Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1=[O:19])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl[Si](C)(C)C>C(OCC)(=O)C>[OH:37][C@H:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:2]([CH2:3][CH2:4][C:5]#[CH:6])[C:1]([N:8]1[C@@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][O:10][C:9]1=[O:19])=[O:7]
Reactant: O=Cc1ccccc1
Reactant: C#CCCCC(=O)N1C(=O)OC[C@@H]1c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCC[C@@H](C(=O)N1C(=O)OC[C@@H]1c1ccccc1)[C@H](O)c1ccccc1
Reaction time: 72 h
Yield: 80.9 %

Procedure:
To a stirred solution of 56.8 g (221 mmol) of (4S)-3-hex-5-ynoyl-4-phenyl-1,3-oxazolidin-2-one from step A above in 265 mL of anhydrous ethyl acetate at ambient temperature under an atmosphere of nitrogen was added 6.31 g (66.2 mmol) of anhydrous magnesium chloride, 61.5 mL (442 mmol) of triethylamine, 26.9 mL (265 mmol) of benzaldehyde and 42.3 mL (331 mmol) of chlorotrimethylsilane and the resulting mixture was stirred for 72 h. The heterogeneous reaction mixture was filtered through a 300 mL plug of silica gel eluting with an additional 1 L of ethyl acetate. The filtrate was evaporated to dryness in vacuo and the residue suspended in 265 mL of methanol and 10 mL of trifluoroacetic acid. The resulting mixture was stirred at ambient temperature under nitrogen for 5 h during which time the reaction became homogeneous. All volatiles were then removed in vacuo and the residue was purified by silica gel chromatography eluting with a 5-15% ethyl acetate in hexanes gradient to afford the title compound as a white solid (65.0 g, 81.2%). 1H NMR (500 MHz, CDCl3): δ 7.30-7.28 (m, 8H), 7.09-7.07 (m, 2H), 5.42 (dd, J=8.7, 3.7 Hz, 1H), 4.76-4.72 (m, 1H), 4.72-4.67 (m, 1H), 4.65 (t, J=8.7 Hz, 1H), 4.18 (dd, J=8.7, 3.7 Hz, 1H), 3.05 (d, J=7.8 Hz, 1H), 2.24 (td, J=7.1, 2.5 Hz, 2H), 2.00-1.93 (m, 2H), 1.67-1.61 (m, 1H). LC-MS: m/z (ES) 346.1 (MH—H2O)+, 386.0 (MNa)+.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.[OH-].[Na+]>C(O)C.O>[CH2:1]([S:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1nc2ccccc2s1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(CSc2nc3ccccc3s2)cc1
Yield: 68.2 %

Procedure:
A solution of 28.1 g (0.2 mol) of benzyl chloride in 50 ml of ethanol is added slowly, with stirring, to a solution of 33.4 g (0.2 mol) of 2-mercaptobenzothiazole and 8 g (0.2 mol) of NaOH in 150 ml of ethanol and 25 ml of water. The resulting solution is refluxed for 2.5 h. After cooling, it is filtered and evaporated to leave 35.1 g of a yellowish solid melting at 39°-40° C. 1H NMR (CDCl3): δ4.41 (2H), δ6.98-7.8 (9H) ppm.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[N:25][CH:26]=1>>[F:27][C:24]1[N:25]=[CH:26][C:21]([O:20][CH2:19][CH2:18][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:22][CH:23]=1
Reactant: Fc1ccc(OCCBr)cn1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CCOc1ccc(F)nc1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-[(2-bromoethyl)oxy]-2-fluoropyridine. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J=8.5 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.45 (m, 1H), 7.03 (dd, J=9.0 and 3.4 Hz, 1H), 6.54 (s, 1H), 4.69 (t, J=5.1 Hz, 2H), 4.35 (t, J=5.1 Hz, 2H), 2.56 (s, 3H); MS (ES) m/z 364 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NCCc2cccc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(NCCc2cccc(F)c2)c2cccc(N)c2)cc1
Yield: 83.9 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-[2-(3-fluorophenyl)ethyl]amine (2.51 g) [prepared as described in step (a) above] in methanol (50 ml), nickel chloride hexahydrate (3.14 g) and sodium borohydride (1.0 g) were reacted, to afford the title compound (1.94 g) as a yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[N:12]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH:16]=[CH:15][N:14]=[CH:13]1.C(N(CC)CC)C>COCCOC>[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: NCCCn1ccnc1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Cc1cc(NCCCn2ccnc2)ccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
A mixture of 31.2 g (0.2 mol) of 4-fluoro-2-methyl-1-nitrobenzene, 37.5 g (0.3 mol) of 3-imidazol-1-ylpropylamine and 34.8 ml (0.25 mol) of triethylamine in 30 ml of 1,2-dimethoxyethane was heated with stirring for 3 hours on a boiling water bath.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O>CN(C=O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([Cl:16])=[O:12]
Reactant: O=C(O)Cc1ccc(F)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,4-difluorophenylacetic acid (206 mg), DMF (1 drop) and tetrahydrofuran (4 ml) was added oxalyl chloride (0.13 ml) dropwise. The resulting mixture was stirred at room temperature for 1 hour and the solvent was then distilled off to give 2,4-difluorophenylacetyl chloride. This chloride was dissolved in dichloromethane (5 ml) followed by addition of 3-amino-4-(2-chlorophenyl)-7,8-dihydro-6H-cyclopenta[g]quinoline (294 mg) and N,N-dimethylaniline (0.13 ml). The mixture was further stirred at room temperature for 3 hours, after which it was washed with water, saturated aqueous solution of NaHCO3 and water in the order mentioned and dried (over MgSO4). The solvent was then distilled off to give 4-(2-chlorophenyl)-3-(2,4-difluorophenylacetylamino)-7,8-dihydro-6H-cyclopenta(g)quinoline as oil. This oil was crystallized from isopropyl ether (yield 342 mg, 76.3%). Recrystallization from ethanol gave colorless prisms, mp. 179°-180° C.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][CH:7]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[C:8]([NH:10][C:11]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[O:9].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:6][CH:7]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:36])([F:35])[F:37])[CH:25]=1)[C:8]([NH:10][C:11]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:12][CH2:13][C:14](=[CH2:1])[CH2:15][CH2:16]1)=[O:9]
Reactant: [Li]CCCC
Reactant: CC(C(=O)NC1(c2ccccc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCC(NC(=O)C(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
n-Butyllithium (1.6 Mol solution in hexanes, 10.3 mL) was added slowly to a stirred, cooled (0° C.) suspension of methyl triphenylphosphonium bromide (5.86 g, 16.4 mmol) in tetrahydrofuran (60 mL) and the mixture was stirred at room temperature for 3 hours. The mixture was cooled to 0° C. and (RS)-α-methyl-N-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide (Example 3, 3.0 g, 6.56 mmol) in tetrahydrofuran (20 mL) was added. The mixture was stirred at room temperature for 1 hour, then under reflux for 3 hours. The mixture was cooled, poured into water and extracted with ethyl acetate. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a short column of silica gel, eluting with dichloromethane, to give the title compound as a colorless solid (2.27 g, 91%). 1H NMR (400 MHz, CDCl3) δ 7.80 (1H, s), 7.75 (2H, s), 7.26–7.20 (5H, m), 5.59 (1H, s), 4.68 (2H, m), 3.70 (1H, d, J 7.1 Hz), 2.53–2.45 (1H, m), 2.38–2.31 (1H, m), 2.29–2.04 (4H, m), 2.00–1.85 (2H, m), and 1.52 (3H, d, J, 7.1 Hz).
Reaction SMILES: C([N:4]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([Cl:47])[CH:45]=2)[C@@:6]2([C@H:11]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[O:19][C:20]([CH2:30][CH3:31])([C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:24])[CH2:21][CH3:22])[CH2:10][C:9](=[O:32])[NH:8][C@@H:7]2[C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[CH3:40])[C:5]1=[O:48])(=O)C.[OH-].[Na+].O>CO>[Cl:47][C:44]1[CH:45]=[C:46]2[NH:4][C:5](=[O:48])[C@:6]3([C@H:11]([C:12]4[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=4[O:19][C:20]([CH2:30][CH3:31])([C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:24])[CH2:21][CH3:22])[CH2:10][C:9](=[O:32])[NH:8][C@@H:7]3[C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:41]2=[CH:42][CH:43]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1[C@@H]1CC(=O)N[C@H](c2cc(Cl)ccc2C)[C@@]12C(=O)N(C(C)=O)c1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(CC)(Oc1ccc(Cl)cc1[C@@H]1CC(=O)N[C@H](c2cc(Cl)ccc2C)[C@@]12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Reaction time: 8 h
Yield: 53.4 %

Procedure:
At room temperature, a mixture of chiral (2′R,3R,4′S)-1-acetyl-6-chloro-4′-[5-chloro-2-(1-ethyl-1-methanesulfonylaminocarbonyl-propoxy)-phenyl]-2′-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (20 mg, 0.027 mmol) (RO5319796-000), NaOH (2 mg, 0.05 mmol), H2O (0.5 mL) and methanol (2 mL) was stirred overnight. Then methanol was removed by vacuum. The aqueous solution was acidified by addition of concentrated HCl to “pH” 1-2 and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give the title compound as a white solid (10 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[N:19]4)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1>CS(C)=O.C(OCC)(=O)C>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([C:30]2[CH2:31][CH2:32][N:27]([CH2:12][CH:13]3[O:26][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[CH:21][CH:20]=[N:19]5)[CH2:28][CH:29]=2)=[CH:34]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nccnc4c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4nccnc4c3O2)C1
Temperature: 80 °C

Procedure:
To a solution of (2R)-2,3-dihydro[1,4]dioxino[2,3-f]quinoxalin-2-ylmethyl 4-methylbenzenesulfonate (0.300 g, 0.856 mmole) in methyl sulfoxide (20 mL) was added 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.639 g, 3.222 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.248 g (77%) of the (S)-enantiomer of the title compound as a pale yellow solid. Rf=0.36 (silica, methanol:ethyl acetate 1:9); mp >220° C. dec.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22](O)[CH2:21]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22]([O:10][C:9](=[O:11])[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH2:21]2
Reactant: O=C(O)C(Nc1cccc(F)c1)c1ccc(F)cc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1cccc(F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
A mixture of (4-fluoro-phenyl)-(3-fluoro-phenylamino)-acetic acid (I83) (510 mg, 1.94 mmol), (R)-quinuclidin-3-ol (246 mg, 1.94 mmol), HOBT (356 mg, 2.32 mmol) and DCC (480 mg, 2.32 mmol) in THF (10 mL) is stirred at RT overnight (UPLC-MS monitoring: complete conversion). The solvent is evaporated, the crude is dissolved in EtOAc and the insoluble is filtered off. The clear solution is washed with 1N K2CO3 and then with brine. The organic layer is dried over Na2SO4, filtered and evaporated. The crude is purified by silica gel chromatography (EtOAc/MeOH=8/2) to give the title compound as a yellow oil (360 mg, 50% yield, mixture of diastereoisomers).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13]3[CH2:17][CH2:16][CH:15]([NH:18][OH:19])[CH:14]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.C[Si]([N:26]=[C:27]=[O:28])(C)C.C(O)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13]3[CH2:17][CH2:16][CH:15]([N:18]([OH:19])[C:27]([NH2:26])=[O:28])[CH:14]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:20][CH:21]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: ONC1C=C(c2cccc(Oc3ccc(F)cc3)c2)CC1
Solvent: CCO
Solvent: C1CCOC1
Product: NC(=O)N(O)C1C=C(c2cccc(Oc3ccc(F)cc3)c2)CC1
Reaction time: 1 h

Procedure:
To a stirred solution of N-[3-[3-(4-fluorophenoxy)phenyl]cyclopent-2-enyl]-N-hydroxylamine (1.07 g; 3.75 mM) in dry THF (10 ml) was added trimethylsilyl isocyanate (0.76 g; 5.63 mM) at room temperature. After stirring for 1 hr, ethanol (10 ml) was added. Volatiles were removed, and the resulting solids were recrystallized from ethyl acetate-n-hexane to give 0.6 g (y. 28%) of the subtitle compound [G] as colorless solids.
Reaction SMILES: [CH3:1][N:2]([CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[C:3]([C:5]1[CH:13]=[CH:12][C:8]2=[N:9][O:10][N:11]=[C:7]2[CH:6]=1)=[O:4].Cl.[NH2:22][OH:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:23][N:22]=[C:17]1[CH2:18][CH2:19][CH:14]([N:2]([CH3:1])[C:3]([C:5]2[CH:13]=[CH:12][C:8]3=[N:9][O:10][N:11]=[C:7]3[CH:6]=2)=[O:4])[CH2:15][CH2:16]1
Reactant: CN(C(=O)c1ccc2nonc2c1)C1CCC(=O)CC1
Reactant: NO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc2nonc2c1)C1CCC(=NO)CC1
Reaction time: 8 h
Yield: 85.6 %

Procedure:
N-Methyl-N-(4-oxocyclohexyl)-[2,1,3]-benzoxadiazole-5-carboxamide (0.41 g, 1.5 mmol) was dissolved in chloroform (10 ml), hydroxylamine hydrochloride (0.63 g) and triethylamine (1.6 ml) were added, and the mixture stirred overnight. Evaporation of the solvent and chromatography of the residue on silica gel, eluting with chloroform/ethyl acetate (3:2), gave a white solid (0.37 g). Mp=197-198° C., 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H); 7.93 (d, J=9.0 Hz, 1H); 7.86 (m, 1H); 7.43 (d, J=9.0 Hz, 1H); 4.90-4.70 and 3.80-3.35 (m, 1H); 2.99 and 2.88 (s+s, 3H); 2.80-1.50 ppm (s, 8H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:13]=[C:14]([C:19](=[O:37])[C:20]([N:23]2[C:28](=[O:29])[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:26]([CH3:36])[O:25][CH2:24]2)([CH3:22])[CH3:21])[CH:15]=[C:16]([F:18])[CH:17]=1.Cl[C:39]([O:41][CH3:42])=[O:40]>O1CCCC1>[F:11][C:12]1[CH:13]=[C:14]([C:19](=[O:37])[C:20]([N:23]2[C:28](=[O:29])[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:26]([CH2:36][C:39]([O:41][CH3:42])=[O:40])[O:25][CH2:24]2)([CH3:22])[CH3:21])[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: COC(=O)Cl
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)c2cc(F)cc(F)c2)CO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)c2cc(F)cc(F)c2)CO1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 11.2 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.5 ml of 1.0M solution) was added to a solution of 1-(3,5-difluorophenyl)-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-propan-1-one (0.5 g) in tetrahydrofuran, under an inert atmosphere at -5° C. After stirring for 0.5 hours, methyl chloroformate (1.22 g) was added and the solution allowed to warm to 20° C. After 18 hours, the solution was poured onto water, extracted (ether) and evaporated. Purification by dry column chromatography on silica gel, eluting with hexane/ethyl acetate (4:1), gave 1-(3,5-difluorophenyl)-2-(2,3-dihydro-6-methoxycarbonylmethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropan-1-one (Compound 700, 0.065 g), NMR 1.5 (s,6H), 3.1 (s,2H), 3.6 (s,3H), 5.4 (s,2H), 6.8 (m,1H), 7.0 (m,2H), 7.2 (m,3H), 7.5 (d,2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([O:8]S(C)(=O)=O)[CH2:5][O:6][CH3:7].[C:13]1(O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][CH2:3][CH:4]([CH2:5][O:6][CH3:7])[O:8][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccccc1
Reactant: COCC(COC)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(COC)Oc1ccccc1
Temperature: 90 °C

Procedure:
A stirred mixture of 2.0 g of methanesulfonic acid 2-methoxy-1-methoxymethyl-ethyl ester, 1.4 g of phenol and 2,8 g of powdered potassium carbonate in 50 mL of dry N,N-dimethylformamide was heated at 90° C. for 24 hours. After cooling, water was added at room temperature and the mixture extracted with diethyl ether. The combined ether extracts were washed with aqueous sodium hydroxide (2 N) and water, dried (sodium sulfate) and concentrated. The crude product (1.0 g) was used in the next step without further purification. EI-MS: 198 (M+).
Reaction SMILES: [N:1]([CH:4]1[CH:13]([OH:14])[C:12]2[C:7](=[CH:8][C:9]([C:15]#[N:16])=[CH:10][CH:11]=2)[O:6][CH2:5]1)=[N+:2]=[N-:3].Cl.[NH2:18][OH:19].C(=O)(O)[O-].[Na+]>CC(O)C.CCOC(C)=O>[N:1]([CH:4]1[CH:13]([OH:14])[C:12]2[C:7](=[CH:8][C:9]([C:15](=[N:18][OH:19])[NH2:16])=[CH:10][CH:11]=2)[O:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: N#Cc1ccc2c(c1)OCC(N=[N+]=[N-])C2O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC1COc2cc(C(N)=NO)ccc2C1O
Temperature: 25 °C
Yield: 97.5 %

Procedure:
Racemic (3R*,4S*)-3-azido-4-hydroxychroman-7-carbonitrile Int-2-C (5.08 g, 23.5 mmol) and hydroxylamine hydrochloride (3.27 g, 47.0 mmol) were mixed in 2-propanol (94.0 mL). To this suspension was added sodium bicarbonate (7.90 g, 94.0 mmol) and the resulting mixture was heated at reflux for 2 h. After the reaction mixture was cooled to room temperature, it was diluted with EtOAc (250 mL) and washed with water and brine. The combined aqueous layers were extracted again with EtOAc. The combined organic layers were dried (MgSO4) and concentrated to afford racemic (3R*,4S*,E/Z)-3-azido-N′,4-dihydroxychroman-7-carboximidamide Int-2-D (5.71 g, 22.9 mmol, 97.5% yield): LCMS=250.08 [M+H]+.
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[Cl:10][SiH:11]([Cl:13])[Cl:12]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:10][Si:11]([Cl:13])([Cl:12])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(Cl)c1ccccc1
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: CC(c1ccccc1)[Si](Cl)(Cl)Cl
Yield: 35.4 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.20 g (0.68 mmol) of tetrabutylphosphonium chloride, 0.96 g (6.83 mmol) of 1-chloroethylbenzene, and 2.71 g (20.00 mmol) of trichlorosilane were reacted at 150° C. for 6 hrs. The resulting mixture was distilled to give 0.58 g 1-trichlorosilylethylbenzene (yield; 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:34]([F:35])=[CH:33][C:28]([O:29][CH2:30][CH2:31][OH:32])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].CCN(C(C)C)C(C)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(Cl)Cl>[CH3:48][S:49]([O:32][CH2:31][CH2:30][O:29][C:28]1[CH:27]=[C:26]([F:36])[C:25]([CH2:24][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:37][CH3:38])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[C:34]([F:35])[CH:33]=1)(=[O:51])=[O:50]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCOS(C)(=O)=O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a stirred solution of 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethanol (3.8 g, 6.75 mmol) and DIPEA (3.52 mL, 20.3 mmol) in DCM (100 mL) at 0° C. was added methanesulfonyl chloride (603 μL, 7.8 mmol). After the reaction was slowly warmed to ambient temperature over 30 min, it was partitioned in DCM (100 mL) and water (100 mL). Organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex/EtOAc=1:3) to give 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethyl methanesulfonate (4.1 g, 95% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J=8.25 Hz, 1H), 7.22 (s, 1H), 6.82-6.72 (m, 2H), 6.58-6.47 (m, 2H), 6.42-6.32 (m, 4H), 4.55 (dd, J=5.27, 3.62 Hz, 2H), 4.18 (dd, J=5.26, 3.64 Hz, 2H), 4.04 (s, 2H), 3.78 (s, 3H), 3.09 (s, 3H), 1.50 (d, J=10.49 Hz, 6H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1)=[O:28]
Reactant: CSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
2-(6-Methylthio-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.28 g, 1.0 mmol) obtained in Example 43 was dissolved in chloroform (30 ml). To the stirred mixture was added dropwise a solution of 3-chloroperbenzoic acid (ca. 70%, 0.25 g, 1.0 mmol) in chloroform (10 ml). The reaction mixture was stirred for 1 hr and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with 10% methanol-chloroform and recrystallized from ethanol to give the titled compound (0.19 g, 64%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][CH:19]=[C:20]([C:22]2[S:23][CH:24]=[C:25]([C:27]([O:29]CC)=O)[N:26]=2)[CH:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[NH3:32]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][CH:19]=[C:20]([C:22]2[S:23][CH:24]=[C:25]([C:27](=[O:29])[NH2:32])[N:26]=2)[CH:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: N
Reactant: CCOC(=O)c1csc(-c2csc(C(O)(Cn3cncn3)c3ccc(F)cc3F)c2)n1
Solvent: CO
Product: NC(=O)c1csc(-c2csc(C(O)(Cn3cncn3)c3ccc(F)cc3F)c2)n1

Procedure:
The thus-obtained compound (A) is dissolved in a saturated methanol solution of ammonia, and the resultant solution is left to stand, thereby reacting the compound and ammonia to obtain 1-(2,4-difluorophenyl)-1-(4-(4-carbamoylthiazol-2-yl)-thiophen-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol (B).