Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:6]([CH3:11])=[N:7][NH:8][C:9]=1[CH3:10].[F:13][C:14]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:15]=1[CH2:16]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:9]([CH3:10])=[N:8][N:7]([CH2:16][C:15]2[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:14]=2[F:13])[C:6]=1[CH3:11]
Reactant: COC(=O)Cc1c(C)n[nH]c1C
Reactant: O=[N+]([O-])c1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2F)c1C
Temperature: 60 °C
Reaction time: 48 h
Yield: 82.7 %

Procedure:
To a solution of (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester (10 g, 48.9 mmol) and 2-fluoro-4-nitrobenzyl bromide (11.5 g, 49.1 mmol) in acetonitrile (150 mL) is added K2CO3 (10.1 g, 73.3 mmol) and the mixture is stirred for 48 hours at 60° C. The solvent is removed by evaporation and the residue is dissolved in dichloromethane/water. After extraction with dichloromethane the organic layer is dried over Na2SO4 and evaporated under reduced pressure. The residue is purified by MPLC (cyclohexane/diethyl ether 7:3) to yield 13 g of [3,5-dimethyl-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid methyl ester (ESI mass spectrum: [M+H]+=322; Retention time (HPLC): 0.85 min (method C)). b) To a solution of [3,5-dimethyl-1-(2-fluoro-4-nitro-benzyl)-1H-pyrazol-4-yl]acetic acid methyl ester (13 g, 40.4 mmol) in methanol (250 mL) is added Raney nickel (6 g) and the mixture is hydrogenated at 50 psi and 50° C. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The mixture is purified by crystallization in diisopropyl ether to yield 12.8 g of the title compound (ESI mass spectrum: [M+H]+=292; Retention time HPLC: 0.61 min (method C)).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:7].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:25]=[CH:26][C:27]([NH:30][N:31]=[C:10]([OH:12])[C:9]2[CH:13]=[CH:14][CH:15]=[N:16][C:8]=2[C:6](=[O:7])[C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([C:2]([F:1])([F:21])[F:20])[CH:4]=2)=[CH:28][CH:29]=1
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C(c1cccc(C(F)(F)F)c1)c1ncccc1C(O)=NNc1ccc(C(F)(F)F)cc1
Yield: 80.7 %

Procedure:
2-(3-Trifluoromethylbenzoyl)nicotinic acid (0.5 g), 4-trifluoromethylphenylhydrazine (0.3 g) and para-toluene sulphonic acid (0.001 g) were stirred in methanol at room temperature for 22 hours. Solvent was evaporated. The residue was triturated in cold toluene then dried to yield the title compound as a beige solid (0.62 g), m.p. 127°-129° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[N:14](C(OCC)=O)[CH:13]=[CH:12][S:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].C[C:23](C)=[O:24]>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([CH2:23][OH:24])[N:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)=O
Reactant: CCOC(=O)N1C=CSC1CNC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1nc(CO)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 0.52 g of ethyl 2-(tert-butoxycarbonylamino)methylthiazole-3-carboxylate in 10 ml of ethanol was added 200 mg of lithium borohydride, and the mixture was stirred at room temperature for 30 minutes. To this reaction solution was added 2 ml of acetone. The mixture was stirred for an additional 30 minutes, and then concentrated under reduced pressure. To the residue were added 15 ml of dichloromethane and 15 ml of a saturated saline solution, and the mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (5 ml×2). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 0.357 g (yield 81%) of the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f22) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]([CH2:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)[CH2:9][C:10]1[N:11]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:13][N:14]=1.C(OC)(OC)OC.[CH2:50]([N:53]([CH2:59][CH2:60][CH3:61])[CH2:54][CH2:55][CH2:56][CH2:57][NH2:58])[CH2:51][CH3:52].[BH4-].[Na+]>CO.O>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]([CH2:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:58][CH2:57][CH2:56][CH2:55][CH2:54][N:53]([CH2:59][CH2:60][CH3:61])[CH2:50][CH2:51][CH3:52])=[CH:37][CH:36]=1)[CH2:9][C:10]1[N:11]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:13][N:14]=1
Reactant: CCCN(CCC)CCCCN
Reactant: Cn1ccnc1CN(Cc1ccc(C=O)cc1)Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCCNCc1ccc(CN(Cc2nccn2C)Cc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
The compound (47.2 mg) obtained in Example 91-1 was dissolved in methanol (1.0 ml) and trimethyl orthoformate (28.0 μl) and a methanol solution containing the compound (14.7 mg) obtained in Example 1-2 were dropped thereto at room temperature under a nitrogen atmosphere. The whole was stirred for 12 hours. Sodium borohydride (10.0 mg) was added thereto under ice-cooling and the whole was warmed back to room temperature and stirred for 2 hours. After completion of the reaction, water was added thereto. The solvent was distilled off under reduced pressure. The resultant was diluted with chloroform and added with water, and the aqueous layer was subjected to extraction with chloroform. The combined organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solution was concentrated and evaporated to dryness under reduced pressure and the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (51.6 mg) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:26])[C@@H:6]([NH2:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[CH2:2][CH3:3].[N:27]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]1([C:39](O)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1)=[N+:28]=[N-:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:1]([O:4][C:5](=[O:26])[C@@H:6]([NH:25][C:39]([C:34]1([CH2:33][CH2:32][CH2:31][CH2:30][N:27]=[N+:28]=[N-:29])[CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:40])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=NCCCCC1(C(=O)O)CCCC1
Reactant: CCCOC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)C1(CCCCN=[N+]=[N-])CCCC1

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 8, starting from (S)-2-amino-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid propyl ester (10.78 g, 30 mmol), 1-[4-azidobutyl]cyclopentanecarboxylic acid (8.24 g, 39 mmol), HBTU (14.79 g, 39 mmol), and DIPEA (11.63 g, 15.68 mL, 90 mmol), and after ISCO column chromatography purification, resulted in an amorphous off-white solid (14.1 g, 85%). ES(+)-HRMS m/e calcd. for C29H40N6O5 (M+H)+ 553.3133, obsd. 553.3133.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.ClCCl.O>[CH2:20]([N:19]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: Cc1ccnc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc(N(Cc2ccccc2)Cc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a stirred solution of 2-chloro-4-methyl-3-nitropyridine (1.06 g, 6.14 mmol) in tetrahydrofuran (12 mL) under an atmosphere of nitrogen were added dibenzylamine (2.4 mL, 13 mmol) and sodium carbonate (684 mg, 6.45 mmol). The mixture was warmed to reflux for 48 h and cooled to room temperature. The mixture was diluted with dichloromethane (100 mL) and water (100 mL), and the layers were separated. The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic extracts were washed with 1 N HCl (100 mL) and brine (100 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel, 10% ethyl acetate/hexanes) to provide 2-(dibenzylamino)-4-methyl-3-nitropyridine (1.53 g, 4.59 mmol, 75%) as a bright yellow oil which solidified upon standing. Rf 0.52 (67:33 hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ2.32 (3H, s), 4.45 (4H, s), 6.70 (1H, d, J=4.9 Hz), 7.16-7.19 (4H, m), 7.21-7.34 (6H, m), 8.16 (1H, d, J=4.9 Hz); ESI MS m/z 334 [C20H19N3O2+H]+.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([CH2:28][O:29][CH:30]2[CH:35]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42]O)[CH:37]=3)[CH2:34][CH2:33][N:32]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:31]2)[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[CH2:10]([O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([CH2:28][O:29][CH:30]2[CH:35]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][F:7])[CH:37]=3)[CH2:34][CH2:33][N:32]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:31]2)[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(CO)c2)C(OCc2cc(OCc3ccccc3)c3ccccc3c2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(CF)c2)C(OCc2cc(OCc3ccccc3)c3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 101.6 %

Procedure:
A solution of 18 mg (0.106 mmol) of diethylamino-sulphur trifluoride (DAST) in 1 ml of methylene chloride was cooled to -65° C. and a solution of 56 mg (0.101 mmol) of tert-butyl (3RS,4RS)-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-4-(3-hydroxymethyl-phenyl)-piperidine-1-carboxylate in 1 ml of methylene chloride was added dropwise thereto at -60° C. to -65° C. within 3 minutes. The resulting yellow solution was warmed to room temperature and stirred for one hour. Subsequently, the mixture was partitioned between methylene chloride and 5% sodium hydrogen carbonate solution, the organic phase was dried over magnesium sulphate and finally the solvent was distilled off under reduced pressure. There were obtained 57 mg of crude tert-butyl (3RS,4RS)-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-4-(3-fluoromethyl-phenyl)-piperidine-1-carboxylate, which was used in the next step without further purification and characterization.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(COC)OC.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CC(C)([O-])C.[Na+]>O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[C:6]3[C:10](=[C:2]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:3]=[CH:4][CH:5]=3)[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=2)=[CH:15][CH:16]=1
Reactant: CCCn1nc(-c2ccc(OC)cc2)c2cccc(Cl)c21
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCCn1nc(-c2ccc(OC)cc2)c2cccc(N3CCOCC3)c21
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To a stirred solution of 7-chloro-3-(4-methoxyphenyl)-1-propyl-1H-indazole (0.218 g, 0.73 mmol) in anhydrous degassed dimethoxyethane (3 mL) was added morpholine (0.076 mL, 0.84 mmol) and sodium t-butoxide (0.098 g, 1.02 mmol). Tris(dibenzylidene-acetone)dipalladium(0) (0.010 g, 0.011 mmol) and 2-dicyclohexyl phosphino-2′-(N,N-dimethylamino)biphenyl (0.09 g, 0.23 mmol) were added and the reaction refluxed for 90 minutes. The reaction was cooled to room temperature and water added. The mixture was extracted with ethyl acetate and the organic layer washed with water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the organic phase was filtered and the filtrate evaporated in vacuo to yield crude title compound. The oil was purified by silica gel column chromatography eluting with hexane/ethyl acetate (5/1 to 3/1) to provide the title compound as a white solid (0.157 g, 0.45 mmol, 63%). An analytical sample was crystallized from hexane.
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=[C:5]([NH2:16])[C:4]=2[N:3]=1.[CH2:17]([O:19][CH2:20][CH2:21][C@H:22]1[CH2:27]N[CH2:25][CH2:24][NH:23]1)[CH3:18]>>[CH2:17]([O:19][CH2:20][CH2:21][C@@H:22]1[NH:23][CH2:24][CH2:25][N:16]([C:5]2[C:4]3[N:3]=[C:2]([CH3:1])[S:11][C:10]=3[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=2)[CH2:27]1)[CH3:18]
Reactant: Cc1nc2c(s1)Nc1ccccc1N=C2N
Reactant: CCOCC[C@H]1CNCCN1
Product: CCOCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)nc32)CCN1

Procedure:
In a manner similar to that described in Example 300, combine 2-methyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-ylamine (0.534 g, 2.01 mmol) and (S)-2-(2-ethoxyethyl)piperazine (0.635 g, 4.01 mmol) to obtain the title compound: Exact Mass, Calc: 372.1858; Found: 372.1867.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[OH:12][CH:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:14]([NH:16][NH2:17])=[O:15]>C(O)C>[OH:9][C:8]1[CH:10]=[CH:11][C:3](/[CH:2]=[N:17]/[NH:16][C:14](=[O:15])[CH:13]([OH:12])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COc1ccc(C(O)C(=O)NN)cc1
Reactant: COc1cc(C=O)ccc1O
Solvent: CCO
Product: COc1ccc(C(O)C(=O)N/N=C/c2ccc(O)c(OC)c2)cc1

Procedure:
Vanillin (23 g, 0.15 mol) is added to a solution of hydroxy-(4-methoxy-phenyl)-acetic acid hydrazide (30 g, 0.15 mol) in 300 ml of ethanol at room temperature. After heating this mixture to reflux for 4 hours, the reaction is poured on water and extracted with ethyl acetate. The combined organic layer is washed with brine, dried over magnesium sulfate and evaporated. The residue, which is hydroxy-(4-methoxy-phenyl)-acetic acid [1-(4-hydroxy-3-methoxy-phenyl)-meth-(E)-ylidene]-hydrazide, is sufficiently pure to be directly used in the next step.
Reaction SMILES: O[CH:2]1[NH:8][C:7](=[O:9])[C:6]2[S:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12.[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18]([CH3:20])=[O:19]>C(OCC)C>[CH2:23]([O:22][C:16]([CH:17]([CH:2]1[NH:8][C:7](=[O:9])[C:6]2[S:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12)[C:18]([CH3:20])=[O:19])=[O:21])[CH3:24]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C1NC(O)c2cccn2-c2ccsc21
Solvent: CCOCC
Product: CCOC(=O)C(C(C)=O)C1NC(=O)c2sccc2-n2cccc21
Yield: 47 %

Procedure:
Using the procedure described in Example 26, starting with 1 g of 6-hydroxy-5,6-dihydro-4-oxo-4H -pyrrolo[1,2-a]thieno[2,3-f][1,4]diazepine and 2 ml of ethyl acetoacetate, 0.7 g of 6-[1-(ethoxycarbonyl) -acetonyl]-5,6-dihydro-4-oxo-4H-pyrrolo[1,2-a]thieno -[2,3-f][1,4]diazepine was obtained in the form of white crystals, melting point 196° C. (ethyl ether).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.C([O:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30]Br)=[CH:26][C:25]=1[CH3:34])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[OH:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30][N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([CH3:2])=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)=[CH:26][C:25]=1[CH3:34]
Reactant: Cc1cc(OCCBr)ccc1OCc1ccccc1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(CC2CCN(CCOc3ccc(O)c(C)c3)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-methylbenzyl)piperidine hydrochloride (339 mg, 1.5 mmol), 2-(4-benzoxy-3-methylphenoxy)ethyl bromide (482 mg, 1.5 mmol) and potassium carbonate (518 mg, 3.8 mmol) in two steps as white-off solid (250 mg): mp 161-163° C. 1H NMR (CD3OD) 1.328 (m, 2 H), 1.697 (m, 3 H), 1.964 (s, 3 H), 2.092 (s, 3 H), 2.384 (m, 2 H), 2.826 (m, 2 H), 3.279 (m, 2 H), 3.427 (m, 2 H), 4.037 (d, J=4.5 Hz, 2 H), 6.469 (m, 2 H), 6.563 (m, 1 H), 6.877 (m, 4 H). Anal. Calcd for C22H30ClNO2.0.6H2O: C, 68.31; H, 8.13; N, 3.62. Found: C, 68.52; H, 7.85; N, 3.65.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=O.[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])#[N:15]>>[C:14](/[C:16](=[C:6]1/[C:7](=[O:12])[NH:8][C:9]2[C:5]/1=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)/[C:17]([O:19][CH3:20])=[O:18])#[N:15]
Reactant: COC(=O)CC#N
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Product: COC(=O)/C(C#N)=C1\C(=O)Nc2ccc(OC)cc21
Yield: 88 %

Procedure:
Following the general method as outlined for Intermediate 1, starting from 5-methoxy-1H-indole-2,3-dione and methyl cyanoacetate, the title compound was isolated, after evaporation, as a dark purple solid in 88% yield. This was a 4.5:1 mixture of geometric isomers (99% purity by HPLC).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:24](O)=[O:25])[C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.S(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:24]([Cl:30])=[O:25])[C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(CC(C(=O)O)c2ccc(C3CCCCC3)cc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CC(C(=O)Cl)c2ccc(C3CCCCC3)cc2)cc1
Yield: 98.3 %

Procedure:
A solution of 4-[2-carboxy-2-(4-cyclohexylphenyl)ethyl]-benzoic acid methyl ester (5.58 g, 15.2 mmol) in toluene was stirred and thionyl chloride (2.79 mL, 38.20 mmol) was added. The mixture was stirred and refluxed for 15 minutes and the toluene removed under reduced pressure. The residue was stripped twice with toluene to afford 5.75 g (98%) of 4-[2-chlorocarbonyl-2-(4-cyclohexylphenyl)ethyl]benzoic acid methyl ester.
Reaction SMILES: [C:1]([OH:10])(=O)[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[Zn:11].[Co:12]>[Ni]>[Zn:11].[Co:12].[O:7]=[C:6]([OH:8])[C@@H:4]([C@H:2]([C@@H:1]([C@@H:2]([CH2:1][OH:10])[OH:3])[OH:10])[OH:3])[OH:5]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: [Co]
Agent: [Ni]
Agent: [Zn]
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
An aqueous cobalt-zinc electrolyte is prepared as in Example 7 but containing 50 g/l tartaric acid instead of sodium glucoheptonate. A nickel plated S-shaped steel panel is plated for 10 minutes at 15 ASF in accordance with the conditions of Example 2. The resultant cobalt-zinc electrodeposit is observed as being more gray in color than that obtained in accordance with Example 6 employing gluconic acid alone. The addition of 10 g/l of citric acid in combination with the 50 g/l tartaric acid followed by pH adjustment resulted in the deposition on a similar S-shaped steel panel of a cobalt-zinc electrodeposit which was of uniform brightness over the entire surface and had an excellent chromium-like appearance equivalent to that obtained in Example 2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C@:8]1([C:21]([O:23][CH3:24])=[O:22])[CH2:13][C@@H:12]([O:14]S(C)(=O)=O)[C@H:11](O)[C@H:10]([OH:20])[CH2:9]1>CO>[OH:7][C@@:8]1([C:21]([O:23][CH3:24])=[O:22])[CH2:13][C@@H:12]([OH:14])[C@@H:11]2[C@@H:10]([O:20]2)[CH2:9]1
Reactant: COC(=O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)[C@]1(O)C[C@@H](O)[C@H]2O[C@H]2C1
Reaction time: 5 h
Yield: 84 %

Procedure:
Potassium carbonate (400 mg, 2.9 mmol) was added to a room temperature mixture of Example 17B (3.0 g, 10.56 mmol) in methanol (100 mL). After stirring for 5 hours, the reaction mixture was filtered and concentrated. The concentrate was purified by flash column chromatography using ethyl acetate to afford 1.67 g (84%) of the desired product as a colorless oil.
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:8])[CH2:6][NH2:7].CO[C:11]([C:13]1[N:14]=[N:15][N:16]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.O>C1(C)C=CC=CC=1>[F:36][C:35]([F:37])([F:38])[C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=1)[CH2:24][N:16]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:13]([C:11]2[NH:7][CH2:6][CH2:5][N:8]=2)[N:14]=[N:15]1
Reactant: NCCN
Reactant: COC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(Cn2nnc(C3=NCCN3)c2-c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 19 %

Procedure:
To a solution of Me3Al (1.36 mL, 2M soln in toluene) at 0° C. under N2, add ethylenediamine (185 μL, 0.36 mmol) and stir for several minutes warming to RT. Add 1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylic acid methyl ester (750 mg, 1.69 mmol) dissolved in toluene to this solution. Reflux reaction for 3.5 hours at 110° C. Cool to RT and stir for 12 hours. Quench reaction with MeOH (2 mL), add H2O (2 mL) and extract with CH2Cl2 (4 mL×2). Dry over Na2SO4 and concentrate to afford title compound (30 mg, 4%). MS (IS) 440.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:23])[CH:19]=3)[NH:14][C:13]2=[O:24])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:25](I)[CH2:26][CH3:27]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:23])[CH:19]=3)[N:14]([CH2:25][CH2:26][CH3:27])[C:13]2=[O:24])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCCI
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3ccc(C)cc3c2=O)CC1
Product: CCCn1c(=O)n(C2CCN(C(=O)OCC)CC2)c(=O)c2cc(C)ccc21
Yield: 97 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 1.0 g (3.02 mmol) of 3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline (Compound f) was used in place of Compound 24 and propyl iodide was used in place of methyl iodide, whereby 1.09 g (yield: 97%) of Compound c was obtained as a colorless oily substance.