Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][NH:3]1.ClC(OCC)=O.[CH3:23][NH:24][CH3:25]>C(N(CC)CC)C>[CH3:23][N:24]([CH3:25])[C:8]([C:6]1[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][NH:3][C:2](=[O:1])[CH:7]=1)=[O:9]
Reactant: O=C(O)c1cc(=O)[nH]nc1-c1ccccc1
Reactant: CNC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cc(=O)[nH]nc1-c1ccccc1

Procedure:
2,3-Dihydro-3-oxo-6-phenyl-5-pyridazinecarboxylic acid is treated with ethyl chloroformate, triethylamine, and dimethylamine according to the procedure of Example 3 to give N,N-dimethyl-2,3-dihydro-3-oxo-6-phenyl-5-pyridazinecarboxamide. A solution of this amide (12.5 g) in 400 ml of tetrahydrofuran is treated with 100 ml of 1 M borane in tetrahydrofuran and the resulting mixture is heated under reflux for 4 hours, then cooled and treated with 5% sodium hydroxide (100 ml) and heated under reflux for 1 hour. The tetrahydrofuran is removed on the rotary evaporator and the pH of the residual liquid is adjusted with acetic acid followed by ammonium hydroxide to 10. The product is extracted into dichloromethane and the dichloromethane is filtered and concentrated on the rotary evaporator. The residue is chromatographed on silica gel with 2% methanol and chloroform to give 5-(dimethylaminomethyl)-6-phenyl-3(2H)-pyridazinone.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([N:33]([CH3:38])[C:34](=[O:37])[CH2:35][OH:36])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[OH:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([N:33]([CH3:38])[C:34](=[O:37])[CH2:35][OH:36])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: ClCc1ccccn1
Reactant: C[C@@H](COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12)N(C)C(=O)CO
Agent: Cl
Product: C[C@@H](COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)N(C)C(=O)CO
Yield: 57 %

Procedure:
The procedure described in Example 3 was repeated using picolyl chloride hydrochloride and N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-2-hydroxy-N-methylacetamide to give the title compound in 57% yield; NMR spectrum (DMSO-d6) 1.20 (dd, 3H), 2.80 (d, 3H), 3.10 (m, 1H), 3.80-4.20 (m, 2H), 4.20-4.50 (m, 2H), 5.15 (m, 1H), 5.30 (s, 2H), 7.20 (m, 2H), 7.30 (m, 2H), 7.50 (d, 1H), 7.60 (d, 1H), 7.70 (m, 1H), 7.80-7.95 (m, 2H), 8.40 (d, 1H), 8.60 (d, 1H), 9.60 (s, 1H); Mass spectrum MH+ 508.2.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:28])[CH2:7][C:8]1[C:9](=[O:27])[O:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)=[CH:15][C:14]([CH3:25])=[C:13]([Cl:26])[CH:12]=2)C.Cl>C(O)C>[Br:24][C:20]1[CH:19]=[C:18]([C:17]2[C:16]3[C:11](=[CH:12][C:13]([Cl:26])=[C:14]([CH3:25])[CH:15]=3)[O:10][C:9](=[O:27])[C:8]=2[CH2:7][C:6]([OH:28])=[O:5])[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)Cc1c(-c2cccc(Br)c2)c2cc(C)c(Cl)cc2oc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2c(-c3cccc(Br)c3)c(CC(=O)O)c(=O)oc2cc1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
2N NaOH (51.6 ml) was added to a mixture of ethyl[4-(3-bromophenyl)-7-chloro-6-methyl-2-oxo-2H-chromen-3-yl]acetate (15 g) and ethanol (135 ml), and the mixture was stirred at 70° C. for 1 hour. After the mixture was cooled to 25° C., pH was adjusted to 2.0 by adding 6N HCl (17.7 ml) dropwise at the same temperature to make crystals precipitate. After the mixture was stirred at 25° C. for 1 hour, crystals were collected, washed with ethanol/water (2/1, 30 ml) and dried under reduced pressure to obtain the title compound (13.5 g, yield 96.4%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1F.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1[N:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: c1cc[nH]c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-n2cccc2)c(F)c1
Temperature: 50 °C
Yield: 66.3 %

Procedure:
A slurry of 403 mg(630 mg of 60% in oil, 15.75 mmol) of sodium hydride in 85 mL THF was treated with 1.01 g(1.04 mL, 15 mmol) of pyrrole, followed by warming at 50° C. foe 15 min. The solution was then treated with 2.51 g(1.74 mL, 15.75 mmol) of 3.4-difluoronitrobenzene, followed by warming at reflux for 18h. The mixture was then cooled and treated with lOmL saturated ammonium chloride solution. The mixture was diluted with ethyl acetate and extracted with water (2×). Drying (Na2SO4) and concentration in vacuo afforded a dark brown solid, which was chromatographed over 75 g of 230-400 mesh silica gel, eluting with 30%(v/v) dichloromethane in hexane. These procedures afforded 2.05 g(66%) of the title pyrrole derivative as a light yellow solid. 1H NMR (CDCl3): δ8.14, 7.57, 7.16, 6.44.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4].Cl.[CH2:24]([O:26][NH2:27])[CH3:25].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[CH2:24]([O:26][NH:27][C:3]([C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4])[CH3:25]
Reactant: COC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Reactant: CCON
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCONC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.1 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester (165.0 mg, 0.40 mmol) and O-ethylhydroxylamine hydrochloride (78.1 mg, 0.80 mmol, 2.0 eq) in anhydrous THF (9.4 mL) at 0° C. was added lithium hexamethyldisilazide (1M in THF, 1.2 mL, 1.2 mmol, 3.0 eq). After stirring at room temperature for 16 h, additional O-ethylhydroxylamine hydrochloride (234.3 mg, 2.40 mmol, 3.0 eq) and lithium hexamethyldisilazide (1M in THF, 3.6 mL, 3.6 mmol, 9.0 eq) were added at 0° C., and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate (5 mL) and diluted with ethyl acetate (50 mL). The organic layer was isolated and washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 45% to 100%, ethyl acetate in hexane, followed by gradient 0 to 15% methanol in ethyl acetate) to give an oil. Crystallization from DCM ether hexane afforded the title compound as a yellow solid (33.7 mg, 19.1%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 11.86 (s, 1H), 10.38 (s, 1H), 8.82 (s, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.73 (d, J=10.4 Hz, 1H), 7.44 (d, 8.4 Hz, 1H), 6.57 (t, J=8.4 Hz, 1H), 3.90 (q, J=7.2 Hz, 2H), 1.18 (t, J=6.8 Hz, 3H); LCMS (method D2): RT=1.24 min, [M+H]+=442.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>O1CCCC1>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccccc2[N+](=O)[O-])cc1
Reaction time: 18 h

Procedure:
A mixture of 1-fluoro-2-nitrobenzene (20 g) and 4-methoxybenzylamine (18.52 ml) in dry tetrahydrofuran (100 ml) was stirred at 23° for 18 h under a nitrogen atmosphere. The mixture was filtered, then the organic layer was concentrated in vacuo to an oil. Ethanol (50 ml) was added and a solid separated. After filtration, the title compound was obtained as an orange solid (16.35 g). The filtrate was concentrated in vacuo and the residue was treated with further ethanol (10 ml) to give a further amount of title compound (7.9 g). M.p. 81°-2° T.l.c. CH-EA (8:2), Rf 0.55.
Reaction SMILES: C([O-])(O)=O.[Na+].OO.NC(N)=O.C([C:15]1[C:32]([F:33])=[CH:31][C:18]2[O:19][CH2:20][C:21](=[O:30])[N:22]([CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:17]=2[CH:16]=1)(=O)C.[C:34]([O:40]C(C(F)(F)F)=O)([C:36](F)(F)F)=[O:35]>C(Cl)Cl>[C:34]([O:40][C:15]1[C:32]([F:33])=[CH:31][C:18]2[O:19][CH2:20][C:21](=[O:30])[N:22]([CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:17]=2[CH:16]=1)(=[O:35])[CH3:36]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(F)c(C(C)=O)cc21
Agent: NC(N)=O
Agent: O=C([O-])O
Agent: OO
Solvent: ClCCl
Product: CCOC(=O)C(C)N1C(=O)COc2cc(F)c(OC(C)=O)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of NaHCO3 (5.38 g, 64.0 mmol) and urea hydrogen peroxide (6.02 g, 64.0 mmol) in DCM (60 mL) at 0° C. was added ethyl 2-(6-acetyl-7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)propanoate (6.6 g, 21.34 mmol). The reaction mixture was stirred for 10 min then TFAA (5.94 mL, 42.7 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h and then allowed to warm to ambient temperature and stirred for 3 days. The reaction mixture was diluted with DCM (30 mL) and washed with water (30 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 15% EtOAc in petroleum ether) to give ethyl 2-(6-acetoxy-7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)propanoate and starting material as a white solid (5.9 g, 85%). 1H NMR (CDCl3, 400 MHz): δ 6.85 (d, J=10 Hz, 1H), 6.59 (d, J=6.8 Hz, 1H), 5.23 (m, 1H), 4.57 (q, J1=15.2 Hz, J2=14.8 Hz, 2H), 4.17 (m, 2H), 2.29 (s, 3H), 1.58 (d, J=7.2 Hz, 3H), 1.17 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH2:15][OH:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:20][S:21]([O:16][CH2:15][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:6](=[C:5]([C:17](=[O:18])[NH2:19])[CH:4]=[CH:3][C:2]=3[Br:1])[NH:7][C:8]=2[CH:9]=1)(=[O:23])=[O:22]
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(CO)ccc12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)OCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
Step 1 A suspension of 4-bromo-7-(hydroxymethyl)-9H-carbazole-1-carboxamide (Example 30-2, 300 mg, 0.940 mmol) and TEA (0.262 mL, 1.880 mmol) in THF (9.4 mL) was treated dropwise with methanesulfonyl chloride (0.077 mL, 0.987 mmol) and the mixture was stirred at rt for 1 hr. It was treated with NaHCO3 (aq) and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated to provide crude (5-bromo-8-carbamoyl-9H-carbazol-2-yl)methyl methanesulfonate as a light yellow solid (390 mg, 89%). This material was suspended in DMF (8.3 mL) and treated with sodium azide (271 mg, 4.17 mmol). After being stirred overnight at rt, the mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated to provide crude 7-(azidomethyl)-4-bromo-9H-carbazole-1-carboxamide as a light yellow solid (350 mg, 97%). 1H NMR (400 MHz, DMSO-d6) δ 11.80 (1H, s), 8.62 (1H, d, J=8.4 Hz), 8.22 (1H, br. s.), 7.88 (1H, d, J=8.1 Hz), 7.83 (1H, s), 7.58 (1H, br. s.), 7.46 (1H, d, J=8.4 Hz), 7.28 (1H, dd, J=8.1, 1.5 Hz), 4.63 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[C:28]([O:32][C:33]([NH:35][C@@H:36]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:43][CH:42]=1)[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:28]([O:32][C:33]([NH:35][C@@H:36]([CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:45][CH:46]=1)[C:37]([O:10][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[CH2:8][C:7]1[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=1[Cl:1])=[O:38])=[O:34])([CH3:30])([CH3:31])[CH3:29]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OS(C)(=O)=O)cc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OS(C)(=O)=O)cc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (100 mg, 0.24 mmol) and (S)-2-(tert-butoxycarbonyl-amino)-3-(4-(methylsulfonyloxy)phenyl)propanoic acid (172 mg, 0.48 mmol) were dissolved in DMF (3 ml). DMAP (35 mg, 0.29 mmol) and EDC (92 mg, 0.48 mmol) were added, and the mixture was stirred at RT for 3 hours, then was quenched with HCl 1N and extracted with EtOAc. The organic layer was washed with HCl 1N and NaHCO3 sat. sol., then was dried over Na2SO4 and evaporated under vacuum to give 155 mg (85%) of the title compound which was employed in the next step without any further purification. MS/ESI+ 761.14 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:22]([O:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])[CH2:23][CH3:24])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([O:20]C)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[Li+].[OH-].Cl>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:22]([O:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])[CH2:23][CH3:24])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCCO[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCCCO[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reaction time: 16 h

Procedure:
To a round-bottom flask equipped with a stir bar was added (2S,4R)-methyl 1-((2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(pent-4-en-1-yloxy)pentanoyl)-4-hydroxypyrrolidine-2-carboxylate (all material from step 2, 1.53 g, 3.57 mmol), THF (10 mL) and MeOH (10 mL). To the solution was added aq. LiOH (1.0 M, 5.36 mL). The mixture was stirred at room temperatuer for 16 h; then was concentrated in vacuo to afford an aqueous solution. The solution was acidified with aq HCl (1M) and then transferred to a separatory funnel. The solution was twice extracted with EtOAc. The combined organics were dried over MgSO4; filtered; then concentrated in vacuo to afford (2S,4R)-1-((2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(pent-4-en-1-yloxy)pentanoyl)-4-hydroxypyrrolidine-2-carboxylic acid as a white solid (1.28 g, 86% over two steps).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8]Cl)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:20]=[C:21]=[S:22]>>[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:20]=[C:21]1[S:22][CH2:8][C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[NH:2]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: NC1(CCl)CCCC1
Agent: Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1

Procedure:
1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.N#N.[C:17]1([S:23]([N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N+:8]([C:6]1[CH:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=[C:2]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:26]([S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[CH:27]=2)[CH:7]=1)([O-:10])=[O:9]
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Product: CC(=O)Nc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)cc([N+](=O)[O-])c1
Yield: 77 %

Procedure:
A solution of N-(3-bromo-5-nitrophenyl)acetamide (0.38 g, 1.48 mmol) in 1,2-dimethoxyethane (15 ml) was degassed by N2 bubbling for 5 min. 1-(Phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.68 g, 1.77 mmol, 1.2 eq.) was added and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (0.12 g, 0.148 mmol, 0.1 eq.) and aqueous sodium carbonate (0.47 g, 4.45 mmol, 3.0 eq.) were added and the procedure of Example 1(d) was followed. The crude residue of the product was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to give the product in 77% yield (0.5 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C.[OH-].[Na+].Cl>CS(C)=O.CO>[CH3:11][C:6]1[CH:5]=[C:4]([CH3:12])[N:3]=[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:19]=2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(Cl)n1
Reactant: COC(=O)CCc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CS(C)=O
Product: Cc1cc(C)c([N+](=O)[O-])c(Nc2ccc(CCC(=O)O)cc2)n1
Temperature: 140 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a solution of 2-chloro-4,6-dimethyl-3-nitropyridine (17.9 g, 96 mmol) and methyl 3-(4-aminophenyl)propanoate (19 g, 96 mmol) in DMSO (100 mL) was added N,N-diisopropylethylamine (26 g, 200 mmol), and the reaction mixture was heated at 140° C. overnight. The reaction mixture was partitioned between water (400 mL) and ethyl acetate/toluene (v/v, 2:1, 300 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate/toluene (v/v, 2:1, 200 mL). The combined organic extracts were washed with brine (200 mL), dried (Na2SO4), and concentrated. To a solution of residual oil in methanol (100 mL) was added 2 N aqueous NaOH (150 mL, 300 mmol) and the resulting mixture was stirred at room temperature for 2 h. The volatile component was removed under reduced pressure and the residue was washed with ethyl acetate (200 mL). The aqueous phase was acidified with 2N hydrochloric acid (200 mL, 400 mmol) and extracted with ethyl acetate (3×200 mL). The extracts were washed with brine (200 mL), dried (Na2SO4), and concentrated to give 23.2 g (77%) of the title compound as pale brown solids.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[C:9]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][C:20]([CH2:22][N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:21][C:15]=4[N:14]=3)=[N:10][NH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[C:29]([OH:34])(=[O:33])[C@H:30]([CH3:32])[OH:31]>CCOC(C)=O.CO>[C:29]([OH:34])(=[O:33])[CH:30]([CH3:32])[OH:31].[CH:1]1([NH:4][C:5]([NH:7][C:8]2[C:9]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][C:20]([CH2:22][N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[CH:21][C:15]=4[N:14]=3)=[N:10][NH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: C[C@H](O)C(=O)O
Agent: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)NC1CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(O)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea (0.7 g, 1.83 mmol) in EtOAc-MeOH was added L-lactic acid (166 mg, 1.85 mmol). The mixture was stirred at ambient temperature then reduced in vacuo. This solid was purified by recrystallisation from boiling EtOH (20 mL) to give after drying 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea, L-lactate salt (0.48 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-])=O>[OH-].[OH-].[Pd+2].CO>[CH3:1][NH:2][C:3]1[C:4]([NH2:13])=[CH:5][C:6]([C:9]([F:10])([F:12])[F:11])=[CH:7][CH:8]=1
Reactant: CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNc1ccc(C(F)(F)F)cc1N

Procedure:
The title compound of Example 6, Step A (150 mmol, 33 g) and Pearlman's catalyst (ca. 400 mg) were agitated in MeOH (200 mL) under H2 (40 psi, Parr shaker) for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. Flash chromatography on silica eluting with 20-25% EtOAc in hexanes afforded the product as a light orange solid. 1H NMR (500 MHz, CDCl3), δ (ppm): 7.17 (1H, d, J=8.3 Hz), 6.97 (1H, d, J=1.9 Hz), 6.68 (1H, d, J=8.2 Hz), 3.78 (1H, bs), 3.38 (2H, bs), 2.94 (3H, s). LC-MS (ESI, Method C): 2.71, m/z 191.1 (M+1).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[I:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=1>>[I:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:2]([CH3:5])([CH3:4])[CH3:3])[CH:8]=1
Reactant: Ic1cccc(I)c1
Reactant: C[Si](C)(C)Cl
Product: C[Si](C)(C)c1cccc(I)c1

Procedure:
1-Iodo-3-trimethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing chlorotrimethylsilane and 1,3-diiodobenzene as the dihalo compound of formula (II).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]1=2.B.C1COCC1.FC(F)(F)C(O)=O.[OH-].[Na+]>C1COCC1>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[CH:4]2[CH2:12][CH2:13][CH:14]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:3]12
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=NCc1ccccc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN1c2ccc(O)cc2C2CCC(NCc3ccccc3)C21
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A solution of 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (14.0 g) was placed in a 3-neck flask and cooled to 0° C. in an ice-water bath. A solution of 1M borane/THF in THF (145 ml) was added in a dropwise manner. The mixture was stirred for 1 hour while it was slowly warmed to room temperature. The mixture was cooled back to 0° C. and trifluoroacetic acid was added in a dropwise manner. The solution was stirred for 15 minutes, neutralized with 10% NaOH (Aq), extracted with CH2Cl2, dried (Na2SO4) and concentrated to give 1,2,3,3a,4,8b-hexahydro-4-methyl-3-phenylmethylaminocyclopent[b]indol-7-ol (14 grams).
Reaction SMILES: C1([C:9]([O-:11])=[O:10])C(C)=CC=CC=1O.[K+].[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>>[C:13]([CH2:14][C:9]([OH:11])=[O:10])(=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(O)c1C(=O)[O-]
Reactant: CC(=O)c1ccccc1
Agent: [K+]
Product: O=C(O)CC(=O)c1ccccc1
Yield: 9.4 %

Procedure:
By operating as in Example 1, starting from 6.75 g of potassium meta-cresolate and from 5.5 g of acetophenone, 0.55 g of benzoylacetic acid were obtained.