Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.Cl.[NH2:64][C:65]1[CH:70]=[CH:69][C:68]([NH:71][S:72]([CH3:75])(=[O:74])=[O:73])=[CH:67][C:66]=1[O:76][CH3:77]>>[CH3:75][S:72]([NH:71][C:68]1[CH:69]=[CH:70][C:65]([NH:64][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[C:66]([O:76][CH3:77])[CH:67]=1)(=[O:74])=[O:73]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc(NS(C)(=O)=O)ccc1N
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(C)(=O)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 46.4 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.38 g, 1.6 mmol), then reacted with N-(4-amino-3-methoxyphenyl)methanesulfonamide hydrochloride (Astatech) (0.2 g, 0.8 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-methanesulfonylamino-2-methoxy-phenyl)-amide as a yellow solid (Yield 0.16 g, 47%).
Reaction SMILES: C(N(CC)[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH2:15][C@H:16]([NH:18][CH2:19][C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[OH:21])[CH3:17])=[CH:11][NH:12]2)=[CH:8][CH:7]=1)=[O:5])C.Cl.[O:32]1CCOCC1>>[Cl:28][C:24]1[CH:23]=[C:22]([C@@H:20]([OH:21])[CH2:19][NH:18][C@H:16]([CH3:17])[CH2:15][C:10]2[C:9]3[C:13](=[CH:14][C:6]([C:4]([OH:5])=[O:32])=[CH:7][CH:8]=3)[NH:12][CH:11]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: C1COCCO1
Reactant: CCN(CC)C(=O)c1ccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c2c1
Agent: Cl
Product: C[C@H](Cc1c[nH]c2cc(C(=O)O)ccc12)NC[C@H](O)c1cccc(Cl)c1
Yield: 44 %

Procedure:
To a solution of 3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxy-ethylamino]propyl}-1H-indole-6-carboxylic acid diethylamide (800 mg, 1.87 mmol) in 1,4-dioxane (10 ml) is added 6N—HCl (10 ml), and the mixture is refluxed for 24 hours. After allowed to cool, the reaction solution is concentrated under reduced pressure, and the residue is purified by octadecylsilyl column chromatography (trifluoroacetic acid/methanol/water), and further crystallized from aqueous methanol (pH 7) to give 3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxyethylamino]-propyl}-1H-indole-6-carboxylic acid (304 mg, 0.815 mmol, 44%) as white crystals.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:17]=[CH:16][C:15]3[O:14][CH2:13][C:12]([C:18](O)=[O:19])=[CH:11][C:10]=3[C:9]=2[CH:21]=1>>[CH3:1][NH:2][C:18]([C:12]1[CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:21][C:9]=3[C:10]=2[CH:11]=1)=[O:19]
Reactant: COc1ccc2ccc3c(c2c1)C=C(C(=O)O)CO3
Reactant: CN
Product: CNC(=O)C1=Cc2c(ccc3ccc(OC)cc23)OC1

Procedure:
Methylamine, condensed with the compound obtained in Step A of Example 5, yields the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.CC(C)=O.Cl[CH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=Cc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1ccc(S)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1ccc(CSc2ccc([N+](=O)[O-])cn2)cc1
Yield: 93.3 %

Procedure:
To 40 mg of 2-mercapto-5-nitropyridine was added 200 mL of acetone, and the solution was stirred while cooled with water. To this reaction solution were added 43.6 of 4-chloromethylbenzaldehyde and 45 g of potassium carbonate, to conduct reaction. After the completion of the reaction, 1 L of water was added to the solution. The precipitated crystal was collected by filtration, washed with water, washed with methanol, and dried (yield amount 65.5 g, and yield 93.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:6].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)=[O:6]
Reactant: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(C(=O)C2CCNCC2)c1OC
Temperature: 60 °C
Yield: 65 %

Procedure:
To the reaction solution of 4-(2,3-dimethoxybenzoyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7) from Example 76, Scheme G, step c, is added about 188 kg of water and 37% hydrochloric acid (39 kg, 395 mol). The solution is heated to about 60° C. for about 18 hours1. The mixture is cooled to about 25° C. and about 47 kg of toluene is added. The phases are separated and the organic phase is discarded. To the aqueous phase is added about 78 kg water, 50 wt % sodium hydroxide solution (31 kg, 391 mol), and about 99 kg of toluene. The phases are separated and the aqueous phase is discarded. The organic phase is concentrated by vacuum distillation. The concentration of 4-(2,3-dimethoxybenzoyl)piperidine (16) in solution ranges from 17 to 53 wt %1, affording 14.6 to 17.9 kg of 4-(2,3-dimethoxybenzoyl)piperidine (16) (65-76% yield).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Br:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH2:25][CH2:26]O)=[CH:20][C:19]=1[CH3:28].[C:29]([O:33][C:34]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:35])([CH3:32])([CH3:31])[CH3:30].C(P(CCCC)CCCC)CCC>ClCCl>[C:40]([O:39][C:37]([N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:26][CH2:25][C:21]1[CH:22]=[C:23]([CH3:24])[C:18]([Br:17])=[C:19]([CH3:28])[CH:20]=1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: Cc1cc(CCO)cc(C)c1Br
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: ClCCl
Product: Cc1cc(CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of di-tert.-butyl azodicarboxylate (2.85 g) in dichloromethane (10 mL) is added dropwise over 15 minutes to a solution of 2-(4-bromo-3,5-dimethylphenyl)ethanol (950 mg), di-tert.butyl-iminodicarboxylate (3.75 g) and tributylphosphine (4.4 mL) in dichloromethane (40 mL) at −10° C. The resulting solution is stirred for 2 hours while warming to room temperature and then partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. Yield: 1.19 g; LC (method 8): tR=1.06 min; Mass spectrum (ESI+): m/z=451 [M+Na]+.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.[ClH:20]>>[ClH:20].[ClH:20].[NH2:8][CH2:9][C@H:10]([N:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCCC1
Agent: Cl
Product: COC(=O)[C@H](CN)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A solution of 2.9 g (11 mmol) of methyl(S)-3-tert-butoxycarbonylamino-2-pyrrolidin-1-ylpropanoate in 20 ml of isopropanolic hydrochloric acid having a concentration of 5-6N is stirred at 40° C. for 18 h. After evaporation under vacuum, the residue is taken up in 100 ml of diethyl ether, stirred at ambient temperature for 1 h, filtered and dried under vacuum. 2.3 g (88%) of methyl(S)-3-amino-2-pyrrolidin-1-ylpropanoate dihydrochloride are obtained in the form of a beige solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=1[O:36][CH3:37].C(#N)C>O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=3[O:36][CH3:37])[CH2:6][CH2:5]2)=[N:8]1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: c1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2n[nH]c3ccccc23)CC1
Yield: 83.4 %

Procedure:
A mixture of 3-(4-piperidinyl)-1H-indazole (3.0 g, 15 mmol), K2CO3 (1.6 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI and acetonitrile (100 ml) was stirred and refluxed for 16 hours. The reaction was poured into water and a white solid separated from solution. The solid was collected, dried and afforded 5.1 g of product. Recrystallization from ethanol yielded 3.6 g, the compound, which upon chromatography (preparative HPLC on silica gel, eluting with methylene chloride/methanol-9:1) gave 3.0 g (49%) of an off-white solid. Recrystallization from ethanol afforded the analytically pure 1-[4-[3-[4-(1-1H-indazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]ethanone as a white solid, m.p.=171-173° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([C:38]1[C:46]2[N:45]=[C:44]([O:47]C)[NH:43][C:42]=2[CH:41]=[CH:40][CH:39]=1)=[O:37])[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])=[O:7]>Cl.CO.O1CCOCC1>[OH:47][C:44]1[NH:43][C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([C:36]([NH:35][C:34]3[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]4[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=4[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[O:23])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])=[O:37])[C:46]=2[N:45]=1
Reactant: COc1nc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)cccc2[nH]1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(O)nc12
Reaction time: 8 h
Yield: 39 %

Procedure:
A solution of 3-methoxy-4-(2-methoxy-1H-benzimidazol-4-yl)carbonylamino-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (139 mg) in 10% hydrogen chloride in methanol (2 ml) was stirred at ambient temperature for 2 hours and 4N hydrogen chloride in 1,4-dioxane (2 ml) was added to the mixture. After being allowed to stand at ambient temperature overnight, the reaction mixture was concentrated in vacuo and the residue was diluted with a mixture of chloroform and saturated aqueous sodium bicarbonate solution. The organic layer was separated and washed with water and brine. The solution was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 4-(2-hydroxy-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (53 mg) as a powder.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O-:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[Na+].C(O)C.S(O[CH:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])(C1C=CC(C)=CC=1)(=O)=O>O>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:36])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: C=CCNc1ccc(CC(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCNc1ccc(CC(=O)OC(C)C(=O)OCC)cc1

Procedure:
To a warm mixture of 7 g. sodium 4-(allylamino)phenylacetate in 100 ml. ethanol is added 4.7 g. ethyl 2-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield 1-(ethoxycarbonyl)ethyl 4-(allylamino)phenylacetate as colorless crystals.
Reaction SMILES: [H][H].[C:3](#[N:12])[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1>[Ni]>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([CH2:3][NH2:12])=[CH:5][CH:6]=1)#[N:9]
Reactant: N#Cc1ccc(C#N)cc1
Reactant: [H][H]
Agent: [Ni]
Product: N#Cc1ccc(CN)cc1

Procedure:
194 kg of p-cyanobenzylamine crude product (p-cyanobenzylamine 92% by weight, p-xylylenediamine 8% by weight) obtained by hydrogen reduction of terephthalonitrile in the presence of sponge metal nickel catalyst was mixed with 1,100 kg of water while stirring at 40° C. or less and the mixture was stirred for 3 hours. The crystals which precipitated were separated by centrifugation while washing with water to obtain 197 kg of p-cyanobenzylamine hydrate (water content: 21% by weight).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[NH:8][CH:9]([CH3:24])[CH2:10][S:11][CH:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][OH:22])=[CH:15][C:14]=3[CH3:23])[C:6]=2[C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:4]1)[CH3:2].CO>[Pd].C1COCC1>[CH2:1]([N:3]1[C:7]2[NH:8][CH:9]([CH3:24])[CH2:10][S:11][CH:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][C:14]=3[CH3:23])[C:6]=2[C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2ccccn2)c2c1NC(C)CSC2c1ccc(C#CCO)cc1C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1nc(-c2ccccn2)c2c1NC(C)CSC2c1ccc(CCCO)cc1C
Yield: 86.5 %

Procedure:
To a flask was added 3-(4-(1-ethyl-7-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylphenyl)prop-2-yn-1-ol (0.126 g, 0.301 mmol, prepared from P with Example #K.1 and prop-2-yn-1-ol), MeOH (7.53 ml) and THF (7.53 ml). The solution was treated with the H-Cube (Pd/C 10 wt %, Manual Control, 20 bar, 1 mL/min, rt) for about 2 h. The mixture was concentrated in vacuo and purified by flash chromatography (25 g silica gel; DCM/MeOH 1:0 to 9:1) to give 3-(4-(1-ethyl-7-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylphenyl)propan-1-ol (0.110 g, 86%); LC-MS (Table 1, Method g) Rt=2.29 and 2.32 min.; MS m/z: 423.14 and 423.14 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[C:8]=1[Br:19])(=O)=O.[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[Br:19][C:8]1[C:9]2[C:14](=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[C:29]1[CH:30]=[CH:31][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc2c(Br)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3c2Br)cc1
Temperature: 80 °C
Yield: 45 %

Procedure:
Followed the coupling procedure described for Example 1, starting from 1-bromo-6-methoxynaphthalen-2-yl trifluoromethanesulfonate (Intermediate 2) and 4-(methoxycarbonyl)phenylboronic acid with modifications: the base used was Na2CO3, the solvent was toluene/EtOH (4/1), and the reaction was heated to 80° C. for 3 h. The crude product was purified by silica gel column (PE/EtOAc=300/1 to 100/1), then washed with EtOAc (10 mL×5) to give the product (980 mg, yield 45%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[C:17](=[O:28])[N:18]([CH3:27])[C:19]4[C:24]([C:25]=3[OH:26])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:36]([F:42])([F:41])C(OC)=O>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[C:17](=[O:28])[N:18]([CH3:27])[C:19]4[C:24]([C:25]=3[O:26][CH:36]([F:42])[F:41])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C(F)(F)Cl
Reactant: Cn1c(=O)c(Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)c(O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c(Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)c(OC(F)F)c2ccccc21
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A solution of example 145, Cs2CO3 (2 eq) in DMF (0.2M) was heated at 100° C. (open flask) then methyl chlorodifluoroacetate (2 eq) was added and the mixture stirred at 90-110° C. for 3 h. After cooling to rt, the mixture was diluted with water, extracted with ethyl acetate and the solvent evaporated. The residue was purified by crystallisation in hexane\ether to give the title compound as a white powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[CH:15][C:10]=1[C:11](OC)=[O:12])[CH3:8]>C1COCC1>[CH2:7]([C:9]1[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[CH:15][C:10]=1[CH2:11][OH:12])[CH3:8]
Reactant: CCc1ccc(C(=O)OC)c(CC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ccc(CO)c(CC)c1
Yield: 101.5 %

Procedure:
To a suspension of lithium aluminum hydride (0.47 g, 11.8 mmol) in anhydrous THF (20 mL) at room temperature under nitrogen was added a solution of methyl 2,4-diethylbenzoate (1.5 g, 7.8 mmol) in THF (15 mL) with stirring over a period of −5 min. The resulting mixture was stirred at room temperature for 60 min and was then quenched by slow addition of ethyl acetate (until bubbling stopped). The mixture was partitioned between ethyl acetate and 1N HCl (aq). The aqueous layer was separated and extracted with ethyl acetate. Organic layers were combined, dried (MgSO4), and evaporated to dryness to give 1.3 g of the desired alcohol as a clear oil (yield of 100%). 1H NMR (300 MHz, CDCl3) δ 1.13 (t, 3H), 1.17 (t, 3H), 2.58 (q, 2H), 2.61 (q, 2H), 4.43 (d, 2H), 5.02 (t, 1H), 7.05-7.11 (m, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[C:34]([C:39]([O:41]C(C)(C)C)=[O:40])=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[C:34]([C:39]([OH:41])=[O:40])=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 53.6 %

Procedure:
To a solution of tert-butyl 4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-carboxylate of Example 64 (0.710 g, 1.186 mmol) in dry dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) and the reaction mixture stirred at room temperature under nitrogen for 1.75 hours. The reaction mixture was then concentrated in vacuo and the resulting solid dissolved in ethyl acetate (50 mL). The organic phase was extracted with 2 M sodium hydroxide (2×50 mL) and the combined aqueous extracts acidified to pH 1 by the addition of concentrated hydrochloric acid. The resulting white suspension was cooled to 4° C. for 1 hour, the solid product filtered, washed with water and then dried in vacuo at 50° C. overnight to afford the title compound (0.345 g, 54%) as a white solid, m.p. 189-191° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([CH:11]=[CH:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3C=CC=CC=3)=[C:17]([O:29][CH3:30])[CH:16]=2)=[O:10])[CH2:4][CH2:3]1.[H][H]>CO.[C].[Pd]>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:10])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:29][CH3:30])[CH:16]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCCCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O

Procedure:
3.62 g of N-(trans-4-methylcyclohexyl)-4-(4-benzyloxy-3-methoxyphenyl)-l,3-butadiene-1-carboxamide (Example 117) was dissolved in 150 ml of methanol. 0.2 g of 10% palladium-carbon was added to the solution. The solution was stirred for 16 hours under normal-pressure hydrogen gas. After reaction, the catalyst was filtered out, and the solvent was removed in vacuo from the filtrate, yielding 2.3 g of N-(trans-4-methylcyclohexyl)-5-(4-hydroxy-3-methoxyphenyl)valeramide (a compound of the present invention) as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([Cl:14])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:15](#[N:19])[CH2:16][C:17]#[N:18]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([Cl:14])[C:12]=1[OH:13])[CH:8]=[C:16]([C:15]#[N:19])[C:17]#[N:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)cc(Cl)c1O
Reactant: N#CCC#N
Product: CC(C)(C)c1cc(C=C(C#N)C#N)cc(Cl)c1O

Procedure:
In a similar manner as described in Example 2 reaction of 3-tert-butyl-5-chloro-4-hydroxybenzaldehyde and malononitrile gave 3-tert-butyl-5-chloro-4-hydroxybenzylidenemalononitrile m.p. 173°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.O1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.Cl.N>O>[CH3:15][CH:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]3)=[CH:3][CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=c1ccocc1
Agent: Cl
Agent: N
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
A stirred mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (1.0 g), 4H-pyran-4-one (0.52 g), water (20 ml), and concentrated hydrochloric acid (0.41 ml) was heated under reflux for 31/2 hours. The resultant solid was dissolved in the minimum of hot water and the solution was neutralised with aqueous ammonia to give the crude product, 1.16 g, m.p. 249°-256° C. The product was recrystallised first from water to which a little 2N NaOH was added, and then from water alone to give the pure title compound, 0.82 g, m.p. 254°-256° C. (after melting and resolidifying at about 150° C.).