Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]2[CH2:16][C@H:15]([CH3:17])[C@@H:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:13]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1.[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55](O)=[O:56])=[O:40])([CH3:37])([CH3:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:29]([O:28][C:27]([NH:26][C@H:13]1[C@H:14]([O:18][Si:19]([C:22]([CH3:23])([CH3:25])[CH3:24])([CH3:20])[CH3:21])[C@@H:15]([CH3:17])[CH2:16][N:11]([C:3]2[C:2]([NH:1][C:55]([C:43]3[N:44]=[C:45]([C:47]4[C:48]([F:54])=[CH:49][CH:50]=[CH:51][C:52]=4[F:53])[S:46][C:42]=3[NH:41][C:39](=[O:40])[O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:56])=[CH:7][N:6]=[C:5]3[O:8][CH2:9][CH2:10][C:4]=23)[CH2:12]1)=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.2 %

Procedure:
To a mixture of tert-butyl ((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (67.8 mg, 0.142 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (65.4 mg, 0.184 mmol) and HATU (168.1 mg, 0.4421 mmol) was added DMF (2.0 mL) followed by DIPEA (144.5 mg, 1.118 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to afford the sub-title compound as a brown solid (29.2 mg, 25%). LCMS calc. for C39H55F2N6O7SSi (M+H)+: m/z=817.4. found 817.3.
Reaction SMILES: C[Mg]Br.[Cl:4][C:5]1[CH:25]=[CH:24][C:8]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=O)=[CH:7][C:6]=1[C:26]([NH:28][CH2:29][C:30]12[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2)=[O:27].S([O-])(O)(=O)=O.[K+].[CH2:46]([O:48]CC)C>>[Cl:4][C:5]1[CH:25]=[CH:24][C:8]([CH:9]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:15][CH2:16]2)[CH2:46][OH:48])=[CH:7][C:6]=1[C:26]([NH:28][CH2:29][C:30]12[CH2:37][CH:36]3[CH2:35][CH:34]([CH2:33][CH:32]([CH2:38]3)[CH2:31]1)[CH2:39]2)=[O:27]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: C[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(C(CO)c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To methyl magnesiumbromide (3M solution in diethyl ether, 0.225 ml) in anhydrous diethyl ether (7 ml) under a nitrogen atmosphere was added slowly 4-[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]benzoyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0.23 g, Example 76a) in anhydrous diethyl ether (7 ml). The reaction mixture was stirred for 14 h at room temperature, then poured onto crushed ice. A solution of 10% aqueous potassium hydrogen sulphate was added keeping the pH of the solution >4. The layers were separated, and the aqueous layer was extracted with ethyl acetate (4×25 ml). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in methanol (3 ml) and hydrochloric acid (4N solution in dioxane, 2 ml) and stirred for 14 h at room temperature. Solvents were then removed under reduced pressure and the product (0.11 g) was redissolved in dichloromethane (3 ml). Triethylamine (0.066 ml) was added followed by di-tert-butyl-dicarbonate (0.055 g) and the reaction mixture was stirred for 1 hour at room temperature. Water was added and the layers were partitioned. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane, then by RPHPLC eluting with a gradient of 75-5% of 0.1% aqueous ammonium acetate in acetonitrile to give the subtitle compound as a white foam (0.06 g).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]3[S:20][C:19]4[N:21]=[CH:22][CH:23]=[N:24][C:18]=4[N:17]([CH2:25][O:26][CH3:27])[C:16]=3[CH:28]=1)[CH:5]=[N:6]2.[CH2:29]([O:31][C:32]([Sn](CCCC)(CCCC)CCCC)=[CH2:33])[CH3:30]>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:32]([O:31][C:29]([C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]3[S:20][C:19]4[N:21]=[CH:22][CH:23]=[N:24][C:18]=4[N:17]([CH2:25][O:26][CH3:27])[C:16]=3[CH:28]=1)[CH:5]=[N:6]2)=[CH2:30])[CH3:33]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COCN1c2cc(Cn3cnc4ncnc(Cl)c43)ccc2Sc2nccnc21
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1ncnc2ncn(Cc3ccc4c(c3)N(COC)c3nccnc3S4)c12
Temperature: 80 °C

Procedure:
To a solution of 0.9 g of 8-(6-chloropurin-7-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in N,N-dimethylformamide (15 ml) were added in a nitrogen atmosphere 1.03 g of 1-ethoxyvinyl-tri-n-butyltin (IV) and 0.015 g of bis(triphenylphosphine) palladium (II) chloride. After degassing, the mixture was heated to 80° C. for 20 hours. Then the insoluble matters were removed by filtering through celite. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.77 g of the title compound as yellow crystals.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.O=[C:22]([CH2:28][C:29](=O)[CH3:30])[C:23]([O:25]CC)=[O:24]>CCO>[CH2:3]([N:10]1[C:29]([CH3:30])=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NNCc1ccccc1
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(C(=O)O)nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
To a solution of 1-benzylhydrazine dihydrochloride (Aldrich, 0.98 g, 5.0 mmol) in EtOH (30 mL) were added DIEA (2.0 mL) and ethyl 2,4-dioxopentanoate (0.70 mL, 5.0 mmol). The mixture was stirred at room temperature for 12 h and was concentrated in vacuo. The residue was dissolved in 1 N NaOH (10 mL). The solution was heated at 60° C. for 1 h. After cooling down, the solution was extracted with DCM (3×50 mL). The aqueous layer was neutralized to pH 2.0 and then was extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. It was filtered and concentrated to give 1-benzyl-5-methyl-1H-pyrazole-3-carboxylic acid (1.0 g, 92% yield). MS(ESI+): m/z 217.12 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[Si:13]([O:20][C:21]1[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([O:20][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(N)c1
Reactant: Clc1ccnc2ccc(Br)cc12
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Nc2ccnc3ccc(Br)cc23)c1
Yield: 80.2 %

Procedure:
6.26 g (25.8 mmol) of 6-bromo-4-chloroquinoline are reacted by method A with 7.5 g (33.6 mmol) of 3-(tert-butyldimethylsilanyloxy)phenylamine. 8.9 g (20.7 mmol, 80%) of the desired product are obtained.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([N+:13]1[C:18](Cl)=[CH:17][C:16]([NH2:20])=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([N+:13]1[CH:18]=[CH:17][C:16]([NH2:20])=[CH:15][N:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cn[n+](Cc2ccccc2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: Nc1cc[n+](Cc2ccccc2)nc1

Procedure:
The procedure of Example 4 is repeated but 13 parts of 1-benzyl-4-amino-6-chloropyridazinium perchlorate is used and 10 parts of sodium bicarbonate is used instead of triethylamine. 9.6 parts (67.3% of theory) of 1-benzyl-4-aminopyridazinium perchlorate is obtained from the filtrate from the reaction mixture; C11H12O4N3Cl, melting point 127° to 129° C after having been recrystallized from water.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14]CC)=O)[N:9]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:6]2=[N:7][CH:8]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[CH:37]=1>>[CH3:36][C:34]1[S:35][C:31]2[CH:30]=[CH:29][C:28]([NH:27][C:12]([C:10]3[N:9]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[C:6]4=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:26])[F:25])[CH:4]=[C:5]4[CH:11]=3)=[O:14])=[CH:37][C:32]=2[N:33]=1
Reactant: Cc1nc2cc(N)ccc2s1
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Product: Cc1nc2cc(NC(=O)c3cc4cc(C(F)(F)F)cnc4n3Cc3cccc(F)c3)ccc2s1
Yield: 73.1 %

Procedure:
The process is performed according to the method described in step 13.5 of Example 13, starting with 0.35 g (0.96 mmol) of ethyl 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Example 13.4) and 0.17 g (1.06 mmol) of 5-amino-2-methylbenzothiazole. 0.34 g of expected compound is isolated.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH2:14][CH:15]([OH:24])[CH2:16][NH:17][CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C(Cl)Cl>[Si:30]([O:24][CH:15]([CH2:14][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:16][NH:17][CH2:18][C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: OC(CNCc1ccco1)Cn1c2ccccc2c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(CNCc1ccco1)Cn1c2ccccc2c2ccccc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a stirred solution of 1-(9H-carbazol-9-yl)-3-((furan-2-ylmethyl)amino)propan-2-ol (1.80 g, 5.6 mmol) and imidazole (1.912 g, 28.1 mmol) in anhydrous methylene chloride (50 mL) was added tert-butyldimethylsilyl chloride (2.117 g, 14.0 mmol). The reaction mixture was stirred overnight at 70° C. The reaction mixture was washed with saturated aqueous sodium chloride and saturated aqueous sodium carbonate, dried (anhydrous sodium sulfate), filtered, and concentrated. The residue was purified by silica gel column chromatography (0-40% ethyl acetate in hexanes) to afford the product as a thick oil (2.4 g, 98%). 1H NMR (300 MHz, CDCl3) δ 8.08 (d, 2H, J=7.8 Hz), 7.53-7.40 (m, 4H), 7.37 (d, 1H, J=1.5 Hz), 7.22 (t, 2H, J=7.2 Hz), 6.32 (dd, 1H, J=3.3, 1.8 Hz), 6.16 (d, 1H, J=3.3 Hz), 4.56 (dd, 1H, J=14.4, 6.0 Hz), 4.41-4.22 (m, 2H), 3.85 and 3.75 (dd, 2H, J=14.4, 14.4 Hz), 2.74 (dd, 1H, J=12.0, 4.5 Hz), 2.61 (dd, 1H, J=12.0, 3.6 Hz), 1.60 (br s, 2H), 0.80 (s, 9H), −0.13 (s, 3H), −0.42 (s, 3H). ESI m/z: 435.2 [M+H].
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].N1C=CN=C1.[CH3:14][Si:15](Cl)([CH3:17])[CH3:16]>C(Cl)Cl>[CH3:14][Si:15]([CH3:17])([CH3:16])[O:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)C(C)(C)O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)C(C)(C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.2 %

Procedure:
To a solution of 1.2 mL (10.4 mmol) of methyl 2-hydroxyisobutyrate in 50 mL of CH2Cl2 were added 1.2 g (17.6 mmol) of imidazole and 2.1 mL (16.6 mmol) of TMSCl. The mixture was stirred at r.t. for 1.5 h and quenched with 20 mL of H2O. The organic layer was dried over MgSO4, concentrated and passed through a short plug of silica gel eluted with 9:1 hexane/EtOAc. Evaporation of solvent afforded 1.27 g of the title compound as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:44])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][N:41]([CH3:43])[CH3:42])=[CH:38][N:37]=[N:36]2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:43][N:41]([CH2:40][C:39]1[N:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:44])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:22])[F:23])[C:12]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[N:36]=[N:37][CH:38]=1)[CH3:42]
Reactant: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(N3CCOCC3)cc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1cnnn1-c1cccc(C2=Nc3cc(N4CCOCC4)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-{3-[3-(5-dimethylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-3-oxo-propionylamino}-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M24) (138 mg, 0.218 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a beige solid (37 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:17])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=O.C(Cl)(=O)OCC>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:18][CH2:19][CH2:20][CH2:21][C:22]1[O:16][C:8](=[O:17])[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)CCCCl
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1oc(CCCCl)nc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
Triethylamine (7.60 ml) was added to a suspension of anthranilic acid (3.52 g) in methylene chloride (35 ml) and then the mixture was cooled with ice. The mixture, with 4-chlorobutyryl chloride (3.62 g) dropwise added thereto, was stirred for 3 hours at room temperature and then cooled with ice. The reaction mixture, with triethylamine (4.00 ml) and ethyl chlorocarbonate (2.70 ml) dropwise added thereto, was stirred for 1 hour at 0° C. and further for 3 hours at room temperature. The reaction mixture, with chloroform added thereto, was washed with water and saturated brine successively. The organic layer was dried over sodium sulfate anhydride and then concentrated. The residue was purified by silica gel column chromatography (silica gel 125 g, chloroform-hexane), thereby yielding 4.00 g of the aimed compound as yellow solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1.Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]>CCCCCC.C1COCC1>[Br:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1
Reactant: O=C(CCl)N1CCCCC1
Reactant: CN1CCc2[nH]c3ccc(Br)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCc2c(c3cc(Br)ccc3n2CC(=O)N2CCCCC2)C1
Reaction time: 0.5 h
Yield: 34 %

Procedure:
Sodium hydride (0.6 g, 15 mmol) washed with hexane for removal of oil and dried under vacuum. Then sodium hydride was taken in THF. To this solution 8-bromo-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2 g, 75 mmol) in THF was added drop wise at 0° C. Then reaction mixture stirred for 0.5 h. The solution of 2-chloro-1-(piperidin-1-yl)ethanone (1.8 g, 11.3 mmol) in THF was added drop wise in reaction mixture. Then reaction mixture stirred at rt for 2 h. Reaction was monitored by TLC. After completion of the reaction, reaction mixture quench with ice-water. THF was evaporated and aqueous layer was extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulphate. The crude compound was washed with hexane and diethyl ether for removal of color impurities then recrystallized by using methanol to gives 1.5 g of desired compound then out of that 0.8 g compound was stirred in ethanolic HCl to give HCl salt of 2-(8-bromo-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(piperidin-1-yl)ethanone.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[F:5][C:6]1[CH:7]=[C:8]([NH:12]N=C2CCCC(O)=C2)[CH:9]=[CH:10][CH:11]=1>O>[F:5][C:6]1[CH:7]=[C:8]2[C:9]([C:11]3[C:1](=[O:4])[CH2:2][CH2:8][CH2:7][C:6]=3[NH:12]2)=[CH:10][CH:11]=1
Reactant: CC(=O)O
Reactant: OC1=CC(=NNc2cccc(F)c2)CCC1
Solvent: O
Product: O=C1CCCc2[nH]c3cc(F)ccc3c21

Procedure:
A mixture of glacial acetic acid (25 ml), 3-(3-fluorophenylhydrazono)-1-cyclohexen-1-ol (1.1 g) and fused zinc chloride (1.0 g) was heated at 100° for 20 h. The cooled reaction mixture was poured into water (35 ml) and extracted with dichloromethane (2×30 ml). The combined, dried organic extracts were evaporated to give an oil which was purified by SPCC eluting with ethyl acetate:hexane (3:2) to give the title compound (0.15 g) as a powder, m.p. 231°-233°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:14]1([CH3:23])[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[C:7]([C:6]1[CH:5]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[S:3][C:2]=1[NH:1][C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([CH3:23])=[CH:15][CH:16]=1)=[O:22])(=[O:8])[NH2:9]
Reactant: CC(C)(C)c1cc(C(N)=O)c(N)s1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)Nc2sc(C(C)(C)C)cc2C(N)=O)cc1
Yield: 39.7 %

Procedure:
A solution of 2-amino-5-tert-butylthiophene-3-carboxamide (0.14 g, 0.7 mmol) and p-tolyl isocyanate (0.093 g, 0.7 mmol) in toluene (5 mL) was stirred at 60° C. overnight. The reaction mixture was separated between with water (10 mL) and EtOAc (10 mL). The aqueous phase was back-extracted with EtOAc (3×10 mL), and the combined organic phases were washed with a saturated NaCl solution (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by chromatography (SiO2; gradient from 20% EtOAc/80% pet. ether to 30% EtOAc/70% pet ether) to give N-(3-carbamoyl-5-tert-butyl-2-thienyl)-N′-(4-methylphenyl)urea (0.092 g, 40%): 1H-NMR (CDCl3) δ1.38 (s, 9H), 2.32 (s, 3H), 5.58 (br s, 2H), 6.53 (s, 1H), 7.13 (app d, 2H), 7.35 (app d, 2H), 7.45 (br, 1H), 11.23 (br s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)[CH2:3][CH2:2]1.O=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:12]=[C:10]1[NH:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[C:4]2([CH2:3][CH2:2][N:1]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH2:6][CH2:5]2)[O:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C1Nc2ccccc2C2(CCNCC2)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCC3(CC2)OC(=O)Nc2ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Spiro[4H-3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (A4) (410 mg, 1.88 mmol) was dissolved in anhydrous 1,2-dichloroethane (10 mL) and treated with tert-butyl 4-oxopiperidine-1-carboxylate (via) (562 mg, 2.82 mmol), glacial acetic acid (226 mg, 3.76 mmol) and sodium triacetoxyborohydride (797 mg, 3.76 mmol). The reaction was stirred under nitrogen at room temperature for 72 hours. The reaction was concentrated under reduced pressure and the residue partitioned between 1.0 N HCl (50 mL) and diethyl ether (25 mL). The aqueous layer was separated and washed with diethyl ether (2×25 mL), basified with 1.0 N NaOH (aq) and extracted with dichloromethane (3×50 mL). The pooled extracts were washed with saturated brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford tert-butyl 4-(2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-yl)piperidine-1-carboxylate (vib) as a crystalline white solid. LC/MS m/z 402.2 [M+H]+, retention time 1.84 min (RP-C18, 10-99% CH3CN/0.05% TFA).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22][C@@H:23]([C:39]3[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=3)[C:24](N3[C@H]4C5C=CC=CC=5C[C@H]4OC3=O)=[O:25])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:46]O.O[Li].O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:22][C@@H:23]([C:39]3[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=3)[C:24]([OH:46])=[O:25])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(-n2nc(C[C@H](C(=O)N3C(=O)O[C@@H]4Cc5ccccc5[C@@H]43)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reactant: OO
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2nc(C[C@H](C(=O)O)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
To a stirred solution of (2S,3aS,8aR)-3-{3-[5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionyl}-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one (20.7 g, 0.0323 mol) in THF (230 mL) and H2O (45 mL) at 0° C. was added 30% H2O2 (15.0 mL, 0.147 mol) followed by LiOH hydrate (2.75 g, 0.0655 mol) in H2O (15 mL). The reaction mixture was allowed to warm to rt and was stirred for 90 min. The mixture was cooled to 0° C. and then quenched with 1.5 N Na2SO3 (20 mL) maintaining pH 9-10. The mixture was concentrated to ¼ volume, then treated with H2O (200 mL) and acidified to pH 1-2 using 3 N HCl. The aqueous layer was washed with EtOAc (3×100 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated to ¼ volume. Solid crystals that developed overnight were filtered and washed with cold 1:1 hexane/EtOAc. The chiral auxiliary was recovered in 66% yield (3.72 g). The filtrate was purified by flash chromatography (7:3 hexane/EtOAc with 0.3% MeOH) to afford 12.7 g (81.5%) of (S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid as orange oil. HPLC: Rt=10.44 (Method E). MS (ES+): mass calculated for C26H22Cl2N3, 481.37; m/z found 503.2 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.12-7.31 (m, 9H), 6.90 (dd, J=6.3, 2.0 Hz, 1H), 6.86 (d, J=9.1 Hz, 2H), 6.21 (s, 1H), 4.07-4.15 (m, 1H), 3.82 (s, 3H), 3.53 (dd, J=9.3, 5.3 Hz, 1H), 3.10 (dd, J=9.1, 5.8 Hz, 1H), 2.35 (s, 3H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].NO[C:8]([NH:10][C:11]([NH2:13])=[NH:12])=O.[N+:14]([O-])(O)=O>>[C:1]([OH:5])(=[O:4])[CH2:2][OH:3].[NH2:13][C:11]1[N:10]=[C:8]([CH2:1][OH:5])[NH:14][N:12]=1
Reactant: O=[N+]([O-])O
Reactant: N=C(N)NC(=O)ON
Agent: O=C(O)CO
Product: Nc1n[nH]c(CO)n1

Procedure:
While stirring 1738 g (16 moles) of a 70% glycolic acid, 1088 g (8 moles) of aminoguanidino-carboxylic acid was added thereto with little by little. To the mixture was added 8 ml of conc. nitric acid and the mixture was stirred under reflux for 24 hours. The reaction mixture was ice-cooled, and then precipitates were collected by filtration, washed with water and then dried.