Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH:16]([C:20]([OH:22])=O)[CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[NH2:30][CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33]>C(Cl)Cl.O>[O:33]=[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][NH:30][C:20]([CH:16]1[O:17][CH2:18][CH2:19][N:14]([CH2:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:15]1)=[O:22]
Reactant: NCC(=O)c1ccccc1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)C1CN(Cc2ccccc2)CCO1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
Oxalyl chloride (1.187 mL, 13.56 mmol) was added to a suspension of 4-(phenylmethyl)-2-morpholinecarboxylic acid (2.0 g, 9.04 mmol) in CH2Cl2 (70 mL) at 0° C. in 10 minutes, and the resulting mixture was stirred at 25° C. for 2 hours. The mixture was concentrated, and the resulting residue was treated with CH2Cl2 (70 mL), triethylamine (2.77 mL, 19.89 mmol) and 2-amino-1-phenylethanone (1.551 g, 9.04 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 3 hours. Water (150 mL) was added, and the resulting aqueous mixture was extracted with EtOAc (3×80 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography to afford the title compound (1.0 g) as a brown solid. LC-MS (ES) m/z=339 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:34]([Cl:37])(=[O:36])[CH3:35].Cl>ClCCl.C(O)C>[ClH:37].[C:25]([C:19]1[CH:20]=[CH:21][C:22]2[O:23][CH2:24][C@H:14]3[C@H:15]([C:17]=2[CH:18]=1)[CH2:16][N:12]([CH2:11][CH2:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([NH:3][C:34](=[O:36])[CH3:35])[CH2:5][CH2:6]1)[CH2:13]3)#[N:26]
Reactant: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](N)CC3)C[C@H]1CO2
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CC[C@H](CCN2C[C@H]3COc4ccc(C#N)cc4[C@@H]3C2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 699 mg (2.1 mmol) of the compound of Example 1 in 15 ml of dichloromethane there are added, at ambient temperature, 354 μl of triethylamine (1.2 eq.) and then 164 μl of acetyl chloride (1.1 eq.). After stirring for 2 hours at ambient temperature, the mixture is washed with water and dried (MgSO4). Evaporating off the solvent followed by purifying on a silica column using a mixture of dichloromethane/methanol/ammonium hydroxide (97/3/0.3) as eluant yields, after converting to a salt in ethanol in the warm state using 1N ethereal HCl, the title product in the form of a white powder.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[C:12](=[O:15])[NH:13]Cl)=[CH:6][CH:5]=1.[C:29]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35]N.COC(=O)C1C=CC=CC=1.Cl.C([O:56][C:57](=[O:62])[C@H:58]([OH:61])[CH2:59][NH2:60])C>>[C:29]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][NH:13][C:12](=[O:15])[N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([NH:60][CH2:59][C@@H:58]([OH:61])[C:57]([OH:62])=[O:56])=[O:28])=[CH:9][CH:8]=1)[C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: NCc1ccccc1-c1ccccc1
Reactant: COC(=O)c1ccc(CN(C(=O)NCl)c2ccc(C3CCCCC3)cc2)cc1
Reactant: CCOC(=O)[C@H](O)CN
Agent: Cl
Solvent: COC(=O)c1ccccc1
Product: O=C(NC[C@@H](O)C(=O)O)c1ccc(CN(C(=O)NCc2ccccc2-c2ccccc2)c2ccc(C3CCCCC3)cc2)cc1

Procedure:
This compound was prepared similarly as described in example 35 from N-chlorocarbamoyl-4-[(4-cyclohexylphenylamino)methyl]benzoic acid methyl ester and biphenyl-2-ylmethylamine followed by hydrolysis of the benzoic acid methyl ester, coupling with (R)-isoserine ethyl ester hydrochloride. Hydrolysis afforded the title compound.
Reaction SMILES: CO[C:3](OC)([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH:4]=[O:5].Cl.[H][H].[CH3:18]O>[Pd]>[CH3:18][O:5][CH2:4][CH2:3][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: CO
Reactant: COC(C=O)(OC)c1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: COCCc1ccc(O)cc1
Yield: 53 %

Procedure:
The procedure of Example 2 was repeated with a solution of 2.00 g (10.2 mmol) 4-hydroxyphenylglyoxal dimethyl acetal in 10 g methanol containing 0.23 g (6.3) mmol) hydrogen chloride and 0.20 g moist 10% Pd/C catalyst being reacted with hydrogen ga pressurized at 170 psig at 25° C. with stirring of 550 rpm. A 53% yield of 4-(2'-methoxyethyl)phenol was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)C(Cl)=O)([O-:17])=[O:16]>N1C=CC=CC=1>[CH3:12][O:11][C:9]1[C:8]([O:13][CH3:14])=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:1][C:25]2[CH:24]=[CH:20][CH:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:26]=2)[CH:10]=1
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: COc1cc(Nc2cccc([N+](=O)[O-])c2)c(C(N)=O)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 2-amino-4,5-dimethoxybenzamide (5.05 g, 25.7 mmole) and 3-nitro benzoyl chloride (5.2 g, 28.0 mmole) CHCl3 (120 ml) was added pyridine (50 ml) drop wise at RT. The reaction mixture was stirred at RT for 24 h. The solvent was removed in vacuo and residue was triturated with Et2O, filtered and dried under high vacuum to give 4,5-dimethoxy-2-(3-nitrophenyl)aminobenzamide, which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=1[CH3:34])=O.N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:25]2[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=2[CH3:34])(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3cc(Cl)cc(Cl)c3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-(3,5-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (356 mg, 1 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (167 mg) and piperidine (cat. amount) in ethanol was stirred at rt for 2 days. The reaction was concentrated and triturated with HCl (2M solution) to give the titled compound.
Reaction SMILES: [C:1](O)(=O)[CH:2](C(C(O)=O)O)[OH:3].[CH3:11][O:12][C:13]([C:15]1([CH2:20][O:21][CH3:22])[CH2:19][CH2:18][NH:17][CH2:16]1)=[O:14].ClCC([N:27]1[CH2:32][CH:31]=[C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=O.C(N(CC)CC)C>C(#N)C>[CH3:11][O:12][C:13]([C:15]1([CH2:20][O:21][CH3:22])[CH2:19][CH2:18][N:17]([C:2](=[O:3])[CH2:1][N:27]2[CH2:32][CH:31]=[C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:39]4[N:44]=[CH:43][CH:42]=[CH:41][N:40]=4)=[CH:35][CH:34]=3)[CH2:29][CH2:28]2)[CH2:16]1)=[O:14]
Reactant: O=C(CCl)N1CC=C(c2ccc(-c3ncccn3)cc2)CC1
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: COCC1(C(=O)OC)CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCC1(C(=O)OC)CCN(C(=O)CN2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 18 h
Yield: 68.6 %

Procedure:
3-Methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester tartaric acid salt 1.54 gm, 4.85 mmol) in 25 ml of acetonitrile was added 2-Chloro-1-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethanone (2.2 gm, 5.82 mmol), triethylamine (3.4 ml, 24.3 mmol) and the reaction mixture stirred at 80 C for 18 hrs. The reaction mixture was evaporated, and extracted into dichloromethane from water. The dichloromethane extracts were dried over Na2SO4, filtered and evaporated. The mixture was chromatographed on silica gel using 2-3% MeOH/dichlormethane to obtain 1.5 gm of title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O-:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]1(C)C=CC(S(O)(=O)=O)=C[CH:15]=1.F[C:26](F)(F)[C:27]([OH:29])=[O:28]>C1C=CC=CC=1>[CH2:14]([O:12][C:11]([CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH2:26][C:27]([OH:29])=[O:28])=[O:13])[CH3:15]
Reactant: O=C([O-])Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: CCOC(=O)C(CC(=O)O)c1ccc([N+](=O)[O-])cc1

Procedure:
Following a similar procedure to that described in reference example 7b, but starting fromethyl 4-nitrophenylacetate instead of ethyl diphenylacetate, and hydrolizing then the tert-butyl ester using p-toluenesulfonic acid in benzene at reflux instead of using trifluoroacetic acid, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[NH:5][C:4](=[O:18])[CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([NH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[NH:5][C:4](=[O:18])[CH:3]=1)(=[O:21])[CH3:20]
Reactant: CCCOc1ccccc1-c1nc(N)cc(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Product: CCCOc1ccccc1-c1nc(NC(C)=O)cc(=O)[nH]1

Procedure:
A stirred solution of 6-amino-2-(2-propoxyphenyl)-pyrimidin-4[3H]-one (0.5 g) and acetic anhydride was heated under reflux for 2.5 hours. The cooled reaction mixture was evaporated under reduced pressure to yield a residue which was washed with water and recrystallised twice from methanol to yield the title compound, 0.29 g, m.p. 230°-1° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH:14][CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)([OH:21])[C:17]([F:20])([F:19])[F:18])[CH3:13]>>[CH2:12]([N:14]([CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:33]1[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=1)([OH:21])[C:17]([F:19])([F:20])[F:18])[C:4](=[O:5])[C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=1[F:11])[CH3:13]
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(Cl)c1c(F)cccc1F
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(F)cccc1F

Procedure:
Prepared similarly to Example 48 from 2,6-difluorobenzoyl chloride and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [CH:1](Br)=[CH2:2].[CH3:4][C:5]1[O:6][C:7]2[CH2:8][CH2:9][C:10]3[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=3[C:12](=O)[C:13]=2[N:14]=1.[CH3:20][S:21]([NH:24][C:25]1[CH:26]=C(B(O)O)[CH:28]=[CH:29][CH:30]=1)(=[O:23])=[O:22]>>[CH3:4][C:5]1[O:6][C:7]2[CH2:8][CH2:9][C:10]3[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=3[C:12](=[CH:28][C:29]3[CH:30]=[C:25]([NH:24][S:21]([CH3:20])(=[O:23])=[O:22])[CH:26]=[CH:1][CH:2]=3)[C:13]=2[N:14]=1
Reactant: C=CBr
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Cc1nc2c(o1)CCc1ccccc1C2=O
Product: Cc1nc2c(o1)CCc1ccccc1C2=Cc1cccc(NS(C)(=O)=O)c1

Procedure:
Prepare the corresponding ketone (2-methyl-9,10-dihydro-1-oxa-3-aza-benzo[f]azulen-4-one) as described by E. E. Galantay, et al, J. Med. Chem. (17) 1316-1327 (1974) and convert to the corresponding Z-isomer of the vinyl bromide using procedures essentially as described in Preparations 23 and 24. Then, following procedures essentially as described in Example 219, combine the ketone with 3-methanesulfonamidophenyl boronic acid (325 mg, 1.5 mmmol). Purify the crude product using column chromatography (30% EtOAc/hexane to 50% EtOAc/hexane) to provide 180 mg (38%) Z-isomer as a light tan solid, mp 184.6° C., MS (ES) 381 (M+1), 379 (M−1). HPLC shows 94% purity at t=1.99 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Br:17][CH2:18][C:19](Br)=[O:20]>C(Cl)Cl>[C:2]1([NH:1][C:19](=[O:20])[CH2:18][Br:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Br)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CBr)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of aniline (7.40 mmol) in methylene chloride (25 mL) at −50° C. was added successively N,N-diisopropylethylamine (1.58 mL, 8.14 mmol, 1.1 eq) and bromoacetyl bromide (0.72 mL, 7.40 mmol, 1 eq) such that the temperature did not exceed −40° C. On completion of the addition, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. After stirring for a further 30 minutes, the mixture was diluted with ether (70 mL) and poured into 1 N sodium bisulfate solution. The phases were separated, and the upper layer was washed successively with water and brine. The organic phase was dried (Na2SO4) and the solvent evaporated to half volume, at which point the product crystallized. The crystals were removed by vacuum filtration to afford the title compound.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH:25]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:25][C:24]2[CH:27]=[CH:28][C:29]([Cl:30])=[C:22]([Cl:21])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Clc1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1Cl
Yield: 74.1 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.1 g, 0.38 mmol) was reacted with 3,4-dichlorobenzaldehyde (0.066 g, 0.38 mmol) in the presence of glacial acetic acid (0.023 g, 0.38 mmol) in 1,2-dichloroethane (20 ml), and NaCNBH3 (0.03 g, 0.45 mmol) in methanol (5 ml) (Procedure D) to give compound 16i (0.12 g, 75%) as an oil.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([NH2:6])=O.[CH2:13](N(CC)CC)C.ClC(OC)=O>C(Cl)Cl>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([O:12][CH3:13])=[O:11])#[N:6]
Reactant: CCN(CC)CC
Reactant: NC(=O)c1ccccc1C(=O)O
Agent: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccccc1C#N
Reaction time: 16 h

Procedure:
Phthalamic acid (240 g, 1.37 moles) in methylenechloride (1.7 l) was stirred and cooled to <5° in an ice bath. Triethylamine (244 ml, 176 g, 1.74 moles) was added and a clear solution was obtained. Methyl chloroformate (200 g, 163 ml, 2.1 moles) was added at such a rate that the temperature did not exceed 5°. As the addition continued, triethylamine hydrochloride precipitated and carbon dioxide was evolved. On completion of the addition, the ice bath was removed and stirring was continued for 12-20 hrs. at room temperature. Triethylamine hydrochloride was removed by filtration and the methylene chloride evaporated. The residue was dissolved in ether (2 l), and this ether solution washed with water, dried over anhydrous sodium sulfate and evaporated. Distillation under reduced pressure gave methyl 2-cyanobenzoate, b.p. 125° at 2.5 mm, 215 g (97%), a solid at room temperature, M.P. 45°-6°.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(CCCc2ccccc2NCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CCCc2ccccc2NCc2ccccc2)cc1
Reaction time: 2 h
Yield: 59.5 %

Procedure:
To a solution of ethyl 4-[3-(2-(benzylamino)phenyl)propyl]benzoate (1 g) in methanol (50 ml) was added 1N sodium hydroxide (13.4 ml). The mixture was stirred for 2 hours, heated at reflux for 10 minutes, the solvent was evaporated, the residue mixed with water (50 ml) and acidified to pH 4 with 2N HCl. The mixture was extracted with ethyl acetate (3×20 ml) and the extracts washed with brine (2×20 ml), dried (MgSO4), filtered and evaporated. The residue was triturated with petroleum ether (60-80) (25 ml) to give the title compound (0.55 g; 118° C.).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:8]=1[C:9]([NH2:11])=[O:10])([OH:3])=[O:2].[OH-].[CH2:20]([N+:24]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>CO>[CH2:33]([N+:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35][CH3:36].[C:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:8]=1[C:9]([NH-:11])=[O:10])([OH:3])=[O:2]
Reactant: NC(=O)c1c(C(=O)O)cnn1-c1cccc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: [NH-]C(=O)c1c(C(=O)O)cnn1-c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
A 3.26 g. portion of 4-carboxy-1-(3-chlorophenyl)-5-pyrazolecarboxamide was slurried in 50 ml. of methanol and 12 ml. of 1M tetrabutyl ammonium hydroxide solution was added. The mixture was stirred for 30 minutes, and evaporated to dryness under vacuum to obtain 5.2 g. of product, m.p. 120°-121°. The product was identified by elemental analysis.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:3]1.[CH2:16]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[CH2:24]([N:23]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12](=[O:14])[C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cn1cc(C(=O)C(=O)O)c2ccccc21
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CC#N
Product: Cn1cc(C(=O)C(=O)N(Cc2ccccc2)Cc2ccccc2)c2ccccc21

Procedure:
N,N-Dibenzyl-2-(1-methyl-1H-indol-3-yl)-2-oxo-acetamide was synthesized following scheme II above starting from (1-methyl-1H-indol-3-yl)-oxo-acetic acid and dibenzylamine. Yield (70%). HPLC ret. time 3.70 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.12 (d, J=7.7 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.43-7.25 (m, 12H), 4.55 (s, 2H), 4.40 (s, 2H), 3.93 (s, 3H); ESI-MS 383.3 m/z (MH+).
Reaction SMILES: [CH3:1][SiH:2]([CH3:13])[C:3]1[CH:12]=[CH:11][C:6]([O:7][SiH](C)C)=[CH:5][CH:4]=1.C[O-].[Na+]>C(OCC)C.CO>[CH3:1][SiH:2]([CH3:13])[C:3]1[CH:12]=[CH:11][C:6]([OH:7])=[CH:5][CH:4]=1
Reactant: C[SiH](C)Oc1ccc([SiH](C)C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: C[SiH](C)c1ccc(O)cc1
Reaction time: 8 h

Procedure:
To a cold solution (~9° C.) of 26.0 g of 4-dimethylsilylphenoxydimethylsilane in 250 ml of diethylether was added 10 ml of a solution of sodium methoxide (0.4 N) in methanol and the mixture stirred overnight. Solvents were removed by evaporation on a rotary evaporator at room temperature to yield 15.6 g (83.0%) of crude product, m.p. 59°-60° C. After recrystallization from hexane, the phenol was obtained as needles, m.p. 61° C.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.C(O[C:11]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=O)=[O:12])C.O.[C:21]1(C)[CH:26]=[CH:25][C:24](S(O)(=O)=O)=[CH:23][CH:22]=1.O>C1C=CC=CC=1>[CH:21]1([C:1]2[CH:6]=[C:5]3[C:4]([N:7]=[C:14]4[C:13](=[C:11]3[OH:12])[CH2:18][CH2:17][CH2:16][CH2:15]4)=[CH:3][CH:2]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: NC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Oc1c2c(nc3ccc(C4CCCCC4)cc13)CCCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Cyclohexylamine (23.15 g) and 2-ethoxycarbonylcyclohexanone (25.0 g) were stirred in 100 mL of benzene containing 0.20 g of p-toluenesulfonic acid monohydrate. After stirring for 4 hours at room temperature the reaction mixture was refluxed for 3 hours with the separation of water. At the end of this time the benzene was evaporated and the residue was dissolved in 150 mL of phenyl ether and the resultant mixture refluxed for 30 minutes. The product which separated upon cooling was filtered off and washed with ether to give 18.22 g of product which was analytically pure without further purification, mp 292°-295° C.
Reaction SMILES: F[C:2]1C=CC(CCN2CCC(N3C4C(=CC=C(CN)C=4)C=C3)CC2)=CC=1.[F:27][C:28]1[CH:57]=[CH:56][C:31]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([N:40]3[C:48]4[C:43](=[CH:44][CH:45]=[C:46]([CH2:49][NH:50][C:51](=[O:55])[CH2:52][CH2:53]Br)[CH:47]=4)[CH:42]=[CH:41]3)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1.BrCCC(Cl)=O.C(N(CC)CC)C>C(#N)C>[F:27][C:28]1[CH:57]=[CH:56][C:31]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([N:40]3[C:48]4[C:43](=[CH:44][CH:45]=[C:46]([CH2:49][N:50]5[CH2:2][CH2:53][CH2:52][C:51]5=[O:55])[CH:47]=4)[CH:42]=[CH:41]3)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1
Reactant: O=C(CCBr)NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Reactant: NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Agent: O=C(Cl)CCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Yield: 156.5 %

Procedure:
1H-NMR(400 MHz,DMSO-d6); δ(ppm) 1.40-1.50(2H,m), 1.60-1.71(4H,m), 2.00-2.08(2H,m), 2.12-2.26(2H,m), 2.37-2.52(2H,m), 2.70-3.10(8H,m), 3.39-3.49(2H,m), 3.52-3.63(2H,m), 4.42(2H,d,J=6.0 Hz), 4.45-4.58(1H,m), 6.43(1H,d,J=3.2 Hz), 6.96(1H,d,J=8.0 Hz), 7.10-7.19(2H,m), 7.26-7.34(2H,m), 7.44(1H,d,J=3.2 Hz), 7.47(1H,s), 7.49(1H,d,J=8.0 Hz), 8.76(1H,t,J=6.0 Hz). m.p.: 113-114° C. Mass: FAB+477(M+H). Example 377: Synthesis of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-bromopropionylamino)methylindole 1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (370 mg) obtained in Example 322-3), 3-bromopropionyl chloride (240 mg), triethylamine (140 mg) and acetonitrile (10 ml) were treated as in Example 373 to give the title compound (290 mg) as an oil (yield: 57%). 1H-NMR(400 MHz,CDCl3); δ(ppm) 2.02-2.10(2H,m), 2.14-2.26(2H,m), 2.29-2.40(2H,m), 2.68-2.76(2H,m), 2.80(2H,t,J=6.4 Hz), 2.85-2.92(2H,m), 3.18-3.26(2H,m), 3.70(2H,t,J=6.4 Hz), 4.20-4.30(1H,m), 4.62(2H,d,J=6.0 Hz), 6.15(1H,br-s), 6.50(1H,d,J=3.2 Hz), 6.96-7.04(3H,m), 7.16-7.24(2H,m), 7.25(1H,d,J=3.2 Hz), 7.37(1H,s), 7.58(1H,d,J=8.0 Hz). Example 378: Synthesis of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-N,N-dimethylaminopropionyl)aminomethylindole