Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)=[CH:5][CH:4]=1.[OH-:33].[Na+]>C1COCC1>[OH:33][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)=[CH:5][CH:4]=1
Reactant: BrCc1ccc(-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Reaction time: 24 h

Procedure:
A mixture of 2.0 g of 5-[4-(bromomethyl)phenyl]-2-(triphenylmethyl)-2H-tetrazole from Example 13 and 1N NaOH (5 mL) in THF (20 mL) was stirred for 24 hours. The solvent was evaporated and the aqueous solution extracted with EtOAc. The organic layer was washed with water, dried, and evaporated to give 1.8 g of 5-[4-(hydroxymethyl)phenyl]-2-(triphenylmethyl)-2H-tetrazole which was used as is for the next step; MS (EI), 418 (m).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7](Cl)[C:6]([CH:10]=[N:11]O)=[C:5]([Cl:13])[N:4]=1.C(O)(=[O:16])C>>[NH2:2][C:3]1[NH:8][C:7](=[O:16])[C:6]([C:10]#[N:11])=[C:5]([Cl:13])[N:4]=1
Reactant: CC(=O)O
Reactant: Nc1nc(Cl)c(C=NO)c(Cl)n1
Agent: Cl
Product: N#Cc1c(Cl)nc(N)[nH]c1=O
Temperature: 115 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
Following the method of Bell et al. (J. Heterocyclic Chem. 1983, 20, 41), hydrogen chloride gas was bubbled for 2 minutes though a solution of 6.00 g (29.0 mmol) 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde oxime in 800 ml acetic acid at 115° C. The mixture was then stirred at 115° C. for 16 hours before being cooled to room temperature. The resulting crystals were removed by filtration, and the filtrate concentrated in vacuo. The residue was triturated in 100 ml ether to afford 4.60 g (93%) 2-amino-4-chloro-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile as a light yellow crystalline solid. EI-MS m/e (%): 172 (M{37Cl}+, 23), 170 (M{35Cl}+, 71), 129 (53), 43 (100).
Reaction SMILES: [CH:1]12[CH2:24][CH2:23][CH:4]([C:5]([C:7]3[N:12]=[C:11]4[N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]4=[CH:9][CH:8]=3)=[CH:6]1)[CH2:3][NH:2]2.[O:25]1[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCOCC1>[CH3:18][C:17]([CH3:19])([CH3:20])[CH2:16][N:15]1[C:10]2[C:11](=[N:12][C:7]([C:5]3[CH:4]4[CH2:23][CH2:24][CH:1]([CH:6]=3)[N:2]([C:30]([C:27]3[CH:28]=[CH:29][O:25][N:26]=3)=[O:31])[CH2:3]4)=[CH:8][CH:9]=2)[N:13]([CH3:22])[C:14]1=[O:21]
Reactant: O=C(O)c1ccon1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CCC3CN4)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CCC3CN4C(=O)c3ccon3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(2-Azabicyclo[2.2.2]oct-5-en-5-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2-5, 291 mg, 0.90 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 151 mg, 1.4 mmol, 1.5 equiv), DIPEA (0.47 mL, 2.7 mmol, 3.0 equiv) and HATU (510 mg, 1.4 mmol, 1.5 equiv) were added to anhydrous 1,4-dioxane (9 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 2-7 as a white solid. MS m/z (M+H): calculated=422.2187; observed=422.2189. 1H NMR δ (ppm)(CHCl3-d): 8.40 (1H, dd, J=27.77, 1.66 Hz), 7.22-7.17 (1H, m), 7.12 (1H, dd, J=8.11, 1.50 Hz), 6.97 (1H, m), 6.70 (1H, dd, J=11.92, 1.66 Hz), 5.55-5.52 (0.4H, m), 5.42-5.38 (0.6H, m), 3.95 (0.4H, m), 3.88 (1H, m), 3.62 (2.6H, m), 3.53 (0.4H, m), 3.47 (3H, d, J=3.86 Hz), 3.36 (0.6H, d, J=12.39 Hz), 2.21-2.11 (1H, m), 1.91-1.80 (1H, m), 1.61-1.52 (2H, m) 0.99 (9H, d, J=1.91 Hz). (Mixture of rotamers at RT).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>CN(C=O)C>[C:25]([N:9]([S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:12])=[O:11])[C:8]1[CH:20]=[CH:21][C:5]([O:4][CH3:3])=[CH:6][C:7]=1[N+:22]([O-:24])=[O:23])(=[O:27])[CH3:26]
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N(C(C)=O)S(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
To a suspension of sodium hydride (60%, 0.08 g (2.00 mmol)) in DMF (3.0 ml), 4′-methoxy-2′-nitro-p-toluenesulfonanilide (0.50 g (1.55 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, acetic anhydride (0.20 ml (2.12 mmol)) was added dropwise. After one hour's stirring at room temperature, water was poured into the reaction mixture and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Crystals separated was added to diethyl ether, filtered and washed to give 0.51 g (90%) of the title compound as pale yellow crystals.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:10]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[O:9][C:7](=[O:8])[C:5]=2[CH:6]=1.O.[OH-].[Na+]>C(O)C.[Zn]>[CH:2]1[CH:3]=[C:4]([CH:10]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[C:5]([C:7]([OH:9])=[O:8])=[CH:6][CH:1]=1
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccccc1C(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a 3 L 3-necked flask containing 60 g of phenolphthalein (A), 450 ml of water and 525 ml of ethanol was added 450 mL of 50% sodium hydroxide solution in ethanol and 300 g of zinc powder. The contents were heated to reflux and maintained at that temperature for 12 hrs. The solution was cooled to room temperature, filtered and acidified until phenolphthalin precipitated as a white powder. This was collected by filtration and dried at 80° C. for 24 hrs at reduced pressure. Yield=95%. m.p.=234°-236° C.
Reaction SMILES: Cl(O)(=O)(=O)=O.C[O:7][CH:8]=[C:9]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:10]([F:13])([F:12])[F:11]>C(OCC)C>[F:21][C:20]([F:22])([F:23])[C:17]1[CH:18]=[CH:19][C:14]([CH:9]([C:10]([F:13])([F:12])[F:11])[CH:8]=[O:7])=[CH:15][CH:16]=1
Reactant: COC=C(c1ccc(C(F)(F)F)cc1)C(F)(F)F
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Product: O=CC(c1ccc(C(F)(F)F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 36.3 %

Procedure:
Under a nitrogen atmosphere, 10 ml of 70% perchloric acid was added to a solution of 6.1 g of 2-(4-trifluoromethylphenyl)-3,3,3-trifluoropropenyl methyl ether in 20 ml of diethyl ether at 0° to 5° C. The reaction solution was stirred at room temperature for 14 hours. The reaction mixture was poured into ice water and extracted twice with diethyl ether. The ether layers were combined and washed with saturated sodium bisulfate solution and saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 2.1 g of the desired crude compound.
Reaction SMILES: [CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O>[CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[CH:27][CH:28]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(Cn2nc(-c3ccc(OC(F)(F)F)cc3)cc2C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(Cn2nc(-c3ccc(OC(F)(F)F)cc3)cc2C2CCCCC2)cc1

Procedure:
A solution of 0.55 g methyl 4-({5-cyclohexyl-3-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-1-yl}methyl)benzoate from Step C Example 1 in 16 mL ethanol and 6 mL water was treated with 2.4 equivalents of 5 N NaOH solution till the hydrolysis was complete based on HPLC. After evaporating ethanol under reduced pressure, the residue was acidified with 20% molar excess of 2 N HCl to precipitate the acid product. Extract the reaction mixture with 2×35 mL EtOAc. Wash the combined organic layer with saturated brine, dry over anhydrous Na2SO4, and evaporate to give the title compound as a white solid. It can be recrystallized from 5:3 MeCN and water to give fine crystalline needles. 1H NMR (CDCl3, 500 MHz) δ 7.95˜7.97 (m, 2H), 7.84˜7.87 (m, 2H), 7.28 (d, J=8.1 Hz, 2H), 7.19 (d, J=8.2 Hz, 2H), 6.56 (s, 1H), 5.48 (s, 2H), 2.60 (tt, J=3.0 & 11.8 Hz, 1H), 1.72˜1.78 (m, 4H), 1.68˜1.72 (m, 1H), 1.37˜1.44 (m, 2H), 1.23˜1.35 (m, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[CH2:17]([SH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([S:24][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: SCc1ccccc1
Reactant: O=C1CCc2cc(OCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCSCc3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(3-bromo-propoxy)-3,4-dihydro-carbostyril (m.p.: 142°-147° C.) and benzyl-mercaptan.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:26])[N:15]([C:18]4[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([CH3:27])=[N:10]2)=[CH:5][CH:4]=1.[CH3:28][NH:29][CH3:30]>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]3[C:14](=[O:26])[N:15]([C:18]4[CH:19]=[CH:20][C:21]([C:22]([N:29]([CH3:30])[CH3:28])=[NH:23])=[CH:24][CH:25]=4)[CH2:16][CH2:17][C:12]=3[C:11]([CH3:27])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2nc(C)c3c2C(=O)N(c2ccc(C#N)cc2)CC3)cc1
Reactant: CNC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(-n2nc(C)c3c2C(=O)N(c2ccc(C(=N)N(C)C)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
Part A. 4-[1-(4-Methoxy-phenyl)-3-methyl-7-oxo-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-benzonitrile (0.250 g, 0.98 mmol) was dissolved in 1:1 MeOH/CHCl3 (30 mL). Hydrogen chloride gas was bubbled through the solution for 15 min, and it was then tightly capped and sealed. The reaction was stirred overnight at rt and then concentrated to dryness. The crude intermediate was dissolved in methanol (30 mL) and 2M dimethylamine (5.23 mL, 10.5 mmol) was added. The reaction was tightly capped and sealed and stirred overnight at rt. The reaction was concentrated and purified by reverse phase HPLC and freeze-dried to yield 4-[1-(4-methoxy-phenyl)-3-methyl-7-oxo-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-N,N-dimethyl-benzamidine (0.255 g, 71%): 1H NMR (CHCl3) δ 9.66 (s, 0.5H), 8.73 (s, 0.5H), 7.51–7.38 (m, 6H), 6.91 (d, j=8.8 Hz, 2H), 4.13(t, j=6.6 Hz, 2H), 3.80 (s, 3H), 3.33 (s, 3H), 3.06 (s, 3H), 2.96 (t,j=6.4 Hz, 2H), 2.35 (s, 3H) ppm; Mass Spec 404.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Br)[CH:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:31]4[CH2:32][CH2:33][N:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)[CH:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1nc2ccc(OCc3cccc(CBr)c3)cc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1nc2ccc(OCc3cccc(CN4CCN(c5ccccc5)CC4)c3)cc2s1
Yield: 48.2 %

Procedure:
To a solution of 2-cyano-6-(3-bromomethylbenzyloxy)benzothiazole (1 g, 2.8 mmol) in 20 mL of dichloromethane was added 1-phenylpiperazine (1.7 mL, 11.2 mmol) dropwise. The resultant solution was stirred at RT for 30 minutes. Then, 20 mL of saturated sodium bicarbonate solution was added. After partition, the aqueous phase was extracted with 20 mL of dichloromethane. The organic extracts were combined, washed with water twice and dried over sodium sulfate. The solvent was removed and the residue was purified by flash chromatography using 1% methanol in dichloromethane. 594 mg of product was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:19])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:3]([OH:19])[CH2:2][NH:1][CH:43]2[CH2:42][CH2:41][N:40]([C:37]3[CH:36]=[CH:35][C:34]([S:31]([NH:30][C:24]4[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=4)(=[O:32])=[O:33])=[CH:39][CH:38]=3)[CH2:45][CH2:44]2)=[CH:7][CH:8]=1
Reactant: NCC(O)COc1cccc2[nH]c3ccccc3c12
Reactant: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1OC
Product: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c6ccccc6c45)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from 1-Amino-3-(9H-carbazol-4-yloxy)-propan-2-ol and Reference Example 73, N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as an off-white solid; mp 58-64° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.80-1.95 (m, 2H), 2.60-2.90 (m, 5H), 3.62 (s, 3H), 3.64 (s, 3H), 3.60-3.80 (m, 2H), 4.00-4.20 (m, 3H), 6.40-7.50 (m, 12H), 7.95 (s, 1H), 8.20 (d, 1H), 11.30 (s, 1H); MS (ES) m/z: 631.1 (MH+); HRMS Calcd. for C34H39N4O6S (MH+): 631.2590. Found: 631.2595.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])[N:5]=[CH:4][N:3]=1.[CH3:15][CH:16]1[CH2:21][CH:20]([CH3:22])[CH2:19][NH:18][CH2:17]1>>[CH3:15][CH:16]1[CH2:21][CH:20]([CH3:22])[CH2:19][N:18]([C:2]2[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])[N:5]=[CH:4][N:3]=2)[CH2:17]1
Reactant: CC1CNCC(C)C1
Reactant: CCC#CCOc1ncnc(Cl)c1F
Product: CCC#CCOc1ncnc(N2CC(C)CC(C)C2)c1F
Reaction time: 3 h
Yield: 84.7 %

Procedure:
0.2 g of 4-chloro-5-fluoro-6-(2-pentynyloxy)pyrimidine and 0.32 g of 3,5-dimethylpiperidine (cis/trans=about 3/1) were mixed and left for 3 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.23 g of 4-(3,5-dimethylpiperidino)-5-fluoro-6-(2-pentynyloxy)pyrimidine (hereinafter, referred to as Compound (11)). Compound (11) had the cis/trans diastereomer originated two methyls on the piperidine ring. The ratio of the cis/trans diastereomer was about 3.8/1.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([OH:13])=[C:8]([CH:11]=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.[Br:15]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:15][C:6]1[C:7]([OH:13])=[C:8]([CH:11]=[O:12])[CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][C:2]2([CH3:14])[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)CCc2cc(O)c(C=O)cc21
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCc2c1cc(C=O)c(O)c2Br
Yield: 90.8 %

Procedure:
A solution of 3.1 g (16.3 mmol) 1,1-dimethyl-5-hydroxyindan-6-carboxaldehyde and 3.1 g (17.4 mmol) of N-bromosuccinimide in 50 ml of methylene chloride was stirred at ambient temperature for 2 days. Water (50 ml) was added. The organic phase was dried and evaporated. The residue was filtered through silica gel (20 g) using a gradient from hexane to 2:98 (v/v) ether:hexane as eluent. There was obtained 4.0 g (14.8 mmol, 91%) of 4-bromo-1,1-dimethyl-5-hydroxyindan-6-carboxaldehyde as yellow crystals after crystallization from ethanol; mp 77.5°-78.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=1)[O:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=1)[O:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-[3-[2-(ethoxycarbonyl)ethenyl]phenoxy]-2-methylpropionate (39.1 g, 0.12 mol) was dissolved in ethanol. Subsequently, 10% palladium in carbon (3.9 g) was added thereto, the mixture was stirred under hydrogen atmosphere overnight at room temperature. The resultant mixture was subjected to filtration by use of Celite, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate=20/1), whereby the target compound was obtained (37.1 g, 94%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]#[N:14])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>CN(C)C=O>[N:25]1([CH2:24][CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[C:10]([C:13]#[N:14])[S:11][CH:12]=3)=[CH:6][CH:7]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: N#Cc1nc(-c2ccc(O)cc2)cs1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1nc(-c2ccc(OCCN3CCCCC3)cc2)cs1
Temperature: 25 °C
Reaction time: 28 h
Yield: 93.1 %

Procedure:
A suspension of 4-(4-hydroxyphenyl)-thiazole-2-carbonitrile (7 g), crushed potassium carbonate (13.1 g) and 1-(2-chloroethyl)piperidine hydrochloride (7.78 g) in dry dimethylformamide (60 ml) was stirred at room temperature for 28 h, and then added to water (400 ml). The precipitated solid was filtered, and then partitioned between dichloromethane and water. The organic layer was dried over sodium sulphate, filtered, and evaporated to dryness to give 4-[4-[2-(piperidin-1-yl)ethyloxy]phenyl]-thiazole-2-carbonitrile (10.1 g), m.p. 85°-86° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.CON(C)[C:16]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[O:17]>O1CCCC1>[CH3:30][C:27]([CH3:28])([O:26][C:24]([N:21]1[CH2:20][CH2:19][CH:18]([C:16]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[O:17])[CH2:23][CH2:22]1)=[O:25])[CH3:29]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccnc2)CC1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 70.6 %

Procedure:
A solution of n-butyllithium (14.2 mL of a 2.51M solution in hexanes, 35.54 mmol) in tetrahydrofuran (50 mL) was cooled to ←85° C. and treated dropwise with a solution of 3-bromopyridine (5.90 g, 37.31 mmol) in tetrahydrofuran (50 mL). The resulting pale yellow-green solution was stirred at ←85° C. for 15 min, then was treated with a solution of N-methoxy-N-methyl 1-(1,1-dimethylethyloxycarbonyl)-4-piperidine carboxamide (8.80 g, 32.31 mmol) in tetrahydrofuran (50 mL). The reaction mixture was allowed to warm to -20° C. over 1 h, then was cooled to -60° C. and quenched by addition of water (20 mL). The mixture was vaned to 0° C., acidified to pH~ 2 by addition of 3M hydrochloric acid and stirred at 0° C. for 10 min. The mixture was then poured into 10% aqueous sodium hydroxide (50 mL) and extracted with ethyl acetate (3×150 mL). The organic extracts were washed sequentially with 1N aqueous sodium hydroxide (100 mL) and brine (100 mL), combined, dried over Na2SO4, filtered and concentrated to leave a yellow semi solid mass. This mass was triturated with hexane (50 mL) and the solid which formed was removed by filtration. The solid was rinsed with hexane (25 mL) and dried to afford the title ketone (6.62 g, 22.8 mmol, 71%) as off-white needles. From the filtrate, an additional 300 mg (1.03 mmol, 3%) of the ketone was obtained. 1H NMR CDCL3 : δ9.16 (d, J=2.2 Hz, 1H, H--C(2')), 8.79 (dd, J=1.7 Hz, 4.8 Hz, 1H, H--C(6')), 8.23 (ddd, J=1.7, 2.2, 8.0 Hz, 1H, H--C(4')), 7.45 (dd, J=4.8, 8.0 Hz, 1H, H--C(5')), 4.17 (brd, J=11 Hz, 2H, eq-H--C(2)), 3.39 (m, 1H, H--C(4)), 2.92 (dd, J=11.6, 11.6 Hz, 2H, ax-H--C(2)), 1.87 (m, 2H, eq-H--C(3)), 1.71 (m, 2H, ax-H--C(3)), 1.47 (s, 9H, (CH3)3C).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.C1(C)C=CC(S([CH2:26][N+:27]#[C-:28])(=O)=O)=CC=1>CCOCC.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:26][NH:27][CH:28]=2)=[CH:15][CH:16]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C=Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1c[nH]cc1-c1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 25.6 %

Procedure:
To a mixture of 5.63 g of a 60% sodium hydride/oil suspension in 200 mL of dry ether under nitrogen is added from an additional funnel a mixture of 23.5 g (122 mmol) of ethyl p-chlorocinnamate and 19.4 g (122 mmol) of (p-tolylsulfonyl)methyl isocyanide in solution in 180 mL of ether and 80 mL of dimethylsulfonide. The addition time is about 20 minutes and results in gentle refluxing of the mixture. After another 10 minutes stirring, the mixture is diluted with 100 mL of water. The mixture is extracted four times with ether which is then dried over magnessium sulfate followed by concentrated in vacuo. The resulting solid is recrystallized from ethylene dichlorite to give 7.8 g of crystals, m.p. 137°-138° C.
Reaction SMILES: [Cl:1][Si:2]([CH3:10])([CH3:9])[CH:3]=[CH:4][Si:5]([Cl:8])([CH3:7])[CH3:6].Cl[CH:12](Cl)[SiH](C)C=C([SiH](C)C(Cl)Cl)C>>[Cl:1][Si:2]([CH3:10])([CH3:9])[CH2:3][CH:4]([Si:5]([Cl:8])([CH3:7])[CH3:6])[CH3:12]
Reactant: C[Si](C)(Cl)C=C[Si](C)(C)Cl
Reactant: CC(=C[SiH](C)C(Cl)Cl)[SiH](C)C(Cl)Cl
Product: CC(C[Si](C)(C)Cl)[Si](C)(C)Cl

Procedure:
Example 1 was repeated with the modification that, instead of 300.0 (1.41 mol) of 1,2-bis(chlorodimethylsilyl)ethene, 300.0 g (1.32 mol) of 1,2-bis(dichlorodimethylsilyl)prop-1-ene were used. The results are summarized in Table 1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:16]([C:15]3[CH:19]=[CH:20][CH:21]=[C:13]([Cl:12])[CH:14]=3)[O:8][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Product: Cc1ccc2nc(-c3cccc(Cl)c3)oc(=O)c2c1
Yield: 91.1 %

Procedure:
When the reaction conditions of Example 1 are employed but 11.3 g of 5-methylanthranilic acid and 13.1 g of 3-chlorobenzoyl chloride are used, 18.5 g (91%) of 6-methyl-2-(m-chlorophenyl)-4H-3,1-benzoxazin-4-one of melting point 160°-162° C. are obtained.