Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].Br[CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].CCN(C(C)C)C(C)C>C(#N)C>[CH2:47]([O:46][C:44]([CH2:43][CH2:42][CH2:41][NH:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33])=[O:45])[CH3:48]
Reactant: CCOC(=O)CCCBr
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN[C@@H](Cn1c(=O)c(-c2cccc(OC)c2F)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 95 °C
Yield: 49.5 %

Procedure:
To compound 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 1f (5 g, 9.4 mmol) in 100 mL of acetonitrile were added ethyl 4-bromobutyrate (4 mL, 28.2 mmol) and Hunig's base (1.6 mL, 9.4 mmol). After reflux at 95° C. overnight, the reaction mixture was cooled to ambient temperature and the volatiles were removed. The residue was chromatographed with 10:10:1 EtOAc/Hexane/Et3N to give 1g as a yellow oil (3.0 g, 4.65 mmol). MS (CI) m/z 646.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.Cl[C:22]1[CH:23]=[C:24]([S:32](Cl)(=[O:34])=[O:33])[CH:25]=[CH:26][C:27]=1[C:28]([F:31])([F:30])[F:29].O.[ClH:37]>N1C=CC=CC=1>[Cl:37][C:25]1[CH:26]=[C:27]([C:28]([F:31])([F:30])[F:29])[CH:22]=[CH:23][C:24]=1[S:32]([NH:20][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:6]([Cl:19])[CH:5]=1)(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)c(Cl)c1
Reactant: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Reactant: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl
Yield: 65 %

Procedure:
A solution of 3,5-dichloro-4-(6-chlorobenzothiazol-2-yloxy)-phenylamine (102) (2.0 g, 5.79 mmol) and 3-chloro-4-trifluoromethylbenzenesulfonylchloride (1.7 g, 6.08 mmol) in pyridine (10 mL) was stirred at room temperature. After 3 h water was added to the reaction mixture, which was then acidify by 2N HCl. Reaction mixture was extracted twice with AcOEt. Organic layer was washed by brine, dried over MgSO4 and concentrated. Crude residue was purified by column chromatography (H/A=4/1, 80 g of silica gel) to afford title compound 103 (2.11 g, 65%) as a white solid. mp 82-84′ 1H NMR (400 MHz, DMSO-d6) δ 7.32 (2H, s), 7.46 (1H, dd, J=2.2, 8.7 Hz), 7.67 (1H, d, J=8.7 Hz), 8.00 (1H, d, 8.0 Hz), 8.14 (1H, d, J=2.2 Hz), 8.20 (1H, s), 8.38 (1H, d, J=8.3 Hz), 11.6 (1H, br s). MS (M+H) 586
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH2:51][CH2:52][CH2:53][C:54]1[N:55]([CH3:59])[CH:56]=[CH:57][CH:58]=1>C(OCC)(=O)C.CN(C)C=O>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)([CH3:29])[C:26]([NH:51][CH2:52][CH2:53][C:54]2[N:55]([CH3:59])[CH:56]=[CH:57][CH:58]=2)=[O:27])=[CH:18]1
Reactant: Cn1cccc1CCN
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cccc1CCNC(=O)C(C)(Cc1c[nH]c2ccccc12)NC(=O)OC1C2CC3CC(C2)CC1C3
Reaction time: 2 h

Procedure:
To a solution of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan (0.401 g, 1.01 mmol) in dry ethyl acetate (4 mL) and N,N-dimethylformamide (4 mL) under nitrogen atmosphere was added 1-hydroxybenzotriazole (0.139 g, 1.03 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.199 g, 1.04 mmol). This mixture was stirred 2 hours and 0.16 g (1.3 mmole) of 2-(2-aminoethyl)-1-methylpyrrole was added. After stirring an additional 18 hours, the resulting mixture was diluted with ethyl acetate (20 mL), and washed with aqueous 1N citric acid, saturated aqueous sodium bicarbonate, and brine solutions. The organic phase was dried over MgSO4 and purified by flash chromatography (SiO2, 4×20 cm, 230-400 mesh, 67% ethyl acetate/hexane eluant). Concentration followed by drying under vacuum for 48 hours at 60° C. provided 0.301 g (59%) at product; 1H NMR (CDCl3) δ1.49-1.60 (2H, m), 1.56 (3H, s), 1.70-2.00 (12H, m), 2.61 (2H, t, J 7 Hz), 3.23-3.55 (4H, m), 3.50 (3H, s), 4.82 (1H, br s), 5.20 (1H, br s), 5.76 (1H, br s), 6.00 (1H, t, J 3 Hz), 6.34 (1H, br s), 6.53 (1H, br s), 6.97 (1H, br s), 7.09-7.19 (2H, m), 7.36 (1H, d, J 8 Hz), 7.59 (1H, d, J 8 Hz), 8.16 (1H, br s).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27]1([CH:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)C(Cl)=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[NH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][N:13]=[C:11]2[CH2:10][C@@H:9]([C:24]([N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[O:26])[N:8]([C:6](=[O:7])[CH:33]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:12]2)=[CH:21][CH:20]=1
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: C1CCNCC1
Product: COc1ccc(CON=C2C[C@@H](C(=O)N3CCCCC3)N(C(=O)C(c3ccccc3)c3ccccc3)C2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and piperidine the title compound was obtained in 87% purity by LC/MS. MS(ESI+): m/z=526.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[N:18][NH:19][CH:20]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:31]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=4)=[N:18][N:19]([CH3:31])[CH:20]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CO
Reactant: COc1cccc(Nc2nccc(-c3c[nH]nc3-c3ccc(C(F)(F)F)cc3)n2)c1
Product: COc1cccc(Nc2nccc(-c3cn(C)nc3-c3ccc(C(F)(F)F)cc3)n2)c1

Procedure:
The title compound is prepared as described in Example 55 starting from (3-methoxy-phenyl)-{4-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-amine (Example 87) and using methanol instead.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[H-].[Na+].[Br:24][CH2:25][CH2:26][C:27]([CH3:32])([CH3:31])[CH2:28][CH2:29]Br.[Cl-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:29][CH2:28][C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][Br:24])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Reactant: CC(C)(CCBr)CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCC(C)(C)CCBr
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of 24 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in 480 ml. of dimethylformamide is treated under argon at -10° C. with 0.16 mol. of sodium hydride (7.0 g. of a 55% dispersion in mineral oil) and then stirred in an ice-bath for 15 minutes. To this, 62 g. of 1,5-dibromo-3,3-dimethylpentane are added in one batch at -5° C., the mixture is then stirred for 1 hour at room temperature and subsequently heated for 18 hours at 60° C. After cooling, the mixture is poured into 4 liters of ice-water, 200 g. of sodium chloride are added, and the separated product is immediately extracted with methylene chloride. The organic phase, shielded from daylight, is washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated to dryness under reduced pressure. The resulting oily residue is chromatographed on 1000 g. of silica gel with methylene chloride as the eluant, care being taken that the eluate is shielded from daylight. The homogeneous fractions are combined, evaporated, and the solid residue recrystallized from ethanol, and there is obtained 2-(5-bromo-3,3-dimethylpentyl)-5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester having a melting point of 87°-88° C.
Reaction SMILES: [C:1]1([CH:7]([NH2:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][NH2:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=CCCC(O)=O>[Ru].C>[CH:1]1([CH:7]([NH2:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH3:19])([CH3:20])[CH2:17][NH2:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(CN)CCCCCCCCC(N)c1ccccc1
Agent: [Ru]
Agent: C=CCCC(=O)O
Product: CC(C)(CN)CCCCCCCCC(N)C1CCCCC1

Procedure:
Hydrogenation of 1-phenyl-10,10-dimethyl-1,11-diaminoundecane in the presence of a ruthenium/charcoal catalyst; b.p. 147° C./4 Pa; nD20 =1.4805.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@H:9]([OH:12])[CH:10]=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[C:18]([Si:22]([CH3:24])([CH3:23])[O:12][C@@H:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:10]=[CH2:11])([CH3:21])([CH3:20])[CH3:19]
Reactant: C=C[C@@H](O)CCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=C[C@H](CCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
A stirred solution of allylic alcohol 66 (3.00 g, 18.5 mmol) in CH2Cl2 (53 ml) was cooled to 0° C. Imidazole (2.27 g, 33.3 mmol) was added in one portion followed by t-butylchlorodimethylsilane (3.34 g, 22.2 mmol). The cooling bath was removed and the reaction mixture stirred at r.t. for 16 h before being poured into 10% aq. HCl (100 ml). The mixture was extracted with 40/60 petroleum ether (2×100 ml). The combined organics were washed with saturated NaCl solution (100 ml), dried (MgSO4), filtered, and concentrated to give the crude material. This was purified by column chromatography, eluting with 40/60 petroleum ether, to give the protected alcohol 67 (4.68 g, 92%) as a colourless liquid. The 1H NMR data and optical rotation matched that reported in the literature (Uenishi, J. i. et al., Organic Letters 2011, 13, 2350).
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.C([Li])CCC.[CH3:30][C:31]([CH3:33])=[O:32]>C1COCC1>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([C:31]([OH:32])([CH3:33])[CH3:30])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C(C)(C)O)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butyllithium at −78° C. After stirring at −78° C. for 10 min, acetone was added and the resulting mixture was stirred at −78° C. for 30 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 7.17(s,2H), 6.08(s,1H), 3.73(d,1H), 3.33(m,1H), 2.19(s,3H), 2.15(s,3H), 2.12(s,6H), 1.4–1.7(m,4H), 1.26(s,6H), 0.96(t,6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][NH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21].[CH3:22]I.[H-].[Na+]>CN(C=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:13]1[N:12]=[CH:11][N:10]([CH3:22])[C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccc(-c2nc[nH]c2-c2ccc(Cl)cc2Cl)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4,5-di-(2,4-dichlorophenyl)imidazole (230 mg, 0.65 mmol) from Step B and methyl iodide (0.062 mL, 1.0 mmol) in DMF (5 mL) was added sodium hydride (60% in mineral oil, 52 mg, 1.3 mmol). The reaction was stirred at rt for 3 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by flash chromatography (50% ethyl acetate in hexanes) to afford the title compound. HPLC/MS: 371 (M+1), 373 (100%, M+3), 375 (M+5); Rt=2.85 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:19][C:18]3[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2c(Cl)ccnc12
Reactant: COc1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cccc3c(Cl)ccnc23)cc1
Temperature: 80 °C
Yield: 88.9 %

Procedure:
A mixture of compound 22 (3.20 g, 17.82 mmol), p-methoxybenzyl chloride (8.37 g, 53.45 mmol), K2OC3 (7.38 g, 53.45 mmol), and n-Bu4NI (1.65 g, 4.45 mmol) in anhydrous DMF (20 mL) was heated at 80° C. for 10 hours. The reaction mixture was extracted with ethyl acetate (3×100 mL), washed with water, dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel column chromatography (Hexane/EtOAc, 3:2) to give 4.75 g (89%) of 23 as yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.81 (s, 3H), 5.38 (s, 2H), 6.78-6.98 (m, 2H), 7.13 (d, 1H, J=7.6 Hz), 7.34-7.60 (m, 4H), 7.80 (d, 1H, J=8.8 Hz), 8.76-8.88 (m, 1H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:21][CH2:20][C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[NH:17][C:16]2=[O:26])[CH2:11][CH2:10]1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:23]1[CH:24]=[CH:25][C:18]2[NH:17][C:16](=[O:26])[N:15]([CH:12]3[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)[CH2:21][CH2:20][C:19]=2[CH:22]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1Nc2ccc(Cl)cc2CCN1C1CCNCC1

Procedure:
801 mg (6.00 mmol) N-chlorosuccinimide were added to 1.23 g (5.00 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one in 10.0 mL carbon tetrachloride and the mixture was refluxed for 72 h. The solvent was eliminated i. vac. and the crude product was purified by flash chromatography. The fractions containing the product were concentrated by rotary evaporation and purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[S:19][C:5]2[NH:6][C:7](=S)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[C:20]([NH:24][NH2:25])(=O)[CH2:21][OH:22]>C(O)CCC>[Cl:1][C:2]1[S:19][C:5]2[N:6]3[C:20]([CH2:21][OH:22])=[N:24][N:25]=[C:7]3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)sc2N1
Reactant: NNC(=O)CO
Solvent: CCCCO
Product: OCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
1.1 g of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione are refluxed for 8 hours with 1.5 g of glycolic acid hydrazide in absolute butanol. The solvent is then distilled off and the residue recrystallized from ethyl acetate containing active carbon to yield 2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine-9-methanol, melting point 219°-221° C.
Reaction SMILES: O1CCCC1.[NH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(N(CC)CC)C>[OH:9][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][NH:6][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: NCC(O)c1ccccc1
Reactant: O=C(CCCc1ccccc1)OCCCCCCCCCCCCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCc1ccccc1)OCCCCCCCCCCCCNCC(O)c1ccccc1

Procedure:
According to method I (tetrahydrofuran, reflux 4 days) from 2-amino-1-phenylethanol and (12-bromo-1-dodecyl)4-phenylbutanoate. Working up by means of chromatography (ethyl acetate/petroleum ether 60-80/triethylamine 6:4:1). Recrystallized from diethyl ether. Melting point: 73°-74° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([CH:13]3[CH2:18][CH2:17][N:16]([C:19](OCC4C=CC=CC=4)=O)[CH2:15][CH2:14]3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[CH:29](=O)[CH2:30][CH2:31][CH2:32]C.[H][H]>CO.[Pd]>[CH2:19]([N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[O:11][C:12]3[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=[CH:7][C:8]=3[N:9]=2)[CH2:18][CH2:17]1)[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCC=O
Reactant: NC(=O)c1cccc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCCN1CCC(c2nc3cccc(C(N)=O)c3o2)CC1
Yield: 12.7 %

Procedure:
A mixture of compound benzyl 4-(7-carbamoylbenzo[d]oxazol-2-yl)piperidine-1-carboxylate (400 mg, 1.1 mmol), Pd/C (10% wt, 40 mg), pentanal (114 mg, 1.6 mmol) in anhydrous methanol (15 mL) was purged with hydrogen at room temperature for 12 hr. The mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was purified by pre-HPLC to give the compound 2-(1-pentylpiperidin-4-yl)benzo[d]oxazol-7-carboxamide (44 mg, yield 14%). 1H-NMR (400 MHz, CDCl3) δ (ppm): 0.91-0.97 (m, 3H), 1.25-1.37 (m, 4H), 1.50-1.57 (m, 2H), 2.03-2.21 (m, 6H), 2.36-2.40 (m, 2H), 3.00-3.06 (m, 3H), 6.11 (s, 1H); 6.99 (s, 1H), 7.85-7.87 (t, 1H), 7.87-8.06 (m, 1H), 8.08 (dd, 1H); LC-MS (ESI) m/z: 316 (M+1)+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH3:17])=[C:10]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:9]=2)[C:6]2[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=2[N:4]=1)[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[C:41]([O:45][C:46]([N:48]1[CH2:51][C:50](=[O:52])[CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>C1COCC1>[C:41]([O:45][C:46]([N:48]1[CH2:51][C:50]([C:13]2[N:14]([CH3:17])[C:15]3[C:11]([N:12]=2)=[C:10]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:9]=[C:8]([N:7]2[C:6]4[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=4[N:4]=[C:3]2[CH2:1][CH3:2])[N:16]=3)([OH:52])[CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2ncn(C)c2n1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Temperature: -40 °C
Yield: 65.3 %

Procedure:
To a mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (2.5 g, 6.88 mmol) and TMEDA (1.6 mL, 10.33 mmol) in THF (40 mL) at −78° C. was added n-BuLi (4.1 mL, 2.5 M in hexanes, 10.33 mmol). The resulting mixture was allowed to warm to −40° C. over 30 min then cooled back to −78° C. before the addition of a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (1.8 g, 10.33 mmol) in THF (10 mL). The reaction mixture was warmed to −10° C. over 2 h then quenched with sat, aq. NH4Cl and extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%) then recrystallised from iPrOAc and pentane affording 3-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester as a cream solid (2.4 g, 64%). LCMS (method A): RT 2.83 min [M+H]+ 535.4
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=O)[CH:6]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH2:33])([CH3:32])[CH3:31])=[CH:25][CH:24]=1.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO.C(O)(=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:33][C:30]([CH3:32])([CH3:31])[CH2:29][C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Reactant: CC(C)(N)Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CNC(C)(C)Cc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
[3-(4-Bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester (0.150 g, 0.43 mmol), 1-(4-fluorophenyl)-2-methyl-2-propylamine (0.079 g, 0.47 mmol), and sodium cyanoborohydride (0.041 g, 0.65 mmol) were combined in MeOH (2 mL). Acetic acid (2 drops) was added, and the reaction was stirred for 5 hours at room temperature. The mixture was worked-up with EtOAc and saturated aqueous NaHCO3, and the organic layer was dried and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:16][CH3:17])=[N:4][C:5]([CH:11]=[CH:12]N(C)C)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.Cl.C(=O)([O-])[OH:20].[Na+].[BH4-].[Na+]>COCCOC.O>[Cl:1][C:2]1[C:3]([S:16][CH3:17])=[N:4][C:5]([CH2:11][CH2:12][OH:20])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=C([O-])O
Reactant: CSc1nc(C=CN(C)C)c([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1nc(CCO)c([N+](=O)[O-])cc1Cl
Reaction time: 0.5 h
Yield: 44 %

Procedure:
3-Chloro-6-[2-(dimethylamino)ethenyl]-2-methylthio-5-nitropyridine (D10) (1.05 g, 3.84 mmol) was dissolved in DME (40 ml) and treated with 2.5M hydrochloric acid (8 ml). After 15h, the reaction mixture was treated with solid sodium hydrogen carbonate until pH7 was reached. Water (20 ml) was then added and the resultant mixture was cooled to 0° C. Sodium borohydride (0.581 g, 15.36 mmol) was added portionwise over 2-3 minutes with stirring. After 0.5 h, water (200 ml) was added, and the reaction mixture was extracted with ethyl acetate (3×100 ml). The combined organic extracts were then dried (Na2SO4) and evaporated under reduced pressure to give a red/brown solid, which was purified by silica gel chromatography (3:1 petrol: EtOAc as eluant) to give the title compound as an orange solid (0.420 g, 44%).