Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.I[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[CH:25]([N:17]1[C:18]2=[N:19][CH:20]=[N:21][C:22]([NH2:24])=[C:23]2[C:15]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=2[O:2][CH3:1])=[N:16]1)([CH3:27])[CH3:26]
Reactant: COc1cccc(B(O)O)c1OC
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COc1cccc(-c2nn(C(C)C)c3ncnc(N)c23)c1OC
Temperature: 80 °C
Yield: 87.4 %

Procedure:
A solution 2,3-dimethoxyphenylboronic acid (105 mg, 0.58 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (70 mg, 0.23 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by silica gel column chromatography [MeOH—CH2Cl2, 2:98] to yield BA65 (63 mg, 88% yield). ESI-MS (M+H)+ m/z calcd 314.1, found 314.1.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1>COC(OC)(C)C>[CH3:12][C:11]1([CH3:16])[NH:10][C:1](=[O:9])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4]1
Reactant: NC(=O)c1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Product: CC1(C)NC(=O)c2ccccc2O1

Procedure:
6.86 g (50 mmol) of salicylamide was suspended in 100 ml of acetone dimethylacetal. After the addition of 2.85 g (15 mmol) of p-toluenesulfonic acid, the mixture was heated to reflux for two hours. The resulting reaction mixture was evaporated under reduced pressure. After the addition of ethyl acetate, the solvent was washed twice with a saturated aqueous solution of sodium hydrogen carbonate and once with brine. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure, to obtain 8.94 g (quantitative) of the title compound as light yellow needle-like crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:21])=O>N1C=CC=CC=1.C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([Cl:21])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
To a 3-necked flask equipped with a magnetic stirrer, thermometer, and water condenser with a drying tube is added 3,5-di-t-butyl-4-hydroxybenzoic acid (12.5 g, 0.05 m), thionyl chloride (10 ml) and 5 drops of pyridine. This mixture is heated at 45° C. for 1.5 hr. After cooling to RT, 50 ml of benzene is added. After stirring for 15 min., the benzene is evaporated under water aspirator vacuum leaving a yellow solid. This is dissolved in petroleum ether (at 35°-55° C.), filtered, and evaporated to afford 11 g of a yellow solid, mp 90°-93° (lit.mp. 96°-99°).
Reaction SMILES: [C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(Cl)Cl>[C:27]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[C:7](\[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reaction time: 18 h
Yield: 86 %

Procedure:
(E)-7-Phenyl-7-(3-pyridyl)-6-hepten-1-ol (0.4 g, 1.5 mmoles) was dissolved in methylene chloride (10 ml) and pyridine (0.4 ml) and acetic anhydride (0.2 ml) were added to the solution. The mixture was allowed to stand at room temperature for 18 hours and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate as the developing solvent to give 1-acetoxy-(E)-7-phenyl-7-(3-pyridyl)-6-heptene (0.4 g, 86%) (Compound I-19) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:13]1([O:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([O:19][C:20]([N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=3[NH:10][C:9]2=[O:12])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: COc1cccc2c1[nH]c(=O)n2C(=O)Oc1ccccc1
Temperature: 0 °C

Procedure:
To a solution of 4-methoxy-2-oxo-2,3-dihydrobenzimidazole (24 g; 0.146 mol) in pyridine (200 ml), phenylchloroformate (18.4 ml; 0.146 mol) was added dropwise. The reaction mixture was refluxed for 14 hours then was poured into ice-water. The precipitated solid was collected and dried to give the title compound. 30 g; m.p. 204-205° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([F:24])[CH:15]=3)[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:29]([NH:33][S:34]([C:37]1[S:38][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:41]=1)(=[O:36])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][S:34]([C:37]1[S:38][C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([C:25]([F:26])([F:27])[F:28])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[C:16]([F:24])[CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:40][CH:41]=1)(=[O:35])=[O:36])([CH3:30])([CH3:31])[CH3:32]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Fc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(F)c4)cc(C(F)(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[6-(3-fluoro-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(3-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.109) (0.465 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.414 g, 1.2 mmol) according to the general procedure VI. Obtained as an off-white solid (0.32 g), which was subsequently deprotected.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:3]=1.[CH2:18]([N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])[CH2:19][CH2:20][C:21]#[CH:22].C(OCC)(=O)C.O>CN(C)C=O.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:22]#[C:21][CH2:20][CH2:19][CH2:18][N:23]2[C:24](=[O:33])[C:25]3[C:26](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:28])=[CH:6][N:5]=[C:4]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:3]=1
Reactant: C#CCCCN1C(=O)c2ccccc2C1=O
Reactant: N#Cc1ccc(Nc2ncc(I)c(Cl)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Nc2ncc(C#CCCCN3C(=O)c4ccccc4C3=O)c(Cl)n2)cc1
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 4-((4-chloro-5-iodopyrimidin-2-yl)amino)benzonitrile (J12, 53 mg) and N-(4-pentynyl)phthalimide (47 mg) in N,N-dimethylformamide (1 mL), triethylamine (103 μL), copper(I) iodide (14 mg), and bis(triphenylphosphine)palladium(II) dichloride (10 mg) were added at room temperature, and the mixture was stirred overnight at the same temperature. To the reaction mixture, ethyl acetate and water were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid matter was washed with chloroform, and then dried under reduced pressure to obtain 4-((4-chloro-5-(5-(1,3-dioxoisoindolin-2-yl)-1-pentyn-1-yl)pyrimidin-2-yl)amino)benzonitrile (J13, 44 mg) as white solid.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9](Cl)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1([F:25])[O:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21](B(O)O)[C:15]=2[O:14]1>>[F:25][C:13]1([F:12])[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[C:18]([C:9]3[N:10]=[C:3]4[CH:2]=[CH:7][CH:6]=[CH:5][N:4]4[N:8]=3)[C:16]=2[O:17]1
Reactant: OB(O)c1cccc2c1OC(F)(F)O2
Reactant: Clc1nc2c(Br)cccn2n1
Product: FC1(F)Oc2cccc(-c3nc4ccccn4n3)c2O1

Procedure:
2-Chloro-8-(2,2-difluoro-1,3-benzodioxol-4-yl-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro[1,2,4]triazolo[1,5-a]pyridine (0.71 g, 3.0 mmol) and 2,2-difluorobenzo[1,3]dioxole-4-boronic acid (0.64 g, 3.2 mmol) in a manner analogous to Example 2c. Product was isolated as a foam (0.63 g, 67%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.84 (d, J=7.5 Hz, 1H), 7.78-7.67 (m, 2H), 7.33-7.23 (m, 2H), 7.36 (d, J=6 Hz, 1H), MS=310 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([CH2:28]O)[CH:3]=1.S(Cl)([Cl:32])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH:11]2[CH3:25])=[O:9])=[C:4]([CH2:28][Cl:32])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CO
Solvent: ClCCl
Product: CC1CN(C(=O)COc2ccc(Cl)cc2CCl)C(C)CN1Cc1ccc(F)cc1
Yield: 91 %

Procedure:
To 2-(4-chloro-2-hydroxymethyl-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.55 g, 1.3 mmol) in methylene chloride (6 ml) was added thionyl chloride (0.26 ml, 3.58 mmol). The reaction was heated to reflux for 2 hours. After cooling the reaction was quenched by the addition of water. The organic layer was washed with saturated sodium bicarbonate followed by saturated aqueous sodium chloride. The organic layer was then concentrated to afford the title compound as a yellow oil (0.52 g).
Reaction SMILES: BrC(F)(F)C(F)(F)O[C:5]1([O:20][C:21](F)([F:26])[C:22]([F:25])([F:24])Br)[CH:10]=[CH:9][C:8]([C:11]([CH3:19])=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH2:6]1>[Zn].C(#N)C>[F:26][C:21]([O:20][C:5]1[CH:6]=[CH:7][C:8]([C:11]([CH3:19])=[CH:12][C:13]2[CH:14]=[CH:15][C:16]([O:20][C:21]([F:26])=[C:22]([F:25])[F:24])=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)=[C:22]([F:25])[F:24]
Reactant: CC(=Cc1ccccc1)C1=CCC(OC(F)(F)C(F)(F)Br)(OC(F)(F)C(F)(F)Br)C=C1
Agent: [Zn]
Solvent: CC#N
Product: CC(=Cc1ccc(OC(F)=C(F)F)cc1)c1ccc(OC(F)=C(F)F)cc1
Temperature: 75 °C
Reaction time: 0.33 h

Procedure:
The intermediate product 4,4-bis(2-bromotetrafluoroethoxy)-α-methylstilbene (106.43 g, 0.18 mole) is added to 100 ml of acetonitrile in a 250 ml dropping addition funnel attached to a 1 liter 5-necked round bottomed flask. Zinc granules (40 mesh, 25.0 g, 0.38 mole) are added to the reactor along with 100 ml of acetonitrile, and the resulting stirred suspension is deoxygenated with nitrogen for 10 minutes by introducing nitrogen gas through a gas dispersion tube. The suspension is then heated to 75° C., at which point the addition of intermediate product solution in acetonitrile is begun. The addition is carried out over 20 minutes, and the resulting mixture is heated at 75° C. overnight. After centrifugation to remove suspended solids, the resulting supernatant is evaporated to dryness, leaving a crude product which is filtered through a short bed (4 cm) of alumina in a 600 ml sintered glass filter funnel using hexane as the eluent. After removal of the hexane by evaporation, the product is heated at 55° C. under high vacuum for 30 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][C@H:16]([CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)[O:15][C:14]2=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[N:10][NH:11][CH:12]=1.[H-].[Na+].Br[CH2:28][C:29]#[N:30]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][C@H:16]([CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)[O:15][C:14]2=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[N:10][N:11]([CH2:28][C:29]#[N:30])[CH:12]=1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2c[nH]nn2)c(F)c1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCn1cc(-c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.6 %

Procedure:
(5R)-3-[3-Fluoro-4-(1H-1,2,3-triazol4-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 7, 1.5 g, 4.6 mmol) was stirred in N,N-dimethylformamide at 0° C. Sodium hydride (0.35 g, 9.2 mmol) was added and the mixture was stirred 30 minutes. Bromoacetonitrile (0.66 g, 5.5 mmol) was added and the reaction was stirred overnight, slowly warming to room temperature. Starting material was present so additional bromoacetonitrile (0.33 g, 2.8 mmol) was added and the reaction was stirred for two additional days. The mixture was diluted with water and extracted using ethyl acetate. The organic layer was washed with water, dried (magnesium sulfate) and concentrated under vacuum to give a yellow solid (1.84 g). The solid was dissolved in dimethylsulfoxide (18 ml) and water (5 ml) and the isomers were separated using Gilson HPLC. Peaks 1 and 2 were collected, concentrated and lyophilized to give a light yellow solid (Example 10, peak 1, 36 mg; Example 11, peak 2, 182 mg). NOE experiments were used to distinguish the two isomers with the cyano group of peaks 1 and 2 corresponding to the 1 and 2 positions of the nitrogen, respectively.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][C:22]1[C:27]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@@H:14]5[CH3:18])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Agent: OB(O)c1cncnc1
Product: Cc1ccc(-c2ccc3nc([C@H]4C[C@@H](N5CCC[C@@H]5C)C4)sc3c2)c(C)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 19A for the product of Example 1E and substituting the product of Example 2A for pyrimidine-5-boronic acid. 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (d, J=8.29 Hz, 1H) 7.76 (d, J=1.53 Hz, 1H) 7.45 (d, J=7.67 Hz, 1H) 7.38 (dd, J=8.44, 1.69 Hz, 1H) 7.06 (d, J=7.67 Hz, 1H) 3.58-3.70 (m, 1H) 3.16-3.30 (m, 1H) 3.00-3.13 (m, 1H) 2.69-2.86 (m, 1H) 2.59-2.68 (m, 1H) 2.59 (s, 3H) 2.49 (s, 3H) 2.42-2.52 (m, 3H) 1.91-2.03 (m, 1H) 1.78-1.87 (m, 1H) 1.67-1.77 (m, 1H) 1.42-1.57 (m, 1H) 1.16 (s, 3H). MS: (M+H)+=378.
Reaction SMILES: [O:1]=[C:2]1[N:6]=[C:5]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4](=[O:15])[NH:3]1.[H-].[Na+].[CH3:18][O:19][CH2:20]Cl>CN(C=O)C.CCOCC.C(OCC)(=O)C>[CH3:18][O:19][CH2:20][N:3]1[C:4](=[O:15])[C:5]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[N:6][C:2]1=[O:1]
Reactant: COCCl
Reactant: CCOP(=O)(OCC)C1=NC(=O)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C1=NC(=O)N(COC)C1=O
Reaction time: 0.08 h

Procedure:
To a solution of diethyl 2,5-dioxo-4-imidazolylphosphonate (3.61 g, 0.015 moles) in DMF (10 mL), under N2, is added sodium hydride (80% dispersion in oil) (0.55 g, 0.018 moles) and stirred for 5 minutes. Chloromethyl methyl ether (tech. grade 85%) (1.9 mL, 0.021 moles) is added. This mixture is stirred at room temperature for 4 hours, diluted with ether and ethyl acetate (300 mL) and then washed with water and brine before drying over MgSO4. The aqueous layer is back extracted with methylene chloride and combined with the previous organic fraction. Evaporation of solvents and chromatography (eluant 1% methanol in chloroform) and evaporation under high vacuum affords the required product.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[CH2:26][C:27]([N:29]([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])=[O:28].[H-].[Na+]>>[CH:30]([N:29]([CH:33]([CH3:35])[CH3:34])[C:27](=[O:28])[CH2:26][N:22]1[CH2:21][CH2:20][N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])([CH3:32])[CH3:31]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: CC(C)N(C(=O)CCl)C(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CC(=O)N(C(C)C)C(C)C)C2=O)CC1
Yield: 31 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), 2-chloro-N,N-diisopropyl-acetamide and sodium hydride, to give the desired product as a white solid (31%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=[C:4]([C:32]([NH2:34])=[O:33])[CH:3]=1.C=O.[OH-].[Na+].[C:39](OCC)(=[O:41])C>COCCOC>[OH:41][CH2:39][NH:34][C:32]([C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([CH:8]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]([F:31])([F:29])[F:30])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=1)=[O:33]
Reactant: CCOC(C)=O
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Reaction time: 48 h
Yield: 32 %

Procedure:
To a solution of 4-methyl-5-[[[4-(trifluoromethoxy)phenyl]sulfonyl](2,3,6-trifluorophenyl) methyl]pyridine-2-carboxamide (177 mg, 0.350 mmol) in ethylene glycol dimethyl ether (3 ml), an aqueous solution of formaldehyde (37%, 78.9 μl) and 1 N aqueous sodium hydroxide (17.5 μl) were added at room temperature, and the mixture was stirred for 2 days. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous ammonium chloride. Subsequently, 1 N hydrochloric acid was added to the organic layer, and the mixture was stirred for 1 hour. After the organic layer was separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of ethyl acetate and diethyl ether, and then was collected by filtration, to obtain the title compound (59.4 mg, 0.111 mmol, 32%) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4]C1CCCCO1.[ClH:11].[CH:12]1[C:21]2[C:16](=[C:17]([NH:22][C@H:23]3[CH2:28][CH2:27][C@@H:26]([NH2:29])[CH2:25][CH2:24]3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1>>[ClH:11].[CH:12]1[C:21]2[C:16](=[C:17]([NH:22][C@H:23]3[CH2:24][CH2:25][C@@H:26]([NH:29][CH2:2][CH2:3][OH:4])[CH2:27][CH2:28]3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: N[C@H]1CC[C@@H](Nc2cccc3cnccc23)CC1
Reactant: BrCCOC1CCCCO1
Agent: Cl
Product: OCCN[C@H]1CC[C@@H](Nc2cccc3cnccc23)CC1

Procedure:
According to the method of Example 144, an alkylation reaction with 2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction were performed by using the compound of Example 23 to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:26])[CH:3]=1.[NH:27]1[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[CH:29]=[N:28]1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O.C1(C)C=CC=CC=1>[F:12][C:11]([F:14])([F:13])[CH2:10][CH2:9][CH:8]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:2]([N:28]2[CH:29]=[C:30]3[C:35]([CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:27]2)=[CH:3][C:4]=1[CH3:26]
Reactant: c1n[nH]c2c1CCCC2
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(Br)cc2C)cc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-n3cc4c(n3)CCCC4)cc2C)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
Under a nitrogen atmosphere, a mixture of methyl 4-((1-(4-bromo-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoate (racemate) (300 mg), 4,5,6,7-tetrahydroindazole (128 mg), copper(I) iodide (159 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.264 mL), potassium carbonate (289 mg) and toluene (1.4 mL) was stirred at 110° C. overnight. To the reaction mixture was added water at room temperature, and the insoluble material was filtered off through celite. The filtrate was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (243.9 mg).
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[C:14]([C:25](=[O:28])[NH:26][CH3:27])=[N:15][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17]=2[OH:18])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br.[Br:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37]>N1C(C)=CC=CC=1C.C(N(C(C)C)CC)(C)C>[Br:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[C:14]([C:25](=[O:28])[NH:26][CH3:27])=[N:15][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17]=2[OH:18])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CNC(=O)c1nn(-c2ccccc2)c(O)c1N=Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCCCCBr
Agent: Br
Solvent: Cc1cccc(C)n1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1nn(-c2ccccc2)c(O)c1N=Nc1ccc(S(=O)(=O)NCCCCCCBr)cc1

Procedure:
A suspension of 4-(4-chlorosulfonylphenylazo)-5-hydroxy-3-methylcarbamoyl-1-phenyl-1H-pyrazole (12 g) and 6-bromohexylamine hydrobromide (12 g) in 2,6-lutidine (300 ml) and di-isopropylethylamine (3 ml) was allowed to react for 18 hours at room temperature. The reaction mixture was filtered; the filtrate was concentrated to yield an oily material which was washed with hot water to yield the above-identified pyrazole derivative; yield 7.4 g (44%), m.p. 234°-236° C.