Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=O.[S:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[S:23].C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:26]=[C:25]1[C:27](=[CH:1][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:21][C:22](=[S:23])[NH:24]1
Reactant: N#Cc1cnc2ccc(C=O)cc2c1-c1cccnc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(C=C3SC(=S)NC3=O)cc2c1-c1cccnc1

Procedure:
Similar procedure as described in example 61j was used, starting from 6-formyl-4-pyridin-3-yl-quinoline-3-carbonitrile (example 63c), rhodanine, sodium acetate, and acetic acid to give 6-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-4-pyridin-3-yl-quinoline-3-carbonitrile. LC-MS m/e 375 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.[C:39]([O:44][CH3:45])(=[O:43])[C:40]([CH3:42])=[CH2:41]>C(N(CC)CC)C.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:39]([C:40](=[CH2:41])[CH2:42][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)([O:44][CH3:45])=[O:43]
Reactant: Brc1ccc(-c2cccc3cncn23)cc1
Reactant: C=C(C)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(Cc1ccc(-c2cccc3cncn23)cc1)C(=O)OC

Procedure:
A solution of 0.34 g of 5-(p-bromophenyl)imidazo[1,5-a]pyridine, 2.7 mg of palladium acetate, 7.5 mg of tri-o-tolyphosphine and 0.22 g methyl methacrylate in 3 ml of triethylamine is refluxed for 7 days, diluted with 50 ml of methylene chloride and washed with water. The methylene chloride is evaporated and the residue is taken up in 50 ml ether, filtered and washed with 2×20 ml of ice-cold 0.5N hydrochloric acid. The aqueous phase is adjusted to pH=8 and is extracted with methylene chloride. The methylene chloride extract is dried over magnesium sulfate and evaporated. Preparative thin layer chromatography (silica gel, ether) yields 5-[p-(2-carbomethoxyprop-2-enyl)phenyl]imidazo[1,5-a]pyridine; Rf=0.37; NMR: (CDCl3) 5.62 (s, 1H), 6.32 (s, 1H); IR (CH2Cl2) 1720 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14]Br.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1
Reactant: BrCCCCBr
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(N2CCCC2)c1

Procedure:
To a stirring solution of 3-methoxy-phenylamine (571 mg, 4.6 mmol) in anhydrous toluene (40 ml) was added 1,4-dibromo-butane (1.0 g, 4.6 mmol) and diisopropylethylamine (0.59 g, 4.6 mmol). The resulting solution was heated to reflux for 24 hours and then concentrated in vacuo. The crude material was purified by column chromatography over silica gel (silica gel 60, EM science, 5% EtOAc:hexanes) and the title compound was obtained as an oil (754 mg, 92%). MS(ES) m/e 178.4 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:35][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([F:36])[C:29]=1[N:26]1[CH2:27][CH2:28][N:23]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:2]3[C:11]4[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:22])[CH2:24][CH2:25]1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(S(=O)(=O)N2CCN(c3c(F)cccc3F)CC2)cc1
Product: O=S(=O)(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CCN(c2c(F)cccc2F)CC1

Procedure:
In the manner given in Example 1C, 4,7-dichloroquinoline is heated with 1-[(p-aminophenyl)-sulfonyl]-4-(2,6-difluorophenyl)piperazine to give 1-(2,6-difluorophenyl)-4-[[4-[[7-chloro-4-quinolinyl]amino]phenyl]sulfonyl]piperazine.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[F:7][C:8]1[CH:9]=[C:10]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:17]2[CH2:19][O:18]2)[CH:11]=[C:12]([F:14])[CH:13]=1>>[C:23]([O:22][C:21](=[O:27])[NH:20][C@@H:16]([CH2:15][C:10]1[CH:9]=[C:8]([F:7])[CH:13]=[C:12]([F:14])[CH:11]=1)[C@H:17]([OH:18])[CH2:19][N:1]=[N+:2]=[N-:3])([CH3:24])([CH3:25])[CH3:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN=[N+]=[N-]
Reaction time: 16 h

Procedure:
Sodium azide (0.22 g, 4 mmole) and ammonium chloride (2 eq) are added to tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3, 0.6 g, 2 mmole). The reaction is heated to 75–80 degrees C. and stirred for 16 hours. The reaction is monitored by TLC to insure completion. The solvent is removed under reduced pressure. The concentrate is partitioned between ethyl acetate and water, the phases are separated and the organic phase is washed with bicarbonate and saline, dried over anhydrous sodium sulfate and concentrated to give the title compound, TLC (ethyl acetate/hexane) Rf=0.45; MS (MH+)=343.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:39][OH:40].C(=O)([O-])O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:39]/[OH:40])/[CH2:9][C@H:10]([C:18]2[CH:19]=[CH:20][C:21]([CH:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3CCNCC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-tert-butyl 4-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)piperidine-1-carboxylate and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=414.4 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1Cl)=[O:5])[CH3:2].[NH3:24]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH2:24])=[O:5])[CH3:2]
Reactant: N
Reactant: CCOC(=O)c1c(C)nc(N2CCN(C)CC2)c([N+](=O)[O-])c1Cl
Product: CCOC(=O)c1c(C)nc(N2CCN(C)CC2)c([N+](=O)[O-])c1N

Procedure:
33.3 g. of 4-chloro-2-methyl-6-(4-methyl-1-piperazinyl)-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 mol) are dissolved in about 100 ml. of alcohol. 50 ml. of aqueous ammonia solution (30%) are added and the mixture is heated in an autoclave at 80° for 10 hours. After this time, the solution is evaporated to dryness and the residue is extracted with hot alcohol. On cooling, 25.2 g. of 4-amino-2-methyl-6-(4-methyl-1-piperazinyl)-5-nitropyridine-3-carboxylic acid ethyl ester precipitate, (78%), m.p. 73°-75° (methanol).
Reaction SMILES: C1CNC(=O)C1.[Br:7][Br-]Br.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](=[O:21])[CH3:20])[CH:17]=2)[CH:12]=[N:11]1.O>C1COCC1>[Br:7][CH2:20][C:19]([C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[N:11][NH:10]2)=[CH:14][CH:15]=1)=[O:21]
Reactant: CC(=O)c1ccc2cn[nH]c2c1
Agent: O=C1CCCN1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1ccc2cn[nH]c2c1
Temperature: 25 °C

Procedure:
Pyrrolidone hydrotribromide (1.8 g, 3.6 mmol) was added to a solution of 1-(1H-indazol-6-yl)ethanone (0.5 g, 3 mmol) in THF (10 mL) and the solution was heated at reflux for 2 h. The solution was allowed to cool to room temperature and H2O (30 mL) was added and the mixture was extracted with EtOAc (3×20 mL) and dried (MgSO4). The solvent was removed at reduced pressure to afford 2-bromo-1-(1H-indazol-6-yl)-ethanone, which was used directly in the next step with no purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH2:10][CH2:9]1>C(Cl)Cl>[CH:8]1([CH2:11][N:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:16][CH2:17]2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(CC3CC3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CC(N2CCN(CC3CC3)CC2)CCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5 mL TFA were added to a solution of 1.36 g (4.2 mmol) tert. butyl 4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidine-1-carboxylate in 30 mL DCM and the reaction mixture was stirred for 4 h at RT. The reaction solution was evaporated down i.vac., the residue combined with diethyl ether, the precipitate was suction filtered and dried. The product was precipitated as the tris-trifluoroacetate salt.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CN=C1.Cl>CN(C)C=O.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(Br)n1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCC(/C=C/c1cccc(Br)n1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
A solution of 4 g of 2-bromo-6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-pyridine in 20 ml of dimethylformamide is mixed with 4.1 g of tert-butyldiphenylsilyl chloride and 2.1 g of imidazole and stirred for 15 hours at room temperature. The reaction mixture is poured into 100 ml of diethyl ether, shaken out twice with 20 ml of 1 n hydrochloric acid, 4 times with 20 ml of saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/0-5% ethyl acetate. 5.5 g of 2-bromo-6[(1E)-(3RS)-3-tert-butyldiphenylsilyloxy-1-undecenyl]-pyridine is obtained as oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[O:16]1[CH2:20]CC[CH2:17]1.COCCl>C(OCC)(=O)C.O>[CH3:17][O:16][CH2:20][O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: OCCN1CCCC1
Reactant: C1CCOC1
Agent: COCCl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCOCCN1CCCC1

Procedure:
To a mixture of 115 g of 1-(2-hydroxyethyl)-pyrrolidine, 106 g of triethylamine and 500 g of tetrahydrofuran at 0° C. was added 81 g of chloromethyl methyl ether. The temperature was raised from 0° C. to 20° C. over 10 hours whereupon 200 g of water was added to stop the reaction. Ethyl acetate was added to the reaction solution, which was allowed to separate. The organic layer was washed with water and concentrated in vacuum. Purification by vacuum distillation yielded 1-[2-(methoxymethoxy)ethyl]-pyrrolidine, designated [B-1].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[S:10])[CH:5]=[CH:6][CH:7]=1.[C:11]([NH:15][C:16](=[O:18])[O-:17])([CH3:14])([CH3:13])[CH3:12].CNC>CO>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:15]([CH3:16])[CH3:11])=[S:10])[CH:5]=[CH:6][CH:7]=1.[C:11]([NH:15][C:16](=[O:17])[O-:18])([CH3:14])([CH3:13])[CH3:12]
Reactant: Oc1cccc(N=C=S)c1
Agent: CC(C)(C)NC(=O)[O-]
Agent: CNC
Solvent: CO
Product: CN(C)C(=S)Nc1cccc(O)c1
Temperature: 15 °C

Procedure:
1-(meta-hydroxyphenyl)-3,3-dimethyl-2-thiourea, tertbutylcarbamate is prepared by charging to a suitable vessel about 25 g. (approximately 0.1 mole) meta-hydroxyphenyl isothiocyanate, tert-butylcarbamate dissolved in about 150 ml. of methanol, and adding, with stirring about 154 g. (approximately 0.12 moles) of 40 percent aqueous dimethylamine mixed with about 50 ml. of methanol in a single increment. The mass quickly solidifies as the temperature rises from about room temperature to about 60°C. The mass is cooled to about 15°C., separated from the residual liquid by filtration, washed with four 150 ml. portions of a 75 percent methanol/25 percent water solution and dried under vacuum overnight.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH2:16])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:4]1[CH2:3][CH2:2][N:1]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=3)[CH2:6][CH2:5]1)[N:8]=[CH:9]2
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc2c(cnn2C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc2c(cnn2C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Yield: 14.5 %

Procedure:
1-(Piperidin-4-yl)-1H-indazol-5-amine (4.85 mmol, 1.05 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4.85 mmol, 1.636 g) and potassium carbonate (9.71 mmol, 1.342 g) were combined and stirred in acetonitrile (15 mL) at room temperature for 3 days. The reaction mixture was concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 5% methanol/dichloromethane) to afford the title compound (332 mg). MS (ESI) m/z 473.0 [M+H]+
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[CH2:6][C:7]([O-:9])=[O:8].[Na+]>O>[C:7]([CH2:6][NH:3][CH2:2][CH2:1][NH:4][CH2:6][C:7]([OH:9])=[O:8])([OH:9])=[O:8]
Reactant: NCCN
Reactant: O=C([O-])CCl
Agent: [Na+]
Solvent: O
Product: O=C(O)CNCCNCC(=O)O
Yield: 99.9 %

Procedure:
Into a four-necked flask containing ethylenediamine (3 g, 0.05 mol) and water (50 g), an aqueous sodium chloroacetate solution (11.7 g, 0.1 mol) was added dropwise over 30 minutes. The contents were mixed at 60° C. for 2 hours, and then washed with ethanol to give 8.8 g of N,N'-bis(carboxymethyl) ethylenediamine (separation yield: 88 wt %).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2([OH:21])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]2[CH:35]=[CH:34]C(N)=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>>[OH:21][C:15]1([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([C:14]4[CH:34]=[CH:35][C:30]([N:26]5[CH2:27][CH2:28][CH2:29][N:23]([CH3:22])[CH2:24][CH2:25]5)=[CH:31][CH:32]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: COC(=O)c1sc(C2(O)CCOCC2)cc1N=CN(C)C
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Product: CN1CCCN(c2ccc(-n3cnc4cc(C5(O)CCOCC5)sc4c3=O)cc2)CC1

Procedure:
3-(Dimethylaminomethyleneamino)-5-(4-hydroxytetrahydropyran-4-yl)thiophene-2-carboxylic acid methyl ester and 4-(4-methyl[1,4]diazepan-1-yl)phenylamine were reacted by method A1. The product with the molecular weight of 440.57 (C23H28N4O3S) was obtained in this way; MS (EST): 441 (M+H+).
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4].N1C=CC=CC=1.[Cl:20][CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24].Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:20][CH2:21][CH2:22][S:23]([O:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4])(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)CCCl
Reactant: O=C1C2C3C=CC(C3)C2C(=O)N1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1C2C3C=CC(C3)C2C(=O)N1OS(=O)(=O)CCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A solution of 12.5 g (70.0 mmol) of N-hydroxy-5-norbornene-2,3-dicarboximide and pyridine (6.2 ml, 77.0 mmol) in CH2Cl2 (105 ml) is treated dropwise with 2-chloroethanesulfonyl chloride (7.36 ml, 70.0 mmol) at 0° C., according to the procedure of W. C. Groutas, M. A. Stanga, J. C. Castrisos, E. J. Schatz, M. J. Brubaker J. Pharm. Sci. 1990, 79, 886-88. After stirring overnight at room temperature, the reaction mixture is diluted with ethyl acetate (280 ml) and then treated with 5% aqueous HCl (130 ml). The layers are separated and the aqueous layer is extracted once with ethyl acetate (280 ml). The combined organic extracts are dried over Na2SO4 and evaporated under reduced pressure, leaving a colorless oil which solidifies when further dried under vacuum. 15.6 g (73%) of the product are obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:50][C:51]1([C:57]2[S:58][CH:59]=[CH:60][C:61]=2[O:62][CH3:63])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][N:54]1[CH2:55][CH2:56][C:51]([OH:50])([C:57]2[S:58][CH:59]=[CH:60][C:61]=2[O:62][CH3:63])[CH2:52][CH2:53]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Reactant: COc1ccsc1C1(O)CCNCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccsc1C1(O)CCN(C[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
2.513 g (10 mmol) of (S)-(-)-2-(t-Butoxycarbonylamino)-3-phenyl-1-propanol was added at once to a magnetically stirred solution of 2.885 g (11 mmol) triphenylphosphine in tetrahydrofuran (100 mL) at 0° C. Thereafter 1.9 mL (12 mmol) diethyl azodicarboxylate was added dropwise over 3 minutes while the temperature was maintained between 0 and 5° C. This was immediately followed by adding a solution of 2.14 g (10 mmol) of 4-hydroxy-4-(3-methoxy-thiophen-2-yl)-piperidine in 100 mL tetrahydrofuran. The reaction mixture was stirred at ambient temperature overnight, evaporated in vacuo to dryness and the residue flash chromatographed on 300 g silica gel using chloroform as eluant yielding 2.6 g of the title compound as a faintly yellow dense oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([NH2:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].Br[C:20]([CH3:29])([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O>C(#N)C>[NH2:12][C:10]([CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][C:20]([CH3:29])([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:11]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: NC(=O)CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CCC(N)=O
Temperature: 80 °C

Procedure:
3-(2-Hydroxyphenyl)propionamide (5.6 g, 33.9 mmol) was dissolved in acetonitrile (15 mL), and potassium carbonate (18.7 g, 135 mmol) was added thereto. Subsequently, tert-butyl 2-bromoisobutyrate (30.3 g, 135 mmol) was added, and the mixture was stirred at 80° C. After completion of reaction, water was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=40/1), whereby the target compound was obtained (2.67 g, 26%).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:23]>C(O)C.[Pd]>[ClH:23].[N:18]1([CH:16]2[CH2:17][NH:14][CH2:15]2)[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: c1ccc(C(c2ccccc2)N2CC(n3cncn3)C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ncn(C2CNC2)n1
Reaction time: 48 h

Procedure:
To a mixture of N-benzhydryl-3-(1,2,4-triazol-1-yl) azetidine (0.6 g) in 20 ml of ethanol was added 2 ml of 1N hydrochloric acid followed by the addition of 0.6 g of Pd/C (10%). The mixture was hydrogenated at 50 psi for two days. After filtration and evaporation, the crude product was crystallized from methanol-ether to afford 0.235 g of white solid. 1H NMR (D2O) δ: 9.14 (S, 1H), 8.57 (S, 1H), 5.97 (m, 1H), 4.8-4.5 (m, 4H).
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13](O)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:28][C:29]1([CH3:37])[O:34][C:33](=[O:35])[CH2:32][C:31](=[O:36])[O:30]1.N1C=CC=CC=1>C(Cl)Cl>[C:1]12([O:11][CH2:12][C:13](=[C:32]3[C:33](=[O:35])[O:34][C:29]([CH3:37])([CH3:28])[O:30][C:31]3=[O:36])[OH:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)COC12CC3CC(CC(C3)C1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(=C(O)COC23CC4CC(CC(C4)C2)C3)C(=O)O1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 97.3 %

Procedure:
A solution of (adamantan-1-yloxy)-acetic acid (32.3 g, 153 mmol) and 1,1′-carbonyl-diimidazole (27.6 g, 170 mmol) in DCM (600 mL) was stirred at 0° C. for 15 minutes, then at room temperature for 75 minutes. The mixture was concentrated in vacuo (˜300 mL) and the solution was then added dropwise, over 20 minutes, to a solution of 2,2-dimethyl-1,3-dioxan-4,6-dione (22.1 g, 153 mmol) and pyridine (30 mL, 371 mmol) in DCM (450 mL) at 0° C. under argon. The mixture was allowed to warm to room temperature and stirred for 16 hours. The organic solution was washed with 2N HCl (2×500 mL), brine (500 mL) and dried (MgSO4). The filtrate was evaporated and the residue triturated with hexane to give the title compound as a white solid (50.1 g, 97%). 1H NMR (CDCl3) 4.91 (2H, s), 2.18 (3H, br s), 1.81-1.81 (6H, m), 1.73 (6H, s), 1.68-1.58 (6H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-])=O)[CH:10]=1)=O)([O-])=O.[H][H].N>[Pd].C(O)C>[CH:13]1[CH:12]=[C:11]([NH2:16])[CH:10]=[C:9]([CH2:7][C:6]2[CH:19]=[CH:20][CH:21]=[C:4]([NH2:1])[CH:5]=2)[CH:14]=1
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CCO
Product: Nc1cccc(Cc2cccc(N)c2)c1
Yield: 85 %

Procedure:
34.1 g (0.1 mol) of 3,3'-dinitro-4,4'-dichlorbenzophenone, 1.5 g of 5% Pd/C, and 100 ml of ethanol were charged in a closed glass vessel equipped with a thermometer and a stirrer. While stirring the mixture at a temperature of 50° to 60° C., hydrogen was introduced thereinto and 22.9 l (1.02 mol) of hydrogen was absorbed in 7.5 hours. Since no more absorption of hydrogen was observed, the reaction was terminated at this point. The reaction solution was neutralized with 13.4 g (0.22 mol) of 28% aqueous ammonia and filtered to remove the catalyst. The filtrate was concentrated to give 3,3'-diaminodiphenylmethane as a brown oil. A high performance liquid chromatography revealed that the purity was 93.8%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[N:22]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:26][CH2:25][CH2:24][CH2:23]1>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:30][CH2:29][CH2:28][CH2:27][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NCCCN1CCCC1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCCCN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and 3-(pyrrolidin-1-yl)propan-1-amine (32.1 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a light brown solid, 73.3 mg, (77% yield) MS (ES+): 378.2, (M+H).