Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([CH:18](Br)Br)[C:15]([Cl:21])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].S(=O)(=O)(O)[OH:24]>>[Cl:21][C:15]1[CH:14]=[C:13]([F:22])[C:12]([C:3]2[C:2]([Cl:1])=[C:6]([O:7][CH:8]([F:10])[F:9])[N:5]([CH3:11])[N:4]=2)=[CH:17][C:16]=1[CH:18]=[O:24]
Reactant: O=S(=O)(O)O
Reactant: Cn1nc(-c2cc(C(Br)Br)c(Cl)cc2F)c(Cl)c1OC(F)F
Product: Cn1nc(-c2cc(C=O)c(Cl)cc2F)c(Cl)c1OC(F)F
Temperature: 10 °C

Procedure:
68 g (0.14 mol) of 4-chloro-3-(4-chloro-5-dibromomethyl-2-fluorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole were dissolved in 200 ml of concentrated sulfuric acid, with ice-cooling, whereupon the mixture was heated at 10° C. until the evolution of gas had ceased. It was then poured into 4 l of ice-water. The mixture was subsequently extracted three times using ethyl acetate. The combined organic phases were washed with water, then dried over magnesium sulfate and finally concentrated. The crude product was purified by means of silica gel column chromatography (eluent: hexane/ethyl acetate=8:1). Yield: 35 g; m.p.: 95-98° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[O:32]1[CH2:33][CH2:34][N:29]([C:35]([O:1][C:2]2[C:3]([C:12]([NH:14][C:15]3[CH:16]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=3)=[O:13])=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:36])[CH2:30][CH2:31]1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc2ccccc2cc1O
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc2ccccc2cc1OC(=O)N1CCOCC1
Yield: 81.2 %

Procedure:
Using 3-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-2-naphthamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:1]
Reactant: CS(=O)(=O)Nc1ccccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was synthesized according to the method described in WO 2008/073956 A2. To a solution of N-(2-(hydroxymethyl)phenyl)methanesulfonamide (3.44 g, 17.1 mmol) in anhydrous methylene chloride (68 mL) was added manganese dioxide (85% Aldrich, 17 g) and the mixture was stirred at ambient temperature overnight. Additional manganese dioxide (1.6 g) was added and the mixture stirred at 30° C. for 8 hours. The mixture was filtered through Celite, washing with methylene chloride, and the organic solution concentrated. The crude residue was purified by silica gel column chromatography (40-60% ethyl acetate in hexanes) to give a white solid (2.1 g, 62%). 1H NMR (CDCl3, 300 MHz) δ 10.59 (br s, 1H), 9.91 (s, 1H), 7.75-7.59 (m, 3H) 7.28-7.23 (t, 1H, J=7.5 Hz), 3.12 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[NH:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:4]2([NH:8][C:7](=[O:9])[NH:6][C:5]2=[O:10])[CH2:3]1.[OH-].[K+].Br[CH:20]([Cl:22])[CH3:21]>CCO>[Cl:22][CH2:20][CH2:21][N:6]1[C:5](=[O:10])[C:4]2([CH2:3][C:2]([CH3:16])([CH3:1])[NH:13][C:12]([CH3:15])([CH3:14])[CH2:11]2)[NH:8][C:7]1=[O:9]
Reactant: CC(Cl)Br
Reactant: CC1(C)CC2(CC(C)(C)N1)NC(=O)NC2=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC2(CC(C)(C)N1)NC(=O)N(CCCl)C2=O
Reaction time: 6 h

Procedure:
A mixture of 7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (5, 22.2 mmol) and KOH (1.24 g, 22.2 mmol) in EtOH was refluxed for 10 min and bromochloroethane (6.35 g, 44.4 mmol) was added and refluxing continued for additional 6 h. Filtered and concentrated to get the crude chloroethylated product which was used as such for the next step (5.5 g). LCMS—[M+H] m/z 228.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH3:21]I.CO>C1COCC1>[CH3:21][N:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[CH:20][CH:19]=1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])=[O:12]
Reactant: CI
Reactant: Cc1ccc(CNS(=O)(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(CN(C)S(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Sodium hydride (80% dispersion in oil) (0.24 g, 10 mmol) was added to a stirred solution of N-4-methylbenzyl phenylsulphonamide (2.47 g, 10 mmol) in dry THF (50 mi) under argon. After 1.5 h the grey solid of sodium hydride disappeared and a white precipitate formed. The mixture was cooled to 0° C. and treated with methyl iodide (0.62 ml, 10 mmol). The reaction was allowed to warm to ambient temperature and stirred or 16 h. Methanol (1 ml) was added and the reaction mixture evaporated to dryness. The residue was partitioned between ethyl acetate (80 ml) and water (80 ml). The organic layer was separated, washed with water (2×50 ml), dried over MgSO4, filtered and the solvent removed to give the crude product. Flash chromatography (flash silica, gradient elution 0-10% ethyl acetate in hexane) gave, after crystallisation from ethyl acetate/hexane, N-methyl N-4-methylbenzyl phenylsulphonamide (0.89 g, 34%) as a white crystalline solid.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[F:23][C:24]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:28][C:25]=1[C:26]#[N:27].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:27]=[C:26]([C:25]2[CH:28]=[C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:30]=[CH:31][C:24]=2[F:23])[N:2]([CH3:1])[N:3]=1
Reactant: CCCCCCc1ccc(F)c(C#N)c1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCCCc1ccc(F)c(-c2nc(-c3c(F)cccc3Cl)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (2.17 g), 2-fluoro-5-hexylbenzonitrile (1.23 4), anhydrous aluminum chloride (0.88 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (200 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.11 g of desired compound (refractive index: 1.5608).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][N:48]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:46]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CC(C)(C)OC(=O)NC1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and piperidin-4-yl-carbamic acid tert-butyl ester according to conditions described in general procedure C. Mp: 211-212° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.18-1.14 (m, 2 H), 1.34 (s, 9H), 1.57-1.61 (m, 8 H), 2.80 (t, J=12.8 Hz, 2 H), 3.21-3.34 (m, 6 H), 4.19 (bs, 1 H), 6.19 (d, J =5.5 Hz, 1 H), 6.76 (d, J=7.6 Hz, 1 H), 6.94-6.98 (m, 1 H), 7.14 (d, J=9.1 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.54-7.61 (m, 3 H), 7.81-7.83 (m, 1 H), 7.96-7.99 (m, 1 H), 8.24 (d, J=5.5 Hz, 1 H), 10.44 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:18][CH:19]([CH3:23])[C:20](Cl)=[O:21]>ClCCl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:20](=[O:21])[CH:19]([CH3:23])[CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: NCCc1cccc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)NCCc1cccc(Br)c1
Reaction time: 3 h

Procedure:
A solution of 2-(3-bromophenyl)ethylamine (3.0 g) in dichloromethane (180 mL) at room temperature was treated sequentially with triethylamine (7.0 mL), DMAP (10 mg), and a solution of 2-methylpropanoyl chloride(1.52 mL) in dichloromethane (30 mL). The mixture was stirred for 3 hours, quenched with N1,N2-dimethyl-1,2-ethanediamine, washed sequentially with 0.5M HCl, water, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: Br[CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].C([O:11][C:12]([C:14]1[N:15]=[C:16]([SH:19])[S:17][CH:18]=1)=[O:13])C.Cl>O>[C:3]([C:2]1[N:15]=[C:16]([S:17][CH2:18][CH2:14][C:12]([OH:13])=[O:11])[S:19][CH:6]=1)([OH:5])=[O:4]
Reactant: CCOC(=O)c1csc(S)n1
Reactant: CC(Br)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCSc1nc(C(=O)O)cs1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
6.9 g of bromopropionic acid were dissolved in 100 ml of water, and the pH was adjusted to 7 with 1N NaOH. This solution was added dropwise to a suspension of 7.5 g of 4-ethoxycarbonyl-2-mercapto-1,3-thiazole in 75 ml of H2O. The pH was adjusted to 8-10 with 2N NaOH, and the mixture was stirred at room temperature for 4 h and at 60° C. for 2 h. The pH was maintained between 8 and 10. While cooling in ice, the mixture was acidified to pH 1 with 2N HCl, and the product was filtered off.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][OH:21])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:22])[CH2:6][C@@H:5]1[CH3:23])(=[O:3])[CH3:2].N1C=CN=C1.Cl[Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C)C=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][O:21][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:22])[CH2:6][C@@H:5]1[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)N1c2ccc(-c3cn(CCO)nn3)cc2[C@H](N)C[C@@H]1C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3cn(CCO[Si](C)(C)C(C)(C)C)nn3)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.1 %

Procedure:
To 2-{4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-1H-1,2,3-triazol-1-yl}ethanol (for a preparation see intermediate 45) (358 mg, 0.834 mmol) and imidazole (114 mg, 1.667 mmol) in N,N-dimethylformamide (DMF) (15 mL), was added chloro(1,1-dimethylethyl)dimethylsilane (151 mg, 1.0 mmol) and the resulting reaction mixture was stirred at room temperature for 16 h. Another equivalent of imidazole (114 mg, 1.667 mmol) and chloro(1,1-dimethylethyl)dimethylsilane (151 mg, 1.000 mmol) were then added and after 15 min the resulting mixture was partitioned between EtOAc and water. The layers were separated and the aqueous phase was extracted three times with EtOAc. The combined organic layers were washed twice with brine, dried over MgSO4 and concentrated in vacuovacuo. Purification of the residue on SP4 using a 25 G silica cartridge (gradient:0 to 10% MeOH in DCM) gave (2S,4R)-1-acetyl-6-[1-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (202 mg, 0.451 mmol, 54.1% yield) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[N:6]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:7](=[O:30])[N:8]([CH:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10](=[O:23])[N:11]3[CH2:16][CH2:15][N:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[CH:44](=O)[CH2:45][CH3:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[N:6]([S:31]([C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)(=[O:33])=[O:32])[C:7](=[O:30])[N:8]([CH:9]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:10](=[O:23])[N:11]3[CH2:12][CH2:13][N:14]([CH:17]4[CH2:18][CH2:19][N:20]([CH2:44][CH2:45][CH3:46])[CH2:21][CH2:22]4)[CH2:15][CH2:16]3)[C:4]=2[CH:3]=1
Reactant: CCC=O
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCN(C4CCNCC4)CC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: C1CCOC1
Product: CCCN1CCC(N2CCN(C(=O)C(c3ccccc3)n3c(=O)n(S(=O)(=O)c4ccc(OC)cc4)c4ccc(Cl)cc43)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 52 mg (0.08 mmol) of 5-chloro-1-(4-methoxybenzenesulfonyl)-3-[2-oxo-1-phenyl-2-(4-piperidin-4-ylpiperazin-1-yl)-ethyl]-1,3-dihydrobenzimidazol-2-one (Example 128) in 3 ml of THF was mixed with 5.32 mg (0.09 mmol) of propionaldehyde and 70 mg of MP-triacetoxyborohydride resin (Argonaut, 2.55 mmol/g, 0.17 mmol) and shaken at room temperature overnight. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase gradient 8-11% methanol in dichloromethane). Yield: 33.2 mg (60%) of colorless solid
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[C:5](F)=[CH:4][N:3]=1.[CH3:12][NH:13][NH2:14]>C(O)CO.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:13]([CH3:12])[N:14]=[C:8]([CH3:9])[C:6]=2[N:7]=1
Reactant: CNN
Reactant: CC(=O)c1nc(Cl)ncc1F
Solvent: OCCO
Solvent: O
Product: Cc1nn(C)c2cnc(Cl)nc12
Temperature: 25 °C

Procedure:
A solution of 1-(2-chloro-5-fluoropyrimidin-4-yl)ethanone (4.00 g, 22.91 mmol) and methylhydrazine (0.724 mL, 13.75 mmol) in ethylene glycol was heated at 120° C. for 2 h. Reaction mixture was cooled to rt, diluted with H2O and extracted with ethyl acetate (3×). The combined organic layer was washed with H2O (2×), brine, dried (MgSO4), filtered and concentrated. The residue was purified by CombiFlash (0 to 30% EtOAc/Hex) to give the title compound. LCMS-ESI+: calc'd for C7H8ClN4: 183.0 (M+H+); Found: 183.0 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 4.12 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[C@@H:9]([O:11]C1CCCCO1)[CH3:10].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[C@@H:9]([OH:11])[CH3:10]
Reactant: C[C@H](OC1CCCCO1)C(=O)c1ccccc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@H](O)C(=O)c1ccccc1F
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 98.4 %

Procedure:
(2S)-2′-Fluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (25 g) was dissolved in ethanol (200 ml), to which pyridinium p-toluenesulfonate (1.28 g) was added. The reaction solution was stirred at 55° C. for 2.5 hours and then concentrated. The residue was subjected to silica gel chromatography (eluent: hexane/ethyl acetate=9/1 to 5/1) to give (2S)-2′-fluoro-2-hydroxypropiophenone (16.4 g) as a colorless oily substance.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)([CH3:6])([CH3:5])[CH3:4].[N:12]1[C:17]2[NH:18][C:19]3[CH:39]=[CH:38][CH:37]=[CH:36][C:20]=3[N:21]([C:23]([C:25]3[CH:30]=[CH:29][C:28](F)=[CH:27][C:26]=3[C:32]([F:35])([F:34])[F:33])=[O:24])[CH2:22][C:16]=2[CH:15]=[CH:14][CH:13]=1>CCCCCC>[C:3]([C:7]1[CH:11]=[CH:10][N:9]([C:28]2[CH:29]=[CH:30][C:25]([C:23]([N:21]3[C:20]4[CH:36]=[CH:37][CH:38]=[CH:39][C:19]=4[NH:18][C:17]4[N:12]=[CH:13][CH:14]=[CH:15][C:16]=4[CH2:22]3)=[O:24])=[C:26]([C:32]([F:33])([F:35])[F:34])[CH:27]=2)[N:8]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1cc[nH]n1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CC(C)(C)c1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(C(F)(F)F)c2)n1
Reaction time: 0.5 h
Yield: 36 %

Procedure:
Sodium hydride (60% suspension in oil, 0.12 g, 3.0 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (10 mL). 3-tert-butylpyrazole (0.20 g, 1.6 mmol) was added in one portion at ambient temperature, and the stirring was continued until the gas evolution subsided. The (6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-[4-fluoro-2-trifluoromethyl-phenyl]-methanone of Example 4, Step B (0.50 g, 1.3 mmol) was added in one portion to the clear solution. The mixture was placed in an oil bath (preheated at 130° C.) for 30 minutes and then heated at reflux for 5 hours. After cooling, the mixture was partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated to dryness. The crude residue was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 25% ethyl acetate in hexane provided the title product (0.23 g) as a foam which crystallized by trituration with hexane-ether, m.p. 136-140° C.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)=[CH2:17].O[CH:28]([CH3:41])[CH2:29][C:30]([CH:32]1[C:37]([CH3:39])([CH3:38])[CH2:36][CH:35]=[CH:34][CH:33]1[CH3:40])=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:24][CH:28]([CH3:41])[CH2:29][C:30](=[O:31])[CH:32]2[C:37]([CH3:39])([CH3:38])[CH2:36][CH:35]=[CH:34][CH:33]2[CH3:40])=[O:23])=[CH:20][CH:19]=1)=[CH2:17]
Reactant: CC(O)CC(=O)C1C(C)C=CCC1(C)C
Reactant: C=Cc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=Cc1ccc(C(=O)OC(C)CC(=O)C2C(C)C=CCC2(C)C)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 74.3 %

Procedure:
A solution of DCC (3.60 g, 17.5 mmol) in 10 ml of CH2Cl2 was added to an ice-cold solution of 4-vinylbenzoic acid (2.35 g, 15.9 mmol), DMAP (1.55 g, 12.7 mmol) and 3-hydroxy-1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-butanone (4.00 g, 19.1 mmol) in 30 ml of CH2Cl2. The reaction mixture was stirred at room temperature for 5 days. The precipitate was filtered off and the filtrate taken up in CH2Cl2, washed twice with 10% aqueous HCl, saturated aqueous Na2CO3 and saturated aqueous NaCl. The organic phases were dried over Na2SO4 and concentrated. Flash-chromatography over SiO2 (heptane/ether 9:1) gave 4.02 g of the desired compound (yield: 74%).
Reaction SMILES: O.[C:2]([CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17])(=[O:4])[NH2:3]>[Fe].C(O)(=O)C>[C:2]([CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17])(=[O:4])[NH2:3]
Reactant: COc1ccc([N+](=O)[O-])cc1NCC(N)=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(N)cc1NCC(N)=O
Temperature: 0 °C

Procedure:
Into 180 ml of water one adds 45 g of powdered iron and 15 ml of acetic acid. One brings this mixture under agitation to a temperature of 85° C. then one adds, little by little, 0.2 mol (45 g) of 2-carbamylmethylamino-4-nitro anisole. One maintains the reaction mixture for 10 minutes at 90° C. One adds soda to obtain a pH of 7.5, and then filters it hot. The filtrate is cooled to a temperature of 0° C. The expected product which precipitates is drained, washed with very little water, dried, recrystallized in methylisobutylketone. It melts at 144° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([B:23]2[O:27][C:26](C)(C)[C:25](C)(C)[O:24]2)=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:32](C)([O-:34])=[O:33].[OH-].[Na+].C1COCC1>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[B:23]([OH:27])[O:24][CH:25]([CH2:26][N+:32]([O-:34])=[O:33])[C:15]=2[CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(B2OC(C)(C)C(C)(C)O2)c1OCCCOCc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1OCCCOCc1ccccc1)B(O)OC2C[N+](=O)[O-]

Procedure:
Synthesized according to the methods of general procedure 8 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 3-(3-benzyloxy-propoxy)-4-methoxy-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (3.36 g, 7.88 mmol), nitromethane (1.28 mL, 23.66 mmol), NaOH (0.22 g, 5.52 mmol), THF (6 mL), water (18 mL). Purification: flash column chromatography (30% EtOAc/hexanes): yield 1.2 g (41%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.36 (s, 1H), 7.40-7.22 (m, 5H), 7.22-7.04 (m, 2H), 5.68 (dd, J=9.4, 2.7 Hz, 1H), 5.29 (dd, J=13.4, 2.5 Hz, 1H), 4.52 (dd, J=13.3, 9.4 Hz, 1H), 4.45 (s, 2H), 4.25 (t, J=6.2 Hz, 2H), 3.75 (s, 3H), 3.61 (t, J=6.2 Hz, 2H), 1.92 (quin, J=6.5 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:16]1[CH:21]=[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])[C:19]([F:35])=[CH:18][C:17]=1[N+:36]([O-:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:35][C:19]1[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:21][C:16]([O:1][C:2]2[C:3]([O:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=2)=[C:17]([N+:36]([O-:38])=[O:37])[CH:18]=1
Reactant: COC(=O)C(C)Oc1ncccc1O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
To a mixture of 0.18 g of 3-hydroxy-2-{1-(methoxycarbonyl)ethoxy}pyridine, 0.19 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and 2.0 ml of N,N-dimethylformamide was added 91 mg of potassium carbonate, and the mixture was stirred for 3 hours at 70° C. The reaction solution was cooled to room temperature, then, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.21 g of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine [present compound 9-42] (as a mixture of two diastereomerical isomers).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[CH:18]=[CH:17][C:16]([C:21](=[O:30])[CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([CH3:20])[CH2:15][C:14]=3[CH:13]=[N:12]2)=[CH:7][CH:6]=1>C1COCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[CH:18]=[CH:17][C:16]([C:21]([OH:30])([CH2:22][CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH3:1])([CH3:20])[CH2:15][C:14]=3[CH:13]=[N:12]2)=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: CC1(C(=O)CCc2ccccc2)C=Cc2c(cnn2-c2ccc(F)cc2)C1
Solvent: C1CCOC1
Product: CC(O)(CCc1ccccc1)C1(C)C=Cc2c(cnn2-c2ccc(F)cc2)C1
Reaction time: 2.5 h
Yield: 82 %

Procedure:
A 3 M THF solution of methylmagnesium bromide (0.15 mL, 5.4 eq) was added to a THF (1 mL) solution of Example 202 (30 mg, 0.083 mmol) at room temperature. After 2.5 h, the reaction was quenched with saturated NH4Cl and extracted with EtOAc. The EtOAc layer was concentrated and purified by flash column chromatography (4 g ISCO silica gel cartridge, 0 to 50% EtOAc-hexanes) to give the title compound (25.7 mg, 82%) as a 1:1 mixture of two isomers. MS found: (M+H)+=377.