Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:36])[C@@H:12]([NH:21][C:22](=[O:35])[C@H:23]([NH2:34])[C:24]2[CH:33]=[CH:32][C:27]3[O:28][CH2:29][CH2:30][O:31][C:26]=3[CH:25]=2)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].C(N(C(C)C)CC)(C)C.[O:46]=[C:47](Cl)OC(Cl)(Cl)Cl.C1(C)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:36])[C@@H:12]([N:21]2[C:22](=[O:35])[C@@H:23]([C:24]3[CH:33]=[CH:32][C:27]4[O:28][CH2:29][CH2:30][O:31][C:26]=4[CH:25]=3)[NH:34][C:47]2=[O:46])[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc3c(c2)OCCO3)[C@@H](C)c2ccccc2)n1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc4c(c3)OCCO4)C2=O)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 54.7 %

Procedure:
A solution of 2-{(2S,3S)-2-[(R)-2-amino-2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (0.380 g, 0.75 mmol)) and diisopropylethylamine (0.52 mL, 3 mmol) in tetrahydrofuran (7.5 mL) were added to a solution of diphosgene (0.48 mL, 4 mmol) in a mixture of toluene (7.5 mol) and tetrahydrofuran (7.5 mol) over 10 minutes at 0° C. The mixture was stirred at 0° C. for 20 minutes and then diluted with ethyl acetate. The mixture was washed with water, brine and dried (sodium sulfate). Evaporation of the solvents and chromatography of the residue over silica gel gradient eluted with 0.2-1% methanol in dichloromethane gave (2-{(2S,3S)-2-[(R)-4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (0.22 g, 55%).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=2)[CH:20]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C1(C)C=CC=CC=1>[Br:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([C:12]1[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=4[CH:13]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:23]=[CH:22]2
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: Brc1ccc2cc(Br)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc2cc(-c3cc4ccccc4c4ccccc34)ccc2c1
Temperature: 85 °C
Reaction time: 7 h
Yield: 43.5 %

Procedure:
In argon atmosphere, a mixture of 15.53 g (69.6 mmol) of 9-phenanthreneboronic acid, 20.00 g (69.9 mmol) of 2,6-dibromonaphthalene, 1.62 g (1.40 mmol) of tetrakis(triphenylphosphine)palladium (0), 150 ml of dimethoxyethane, 150 ml of toluene, and 106 g of a 2 M sodium carbonate aqueous solution was stirred at a bath temperature of 85° C. for 7 h. The reaction mixture was added with water and extracted with toluene. After washing with water, the organic phase was dried over magnesium sulfate. Then the toluene was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography to obtain 11.6 g (yield: 43%) of 6-bromo-2-(9-phenanthrenyl)naphthalene.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1([C:20]([O:22]C)=O)[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1.Cl.[NH2:25][C@@H:26]1[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[OH:32][C@@H:29]1[CH2:30][CH2:31][C@H:26]([N:25]2[CH2:2][CH2:3][C:4]3([CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[O:11])[CH2:8][CH2:9]3)[C:20]2=[O:22])[CH2:27][CH2:28]1
Reactant: COC(=O)C1(CC=O)CCN(C(=O)OCc2ccccc2)CC1
Reactant: N[C@H]1CC[C@@H](O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CCN([C@H]1CC[C@@H](O)CC1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-benzyl 4-methyl 4-(2-oxoethyl)piperidine-1,4-dicarboxylate (4.80 g, 0.0150 mol), cis-4-aminocyclohexanol hydrochloride (2.5 g, 0.016 mol) and triethylamine (3.3 mL, 0.024 mol) in 1,2-dichloroethane (30.0 mL) was stirred at room temperature for 30 min. To the mixture was added sodium triacetoxyborohydride (7.9 g, 0.038 mol) with stirring. The mixture was stirred at room temperature for 1 h, then was heated at 80° C. for 2 h. After cooling, the mixture was diluted with dichloromethane, and washed with IN HCl solution, NaHCO3 (7.5%), water, and brine successively, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography to give benzyl 2-(cis-4-hydroxycyclohexyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (4.20 g, 72.0%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[N:7]([CH2:8][C:9]2[S:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:13]=2)[N:6]=[CH:5][C:4]=1[C:24]([O:26]CC)=[O:25].[OH-].[Na+].C(O)C.Cl>O.C(OCC)(=O)C.O1CCCC1>[F:30][C:2]([F:1])([F:29])[C:3]1[N:7]([CH2:8][C:9]2[S:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:13]=2)[N:6]=[CH:5][C:4]=1[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.5 %

Procedure:
A mixture of the compound (0.13 g) obtained in Example 103d, 4N sodium hydroxide (1 mL), ethanol (2 mL) and tetrahydrofuran (0.5 mL) was stirred at room temperature for 20 hr. The reaction mixture was adjusted to pH 5 with 1N hydrochloric acid, and ethyl acetate and water were added. The ethyl acetate layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (0.12 g) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7](Br)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:22]1[C:26]2[CH:27]=[C:28](Br)[CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH2:32])[CH:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:18]([N:22]1[C:26]2[CH:27]=[C:28]([C:7]3[O:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:9][C:8]=3[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH2:32])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)Cn1c(N)nc2ccc(Br)cc21
Reactant: CC(C)(C)c1nc(-c2ccc(F)cc2)c(Br)o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N)nc2ccc(-c3oc(C(C)(C)C)nc3-c3ccc(F)cc3)cc21
Temperature: 100 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
Bubble nitrogen through a suspension of 2-(tert-butyl)-4-(4-fluorophenyl)-5-bromooxazole (2.0 g, 9.1 mmol), 1-isobutyl-2-amino-6-bromobenzimidazole (4.98 g, 18.6 mmol), cesium carbonate (6.06 g, 18.6 mmol), palladium(II) acetate (0.201 g) and triphenylphosphine (1.2 g, 4.5 mmol) in 15 mL dimethylformamide for 3 minutes. Stir the reaction mixture at 100° C. for 18 hours. Cool to room temperature. Partition between ethyl acetate and saturated aqueous sodium chloride. Wash the organic layer with saturated aqueous sodium chloride, dry over sodium sulfate, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 50:1 dichloromethane:methanol containing 2M ammonium hydroxide to provide 1-isobutyl-2-amino-6-(2-(tert-butyl)-4-(4-fluorophenyl)oxazol-5-yl)-1H-benzimidazole (1 g, 27%). This material is treated with methanesulfonic acid as previously described to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([NH:24][C:25](OC(C)(C)C)=O)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:38]=[CH:37][C:36]([CH:39]2[CH2:43]C(OC)O[CH:40]2OC)=[CH:35][CH:34]=1.FC(F)(F)C(O)=O>ClCCCl>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([N:24]1[CH:25]=[CH:40][C:39]([C:36]2[CH:37]=[CH:38][C:33]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:34][CH:35]=2)=[CH:43]1)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1c[nH]cn1
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@H](C(=O)N[C@H](CO)Cc1c[nH]cn1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1)OCc1ccccc1
Yield: 37 %

Procedure:
According to the procedure described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo-[9.6.1.012,17]-octadeca-11(18),12,14,1 6-tetraen-9S-yl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-(t-butoxycarbonylamino)-N-[2-hydroxy-1(S)-[(1H-imidazol-4-yl)methyl]ethyl]succinamic acid benzyl ester was deprotected, and the resultant crude amine salt was condensed with 3-(biphenyl-4-yl)-2,5-dimethoxy-tetrahydrofuran (produced as described in Example 1(a)) in 1,2-dichloroethane in the presence of trifluoroacetic acid to give in 37% yield 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1(S)-[(1H-imidazol-4-yl)methyl]ethyl]succinamic acid benzyl ester as a yellow solid. 1H NMR (CDCl3): δ 7.65-7.59 (m, 4H), 7.53 (d, 2H, J=8.5 Hz), 7.45 (t, 2H, J=7.4 Hz), 7.37-7.26 (m, 7H), 6.95 (s, 1H), 6.70 (t, 1H, J=2.2 Hz), 6.65 (s, 1H), 6.52 (s, 1H), 6.45 (bs, 1H), 5.10 (s, 2H), 5.06-5.02 (m, 1H), 4.13-4.11 (m, 1H), 3.69 (dd, 1H, J=3.9, 11.6 Hz), 3.56 (dd, 1H, J=4.8, 11.8 Hz), 3.42 (dd, 1H, J=5.5, 16.9 Hz), 3.06 (dd, 1H, J=8.8, 16.9 Hz), 2.84 (t, 2H, J=4.8 Hz). Anal. Calculated for C33H32N4O4•0.8 H2O•0.15 MTBE: C, 70.34; H, 6.19; N, 9.72. Found: C, 70.51; H, 6.05; N, 10.15.
Reaction SMILES: [CH3:1][O:2][C@:3]1([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[N:25]2[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH2:20][C@H:19]2[CH2:21][C@@H:5]([CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH:11]=[CH:12][CH2:13][CH2:14][C:15]([CH3:23])=[CH:16][C:17](=[O:22])[O:18]2)[O:4]1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[CH3:1][O:2][C@:3]1([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[N:25]2[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH2:20][C@H:19]2[CH2:21][C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:23])=[CH:16][C:17](=[O:22])[O:18]2)[O:4]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CC=CCCC(C)=CC(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCCCCCCCC(C)=CC(=O)O3)O2)cc1

Procedure:
Application of the method shown in Example 41, with the modification that (R)-4-((1R,4Z,8E,10Z,15R,17R)-17-methoxy-5-methyl-3-oxo-2,16-dioxa-bicyclo[13.3.1]nonadeca-4,8,10-trien-17-yl)-3-(4-methoxybenzyl)thiazolidin-2-one is substituted for (R)-4-((1R,4Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, affords the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:21])=[C:9]([NH:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:21])=[C:9]([NH:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][N:15]=[C:14]([N:34]3[CH2:35][CH2:36][CH:31]([CH2:30][C:27]4[CH:26]=[CH:25][N:24]=[CH:29][CH:28]=4)[CH2:32][CH2:33]3)[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cnc(Cl)nc1Nc1cc(C(C)(C)C)ccc1C
Reactant: c1cc(CC2CCNCC2)ccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1cnc(N2CCC(Cc3ccncc3)CC2)nc1Nc1cc(C(C)(C)C)ccc1C
Yield: 68.2 %

Procedure:
A solution of the product of Step 1 (166 mg, 0.543 mmol), 4-piperidin-4-ylmethylpyridine dihydrochloride (162 mg, 0.651 mmol) and diisopropylethylamine (1.5 mL) was irradiated in 2-propanol (1.5 mL), in a microwave oven, at 180° C. for 2.5 hrs. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage system, MeOH/dichloromethane, 0%-15%) to give the product (165 mg, 68.2%) as a solid. 1H-NMR (600 MHz, CDCl3) δ=1.21 (2H, m), 1.28 (9H, s), 1.60 (2H, d, J=13.19), 1.74 (1H, m), 2.23 (3H, s), 2.49 (2H, d, J=7.35), 2.72 (2H, td, J=12.76, 1.51), 3.80 (3H, s), 4.64 (2H, d, J=13.35), 6.96 (1H, s), 6.99 (1H, dd, J=7.88, 1.9), 7.03 (2H, d, J=5.43), 7.08 (1H, d, J=8.15), 7.60 (1H, s), 8.27 (1H, d, J=1.9), 8.44 (2H, d, J=5.7), LC-ESMS observed [M+H]+ 446.2 (calcd 446.6).
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH2:3][CH:4]=[CH:5][C:6](=[O:8])[CH3:7].[OH-].[K+].[BH4-].[Na+].[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][C:12]([CH3:13])([CH3:14])[CH2:11][CH2:10][CH2:9][CH:2]([CH3:1])[CH2:3][CH:4]=[CH:5][C:6](=[O:8])[CH3:7])[CH3:20]
Reactant: CC(=O)C=CCC(C)CCC=C(C)C
Reactant: CCO
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Product: CCOC(C)(C)CCCC(C)CC=CC(C)=O
Reaction time: 2 h

Procedure:
To a solution of 1.8 g. of 6,10-dimethylundeca-3,9-dien-2-one in 20 ml. of ethanol, cooled to 0° by an ice bath is added a suspension of 2.32 g. of mercuric acetate in 50 ml. of ethanol over 15 minutes. The reaction mixture is stirred for 2 hours and then, with cooling, to -20°, 1.22 g. of potassium hydroxide in 20 ml. of ethanol is added. Then 0.139 g. of sodium borohydride is added in small portions and stirring continued for 30 minutes at -20°. The solution is decanted, then concentrated to half volume, diluted with 100 ml. of water and extracted with ether (3 × 50). The ethereal phase is washed with water, dried over magnesium sulfate and the crude product chromatographed on silica to yield 10-ethoxy-6,10-dimethylundec-3-en-2-one.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([C@@H:14]1[C:20]2=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[CH:27]=[C:19]2[NH:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH:37]([C:39]1[S:43][C:42]([C:44]([OH:46])=[O:45])=[CH:41][CH:40]=1)=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.ClCCl>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[CH2:6][N:7]([C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1)[C@@H:14]1[C:20]2=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[CH:27]=[C:19]2[N:18]([CH2:37][C:39]2[S:43][C:42]([C:44]([OH:46])=[O:45])=[CH:41][CH:40]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc4c(cc32)COC4)n1
Reactant: O=Cc1ccc(C(=O)O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(Cc3ccc(C(=O)O)s3)c3cc4c(cc32)COC4)n1

Procedure:
To a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 73, Step 7) (0.16 mmol) in dichloroethane (5 mL), add 5-formyl-thiophene-2-carboxylic acid (0.63 mmol) followed by acetic acid (cat.). Add NaB(OAc)3H (0.78 mmol) and stir the mixture at room temperature for 14 h. Dilute the reaction with dichloromethane (10 mL) and quench with water (5 mL). Separate the organics and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over Na2SO4, filter, and remove the solvent under vacuum. Chromatograph the product over silica gel eluting with MeOH/DCM (1-5%) to provide the title compound as a colorless foam. MS (ES+): 651 (M−H).
Reaction SMILES: Cl.C[O:3]C(=O)[C@H](C)N.CCN(CC)CC.N(C)(C)C.BC(O)=O.[CH:24]1([N:30]=[C:31]=[N:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl>[CH:33]1([NH:32][C:31]([NH:30][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:3])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: COC(=O)[C@H](C)N
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: BC(=O)O
Agent: CN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of L-alanine methyl ester hydrochloride (5.97 g, 42.8 mmol) in CH2Cl2 (100 ml) was added Et3N (4.33 g, 42.8 mmol), and the mixture was stirred for 20 minutes at room temperature. A solution of Me3N.BH2COOH (5.00 g, 42.8 mmol) in CH2Cl2 (50 ml) was then added to the reaction mixture, followed by N,N'-dicyclohexylcarbodiimide (DCC) (9.27 g, 49.1 mmol) in CH2Cl2 (50 ml). After 72 hours, the N,N'-dicyclohexylurea (DCU) precipitate which formed was filtered off, and the solvent was removed under reduced pressure. The solid residue was then washed with diethyl ether (3×300 ml), and the combined washes were filtered prior to removal of the ether under reduced pressure. This procedure was repeated with water (3×300 ml) as solvent, following which, evaporation of the water from the combined washes was aided by passage of a dry air stream over the solution. Further purification of the resulting yellow oil was performed by flash chromatography using ethyl acetate/acetone (95:5) as the mobile phase. After the peptide-containing fractions were combined and the solvent removed in vacuo, the peptide oil was distilled under vacuum at 50° C. Final purification of the distilled oil was performed by flash chromatography on a column packed with petroleum ether and eluted with ethyl acetate/n-butyl alcohol (95:5). The peptide-containing fractions were combined, and the solvent was removed by the passage of a dry air stream over the solution to give the desired crystalline dipeptide. (Due to the hygroscopic nature of (1), a clear oil may result, which may be crystallized by storage under high-vacuum for several weeks.) Yield: 0.452 g (5.23%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[N:8]=2)=[O:4].C1C(=O)N([Br:34])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH2:15][Br:34])=[CH:11][CH:10]=[C:9]([C:17]([F:18])([F:19])[F:20])[N:8]=2)=[O:4]
Reactant: COC(=O)c1c(C)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1c(CBr)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Yield: 98.1 %

Procedure:
In a 50 mL pear-shaped flask, 3-methyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (0.45 g, 1.24 mmol), NBS (221 mg, 1.24 mmol) and benzoyl peroxide (60.2 mg, 0.248 mmol) were combined with carbon tetrachloride (12 mL) to give a light yellow suspension. The reaction mixture was refluxed for 2 hr. The reaction mixture was cooled, diluted with methylene chloride (50 mL), washed with saturated aqueous NaHCO3 (1×20 mL), and brine (1×20 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give crude 3-bromomethyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (536.6 mg, 97.9%) as a pale yellow solid. The material was not further purified. 1H NMR (DMSO-d6) δ ppm 8.89 (d, J=8.2 Hz, 1H) 7.99 (d, J=8.2 Hz, 1H) 7.44-7.62 (m, 5H) 4.53 (s, 2H) 3.55 (s, 3H). MS calcd. for C18H12BrF3N2O3 [(M+H)+] 442.0, obsd. 443.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[CH2:6][CH2:5]2.[CH:15]1([C:18]2[N:22]=[C:21]([C:23]3([C:26]4[CH:27]=[C:28](B(O)O)[CH:29]=[N:30][CH:31]=4)[CH2:25][CH2:24]3)[O:20][N:19]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].C(O)(C)(C)C>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[CH:15]1([C:18]2[N:22]=[C:21]([C:23]3([C:26]4[CH:27]=[C:28]([C:2]5[CH:3]=[C:4]6[C:9](=[CH:10][CH:11]=5)[N:8]5[CH:12]=[N:13][N:14]=[C:7]5[CH2:6][CH2:5]6)[CH:29]=[N:30][CH:31]=4)[CH2:25][CH2:24]3)[O:20][N:19]=2)[CH2:17][CH2:16]1
Reactant: Brc1ccc2c(c1)CCc1nncn1-2
Reactant: OB(O)c1cncc(C2(c3nc(C4CC4)no3)CC2)c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: c1cc2c(cc1-c1cncc(C3(c4nc(C5CC5)no4)CC3)c1)CCc1nncn1-2
Temperature: 80 °C

Procedure:
To a vial containing the title compound from Example 22 Step B (0.025 g, 0.100 mmol), the title compound from Example 72 Step C (0.027 g, 0.100 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (1.4 mg, 2.0 μmol), and potassium carbonate (0.041 g, 0.300 mmol) were added tert-butanol (1.1 mL) and water (0.14 mL). The vial was flushed with nitrogen, sealed tightly and heated to 80° C. overnight. The reaction solution was then cooled to room temperature and concentrated under reduced pressure. The resulting material was diluted with acetonitrile and purified by HPLC (C18 column, 10 to 100% acetonitrile/water, both 0.1% v/v trifluoroacetic acid). Fractions containing product were combined, aqueous 1 N HCl solution was added, and the resulting solution concentrated under reduced pressure to provide the title compound: LCMS m/z 397.02 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 9.37 (s, 1H), 9.01 (s, 1H), 8.85 (s, 1H), 8.60 (s, 1H), 7.92-7.86 (m, 3H), 3.27-3.24 (m, 4H), 2.02-1.99 (m, 1H), 1.92-1.90 (m, 2H), 1.78-1.76 (m, 2H), 1.04-1.00 (m, 2H), 0.91-0.89 (m, 2H).
Reaction SMILES: ClC1C=CC(CN2CCC(NC3C=C(NC(=O)C)C=CC=3)CC2)=CC=1OCC.Cl.Cl.[CH3:31][O:32][C:33]([C:35]1[CH:40]=[N:39][C:38]([NH:41][CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:37][N:36]=1)=[O:34].[CH2:48]([O:50][C:51]1[CH:56]=[C:55]([CH:57]=O)[CH:54]=[C:53]([O:59][CH2:60][CH3:61])[C:52]=1[C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)[CH3:49]>>[CH3:31][O:32][C:33]([C:35]1[CH:40]=[N:39][C:38]([NH:41][CH:42]2[CH2:47][CH2:46][N:45]([CH2:57][C:55]3[CH:54]=[C:53]([O:59][CH2:60][CH3:61])[C:52]([C:62]4[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=4)=[C:51]([O:50][CH2:48][CH3:49])[CH:56]=3)[CH2:44][CH2:43]2)=[CH:37][N:36]=1)=[O:34]
Reactant: COC(=O)c1cnc(NC2CCNCC2)cn1
Reactant: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Agent: CCOc1cc(CN2CCC(Nc3cccc(NC(C)=O)c3)CC2)ccc1Cl
Agent: Cl
Product: CCOc1cc(CN2CCC(Nc3cnc(C(=O)OC)cn3)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared in analogy to the synthesis of 6-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-nicotinonitrile (example 38/step 3) from 5-(piperidin-4-ylamino)-pyrazine-2-carboxylic acid methyl ester dihydrochloride (intermediate B14) and 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (intermediate E22) in a yield of 5.8 mg (7%). MS (ISP): 509.4 [M+H]+.