Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[C:32]1([CH2:38][CH2:39]CCC(O)=O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:27][CH2:26][C@H:25]([N:11]([CH2:10][CH2:9][CH2:8][CH2:39][CH2:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:30][CH2:29]1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)CCCCc1ccccc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCCCc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 5-phenyl-pentanoic acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C:10]1[C:11]([CH3:28])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH3:27])([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:14][CH2:13]2.N1C=CN=C1>CN(C=O)C.C(=O)([O-])O.[Na+].C(OCC)C>[O:9]([C:10]1[C:11]([CH3:28])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH3:27])([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:14][CH2:13]2)[Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CC1(C)CCc2c(C)c(O[Si](C)(C)C(C)(C)C)c(C)c(C)c2O1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Under nitrogen, 5.41 g (35.9 mM) of tert-butyldimethylsilyl chloride was added to a solution of 7.69 g (27.63 mM) of methyl 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetate and 2.82 g (41.4 mM) of imidazole in DMF (54 ml) at room temperature and the mixture was stirred at 0° C. for 20 hours. This reaction mixture was poured in saturated aqueous sodium hydrogen carbonate-diethyl ether under intense agitation to stop the reaction and, then, extracted with diethyl ether. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (ethyl acetate-hexane: 10%) to provide the title compound as yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=O)=[CH:6][C:5]=1[NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])([O-:3])=[O:2].[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][CH:10]2[C:11]3[C:7](=[CH:6][C:5]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH2:8][CH2:9]2)=[CH:23][CH:22]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CCOC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(Nc1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A mixture of ethyl 6-nitro-1-oxo-2,3-dihydro-1H-inden-5-ylcarbamate (0.47 g, 1.8 mmol), 4-fluoroaniline (0.24 g, 2.2 mmol), and decaborane (200 mg) in 20 ml of anhydrous methanol was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by column (hexane/EtOAc, 5:1) to give a pure product (0.51 g, 81%).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:10]([CH3:27])[O:9][N:8]=1)(=O)=O.CN(C=O)C.[N-:33]=[N+:34]=[N-:35].[Na+]>O>[N:33]([CH2:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:26])=[C:10]([CH3:27])[O:9][N:8]=1)=[N+:34]=[N-:35]
Reactant: Cc1onc(COS(C)(=O)=O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1onc(CN=[N+]=[N-])c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottomed flask was added (4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanone (47.2 mg, 0.144 mmol), DCM, and Et3N (40.1 μl, 0.288 mmol). The solution was cooled to 0° C. before addition of Ms-Cl (13.47 μl, 0.173 mmol). The reaction was stirred at 0° C. for 30 min before addition of water. The layers were separated and the aqueous was extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated to afford crude (4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)methyl methanesulfonate. To a round bottomed flask was added (4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)methyl methanesulfonate (58.4 mg, 0.144 mmol), DMF, and sodium azide (28.1 mg, 0.432 mmol). The reaction was stirred at room temperature for 2 h before diluting with water and extracting the aqueous with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated to afford crude (2-(3-(azidomethyl)-5-methylisoxazol-4-yl)phenyl) (4-chlorophenyl)methanone. To a round bottomed flask was added (2-(3-(azidomethyl)-5-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone (50.8 mg, 0.144 mmol), toluene (3 mL), and trimethylphosphine solution (216 μl, 1M in toluene, 0.216 mmol). The reaction was stirred at room temperature over 2 days before purifying via Biotage (EtOAc/hex) to afford 6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepine. LC/MS m/z 309 [M+H]+; 1H NMR (400 MHz, Acetone) δ 7.70-7.76 (m, 1H), 7.63-7.70 (m, 1H), 7.32-7.49 (m, 6H), 5.10 (br. s, 1H), 4.10 (br. s, 1H), 2.68 (s, 3H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=O)=O.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[N:19]1[CH:20]=[CH:21][C:22]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:6][CH2:7][C:8]3[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: c1cc(C2CCNCC2)ccn1
Reactant: CCOC(=O)c1cccc(CCOS(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cccc(CCN2CCC(c3ccncc3)CC2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
Ethyl 3-{2-[(methylsulfonyl)oxy]ethyl}benzoate (170 mg) was mixed with MeCN (3.4 ml), and 1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl (122 mg) and potassium carbonate (173 mg) were added thereto, followed by stirring at 60° C. overnight. After cooling to room temperature, the insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain ethyl 3-{2-[4-(pyridin-4-yl)piperidin-1-yl]ethyl}benzoate (121 mg).
Reaction SMILES: CN(C=O)C.[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.Cl>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)=[CH:18][CH:17]=1
Reactant: C1=Cc2ccccc2C1
Reactant: Nc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc(C2C=Cc3ccccc32)cc1

Procedure:
20 ml of DMF, 2.2 g (20 mmol) of indene, 4,4 g (20 mmol) of para-amino-iodo-benzene, 2 ml of triethylamine and 0,134 (0,6 mmol) of Pd(OAc)2 were stirred under reflux for 10 h. The resulting mixture was poured into 200 ml of 15% HCl. Forming precipitate was separated and washed with dichloromethane. The resulting substance was treated with the mixture 50 ml of dichloromethane and 50 ml of 5% KOH in water. Organic layer was separated, washed twice with water, filtered and dried over Na2SO4. Dichloromethane was removed and the residue was recrystallized from 20 ml of EtOH. The yeld of product was 70%.
Reaction SMILES: [CH:1]1([C@H:4]([NH:8]C(=O)[O-])[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1.C(Cl)(Cl)[Cl:13].Cl>CCO.O1CCOCC1.[Pd]>[ClH:13].[CH:1]1([C@H:4]([NH2:8])[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1
Reactant: COC[C@@H](NC(=O)[O-])C1CC1
Reactant: ClC(Cl)Cl
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COC[C@@H](N)C1CC1
Yield: 100 %

Procedure:
To a solution of (S)-1-cyclopropyl-2-methoxyethylcarbamate (4.36 g, 17.5 mmol) from Part D in EtOH (80 mL) and CHCl3 (3 mL) in a Parr bottle was added 4 N HCl in dioxane (5 mL) and Pd/C (476 mg, 10%, wet, Degussa type). The mixture was placed on a Parr shaker under H2 atm at 45 psi for 16 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated then reconcentrated from hexanes (2×) to afford (S)-1-cyclopropyl-2-methoxyethanamine hydrochloride (2.65 g, 100% yield) as a white solid: mp 190-192° C.; [α]25D +14.3 (c 0.446, MeOH); 1H NMR (400 MHz, CDCl3) δ 8.41 (s br, 3H), 3.68 (d, J=5.6 Hz, 2H), 3.39 (s, 3H), 2.64-2.60 (m, 1H), 1.20-1.13 (m, 1H), 0.71-0.58 (m, 3H), 0.32-0.28 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 72.1, 59.2, 57.5, 10.7, 4.2, 4.1; LRMS (ESI) m/e 231.2 [(2M+H)+, calcd for C12H27N2O2 231.2].
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].O>CN(C=O)C>[CH:10]1[C:11]2[N:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a solution containing carbazole (20 g; 0.12 mol) in DMF (130 ml) was added portionwise sodium hydride (50% suspension) (6.9 g; 0.14 mol); the suspension thus obtained was stirred at room temperature for 30 minutes and then heated to 60° C. A solution containing ethyl 2-bromoacetate (24 g; 0.14 mol) in DMF (20 ml) was added dropwise, and the resulting mixture was stirred for 16 hours. The mixture was poured into H2O (0.5 L) and filtered, and the solid obtained was crystallized from hexane to give ethyl 9H-carbazol-9-ylacetate (20 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Cl[C:13]1[N:14]=[C:15]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:16]2[S:21][C:20]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([N:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]3)=[CH:19][C:17]=2[N:18]=1>CN(C=O)C.O>[N:1]1([C:13]2[N:14]=[C:15]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[C:16]3[S:21][C:20]([CH2:22][N:23]4[CH2:24][CH2:25][CH:26]([N:29]([CH3:31])[CH3:30])[CH2:27][CH2:28]4)=[CH:19][C:17]=3[N:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1CCN(Cc2cc3nc(-n4ccc5ccccc54)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 32.8 %

Procedure:
A solution of indole (0.117 g) in DMF (8 mL) was cooled to 0° C. then sodium hydride (0.06 g) was added. After 15 min, [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.395 g) was added. The reaction flask was sealed, heated at 150° C. for 1 h, cooled to room temperature, and diluted with water. The solid precipitate was collected by filtration then purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish the title compound (0.156 g, 33%) as an off-white solid. MS m/e 477 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.27-1.57 (m, 2H) 1.55-1.79 (m, 2H) 1.95-2.13 (m, 3H) 2.16 (s, 6H) 2.75-3.06 (m, 2H) 3.74-3.89 (m, 6H) 3.91-4.08 (m, 4H) 6.71 (d, J=3.39 Hz, 1H) 7.18 (s, 1H) 7.30 (s, 1H) 7.36 (s, 1H) 7.61 (s, 1H) 8.30 (d, J=3.77 Hz, 1H) 8.78 (d, J=7.91 Hz, 1H)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[CH3:26])(=[O:35])=[O:34])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:22][CH2:23][N:24]3[C@H:29]4[CH2:30][CH2:31][C@@H:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[C:15]([CH3:20])([NH2:19])[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:42][CH:43]([Cl:47])[C:44](Cl)=[O:45].CCN(C(C)C)C(C)C>>[Cl:42][CH:43]([Cl:47])[C:44]([NH:19][C:15]([C:14]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)([CH2:22][CH2:23][N:24]2[C@H:29]3[CH2:30][CH2:31][C@@H:25]2[CH2:26][CH:27]([N:32]2[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:34]=[C:33]2[CH3:41])[CH2:28]3)[CH2:9][CH2:10]1)=[O:21])([CH3:20])[CH:16]([CH3:17])[CH3:18])=[O:45]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(N)C(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(NC(=O)C(Cl)Cl)C(C)C)CC1
Yield: 69.6 %

Procedure:
2,2-dichloro-N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}acetamide was obtained from treating 1,1-dimethylethyl {1-[(4-(3-fluorophenyl-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}carbamate, example 915, (0.623 g, 0.94 mmol) with HCl as outlined in the procedure for Example 890 to form 1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine (0.524 g, 99%). 1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), Dichloro-acetyl chloride (0.013 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2,2-dichloro-N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-1,2-dimethylpropyl}acetamide (0.042 g, 69%) as an oil. ES-LCMS m/z 643 (M+1).
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:30])=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc(Cl)cc1)C2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-chlorophenyl isocyanate (0.31 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for seven hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a tan solid (0.39 g, 56% yield), mp=88–90° C.; MS (−) ESI m/z=334 (M+H)+; [α]D25=+22.8° (c=1, EtOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.C(O)(C)(C)C.[Li].N>C1COCC1>[CH3:1][O:2][C:3]1[CH2:8][CH:7]=[C:6]([C:9]([OH:12])([CH3:10])[CH3:11])[CH2:5][CH:4]=1
Reactant: COc1ccc(C(C)(C)O)cc1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COC1=CCC(C(C)(C)O)=CC1
Temperature: -30 °C
Reaction time: 24 h
Yield: 74.2 %

Procedure:
2-(4-methoxy-phenyl)-propan-2-ol (750 g, 4.5 mol), anhydrous THF (7.5 L) and tert-BuOH (2001.4 g, 27 mol) were added under argon to a 22 L round bottomed flask equipped with an overhead stirrer, thermometer and dropping funnel. The mixture was cooled to −30° C. Gaseous ammonia was bubbled through the reaction mixture for 30 min. Granulated lithium (125 g, 18 mol) was added portion wise to the solution during 1-1.5 hr. The stirring was continued with slow flow of ammonia for 20 rh. The reaction was quenched with a solution of 961 g NH4Cl in 2.7 L water at −20° C. The top layer was separated and evaporated on a rotary evaporator at a bath temperature of 30° C. (all these and subsequent operations are performed under inert atmosphere). The aqueous layer was extracted with MTBE (3×1 L). The concentrate and extract were combined, washed with water and brine, dried over Na2SO4 and evaporated to dryness at a bath temperature of 35° C. The crude oily product was mixed with 725 ml Hexane and filtered. The filtrate was placed in a freezer at −70° C. and left for 24 hr. The solid was decanted and rinsed with Hexane pre-cooled to −70° C. (2×100 mL) with decantation after each rinsing. After drying under vacuum at 20° C., 562 g of the target product was obtained (yield 74%), having an HPLC purity of 89%.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=1.[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:19])=[CH:8][C:9]=3[N+:16]([O-:18])=[O:17])=[O:13])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1[N+](=O)[O-]
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3[N+](=O)[O-])CC2)c(C)c1
Yield: 63 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-nitrobenzoic acid (1.05 g) described in Preparation Example 24 and 1-(3,5-dimethylpyridin-2-yl)piperazine (0.70 g) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (1.06 g) was obtained.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Br:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Br:16])=[CH:25][C:24]=3[Br:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: Brc1cc(Br)c2c(c1)CCN2
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(Br)cc(Br)c32)c1=O

Procedure:
Part B: Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5,7-dibromoindoline as the starting materials. mp 164–165° C.; 1H NMR (300 MHz, CDCl3): δ 7.42 (d, J=1.8 Hz, 1 H), 7.22 (d, J=1.5 Hz, 1 H), 6.96 (s, 1 H), 4.26 (t, J=8.1 Hz, 2 H), 3.99 (app. q, J=8.3 Hz, 1 H), 3.08 (t, J=7.9 Hz, 2 H), 1.94–1.69 (m, 2 H), 1.02–0.92 (m, 1 H), 0.87 (t, J=7.5 Hz, 3 H), 0.78–0.68 (m, 1 H), 0.50–0.39 (m, 2 H), 0.29–0.22 (m, 1 H); HRMS (ESI) calcd for C18H19N3OBr2Cl (M+H)+: 485.9583; found m/z 485.9592.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)(=O)C.C1(S([O-])(=O)=O)C=CC=CC=1.[Na+].[CH3:24][O-:25].[Na+]>CO>[CH3:1][O:4][CH:5]([O:25][CH3:24])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1
Reactant: C[O-]
Reactant: CC(=O)OCc1ccc(F)cc1
Agent: O=S(=O)([O-])c1ccccc1
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccc(F)cc1

Procedure:
Electrolyte: 250 g (1.488 mol) of 4-fluorobenzyl acetate, 12.5 g of sodium benzenesulfonate, 12.5 g of sodium methylate and 2225 g of methanol
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33].O.[NH2:37][NH2:38].C(=O)([O-])O.[Na+]>CN(C=O)C>[N+:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][C:24]1[C:3]2[C:4](=[O:23])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:21])([F:22])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:38][N:37]=1)([O-:34])=[O:33]
Reactant: O=C(Cc1ccccc1[N+](=O)[O-])c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccccc3[N+](=O)[O-])n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 115 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-hydroxy-3-(2-nitrophenylacetyl)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (450 mg, 0.93 mmol) produced in Synthesis Example 31 in DMF (4 mL) was added hydrazine monohydrate (purity of 80%, 148 μL), and the mixture was stirred at 110 to 120° C. for 3 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-nitrobenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (373 mg, yield 84%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9](NC1C=CC=CC=1)=[O:10].[Na].Cl>CO>[CH3:1][N:2]([CH:9]=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=CNc1ccccc1
Reactant: CNc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CN(C=O)c1ccccc1
Temperature: 100 °C

Procedure:
To the reactor described in Example 1 is charged 107 grams (1.0 mole) of N-methyl aniline, 14 grams (0.1 mole) of sodium formanilide and 150 milliliters of methanol. The autoclave is closed, purged with carbon monoxide and the temperature raised to 100° C. with atmospheric steam. Carbon monoxide is then introduced at 28 kg/cm2 pressure for about 30 minutes. The basic reaction mixture is neutralized with hydrochloric acid and extracted with xylene. Gas liquid chromatographic analysis shows that a high conversion to N-methyl formanilide is obtained.