Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22]COC)=[CH:18][CH:17]=1)[C:11]([CH3:26])=[CH:10]2.CN(C)[CH:29]=[O:30]>>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:11]([CH3:26])=[C:10]2[CH:29]=[O:30]
Reactant: COCOc1ccc(-n2c(C)cc3cc(Cl)ccc32)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)c2cc(Cl)ccc2n1-c1ccc(O)cc1
Yield: 85 %

Procedure:
Phosphorous oxychloride (5 mL) was added to anhydrous dimethylformamide (10 mL) and stirred at room temperature for 15 min whereupon a solution of 5-chloro-1-(4-methoxymethyloxyphenyl)-2-methyl-1H-indole (1.22 g, 3.5 mmol) in dimethylformamide (10 mL) was added. The solution was reacted according to the procedure used in Example 2a to afford a tan solid (85%): mp>240° C.; 1H NMR (DMSO-d6): δ 2.52 (3H, s), 6.97-7.02 (3H, m), 7.22 (1H, dd, J=2.3 Hz, J=8.7 Hz), 7.30 (2H, d, J=8.6 Hz), 8.40 (1H, d, J=2.1 Hz), 10.02 (1H, s), 10.16 (1H, s); MS m/Z (M+H)+ 286/288 (1 Cl).
Reaction SMILES: [Si](OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(N3C4=NC=CC=C4C=C3)CCCC2)N=1)=O)(C(C)(C)C)(C)C.[CH2:45]([O:52][C:53]1[C:54]([C:75](O)=[O:76])=[N:55][C:56]([CH2:60][C:61]2([N:66]3[C:70]4=[N:71][CH:72]=[CH:73][CH:74]=[C:69]4[CH:68]=[CH:67]3)[CH2:65][CH2:64][CH2:63][CH2:62]2)=[N:57][C:58]=1[OH:59])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[Si:78]([O:85][CH2:86][CH2:87][NH:88][CH:89]([CH3:91])[CH3:90])([C:81]([CH3:84])([CH3:83])[CH3:82])([CH3:80])[CH3:79]>>[Si:78]([O:85][CH2:86][CH2:87][N:88]([CH:89]([CH3:91])[CH3:90])[C:75]([C:54]1[C:53]([O:52][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[C:58]([OH:59])[N:57]=[C:56]([CH2:60][C:61]2([N:66]3[C:70]4=[N:71][CH:72]=[CH:73][CH:74]=[C:69]4[CH:68]=[CH:67]3)[CH2:62][CH2:63][CH2:64][CH2:65]2)[N:55]=1)=[O:76])([C:81]([CH3:84])([CH3:83])[CH3:82])([CH3:80])[CH3:79]
Reactant: O=C(O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Agent: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (409) was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (405) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (404) (250 mg, 0.56 mmol) and [2-(tert-tutyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (367 mg, 1.69 mmol) (8b) to get an off-white sticky solid (220 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13](=[S:15])[NH2:14].Br[CH2:17][C:18](=O)[CH:19]([CH3:21])[CH3:20]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13]1[S:15][CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[N:14]=1
Reactant: CC(C)C(=O)CBr
Reactant: NC(=S)/C=C/c1cc([N+](=O)[O-])ccc1Cl
Solvent: CCO
Product: CC(C)c1csc(/C=C/c2cc([N+](=O)[O-])ccc2Cl)n1

Procedure:
A solution composed of 2.0 g of (E)-3-(2-chloro-5-nitrophenyl)-2-propenethioamide, 3.0 g of 1-bromo-3-methyl-2-butanone and 25 ml of ethyl alcohol was warmed to gentle reflux for 5 hr. The volatiles were then removed in vacuo and the residual materials separated by chromatography over 100 g of alumnia using methylene chloride as the eluant to yield (E)-2-[2-(2-chloro-5-nitrophenyl)ethenyl]-4-(1-methylethyl)thiazole as a yellow solid; m.p. 86°-89° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CO.[H][H]>[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(Cc2ccc(N)cc2)CC1
Yield: 93.1 %

Procedure:
1-Methyl-4-(4-nitro-benzyl)-piperazine (3.70 g, 15.7 mmol) was dissolved in Methanol (40.0 mL, 987 mmol) and was carefully added to a Parr vessel containing 10% Palladium on Carbon (1.00 g, 74.9 mmol) under nitrogen. The mixture was then placed on a Parr hydrogenation apparatus and was allowed to shake at 55 psi until uptake of hydrogen ceased. The catalyst was then filtered to afford 3.00 g of 4-(4-Methyl-piperazin-1-ylmethyl)-phenylamine without further purification. (M+H)=205.96.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]\[C:16]([O:18]C)=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]\[C:16]([OH:18])=[O:17])=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C\c1cnn(C)c1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1ncc(/C=C\C(=O)O)c1-c1ccc(F)cc1
Yield: 77.5 %

Procedure:
A mixture of methyl (2Z)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylate (300 mg), methanol (5 mL) and a 1N aqueous sodium hydroxide solution (5 mL) was stirred at 60° C. for 30 min. 1N Hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the residue from ethyl acetate-hexane gave (2Z)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid as crystals (220 mg, yield 78%). melting point: 205-206° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=O)[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[S:9]2)=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2SC1c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Product: Fc1ccc(C2CNc3ccccc3S2)cc1
Temperature: 0 °C
Yield: 91.2 %

Procedure:
To a mixture of 2-(4-fluorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (4.0 g), sodium borohydride (2.91 g) and tetrahydrofuran (100 ml) is added dropwise with stirring boron trifluoride etherate complex (12. 5 ml) at room temperature, and the mixture is refluxed for 1.5 hour. After cooling, to the mixture is added dropwise 10% hydrochloric acid (35 ml), and the mixture is further refluxed for one hour. The reaction mixture is poured into ice water and made alkaline with potassium carbonate and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and distilled to remove the solvent. The residue is recrystallized from isopropyl ether to give 2-(4-fluorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (3.45 g, yield 91%) as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH:22]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH:22]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1CC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1CC=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 197 %

Procedure:
Combine and cool to 0° C. a solution of (S)-4-benzyl-2-(2-oxo-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.95 g, 6.13 mmol) and diethyl benzyl phosphonate (4.23 g, 18.55 mmol) in dry DMF (25 mL), and add solid sodium methoxide (95%, 1.15 g, 21.3 mmol) in a single portion, and stir at 0° C. for 30 minutes. Dilute the mixture with CH2Cl2, wash with brine and dry the organic layer over Na2SO4. Purification by silica gel chromatography of the crude product using EtOAC/CH2Cl2 (2% to 10%) as eluent gives the title compound (2.37 g) as a white solid: mass spectrum (Electrospray): m/z=393.3 (M+1); 1H NMR (400 MHz, CDCl3): δ7.37–7.21 (m, 10H), 6.34–6.30 (m, 1H), 6.12–6.02 (m, 1H), 4.10 (br, 1H), 3.87 (br, 1H), 3.59–3.52 (m, 1H), 3.41–3.35 (m, 1H), 3.13 (m, 1H), 2.82–2.59 (m, 4H), 2.18–2.04 (m, 2H), 1.39 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]([OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-])=O.[H][H]>C(O)C.[Ni]>[F:1][C:2]([F:14])([F:15])[CH:3]([OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10]
Reactant: O=[N+]([O-])c1ccccc1C(O)C(F)(F)F
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccccc1C(O)C(F)(F)F

Procedure:
A solution of 1,1,1-trifluoro-2-hydroxy-2-(2-nitrophenyl)ethane from Step 1 (5.45 g, 24.64 mmol) in 90 mL of ethanol was hydrogenated over 200 mg of Raney Nickel at 5 psi hydrogen over a 8 h period at 23° C. After removing the catalyst by filtration, concentration in vacuo afforded a quantitative yield of 1,1,1-trifluoro-2-hydroxy-2-(2-aminophenyl)ethane as a orange-yellow solid: 1H NMR (CDCl3) δ4.32 (br s), 5.03 (q, J=6 Hz), 6.28 (br s), 6.67-6.78 (m), 7.08-7.23 (m); 13C NMR (CDCl3) 66.6 (q, J=33 Hz), 121.9, 124.9, 127.2 (q, J=280 Hz,), 129.3, 130.1, 133.6; MS (EI) 191 (M+), 173, 122. IR (neat) 3395, 3325, 3400-3100. Anal. Calc'd. for C8H8NOF3: C, 50.26; H, 4.22; N, 7.33. Found: C, 50.47; H, 4.57; N, 7.05.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][NH:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[CH3:28][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:13][NH:14][CH:15]([CH3:28])[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCCCOc1cccc(C(CNCC(=O)N(C)C)C(=O)OC(C)(C)C)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCCOc1cccc(C(CNC(C)C(=O)N(C)C)C(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A solution of 2-[2-(3-butoxyphenyl)-(tert-butoxycarbonyl)ethylamino]-N,N-dimethylacetamide (0.410 g, 1.1 mmol; prepared according to Step 3 of Example 1) in dry THF (5 ml) was cooled to −78° C. and LiHMDS (lithium hexamethyldisilazide), 1 M in THF, (1.43 ml, 1.4 mmol) was added dropwise. The mixture was stirred 30 min then a solution of methyl iodide (0.187 g, 1.3 mmol) in dry THF (1 ml) was added dropwise. The mixture was stirred for 2 h allowing the cooling bath to expire. The solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc (15 ml) and washed with water (2×15 ml). The organic phase was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (silica, petroleum ether:EtOAc from 8:2 to 6:4) affording the title compound (0.22 g, 52% yield) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][C:8]2[CH:13]=[N:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.[OH:17][C:18]([CH3:33])([CH3:32])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[O:30][CH3:31].N1C=CC=CC=1.Cl>C(Cl)Cl.CO.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7][C:8]2[CH:13]=[N:12][N:11]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:18]([OH:17])([CH3:33])[CH3:32])=[C:22]([O:30][CH3:31])[CH:23]=3)[C:10](=[O:14])[CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=c1cc(SCc2ccc(Cl)cc2)cn[nH]1
Reactant: COc1cc(B(O)O)ccc1OCC(C)(C)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: COc1cc(-n2ncc(SCc3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O

Procedure:
A solution of 5-(4-chlorobenzylthio)pyridazin-3(2H)-one Part A (21 mg, 0.083 mmol), 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid Part D of Procedure 4 (39.9 mg, 0.17 mmol), pyridine (0.067 mL, 0.83 mmol) and Cu(OAc)2 (45.3 mg, 0.25 mmol) in CH2Cl2 (13.0 mL) and MeOH (2.0 mL) was stirred at RT open to air for 4 hours. The mixture was poured into 1.0 N aqueous HCl (100 mL) and extracted with CH2Cl2. The CH2Cl2 layer was dried over Na2SO4 and concentrated. The crude product was purified by prep-HPLC (C18 column/Water:MeOH:TFA 90:10:0.1 to 10:90:0.1 gradient) giving the title compound 5-(4-chlorobenzylthio)-2-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridazin-3(2H)-one F-1 (23 mg, 61% yield) as white solid. LC/MS 447 (M+H)+, tR 4.14 min (method 3); 1H NMR (500 MHz, Chloroform-D) δ ppm 7.65 (1H, d, J=2.20 Hz), 7.35 (4H, s), 7.07-7.13 (2H, m), 6.96 (1H, d, J=8.80 Hz), 6.66 (1H, d, J=2.20 Hz), 4.15 (2H, s), 3.81-3.91 (5H, m), 1.35 (6H, s).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH3:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:36]=O>CO.N1CCCCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:36]/[C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([CH3:26])[CH:28]=4)[NH:32][CH:31]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: Cc1ccc2[nH]cc(C=O)c2c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: Cc1ccc2[nH]cc(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 571.9 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.070 g, 0.020 mmol) in methanol (2.0 mL) was added with 5-methyl-1H-indole-3-carboxaldehyde (0.034 g, 0.021 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, and then filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (93:7)) to obtain tert-butyl (Z)-4-({6-hydroxy-2-[(5-methyl-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.056 g, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][Br:12])[C:5](O)=[O:6].[CH3:13][Si:14]([CH3:18])([CH3:17])[CH2:15][NH2:16].Cl.CN(C)CCCN=C=NCC.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][Br:12])[C:5]([NH:16][CH2:15][Si:14]([CH3:18])([CH3:17])[CH3:13])=[O:6]
Reactant: C[Si](C)(C)CN
Reactant: O=C(O)c1ccc(CBr)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CNC(=O)c1ccc(CBr)c(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
3-bromo-4-(bromomethyl)benzoic acid (5 g), 1-(trimethylsilyl)methylamine (1.76 g), N,N-dimethylaminopyridine (0.1 g) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (4.3 g) were dissolved in dichloromethane (30 ml), and stirred for 5 hours at room temperature. Water was added to the reaction mixture, and then organic layer was separated and dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 3-bromo-4-(bromomethyl)-N-[(trimethysilyl)methyl]benzamide (4 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([O:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([O:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24]
Reactant: CCOC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 60 °C
Yield: 53.9 %

Procedure:
To a solution of methyl 2-[2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-ethoxyacetate (0.025 g; 0.061 mmol) in methanol (0.75 mL) was added a solution of sodium hydroxide 10 N (0.075 mL; 0.750 mmol) and the mixture was heated at 60° C. for 18 h. The volatiles were removed under reduced pressure and the residue was dissolved in water, the mixture was then acidified by adding 6N HCl until a precipitate was formed. The solid was filtered, washed with water and dried under reduced pressure to furnish 0.013 g (52%) of the title compound as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Br:17][C:18]1[CH:24]=[C:23]([F:25])[C:21]([NH2:22])=[C:20]([F:26])[CH:19]=1>C(O)(C)C>[ClH:2].[Br:17][C:18]1[CH:24]=[C:23]([F:25])[C:21]([NH:22][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:20]([F:26])[CH:19]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3c(F)cc(Br)cc3F)c2cc1OC
Yield: 31.2 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride, (152 mg, 0.6 mmol), (prepared as described for the starting material in Example 1 but without the aqueous work up), and 4-bromo-2,6-difluoroaniline (121 mg, 0.6 mmol) in isopropanol (7 ml) was heated at reflux for 2 hours. The mixture was allowed to cool, the solid product collected by filtration, washed with isopropanol and dried to give 4-(4-bromo-2,6-difluoroanilino)-6,7-dimethoxyquinazoline hydrochloride (81 mg, 35%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH3:6])[CH3:2]>CCO>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:11][CH2:12]1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)=C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCO
Product: CCOC(=O)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 47.6 %

Procedure:
The product from Step 1 above was dissolved in absolute EtOH (10 mL) and hydrogenated over Pt2O (150 mg) for 14 h. After this time, the reaction was filtered to remove the catalyst and concentrated on a rotary evaporator to give tert-butyl 4-(1-ethoxy-1-oxopropan-2-yl)piperidine-1-carboxylate (1.5 g, 5.26 mmol, 47.6% yield, 2 steps) as a colorless liquid. 1H-NMR (400 MHz, CDCl3) δ ppm 4.03-4.15 (4 H, m), 2.63 (2 H, t, J=11.58 Hz), 2.18-2.26 (1 H, m, J=7.18, 7.18, 7.18, 7.18 Hz), 1.59-1.70 (2 H, m), 1.47-1.57 (1 H, m), 1.41 (9 H, s), 1.22 (3 H, t, J=7.18 Hz), 1.24-1.18 (m, 2 H), 1.14 (1 H, dd, J=13.22, 4.41 Hz), 1.09 (3 H, d, J=7.05 Hz).
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[S-:26][C:27]#[N:28].[Ba+2].[S-]C#N>CC(C)=O.O>[OH:24][C@@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[C:19](=[O:23])[CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:25])[CH2:2][S:26][C:27]#[N:28])[CH2:12]1
Reactant: N#C[S-]
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Agent: [Ba+2]
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CSC#N)[C@@]3(C)CC(=O)[C@@H]12
Yield: 96.4 %

Procedure:
A solution of 21-bromo-3α-hydroxy-5α-pregnane-11,20-dione (0.75 g.) in acetone (50 ml.) was treated with a solution of barium thiocyanate (2.6 g.) in water (10 ml.). The resulting mixture was refluxed for 4 hr., cooled and then partitioned between water and ether. The organic layer was washed with water, dried (Na2SO4) and evaporated. The residue (720 mg.) was purified by preparative t.l.c. (EtOAc) to afford title compound (685 mg.) as a white foam, [α]D + 67°.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[C:1]1([C:7]2[N:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:23]([C:22]4[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=4[C:20]([F:19])([F:30])[F:31])=[O:24])[CH2:15][CH2:14]3)=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc(N3CCNCC3)nn2)cc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(-c3ccccc3)nn2)CC1
Yield: 67 %

Procedure:
Following the procedure as described in Example 5, making variations only as required to use 3-phenyl-6-piperazin-1-ylpyridazine in place of 3-piperazin-1-yl-6-pyridin-2-ylpyridazine to react with 2-trifluoromethylbenzoyl chloride, the title compound was obtained as an off-white solid in 67% yield (0.312 g). 1H NMR (300 MHz, CDCl3) δ 7.97-7.95 (m, 2H), 7.73-7.71 (m, 2H), 7.63-7.51 (m, 2H), 7.47-7.39 (m, 3H), 7.34 (d, J=7.3 Hz, 1H), 7.06 (d, J=9.9 Hz, 1H), 4.10-3.67 (m, 6H), 3.35-3.32 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.6, 158.2, 151.7, 135.9, 134.3, 132.4, 129.5, 129.2, 128.9, 127.3, 126.9, 126.1, 114.2, 46.5, 45.2, 44.9, 41.3. MS (ES+) m/z 413.0 (M+1).
Reaction SMILES: [CH2:1]([CH2:8][C:9](=[O:11])[CH3:10])[C:2]1C=C[CH:5]=[CH:4][CH:3]=1.C=CCCCC>C1(C)C=CC=CC=1>[CH3:10][C:9](=[O:11])[CH2:8][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(=O)CCc1ccccc1
Solvent: C=CCCCC
Solvent: Cc1ccccc1
Product: CCCCCCC(C)=O

Procedure:
Under the same reaction procedure and conditions as in Example 2 (tristriphenylphosphine rhodium (I) chloride 10 mol %, 150° C., 48 hours, toluene 100 mg), benzyl acetone 32 mg (0.22 mmol) and 1-hexene 182 mg (2.16 mmol) were reacted in the presence of various amounts of 2-amino-3-pycoline. A measurement was made of the yields of 2-octanone, and the results are given in Table 4, below. When 2-amino-3-pycoline was absent, 2-octanone was not obtained at all and benzyl acetone was recovered in its entirety.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH3:28][O:29][C:30](=[O:32])[NH2:31]>>[CH3:28][O:29][C:30](=[O:32])[NH:31][C:24]1[CH:23]=[CH:22][C:21]([C:19]([N:16]2[CH2:15][CH2:14][N:13]([C:5]3[C:4]([CH:1]4[CH2:2][CH2:3]4)=[CH:9][C:8]([CH:10]4[CH2:12][CH2:11]4)=[CH:7][N:6]=3)[CH2:18][CH2:17]2)=[O:20])=[CH:26][CH:25]=1
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: COC(N)=O
Product: COC(=O)Nc1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1
Yield: 38.3 %

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (473 mg) described in Preparation Example 186 and carbamic acid methyl ester (113 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (161 mg) was obtained.
Reaction SMILES: Br[CH:2]1[CH:11]([OH:12])[C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[S:4][CH2:3]1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(#N)C>O>[Cl:13][C:7]1[CH:8]=[CH:9][C:10]2[C@H:11]([OH:12])[C@H:2]([CH2:3][C:15]3[NH:14][CH:18]=[CH:17][N:16]=3)[S:4][C:5]=2[CH:6]=1
Reactant: c1c[nH]cn1
Reactant: OC1c2ccc(Cl)cc2SCC1Br
Solvent: CC#N
Solvent: O
Product: O[C@H]1c2ccc(Cl)cc2S[C@H]1Cc1ncc[nH]1

Procedure:
Add 3-bromo-7-chlorothiochroman-4-ol (5.27 gms., 18.8 mmols) and imidazole (12.8 gms., 188 mmols) to acetonitrile (100 ml.), and heat at reflux temperature for 4 hours. Pour the reaction mixture into water (500 ml.), and extract with chloroform (500 ml.). Wash the organic layer with water (500 ml.), dry the organic layer over anhydrous magnesium sulfate, filter and evaporate in vacuo. Triturate the resultant resultant residue with anhydrous ether, filter and recrystallize from acetonitrile to give cis-6-chloro-2,3-dihydro-3-hydroxy-2-(1'-imidazolylmethyl)benzo(b)thiophene.