Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5](C(O)=O)[CH2:4]1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[NH2:29][C:30]1[C:31]([OH:41])=[C:32]([S:37]([NH2:40])(=[O:39])=[O:38])[C:33]([Cl:36])=[CH:34][CH:35]=1.C[N:43]([CH:45]=[O:46])C>>[Cl:36][C:33]1[C:32]([S:37]([NH2:40])(=[O:39])=[O:38])=[C:31]([OH:41])[C:30]([NH:29][C:45]([NH:43][CH:5]2[CH2:6][CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4]2)=[O:46])=[CH:35][CH:34]=1
Reactant: CN(C)C=O
Reactant: COC1CCCC(C(=O)O)C1
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: COC1CCCC(NC(=O)Nc2ccc(Cl)c(S(N)(=O)=O)c2O)C1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of 3-Methoxy-cyclohexanecarboxylic acid (0.143 mL) in DMF (0.5 mL) was added DPPA (0.25 mL ) and TEA (0.25 mL) and the reaction heated at 70° C. After 18 hrs, 3-Amino-6-chloro-2-hydroxy-benzenesulfonamide (0.222 g) was added and the reaction heated at 70° C. After 18 hrs, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were dried over anhydrous magnesium sulfate, and concentraed under reduced pressure. The crude residue was purified via HPLC to give 3 mg of 6-Chloro-2-hydroxy-3-[3-(3-methoxy-cyclohexyl)-ureido]-benzenesulfonamide. LC-MS (m/z) 378 (M+).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.[CH3:34][O:35][C:36]1[C:41](B(O)O)=[CH:40][CH:39]=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:41]2[C:36]([O:35][CH3:34])=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:3]=1
Reactant: COc1ncccc1B(O)O
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ncccc1-c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 90 °C
Yield: 72.6 %

Procedure:
Intermediate 174, N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.350 g, 0.62 mmol) in a mixture of acetonitrile (12 ml) and water (12 ml) was treated with 2-methoxypyridin-3-ylboronic acid (0.190 g, 1.24 mmol), sodium carbonate (0.20 g, 1.88 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.15 g). The reaction mixture was degassed, flushed with argon and heated at 90° C. for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.245 g (72% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.63 (6H, s, 2×CH3), 3.89 (3H, s, OCH3), 4.04 (4H, m, 2×CH2), 4.37 (2H, broad, NCH2), 5.26 (2H, s, OCH2), 6.93 (1H,dd, J=2.5 Hz and J=9 Hz, aromatic), 7.0 (1H,dd, J=5 Hz and J=7 Hz, aromatic), 7.06 (1H, m, aromatic), 7.3–7.5 (8H, m, aromatics and NH), 8.24 (1H, m, aromatic). HRMS (ESI+) calculated for C30H30FN4O5 [M+H+]: 545.2200. found: 545.2184.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:22][NH2:23]>>[O:1]=[C:2]1[CH2:3][CH2:4][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:8]([NH:23][CH2:22][C:21]2[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=[C:19]([C:18]([F:17])([F:31])[F:32])[CH:20]=2)=[O:10])[CH2:6][CH2:7]1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCC(C(=O)O)(c2ccccc2)CC1
Product: O=C1CCC(C(=O)NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1

Procedure:
Prepared from 4-oxo-1-phenylcyclohexanecarboxylic acid (Description 2) and 3,5-bis(trifluoromethyl)benzylamine according to the method of Example 177. m/z (ES+) 444 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]3[C@H:19]4[C@H:29]([C:30](=[O:32])[CH2:31][C@:14]23[CH3:15])[C@:27]2([CH3:28])[C@H:22]([CH2:23][C:24](=[O:33])[CH2:25][CH2:26]2)[CH2:21][CH2:20]4)=[O:12])[CH2:3][CH2:2]1.C(N(CC)CC)C>C(O)(C)C.O.Cl.Cl.Cl[Ir](Cl)(Cl)Cl>[OH:33][C@@H:24]1[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@@H:22]([CH2:21][CH2:20][C@@H:19]3[C@@H:29]2[C:30](=[O:32])[CH2:31][C@@:14]2([CH3:15])[C@H:16]3[CH2:17][CH2:18][C@@H:13]2[C:11]([O:10][CH2:9][CH2:8][CH2:7][N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[O:12])[CH2:23]1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)OCCCN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Agent: Cl[Ir](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)OCCCN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A solution of 17β(3'-morpholinopropoxycarbonyl)-5α-androstan-3,11-dione (140 mg.) in isopropanol (1 ml.) was added to a "stock" solution of the chloroiridic acid reagent (7 ml.) which had been neutralised to ca. pH 6 with triethylamine immediately prior to the addition. After refluxing for 7 hr., isolation of the product afforded a gum (150 mg.) which, after purification by preparative t.l.c., gave the title compound as a white froth; 112 mg., [α]D + 51° (c, 0.6,).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([N:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(C=Nc2cccc(Cl)c2)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=Nc2cccc(Cl)c2)cc1
Yield: 59.7 %

Procedure:
(a) To 60 ml of absolute ethanol is added 0.58 g of sodium, and 4.6 g of 4-[N-(3-chlorophenyl)formimidoyl]phenol and then 5.84 g of ethyl 2-bromo-2-methylpropionate are added to the solution at room temperature with stirring. The mixture is refluxed under heating and with stirring for 5 hours. After distilling off the ethanol from the reaction mixture, the residue is dissolved in ether. The solution is washed with 5% aqueous solution of sodium hydroxide until disappearance of the color of the aqueous layer, then washed with water and dried. After drying, the solvent is distilled off to give 4.1 g of ethyl 2-[4-{N-(3-chlorophenyl)formimidoyl}phenoxy]-2-methylpropionate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Yield: 93.7 %

Procedure:
A mixture of 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (3.40 g, 11.0 mmol) and 10% Pd—C (400 mg, 0.376 mmol) in ethanol (100 ml) and ethyl acetate (100 ml) is agitated under 1 atmosphere pressure of hydrogen overnight. The mixture is filtered and concentrated to give of 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.87 g, 94% yield). MS(ESI) m/z 278 (M+H)+
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH:27]=O)[C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:29][C:30]1([CH3:46])[CH2:39][C@H:38]([NH2:40])[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:36]=2)[NH:31]1.C(Cl)Cl.COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Si:1]([O:8][C@H:9]([CH2:27][NH:40][C@@H:38]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:36]=2)[NH:31][C:30]([CH3:46])([CH3:29])[CH2:39]1)[C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(F)c1)[C@@H](C=O)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)Cc1ccc2c(c1)[C@@H](N)CC(C)(C)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: ClCCl
Product: CC(C)(C)Cc1ccc2c(c1)[C@@H](NC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1cccc(F)c1)NC(=O)OC(C)(C)C)CC(C)(C)N2
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)-4-oxobutan-2-ylcarbamate (0.148 g, 0.360 mmol) and (S)-2,2-dimethyl-6-neopentyl-1,2,3,4-tetrahydroquinolin-4-amine (0.0886 g, 0.360 mmol) in DCM (7.19 ml, 0.360 mmol) was added trimethoxymethane (0.394 ml, 3.60 mmol). The resulting solution was stirred for 1 hour at which time, sodium triacetoxyborohydride (0.229 g, 1.08 mmol) was added. The solution was then stirred for 30 minutes, quenched with saturated Rochelle's salt and stirred for an additional 20 minutes. The mixture was transferred to a sep. funnel containing DCM and H2O. The aqueous layer was washed 4× with DCM. The organic layers were combined, washed 1× with brine, dried with MgSO4, filtered and concentrated to afford the title compound. MS m/z: 642 (M+1).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].CN(C)[CH:16]=[CH:17][C:18](=O)[CH:19](OC)[O:20]C>C(O)C>[CH3:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[N:13]2)=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: COC(OC)C(=O)C=CN(C)C
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-n2nccc2C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)phenylhydrazine hydrochloride (0.75 g, 4.02 mmol, 1.00 equiv) in ethanol (20 mL) was added 4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (0.7 g, 4.0 mmol, 1.0 equiv). The resulting mixture was heated at reflux (48 hr) then concentrated. To a solution of the crude residue in acetone (10 mL) was added 6N HCl (2 mL). The resulting solution was allowed to stir at room temperature for 30 min, then was partitioned between ethyl acetate and water. The organic extract was washed with water, saturated sodium bicarbonate, brine and dried (sodium sulfate). Concentration afforded 2-(4-methanesulfonyl-phenyl)-2H-pyrazole-3-carbaldehyde admixed with regioisomer 1-(4-methanesulfonyl-phenyl)-1H-pyrazole-3-carbaldehyde (ca. 10/1). The crude material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][C:27]2[C:28](=[O:35])[N:29]=[C:30](SC)[NH:31][CH:32]=2)=[CH:22][N:21]=1>C(O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:30]3[NH:31][CH:32]=[C:27]([CH2:26][C:23]4[CH:22]=[N:21][C:20]([O:19][CH3:18])=[N:25][CH:24]=4)[C:28](=[O:35])[N:29]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: COc1ncc(Cc2c[nH]c(SC)nc2=O)cn1
Reactant: NCCc1ccc(Oc2ccc(F)cc2)cc1
Solvent: CCO
Product: COc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Temperature: 125 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
2-[4-(4-fluoro-phenoxy)-phenyl]ethylamine (0.216 mmol, 1 eq) and 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.108 mmol, 0.5 eq) were dissolved in dry ethanol (300 μL) and stirred at 125° C. for 16 hours. Solvent was evaporated and crude product was purified by Waters Mass Direct Autopurification system giving 2-{2-[4-(4-fluoro-phenoxy)phenyl]-ethylamino}-5-(2-methoxy-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (0.090 mmol; yield: 18%, HPLC-MS/UV: [M+H]=448.34; rt: 10.25 min; purity: 94%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.88 (t, J=7.17, 2H), 3.51 (s, 2H), 3.55-3.67 (m, 2H), 3.95 (s, 3H), 5.11 (br.s., 1H), 6.87-7.05 (m, 5H), 7.14-7.21 (m, 2H), 7.23-7.30 (m, 1H), 7.65 (s, 1H), 8.39 (s, 1H)
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[CH:20]=[C:19]2[C:9]([NH:10][CH:11]=[C:12]2[CH2:13][CH:14]([C:16]([OH:18])=[O:17])[NH2:15])=[CH:8][CH:7]=1.[CH3:21]O>>[ClH:3].[CH3:21][O:17][C:16](=[O:18])[CH:14]([CH2:13][C:12]1[C:19]2[C:9](=[CH:8][CH:7]=[C:6]([OH:5])[CH:20]=2)[NH:10][CH:11]=1)[NH2:15]
Reactant: O=S(Cl)Cl
Reactant: NC(Cc1c[nH]c2ccc(O)cc12)C(=O)O
Reactant: CO
Product: COC(=O)C(N)Cc1c[nH]c2ccc(O)cc12
Product: Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
Thionyl chloride (2.14 mL, 29.4 mmol) was added dropwise to a slurry of 5-hydroxy-DL-tryptophan (3.8 g, 17.3 mmol) in anhydrous methanol (40 mL) at 0° C. under a nitrogen blanket. The resulting mixture was warmed slowly to room temperature and stirred for 17 hours. Then the solvent was removed under reduced pressure to provide 5-hydroxy-DL-tryptophan methyl ester hydrochloride (Intermediate 1) as a light brown foam (5.0 g, 100%): 1H NMR (300 MHz, DMSO-d6): δ 10.78 (bs, 1H), 8.62-8.25 (m, 3H), 7.18-7.11 (m, 2H), 6.79 (s, 1H), 6.67-6.61 (m, 1H), 4.18 (m, 1H), 3.69 (s, 3H), 3.25-3.12 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([C@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)(=[O:16])=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24].C=O.[CH:30](O)=O>O1CCOCC1>[CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([C@H:17]3[CH2:21][CH2:20][N:19]([CH3:30])[CH2:18]3)(=[O:15])=[O:16])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: O=CO
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)[C@H]3CCNC3)ccc21
Agent: C=O
Solvent: C1COCCO1
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)[C@H]3CCN(C)C3)ccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To solution of (S)—N,N-dimethyl-2-(2-neopentyl-5-(pyrrolidin-3-ylsulfonyl)-1H-benzo[d]imidazol-1-yl)ethanamine (STEP F, 776 mg, 1.98 mmol) in 1,4-dioxane (5 mL) were added 37% formalin (588 microL, 7.31 mmol) and formic acid (379 microL, 9.88 mmol). The mixture was stirred at 60° C. for 1 h. The mixture was concentrated in vacuo. The residue was diluted with saturated sodium bicarbonate aqueous solution (4 mL) and extracted with ethyl acetate (60 mL×2). The combined organic layers were washed with brine and dried over sodium sulfate. The resulting solution was concentrated in vacuo and residue was purified by amine gel column chromatography (dichloromethane-ethyl acetate, gradient) to give the title compound (704 mg, 87%) as clear grease.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]([CH:18]=[O:19])=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.[CH:21]1([CH2:25][NH:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22]1.O>CN(C)C=O.C(OCC)(=O)C>[CH:21]1([CH2:25][N:26]([CH2:27][CH3:28])[C:8]2[C:17]([CH:18]=[O:19])=[CH:16][C:15]3[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: CCNCC1CCC1
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC1CCC1)c1nc2c(C)cccc2cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Potassium carbonate (0.62 g, 4.5 mmol) was added to a solution of 2-chloro-8-methyl-quinoline-3-carbaldehyde (0.45 g, 2.2 mmol) and cyclobutylmethyl-ethyl-amine (0.47 g, 4.1 mmol) in anhydrous dimethyl formamide (5 mL) under nitrogen. After stirring for 0.5 h at RT, the reaction mixture was heated for 20 h at 80-95° C. Thereafter, the reaction was cooled to RT, water (30 mL) and ethyl acetate (30 mL) were added, and the organic layer was separated from the aqueous mixture. The organic extract was washed with brine, dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by chromatography using silica gel to afford the title compound as a pale yellow liquid (0.46 g, 75%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23].Cl.[CH3:28][N:29]1[C:34]([CH3:36])([CH3:35])[CH2:33][CH:32]([OH:37])[CH2:31][C:30]1([CH3:39])[CH3:38]>C1C=CC=CC=1>[CH3:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([O:10][C:13](=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:37][CH:32]2[CH2:31][C:30]([CH3:38])([CH3:39])[N:29]([CH3:28])[C:34]([CH3:36])([CH3:35])[CH2:33]2)=[O:23])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: O=C(Cl)CCCCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccccc1
Product: CN1C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C

Procedure:
A solution of 17.10 parts of 1,2,2,6,6-pentamethylpiperidin-4-ol in 50 parts of dry benzene was stirred at 15°-20° C. whilst adding 6.0 parts of sebacoyl chloride dropwise over 15 minutes. The mixture was stirred for a further 12 hours at room temperature after which the 1,2,2,6,6-pentamethylpiperidin-4-ol hydrochloride formed during the reaction was filtered off. The benzene was removed by distillation under reduced pressure to give a yellow oil, which was distilled under reduced pressure to give bis(1,2,2,6,6-pentamethyl-4-piperidinyl)sebacate as a colorless oil having a boiling point of 218°-20° C. at 0.4 mm of Hg and the following elemental analysis by weight:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][N:14]3C(=O)C4C(=CC=CC=4)C3=O)=[C:11]([CH3:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.O.NN>C1COCC1.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][NH2:14])=[C:11]([CH3:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cc2)c1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a solution of 2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-isoindole-1,3-dione (5.9 g, 18 mmol) in THF (248 mL) and ethanol (21 mL) at 0° C. was added hydrazine hydrate (6.7 g, 6.5 mL, 134 mmol) and the resulting mixture stirred at room temperature overnight. The mixture was then filtered and the filtrate diluted with HCl (1 N) and extracted with ethyl acetate. The combined organic extracts were then washed with HCl (1 N) and the aqueous layer made basic with NaOH (6 N). The aqueous layers were extracted with ethyl acetate and the combined organic layers washed with brine and dried over sodium sulfate. Concentration afforded the title compound (2.0 g, 54%) as a light yellow oil. MS: m/e=190.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[CH2:10]([OH:12])[CH3:11].C=CC1C=CC=CC=1.[CH3:21][OH:22]>[Pd](Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:7][C:21]([O:12][CH2:10][CH3:11])=[O:22])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CO
Reactant: C=Cc1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Solvent: C=Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(Cl)cc1
Yield: 60.2 %

Procedure:
The procedures of Example 27 were exactly followed except that p-chlorostyrene and ethanol were used respectively instead of styrene and methanol and the amount of palladium chloride was changed to 0.1 millimole. Ethyl 4-chlorocinnamate was obtained with a yield of 60.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[O:16])[O:14][C:12](=O)[C:11]3=[CH:17][CH:18]=2)=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:11](=[CH:17][CH:18]=2)[C:12](=[O:14])[N:25]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[C:15]3=[O:16])=[O:7])=[CH:19][CH:20]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(=O)OC2=O
Reactant: NCc1cccnc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(=O)N(Cc1cccnc1)C2=O
Yield: 97.1 %

Procedure:
To a mixture of 870 mg of 4-(4-chlorobenzoyl)phthalic acid anhydride, 10 ml of acetic acid and 10 ml of toluene was added 394 mg of 3-aminomethylpyridine, and the resultant mixture was refluxed under heating for 2 hours. The reaction mixture was concentrated in vacuo, and the resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate to give 1.11 g of the titled compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C@@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:23]>C(Cl)Cl.O1CCOCC1.CCOCC>[ClH:23].[CH2:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C@@H:12]([NH2:15])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](COCc2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N[C@@H]1CC[C@H](COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
To a solution of 1.52 g (5 mmol) of tert-butyl {(1R,3S)-3-[(benzyloxy)methyl]-cyclopentyl}carbamate in 20 mL of DCM are added, at 0° C., 5 mL (20 mmol) of a 4N solution of HCl in dioxane. The medium is then stirred for 12 hours at room temperature, and then concentrated under reduced pressure. The residue obtained is solidified in 20 mL of Et2O, filtered and dried under vacuum. 1 g of (1R,3S)-3-[(benzyloxy)methyl]cyclopentanamine hydrochloride is obtained in the form of a powder.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:32]([CH:33]=1)[C:15]1[N:16]([C:25]3[CH:26]=[N:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[C:17](=[O:24])[C:18]3[C:23]([C:14]=1[N:13]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3.C(N(CC)CC)C>ClCCl>[Cl:31][C:28]1[N:27]=[CH:26][C:25]([N:16]2[C:15]3[N:32]4[CH:33]=[C:9]([NH:8][C:5](=[O:7])[CH3:6])[CH:10]=[CH:11][C:12]4=[N:13][C:14]=3[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:24])=[CH:30][CH:29]=1
Reactant: Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 47 %

Procedure:
Acetic anhydride (1.5 equiv., 0.829 mmol, 0.084 g) was added to a cooled (0° C.) solution of compound 53 (1.0 equiv., 0.553 mmol, 0.200 g) and triethylamine (1.5 equiv., 0.829 mmol, 0.085 g) in dichloromethane (6 ml). The reaction mixture was stirred at room temperature for 20 h. The solvent was evaporated under reduced pressure, and the resulting residue purified by column chromatography (dichloromethane/methanol 9:1; Rf=0.3) affording N-[6-(6-chloro-pyridin-3-yl)-5,6-dihydro-5-oxo-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-9-yl]-acetamide (56) (0.105 g, yield=47%, purity (LC)=90%).
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[NH:5][C:6]([Cl:13])=[CH:7][C:8]2[C:9]=1[NH:10][CH2:11][N:12]=2>O>[Cl:13][C:6]1[NH:5][C:4](=[O:1])[C:9]2[NH:10][CH:11]=[N:12][C:8]=2[CH:7]=1
Reactant: ClC1=CC2=NCNC2=C(Cl)N1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(Cl)cc2nc[nH]c12
Temperature: 90 °C

Procedure:
An aqueous NaOH solution (2 equiv.) was added to a solution of 4,6-dichloro-3,5-dihydro-imidazo[4,5-c]pyridine in water. The reaction mixture was stirred at 90° C. until the completion of the reaction (monitored by TLC). The reaction mixture was allowed to cool down to room temperature and filtered to give light yellow residue. The residue was dissolved in water and acidified to pH 3-4 and was filtered to give 2.