Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[K+].[Br-]>>[CH2:22]([N:15]1[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16]1=[O:17])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Agent: [Br-]
Agent: [K+]
Product: O=C1C(CCO)Oc2ccccc2N1Cc1ccccc1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with benzyl chloride, in 49% overall yield and crystallized from ether/hexane to produce a white solid, mp 83°-85.5° C.; IR (KBr) 3213, 1680, 1505, 1399, 1250, 1050, 753 cm-1 ; 1H NMR (CDCl3) δ2.17-2.38 (m, 3H), 3.92 (q, J=5.7 Hz, 2H), 4.84 (dd, J=7.5, 5.6 Hz, 1H), 5.16 (s, 2H), 6.86-7.03 (m, 4H), 7.21-7.37 (m, 5H); MH+ at m/z=284; Anal. Calc'd for C17H17NO3 : C, 72.07; H, 6.05; N, 4.94. Found: C, 72.08; H, 6.20; N, 4.87.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14][CH2:13]3)[C:8]2=[O:19])=[C:4]([Cl:22])[CH:3]=1.[H-].[Na+].[CH2:25]1COCC1>>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([C@H:12]3[CH2:13][CH2:14][C@@H:15]([O:18][CH3:25])[CH2:16][CH2:17]3)[C:8]2=[O:19])=[C:4]([Cl:22])[CH:3]=1
Reactant: C1CCOC1
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCN1[C@H]1CC[C@@H](O)CC1
Agent: [H-]
Agent: [Na+]
Product: CO[C@H]1CC[C@@H](N2CCC(Cc3ccc(Br)cc3Cl)C2=O)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
Dissolve 3-(4-bromo-2-chloro-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one (Example 134) (0.20 g, 0.52 mmol) in THF (10 mL) and cool to 0° C. Add NaH (0.062 g, 1.55 mmol, 60% wt.) and stir the reaction mixture for 1 hour at 0° C. Then add Mel (0.11 g, 0.78 mmol) and continue to stir the reaction mixture overnight until LC-MS shows the starting material has gone. Add water (10 mL) and extract the aqueous layer with EtOAc (3×50 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 20-50% of EtOAc/Hexane) to give 0.17 g (83%) of the title compound as colorless oil: MS (APCI-pos mode) m/z (rel intensity) 400.0 (70), 402.0 (100).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.C(N(CC)CC)C.Cl.[NH2:25][C@H:26]([CH2:31][OH:32])[C:27]([O:29][CH3:30])=[O:28]>>[OH:32][CH2:31][C@@H:26]([N:25]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@H](N)CO
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CO)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 70 °C

Procedure:
A round bottom flask was charged with 5-nitro-isochromen-1-one (10 g, 0.05 mol), methanol (200 mL, 5 mol), triethylamine (18 mL, 0.13 mol) and (R)-methyl 2-amino-3-hydroxypropanoate hydrochloride (9.8 g, 0.063 mol) where by the reaction became homogeneous. The reaction was then heated at 70° C. overnight. The solvent was removed and the residue purified by flash chromatography (120 g, 0-10% MeOH/DCM) to yield the product as a yellow solid. MS m/z=293.5 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:4]=2[O:3]1.CN(C=O)C.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)Cl>[Br:27][C:10]1[C:11]([CH3:13])=[CH:12][C:4]2[O:3][C:2]([CH3:14])([CH3:1])[C:7](=[O:8])[NH:6][C:5]=2[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)OC(C)(C)C(=O)N2
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1Br)NC(=O)C(C)(C)O2
Reaction time: 4 h
Yield: 58 %

Procedure:
A solution of Compound 1A (4.24 g, 22.2 mmol) in 150 mL of chloroform was treated with 5 mL of dry DMF followed by 4.4 g (24.4 mmol) of NBS at room temperature. After 4 hours, the reaction was quenched with 150 mL of a saturated sodium thiosulfate solution. The aqueous layer was extracted with chloroform and the combined organic layers were dried with magnesium sulfate, filtered, and excess solvent removed on the rotary evaporator. The crude product was purified via silica gel chromatography (5% EtOAc/Hexanes) to yield 3.48 g of brominated product (58%). MS (electrospray): mass calculated for C11H12BrNO2, 269.01; m/z found 268, [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10][C:11]2[C:16](Br)=[CH:15][CH:14]=[C:13]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]=2[F:26])=[O:9])=[C:6]([F:27])[C:5]([O:28][CH2:29][CH3:30])=[CH:4][CH:3]=1>CN(C=O)C.O.[Cu]>[CH2:29]([O:28][C:5]1[CH:4]=[CH:3][C:2]2[C:16]3[C:11](=[C:12]([F:26])[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:14][CH:15]=3)[O:10][C:8](=[O:9])[C:7]=2[C:6]=1[F:27])[CH3:30]
Reactant: CCOc1ccc(Br)c(C(=O)Oc2c(Br)ccc(OCc3ccccc3)c2F)c1F
Agent: [Cu]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2c(c1F)c(=O)oc1c(F)c(OCc3ccccc3)ccc12
Yield: 20.9 %

Procedure:
103 g (0.188 mol) of 3-benzyloxy-6-bromo-2-fluorophenyl 6-bromo-3-ethoxy-2-fluorobenzoate were dissolved in 1 l of DMF and refluxed for 72 hours in the presence of 119 g (1.88 mol) of copper powder. The batch was subsequently diluted with water and extracted with ethyl acetate, and the combined extracts were dried over sodium sulfate and evaporated. Crystallisation of the crude product from THF gave 15 g (21% of theory) of 8-ethoxy-4,7-difluoro-3-benzyloxybenzo[c]chromen-6-one as pale-yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:25](=[O:27])[CH3:26])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of 5.0 g (24.1 mmol) of 1-(4-nitro-phenyl)-piperazine in 100 mL of dichloromethane was added 5.04 mL (28.9 mmol) of diisopropyl-ethylamine. The solution is cooled in an ice-bath, treated with 1.89 mL (26.5 mmol) of acetyl chloride, and stirred at room temperature overnight. The reaction is washed successively with water, 0.5 M HCl, saturated sodium hydrogen carbonate, and brine, and dried over magnesium sulfate, and concentrated to give 5.91 g (98.5%) of the product as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[NH2:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1.[F:20][C:21]([F:31])([F:30])[C:22](=O)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:1]([O:3][C:4]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]2[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([C:21]([F:20])([F:30])[F:31])[NH:14][C:15]3=[N:16][NH:17][CH:18]=[C:19]23)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C=O)cc1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Product: CCOC(=O)C1=C(C(F)(F)F)Nc2n[nH]cc2C1c1ccc(C(=O)OCC)cc1

Procedure:
The title compound was prepared from 4-ethoxycarbonylbenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[CH:10]([CH2:23][C:24]([OH:26])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>[Pt].CO.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][C:24](=[O:26])[CH2:23][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC1CN(Cc2ccccc2)CCN1c1ccccc1[N+](=O)[O-]
Agent: [Pt]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C1CC2CN(Cc3ccccc3)CCN2c2ccccc2N1
Reaction time: 18 h

Procedure:
Platinum on carbon (5%, 30 mg) was added to a solution of the product of Example 26B (0.67 g, 1.88 mmol) in methanol (100 mL). The reaction flask was evacuated and purged with nitrogen (5 cycles) and then with hydrogen (5 cycles), and the suspension was stirred under hydrogen (1 atm) for 18 hours. The reaction flask was evacuated and purged with nitrogen (5 cycles), and the mixture was filtered through diatomaceous earth with ethyl acetate (50 mL) and methanol (50 mL) rinses. The filtrate was concentrated under vacuum and the residue was dissolved in N,N-dimethylformamide (8 mL). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (720 mg, 1.89 mmol) and diisopropylethylamine (0.395 mL, 2.262 mmol) were added, and the solution was stirred at room temperature for 3 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed successively with 1 N NaOH (50 mL) and brine (40 mL), and then concentrated under vacuum. The residue was purified by flash chromatography (SiO2 eluted with CH2Cl2—CH3OH, 100:0-95:5) to provide the title compound: 1H NMR (300 MHz, CD3OD) δ ppm 1.98 (dd, J=13.4, 1.2 Hz, 1H), 2.27 (dt, J=11.4, 3.1 Hz, 1H), 2.40 (t, J=10.9 Hz, 1H), 2.67 (dd, J=13.2, 7.5 Hz, 1H), 2.82-2.89 (m, 1H), 2.89-2.97 (m, 1H), 3.01-3.09 (m, 1H), 3.22 (dd, J=11.5, 2.7 Hz, 1H), 3.35-3.44 (m, 1H), 3.61 (s, 2H), 6.98 (dd, J=8.1, 1.7 Hz, 1H), 7.03 (td, J=7.3, 1.7 Hz, 1H), 7.10-7.22 (m, 2H), 7.25-7.39 (m, 5H); MS (DCI) m/z 308 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)=[O:19])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:43])(C)C.CCOCC>CC(CC)=O>[ClH:43].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)=[O:19])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: O=C(c1ccc2ccccc2c1)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: CCOCC
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-(naphthalin-2-carbonyl)-1,4,8-triazaspiro[4,5]decan-2-one (400 mg, 0.8 mmol) was dissolved in ethyl methyl ketone (3.2 mL), water (8 μL), TMSCl (114 μL), and ether (20 mL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1,3-(S)-dibenzyl-8-(naphthalin-2-carbonyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 407 mg (95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[C:12](=[N:16][OH:17])[C:13](=O)[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:19][NH2:20].C(=O)([O-])[O-:22].[Na+].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:20][N:19]=[C:13]([CH3:14])[C:12]=2[N+:16]([O-:17])=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: NN
Reactant: COc1ccc(C(=O)C(=NO)C(C)=O)cc1OC
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(-c2[nH]nc(C)c2[N+](=O)[O-])cc1OC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
6.77 g of 1-(3,4-dimethoxyphenyl)butane-1,2,3-trione 2-oxime (42) were dissolved in 54 ml of acetic acid, after which 0.96 g of hydrazine was added dropwise at RT and the mixture was subsequently stirred at 60° C. for 2 h. Ice was added to the reaction solution, which was then neutralized with sodium carbonate and extracted with MTB-ether. The organic phase was dried over magnesium sulfate and subjected to rotary evaporation. The following was obtained: 43. C12H13N3O3 (247.26); MS (ESI) 248 (M+H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9]2[C:13]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:24][CH:23]=3)[N:10]=2)[CH:2]=1.[OH-].[Na+].O1CCCC1.C(O)C>Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9]2[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:24][CH:23]=3)[N:10]=2)[CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3)cc2)nc1OCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3cccnc3)cc2)nc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
A mixture of ethyl 3-[3-(3-pyridylmethoxy)-1-[4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (529 mg), 1 N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for one hour, diluted with 1 N hydrochloric acid (3 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-(3-pyridylmethoxy)-1-[4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (427 mg, yield: 86%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 116–117° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH2:12][C:13]1[C:20]([I:21])=[CH:19][C:16]([C:17]#[N:18])=[C:15]([S:22][CH3:23])[N:14]=1.C(OCC)(=O)C>ClCCl>[NH2:12][C:13]1[C:20]([I:21])=[CH:19][C:16]([C:17]#[N:18])=[C:15]([S:22]([CH3:23])=[O:9])[N:14]=1
Reactant: CSc1nc(N)c(I)cc1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)c1nc(N)c(I)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
1.77 g (1.1 eq) of 70% 3-chloroperbenzoic acid is added to a solution of 1.89 g (6.51 mmol) of 6-amino-5-iodo-2-(methylthio)nicotinonitrile in 60 ml of dichloromethane. The reaction medium is stirred at room temperature for 1 hour. Ethyl acetate is added and the organic phase is washed with saturated sodium bicarbonate solution, dried on magnesium sulfate, filtered and evaporated to yield 1.5 g (75%) of 6-amino-5-iodo-2-(methylsulfinyl)nicotinonitrile in the form of a white powder which may also contain 6-amino-5-iodo-2-(methylsulfonyl)nicotinonitrile in small proportions (<20%). If necessary, the mixture is used as-is in the following steps.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[K].Cl[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[F:18].[C:19]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]#[N:33])[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>C1(C)C=CC=CC=1>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][C:29]([C:32]#[N:33])([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[F:18])[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: Fc1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccncc2F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
Potassium hexamethyldisilazane (1.2 ml, 0.5 M solution in toluene) was slowly added to a solution of 4-chloro-3-fluoro-pyridin (0.5 g) and N-Boc-4-Cyano-Piperidine (0.312 g) in 1.5 ml toluene at room temperature, under nitrogen. The mixture was stirred at 80° C. for 2 hrs. After cooling, the reaction mixture was quenched in 1N HCl. The aqueous phase was extracted twice with toluene and the combined organic were dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified by chromatography [SiO2; ethyl acetate-hexane (1:1)] to give 104 mg (90%) of 4-cyano-3′-fluoro-3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-carboxylic acid tert-butyl ester; MS (ES+) 306 (M+H+).
Reaction SMILES: [OH:1][C:2]1([CH2:25][OH:26])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C=O.[C:29]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:1]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]3[CH:9]=[CH:10][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:12][CH:13]=3)[CH2:6][CH2:7]2)[CH2:25][O:26][CH2:29]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CO)CC3)cc2)C(=O)O1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: c1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)COCO4)cc2)C(=O)O1
Yield: 57 %

Procedure:
A mixture of (S)-N-{3-[4-(4-hydroxy-4-hydroxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.209 mmol), paraformaldehyde (0.233 mmol), p-toluene sulfonic acid (0.248 mmol), 4° A molecular sieves (0.160 g) in benzene (20 ml) was heated at reflux for 2 to 3 hours under stirring. The solvent was removed under vacuum to provide a residue. The residue was extracted with ethyl acetate water mixture. The combined organic layer was dried and concentrated to afford a crude product. The silica gel column chromatography afforded title compound in 57% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C@H:49]([NH2:51])[CH3:50])=[CH:45][CH:44]=1>C(Cl)(Cl)Cl>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C@H:49]([NH:51][C:31]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[O:33])[CH3:50])=[CH:45][CH:44]=1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4ccc(Cl)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 131.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 75 min. Next, a solution of (1R)-1-(4-chlorophenyl)ethylamine (36 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (70 mg, yield 62%).
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:23]=[CH:24][C:25]([C:28]([N:6]2[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][N:10]3[N:1]=[CH:2][CH:3]=[C:4]3[CH2:5]2)=[O:29])=[CH:26][CH:27]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccnn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
To a stirred solution of 185 mg of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine in 50 ml of methylene chloride containing 2.0 ml of triethylamine is slowly added a solution of 300 mg of 4-biphenylcarbonyl chloride in 10 ml of methylene chloride at room temperature. The reaction mixture is stirred at room temperature for 16 hours and evaporated in vacuo to give a residue. The residue is extracted with chloroform, washed with water, dried over Na2 SO4, filtered and the filtrate evaporated in vacuo to give a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 250 mg of the desired product as a solid. Mass spectrum: M+H:366.
Reaction SMILES: [Si]([O:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH:23]([C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[F:41])[S:24]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.CCCCCC>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([CH:23]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[F:41])[CH2:22]/[CH:21]=[CH:20]\[CH2:19][OH:18])(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](OC/C=C\CC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C(C/C=C\CO)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
In tetrahydrofuran (5 ml) was dissolved (Z)-2-[5-(t-butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-3-pentenyl]-1,4-difluorobenzene (Isomer 246-A) (145 mg, 0.237 mmol). After dropwise addition of a tetrahydrofuran solution (1.0M, 0.5 ml, 0.5 mmol) of tetrabutylammonium fluoride, the mixture was stirred at room temperature for 2 hours. Water (0.2 ml) was added to the reaction mixture, followed by concentration under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with hexane, whereby the title compound (51 mg, 0.137 mmol, 58%) was obtained as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[F:14][C:15]([F:26])([F:25])[S:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:21]/[C:20]1[CH:23]=[CH:24][C:17]([S:16][C:15]([F:26])([F:14])[F:25])=[CH:18][CH:19]=1)/[CH2:5]2
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Reactant: COc1cc2c(cc1Br)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Br)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 11 (250 mg, 1.04 mol) in toluene 15 mL was added 4-((trifluoromethyl)thio)benzaldehyde 72 (235 mg, 1.144 mol). PTSA (357 mg, 2.08 mol) was added to the reaction mass, which was stirred at 120° C. for 6 h, diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 104 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound 104 was eluted at 10% ethyl acetate in hexane to afford yellow coloured solid (E)-5-bromo-6-methoxy-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one 104.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:17])[C:14]([OH:16])=O)=[CH:11][C:5]=2[O:4][CH2:3]1.[O:18]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[O:16]=[C:14]([N:28]1[CH2:29][CH2:30][CH:25]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:26][CH2:27]1)[C:13]([NH:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2](=[O:1])[CH2:3][O:4][C:5]=2[CH:11]=1)=[O:17]
Reactant: O=C1COc2cc(NC(=O)C(=O)O)ccc2N1
Reactant: c1ccc(OC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C1COc2cc(NC(=O)C(=O)N3CCC(Oc4ccccc4)CC3)ccc2N1

Procedure:
The title compound is prepared from N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-oxalamic acid (Example 53b) and 4-phenoxypiperidine according to the method described in Example 2. Melting Point: 196-199° C. (diethylether)