Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:25])=[C:13]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:14]=2)=[CH:4][CH:3]=1.[N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]=[S:28]>CS(C)=O.O>[CH3:23][N:22]1[C:18]([C:16]([NH:15][C:13]2[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=2[F:25])[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:29](=[O:30])[O:31][CH2:32][CH3:33])=[S:28])=[N:7][CH:6]=2)=[O:17])=[CH:19][C:20]([CH3:24])=[N:21]1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc(N)nc3)ccc2F)n(C)n1
Reactant: CCOC(=O)N=C=S
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(F)c(NC(=O)c3cc(C)nn3C)c2)cn1
Reaction time: 15 h
Yield: 97.8 %

Procedure:
To a solution of N-{5-[(6-aminopyridin-3-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (860 mg, 2.51 mmol) in DMSO (5 mL) was added ethyl isothiocyanatoformate (428 mg, 3.27 mmol), and the mixture was stirred for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (1.16 g, 98%) as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:11][C:10](=[O:12])[CH2:9][CH2:8][CH:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH3:19]
Reactant: CC(CCC(=O)O)CCC(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCC(C)CCC(=O)O

Procedure:
145 g of crude 4-methylpimelic acid, 68 ml of absolute ethanol and 12 ml of concentrated sulfuric acid were refluxed for 5 hours. The mixture was poured into ice and extracted several times. The combined ether solutions were extracted with saturated NaHCO3 until the development of CO2 was finished. The aqueous extracts were covered with a layer of ether and adjusted while stirring to pH 2 to 3 with diluted sulfuric acid. The ether layer was separated and the aqueous phase was saturated with (NH4)2SO4 and extracted three times with ether.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO.C([O:8][C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][C:17]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:13][N:12]=1)=O)C>C(O)C>[CH2:1]([NH:3][C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][C:17]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:13][N:12]=1)=[O:8])[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Solvent: CO
Solvent: CCO
Product: CCNC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of ethylamine in methanol solution (2.0M; 40 mL; 80 mmol) was added to a stirred suspension of 5-(2,4-bis-benzyloxy-5-chlorophenyl)-isoxazole-3-carboxylic acid ethyl ester (4.40 g; 9.51 mmol) in absolute ethanol (50 ml). The reaction mixture was heated to 80° C. (oil-bath temperature) for five hours. The reaction mixture was allowed to cool to ambient temperature and left to stand overnight. A colourless solid product formed and the reaction mixture was further cooled in an ice-water bath, filtered and washed with cold ethanol (2×20 ml). The colourless product was dried in vacuo to afford 5-(2,4-bis-benzyloxy-5-chlorophenyl)-isoxazole-3-carboxylic acid ethylamide 3.42 g (78%) LCMS: [M+H]+ 465, 463 (37Cl; 35Cl). 1H NMR (400 MHz, CDCl3) δ 1.25 (t, 3H), 3.48 (m, 2H), 5.10 (s, 2H), 5.2 (s, 2H), 6.59 (s, 1H), 6.83 (bit, 1H), 7.08 (s, 1H), 7.30-7.41 (m, 10H), 7.97 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=O)[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH:38]1([N:37]([CH3:36])[C:33]([CH:30]2[CH2:29][CH2:28][N:27]([C:24]3[N:23]=[CH:22][C:21]([C:17]4[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=4)[CH2:14][N:12]([CH3:13])[C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:26][N:25]=3)[CH2:32][CH2:31]2)=[O:35])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CNC1CCCCC1
Reactant: CN(Cc1cccc(-c2cnc(N3CCC(C(=O)O)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(Cc1cccc(-c2cnc(N3CCC(C(=O)N(C)C4CCCCC4)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
1-{5-[3-({[N-(tert-Butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperidine-4-carboxylic acid (200 mg) and N-methylcyclohexanamine (94 mg) were suspended in methylene chloride (4 ml), and WSC hydrochloride (159 mg) and HOBt (112 mg) were added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was subjected to liquid separation with CHCl3 and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and then the aqueous layer was extracted with CHCl3 again. These organic layers were combined and dried over Na2SO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 5% MeOH/CHCl3) to obtain tert-butyl (2-{[3-(2-{4-[cyclohexyl(methyl)carbamoyl]piperidin-1-yl}pyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (169 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][C:5]2([CH3:15])[CH3:14].[CH3:16][CH:17](O)[CH:18]=[CH2:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:16]([CH:6]1[C:5]([CH3:15])([CH3:14])[C:4]2[C:8](=[CH:9][C:10]([O:11][CH3:12])=[C:2]([Cl:1])[CH:3]=2)[C:7]1=[O:13])[CH:17]=[CH:18][CH3:19]
Reactant: C=CC(C)O
Reactant: COc1cc2c(cc1Cl)C(C)(C)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1C(=O)c2cc(OC)c(Cl)cc2C1(C)C
Yield: 66 %

Procedure:
A solution of 14.5 g of 5-chloro-6-methoxy-3,3-dimethyl-1-indanone, 13.3 ml of 3-buten-2-ol and 300 mg of p-toluenesulfonic acid in 150 ml of 2,2-dimethoxy-propane was boiled under reflux for 71 hours on a water separator filled with molecular sieve (0.4 nm 2 mm, pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 6:1). In addition to 2.25 g of educt, there were obtained 11.9 g (66%) of (RS)-2-(2-buten-1-yl)-5-chloro-6-methoxy-3,3-dimethyl-1-indanone as a pale yellow solid with m.p. 86°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]([O-])(O)=[O:12].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]=[C:11]=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: O=C([O-])O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(N=C=O)c1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To a solution of (S)-1-(4-bromophenyl)ethanamine (240 g, 1.2 mol) in methylene chloride (3 L) and satd aq NaHCO3 (3 L) solution was added triphosgene (118 g, 0.396 mol) at 0° C. The mixture was stirred for 15 min. The organic phase was separated, dried over Na2SO4 and concentrated to give 1-bromo-4-(1-isocyanato-ethyl)-benzene (170 g, 63%).
Reaction SMILES: O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH3:34])[CH2:29][C@@H:28]1[C:35]([OH:37])=O)=[O:26])([CH3:23])([CH3:22])[CH3:21].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>ClCCl>[CH2:33]([N:30]1[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:26])[C@@H:28]([C:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[O:37])[CH2:29]1)[CH3:34]
Reactant: C1CNCCN1
Reactant: CCN1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCN1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCNCC2)C1
Reaction time: 18 h
Yield: 50.4 %

Procedure:
4-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (253 mg, Acros chemicals) was added to a solution of (2R)-1-(tert-butoxycarbonyl)-4-ethylpiperazine-2-carboxylic acid (212 mg) in dry dichloromethane (6 ml) followed by addition on N-methyl morpholine (0.28 ml) and stirring under argon for 1 h. piperazine (234 mg) was then added and stirring was continued for 18 h. Dichloromethane (30 ml) was added and extracted with 1M NaOH (2×10 mL). The organic layer was dried (MgSO4), filtered and evaporated. Purification by chromatography (5-50% MeOH:DCM) afforded the title compound (135 mg) as a foam.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:15][C@@H:16]1[CH2:44][O:43][C@@:19]2([O:23][C@H:22]3[CH2:24][C@H:25]4[C@@H:30]5[CH2:31][CH2:32][C@@H:33]6[CH2:38][C@H:37]([OH:39])[CH2:36][CH2:35][C@:34]6([CH3:40])[C@H:29]5[CH2:28][CH2:27][C@:26]4([CH3:41])[C@H:21]3[C@@H:20]2[CH3:42])[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:64](O)(=[O:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>C1COCC1>[CH3:15][CH:16]1[CH2:44][O:43][C:19]2([O:23][CH:22]3[CH2:24][CH:25]4[CH:30]5[CH2:31][CH2:32][CH:33]6[CH2:38][CH:37]([O:39][C:64]([C:65]7[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=7)=[O:71])[CH2:36][CH2:35][C:34]6([CH3:40])[CH:29]5[CH2:28][CH2:27][C:26]4([CH3:41])[CH:21]3[CH:20]2[CH3:42])[CH2:18][CH2:17]1
Reactant: C[C@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Reactant: O=C(O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1CCC2(OC1)OC1CC3C4CCC5CC(OC(=O)c6ccccc6)CCC5(C)C4CCC3(C)C1C2C
Temperature: 25 °C

Procedure:
A solution of diisopropylazodicarboxylate (0.81 g, 4.0 mmol) in dry THF (2 ml) was added to a stirred solution of episarsasapogenin (0.83 g, 2.0 mmol), triphenylphosphine (1.05 g, 4.0 mmol) and benzoic acid (0.49 g, 4.0 mmol) in dry THF (20 ml). The mixture was stirred at room temperature and monitored by TLC. After 2 h all the starting material had been consumed. The solvent was removed in vacuo, the residual syrup dissolved in ether (30 ml) and the solution washed with aqueous saturated sodium hydrogen carbonate (25 ml). The organic layer was dried over MgSO4 and passed down a short silica pad, the pad being washed with ether. The combined washings and filtrate were concentrated in vacuo to afford sarsasapogenin benzoate as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CNc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCCCC(=O)O
Product: CN(C(=O)CCCCCCNC(=O)OC(C)(C)C)c1ccccc1

Procedure:
Prepare by a method similar to Example 70 using 7-(t-butoxycarbonyl)amino-heptanoic acid and N-methylaniline.
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][C:19]=2[O:30][CH3:31])=[N:15][N:14]=1.Cl.[CH3:33][NH:34][CH3:35].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:31][O:30][C:19]1[CH:20]=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:22]=[CH:23][C:18]=1[C:16]1[O:17][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[N:34]([CH3:35])[CH3:33])=[N:14][N:15]=1
Reactant: CNC
Reactant: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2Cl)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2N(C)C)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To a suspension of 4-{4-[5-(5-chloro-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2yl]-3-methoxy-phenyl}-morpholine (100 mg, 0.23 mmol) in DMSO (1 mL) was added dimethylamine hydrochloride (93 mg, 1.14 mmol) and potassium carbonate (158 mg, 1.14 mmol). The reaction mixture was stirred for 2 h at ambient temperature. It was diluted with water (5 mL) and the resulting suspension was stirred for 15 min at this temperature. Filtration and washing with water (5 mL) and tert-butylmethylether (5 mL) afforded the title compound (80 mg, 78%) which was obtained as an off-white solid. MS: m/e=448.2 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH:13]1[CH2:15][O:14]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:26][CH2:25]1
Reactant: c1ccc2cc(OCC3CO3)ccc2c1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(O)COc2ccc3ccccc3c2)CC1
Yield: 99.9 %

Procedure:
To a solution of 2-((2-naphthyloxy)methyl)oxirane (75 mg, 0.38 mmol) in ethanol (0.75 mL) was added 4-(2-methoxyphenyl)piperazine (79 uL, 0.45 mmol) at room temperature. The mixture was stirred under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give HUHS1005 (149 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:31]=[CH:30][C:19]([CH2:20][CH:21]([C:26]([O:28]C)=O)[C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1.[CH3:32][NH2:33]>CO.O1CCCC1>[CH3:32][NH:33][C:26]([CH:21]([CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:31][CH:30]=1)[C:22]([O:24][CH3:25])=[O:23])=[O:28]
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Dimethyl 2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]malonate (3.00 g, 7.08 mmol) synthesized according to the method described in WO95/18125 was dissolved in methanol-tetrahydrofuran (1:1, 100 ml), and 40% aqueous methylamine solution (50 ml) was added. The mixture was stirred at room temperature for 0.5 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=1:2) to give the title compound (1.50 g, yield 50%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.CN([CH:17]=[O:18])C>C1COCC1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:17]=[O:18])[N:3]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(Br)n1
Reaction time: 0.75 h
Yield: 28.7 %

Procedure:
To a solution of 5.0 g (21.2 mmol) of 2,6-dibromopyridine in THF at −78° C. was added 9.2 mL (21 mmol) of 2.3 M solution of n-BuLi in hexanes, followed by 2.3 mL (30 mmol) of DMF. The mixture was stirred for 45 min in the cold, quenched with saturated NaHCO3, extracted with ethyl acetate and the product purified by column chromatography (3% ethyl acetate in hexanes) to furnish 1.13 g of 2-bromo-6-formylpyridine.
Reaction SMILES: O.[OH-].[Li+].[C:4]1([C@H:10]2[O:16][C@H:11]2[C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.CO>[C:4]1([C@H:10]2[O:16][C@H:11]2[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H]1O[C@@H]1c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1O[C@@H]1c1ccccc1
Reaction time: 1 h
Yield: 80.5 %

Procedure:
Under ice cooling, a solution of 0.504 g of lithium hydroxide monohydrate dissolved in 25 ml of water was added dropwise to a solution of 1.78 g of methyl (2R,3R)-3-phenyl-2,3-epoxypropionate dissolved in 50 ml of methanol. The mixture was allowed to room temperature and stirred for 1 hour at the same temperature. Methanol was removed from the reaction mixture, and the pH of the residue was adjusted to 3 to 4 by adding a 5% aqueous citric acid solution thereto under ice cooling, and then extracted with chloroform. The chloroform layer was washed with brine and then dried over magnesium sulfate. The solvent was removed under reduced pressure, and hexane was added to the residue. Crystals precipitated were collected by filtration, washed with hexane and then dried to obtain 1.32 g of (2R,3R)-3-phenyl-2,3-epoxypropionic acid. Yield: 80%
Reaction SMILES: Cl[C:2]1[O:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[CH2:22][O:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:8])[N:6]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[O:33]1[CH2:34][CH2:35][N:30]([C:2]2[O:3][CH:4]=[C:5]([C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]3[CH2:22][O:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:8])[N:6]=2)[CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(Cl)n2)C(COc2cccnc2)C1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(N3CCOCC3)n2)C(COc2cccnc2)C1
Temperature: 25 °C
Yield: 125.8 %

Procedure:
A solution of tert-butyl 4-(2-chlorooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (117 mg, 0.277 mmol), morpholine (48 mg, 0.554 mmol) and potassium carbonate (76 mg, 0.554 mmol) in THF (2 mL) was heated to 70° C. overnight. Upon cooling to rt, the reaction mixture was filtered and concentrated under reduced pressure. The material was purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient), yielding 165 mg (1000%) of the title compound as the TFA salt. LC-MS: RT=6.60 min, [M+H]+=474.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:15][CH2:14][C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[C:7](=[O:16])[C:6]=2[CH:17]=1.[BH4-].[Na+].O>C(O)C>[OH:16][CH:7]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:14][CH2:15][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:17][C:6]1=2
Reactant: Cc1ccc2c(c1)C(=O)c1cccnc1CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)C(O)c1cccnc1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
4.46 g of 7-methyl-10,11-dihydro-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-5-one was dissolved in 22 ml of ethanol. To the solution was added 0.39 g of sodium borohydride with water-cooling. The resulting mixture was stirred for 1 hour at room temperature. To the reaction mixture was added 44 ml of water. The resulting crystals were collected by filtration and dried to obtain 4.19 g of 5-hydroxy-7-methyl-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine. They were recrystallized from ethanol to obtain 3.90 g of colorless crystals having a melting point of 202°-203° C.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH2:19][CH2:18]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5](O)=[O:6].[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:31]1([N:30]2[CH:2]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][N:17]4[CH2:18][CH2:19][N:20]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=5)[CH2:21][CH2:22]4)=[CH:10][CH:9]=3)[CH2:3][CH2:4][C:5]2=[O:6])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccccc1
Reactant: Cc1cccc(N2CCN(CCCc3ccc(C(=O)CCC(=O)O)cc3)CC2)c1
Product: Cc1cccc(N2CCN(CCCc3ccc(C4CCC(=O)N4c4ccccc4)cc3)CC2)c1

Procedure:
4-Oxo-4-[4-(3-(4-(3-methylphenyl)piperazin-1-yl)propyl)phenyl]butyric acid and aniline are reacted together to give N-phenyl-5-[4-(3-(4-(3-methylphenyl)piperazin-1-yl)propyl)phenyl]pyrrolidin-2-one.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([S:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[Cl:24])[CH:20]=[N:19][CH:18]=[CH:17]3)[CH2:9]1)=O)(C)(C)C>ClCCl.Cl.C(O)(C)C>[ClH:24].[Cl:24][C:23]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][N:19]=[CH:20]2)=[CH:15][C:14]=1[S:13][C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Sc2cc3ccncc3cc2Cl)C1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: Clc1cc2cnccc2cc1S[C@H]1CCNC1
Yield: 215.5 %

Procedure:
4.5 g (6.1 mmol) (S)-3-(7-Chloro-isoquinolin-6-ylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 15 ml dichloromethane and 7.5 ml 6N HCl in isopropanol were stirred over night. After evaporation water was added and lyophilized. 1.98 g of 7-Chloro-6-((S)-pyrrolidin-3-ylsulfanyl)-isoquinoline hydrochloride were obtained. Rt=0.76 min (Method B). Detected mass: 264.1/266.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([O:10][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COCCOCCl
Reactant: CC(C)(C)c1cc(Br)cc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCOc1c(C=O)cc(Br)cc1C(C)(C)C
Temperature: 20 °C
Yield: 106.7 %

Procedure:
A mixture of 5-bromo-3-(tert-butyl)-2-hydroxybenzaldehyde (4.74 g, 18.42 mmol) and anhydrous potassium carbonate (2.83 g, 20.45 mmol) in anhydrous DMF (20.0 mL) was stirred under nitrogen in a water bath (20° C.) to give an orange-yellow suspension. After stirring for 20 min, 2-methoxyethoxymethyl chloride (2.40 mL, 21.19 mmol, technical grade) was added drop wise (20 min) to above suspension while maintaining an internal temperature of 20° C. The reaction mixture was stirred at room temperature for 3 h to give a canary yellow suspension. The reaction mixture was poured into ice-water (150 mL) and stirred at room temperature to give a yellow oily liquid, no solid formation was observed. After 30 min of stirring, the reaction mixture was extracted with dichloromethane (2×75 mL). The organic layer was removed, washed with water (1×50 mL) and dried over anhydrous magnesium sulfate, filtered and evaporated in-vacuo to give a pale yellow viscous liquid (6.7832 g). No purification was necessary and the crude product (purity >97%) was used directly in the next Step #3.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:25]=[CH:24][C:12]2[N:13]=[C:14]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[O:15][C:11]=2[CH:10]=1.[H][H].Cl>[Ni].N>[NH2:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([C:14]2[O:15][C:11]3[CH:10]=[C:9]([C:3]4[CH:2]([CH3:1])[CH2:7][C:6](=[O:8])[NH:5][N:4]=4)[CH:25]=[CH:24][C:12]=3[N:13]=2)=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(C#N)cc3)oc2c1
Agent: [Ni]
Agent: Cl
Agent: N
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(CN)cc3)oc2c1

Procedure:
100 mg (303 μmol) 4-[6-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-benzoxazol-2-yl]-benzonitrile, 10 mg Raney nickel and 20 ml of methanolic ammonia are hydrogenated at RT and 3.45 bar hydrogen pressure for 4 h. Then the mixture is neutralised with conc. hydrochloric acid and the solv. is eliminated from the reaction mixture by rotary evaporation in vacuo. The residue is purified by RP-HPLC.