Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c(-c2ccc(Cl)cc2)csc1N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-(4-chlorophenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 9, Part C). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][C:5]2[CH:8]=[C:9]([C:12]3[C:13]([CH:17]=O)=[N:14][NH:15][N:16]=3)[CH:10]=[CH:11][C:4]=2[O:3]1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]2[CH3:33])=[N:25][CH:26]=1.C(O)(=O)C.B.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Na+].[Na+].[Na+]>CN(C=O)C>[F:35][C:20]([F:19])([F:34])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:17][C:13]3[C:12]([C:9]4[CH:10]=[CH:11][C:4]5[O:3][C:2](=[O:1])[NH:7][CH2:6][C:5]=5[CH:8]=4)=[N:16][NH:15][N:14]=3)[CH2:29][C@H:28]2[CH3:33])=[N:25][CH:26]=1
Reactant: C[C@@H]1CNCCN1c1ccc(C(F)(F)F)cn1
Reactant: O=Cc1n[nH]nc1-c1ccc2c(c1)CNC(=O)O2
Agent: B
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2n[nH]nc2-c2ccc3c(c2)CNC(=O)O3)CCN1c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-(3,4-dihydro-2-oxo-2H-benzo[e][1,3]oxazin-6-yl)-2H-1,2,3-triazole-4-carbaldehyde (15 mg, 0.06 mmol) and (R)-1-(5-(trifluoromethyl)pyridin-2-yl)-2-methylpiperazine (20 mg, 0.08 mmol) are mixed in DMF (1 ml) followed by addition of acetic acid (AcOH) (30 ul). The mixture is stirred at room temperature for 30 minute and then sodium triacetate boron hydride (42 mg, 0.2 mmol) is added. The resulting suspension is then stirred at room temperature overnight. The reaction is quenched using an aqueous saturated solution of sodium bicarbonate and then extracted with ethyl acetate (10 ml×4). The combined organic phase is concentrated and the resulting crude product is purified by HPLC giving 6-(5-(((R)-4-(5-(trifluoromethyl)pyridin-2-yl)-3-methylpiperazin-1-yl)methyl)-2H-1,2,3-triazol-4-yl)-3,4-dihydrobenzo[e][1,3]oxazin-2-one as a white powder. m/e:474 (M+1).
Reaction SMILES: C[O:2][CH:3]=[CH:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[NH:10][N:9]=[CH:8]2.Cl(O)(=O)(=O)=O>O1CCCC1.O.C(OCC)(=O)C>[CH3:14][C:12]1[CH:13]=[C:5]([CH2:4][CH:3]=[O:2])[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[CH:8]2
Reactant: COC=Cc1cc(C)c2[nH]ncc2c1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(CC=O)cc2cn[nH]c12
Reaction time: 2 h

Procedure:
To a solution of 5-(2-methoxy-vinyl)-7-methyl-1H-indazole (365 mg, 1.94 mmol, 1.0 equiv.) in tetrahydrofuran (8 mL) was added 60% perchloric acid (0.63 mL, 3 equiv) in one portion under nitrogen. After 2 h, more perchloric acid (0.63 mL) was added. After 4 h, LCMS indicated that no starting material was present. The reaction mixture was diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with water (3×). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give an off-white solid. The crude material was carried on without further purification. MS (ESI) [M+H]+=175.
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:40])[NH:14][C@H:15]([C@@H:33]1[CH2:37][C@@H:36]([CH3:38])[C:35](=[O:39])[O:34]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:19][C:18]1([CH3:32])[CH3:31])([CH3:11])([CH3:10])[CH3:9].O.[CH:42]1([NH2:48])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[C:8]([O:12][C:13](=[O:40])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:19][C:18]1([CH3:31])[CH3:32])[C@@H:33]([OH:34])[CH2:37][C@H:36]([C:35](=[O:39])[NH:48][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[CH3:38])([CH3:10])([CH3:11])[CH3:9]
Reactant: Cc1ccccc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](C)C(=O)O2)CC1=O
Reactant: NC1CCCCC1
Agent: Oc1ccccn1
Solvent: O
Product: Cc1ccccc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NC2CCCCC2)CC1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
6.8 mg of 2-hydroxypyridine (0.072 mmol) was added to a solution of 165 mg of {(S)-2-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (85b) (0.36 mmol) in cyclohexylamine (1.5 ml), and the mixture was stirred at 80° C. for one hour. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 191 mg of the title compound (yield: 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=3)(=[O:24])=[O:23])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(-c3ccc(C#N)n3C)cc2)cc1

Procedure:
The title compound was prepared according to general procedure for sulfonylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using p-toluenesulfonyl chloride (105 mg, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-4-methyl benzenesulfonamide (0.036 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][CH:3]=1.N12CCN(CC1)CC2.[CH3:17][CH:18]([N:20]=[C:21]=[O:22])[CH3:19]>CN(C)C=O>[Cl:8][C:6]1[N:5]=[N:4][CH:3]=[C:2]([NH:1][C:21]([NH:20][CH:18]([CH3:19])[CH3:17])=[O:22])[CH:7]=1
Reactant: CC(C)N=C=O
Reactant: Nc1cnnc(Cl)c1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Nc1cnnc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 0.8 gram of 4-amino-6-chloro-pyridazine in 30 ml of dimethylformamide is added 0.2 gram of 1,4-diazabicyclo[2.2.2]octane, followed by 0.6 gram of 1-methylethyl isocyanate. The reaction mixture is stirred at ambient temperature for 18 hours, then at 60° C. for six hours. The majority of the dimethylformamide is removed under reduced pressure, and the residue is slurried in water. The resultant solid is collected by filtration and dried to yield N-(6-chloro-4-pyridazinyl)-N'-(1-methylethyl)urea.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([N:23]([CH3:35])[CH2:24][C:25]2[N:26]([CH3:34])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:22])=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[O:11]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:6])[N:12]1[C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([N:23]([CH3:35])[CH2:24][C:25]2[N:26]([CH3:34])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:22])=[CH:15][CH:14]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N2C(=O)c3ccccc3C2=O)nc1
Reaction time: 48 h
Yield: 34 %

Procedure:
Phthalic anhydride (0.81 g, 5.48 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (0.44 g, 1.37 mmole) and sodium bicarbonate (0.58 g, 6.85 mmole) in THF (70 mL) at RT, and the reaction was heated at reflux under nitrogen. After 48 hr, the reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (ethyl acetate). The title compound (0.21 g, 33%) was obtained as a white solid: MS (ES) m/e 451 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([NH2:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O>C(O)C>[CH2:26]([NH:31][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)CN
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)CNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (200 mg, 0.774 mmol) in ethanol (5 mL) was added potassium carbonate (214 mg, 1.55 mmol) and neopentylamine (135 mg, 1.55 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (245 mg, 97% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:8][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH:24]=[CH:23][N:22]=1.CN(C)C=O.ClCCl>C(O)C.CO>[CH3:33][N:30]1[CH2:29][CH2:28][N:27]([C:25]2[CH:24]=[CH:23][N:22]=[C:21]([NH:1][C:2]3[CH:19]=[CH:18][C:5]4[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[S:8][C:4]=4[CH:3]=3)[N:26]=2)[CH2:32][CH2:31]1
Reactant: CN1CCN(c2ccnc(Cl)n2)CC1
Reactant: Nc1ccc2nc(NC(=O)c3ccccc3)sc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2ccnc(Nc3ccc4nc(NC(=O)c5ccccc5)sc4c3)n2)CC1

Procedure:
N-{6-[4-(4-Methylpiperazin-1-yl)pyrimidin-2-ylamino]benzothiazol-2-yl}benzamide was prepared by heating a mixture of N-(6-aminobenzothiazol-2-yl)benzamide (IM 2, 50 mg, 0.186 mmol) and 2-chloro-4-(4methylpiperazin1-yl)pyrimidine (IM 10, 40 mg, 0.186 mmol) in ethanol (3 mL) to 80° C. for 4 days. After dissolving the precipitate by addition of dimethylformamide, pTLC (dichloromethane:methanol=4.1) yielded a solid (44 mg, 0.100 mmol, 54%). LC/ESI-MS: m/z=446 [M+H]+; m/z=444 [M−H]−; Rt=2.12 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6]1.[H-].[Na+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:33])(=O)=O)=CC=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]([S:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:12])=[O:13])([F:33])[CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6]1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COC(=O)C(C1CCC(=O)C1)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(F)(C1CCC(=O)C1)S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 28.3 %

Procedure:
To a stirred solution of 1.34 g (4.5 mmol) of benzenesulfonyl-(3-oxo-cyclopentyl)-acetic acid methyl ester in 15 mL of DMF at 0° C., 199 mg (5.0 mmol, 1.1 eq) of NaH (60%) were added. The reaction mixture was stirred at this temperature for one hour, and 2.14 g (6.75 mmol, 1.5 eq) of N-fluorobenzenesulfonimide were added. After 2 hours at RT, the reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. The resulting two diastereomers were separated by column chromatography on silica gel with heptane/EtOAc (from 2:1 to 2:1) yielding 0.40 g (28%) of (RS,SR)-benzenesulfonyl-fluoro-(3-oxo-cyclopentyl)-acetic acid methyl ester as a white solid, MS: 332 (MNH4+) and 0.52 g (37%) of (RR,SS)-benzenesulfonyl-fluoro-(3-oxo-cyclopentyl)-acetic acid methyl ester as a white solid, MS: 332 (MNH4+).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:21]Br>C(O)(=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:21][C:12]1[CH:11]=[CH:10][C:9]([NH:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])=[C:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:13]=1
Reactant: BrBr
Reactant: CC(C)(C)C(=O)Nc1ccccc1-c1ncccc1F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)Nc1ccc(Br)cc1-c1ncccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.6 %

Procedure:
To a room temperature suspension of N-[2-(3-fluoro-pyridin-2-yl)-phenyl]-2,2-dimethyl-propionamide (˜77 mmoles) in acetic acid (300 mL) was added bromine (12 mL, 228 mmoles) as a solution in 50 mL of acetic acid over a 1 hour period. The heterogenous mixture was stirred at room temperature for 5 hours over which time a thick precipitate formed. The mixture was then poured over ice, diluted with 1N Na2S2O3 (500 mL), and stirred for 1 hour. The solids were filtered, re-suspended in water (2 L), stirred for 1 hour, then filtered and washed with water again. The resulting solids were pumped to dryness at 50° C., re-suspended in HOAc (400 mL), and treated with bromine (4 mL, 76 mmoles) in acetic acid solution (20 mL) over a 20 minute period. The resulting heterogenous mixture was stirred for 5 hours, then quenched and treated as described above. The resulting solids were vacuum dried at 50° C. to afford the title compound (19.1 grams, 72%) as a tan powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=1[O:21]C)=[O:10].B(Cl)(Cl)Cl.O.CCO>C(Cl)Cl>[Cl:23][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=1[OH:21])=[O:10]
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c(OC)c1OC
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c(O)c1OC

Procedure:
2-(3,5-Dichloro-pyridin-4-yl)-1-(2,3,4-trimethoxy-phenyl)-ethanone from preparation 2 (20 g, 56 mmol) was dissolved in DCM (75 mL) under argon. BCl3 (95 mL of a 1M solution in DCM) was added slowly at room temperature for 2 hours. Water (50 mL) was added slowly followed by EtOH (200 mL). The white precipitate was filtered and re-crystallised from EtOH. 2-(3,5-Dichloro-pyridin-4-yl)-1-(2-hydroxy-3,4-dimethoxy-phenyl)-ethanone was obtained as a white solid. 1H NMR (CDCl3) δ=11.92 (1H, s), 8.54 (2H, s), 7.68 (1H, d), 6.60 (1H, d), 4.67 (2H, s), 3.98 (3H, s), 3.90 (3H, s). Yield 14.2 g (74%)
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][CH:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:13]=[CH:12][C:11]([C:9]2[S:10][C:6]([CH2:4][OH:3])=[CH:7][N:8]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cnc(-c2ccc(C(F)(F)F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
To a solution of 2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester (5.122 g, 17.00 mmol) in THF (85 ml) was added dropwise with cooling (15° C.) LAH (1M in THF, 17.34 ml, 17.34 mmol). The resulting mixture was stirred 30 min at RT and the reaction was quenched at ca 15° C. by the cautious addition of 20 ml saturated aqueous NH4Cl solution. The precipitate was filtered, washed with THF, evaporated and suspended in CH2Cl2. Na2SO4 was added and the organic phase filtered and evaporated to give 4.46 g (quantitative) of [2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol as a yellow crytalline residue, MS: 259 (M+), MP: 95-98° C., dec.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([CH3:36])([CH3:35])[CH2:6][C:7]1[N:8]=[C:9]([C:18](=[O:34])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=3)=[CH:22][C:21]=2[F:33])[N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=1>O1CCCC1>[CH3:4][C:5]([CH3:36])([CH3:35])[CH2:6][C:7]1[N:8]=[C:9]([C:18]([OH:34])([CH3:1])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=3)=[CH:22][C:21]=2[F:33])[N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(-c2ccc(F)cn2)cc1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(-c2ccc(F)cn2)cc1F
Temperature: 25 °C

Procedure:
Methylmagnesium bromide (3 M in diethyl ether) (28 μL, 0.08 mmol) was added to a 0° C. solution of 4-(2,2-dimethylpropyl)-2-{[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (20 mg, 0.04 mmol) in tetrahydrofuran (3 mL). After warming slowly to ambient temperature, the reaction was quenched with a few drops of water and concentrated in vacuo to afford 4-(2,2-dimethylpropyl)-2-{2-[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide which was used in the subsequent step without further purification.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:7]([OH:10])(=[O:9])[CH3:8]>>[C:7]([O:10][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:9])[CH3:8]
Reactant: CC(=O)O
Reactant: C1=CCCCC1
Product: CC(=O)OC1CCCCC1
Temperature: 100 °C

Procedure:
In a 200 ml autoclave were placed the above-mentioned commercially available dodecatungstosilicic acid 5.0 g, the above-mentioned commercially available acetic acid 61.5 g and the above-mentioned commercially available cyclohexene 13.5 g and nitrogen gas was fed thereinto until the pressure reached 5 kg/cm2 (gauge), and then a reaction was carried out with stirring by heating at 100° C. for 1 hour. The result is shown in Table 1, that is, cyclohexyl acetate was produced in high yield.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:1]([N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:9][CH2:10][CH2:11][C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=2)=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCBr
Reactant: NC(=O)c1ccc(Oc2ccc(CCCNCc3ccccc3)cc2)nc1
Product: CCCCCN(CCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1)Cc1ccccc1

Procedure:
Using a method similar to example 2, using 6-[4-(3-benzylamino-propyl)-phenoxy]-nicotinamide (Step 3, Example 131) and 1-bromopentane gives the title compound: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 8.40 minutes, Purity: 99.8%; mass spectrum (ion spray): m/z=432.3 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:11]1[CH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([Cl:32])[CH:26]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:32][C:27]1[CH:26]=[C:25]([CH2:24][C@H:11]2[C@@H:10]([CH2:9][OH:8])[O:14][C:13]([CH3:16])([CH3:15])[N:12]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:30]=[C:29]([CH3:31])[N:28]=1
Reactant: Cc1cc(C[C@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)cc(Cl)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(C[C@H]2[C@@H](CO)OC(C)(C)N2C(=O)OC(C)(C)C)cc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-4-((2-chloro-6-methylpyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.206 g, 0.425 mmol) was dissolved in THF (4 mL) and cooled to 0° C. TBAF (0.637 ml, 0.637 mmol) was added to the mixture dropwise and the reaction was stirred 1 hr and then quenched with saturated ammonium chloride and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated. The crude material was purified by silica column chromatography (19:1 DCM/MeOH) and then reverse phase HPLC to give the title compound. MS m/z: 371.3 (100%, M+1).
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][S:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])=[O:31]>>[CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]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]([S:30]([CH3:29])(=[O:32])=[O:31])[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: CS(=O)(=O)N1CCNCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CCN(S(C)(=O)=O)CC4)cn3)nc2n1C1CCCC1

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (150 mg, 0.396 mmol) and 1-methanesulfonyl-piperazine (72 mg, 0.436 mmol) gave 7-cyclopentyl-2-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as an off white solid (97 mg, 46%) [following SiO2 chromatography, eluting with 0-10% (2M NH3 in MeOH)/DCM].
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:11]=[CH:12][C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2)[CH2:3][CH2:4]OS(C)(=O)=O.[H-].[Na+].CN(C)C=O>O>[CH3:1][N:2]1[C:10]2[CH:11]=[CH:12][C:13]([C:24]([F:25])([F:26])[F:27])=[C:14]3[CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]([C:18]=23)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)ccc(N(C)CCOS(C)(=O)=O)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(C(F)(F)F)ccc3c2n1CCN3C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 7-[N-methyl-N-(2-methanesulfonyloxyethyl)amino]-4-trifluoromethyl-1H-indole-2-carboxylate (3.15 g, 7.71 mmol), 60% sodium hydride (0.31 g, 7.71 mmol) and N,N-dimethylformamide (200 ml) was stirred at room temperature for 1 hour. The reaction mixture was poured into cold water and extracted with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was recrystallized from isopropanol to obtain ethyl 2,3-dihydro-1-methyl-7-trifluoromethyl-1H-pyrrolo[1,2,3-de]quinoxaline-5-carboxylate. M.p. 91-92° C.