Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)CCCCCCC1.[C:10]1([NH:18][CH:19]=[C:20]([C:26]([O:28]CC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1>>[OH:28][C:26]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]=12
Reactant: CCOC(=O)C(=CNC1=CCCCCCC1)C(=O)OCC
Agent: O=C1CCCCCCC1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(c1O)CCCCCC2
Temperature: 25 °C

Procedure:
A solution of 85 g of the mixture of cyclooctanone and diethyl N-(1-cyclooctenyl)-aminomethylenemalonate in 20 ml. of Dowtherm® (a eutectic mixture of diphenyl ether and biphenyl) is added to 380 ml. Dowtherm® at 250°-255° under nitrogen. The distillate is collected in a water separator. After 0.5 hour the mixture is cooled to room temperature and solvent is removed under reduced pressure. The residual solid is triturated with ether to give ethyl 5,6,7,8,9,10-hexahydro-4-hydroxycycloocta[b]pyridine-3-carboxylate, m.p. 219°-222°.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C@H:3]([OH:31])[CH2:4][NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=2)[N:9]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:8][CH2:7]1.[C:41](N(C(=O)C)OC)(=[O:43])[CH3:42]>ClCCl>[C:41]([NH:1][C@@H:2]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C@H:3]([OH:31])[CH2:4][NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=2)[N:9]([C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:8][CH2:7]1)(=[O:43])[CH3:42]
Reactant: CC(C)(C)Cc1ccc2c(c1)C(NC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)CCN2C(=O)OCc1ccccc1
Reactant: CON(C(C)=O)C(C)=O
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1CCN(C(=O)OCc2ccccc2)c2ccc(CC(C)(C)C)cc21
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of benzyl 4-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-6-neopentyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.226 g) in dichloromethane (5 mL) was added N,N-diacetyl-O-methylhydroxylamine (0.064 g). The mixture was stirred over the weekend at room temperature. The solvent was then removed under reduced pressure and the residue was partitioned between 1N HCl and ethyl acetate, dried with magnesium sulfate, filtered, and concentrated to give 0.243 g of the title compound. (99% yield). MS (ESI+) for C34H41F2N3O4 m/z 594.31 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([NH:11][CH2:12][C:13]2[N:14]=[CH:15][S:16][CH:17]=2)=[C:5]([F:10])[C:6](=[N:8][NH2:9])[N:7]=1.[CH:18]1([CH2:23][C@H:24]([CH2:28][N:29]([CH:37]=[O:38])[O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:25](O)=[O:26])[CH2:22][CH2:21][CH2:20][CH2:19]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:25](=[O:26])[C@H:24]([CH2:23][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:28][N:29]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH:37]=[O:38])[C:5]([F:10])=[C:4]([NH:11][CH2:12][C:13]2[N:14]=[CH:15][S:16][CH:17]=2)[N:3]=1
Reactant: NN=c1nc(Cl)[nH]c(NCc2cscn2)c1F
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCc2cscn2)c1F)OC1CCCCO1
Reaction time: 48 h

Procedure:
2-Chloro-5-fluoro-6-[(1,3-thiazol-4-ylmethyl)amino]-4(1H)-pyrimidinone hydrazone (0.105 g) and (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (0.182 g, 0.422 mmol) were dissolved in DMF (5 mL). NMM (0.21 mL, 1.91 mmol) was added, followed by HOAt (0.063 g, 0.463 mmol) and EDC (0.088 g, 0.459 mmol). After stirring for 2 days, the reaction mixture was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(1,3-thiazol-4-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as a maroon solid (0.1133 g). LCMS: (M+H)+=556.0.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([O:20][CH2:21][CH:22]=[CH2:23])=[CH:18][C:17]([CH3:24])=[CH:16][C:15]=3[O:25][C@@H:26]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@H:27]3[OH:28])=[O:13])[CH:8]=[CH:9][C:2]1=2.N1C(C)=CC(C)=CC=1C.[P:46](Cl)([O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)([O:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:47].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([O:20][CH2:21][CH:22]=[CH2:23])=[CH:18][C:17]([CH3:24])=[CH:16][C:15]=3[O:25][C@@H:26]3[O:34][C@H:33]([CH2:35][O:36][P:46]([O:48][C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)([O:55][C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)=[O:47])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@H:27]3[OH:28])=[O:13])[CH:8]=[CH:9][C:2]1=2
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: C=CCOc1cc(C)cc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1C(=O)CCc1ccc2occc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: Cc1cc(C)nc(C)c1
Product: C=CCOc1cc(C)cc(O[C@@H]2O[C@H](COP(=O)(Oc3ccccc3)Oc3ccccc3)[C@@H](O)[C@H](O)[C@H]2O)c1C(=O)CCc1ccc2occc2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 74.4 %

Procedure:
3-(5-Benzo[b]furanyl)-2'-(β-D-glucopyranosyloxy)-6'-allyloxy-4'-methylpropiophenone (300 mg) obtained in Example 2 is dissolved in tetrahydrofuran (3 ml), and thereto are added 2,4,6-collidine (315 mg) and diphenyl chlorophosphate (486 mg) under ice-cooling. The mixture is stirred at room temperature for 22 hours under argon atmosphere. The reaction mixture is poured into chilled 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer is washed successively with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give 3-(5-benzo[b]furanyl)-2'-(6-O-diphenylphosphono-β-D-glucopyranosyloxy)-6'-allyloxy-4'-methylpropiophenone (327 mg).
Reaction SMILES: [C:1]12([C:11]34[CH2:20][CH:15]5[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]5)[CH2:12]3)[CH2:18]4)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[C:22]12CC3CC(CC(C45CC6CC(CC(C6)C4)C5)(C3)[CH2:23]1)C2>>[CH:22]([C:5]12[CH2:6][CH:7]3[CH2:9][CH:3]([CH2:2][C:1]([C:11]45[CH2:18][CH:17]6[CH2:19][CH:13]([CH2:14][CH:15]([CH2:16]6)[CH2:20]4)[CH2:12]5)([CH2:8]3)[CH2:10]1)[CH2:4]2)=[CH2:23]
Reactant: C1C2CC3CC1CC(C14CC5CC(CC(C5)C1)C4)(C2)C3
Reactant: BrC12CC3CC(C1)CC(C14CC5CC(CC(C5)C1)C4)(C3)C2
Product: C=CC12CC3CC(C1)CC(C14CC5CC(CC(C5)C1)C4)(C3)C2

Procedure:
Biadamantane is brominated into 3-bromo-1,1′-biadamantane. In accordance with the synthesis process shown in Example 12, Exemplified compound (D-101) (3-vinyl-1,1′-biadamantane) is obtained as a target product.
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:16]2)=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:16]2)=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)cc2C#N)CC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
Ammonium chloride (5.9 g) and iron powder (32 g) were added to a mixed solvent of water (160 ml) and ethanol (470 ml), and the mixture was heated to 65° C. Then, 5-nitro-2-(4-tert-butoxycarbonylhomopiperazin-1-yl)benzonitrile (56 g) was added in parts over 30 min and the mixture was stirred at a refluxing temperature for 1 h. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (32 g), melting point: 38° C.
Reaction SMILES: [CH2:1]([N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:14]1[N:19]=[C:18]([NH2:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][CH:15]=1.C(N(CC)CC)C>CS(C)=O>[NH2:20][C:18]1[N:19]=[C:14]([N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([N:3]([CH2:1][CH3:2])[CH3:12])=[O:5])[CH2:7]2)[CH:15]=[CH:16][C:17]=1[N+:21]([O-:23])=[O:22]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CCN(C)C(=O)[C@@H]1CCCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCN(C)C(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Temperature: 80 °C
Yield: 49.3 %

Procedure:
To a solution of (R)—N-ethyl-N-methylpiperidine-3-carboxamide (600 mg, 4.1 mmol) in dimethylsulfoxide (6 mL) were added 6-chloro-3-nitropyridin-2-amine (0.58 g, 3.3 mmol) and triethylamine (1.2 mL, 8.3 mmol) at room temperature. The reaction mixture was heated to 80° C. for 18 h. The reaction mixture was poured into ice water, extracted with ethyl acetate and concentrated under reduced pressure. The crude material was purified via column chromatography (10% ethyl acetate in petroleum ether) to afford (R)-1-(6-amino-5-nitropyridin-2-yl)-N-ethyl-N-methylpiperidine-3-carboxamide (500 mg, 28.4%). MS (ES+) (M+H) 308.31.
Reaction SMILES: [S:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:14][C:15]1[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.O>[CH2:24]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]2[CH2:4][CH2:3][CH:2]([CH2:14][C:15]3[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=3)[S:1][C:6]1=2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC1(C)COC(CC2CCc3c([nH]c4ccccc34)S2)=N1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)COC(CC2CCc3c(n(Cc4ccccc4)c4ccccc34)S2)=N1
Reaction time: 0.5 h

Procedure:
71 mg of 2-(2,3,4,9-tetrahydrothiopyrano[2,3-b]indol-2-yl)methyl-4,4-dimethyl-2-oxazoline (prepared as described in Example 80) in 1 ml of dimethylformamide was added to a suspension of 11 mg of sodium hydride (55% w/w dispersion in mineral oil) in 1 ml of dimethylformamide, with stirring and ice-cooling. Stirring was continued at this temperature for 30 minutes and then 0.03 ml of benzyl bromide was added to the reaction mixture, with stirring and ice-cooling. Stirring was continued for a further hour. At the end of this time, the reaction mixture was diluted with water and then extracted with ethyl acetate. The ethyl acetate fraction was then washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography, using a mixture of 20% v/v ethyl acetate in hexane as the eluent, to afford 71 mg of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:23][C:24]1[O:28][C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[N:26][C:25]=1[CH2:34][CH2:35]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH2:1]([O:3][C:4](=[O:22])[C@:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:25]2[N:26]=[C:27]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[O:28][C:24]=2[CH3:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@@](C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: CCOC(=O)[C@@](C)(Cc1ccc(OCCc2nc(-c3cccs3)oc2C)cc1)Oc1ccccc1

Procedure:
(R)-3-(4-Hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester were reacted, as described in Example 1, Step D, to provide (R)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]phenyl}-2-phenoxypropionic acid ethyl ester, shown below, as a colorless oil (54%). 1H NMR (300 MHz, CDCl3): δ 7.59 (d, 1H), 7.37 (d, 1H), 7.24 (t, 2H), 7.13 (d, 2H), 7.09 (t, 1H), 6.96 (t, 1H), 6.83 (d, 2H), 6.82 (d, 2H), 4.21 (t, 2H), 4.19 (q, 2H), 3.26 (d, 1H), 3.12 (d, 1H), 2.95 (t, 2H), 2.35 (s, 3H), 1.39 (s, 3H), 1.21 (t, 3H). MS [EI+] 492 (M+H)+, [EI−] 490 (M−H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]2[CH:16]=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[S:14][CH:13]=2)=[N:5]S(=O)[N:3]=1.[ClH:25]>CO>[ClH:25].[ClH:25].[ClH:25].[N:18]1([CH2:17][C:15]2[S:14][CH:13]=[C:12]([CH2:11][S:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])[CH:16]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1=NS(=O)N=C1NCCSCc1csc(CN2CCCCC2)c1
Agent: Cl
Solvent: CO
Product: N=C(N)C(=N)NCCSCc1csc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A suspension of 3-amino-4-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide (6.1 g; 15.8 mmoles) [prepared according to published United Kingdom Patent Application No. 2,067,987] in 80 ml of methanol was treated with 10.5 ml of concentrated HCl. After stirring at ambient temperature for 3 hours, the solution was concentrated and the residue triturated with 50 ml of 1-propanol, filtered and dried to give 5.86 g (83%) of product. A sample was recrystallized from methanol-acetone to give the title compound, mp 201°-214° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH3:10][N:11]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1N1CCCCC1C)C(=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1>>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([C:33]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]=2[NH:11][CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: Fc1c(I)ccnc1Cl
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CNc1cnccc1-c1ccnc(Cl)c1F

Procedure:
The title compound was prepared in analogy to example 55, intermediate, from 2-chloro-3-fluoro-4-iodo-pyridine (CAS RN 148639-07-0) and (4-iodo-pyridin-3-yl)-methyl-amine (example 36, intermediate b). Brown sticky solid (86%). MS (ESI): m/z=238.0 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][Si:3]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)OC(C)C.[FH:22]>C(O)C>[Cl:1][CH2:2][Si:3]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1
Reactant: F
Reactant: CC(C)O[Si](CCl)(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CCO
Product: Fc1ccc([Si](F)(CCl)c2ccc(F)cc2)cc1
Yield: 100 %

Procedure:
A solution of 11.0 g (33.7 mmol) of chloromethyl[bis(4-fluorophenyl)](2-propoxy)silane and 10 ml of 49% aqueous hydrofluoric acid in ethanol was refluxed for 2 hours under nitrogen, cooled, and partitioned between water and ether. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated to leave 9.7 g (100%) of chloromethyl(fluoro)[bis(4-fluorophenyl)]silane as a mobile oil: nD22 1.5387; nmr (CDCl3) 3.2 (2H, d), 7.2 (4H, t), 7.8 (4H, d of d).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][C:9]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:31]([OH:33])=[O:32])=[CH:26][N:25]=1.ClCCl>CC(C)=O.C(OCC)(=O)C>[CH3:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:31]([O:33][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([F:7])=[C:9]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)=[O:32])=[CH:26][N:25]=1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Reactant: Cc1ncc(C(C(=O)O)C(C)(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1ncc(C(C(=O)OCc2ccc(F)c(Oc3ccccc3)c2)C(C)(C)C)cn1
Reaction time: 6 h
Yield: 56.8 %

Procedure:
Solid potassium carbonate (0.4 g) was added to a solution of 4-fluoro-3-phenoxybenzyl bromide (0.4 g) and (RS)-2-(2-methylpyrimidin-5-yl)-3,3-dimethylbutanoic acid (0.3 g) in acetone (20 cm3), and the mixture was stirred for a period of 6 hours. After standing for a further 2 days, the reaction mixture was filtered, the residue washed with acetone, and the combined filtrate and acetone washings concentrated by evaporation of the solvent under reduced pressure to give an orange oil. Column chromatography on silica gel using dichloromethane followed by ethyl acetate as eluent gave 4-fluoro-3-phenoxybenzyl (RS)-2-(2-methylpyrimidin-5-yl)-3,3-dimethylbutanoate (0.33 g) as an orange oil, which solidified on standing.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:7][CH:6]([F:22])[CH2:5]1.[O:25]=S(Cl)Cl.[O-][Mn](=O)(=O)=O.[K+].OS([O-])=O.[Na+]>N1C=CC=CC=1.CC(C)=O>[F:24][C:2]([F:1])([F:23])[CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:7][CH:6]([F:22])[C:5]1=[O:25]
Reactant: FC1CN(CC(F)(F)F)c2ccc(Cl)cc2C(c2ccccc2)=N1
Reactant: O=S(Cl)Cl
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C1C(F)N=C(c2ccccc2)c2cc(Cl)ccc2N1CC(F)(F)F

Procedure:
3.57 g. of 1-(2,2,2-trifluoroethyl)-3-fluoro-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepine, obtainable from the corresponding 3-hydroxy compound by reaction with SOCl2 and then AgF, is dissolved in a mixture of 35 ml. of acetone and 20 ml. of pyridine; 1.35 g. of KMnO4 are added in portions. During the addition, the mixture is briefly boiled up after each addition until the violet color has disappeared. The mixture is then heated at 100° for 1 hour more. NaHSO3 solution is added to decompose the excess oxidizing agent and the mixture is worked up in the customary manner to give 1-(2,2,2-trifluoroethyl)-3-fluoro-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[CH2:9][C:10](Cl)=[O:11])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:14])([CH3:13])[CH2:9][C:10]2=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(CC(=O)Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CC(=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.7 %

Procedure:
A solution of 3-(4-fluorophenyl)-3-methylbutyryl chloride (19.0 g, 0.0815 mol) in dichloromethane (100 ml) was added dropwise over 2.5 h to a stirring mixture of aluminum chloride (13.57 g, 0.102 mol, Aldrich) in dichloromethane (200 ml) while protected from moisture by a nitrogen atmosphere. After stirring 18 h at 25° C., the reaction solution was poured over ice (400 g) and the resulting solution was extracted with dichloromethane (2×200 ml). The dichloromethane layers were combined, washed with deionized water (50 ml), and concentrated by spin evaporation in vacuo. The residue was dissolved in ethyl acetate and washed through a pad of silica gel. The pad was washed with additional ethyl acetate. Removal of the volatiles from the combined washes by spin evaporation in vacuo gave 15.2 g (99%) of 6-fluoro-3,3-dimethyl-1-indanone as a light yellow oil which crystallized on standing, m.p., 57°-62° C.;
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Na].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1>CN(C=O)C>[N+:8]([C:7]1[C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1-n1cncn1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A solution of 10 g of 2-chloro-3-nitropyridine dissolved in 30 ml of dry DMF was added dropwise to a suspension containing 6.9 g of 1,2,4-triazole sodium salt (90%, Aldrich Chemical Co.) in 40 ml of dry DMF. After a slow exotherm had subsided, the suspension was heated at 60° for three hours, then cooled to 25° C. and poured onto 500 ml of ice-water to yield a precipitate. After the mixture was filtered, the isolated solid was washed 2×50 ml of water and suction-dried to yield 12 g of crude product. The product was recrystallized from 2-propanol to yield 8 g of the subject compound; m.p. 131°-133°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[CH2:26]([C:28]1[NH:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1)[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=[C:28]3[CH2:26][CH3:27])=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:9])=[O:10]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Reactant: CCc1nc2ccccc2[nH]1
Product: CCc1nc2ccccc2n1Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2Cl)cc1
Yield: 65 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide (Intermediate 8), and 2-ethyl benzimidazole, the title compound was isolated as a yellow solid in 65% yield (96% purity by HPLC).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][C:29]([CH:26]3[CH2:28][CH2:27]3)=[O:30])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNC(=O)C2CC2)no1
Yield: 107.5 %

Procedure:
Method as for preparation 50 using tert-butyl (3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (204 mg, 0.57 mmol) and cyclopropane carboxylic acid chloride (62 μl, 0.68 mmol) as starting materials to afford the title compound as a colourless oil (257 mg).