Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:38][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:33])([F:35])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCNCC3)cc2)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.8 %

Procedure:
To a suspension of 2-(2-(2-(2-((4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (1) (0.015 g, 0.031 mmol) in anhydrous methanol (1.5 mL) were added a 37% aq. solution of formaldehyde (0.005 mL, 0.062 mmol) followed by sodium triacetoxyborohydride (0.033 g, 0.155 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 1.5 hours, the volatiles were removed in vacuo and the residue was diluted with EtOAc (15 mL) and sat. aq. NaHCO3 (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×10 mL), the combined organic layers were washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (3) (14.5 mg, 97% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 8.60 (s, 1H), 7.57 (d, J=9.0 Hz, 2H), 7.43 (s, 1H), 7.26-7.13 (m, 4H), 6.96-6.87 (m, 3H), 3.50 (s, 2H), 3.12-3.03 (m, 6H), 3.03-2.94 (m, 2H), 2.47-2.42 (m, 4H), 2.22 (s, 3H). LCMS Method C: rt 4.74 min; m/z 499.3 [M+H]+.
Reaction SMILES: [P:1]([O:6][CH3:7])([O:4][CH3:5])[O:2]C.[Br:8][C:9]1[C:10]([OH:19])=[C:11]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[CH2:12]Br>>[CH3:5][O:4][P:1]([CH2:12][C:11]1[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:9]([Br:8])[C:10]=1[OH:19])(=[O:2])[O:6][CH3:7]
Reactant: COP(OC)OC
Reactant: COc1cc(Br)c(O)c(CBr)c1
Product: COc1cc(Br)c(O)c(CP(=O)(OC)OC)c1

Procedure:
8.8 g of trimethyl phosphite are added to 20.0 g of 3-bromo-2-hydroxy-5-methoxy-benzyl bromide and, with stirring, the mixture is heated for 3 hours at 140° (complete conversion according to TLC). The resulting oil is filtered with toluene/ethyl acetate (4:1) as eluant over a small amount of silica gel. [(3-Bromo-2-hydroxy-5-methoxy-phenyl)methyl]phosphonic acid dimethyl ester is thus obtained [1H-NMR (360 MHz, CDCl3): 3.20 (d, 2H, CH2P, 2JP-H =21 Hz), 3.70 (s, 3H, OCH3), 3.74 (d, 6H, 2×OCH33JP-H =1 Hz), 6.70 (m, 1H), 7.07 (m, 1H) ppm].
Reaction SMILES: [F:1][C:2]1([F:44])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18](CC3C=CC(OC)=CC=3OC)[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:17])=[O:16])=[C:11]([F:36])[C:10]=2[CH3:37])[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:16])=[O:17])=[C:11]([F:36])[C:10]=2[CH3:37])[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CC(F)(F)CC[C@@H]3c3ccnn3C)c(C)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(O[C@H]2CC(F)(F)CC[C@@H]2c2ccnn2C)ccc(S(=O)(=O)Nc2ccncn2)c1F
Yield: 79.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (51 mg, 0.081 mmol) prepared in Example 84a, triethylsilane (0.10 mL), trifluoroacetic acid (0.5 mL) and dichloromethane (2.0 mL), to yield the title compound (31 mg, 79%) as a colorless solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[N:7]=1.[NH2:14][C:15]1[S:16][C:17]([C:23]2[C:28]([F:29])=[CH:27][C:26]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:25][C:24]=2[F:34])=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21]>>[CH3:1][NH:2][C:3](=[O:13])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:14][C:15]2[S:16][C:17]([C:23]3[C:24]([F:34])=[CH:25][C:26]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:27][C:28]=3[F:29])=[CH:18][C:19]=2[C:20]([NH2:22])=[O:21])[N:7]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CNC(=O)OCc1cccc(Br)n1
Product: CNC(=O)OCc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using (6-bromopyridin-2-yl)methyl methylcarbamate (149 mg, 0.61 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (200 mg, 0.64 mmol) as the starting materials.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:8]2[CH:9]=[CH:10][NH:11][C:12]=2[CH:13]=[CH:14][CH:15]=1.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=3)=[CH:22][NH:23]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]3[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]4[CH:15]=[CH:14][CH:13]=[C:12]5[C:8]=4[CH:9]=[CH:10][NH:11]5)[CH2:30][CH:31]=3)=[CH:22][NH:23]2)=[CH:19][CH:18]=1
Reactant: ClCCCCOc1cccc2[nH]ccc12
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(C3=CCN(CCCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 99 using 1-chloro-4-(1H-indole-4-oxy)butane (0.479 g, 2.15 mmol) and 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.500 g, 2.13 mmol) in the presence of 2.5 equivalents of potassium carbonate (0.742 g, 5.38 mmol) in dimethylformamide at 90° C. Yield 0.220 g (24%) of a tan foam. FDMS m/e=420 (M+ of free base).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[C:18]([Mg]Br)([CH3:20])=[CH2:19]>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([C:18]([CH3:20])=[CH2:19])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: C=C(C)[Mg]Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C(C)C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (793 mg) in THF (5 mL) at −78° C. was added isopropenyl magnesium bromide (12.3 mL of 0.5 M in THF) dropwise. The resulting mixture was then stirred at 0° C. for 5 hr. The reaction was quenched with H2O and 1 N HCl, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield an orange gum. The orange gum was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as a peach-colored solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[F:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=1)(=[O:26])=[O:25])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1cccc(F)c1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-phenyl-methanone and 3-fluoro-benzenesulfonyl chloride. 1H NMR (CDCl3): δ (ppm): 7.00-7.05 (m, 1H), 7.35 (m, 1H), 7.37 (m, 1H), 7.39-7.44 (m, 4H), 7.37-7.43 (m, 4H), 7.45-7.46 (m, 1H), 7.49-7.50 (m, 1H), 7.51-7.52 (m, 2H), 7.58-7.62 (m, 1H), 9.80 (s, 1H). MS: m/z 390.0 (M++1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@H:8]([OH:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C@H:8]([O:10][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])[CH3:9])[N:7]=1
Reactant: C[C@H](O)c1cccc(Br)n1
Reactant: Oc1ccccc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccccc1Cl)c1cccc(Br)n1
Temperature: 0 °C
Yield: 93.7 %

Procedure:
A solution of (S)-1-(6-bromopyridin-2-yl)ethanol (1 g) (prepared by the method of S. Ishikawa, T. Hamada, K. Manabe, and S. Kobayashi, Synthesis 2005, 13, 2176-2182), 2-chlorophenol (0.615 mL, 0.764 g) and triphenylphosphine (1.558 g) in tetrahydrofuran (20 mL) under N2 and cooled to 0° C. A solution of diisopropyl azodicarboxylate (1.17 mL, 1.2 g) in tetrahydrofuran (10 mL) was then added dropwise and reaction warmed to room temperature overnight. The solvent was removed under reduced pressure, then heptane added to precipitate the triphenylphosphine oxide side product. Filtration and evaporation of the filtrate followed by purification by flash chromatography on silica eluting with heptane/ethyl acetate 8:2 gave the title compound (1.45 g) as a clear liquid.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[CH2:19][C:20]3[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=3)=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:4][CH:3]=1.Cl.[C:34]([O:38][C:39](=[O:46])[C@H:40]([CH2:42][CH2:43][S:44][CH3:45])[NH2:41])([CH3:37])([CH3:36])[CH3:35].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[CH2:19][C:20]3[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=3)=[CH:13][C:9]=2[C:10]([NH:41][C@@H:40]([CH2:42][CH2:43][S:44][CH3:45])[C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:46])=[O:11])=[CH:4][CH:3]=1
Reactant: CSCC[C@H](N)C(=O)OC(C)(C)C
Reactant: Cn1cncc1CC(Oc1ccc(CCc2ccc(F)cc2)c(C(=O)O)c1)c1nccs1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CSCC[C@H](NC(=O)c1cc(OC(Cc2cncn2C)c2nccs2)ccc1CCc1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(4-fluorophenethyl)-5-[2-(1-methylimidazol-5-yl)-1-(thiazol-2-yl)ethoxy]benzoic acid (0.74 g, 1.63 mmol), DMAP (1.0 g, 8.2 mmol), L-methionine tert-butyl ester HCl (1.0 g, 4.92 mmol), EDC (0.63 g, 3.27 mmol) and HOBT (0.22 g, 1.63 mmol) in DMF (50 ml) was stirred at ambient temperature under a nitrogen atmosphere for 16 hours. The reaction was evaporated to dryness and washed with aqueous citric acid (1M, 20 ml) and extracted with dichloromethane (20 ml). The extracts were washed with saturated brine and dried and applied directly onto a silica flash column which was eluted with ethyl acetate/methanol (9:1 and 4:1) to give tert-butyl (2S)-2- {2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxy]benzoylamino}-4-methylsulfanylbutyrate. The product was dissolved in ethyl acetate and treated with 1M ethereal HCl (10 ml). The resulting solid was isolated by centrifuging, flirther washing with diethyl ether and finally drying under high vacuum to give tert-butyl (2S)-2-{2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxy]benzoylamino}-4-methylsulfanylbutyrate as a white solid, (0.57 g, 54% Yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:10][O:11][C:12]=2[CH2:13]Br)[CH:5]=[CH:4][N:3]=1.[CH3:22][O-:23].[Na+]>[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:10][O:11][C:12]=2[CH2:13][O:23][CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Fc1ccc(-c2noc(CBr)c2-c2ccnc(Br)c2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COCc1onc(-c2ccc(F)cc2)c1-c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
To the above Compound 18b (200 mg, 0.485 mmol) was added NaOMe (0.5 M in MeOH, 2.0 mL, 1.0 mmol). The solution was stirred at 25° C. for 90 min. Then, the solution was poured into brine, extracted with EtOAc (4×15 mL), dried (MgSO4), filtered through a silica plug. Evaporation of the solvent provided the title compound (175 mg, 0.482 mmol, 99%).
Reaction SMILES: [C:1](OC)(=O)CC[C@H]([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)C(CCCC2)CC3)CC1)C.C(Cl)(=O)C.[CH3:32][C@@H:33]([C@@H:39]1[C@@:43]2([CH3:60])[C@@H:44]([OH:59])[CH2:45][C@@H:46]3[C@@:51]4([CH3:57])[CH2:52][CH2:53][C@@H:54]([OH:56])[CH2:55][C@H:50]4[CH2:49][C@@H:48]([OH:58])[C@H:47]3[C@@H:42]2[CH2:41][CH2:40]1)[CH2:34][CH2:35][C:36]([OH:38])=[O:37]>CO>[CH3:32][C@@H:33]([C@@H:39]1[C@@:43]2([CH3:60])[C@@H:44]([OH:59])[CH2:45][C@@H:46]3[C@@:51]4([CH3:57])[CH2:52][CH2:53][C@@H:54]([OH:56])[CH2:55][C@H:50]4[CH2:49][C@@H:48]([OH:58])[C@H:47]3[C@@H:42]2[CH2:41][CH2:40]1)[CH2:34][CH2:35][C:36]([O:38][CH3:1])=[O:37]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: CC(=O)Cl
Solvent: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
Preparation of the starting compounds of the formula III using the example of methyl cholanate (Fieset et al., J. Am. Chem. Soc. 74, 1952, 3309) ##STR6## 450 ml of acetyl chloride are slowly added dropwise to 4.5 l of methanol, while cooling with ice, such that the temperature does not exceed 10° to 15° C. After the addition, the mixture is subsequently stirred at about 10° C. for a further 15 minutes. 600 g (1.47 mol) of cholic acid are then introduced at about 5° C. The ice-bath is removed, and after a further hour, while stirring, the reaction is ended. The reaction mixture is slowly added to 12 l of water. The mixture is stirred for a further 2 hours and then filtered with suction, and the residue is rinsed with 3 l of water. The crystalline substance is dried in vacuo at 50° C. 610 g (98%) of methyl cholate (melting point 154° C.) are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15]([NH:17][C:18]1[CH:49]=[CH:48][C:21]([C:22]([N:24]([CH3:47])[C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=3[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)=[O:39])=[O:23])=[CH:20][C:19]=1[O:50][CH3:51])=[O:16])[CH:11]=[CH:10][CH:9]=2)=[O:5])C.Cl.CO>[OH-].[Na+].C(O)C>[C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15]([NH:17][C:18]1[CH:49]=[CH:48][C:21]([C:22]([N:24]([CH3:47])[C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=3[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)=[O:39])=[O:23])=[CH:20][C:19]=1[O:50][CH3:51])=[O:16])[CH:11]=[CH:10][CH:9]=2)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)cccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 72.9 %

Procedure:
The solution of 4-[(2-ethoxycarbonylindol-4-yl)-carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (100 mg) in a mixture of 1N aqueous sodium hydroxide solution (0.43 ml) and ethanol (4.0 ml) was stirred at ambient temperature for 5.5 hours. The resulting solution was neutralized with 1N hydrochloric acid and methanol was removed in vacuo. The residue was diluted with water and the aqueous layer was extracted with chloroform. Drying, filtering and removal of solvents afforded 4-[(2-carboxyindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (70 mg) as a yellow amorphous.
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH2:21][CH3:22])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:37][CH2:36][C:35]2[CH:38]=[CH:39][C:40]([NH2:42])=[CH:41][C:34]=2[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:37][CH2:36][C:35]2[CH:38]=[CH:39][C:40]([NH:42][C:2]3[N:23]=[C:5]4[C:6]([C:10]5[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=5[O:20][CH2:21][CH3:22])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:41][C:34]=2[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Product: CCOc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nc12

Procedure:
2-Chloro-8-(2-ethoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.500 g, 2.15 mmol) and 2-ethoxy-5-trifluoromethylbenzeneboronic acid (0.755 g, 3.23 mmol) in a manner analogous to Example 311a to give product (0.645 g, 88%). MS=342 (MH)+. 318b) 7-[8-(2-Ethoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-ethoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.640 g, 1.87 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.590 g, 2.25 mmol) in a manner analogous to Example 311b to give product (1.06 g, 99%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.55 (s, 1H), 8.78 (d, 1H), 7.98 (s, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.42 (m, 2H), 7.35 (d, 1H), 7.08 (t, 1H), 7.00 (d, 1H), 4.15 (q, 2H), 3.42 (m, 4H), 2.78 (m, 4H), 1.41 (s, 9H), 1.22 (t, 3H): MS=568 (MH)+.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[NH:18][C:19](=[O:32])[CH:20]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[CH3:21].[OH-].[Na+].Cl>>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]([NH:18][C:19](=[O:32])[CH:20]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH3:21])=[C:11]([CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:33])=[O:2])[CH:16]=1
Reactant: COC(=O)c1ccccc1Cc1cc(Cl)ccc1NC(=O)C(C)c1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)Nc1ccc(Cl)cc1Cc1ccccc1C(=O)O)c1cccc2ccccc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
To a solution of 2-[5-chloro-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid methyl ester (440 mg; prepared in Example 1.) in methanol-dioxane (1:1; 8 ml) was added 2 mol/L aqueous solution of sodium hydroxide (3 ml) and the mixture was stirred for 3 hours at 50° C. The solution was acidified with hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried and concentrated to give a crude crystal. It was washed with ethyl acetate-hexane to give the title compound (342 mg; white powder) having the following physical data.
Reaction SMILES: C(N(CC)CC([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)C)C.C(N(CC)CC)C.[SH2:32]>N1C=CC=CC=1>[CH:19]1[C:20]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[S:14][C:15]=2[CH:16]=[CH:17][C:18]=1[C:21](=[S:32])[NH2:22]
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1ccc2c(c1)Nc1ccccc1S2
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A solution of 10-[(2RS)-1-diethylamino-2-propyl]2-phenothiazinecarbonitrile (5.66 g) and triethylamine (2.35 cc) in pyridine (113 cc) is treated with hydrogen sulphide for 1 hour and then stirred for 3 days at a temperature in the region of 20° C. The greenish solution obtained is purged with nitrogen, poured into distilled water (500 cc) and extracted with ethyl acetate (2×500 cc). The combined organic phases are washed successively with distilled water (2×200 cc) and with saturated aqueous sodium chloride solution (200 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg, 4 kPa) at 40° C. The residual orange oil (9.1 g) is purified by chromatography on a column (height: 25 cm, diameter: 3 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with ethyl acetate (750 cc) and collecting 50-cc fractions. The combined fractions 4 to 10 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-[2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbothioamide (6.2 g) is thereby obtained in the form of an orange oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-])=O)=[CH:12][C:7]=2[NH:6][C:5](=[O:16])[CH:4]([NH:17][C:18](=[O:20])[CH3:19])[CH2:3]1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:31]=2[C:32]([NH:34][CH2:35][C:36]#[CH:37])=[O:33])[C:26]([Cl:43])=[CH:25][N:24]=1>>[C:18]([NH:17][CH:4]1[CH2:3][C:2]([CH3:21])([CH3:1])[C:8]2[CH:9]=[CH:10][C:11]([NH:13][C:23]3[N:28]=[C:27]([NH:29][C:30]4[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:31]=4[C:32]([NH:34][CH2:35][C:36]#[CH:37])=[O:33])[C:26]([Cl:43])=[CH:25][N:24]=3)=[CH:12][C:7]=2[NH:6][C:5]1=[O:16])(=[O:20])[CH3:19]
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)NC1CC(C)(C)c2ccc([N+](=O)[O-])cc2NC1=O
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(C)=O)CC3(C)C)ncc1Cl

Procedure:
Title compound was prepared from N-(5,5-Dimethyl-8-nitro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-acetamide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a white solid. (65 mg, 43%) LCMS 566 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 9.39 (s, 1H), 9.17 (s, 1H), 8.93 (t, J=5.3 Hz, 1H), 8.18 (s, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.51-7.46 (m, 2H), 7.37-7.34 (m, 1H), 7.24 (d, J=8.1 Hz, 1H), 7.14 (s, 1H), 7.08 (d, J=8.2 Hz, 1H), 4.23-4.16 (m, 1H), 4.00 (d, J=2.7 Hz, 2H), 3.10 (s, 1H), 2.09-2.04 (m, 1H), 1.88-1.84 (m, 1H), 1.84 (s, 3H), 1.32 (s, 3H), 1.23 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:20][C:21]1([CH3:30])[CH2:26][C:25](=O)[CH2:24][C:23]([CH3:29])([CH3:28])[O:22]1>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:25]2[CH2:24][C:23]([CH3:29])([CH3:28])[O:22][C:21]([CH3:30])([CH3:20])[CH2:26]2)[C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(=O)c2ccc(O)cc2)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)O1
Product: COC(=O)c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1
Yield: 93.5 %

Procedure:
The general McMurry protocol, described for 14 was followed. Thus, methyl 4-[(4-hydroxyphenyl)carbonyl]benzoate (24) (0.196 g, 0.765 mmol) and 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (52) (0.370 g, 2.37 mmol) were subjected for McMurry coupling reaction conditions. Standard work-up followed by purification by column chromatography gave 0.272 g (93%) of the title compound 101 as a white foam. 1H NMR (300 MHz, CDCl3): δ 7.98 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.7 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 3.92 (s, 3H), 2.27 (s, 2H), 2.21 (s, 2H), 1.28 (s, 6H), 1.25 (s, 6H). LCMS (ESI): m/z 379 (M−H)−.