl 2-(5-aminoindolin-1-yl)acetate (0.626 g, 2.217 mmol, 99% yield). MS/ESI+ 283.0 [MH]+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:14][CH2:15][O:16][CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:17][O:16][CH2:15][CH2:14][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COCCBr
Reactant: OCc1ccc2c(c1)NCCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCN1CCCc2ccc(CO)cc21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of (1,2,3,4-tetrahydroquinolin-7-yl)methanol (370 mg, 1.496 mmol), 1-bromo-2-methoxyethane (0.141 ml, 1.496 mmol) and Cs2CO3 (731 mg, 2.244 mmol) in DMF (10 ml). was stirred for 16 hr at 80° C. Additional 1-bromo-2-methoxyethane (0.070 ml, 0.748 mmol) was added and stirring was continued for 16 hr at 80° C. A third batch of 1-bromo-2-methoxyethane (0.070 ml, 0.748 mmol) was added and stirring was continued for 1 additional hour at 80° C. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give the title compound. HPLC (Method A) Rt=1.173 min; MS (Method A) [M+H]+=221.9
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:30][CH2:29][CH2:28][CH2:27][C:12]21[CH2:17][N:16]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:15][CH2:14][CH2:13]2)C1C=CC=CC=1>CO.[Pd]>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:16]2[CH2:15][CH2:14][CH2:13][C:12]3([CH2:27][CH2:28][CH2:29][CH2:30][CH:11]3[NH2:10])[CH2:17]2)=[CH:21][CH:22]=1
Reactant: O=C(NC1CCCCC12CCCN(CCc1ccc(F)cc1)C2)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC1CCCCC12CCCN(CCc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.1 %

Procedure:
A solution of {2-[2-(4-fluoro-phenyl)-ethyl]-2-aza-spiro[5.5]undec-7-yl}-carbamic acid benzyl ester (0.60 g, 1.4 mmol) in methanol (30 mL) was treated with 10% palladium on carbon (1.0 g) and shaken under a hydrogen atmosphere (60 psig) for 20 hours at room temperature. The catalyst was removed by filtration and the solvent was removed under vacuum to give a white foam (0.35 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:14]([C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[OH:15])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: Br[Mg]c1ccc(OCc2ccccc2)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1ccc(OCc2ccccc2)cc1

Procedure:
Prepared according to the procedure described in Example 25, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 4-(benzyloxy)phenyl magnesium bromide.
Reaction SMILES: Br[C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([F:14])=[C:6]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:7]=1.[CH3:17][N:18]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:37]3[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=3)[CH:24]=2)[C:19]1=[O:43].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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]>[F:14][C:5]1[CH:4]=[C:3]([O:15][CH3:16])[C:2]([C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:37]4[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=4)[CH:24]=3)[C:19](=[O:43])[N:18]([CH3:17])[CH:27]=2)=[CH:7][C:6]=1[NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10]
Reactant: Cn1cc(-c2ccc3c(=O)n(C)cc(B4OC(C)(C)C(C)(C)O4)c3c2)cn1
Reactant: CCS(=O)(=O)Nc1cc(Br)c(OC)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1cc(-c2cn(C)c(=O)c3ccc(-c4cnn(C)c4)cc23)c(OC)cc1F
Yield: 26.6 %

Procedure:
A mixture of N-(5-bromo-2-fluoro-4-methoxyphenyl)ethanesulfonamide (63 mg, 0.20 mmol), the title compound of Example 46, step 2 (75 mg, 0.21 mmol), Pd(dppf)Cl2 (19 mg, 0.03 mmol) and aqueous K3PO4 (1 M, 0.5 mL, 0.5 mmol) in dioxane (3 mL) was microwaved at 100° C. for 1 h. Purification by silica gel chromatography (PE:EA=1:1 to 1:4) followed by preparative HPLC gave the title compound (25 mg, 26.3%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=8.4 Hz, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.49 (d, J=9.2 Hz, 1H), 7.25 (s, 1H), 7.04 (s, 1H), 6.85 (d, J=12.0 Hz, 1H), 6.37 (s, 1H), 3.94 (s, 3H), 3.75 (s, 3H), 3.65 (s, 3H), 3.17 (q, J=7.2 Hz, 2H), 1.46 (t, J=7.2 Hz, 3H). LCMS: 471.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.CS(C)=O.[H-].[Na+].Br[C:35]1[S:36][CH:37]=[CH:38][N:39]=1>CC1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][O:27][C:35]3[S:36][CH:37]=[CH:38][N:39]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Brc1nccs1
Reactant: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Fc1ccc(Cn2c(NC3CCN(CCOc4nccs4)CC3)nc3ccccc32)cc1
Reaction time: 8 h
Yield: 14.5 %

Procedure:
To a stirred and cooled (below 10° C.) mixture of 5.52 parts of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidine ethanol, 100 parts of dimethyl sulfoxide and 90 parts of methylbenzene were added 0.75 parts of a sodium hydride dispersion 50%. After stirring for 30 minutes at a temperature below 10° C., 2.5 parts of 2-bromothiazole were added and stirring was continued overnight while the mixture was allowed to reach room temperature. The reaction mixture was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1 part (14.5%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(2-thiazolyloxy)ethyl]- 4-piperidinyl]-1H-benzimidazol-2-amine; mp. 156.5° C. (compound 72).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][C@@H:39]([C:45]([NH:47][C@H:48]([C:53]([OH:55])=[O:54])[CH2:49][C:50](=[O:52])[OH:51])=[O:46])[CH2:40][CH2:41][C:42](=[O:44])[OH:43])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34])=[O:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.N1CCCCC1.C(O)(=O)C>CS(C)=O>[NH2:1][C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][C@@H:39]([C:45]([NH:47][C@H:48]([C:53]([OH:55])=[O:54])[CH2:49][C:50](=[O:51])[OH:52])=[O:46])[CH2:40][CH2:41][C:42](=[O:43])[OH:44])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])=[O:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O

Procedure:
Fmoc-L-Trp-L-Leu-Gly-L-Arg-D-Glu-L-Asp-OH (50 mg), was dissolved in 0.5 ml of dimethylsulfoxide and 0.5 ml of piperidine was added to the solution. After reacting for an hour, the reaction mixture was neutralized with acetic acid under cooling.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([NH2:21])[C:18]([C:22](=[O:32])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[O:30][CH3:31])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH2:21][C:19]1[C:18]([C:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[O:30][CH3:31])=[O:32])=[CH:17][N:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[N:20]=1
Reactant: COc1cc(F)ccc1C(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(F)ccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Yield: 132.7 %

Procedure:
The compound of Example 175 (70 mg) in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was stirred for 2 hours at room temperature and evaporated to give the title compound (72 mg) as the trifluoroacetic acid salt.
Reaction SMILES: C[O:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:18]([O:20]C)=[O:19])=[C:12]([CH3:14])[N:13]=2)[CH2:5][CH2:4]1>I>[OH:2][CH:3]1[CH2:4][CH2:5][CH:6]([C:9]2[NH:10][C:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:18]([OH:20])=[O:19])=[C:12]([CH3:14])[N:13]=2)[CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C3CCC(OC)CC3)nc2C)c1
Agent: I
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCC(O)CC2)nc1C

Procedure:
A solution of methyl 3-(2-(4-methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 300.2, 300 mg, 0.88 mmol) in HI (45% in water) (3 mL) was stirred for 2 h at 60° C., then concentrated under reduced pressure. This resulted in 500 mg (crude) of the title compound as brown oil which was used into the next step without further purification.
Reaction SMILES: C(O[C:5](=[CH:19][C:20](=[O:22])C)[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[Br:18])=[O:8])(=O)C.S(=O)(=O)(O)[OH:24]>>[Br:18][C:11]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[C:15]2[C:10]=1[NH:9][C:7](=[O:8])[CH:6]=[C:5]2[CH2:19][C:20]([OH:22])=[O:24]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(Br)c(NC(=O)CC(=CC(C)=O)OC(C)=O)c1
Product: COc1ccc(Br)c2[nH]c(=O)cc(CC(=O)O)c12
Reaction time: 0.5 h
Yield: 89 %

Procedure:
1-(2-bromo-5-methoxyphenylamino)-1,5-dioxohex-3-en-3-yl acetate (8 g; 21.50 mmol) was added in small portions to concentrated sulfuric acid (30 ml) at room temperature and the mixture was stirred for 30 min. Ice was added to the reaction mixture and the formed precipitate was filtered, washed with water and dried over phosphorus pentoxide under reduced pressure to afford 5.97 g (89%) of 2-(8-bromo-5-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acetic acid as a grey solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[S:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[O-][CH2:24][CH3:25].[Na+].II>C(O)C>[S:22]([C:11]1[NH:12][C:13]([C:25]2[CH:24]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)[C:11]1[NH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)[N:12]=1
Reactant: CC[O-]
Reactant: CSc1ccc(-c2[nH]c(=S)[nH]c2-c2ccc(SC)cc2)cc1
Agent: II
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc(-c2nc(Sc3nc(-c4ccc(SC)cc4)c(-c4ccc(SC)cc4)[nH]3)[nH]c2-c2ccc(SC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4,5-bis(4-methylthiophenyl)-1H-imidazole-2-thione (5.2 g, 0.015 mol), sodium ethoxide (1.0 g, 0.015 mol) and iodine (1.9 g, 0.0075 mol) in ethanol (70 ml) was stirred at ambient temperature for three hours. The resulting solid was collected, washed with ethanol and then ether. Recrystallization from N,N-dimethylformamide give the title compound, m.p. 297°-298°.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]=O)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28]>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:19][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH3:28])=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1
Reactant: NC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: CNCCOC
Product: COCCN(C)Cc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide (75 mg) was reacted with N-(methoxyethyl)methylamine similarly to as described in the synthesis of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(4-methylpiperazin-1-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide to afford 10-bromo-9-fluoro-3-(((2-methoxyethyl)(methyl)amino)methyl)-6,7-dihydro-5H-5,7-methanobenzo [c]imidazo[1,2-a]azepine-2-carboxamide which was directly reacted with 2-Methyl-3-butyne-ol via General Procedure E to afford 24 mg (26%) of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[[2-methoxyethyl(methyl)amino]methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=441.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]([F:18])([F:17])[F:16])=[N:4][N:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=O)[C:6]=1[CH3:7].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:34]3[CH2:33][CH2:32][CH2:31][NH:30][C:29]=3[CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[C:3]([C:15]([F:18])([F:17])[F:16])=[N:4][N:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([N:30]2[CH2:31][CH2:32][CH2:33][C:34]3[N:26]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)[N:27]=[CH:28][C:29]2=3)=[O:11])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1C(C(=O)O)C(C)C
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)C(C)C
Yield: 74 %

Procedure:
The title compound was prepared from 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-3-methylbutanoic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 2×1 M NaHSO4. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-50% EtOAc in hexanes) to provide 89 mg (74%) of the title compound as a glassy white solid. 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.44 (m, 2H), 7.16 (m, 2H), 5.03 (d, J=10.9 Hz, 1H), 3.89 (ddd, J=2.7, 8.2, 10.9 Hz, 1H), 3.78 (ddd, J=2.7, 7.8, 10.9 Hz, 1H), 2.96 (m, 1H), 2.79 (m, 2H), 2.37 (s, 3H), 1.99 (m, 1H), 1.82 (m, 1H), 1.12 (d, J=6.3 Hz, 3H), 0.79 (d, J=7.1 Hz, 3H); MS: (ES) m/z calculated for C22H23ClF4N5O [M+H]+ 484.1, found 484.1.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[NH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:11]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[C:3]=1[C:24]#[N:25].C[Sn](C)(C)[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:29]=1.[Cl-].[Li+]>O1CCOCC1.[Cu]I.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:35]([NH:34][C:30]1[CH:29]=[C:28]([C:2]2[S:6][C:5]([C:7]3[NH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:11]=3)=[C:4]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[C:3]=2[C:24]#[N:25])[CH:33]=[CH:32][N:31]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Reactant: COC(=O)c1cnc(-c2sc(Br)c(C#N)c2-c2ccc(Cl)cc2Cl)[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: COC(=O)c1cnc(-c2sc(-c3ccnc(NC(C)=O)c3)c(C#N)c2-c2ccc(Cl)cc2Cl)[nH]1
Temperature: 110 °C
Yield: 10.3 %

Procedure:
Methyl 2-[5-bromo-4-cyano-3-(2,4-dichlorophenyl)-2-thienyl]-1H-imidazole-5-carboxylate (0.216 g, 0.472 mmol), N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (0.170 g, 0.567 mmol), lithium chloride (0.0601 g, 1.42 mmol), copper(I) iodide (0.0270 g, 0.142 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0273 g, 0.0236 mmol) were combined in dioxane (10 mL) under an atmosphere of Argon. The solution was heated at 110° C. for 3 hours. The solvent was evaporated, and column chromatography was performed to yield the title compound (0.0250 g, 10%). LCMS: (FA) ES+ 513. 1H NMR (300 MHz, d6-DMSO) 8.59-8.57 (m, 1H), 8.54-8.50 (m, 1H), 7.88-7.82 (m, 2H), 7.61-7.58 (m, 2H), 7.56-7.52 (m, 1H), 3.75 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[I:13]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[C:3]([I:13])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)ccc1C
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)c(I)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
Methyl 5-amino-2-methylbenzoate (1.0 eq, 3.75 g) was dissolved in acetic acid (70 ml). N-Iodosuccinimide (1.0 eq, 5.27 g) was added portionwise over 60 minutes. The mixture was stirred at room temperature for 30 minutes. Acetic acid was evaporated. The residue was diluted with ethyl acetate (80 ml) and neutralized with saturated sodium carbonate (80 ml). The organic layer was washed with 1M sodium thiosulfate (2×40 ml), then water (2×40 ml) and brine (2×40 ml). The material was purified by flash chromatography on silica gel (gradient 10% to 30% ethyl acetate in hexanes) to provide methyl 5-amino-4-iodo-2-methylbenzoate as a yellow-orange solid (3.19 g, 49% yield). GCMS>95% pure, m/z 291. 1H NMR (400 MHz, DMSO, d6) δ 2.30 (s, 3H), 3.78 (s, 3H), 5.27 (br s, 2H), 7.24 (s, 1H), 7.54 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:3]1.C([O:16][C:17](=O)[CH2:18][C:19]([C:21]([F:24])([F:23])[F:22])=[O:20])C>C(O)(=O)C>[OH:20][C:19]1([C:21]([F:24])([F:23])[F:22])[CH2:18][C:17](=[O:16])[NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:5]1=2
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Cn1nc(-c2ccccc2)cc1N
Solvent: CC(=O)O
Product: Cn1nc(-c2ccccc2)c2c1NC(=O)CC2(O)C(F)(F)F
Reaction time: 2.5 h
Yield: 15.5 %

Procedure:
2-Methyl-5-phenyl-2H-pyrazol-3-ylamine (vii) (100 mg, 0.58 mmol) was dissolved in glacial acetic acid (1 mL), ethyl-4,4,4-trifluoracetoacetate (0.13 mL, 0.85 mmol) was added at RT and stirring was continued for 2.5 h at 120° C. The mixture was evaporated to dryness and the isomeric mixture was directly purified by preparative HPLC (Agilent 1100 Series, Chromolith prep RP-18e, 100-25). A colorless solid (29 mg, 0.09 mmol, 16%) was obtained, characterized as compound (viii).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.[CH3:12]S(C)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][C:7](=[CH2:12])[CH2:6][CH2:5]1
Reactant: CS(C)=O
Reactant: CC1(C)CCC(=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=C1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methyltriphenylphosphonium bromide (2.97 g, 8.3 mmol) was added in the dehydrated DMSO (8 mL) solution of sodium hydride (0.35 g, 8.7 mmol) in an ice bath. The reaction mixture was stirred at room temperature for 10 minutes, and the dehydrated DMSO solution (1.5 mL) of 4,4-dimethyl-cyclohexanone (1.0 g, 7.9 mmol) was added slowly in an ice bath. The reaction mixture was stirred at room temperature for 18 hours and poured into ice water. The organic layer was extracted with diethyl ether, and then the layer was washed with water and dried with anhydrous magnesium sulfate, and removed by filtration. The filtrate was concentrated until becoming about half in volume. The formed insoluble matter was removed by filtration, then the filtrate was removed by distillation under reduced pressure, and colorless oily matter (0.91 g) was obtained.
Reaction SMILES: N1(C(N2C=CN=C2)=O)C=CN=C1.[C:13]([OH:17])(=O)[C:14]#[CH:15].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26](=[O:39])[CH2:27][C:28]1[NH:32][C:31]2[CH2:33][CH:34]([CH3:38])[CH2:35][CH:36]([CH3:37])[C:30]=2[N:29]=1>C1COCC1>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]([C:27]1[CH:15]=[CH:14][C:13](=[O:17])[N:32]2[C:31]3[CH2:33][CH:34]([CH3:38])[CH2:35][CH:36]([CH3:37])[C:30]=3[NH:29][C:28]=12)=[O:39]
Reactant: C#CC(=O)O
Reactant: CC1Cc2[nH]c(CC(=O)c3ccc(F)cc3F)nc2C(C)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1Cc2c([nH]c3c(C(=O)c4ccc(F)cc4F)ccc(=O)n23)C(C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
126.8 mg (0.78 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole and 45.5 mg (0.65 mmol) of propiolic acid are dissolved in 8 ml THF. The mixture is stirred for 3 h at rt. To this solution 131.7 mg (0.43 mmol) of 1-(2,4-Difluorophenyl)-2-(4,6-dimethyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example X) are added and the mixture is stirred for 20 h at rt. The solvent is evaporated under vacuum and the crude is purified over preparative HPLC (RP18-column, eluent: acetonitrile-water-gradient. The isomers are isolated after purification over preparative HPLC (Daicel Chiralpak AD, eluent: iso-hexane-ethanol v/v 30:70):
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]([OH:16])=O)[N:7]=3.[C:19]([O:23][C:24]([NH:26][NH:27][CH:28]([CH3:30])[CH3:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:19]([O:23][C:24]([NH:26][N:27]([C:14]([C:8]1[N:7]=[C:6]2[N:10]([CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Br:1])[CH:18]=[CH:17][C:5]=32)[CH:9]=1)=[O:16])[CH:28]([CH3:30])[CH3:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)NNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)OC(C)(C)C)C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reaction time: 8 h
Yield: 104.7 %

Procedure:
To a mixture of 8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (1.92 g, 6.2 mmol) and N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester (1.30 g, 7.5 mmol) in DMF (20 mL) at 0° C. was added DIPEA (2.70 mL, 15.5 mmol) and HATU (3.54 g, 9.3 mmol). The reaction mixture was stirred for 7 h at RT before the addition of DMF (40 mL) and stirring overnight. The reaction mixture was concentrated in vacuo and the resultant residue partitioned between DCM and water. The aqueous phase was extracted with DCM (×2) before the combined organic extracts were washed sequentially with 10% citric acid solution, saturated sodium bicarbonate solution then brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-90% ethyl acetate in cyclohexane) to give N′-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonyl)-N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester as a white solid (3.02 g, quantitative yield). LCMS RT=4.76 min, [M+H]+=465/467. 1H NMR 400 MHz (DMSO-d6) δ: 8.62 (1H, s), 8.40 (1H, d, J=8.59 Hz), 7.69 (1H, s), 7.23-7.22 (2H, m), 4.81 (1H, s), 4.44 (4H, s), 1.32 (9H, s), 1.13 (6H, d, J=6.64 Hz)