Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1>>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: CN1CCc2ccccc21
Reactant: O=S(=O)(O)Cl
Product: CN1CCc2cc(S(=O)(=O)Cl)ccc21
Temperature: 25 °C

Procedure:
A solution of chlorosulfonic acid at 0° C. (5 mL, 75 mmol) was treated portionwise with 1-methylindoline (CAS No. [824-21-5], 1.96 g, 14.7 mmol), warmed to room temperature, heated at 75° C. for 40 minutes, cooled, and poured onto ice to provide a solid. The solid was collected by suction filtration, washed with water, and dried to provide 927 mg of the desired product.
Reaction SMILES: [Br-:1].[Li+].[CH3:3][O:4][N:5]=[CH:6][C@@H:7]([F:41])[C@H:8]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C@H:9](OC1C=C(Cl)C(Cl)=CC=1Cl)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(OCC)(=O)C>O1CCCC1.CN1CCN(C)C1=O>[CH3:3][O:4][N:5]=[CH:6][C@H:7]([F:41])[C@H:8]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C@@H:9]([Br:1])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: [Br-]
Reactant: CON=C[C@@H](F)[C@H](OCc1ccc(OC)cc1)[C@@H](COCc1ccc(OC)cc1)Oc1cc(Cl)c(Cl)cc1Cl
Agent: [Li+]
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CON=C[C@H](F)[C@H](OCc1ccc(OC)cc1)[C@@H](Br)COCc1ccc(OC)cc1
Temperature: 65 °C
Reaction time: 7 h
Yield: 92.5 %

Procedure:
451 mg of lithium bromide was added to a solution of 1.15 g of (2R,3R,4R)-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)-4-(2,4,5-trichlorophenoxy)pentan al O-methyloxime in 6 mL of tetrahydrofuran and 6 mL of 1,3-dimethyl-2-imidazolidinone, and the obtained mixture was then stirred at 65° C. for 7 hours. Thereafter, ethyl acetate and a 25% lithium bromide aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was washed with a 12% lithium bromide aqueous solution and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40), so as to obtain 857 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)pentanal O-methyloxime in the form of a colorless oily product.
Reaction SMILES: [CH3:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.ClS(O)(=O)=O.[CH3:19][N:20]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]1[CH2:26][C:27]([O:29][CH3:30])=[O:28].[Cl:31]([OH:35])(=[O:34])(=[O:33])=[O:32]>>[Cl:31]([OH:35])(=[O:34])(=[O:33])=[O:32].[CH3:19][N:20]1[C:24]([C:3](=[N:2][CH3:1])[C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)=[C:23]([CH3:25])[CH:22]=[C:21]1[CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)Cc1cc(C)cn1C
Reactant: CN=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: CN=C(c1ccc([N+](=O)[O-])cc1)c1c(C)cc(CC(=O)OC)n1C

Procedure:
The title compound was prepared as in Example X from N-methyl 4-nitrobenzimidoyl chloride (2.0 g, 10.1 mmole) in alcohol free chloroform (30 ml), chlorosulfonic acid (0.12 g, 1 mmole), methyl 1,4-dimethyl-1H-pyrrole-2-acetate (1.68 g, 10.06 mmole) and 70% perchloric acid (1.57 g, 11 mmole) to yield 2.77 g (65%) of a yellow solid, m.p. 108° C. (dec).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[CH2:12][CH2:13]Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C.CCOC(C)=O>[N:22]([CH2:13][CH2:12][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OCCC(O)(CCCl)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCC(O)(CCN=[N+]=[N-])c1ccccc1

Procedure:
A solution of 1-{[tert-butyl(dimethyl)silyl]oxy}-5-chloro-3-phenylpentan-3-ol ((5.2 g, 15.7 mmol) and NaN3 (7.8 g, 120 mmol) in 50 mL DMF was stirred for 24 h at 65° C. The reaction mixture was then diluted with EtOAc, washed with water, dried, filtered and evaporated in vacuo to provide 1-azido-5-{[tert-butyl(dimethyl)silyl]oxy) 3-phenylpentan-3-ol in quantitative yield as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.40-7.32 (m, 4H), 7.24 (m, 1H), 4.89 (s, 1H), 3.72 (dt, 1H, J=10.3, 3.9 Hz), 3.47-3.36 (m, 2H), 2.97 (ddd, 1H, J=12.3, 10.1, 5.5 Hz), 2.24-2.10 (m, 2H), 2.07-1.93 (m, 2H), 0.86 (s, 9H), −0.02, (s, 3H), −0.09 (s, 3H); ESI-MS 358 (M+Na).
Reaction SMILES: CO/[CH:3]=[C:4]1/[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]2[C:13]/1=[CH:12][CH:11]=[CH:10][CH:9]=2.CN(C=O)C.[N:21]1([CH2:28][C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CCCCCC>[N:21]1([CH2:28][C:29]2[CH:30]=[C:31]([NH:32]/[CH:3]=[C:4]3\[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:33]=[CH:34][CH:35]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccccc21
Reactant: Nc1cccc(CN2CCCCCC2)c1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2/C1=C/Nc1cccc(CN2CCCCCC2)c1
Temperature: 120 °C
Yield: 50.3 %

Procedure:
An amount of (4E)-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (1.0 g, 4.9 mmol) is added to N,N′-dimethylformamide, followed by 3-(azepan-1-ylmethyl)aniline (1.0 g, 4.9 mmol). The reaction mixture is heated at 120° C. under N2 for 40 minutes. After evaporating to dryness, the red oil is dissolved in warm ethyl acetate and filtered through a pad of celite to give a yellow solution. Addition of hexane into this organic solution yielded an orange precipitate, which is collected and recrystallized from EtOAc/Hex to give orange crystal (0.925 g, 50.05% yield): mp 116-117° C.; 1H NMR (DMSO-d6) δ 12.43 (d, J=9 Hz, 1H), 11.33 (s, 1H), 8.80 (d, J=9 Hz, 1H), 8.18 (d, J=9 Hz, 1H), 8.04 (d, J=9 Hz, 1H), 7.63 (t, J=6 Hz, 1H), 7.46 (s, 1H), 7.39 (m, 2H), 7.30 (t, J=3 Hz, 1H), 7.17 (d, J=6 Hz, 1H), 3.64 (s, 2H), 2.60 (s, 4H), 1.58 (m, 8H); MS (ESI) m/z 376.1 (M+H)+1; Analysis for C23H25N3O2; Calcd: C, 73.6; H, 6.71; N, 11.2. Found: C, 72.92; H, 6.45; N, 11.03.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][O:33][CH2:32]1>>[CH3:8][C@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][O:33][CH2:32]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCCC1CCCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 243 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([F:10])=[CH:8][N:9]=1)[CH:5]=O.[F:11][C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[CH2:14]P(=O)(OCC)OCC.CC(C)([O-])C.[K+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:14]/[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[F:11])[C:7]([F:10])=[CH:8][N:9]=1
Reactant: O=Cc1cc(Br)ncc1F
Reactant: CCOP(=O)(Cc1ccccc1F)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccccc1/C=C/c1cc(Br)ncc1F
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-bromo-5-fluoroisonicotinaldehyde (2 g, 9.80 mmol) and diethyl 2-fluorobenzylphosphonate (2.66 g, 10.78 mmol) in tetrahydrofuran (80 mL) at 0° C., was added potassium tert-butoxide(1M in tetrahydrofuran, 12.75 mL, 12.75 mmol) dropwise over a couple of minutes. When addition was complete, the reaction was allowed to stir at 0° C. for 45 min and quenched by addition of saturated ammonium chloride. The reaction was diluted with ether, washed with water (4×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (8%→15% EtOAc/Hex) gave 450 mg as an oil with solid crystallizing from the mixture. The material was triturated with hexanes (2×) to give a fine white powder. 1H NMR (CDCl3) δ: 8.26 (d, J=1.5 Hz, 1H), 7.69 (d, J=5.5 Hz, 1H), 7.64 (td, J=7.6, 1.5 Hz, 1H), 7.54 (d, J=16.8 Hz, 1H), 7.30-7.41 (m, 1H), 7.17-7.26 (m, 2H), 7.11-7.17 (m, 1H). 13C NMR (CDCl3) δ: 161.0, 156.7, 138.8, 136.6, 135.5, 131.0, 129.3, 127.9, 124.6, 123.7, 119.4, 116.3. 19F NMR (CDCl3) δ: −116.72 (br. s., 1F), −136.08 (br. s., 1F).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3)[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[N+:27]([O-])([O-:29])=[O:28].[K+]>>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:27]([O-:29])=[O:28])[C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3)[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1cc2c(=O)c(C(=O)O)cn(C3CC3)c2cc1OC
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc2c(c([N+](=O)[O-])c1OC)c(=O)c(C(=O)O)cn2C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
1-Cyclopropyl-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 50b) (20 g, 69.1 mmol) was dissolved in sulfuric acid (44.2 ml, 830 mmol) with stirring. The thick dark solution was cooled to 0° C. and potassium nitrate (10.48 g, 104 mmol) was added in small portions, while the temperature was maintained below 10° C. by use of an ice-water bath. After the addition, the mixture was kept under 10° C. for 1 h, and then was allowed to warm up to r.t. and stirred overnight. LCMS showed completion of reaction. The mixture was poured into ice-water (300 mL). A yellow solid precipitated out and was collected by filtration, washed with water and ethanol, and dried in vacuo to afford 1-cyclopropyl-6,7-dimethoxy-5-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (14 g, 41.9 mmol, 60.6% yield) as a pale yellow solid. LCMS: [M+H]+: 335.1.
Reaction SMILES: O.[ClH:2].Cl.[O:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][NH:12][CH2:13][C:14]2([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:17][CH2:16][CH2:15]2)[CH2:6][CH2:5]1.[CH2:26]=O.[OH-].[Na+]>C(O)=O>[ClH:24].[ClH:2].[CH3:26][N:12]([CH2:13][C:14]1([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:15][CH2:16][CH2:17]1)[CH2:11][CH2:10][N:7]1[CH2:6][CH2:5][O:4][CH2:9][CH2:8]1
Reactant: Clc1ccc(C2(CNCCN3CCOCC3)CCC2)cc1Cl
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CN(CCN1CCOCC1)CC1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
The product of Example 74 in the form of its free base (0.55 g) 98% formic acid (4 ml) and 37-40% aqueous formaldehyde were heated at 70°-80° C. for four hours. The reaction mixture was cooled and basified with aqueous sodium hydroxide solution. The mixture was then extracted with ether and the ether extract washed and dried. Hydrogen chloride gas was passed through the extract to give N-methyl-N-(2-morpholinoethyl)-[1-(3,4-dichlorophenyl)cyclobutyl]methylamine dihydrochloride (m.p. 233°-235° C.).
Reaction SMILES: Br[CH2:2][C:3]([CH3:5])=[CH2:4].CN(C=O)C.[Cl:11][C:12]1[C:13]([CH3:19])=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:4][C:3]([CH3:5])=[CH2:2])[C:13]=1[CH3:19]
Reactant: Cc1c(O)cccc1Cl
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)COc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.4 %

Procedure:
3-bromo-2-methylpropene (8.5 mL, 84.2 mmol) was added to a mixture of DMF (200 mL) containing 3-chloro-2-methylphenol (10.0 g, 70.1 mmol) and potassium carbonate (19.4 g, 140 mmol), and the mixture was stirred at room temperature for 15 hours. The reaction solution was distributed using ethyl acetate and water, and the organic layer was washed with water and saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 10:1) to give 13.7 g of the title compound as an amorphous solid (yield: 99%).
Reaction SMILES: [CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=O)[CH3:23])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:33][N:34](C(OCCCC)=O)[NH2:35].C(O)=O>C(O)(=O)C>[CH:1]1([N:4]([CH:30]2[CH2:31][CH2:32]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:21]=[C:22]([CH3:23])[N:34]([CH3:33])[N:35]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCCCOC(=O)N(C)N
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(C)=O)SC)nc21
Solvent: CC(=O)O
Solvent: O=CO
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3cc(C)n(C)n3)nc21
Temperature: 35 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
A mixture of (Z)-N,N-dicyclopropyl-6-ethyl-1-methyl-4-(1-(methylthio)-3-oxobut-1-enylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 72B, 70 mg, 0.155 mmol) and tent-butyl 1-methylhydrazinecarboxylate (0.046 mL, 0.309 mmol) in acetic acid (1 mL) wan stirred at 35° C. for 4 h (monitored by LC/MS until no starting material left). Formic acid (0.5 mL) was added and stirred at 60° C. for 6 h. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 2-10% methanol/dichloromethane). The impure product was further purified by preparative HPLC to give N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (45 mg, 63.9% yield) as an off-white solid.
Reaction SMILES: CON(C)[C:4](=[O:20])[CH:5]([O:18][CH3:19])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([CH3:17])=[N:15][N:16]=2)=[CH:8][CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=[C:28]([O:31][CH3:32])[C:29]=1[CH3:30]>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:33]2[O:34][C:35]([C:4](=[O:20])[CH:5]([O:18][CH3:19])[C:6]3[CH:7]=[CH:8][C:9]([C:12]4[O:13][C:14]([CH3:17])=[N:15][N:16]=4)=[CH:10][CH:11]=3)=[CH:36][CH:37]=2)[CH:27]=[C:28]([O:31][CH3:32])[C:29]=1[CH3:30]
Reactant: COc1cc(-c2ccco2)cc(OC)c1C
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)o2)cc(OC)c1C
Yield: 29 %

Procedure:
N,2-Dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide was reacted with 2-(3,5-dimethoxy-4-methylphenyl)furan according to the procedure used for the synthesis of Example 12. Purification by chromatography (EtOAc-hexanes) gave 1-(5-(3,5-dimethoxy-4-methylphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone as a yellow foam (0.148 g, 29% yield). MS: m/z 449.2 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:13]3[CH:12]([C:16]([O:18]C)=[O:17])[CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[OH-].[Li+].O.Cl>O1CCCC1>[N:1]1([C:6]2[CH:15]=[CH:14][C:13]3[CH:12]([C:16]([OH:18])=[O:17])[CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: COC(=O)C1CCCc2nc(-n3cnnn3)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCCc2nc(-n3cnnn3)ccc21
Reaction time: 1 h

Procedure:
Methyl 2-(1H-tetrazol-1-yl)-5,6,7,8-tetrahydroquinoline-5-carboxylate (1.04 g, 4.01 mmol) and lithium hydroxide (0.202 g, 4.81 mmol) were stirred in a mixture of tetrahydrofuran (10 ml)/water (10.00 ml) for 75 mins. The tlc showed some 20% starting material so more LiOH (50 mg, 1.19 mmol) was added and stirred for another 1 hr. The reaction was adjusted with 2N HCl (3 ml, 6 mmol) to pH 4-5 then extracted with ethyl acetate 2×. The ethyl acetate layers were combined and dried over Na2SO4, filtered and evaporated to dryness to yield 2-(1H-tetrazol-1-yl)-5,6,7,8-tetrahydroquinoline-5-carboxylic acid. 1H-NMR (600 MHz, CDCl3): δ ppm 9.53 (s, 1H), 7.85-7.89 (q, 2H), 3.945 (t, J=5.46 Hz, 1H), 3.01-3.05 (m, 1H), 2.90-2.96 (m, 1H), 2.29-2.44 (m, 1H), 2.04-2.13 (m, 2H), 1.95-2.01 (m, 1H); LC-MS: (M+1)-28=218.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(OC)cc2[N+](=O)[O-])cc1
Yield: 90 %

Procedure:
4-Methoxyphenylboronic acid was reacted with 4-bromo-3-nitroanisole as described for 1a to furnish a yellow solid (90% yield): mp 122°-124° C.; [Lund, H. et al, Acta. Chem. Scand., 20, 1631-1644 (1966)]1H NMR (CDCl3) δ7.30 (m, 2H), 7.18 (d, 2H, J=9.0 Hz), 7.10 (d, 1H, J=8.4 Hz), 6.92 (d, 2H, J=9.0 Hz), 3.87 (s, 3H), 3.82 (s, 3H); 13C NMR (CDCl3): δ159.37, 158.80, 149.69, 132.76, 129.43, 129.19, 128.21, 118.60, 114.12, 108.90, 55.89, 55.28. Anal. Calcd for C14H13NO4 : C, 64.86; H, 5.05; N, 5.40. Found: C, 64.77; H, 4.96; N, 5.24.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:29][O:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:36]4[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][O:30][CH3:29])[CH2:34][CH2:35]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(Cc2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 74.8 %

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.264 mmol) and 1-(2-methoxyethyl)piperazine (42 mg, 0.291 mmol) gave 7-cyclopentyl-2-{5-[4-(2-methoxy-ethyl)-piperazin-1-ylmethyl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 71%) [following SiO2 chromatography, eluting with 0-10% (2M NH3 in MeOH)/dichloromethane]. MS(ESI) m/z 507.3 (M+H)+ (method A).
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[CH3:7].[OH:13][C@@H:14]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:31]2[C:30](=[O:36])[CH2:29][C@@:28]2([CH3:37])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C:24](=[O:27])[CH:25]=[CH2:26])[CH2:15]1>C(O)C.O>[C:6]([CH:9]([C:10](=[O:12])[CH3:11])[CH2:26][CH2:25][C:24](=[O:27])[C@@H:23]1[C@:28]2([CH3:37])[C@H:20]([C@H:19]3[C@H:31]([C:30](=[O:36])[CH2:29]2)[C@:32]2([CH3:35])[C@H:16]([CH2:15][C@H:14]([OH:13])[CH2:34][CH2:33]2)[CH2:17][CH2:18]3)[CH2:21][CH2:22]1)(=[O:8])[CH3:7]
Reactant: CC(=O)CC(C)=O
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC(=O)C(CCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C)C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of sodium ethoxide, prepared from 120 mg of sodium in ethanol (20 ml), was treated with acetylacetone (1 ml) and the resulting solution added to a solution of 3α-hydroxy-21-methylene-5α-pregnane-11,20-dione (500 mg) in ethanol (20 ml). The mixture was stirred at room temperature for 1 hour, poured into water, and extracted into ether. The extract was washed with water, dried (Na2SO4) and evaporated to a white foam which was purified by preparative t.l.c. (ethyl acetate/petrol) to give title compound (480 mg) as a white foam [α]D + 79.5 °(c, 0.59).
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[C:3]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=2)[C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[OH:16])=[O:8])=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide and 4-chlorophenylboronic acid as starting materials, MS (ISP) 497.2 (M)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][S:14]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:15])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][S:14]([CH2:13][C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[O:15])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CS(=O)Cc2ccc(F)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(Cc1ccc(F)cc1)C[C@@H]1CCNC1

Procedure:
Using a similar procedure to that described in Example 93, step 2, (3R)-1-(tert-butoxycarbonyl)-3-[(4-fluorobenzylsulfinyl)methyl}pyrrolidine (0.5149 g, 1.51 mmol) was reacted with trifluoroacetic acid (2ml) in dichloromethane (6ml) to give, after work up, 0.3447 g (95%) of the title compound as a white solid, which was used without further purification. δH (360 MHz, CDCl3) 1.57 (1H, m), 2.13 (1H, m), 2.54-2.72 (4H, m), 3.05 (2H, m), 3.27 (1H, m), 3.96 (2H, m), 708 (2H, t, J=8.6 Hz), 7.26-7.30 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[C:12]=2[C:11]2[C:19]3[CH:25]=[C:24]([O:26]C)[CH:23]=[CH:22][C:20]=3[S:21][C:10]=2[CH:9]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[C:12]=2[C:11]2[C:19]3[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:20]=3[S:21][C:10]=2[CH:9]=1
Reactant: COc1ccc2sc3cc(-c4ccccc4Cl)c4c(c3c2c1)C(=O)NC4=O
Agent: BrB(Br)Br
Product: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1sc3ccc(O)cc3c21
Reaction time: 48 h
Yield: 65 %

Procedure:
Demethylation of (839) prepared as described in example 374 with BBr3 using the procedure described in example 80 except that the reaction time was 48 h gave (840) (65%) as a yellow solid, mp 311–313° C. 1H NMR δ [(CD3)2SO] 11.42 (s, 1H), 9.85 (s, 1H), 9.17 (d, J=2.5 Hz, 1H), 8.32 (s, 1H), 7.9 (d, J=9 Hz, 1H), 7.62 (m, 2H), 7.5 (m, 3H), 7.17 (dd, J=2.5, 9 Hz, 1H). MH+346. Found C, 68.75; H, 3.43; N, 3.89; S, 9.35. C20H11NO3S.0.2H2O requires: C, 68.83; H, 3.29; N, 4.01; S, 9.19.