Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH2:7]([N+:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])([CH3:27])[CH3:26])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].S(=O)(=O)(O)O>CO.O>[S:3](=[O:4])(=[O:2])([OH:6])[O-:5].[CH2:28]([N+:25]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:27])[CH3:26])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: COS(=O)(=O)[O-]
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: O=S(=O)([O-])O
Temperature: 350 °C
Reaction time: 18 h

Procedure:
In a 1 liter 3-necked round bottomed flask equipped with a mechanical stirrer and reflux condenser were suspended 60 grams (90.8 millimoles) of distearyl dimethyl ammonium methylsulfate in a mixture of 168.75 grams of methanol and 56.25 grams of deionized water. 9.57 grams of 95 percent sulfuric acid (90.8 millimoles) were then added and the reaction mixture was heated at gentle reflux, at about 71° to 72° C., for 4 hours. The resulting cloudy, emulsion-like mixture was then cooled slowly. After about one hour of slow cooling at about 350° C., droplets formation was observed and at about 300° C. solid particles formation was noticed. The crystallization was continued overnight, about 18 hours, under agitation at about 20° to 25° C. The waxy slurry was filtered under vacuum on an 11 centimeter Whatman #4,filter paper on a Buchner funnel. The filtration time recorded was 20 minutes. The filter cake was reslurried In 225 grams of a 75/25 mixture of methanol and water to remove residual acidity. The mixture of methanol and water was used in order to attempt to avoid the formation of gel experienced when water only is used to wash the highly acidic wet cake. A waxy, semigelatinous slurry was obtained, which required 20 minutes to filter. One additional reslurry washing was accomplished as described above requiring a filtration time of 35 minutes. A final reslurry wash with 225 grams of acetone was accomplished after which the product was recovered by filtration and dried overnight in vacuum at about 50° C. 41.7 grams (71.0 percent yield) of distearyl dimethyl ammonium bisulfate was recovered. Analyticals: melting point (DSC) 93.1° C., H2O content 0.11 percent, bisulfate content (by titration) 14.22 percent (theoretical 14.99 percent), and a different IR fingerprint from the material of COMPARATIVE Example I.
Reaction SMILES: [C:1]([NH:9][CH2:10][C@H:11]1[N:16](CC2C=CC=CC=2)[CH2:15][CH2:14][N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO>[C:1]([NH:9][CH2:10][C@H:11]1[NH:16][CH2:15][CH2:14][N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:12]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)[C@H](CNC(=O)c2ccccc2)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN[C@H](CNC(=O)c2ccccc2)C1
Yield: 81.6 %

Procedure:
Into a 40 mL scintillation vial was added 15U (865 mg, 2.11 mmol) and methanol (21 mL). The solution was passed through the H-Cube hydrogentator three times at 40 psi of hydrogen pressure at 50° C. The resultant solution was concentrated under vacuum and the residue was purified by column chromatography with 5% methanol in dichloromethane to give (R)-tert-butyl 3-(benzamidomethyl)piperazine-1-carboxylate (15Fb) as an oil (550 mg, 81%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[H][H]>[Pt]=O.C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(/C=C/C1CCN(Cc2ccccc2)CC1)c1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(C(=O)CCC2CCN(Cc3ccccc3)CC2)cc1
Yield: 37.5 %

Procedure:
2.00 g of (E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]nitrobenzene was added to a mixed solvent of 30 ml of ethanol and 5 ml of acetic acid, and then 0.20 g of platinum oxide was added thereto. Thereafter, the mixture was stirred in a hydrogen stream at room temperature for 7.5 hours. After the reaction, the catalyst was removed by filtration, and the filtrate was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 0.69 g of the title compound as pale yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:29]1[C:30]([CH3:37])=[CH:31][C:32]([C:35]#[N:36])=[N:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:29]1[CH:34]=[N:33][C:32]([C:35]#[N:36])=[CH:31][C:30]=1[CH3:37]
Reactant: CN(C(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1)c1ccccc1O
Reactant: Cc1cc(C#N)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C#N)ncc1-c1cc(C(=O)N(C)c2ccccc2O)ccc1Cl
Temperature: 95 °C
Yield: 69.2 %

Procedure:
A mixture of 4-chloro-N-(2-hydroxy-phenyl)-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (100 mg, 0.26 mmol), 5-bromo-4-methyl-pyridine-2-carbonitrile (61 mg, 0.31 mmol), Pd(PPh3)4 (15 mg, 0.013 mmol), K2CO3 (90 mg, 0.65 mmol) in dioxane (1.2 mL), was heated at 95° C. for 12 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4) and concentrated in vacuo. Silica gel column chromatography (eluent: ethyl acetate/hexane (1/4 up to 4/1)) yielded 4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide 8-1 (68 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[H-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:14]([CH:13]2[CH2:11][CH2:12]2)=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)CCCBr
Reactant: Cc1c(N)cccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(Br)cccc1NC(=O)C1CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 32.9 %

Procedure:
A solution of 3-bromo-2-methylaniline (2.00 g, 10.75 mmol) in DCM (20 mL) was treated with TEA (3.00 mL, 21.50 mmol) and then with a solution of 4-bromobutanoyl chloride (2.392 g, 12.90 mmol) in DCM (10 mL), and the resulting mixture was stirred at rt. After 2.5 h, the mixture was diluted with DCM, washed with NaHCO3 (aq) and water, and dried and concentrated. The residue was dissolved in THF (20 mL) and treated with hexane-washed sodium hydride (60% oil dispersion, 0.860 g, 21.50 mmol). The mixture was stirred at rt for 1.5 h, then was concentrated. The residue was dissolved in DCM, washed with water, 1 M hydrochloric acid and brine, and dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 80:20 hexane-EtOAc to EtOAc) to provide N-(3-bromo-2-methylphenyl)cyclopropanecarboxamide (900 mg, 33%) as a white solid. Mass spectrum m/z 254, 256 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:22]2[CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)C1
Reactant: Clc1cc(I)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(Cl)nc(Cl)c2)C1
Temperature: 65 °C
Yield: 52.8 %

Procedure:
To a mixture of 2,6-dichloro-4-iodo-pyridine (500 mg, 1.826 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (646.7 mg, 2.191 mmol, 1.2 equiv.), potassium carbonate (510 mg, 3.651 mmol, 2 equiv.), and PD(dppf)Cl2 DCM (223.6 mg, 0.274 mmol, 0.15 equiv.) in 1,4-dioxane (6 mL) and water (2 mL) was capped in a large CEM vial, de-gassed with N2, heated in oil bath @ 65° C. o/n. It was diluted with water, extracted with EtOAc (2×50 mL), dried over Na2SO4, filtered, concentrated in vacuo. Purification by column chromatography (ISCO), 40 g column, eluded with 0-10% EtOAc/Heptane to afford 304 mg (52.8%) of product as white foam. 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 0.5H), 7.22 (s, 0.5H), 7.04 (s, 2H), 3.93 (s, 2H), 2.90 (s, 2H), 1.53 (s, 9H). LC-MS: m/z=316 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[N:27]=[C:26]([CH:35]([CH3:37])[CH3:36])[C:25]=2/[CH:38]=[CH:39]/[CH:40]=[O:41])=[CH:20][CH:19]=1>C1COCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[N:27]=[C:26]([CH:35]([CH3:37])[CH3:36])[C:25]=2/[CH:38]=[CH:39]/[CH:40]([OH:41])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8])=[CH:20][CH:19]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)c1nn(-c2cnccn2)c(-c2ccc(F)cc2)c1/C=C/C=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)/C=C/c1c(C(C)C)nn(-c2cnccn2)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
To a hexane washed suspension of NaH (0.90 g, 22.5 mmol) in THF (30 ml) at 0° C. under an inert atmosphere, was added a solution of ethyl acetoacetate (2.69 ml, 21.1 mmol) in THF (30 ml). The resulting clear solution was stirred at 0° C. for 15 minutes before n-BuLi (9.6 ml, 21.1 mmol) was added dropwise. The orange solution was stirred at 0° C. for 15 minutes before it was cooled to -78° C. and a solution of the unsaturated aldehyde (4.73 g, 14.1 mmol, Step E) in THF (80 ml) was added dropwise. This was stirred at -78° C. for two hours and then it was quenched by adding~5 ml HOAc and removing the cooling bath. The reaction was partitioned between Et2O and 5% K2CO3 (aq). The organics were dried (MgSO4) and evaporated to give a yellow oil. Elution from a 4-inch silica column gave 3.17 g (48%) of product as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][C:5](/[CH:6]=[CH:7]/N(C)C)=[C:4]([N+:14]([O-])=O)[CH:3]=1.C[O:18][C:19]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)C(Cl)=O)=[O:20]>>[Cl:13][C:12]1[CH:11]=[C:5]2[C:4](=[CH:3][C:2]=1[Cl:1])[NH:14][C:7]([C:28]1[CH:29]=[C:21]([CH:22]=[CH:23][CH:27]=1)[C:19]([OH:20])=[O:18])=[CH:6]2
Reactant: CN(C)/C=C/c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Product: O=C(O)c1cccc(-c2cc3cc(Cl)c(Cl)cc3[nH]2)c1

Procedure:
Starting from trans-4,5-dichloro-2-nitro-β-dimethylaminostyrene and 3-(methoxycarbonyl)benzoyl chloride and following successively the procedures of Descriptions 2, 3 and 4 afforded the title compound as a beige solid which was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[NH:5][C:4](=[S:16])[N:3]=1.I[CH2:18][CH3:19].C(=O)(O)[O-].[Na+].O>CS(C)=O>[Cl:15][C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[C:6]1[N:5]=[C:4]([S:16][CH2:18][CH3:19])[N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: CCI
Reactant: Nc1cc(-c2ccc(Cl)cc2Cl)[nH]c(=S)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCSc1nc(N)cc(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
67.5 g (248 mmol) of 4-amino-6-(2,4-dichlorophenyl)pyrimidine-2(1H)-thione and 77.37 g (496.04 mmol) of iodoethane are dissolved in 560 ml of dry DMSO and, at RT, 270 ml of a saturated aqueous sodium bicarbonate solution are slowly added. The mixture is stirred at RT for 5 h and then 440 ml of water are added. The precipitate is filtered off with suction, washed with water and sucked dry. It is stirred twice with 100 ml of isopropanol each time and again filtered off with suction. It is washed once more with petroleum ether and the residue is dried under high vacuum. 50.0 g (67% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][C:6]=1[N+:28]([O-])=O)[CH3:2].O.C(O)(=O)C>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]([C:20]3[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=3)([C:16]([F:17])([F:18])[F:19])[O:13][N:12]=2)=[CH:7][C:6]=1[NH2:28])[CH3:2]
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1N
Temperature: 75 °C
Reaction time: 2 h
Yield: 106.7 %

Procedure:
In a solution of 0.60 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-nitro benzoic acid ethyl ester synthesized in Steps 1 to 3 of Synthetic Example 5 in 6 ml of ethyl acetate, 2.0 ml of water, 0.6 ml of acetic acid and 0.46 g of reduced iron were added, and stirred at 75° C. for 2 hours. After the completion of the reaction, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (10 ml×2). The organic phases together were washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.60 g of crude aimed product as brown oily substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH2:8]I)=[O:2].Cl.[CH3:23][NH:24][CH3:25].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:23][N:24]([CH2:8][CH2:7][CH2:6][C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][NH:3][CH:1]=[O:2])[CH3:25]
Reactant: O=CNCC(CCCI)(c1ccccc1)c1ccccc1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)CCCC(CNC=O)(c1ccccc1)c1ccccc1
Yield: 67.1 %

Procedure:
A mixture of 5-formylamino-1-iodo-4,4-diphenylpentane (8.5 g), dimethylamine hydrochloride (17.63 g), triethylamine (30.1 ml), and potassium carbonate (3 g) was heated in acetonitrile (250 ml) at 60° C. for 2 hours. This reaction mixture was concentrated to dryness and the group was extracted using ethyl acetate and water. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness. The group was crystallized from ethyl acetate-isopropyl ether to provide the title compound (4.5 g) as white powder.
Reaction SMILES: [O:1]([CH:9]([CH3:49])[CH2:10][C:11]1[C:19]2[C:18]([Cl:20])=[N:17][CH:16]=[N:15][C:14]=2[N:13]([C@@H:21]2[O:36][C@H:35]([CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=3[Cl:47])[C@@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[C@@:22]2([CH3:48])[OH:23])[CH:12]=1)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>C1COCC1>[Cl:20][C:18]1[C:19]2[C:11]([CH2:10][CH:9]([OH:1])[CH3:49])=[CH:12][N:13]([C@@H:21]3[O:36][C@H:35]([CH2:37][O:38][CH2:39][C:40]4[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=4[Cl:47])[C@@H:24]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=4[Cl:34])[C@@:22]3([CH3:48])[OH:23])[C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: CC(Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2ncnc(Cl)c12)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(O)Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
To a solution of compound 4.2 (800 mg, 1.01 mmol) in THF (20 mL) was added a 1.0 M solution of tetrabutylammonium fluoride in THF (1.5 mmol) at room temperature. The colorless solution was stirred for 4 hr at room temperature and then diluted by addition of 150 mL of CH2Cl2 and water (50 mL). The aqueous layers were extracted three times with CH2Cl2, and then dried over Na2SO4, filtered and evaporated. Purification by silica gel column chromatography using 1-2% MeOH in CH2Cl2 as eluent gave the desired compound 4.3 (460 mg, 67%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[O:5][CH:6]=1.C([Li])CCC.CN(C)[CH:23]=[O:24].[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[Si:9]([O:8][CH2:7][C:4]1[O:5][CH:6]=[C:2]([CH:23]=[O:24])[CH:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)co1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(C=O)co1
Yield: 55 %

Procedure:
To a solution of [(4-bromo-2-furyl)methoxy](t-butyl)dimethylsilane (7.3 g, 25 mmol) that was obtained in Example 1 (1a) in tetrahydrofuran (50 ml) was slowly added dropwise n-butyllithium (a 1.6 M solution in hexane, 17 ml, 28 mmol) at −78° C. with stirring, and the resulting mixture was stirred for 5 minutes. Subsequently, to the reaction mixture was furthermore added N,N-dimethylformamide (3.8 ml, 50 mmol) at the same temperature with stirring, and the resulting mixture was stirred for 45 minutes. After stirring, a saturated aqueous solution of ammonium chloride (10 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (100 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:49 to 1:19) as the eluent to afford the title compound (3.3 g) in a yield of 55% as a colourless oily product.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:26])[C:5]2[C:10]([C:11]#[C:12][CH2:13][OH:14])=[CH:9][N:8]([CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=3)[C:6]=2[N:7]=1.Cl.[CH3:28][N:29]([CH2:31][C:32](Cl)=[O:33])[CH3:30].C1(C)C=CC=CC=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([Cl:26])[C:5]2[C:10]([C:11]#[C:12][CH2:13][O:14][C:32](=[O:33])[CH2:31][N:29]([CH3:30])[CH3:28])=[CH:9][N:8]([CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=3)[C:6]=2[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CCO)c3c(Cl)nc(N)nc32)c1C
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1c(C)cnc(Cn2cc(C#CCOC(=O)CN(C)C)c3c(Cl)nc(N)nc32)c1C

Procedure:
A solution of 3-[2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-prop-2-yn-1-ol (see example 1, 177 mg, 0.48 mmol) in anhydrous pyridine (3 mL) was treated with N,N-dimethylamino-acetyl chloride hydrochloride (113 mg, 0.72 mmol) at rt for 30 min. Addition of toluene (10 mL) caused the formation of a sticky pellet. The toluene solution was discarded, and the pellet was partitioned between water and DCM. The DCM layer was concentrated, and purifed by flash chromatography (EtOAc/DCM/Et3N 33:66:1, gradually adding MeOH (0-2%)) to afford the title compound. tR=4.51 min. 1H NMR (CDCl3) δ 8.23 (s, 1H), 7.14 (s, 1H), 5.31 (s, 2H), 5.00 (s, 2H), 4.98 (s, 2H), 3.76 (s, 3H), 3.25 (s, 2H), 2.38 (s, 6H), 2.28 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH:11]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[N:13]([CH2:19][CH:20]=[CH2:21])[CH2:12]1.[BH4-].[Na+].CO.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH:11]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[N:13]([CH2:19][CH:20]=[CH2:21])[CH2:12]1
Reactant: C=CCN1CC(c2ccc([N+](=O)[O-])cc2F)CCS1(=O)=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCN1CC(c2ccc(N)cc2F)CCS1(=O)=O
Reaction time: 0.33 h
Yield: 99.8 %

Procedure:
4-(2-Fluoro-4-nitrophenyl)tetrahydro-2-(2-propenyl)-2H-1,2-thiazine 1,1-dioxide (1.303 g, 4.15 mmol) and cuprous bromide: dimethyl sulfide complex (0.855 g, 4.15 mmol) are stirred at ice temperature in dry THF (30 ml). Sodium borohydride (1.25 g, 33.07 mmol) is added and the mixture stirred for 20 min. Methanol (10 ml) is carefully added over 30 min followed by ammonium chloride solution (50 ml). The mixture is extracted with methylene chloride (2×100 ml), washed with water (50 ml) and brine (50 ml), dried (MgSO4) and evaporated to yield the product as a cream solid (1.178 g, 100%) mp 96°.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.[CH3:11][N:12]([CH3:20])[C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1O>>[CH3:11][N:12]([CH3:20])[C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: COC(=O)c1cc(O)no1
Reactant: CN(C)[C@@H]1CCCC[C@H]1O
Product: COC(=O)c1cc(O[C@@H]2CCCC[C@H]2N(C)C)no1
Yield: 73 %

Procedure:
The title compound was prepared in 73% yield by essentially following the procedures outlined in Example 20, Part B from methyl 3-hydroxyisoxazole-5-carboxylate and (±)-trans-2-(dimethylamino)cyclohexanol (Example 79, Part A).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8].[N-:9]=[N+:10]=[N-:11].[Na+]>>[N:9]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: COCCOCCBr
Agent: [Na+]
Product: COCCOCCN=[N+]=[N-]
Yield: 76.5 %

Procedure:
1-Azido-2-(2-methoxy-ethoxy)-ethane (607 mg) was prepared by following General Procedure U starting from 1-bromo-2-(2-methoxy-ethoxy)-ethane (1.0 g) and sodium azide (1.07 g). The crude product was used in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:12][NH2:13]>>[CH3:11][O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[N:12][NH:13]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(F)c1
Reactant: NN
Product: COc1ccc2cn[nH]c2c1
Yield: 59 %

Procedure:
A mixture of 2-fluoro-4-methoxybenzaldehyde (1 g, 6.5 mmol) and hydrazine (7 mL) was heated to reflux for 4 h. The mixture was extracted with CH2Cl2. The combined organic layers were washed with water, brine, concentrated in vacuo, and purified by column chromatography (elution with PE/EtOAc=5:1) to afford 6-methoxy-1H-indazole (intermediate 42) (568 mg, 59%) as a yellow solid. HPLC: 99%, RT 2.159 min. MS (ESI) m/z 149.1[M+H]+.