Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][N:23]=1.O>CN(C)C=O>[CH3:20][O:19][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([C:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][N:23]=1)[C:4]([CH3:3])=[C:12]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Clc1ncnc2ccccc12
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1c(C)n(-c2ncnc3ccccc23)c2ccc(OC)cc12
Reaction time: 0.25 h

Procedure:
A stirred suspension of sodium hydride (0.24g.) in dry dimethylformamide (20ml.; dried with calcium hydride) was treated at 5°-10° C. with a solution of ethyl 2-methyl-5-methoxyindol-3-ylacetate (2.3g.) in dry dimethylformamide (10ml.). The mixture was stirred at 25°-30° C. for 15 minutes, and the solution obtained was treated with a freshly prepared solution of 4-chloroquinazoline (1.65g.) in dry dimethylformamide (10ml.). The mixture was stirred at 30°-40° C, for 4 hours, and then poured into water (500ml.). The mixture was extracted with ethyl acetate (4 × 100ml.) and the extracts washed successively with water (2 × 100ml.) and brine (100ml.), and then dried (sodium sulphate). Evaporation of solvent gave an oil which was purified by chromatography on silica gel (250g.) using an increasing gradient of ether in petroleum ether (b.p. 40°-60° C.) (the polarity increased by incremental addition of 10% v/v ether) to give ethyl 5-methoxy-2-methyl-1-(quinazolin-4-yl)indol-3-ylacetate, m.p. 121°-123° C.
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[C:21]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:33][CH2:34][N:29]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=3)[CH2:30][CH2:31]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 68 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3,5-xylyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])[CH2:2][CH2:3][CH3:4].CC([O-])(C)C.[K+].[C:21]([O:25]C(C)(C)C)(=[O:24])[CH:22]=[CH2:23]>C1(C)C=CC=CC=1>[C:21]([OH:25])(=[O:24])[CH2:22][CH2:23][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOCCOCCO
Reactant: C=CC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCOCCOCCOCCOCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4.13 g of triethylene glycol mono-n-butyl ether in toluene (150 mL) are added 264 mg of t-BuOK (potassium tert-butanolate) in portions and then 5.81 g of t-butyl acrylate in toluene (20 mL) at room temperature. The mixture is stirred at room temperature overnight, and toluene is removed in vacuo. To this residue are added 40 mL of 0.5 N KOH ethanol solution, and the reaction mixture is heated to reflux for 2 h (hours). After acidifying to pH 3 with diluted HCl aq. solution, EtOAc (ethyl acetate) is added to the mixture. The extract with EtOAc is concentrated, and the residue is applied to silica gel column with CH2Cl2-MeOH (methylene chloride-methanol) mixture as eluent. I1 is obtained as colorless oil, 5.34 g.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[F:21][C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=2)(=[O:30])=[O:29])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-Boc-piperazine (500 mg) in DCM (10 ml) was added triethylamine (450 μl) and 3-fluorobenzenesulfonyl chloride (390 μl). The reaction mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water, washed with brine, organics were dried over MgSO4, filtered and volatiles removed in vacuo to give 4-(3-fluoro-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (919 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH:7][C:8](O[C@H](C2C=CC=CC=2)C)=[O:9])=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4([C:34](O)=[O:35])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[O:4][N:3]=1.[CH:37]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:39][CH2:38]1>>[CH:37]1([S:40]([NH:43][C:8](=[O:9])[NH:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4([C:34]([NH:43][S:40]([CH:37]5[CH2:39][CH2:38]5)(=[O:42])=[O:41])=[O:35])[CH2:32][CH2:33]4)=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)(=[O:42])=[O:41])[CH2:39][CH2:38]1
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC(=O)O[C@@H](C)c1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(=O)(=O)C5CC5)CC4)cc3)cc2)c1NC(=O)NS(=O)(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 315 using 1-{4′-[3-Methyl-4-((S)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid and cyclopropanesulfonamide.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:33])[C:3]([NH:5][C@@H:6]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:7]([NH:9][C@@H:10]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]([C@@:13]1([CH3:16])[CH2:15][O:14]1)=[O:12])=[O:8])=[O:4].[O:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[C:39](O)=[O:40].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>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:39]([C@H:35]2[CH2:36][CH2:37][CH2:38][O:34]2)=[O:40])[CH3:33])[C:7]([NH:9][C@@H:10]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:11]([C@@:13]2([CH3:16])[CH2:15][O:14]2)=[O:12])=[O:8])=[CH:26][CH:27]=1
Reactant: O=C(O)[C@H]1CCCO1
Reactant: COc1ccc(C[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)[C@H]2CCCO2)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.2 %

Procedure:
To (S)-2-((S)-2-aminopropanamido)-3-(4-methoxyphenyl)-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide (0.412 mmol assumed) was added a mixture of (R)-tetrahydrofuran-2-carboxylic acid (57 mg, 0.494 mmol), HATU (187 mg, 0.494 mmol), and DMF (3 mL). The mixture was cooled to 0° C. and DIEA (0.352 mL, 2.06 mmol) was added. The reaction mixture was stirred at ambient temperature for 15 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3:1 DCM/ethyl acetate+0-10% methanol) provided (R)-N-((S)-1-(((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)tetrahydrofuran-2-carboxamide (130 mg, 57%) as a colorless amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 8.46 (d, J=7.6 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.31-7.20 (m, 5H), 7.08 (d, J=8.4 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 4.59-4.54 (m, 1H), 4.48-4.42 (m, 1H), 4.21-4.16 (m, 2H), 3.80-3.69 (m, 5H), 3.18 (d, J=5.2 Hz, 1H), 2.98 (d, J=6.4 Hz, 1H), 2.95-2.86 (m, 2H), 2.73-2.59 (m, 2H), 2.05-1.99 (m, 1H), 1.80-1.66 (m, 3H), 1.11 (d, J=7.2 Hz, 3H). MS (EI) for C30H37N3O7, found 552.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH:50]1[CH2:55][CH2:54][CH2:53][C@@H:52]([C:56]([OH:59])([CH3:58])[CH3:57])[CH2:51]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:50]3[CH2:55][CH2:54][CH2:53][C@@H:52]([C:56]([OH:59])([CH3:58])[CH3:57])[CH2:51]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Reactant: CC(C)(O)[C@@H]1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CCC[C@@H](C(C)(C)O)C2)cc1Cl
Yield: 72.6 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 2-[(3R)-piperidin-3-yl]propan-2-ol hydrochloride (7 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC, evaporated and dried in vacuum to yield the title compound (11 mg). MS (ESI, pos. ion) m/z 379 (M+1); HRMS, calcd for C19H23ClN2O4: 378.1346, found 378.1340.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)([CH2:10][OH:11])[CH2:8][OH:9])=[CH:4][CH:3]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[H-].[Na+]>CN(C=O)C>[CH2:28]([O:9][CH2:8][C:7]([CH2:10][O:11][CH2:6][C:5]1[CH:26]=[CH:27][CH:2]=[CH:3][CH:4]=1)([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:27][CH:26]=1)[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])=[CH:17][CH:18]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(OCC)c1ccc(CC(CO)(CO)Cc2ccc(Br)cc2)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(OCC)c1ccc(CC(COCc2ccccc2)(COCc2ccccc2)Cc2ccc(Br)cc2)cc1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
A mixture of 2-(4-Bromobenzyl)-2-[4-(diethoxymethyl)benzyl]-1,3-propanediol(3 g, crude), benzyl bromide (3 mL), and NaH (1.2 g, 60% in mineral oil) in 30 mL of DMF was stirred for 14 h at 70° C. The mixture was then quenched with 5 mL of MeOH followed by 50 mL of saturated NH4Cl and extracted with 200 mL of 2:1 hexane/EtOAc. The extract was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 15:1 hexane EtOAc containing 1% of Et3N to give 2.5 g of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(OCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution containing ethyl 6-methyl-3-pyridyloxyacetate (0.026 g, 0.13 mmol) in a mixture of THF (0.5 mL) and water (0.5 mL) was treated with lithium hydroxide monohydrate (0.008 g, 0.19 mmol), stirred at 25° C. for 18 hours, aid concentrated to give the crude product, which was used without purification.
Reaction SMILES: Br[C:2]1[C:3]2[N:11]([CH2:12][CH3:13])[C:10]([C:14]3[C:15]([NH2:19])=[N:16][O:17][N:18]=3)=[N:9][C:4]=2[C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.B(OC)(OC)[O:26]C.C(=O)=O.CC(C)=O>C1COCC1>[NH2:19][C:15]1[C:14]([C:10]2[N:11]([CH2:12][CH3:13])[C:3]3[C:2]([OH:26])=[CH:7][N:6]=[C:5]([Cl:8])[C:4]=3[N:9]=2)=[N:18][O:17][N:16]=1
Reactant: COB(OC)OC
Reactant: CCn1c(-c2nonc2N)nc2c(Cl)ncc(Br)c21
Agent: CC(C)[Mg]Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCn1c(-c2nonc2N)nc2c(Cl)ncc(O)c21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
A suspension of 4-(7-bromo-4-chloro-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine (VI, 50 g, 0.14 mol) in THF (1 L) was cooled in a dry-ice/acetone bath until the internal temperature was below −75° C. Isopropyl magnesium chloride (225 mL, 2M in ether, 0.45 mol) was added slowly at a rate to keep the reaction temperature below −70° C. After an additional 10 min., trimethyl borate (54 mL, 0.48 mol) was added and the reaction was maintained in the dry-ice acetone bath for 1 h. The bath was removed and the reaction was allowed to reach ambient temperature. After 18 h., the resultant yellow suspension was cooled to 0° C. A solution of 30% hydrogen peroxide (250 mL) and 3N NaOH (100 mL) was added at a rate to keep the reaction temperature below 40° C. The ice bath was then removed and the reaction was stirred vigorously at ambient temperature for 2 h. The bulk of the organic solvent was removed under reduced pressure and the aqueous layer was acidified to pH 3 with 1N HCl. After stirring the resulting suspension for 30 min., ethyl acetate (200 mL) was added. After stirring for another 1 h, the solid was collected by filtration. The filter cake was washed sequentially with water, ethyl acetate, toluene and ethyl acetate. The solid was dried to a constant weight to give 35.9 g (88% yield) of the desired compound (VII) as a pale yellow solid. This was used without further purification. MS (ES+) m/z 281.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13](=[O:17])OCC)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>CC1C=CC=CC=1C>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][C:13]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)=[O:17]
Reactant: Nc1ccccn1
Reactant: CCOC(=O)Nc1nc(-c2ccccc2)cs1
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccn1)Nc1nc(-c2ccccc2)cs1
Reaction time: 2.5 h
Yield: 67 %

Procedure:
Into 45 ml of o-xylene, were added 1.5 g of ethyl N-(4-phenyl-2-thiazolyl)carbamate and 4.0 g of 2-aminopyridine. The mixture was stirred for 2.5 hours under refluxing. The reaction solution was allowed to stand for cooling. Deposited crystals were collected by filtration and washed with methyl alcohol. The crystals were then recrystallized from an N,N-dimethylformamide/methyl alcohol mixed solvent to obtain 1.2 g of N-(2-pyridyl)-N'-(4-phenylthiazol-2-yl)urea.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[OH:11].[CH3:12][N:13]1C(=O)O[C:16](=[O:17])[C:15]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:14]12>>[CH3:12][NH:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([OH:11])=[N:6]1)=[O:17]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: Oc1n[nH]c2ccc(Cl)cc12
Product: CNc1ccccc1C(=O)n1nc(O)c2cc(Cl)ccc21
Yield: 32.3 %

Procedure:
5-Chloro-1H-indazol-3-ol was reacted with N-methylisatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 32.3% yield; m.p. 206°-208° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13](=O)[CH2:14][CH3:15])=[C:6](OS(C)(=O)=O)[CH:7]=1.Cl.Cl.[CH2:19]([NH:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:13]([CH2:14][CH3:15])=[N:27][N:26]2[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)c1ccc(Br)cc1OS(C)(=O)=O
Reactant: NNCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nn(Cc2ccccc2)c2cc(Br)ccc12
Temperature: 135 °C
Yield: 40.9 %

Procedure:
Methanesulfonic acid 5-bromo-2-propionyl-phenyl ester (5.00 g, 16.3 mmol) was combined with benzylhydrazine dihydrochloride (4.45 g, 22.8 mmol) and sodium acetate (4.01 g, 48.9 mmol) in xylenes (30 mL). The reaction mixture was heated to 135° C. for two days using a Dean Stark apparatus. The reaction was cooled to room temperature, diluted with dichloromethane (75 mL), and washed with water (75 mL) and 1N aqueous hydrochloric acid (75 mL). The organic extracts were dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel eluting with 4:1 hexanes/ethyl acetate to yield 2.10 g of 6-bromo-1-benzyl-3ethyl-1H-indazole (41% yield). 1H NMR (400 MHz, CDCl3) δ 1.39 (t, 3, J=7.7), 2.96 (q, 2, J=7.7), 5.48 (s, 2), 7.14-7.23 (m, 3), 7.26-7.31 (m, 3), 7.42 (s, 1), 7.54 (d, 1, J=8.5). 13C NMR (100 MHz, CDCl3) δ 13.70, 20.37, 52.68, 112.12, 120.77, 121.69, 121.83, 123.34, 126.97, 127.76, 128.75, 136.74, 141.37, 147.60. IR 3064, 3031, 2970, 2934, 2875, 1606, 1504, 1497, 1454, 1236, 1048, 831, 701 cm1. Analysis calculated for C16H15BrN2 : C, 60.97; H, 4.80; N, 8.89. Found: C, 61.21; H, 4.92; N, 8.73.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][NH:13][CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][N:13]([C:26](=[O:27])[C:25]4[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=4)[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccc(F)cc21
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccc(F)cc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 by using ethyl 9-fluoro-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 4-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 10.57 (1H, br s), 8.04 (1H, s), 7.62 (2H, dd), 7.29 (1H, m), 7.16 (3H, m), 6.95 (1H, m), 4.24 (4H, m), 3.20 (2H, m), 1.22 (3H, t); MS (ES): 397 (MH+).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[N:18]=[N:19][C:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:21][CH:22]=1.[Si:28]([O:35][C:36]1([CH2:40]/[CH:41]=[N:42]/[S:43]([C:45]([CH3:48])([CH3:47])[CH3:46])=[O:44])[CH2:39][CH2:38][CH2:37]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C1COCC1.O>[Si:28]([O:35][C:36]1([CH2:40][CH:41]([NH:42][S:43]([C:45]([CH3:48])([CH3:47])[CH3:46])=[O:44])[C:22]2[CH:21]=[C:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:19]=[N:18][C:17]=2[Cl:16])[CH2:39][CH2:38][CH2:37]1)([C:31]([CH3:33])([CH3:34])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)Cc1ccc(Cl)nn1
Reactant: CC(C)(C)S(=O)/N=C/CC1(O[Si](C)(C)C(C)(C)C)CCC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)Cc1cc(C(CC2(O[Si](C)(C)C(C)(C)C)CCC2)NS(=O)C(C)(C)C)c(Cl)nn1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2,2,6,6-Tetramethylpiperidine (0.68 ml, 4.0 mmol) was dissolved in 120 ml THF and 1-butyllithium (1.5 ml, 3.8 mmol) was added at −78° C. drop wise. The mixture was allowed to warm to 0° C. (over a period of 5 min) and kept there for 5 min. The mixture was cooled back to −78° C. and a solution of 3-chloro-6-neopentylpyridazine (0.45 g, 2.4 mmol) in 10 ml of THF was added drop wise. Stirring was continued for 20 min and a solution of (E)-N-(2-(1-(tert-butyldimethylsilyloxy)cyclobutyl)ethylidene)-2-methylpropane-2-sulfinamide (1.450 g, 4.4 mmol) in 5 ml THF was added drop wise. Stirring was continued for 10 min and the mixture was hydrolyzed with H2O. The mixture was extracted with EtOAc (3×300 ml) dried over MgSO4 and evaporated. The crude product was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+]([O-])=O)=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.[H-].[Na+].Cl.[CH3:16][CH:17]([CH3:20])[CH2:18][OH:19]>>[Br:1][C:2]1[C:3]([O:19][CH2:18][CH:17]([CH3:20])[CH3:16])=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Reactant: CC(C)CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(OCC(C)C)c(Br)c[n+]1[O-]
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, to a solution of 5-bromo-2-methyl-4-nitropyridine 1-oxide (4.10 g) in 2-methyl-1-propanol (80 mL) was added 60% sodium hydride (2.69 g) at 0° C., and the mixture was stirred for 2 hr. 6N Hydrochloric acid was added to the reaction mixture, and the resulting brown solid was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (3.40 g) as a pale-yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=2[F:16])[CH2:5][O:4]1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.[Na]>C(O)(C)(C)C>[F:16][C:7]1[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=1[C:3]1([CH2:2][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:5][O:4]1
Reactant: c1nc[nH]n1
Reactant: Fc1cc(C(F)(F)F)ccc1C1(CCl)CO1
Agent: [Na]
Solvent: CC(C)(C)O
Product: Fc1cc(C(F)(F)F)ccc1C1(Cn2cncn2)CO1

Procedure:
A solution of 2-chloromethyl-2-(2-fluoro-4-trifluoromethylphenyl)oxirane (6 g.) in tert-butyl alcohol was treated with sodium 1,2,4-triazole (2.7 g.) and heated at 100° for 1 hour. The mixture was evaporated and the residual gum partitioned between ethyl acetate and water. the organic layer was washed with water, dried and evaporated to dryness. The residual gum was chromatographed on K60 silica gel using chloroform/petroleum ether (b.p. 60°-80°) 1:1 v/v and chloroform as eluting solvents to give 2-(2-fluoro-4-trifluoromethylphenyl)-2-(1,2,4-triazol-1-ylmethyl)oxirane, as a gum with NMR data as follows:
Reaction SMILES: [CH:1]1([CH:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C@@H:17]4[CH2:21][N:20](CC5C=CC=CC=5)[CH2:19][C@:18]4([CH2:30][OH:31])[CH3:29])=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(O)C>[CH:1]1([CH:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C@@H:17]4[CH2:21][NH:20][CH2:19][C@:18]4([CH2:30][OH:31])[CH3:29])=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(c1n[nH]c2cc([C@@H]3CN(Cc4ccccc4)C[C@@]3(C)CO)ccc12)C1CCCC1
Agent: [Pd]
Solvent: CCO
Product: CC(c1n[nH]c2cc([C@@H]3CNC[C@@]3(C)CO)ccc12)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a stirred solution of Example 3 (25.5 mg; 0.0611 mmol) in 190 proof ethanol (2.0 mL) was added 10% Pd/C (5 mg; 20 wt. % catalyst). Hydrogen was vigorously bubbled through the solution for 5 minutes. The reaction was allowed to stir at room temperature for 2 hours, then the catalyst was removed by filtration through celite. The solvent then was removed in vacuo to provide the named pyrrolidine (14 mg; 71%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:29])[NH:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:29])[N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: CC1Cc2c(F)cccc2N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1Cc2c(F)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 52.6 %

Procedure:
The product is prepared by following the procedure described in example 1c using 0.2 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 127 mg of (+)-4-fluoro-2-methyl-2,3-dihydro-1H-indole [reference example 8c, step 6c] and 0.20 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 123 μl of pyridine and 3.5 ml of N,N-dimethylformamide. 0.15 g of (−)-2-{2-[4-fluoro-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one is thus obtained in the form of a white solid, the characteristics of which are the following: