Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1.I[CH2:16][CH2:17][CH3:18].Cl>CN(C)C=O>[F:3][C:4]1[CH:14]=[CH:13][C:7]2[N:8]([CH2:16][CH2:17][CH3:18])[C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: CCCI
Reactant: O=C1COc2cc(F)ccc2N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)COc2cc(F)ccc21
Temperature: 40 °C
Yield: 79.7 %

Procedure:
Under a dry argon atmosphere 2.7 grams of a 60% suspension of sodium hydride in oil (0.068 mole of sodium hydride) was waashed with petroleum ether to remove the oil. To the washed sodium hydride was added 50 ml of N,N-dimethylformamide (DMF), and the mixture was stirred. A solution of 7-fluoro-2H-1,4-benzoxazin-3 (4H)-one (10.0 grams, 0.060 mole) in 50 ml of DMF was added. This mixture was warmed to approximately 40° C. for 30 minutes, and then was cooled to room temperature. A solution of 11.2 grams (0.066 mole) of 1-iodopropane in 10 ml of DMF was added, and the mixture was stirred at room temperature for approximately 18 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 10.0 grams of 7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-one as an oil.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1>ClCCl.N1C=CC=CC=1>[CH3:28][C:24]1[CH:23]=[C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)=[O:13])[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Cc1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2cccc(C)c2)c1
Yield: 42 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and m-toluidine (1.24 g, 11.6 mmol) in 10 mL of pyridine. The crude product was recrystallized from ethyl ether-ethyl acetate to yield 1.18 g of the title compound, mp 193°-195° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=O)[NH:14][N:15]=[CH:16][C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[CH2:1]([N:8]1[C:12]2=[C:13]([Cl:21])[N:14]=[N:15][CH:16]=[C:11]2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2cn[nH]c(=O)c2n1Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc2cnnc(Cl)c2n1Cc1ccccc1
Temperature: 85 °C
Reaction time: 7 h
Yield: 84 %

Procedure:
A suspension of 2.0 g (8.3 mmol) of 1-benzyl-2-methyl-6,7-dihydropyrrolo[2,3-d]pyridazine 7-one in 20 ml of phosphorus oxychloride is stirred at 85° C. for 7 h. The excess phosphorus oxychloride is subsequently distilled off and the residue is hydrolyzed in 50 ml of water. After neutralization with 2 N sodium hydroxide solution, the mixture is extracted with 3×50 ml of dichloromethane. The organic extracts are washed with 50 ml of water, dried over magnesium sulfate and concentrated. The residue is recrystallized from methanol. 1.8 g (84%) of the title compound are isolated. M.p.: 152°-156° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4](N)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:19]>O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].CO>[OH:15][CH2:14][CH2:13][O:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:19])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Nc1nc(N)c2ncn(COCCO)c2n1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1

Procedure:
To a solution of 2-amino-9-(2-hydroxyethoxymethyl) adenine (0.22 g) in water (30 ml) was added a suspension of adenosine deaminase in aqueous ammonium sulfate (0.44 ml, containing 4.4 mg of the enzyme). The reaction mixture, which initially had a pH of 7.0, was heated at 37° C. for 18 hours, at which time the pH was 8.5 and TLC (silica gel plates developed in 15% methanol - 85% chloroform) indicated a single product different from starting material. The reaction mixture was thoroughly chilled in an ice bath and the resulting white solid removed by filtration and thoroughly washed with cold water. The product was dried at 100° C./0.1 mm Hg for 16 hours to give 0.20 g of 9-(2-hydroxyethoxymethyl)guanine. 1/4 H2O, the structure of which was confirmed by m.p., TLC, U.V., NMR and mass spectroscopy analysis. Recrystallization from methanol gave the anhydrous 9-(2-hydroxyethoxymethyl)quanine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:27]=[C:28]1[O:32][C:30](=[O:31])[CH2:29]1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:30](=[O:31])[CH2:29][C:28]([CH3:27])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: C=C1CC(=O)O1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
2-({4-[2-(Heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (3.41 g) synthesized in Example 303-2 was dissolved in N,N-dimethylformamide (43 mL), and diketene (0.75 g) was added dropwise under ice-cooling. After warming to room temperature, the mixture was stirred for one hour. The mixture was diluted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 2-[(4-{2-[acetoacetyl(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (3.4 g) as a colorless oil. The present compound was used in the next step without particular purification. The present compound (1.0 g) was dissolved in ethanol (10 mL), hydrazine monohydrate (0.103 g) was added thereto at room temperature, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL), diphosphorus pentasulfide (0.459 g) and sodium carbonate (0.437 g) were added thereto, and the mixture was heated under reflux for 2 hr. The solvent was evaporated, and the residue was directly purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 1:2) to give the title compound (0.54 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:24]([C:20]5[O:19][CH:23]=[CH:22][CH:21]=5)=[O:25])[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Product: O=C(c1ccco1)N1CCc2[nH]c3c(cnc4cc(Cl)ccc43)c2C1
Yield: 17.6 %

Procedure:
The same reaction procedure and workup is followed as for the compound of Example 8 using 0.50 g (1.94 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline and 0.253 g (1.94 mmol) of 2-furoylchloride to yield 0.12 g (17%) of the title compound as a white solid: m.p >250° C.; m/e 351.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:25](OCC)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:27])[CH3:26]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(F)cc21
Reactant: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2ccc(F)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-2-benzoyl-1-(ethoxycarbonyl)-6-fluoroindole (step 2). tlc: Rf=0.2 (33% ethyl acetate in hexanes)
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.Br[CH2:20][CH:21]([OH:23])[CH3:22]>>[OH:23][CH:21]([CH3:22])[CH2:20][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1
Reactant: O=c1[nH]c(C2CCNCC2)cc2ccccc12
Reactant: CC(O)CBr
Agent: Cl
Product: CC(O)CN1CCC(c2cc3ccccc3c(=O)[nH]2)CC1
Yield: 16.1 %

Procedure:
By the reaction in the same manner as in Example 2a, using 3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (500 mg) and 1-bromo-2-propanol (394 mg), 3-[1-(2-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-1-one (87 mg) was obtained,
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=2)=[N:11][CH:12]=1.C([N:27]([CH:31]([CH3:33])C)[CH:28]([CH3:30])C)C.N1CCCC1>C(Cl)Cl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:27]3[CH2:28][CH2:30][CH2:33][CH2:31]3)=[CH:19][CH:18]=2)=[N:11][CH:12]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: OCc1ccc(CCC#Cc2ccc(Br)cn2)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: Brc1ccc(C#CCCc2ccc(CN3CCCC3)cc2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.24 mL (3.04 mmol) methanesulphonic acid chloride are added to a solution, cooled to 0° C., of 800 mg (2.53 mmol) {4-[4-(5-bromo-pyridin-2-yl)-but-3-ynyl]-phenyl}-methanol in 17 mL DCM and then a solution of 0.52 mL ethyldiisopropylamine in 3 mL DCM is added dropwise. The mixture is stirred for a further 30 min at 0° C., 0.51 mL (6.08 mmol) pyrrolidine is added, the reaction mixture is heated to RT and kept at this temperature for 5 h. To complete the reaction another 0.26 mL (3 mmol) pyrrolidine are added and stirred for 1 h at RT. The mixture is evaporated down i.vac., combined with 10 mL water and 20 ml EtOAc, acidified with 1 M HCl and the organic phase is separated off. The aqueous phase is made alkaline with 2 M Na2CO3 solution, extracted with 20 mL EtOAc, the organic phase is separated off and dried over Na2SO4. After the desiccant and solvent have been eliminated the desired product is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15]([CH3:18])(=O)=O)[N:3]=1.C(S)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([S:15][CH2:18][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: SCc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(SCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, benzyl mercaptan and DBU in DME. EI-MS m/e (%): 308 (M+, 68), 307 ([M—H]+, 48), 275 (24), 91 (100).
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([CH:16]([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:19][CH2:20][CH:21]([F:23])[F:22])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:38][CH2:37][C:36]2[CH:39]=[CH:40][C:41]([NH2:43])=[CH:42][C:35]=2[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:38][CH2:37][C:36]2[CH:39]=[CH:40][C:41]([NH:43][C:2]3[N:24]=[C:5]4[C:6]([C:10]5[CH:15]=[C:14]([CH:16]([F:18])[F:17])[CH:13]=[CH:12][C:11]=5[O:19][CH2:20][CH:21]([F:23])[F:22])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:42][C:35]=2[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Reactant: FC(F)COc1ccc(C(F)F)cc1-c1cccn2nc(Cl)nc12
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5cc(C(F)F)ccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
7-{8-[2-(2,2-difluoro-ethoxy)-5-difluoromethyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-[2-(2,2-difluoro-ethoxy)-5-difluoromethyl-phenyl]-[1,2,4]-triazolo[1,5-a]pyridine (0.182 g, 506 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.199 g, 759 mmol) in a manner analogous to Example 311a and 311b to give product: 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.78 (d, 1H), 7.90 (s, 1H), 7.65 (m, 2H), 7.42 (m, 3H), 7.10 (br m, 1H) 7.05 (m, 2H), 6.35 (br m, 1H), 4.43 (m, 2H), 3.40 (m, 4H), 2.75 (m, 4H), 1.41 (s, 9H). MS=586 (MH)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N+:22]([O-])=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1.C1(C)C=CC=CC=1.CNC.[H][H]>[C].[Pd].O>[OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N:22]=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1
Reactant: CCC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)CC)c1
Reactant: [H][H]
Agent: [Pd]
Agent: CNC
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1
Yield: 90.8 %

Procedure:
36.7 g (0.1 mol) of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole-N-oxide, 0.125 g of 5% palladium carbon, 150 ml of a solvent mixture comprising toluene and water (ratio by volume, 4:1) and 7 g of 50% dimethylamine were charged into a 500-ml four neck flask. After the air in the flask had been replaced by nitrogen, the resultant mixture was agitated at room temperature. Hydrogen was then supplemented to allow for the amount of hydrogen absorbed by the mixture, which was then subjected to reaction until no more hydrogen was absorbed by it. After the reaction had been completed, the catalyst was filtered off, and part of the filtrate was subjected to quantitative analysis using gas chromatography (GC). The results revealed a yield of 90.8% of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole. The solvent was then distilled off from the filtrate, and the residual solid was crystallized using ethanol and then washed with ethanol to obtain 28 g of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole (yield, 80%; melting point, 79° to 82° C.).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=O)=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>ClCCl.C(O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:12](=[O:14])/[CH:11]=[CH:10]/[C:7]3[CH:6]=[CH:5][C:4]([CH:3]([O:2][CH3:1])[O:15][CH3:16])=[CH:9][CH:8]=3)=[CH:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: COC(OC)c1ccc(/C=C/C(=O)O)cc1
Solvent: ClCCl
Solvent: CCO
Product: COC(OC)c1ccc(/C=C/C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1

Procedure:
Prepared analogously to Example 3.1.e. from (E)-3-(4-dimethoxymethylphenyl)acrylic acid and 4′-chlorobiphenyl-4-ylamine. Yield: 9.8 g, C24H22ClNO3 (M=407.90); calc.: molecular ion peak (M+H)+: 408/410; found: molecular ion peak (M+H)+: 408/410; Rf value: 0.3 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:11]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][NH:16]3)=[C:12]([NH:19][C:20]3[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=3)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CCOC(=O)c1cccc(Nc2nc(Cl)nc3[nH]cnc23)c1
Product: CCOC(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3[nH]cnc23)c1

Procedure:
570 mg of trans 1,4-diaminocyclohexane are heated to its melting point (70° C.) and 158 mg of the product obtained in stage 1 above are added. 32 mg of the expected product are thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]2([CH3:14])[CH2:13][CH2:12]2)[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:15]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]2([CH3:14])[CH2:12][CH2:13]2)[C:5]([O:10][CH3:15])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CC1(c2cc(Br)cc(C=O)c2O)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C=O)cc(Br)cc1C1(C)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
step 3—To a solution of 74a (0.44 g, 1.7 mmol) in DMF (4 mL) was added K2CO3 (0.60 g, 4.4 mmol) and iodomethane (0.32 g, 2.3 mmol). The resulting mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to RT and partitioned between water and Et2O. The organic layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated to afford 0.47 g (96%) of 5-bromo-2-methoxy-3-(1-methylcyclopropyl)benzaldehyde (74b) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.O[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[N:15]1([CH2:14][CH2:13][O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH2:1])[S:3][C:4]=3[CH:10]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Nc1nc2ccc(O)cc2s1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1nc2ccc(OCCN3CCOCC3)cc2s1
Reaction time: 3.5 h
Yield: 95.7 %

Procedure:
To a solution of benzothiazole 225 (3.62 g, 21.8 mmol) in THF at room temperature under nitrogen, were successively added 4-(2-hydroxyethyl)morpholine (3.17 mL, 26.1 mmol), triphenylphosphine (7.43 g, 28.3 mmol) followed by a dropwise addition of diethyl azodicarboxylate (4.46 mL, 28.3 mmol). The solution was stirred for 3.5 h and THF was partially removed in vacuo. The mixture was partitioned between ethyl acetate and H2O. The combined organic layers were extracted with 1N HCl. The combined acidic extracts were neutralized using a saturated aqueous solution of NaHCO3 and the precipitate was dissolved with ethyl acetate. These combined organic layers were washed with brine, dried over MgSO4, and concentrated. The filtrate was concentrated to afford the title compound 226 (5.83 g, 96% yield) as a light yellow oil. 1H NMR: (Acetone-d6) δ (ppm): 7.37 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.6 Hz, 1H), 6.94 (dd, J=8.8, 2.6 Hz, 1H), 6.60 (bs, 2H), 4.19 (t, J=6.2 Hz, 2H), 3.70-3.67 (m, 4H), 2.90 (s, 2H), 2.81 (t, J=6.2 Hz, 2H), 2.62-2.58 (m, 4H).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].C(N(CC)CC)C>C(Cl)Cl>[CH2:19]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:13]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1ccccc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Yield: 88.9 %

Procedure:
A mixture of ethyl isonipecotate (69.25 g, 0.441 mol). -bromotoluene (75.44 g, 52.4 ml, 0.441 mol) and triethylamine (44.74 g, 61.5 ml, 0.441 mol) in 1000 ml methylene chloride was stirred at r.t. for 20 hr. The mixture was washed with brine and the organic layer was separated, dried and concentrated to give 97.016 g of ethyl 1-benzylpiperidine-4-carboxylate as a yellow oil. HNMR (CDCl)δ 1.2(t, 3H), 1.6-1.9 (m, 4H), 2.0 (dt, 2H), 2.2-2.3 (m, 1H), 2.85 (m, 2H), 3.5 (s, 2H), 4.1 (q, 2H), 7.2-7.36 (m, 5H) ppm.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:15]#[N:16])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([CH:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:15]#[N:16])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC(=C1CCN(Cc2ccccc2)CC1)c1cccs1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: N#CC(c1cccs1)C1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 70 parts of α-[1-(phenylmethyl)-4-piperidinylidene]-2-thiopheneacetonitrile in 800 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladiumon charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 70 parts of 1-(phenylmethyl)-α-(2-thienyl)-4-piperidineacetonitrile as a residue.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]([OH:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: [Li]
Solvent: CCOCC
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1-benzyl-3-oxo-4-piperidinecarboxylate (1.0 g, 3.8 mmol) in diethyl ether (50 mL) was treated with lithium aluminumhydride (150 mg, 3.9 mmol) at and −78° C. After stirring at −78° C. for 30 minutes, the mixture was allowed to warm to room temperature over 2 hours. The mixture was quenched with saturated ammonium chloride. Standard work-up gave a crude product which was purified via chromatography (SiO2, ethyl acetate:hexanes, 1:6) to provide the title compound. MS (EI, M+H)+264.
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[CH2:5][OH:6].Cl[CH2:16][C:17](OCC)=[O:18]>C1COCC1>[F:14][C:9]1[CH:8]=[C:7]([CH:4]2[NH:3][C:17](=[O:18])[CH2:16][O:6][CH2:5]2)[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: CCOC(=O)CCl
Reactant: NC(CO)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCC(c2ccc(F)c(F)c2)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of NaH (8.0 mmol, 0.19 g) in 10 mL THF at 0° C. was added a solution of 2-amino-2-(3,4-difluorophenyl)-ethanol (7.51 mmol, 1.3 g) in 20 mL THF dropwise via an addition funnel and after 30 min ethyl chloroacetate was added dropwise via syringe. The orange colored reaction mixture was stirred for 2 hours at 0° C. and then for 2 hours at 35° C. The solvent was removed and the 5-(3,4-difluoro-phenyl)-morpholin-3-one was isolated as a thick yellow oil (0.5 g). 1H NMR showed that the product was about 85% pure and any attempts to purify it further by column chromatography were not successful. It was used in the next reaction as described below without further purification.