Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([C:33]4[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=4)=[C:29]4[C:25]=3[C:26](=[O:40])[N:27]([CH3:39])[CH2:28]4)[C:20]([C:41]([F:44])([F:43])[F:42])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH:45]([OH:47])=[O:46].C=O.C([BH3-])#N.[Na+]>CO>[CH2:6]([O:5][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([C:33]4[CH2:34][CH2:35][N:36]([CH3:45])[CH2:37][CH:38]=4)=[C:29]4[C:25]=3[C:26](=[O:40])[N:27]([CH3:39])[CH2:28]4)[C:20]([C:41]([F:43])([F:44])[F:42])=[CH:19][N:18]=2)=[CH:14][CH:15]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7].[F:42][C:41]([F:44])([F:43])[C:45]([OH:47])=[O:46]
Reactant: O=CO
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4=CCNCC4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4=CCN(C)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 403.9 %

Procedure:
Diethyl(4-{[4-{[2-methyl-3-oxo-7-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 246, 20.0 mg, 0.0317 mmol), formic acid (5 uL, 0.1 mmol) and formaldehyde (3.0 uL, 0.11 mmol) were mixed in methanol (1.0 mL) at room temperature for 30 minutes. Sodium cyanoborohydride (20.0 mg, 0.318 mmol) was added and the mixture was stirred at room temperature overnight. The crude mixture was purified by MDP to obtain the title compound as a trifluoroacetic acid salt (7.3 mg, 35.7% yield). 1H NMR (400 MHz, methanol-d4) δ=1.27 (t, J=7.1 Hz, 6H), 2.87 (br. s., 1H), 2.93 (br. s., 1H), 3.05 (s, 3H), 3.19 (s, 3H), 3.29 (d, J=21.5 Hz, 2H), 3.36-3.46 (m, 1H), 3.73 (br. s., 1H), 3.80-3.90 (m, 1H), 4.00-4.16 (m, 5H), 4.59 (s, 2H), 5.95-6.04 (m, 1H), 7.34 (dd, J=8.6, 2.5 Hz, 2H), 7.50 (d, J=8.6 Hz, 1H), 7.58 (d, J=8.1 Hz, 2H), 8.36-8.43 (m, 1H), 8.75 (br. s., 1H). MS (ES+): m/z 645.23 (100) [MH+]; HPLC: tR=0.69 min (UPLC, purity).
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#N.CC[O:22]CC>>[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14](=[O:22])[CH2:7][C:6]1[CH:9]=[CH:10][C:3]([Cl:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccccc1Cl
Reactant: Clc1ccc(CBr)cc1
Reactant: CCOCC
Agent: [Mg]
Product: O=C(Cc1ccc(Cl)cc1)c1ccccc1Cl
Temperature: 34 °C
Reaction time: 3 h

Procedure:
To a dried three-neck round bottom flask fitted with a condenser and addition funnel was added magnesium (2.217 g, 91.2 mmol) and anhydrous ether (60 mL). A solution of 4-chlorobenzyl bromide (18.74 g, 91.2 mmol) in ether (100 mL) was added dropwise via the addition funnel at room temperature. After the addition, the reaction mixture was heated at 34° C. for 1 hour. The reaction mixture was allowed to cool to room temperature. One half of the volume of the ether solution was then added to another dried flask charged with a solution of 2-chlorobenzonitrile (5.228 g, 38.0 mmol) in ether (70 mL). The resulting reaction mixture was stirred at 34° C. for 3 hours. The reaction was cooled to room temperature and quenched slowly with 2 M aq. HCl. The solution was diluted with ethyl acetate, and the organic portion was washed with 2N aq. HCl, water, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel) eluting with 7% ethyl acetate/hexane) to afford product.
Reaction SMILES: Br[CH2:2][C:3](Cl)=[O:4].[NH2:6][C@@H:7]([CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][OH:9].[OH-].[Na+].C1(C)C=CC=CC=1.C1COCC1>C1(C)C=CC=CC=1>[CH2:12]([O:11][CH2:10][C@@H:7]1[NH:6][C:3](=[O:4])[CH2:2][O:9][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@H](CO)COCc1ccccc1
Reactant: O=C(Cl)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1COC[C@H](COCc2ccccc2)N1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Bromoacetyl chloride (5.06 mL) was added to a mixed solution of (R)-(+)-2-amino-3-benzyloxy-1-propanol (10 g) in toluene (100 mL) and a 2 N sodium hydroxide solution (100 mL) under ice-cooling. The reaction solution was stirred at 0° C. for 30 minutes and then at 60° C. for one hour. The reaction solution was returned to room temperature. Then, a toluene-THF (1:1) mixed solution was added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.36 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[N:17]2[C:18]3[N:9]([C:10](=[O:30])[CH2:11][N:12]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])[C:13]=3[CH:14]=[CH:15][C:16]2=[O:19])[CH2:8]1)(=O)=O.N1C=CC=CC=1.[NH:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>C(#N)C>[CH3:48][C:46]([O:45][C:44]([NH:43][CH:40]1[CH2:39][CH2:38][N:37]([CH2:6][C@H:7]2[N:17]3[C:18]4[N:9]([C:10](=[O:30])[CH2:11][N:12]([C:20]([O:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:21])[C:13]=4[CH:14]=[CH:15][C:16]3=[O:19])[CH2:8]2)[CH2:42][CH2:41]1)=[O:50])([CH3:47])[CH3:49]
Reactant: CS(=O)(=O)OC[C@@H]1CN2C(=O)CN(C(=O)OCc3ccccc3)c3ccc(=O)n1c32
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2CN3C(=O)CN(C(=O)OCc4ccccc4)c4ccc(=O)n2c43)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
Phenylmethyl (1S)-1-{[(methylsulfonyl)oxy]methyl}-3,8-dioxo-1,2,3,4-tetrahydro-5H,8H-2a,5,8a-triazaacenaphthylene-5-carboxylate (232 mg, 0.508 mmol) was dissolved in dry acetonitrile (10 ml) at room temperature under argon and treated with pyridine (0.049 ml, 0.610 mmol). 1,1-Dimethylethyl 4-piperidinylcarbamate (127 mg, 0.610 mmol) was then added and the reaction was heated at 70° C. overnight. Then 0.049 ml of pyridine and 127 mg of 1,1-dimethylethyl 4-piperidinylcarbamate were added to the reaction and the temperature was increased to 80° C. for 8 h and then the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue partitioned between sat NaHCO3 and DCM (50/50 ml). The layers were separated and the aqueous layer was extracted with DCM again (2×50 ml). The combined organic extracts were dried (MgSO4) filtered and evaporated to afford 280 mg of crude product which was purified by silica chromatography using a 0-5% methanol/dichloromethane gradient to afford the product as a yellow gum (130 mg, 47.6%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([O:22]C)[CH:3]=1.[F:24][C:25]([F:34])([F:33])[C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.Cl.CCOCC>C(O)(C)C>[F:24][C:25]([F:33])([F:34])[C:26]1[CH:27]=[CH:28][C:29]([NH:30][C:2]2[C:11]3[C:6](=[N:7][C:8]([C:12]4[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=4)=[CH:9][CH:10]=3)[N:5]=[C:4]([OH:22])[CH:3]=2)=[CH:31][CH:32]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COc1cc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: Oc1cc(Nc2ccc(C(F)(F)F)cc2)c2ccc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
Heat 4-chloro-2-methoxy-7-(3-trifluoromethyl-pyridin-2-yl)-[1,8]naphthyridine (600 mg, 1.8 mmol), 4-trifluoromethylaniline (322 mg, 2.0 mmol) and 2M hydrochloric acid in ether (1 mL, 2.0 mmol) in isopropanol (15 mL) at 80° C. for 16 hours. Cool the mixture and collect the precipitate by filtration. Partition the solid between ethyl acetate and saturated sodium bicarbonate solution. Separate the layers and extract the aqueous layer with further ethyl acetate. Wash the combined organic extracts with brine, dry (MgSO4) and evaporate to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C@H:8]([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.CC1C=CC(S(Cl)(=O)=O)=CC=1>ClC(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C@@H:8]([OH:11])[CH2:9][OH:10])=[CH:12][CH:13]=1
Reactant: OC[C@@H](O)COc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: OC[C@H](O)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To a stirred mixture of 11 parts of (-)-(R)-3-(4-fluorophenoxy)-1,2-propanediol, 23.3 parts of pyridine and 240 parts of trichloromethane were added 12.3 parts of 4-methylbenzenesulfonyl chloride. The whole was stirred overnight at room temperature. It was washed successively with acid water, a sodium carbonate solution and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 13.5 parts (67.2%) of (+)-(S)-3-(4-fluorophenoxy)-1,2-propanediol, O1 -4-methylbenzenesulfonate; [α]D =+11.11° (c=0.5% in trichloromethane) (147).
Reaction SMILES: C1(C2CCC(=O)CC2)C=CC=CC=1.N1CCC([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])CC1.CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1>O>[N:20]1[C:21](=[O:29])[N:22]=[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=12
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC(c2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1N=c2ccccc2=N1

Procedure:
A mixture of 7 parts of 4-phenylcyclohexanone, 8.8 parts of 1-(4-piperidinyl)-2H-benzimidazol-2-one, 0.3 parts of 4-methylbenzenesulfonic acid and 225 parts of methylbenzene is stirred and refluxed for 40 hours with water-separator. The reaction mixture is cooled and the solvent is removed in vacuo, yielding 15 parts of 1-[4-phenyl-1-cyclohexenyl)-4-piperidinyl]-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3[N:30]=[CH:31][N:32]=[C:33]([NH2:34])[C:28]=3[C:27]([C:35](=[O:43])[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([NH2:42])[CH:37]=3)=[CH:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3[N:30]=[CH:31][N:32]=[C:33]([NH2:34])[C:28]=3[C:27]([C:35](=[O:43])[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:10]([NH:9][C:4]4[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=4)=[O:11])[CH:37]=3)=[CH:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)c3cccc(N)c3)c3c(N)ncnc32)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)c3cccc(NC(=O)Nc4cc(Cl)cc(Cl)c4)c3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.7 %

Procedure:
3,5-Dichlorophenyl isocyanate (0.26 g, 1.37 mmol) was added to a solution of 4-[4-amino-5-(3-amino-benzoyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.15 mmol) in pyridine (13 mL). The reaction mixture was stirred at 75 C for 4.5 h and room temperature for 12 h in a sealed tube, quenched with H2O (13 mL), and extracted with EtOAc (4×15 mL). The combined organic extracts were washed with CuSO4 (3×15 mL), H2O (20 mL), and brine (30 mL) and dried (MgSO4), filtered, and concentrated in vacuo. The crude reaction mixture was triturated in CH2Cl2 and filtered to obtain the titled compound as a white solid (0.45 g, 63%). MS: 625.5 (MH+); HPLC Rf: 7.48 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH3:14]C1C=C(C=CC=1)N>>[CH3:13][N:8]([C:5]1[CH:4]=[C:3]([CH3:14])[CH:2]=[CH:7][CH:6]=1)[S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: Cc1cccc(N)c1
Reactant: CN(c1ccc(I)cc1)S(C)(=O)=O
Product: Cc1cccc(N(C)S(C)(=O)=O)c1

Procedure:
N-Methyl-N-(3-tolyl)methanesulphonamide was prepared as for the preparation of N-(4-iodophenyl)-N-methylmethanesulphonamide described in Example 3, except that 3-methylaniline was used in place of 4-iodoaniline.
Reaction SMILES: [OH:1][C:2]1[CH2:6][O:5][C:4](=[O:7])[CH:3]=1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH2:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])=[CH:17]1>>[OH:1][C:2]1[CH2:6][O:5][C:4](=[O:7])[C:3]=1[CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:17]1[NH:16][C:24]2[C:19]([C:18]=1[CH2:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])=[CH:20][CH:21]=[CH:22][CH:23]=2
Reactant: O=C1C=C(O)CO1
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccccc1
Product: CC(=O)NCCc1c(C(C2=C(O)COC2=O)c2ccccc2)[nH]c2ccccc12

Procedure:
Using general procedure C, 4-hydroxy-5H-furan-2-one was reacted with benzaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide to give the title compound as orange foam. MS: 391.1 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][C:28]#N)=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.COCCO.[OH-:37].[K+].Cl.[OH2:40]>>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][C:28]([OH:40])=[O:37])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1
Reactant: O
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC#N)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: COCCO
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC(=O)O)cc1
Yield: 59 %

Procedure:
To a mixture of 2-[2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile (0.94 g) and 2-methoxyethanol (8 mL) was added a 4N aqueous potassium hydroxide solution (4 mL) and the mixture was heated under reflux for 5 hrs. 1N Hydrochloric acid (16 mL) and water were added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.58 g, 59%) of 2-[2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]-3-pyridyl]acetic acid from a fraction eluted with acetone-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 128-129° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccc(Nc2ccc3[nH]ccc3c2)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A mixture of 2-amino-4,6-dichloropyrimidine (1.64 g, 10 mmol), 5-aminoindole (1.32 g, 10 mmol), diisopropylethylamine (5.23 ml, 30 mmol) and N,N-dimethylformamide (30 ml) was heated at 60° C. and stirred overnight under nitrogen atmosphere. The reaction mixture was partitioned between ethyl acetate and water after cooled to room temperature; and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off; the obtained residue was dissolved in tetrahydrofuran (100 ml); 10% Palladium on carbon (50% wet, 1.0 g) was added thereto under nitrogen atmosphere; and the reaction mixture was stirred for 4 days under hydrogen atmosphere at atmospheric pressure. The reaction system was purged with nitrogen; the catalyst was filtered off; the filtrate was concentrated under reduced pressure; the residue was purified by NH silica gel column chromatography (eluent; ethyl acetate:methanol=95:5); diethyl ether was added to the residue to crystallize; and the crystals were filtered off, and dried under aeration to yield the title compound (852 mg, 3.8 mmol, 38%) as pale brown crystals.
Reaction SMILES: CS(O[CH2:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=2)[CH:8]=1)(=O)=O.[N:20]1([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CS(C)=O>[F:17][C:16]([F:19])([F:18])[C:12]1[CH:13]=[C:14]2[S:15][C:7]([CH2:6][N:23]3[CH2:22][CH2:21][N:20]([C:26]4[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=4)[CH2:25][CH2:24]3)=[CH:8][C:9]2=[N:10][CH:11]=1
Reactant: CS(=O)(=O)OCc1cc2ncc(C(F)(F)F)cc2s1
Reactant: Oc1ccc(N2CCNCC2)cc1
Solvent: CS(C)=O
Product: Oc1ccc(N2CCN(Cc3cc4ncc(C(F)(F)F)cc4s3)CC2)cc1
Reaction time: 72 h

Procedure:
The solution from Example 25C (2 mL) was treated with 4-(1-piperazinyl)phenol (178 mg) in DMSO (1 mL). After 72 hours, the mixture was concentrated under a stream of nitrogen gas and the residue recrystallized from DMSO:methanol (1:1) to provide the title compound. 1H NMR(CDCl3, 300 MHz) 82.81 (4H, t, J=4.8 Hz), 3.18 (4H, J=4.8 Hz), 3.95 (s, 2H), 6.78 (2H, d, J=9 Hz), 6.90 (2H, J=9 Hz), 7.48 (1H, s), 8.38 (1H, m), 8.80 (1H, m). MS (DCI/NH3) m/z 394 (M+H)+. Anal. Calcd for C19H18N3F3OS: C, 56.72; H, 4.76; N, 10.44. Found: C, 56.43; H, 4.50; N, 10.35.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1N)([O-])=O.[C:16]([CH2:18]C(OCC1C=CC=CC=1)=O)#N.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CN(C=O)C>[F:13][C:12]([F:15])([F:14])[O:11][C:9]1[CH:10]=[C:4]2[C:5]([CH:16]=[CH:18][NH:1]2)=[CH:7][CH:8]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Reactant: N#CCC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: FC(F)(F)Oc1ccc2cc[nH]c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a suspension of t-BuONO (8.01 mL, 67.5 mmol) and CuCl2 (7.26 g, 54 mmol) in acetonitrile (50 mL), at 61° C. with gentle stirring, is added 2-nitro-4-trifluoromethoxyaniline (10.0 g, 45.0 mmol) portionwise. The mixture is stirred at this temperature for 2 h after the addition. The solvent is removed on a rotovap and the residue is treated with HCl (6 N, 200 mL), and extracted with dichloromethane (3×100 mL). The extracts are combined, dried over anhydrous Na2SO4, and passed through a short silica gel pad. The solvent is removed and the residue is added to a suspension of benzyl cyanoacetate (7.88 g, 45 mmol) and K2CO3 (12.42 g, 90 mmol) in DMF (100 mL). This mixture is then stirred at 45° C. overnight and poured into ice-water (700 mL), and extracted with dichloromethane (3×100 mL). The organics are dried over anhydrous Na2SO4 and again passed through a short silica gel pad, eluting with ethyl acetate. The solvent is then replaced with EtOH (160 mL), acetic acid (16 mL) and water (16 mL), and the reaction mixture is hydrogenated over 5% Pd/C (2.80 g) at 50 psi overnight. The mixture is filtered over Celite and the volatiles are removed in vacuo. The residue is dissolved in dichloromethane (200 mL), washed with Na2CO3 (2 M, 2×50 mL), water (2×50 mL), brine (50 mL) and dried over anhydrous Na2SO4. The crude product, obtained after the removal of the solvent, is chromatographed (silica gel, DCM/Hexanes, 1/1) to provide 6-trifluoromethoxyindole (5.70 g, 63% based on 2-nitro-4-trifluoromethoxyaniline).
Reaction SMILES: [Mg].C(O[Ge:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])C.Br[C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:19][C:18]=2[CH:17]=1>C1COCC1>[CH2:13]([O:12][Ge:5]([O:6][CH2:7][CH3:8])([O:9][CH2:10][CH3:11])[C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:19][C:18]=2[CH:17]=1)[CH3:14]
Reactant: Brc1ccc2c(c1)Sc1ccccc1S2
Reactant: CCO[Ge](OCC)(OCC)OCC
Agent: [Mg]
Solvent: C1CCOC1
Product: CCO[Ge](OCC)(OCC)c1ccc2c(c1)Sc1ccccc1S2
Yield: 25.6 %

Procedure:
A 3-neck 500 mL flask was filled with magnesium turnings (8 g), THF (100 g) and tetraethoxygermane (35 g), and heated to reflux. Crude 2-bromothianthrene (30 g) from Example 1 was added to the flask in small portions. Grignard started after a few minutes and kept refluxing by its own heat for ten minutes. The reaction was allowed to cool for 1 hour, after which magnesium salts were precipitated with heptanes (300 mL). The solution was filtered, followed by evaporation of volatiles by rotary evaporator. The material was distilled three times at <1 mbar, giving colorless 2-(triethoxygermyl)-thianthrene (bp. 180 . . . 210° C., 11 g, 30.5% overall yield based on 2-bromothianthrene, purity 99.5% by GC/MS). FIG. 8 shows the mass spectrum of the compound.
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][NH:8][CH:9]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=1)[C:10]([O:12][CH3:13])=[O:11].[CH3:35][O-].[Na+]>C(O)C.CO>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][NH:8][CH:9]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=1)[C:10]([O:12][CH2:13][CH3:35])=[O:11]
Reactant: C[O-]
Reactant: COC(=O)C(NCc1cccc(C(F)(F)F)c1)c1cn(Cc2ccccc2)c2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)C(NCc1cccc(C(F)(F)F)c1)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a magnetically stirred solution of methyl α-[3-(trifluoromethyl)benzylamino-]-1-benzylindole-3-acetate hydrochloride (100 mg) in 8 mL of ethanol was added 70 μL of 25% sodium methoxide in methanol. After stirring at room temperature for two hours, TLC analysis showed 90% conversion to the title compound.
Reaction SMILES: C([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([NH:20][C:21]4[CH:32]=[CH:31][CH:30]=[CH:29][C:22]=4[C:23]([NH:25][CH2:26][C:27]#[CH:28])=[O:24])=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[N:7][CH:8]=1)C.[CH2:33](C1C=CN=C(C)C=1)C.ClC1C=C2C(C(C(O)CC3C=CC(CC)=CN=3)=NN2)=CC=1.C1(N)CC1>>[CH:26]1([NH:25][C:23](=[O:24])[C:22]2[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=2[NH:20][C:16]2[CH:15]=[C:14]3[C:19]([C:11](/[CH:10]=[CH:9]/[C:6]4[CH:5]=[C:4]([CH3:33])[CH:3]=[CH:8][N:7]=4)=[N:12][NH:13]3)=[CH:18][CH:17]=2)[CH2:27][CH2:28]1
Reactant: C#CCNC(=O)c1ccccc1Nc1ccc2c(C=Cc3ccc(CC)cn3)n[nH]c2c1
Reactant: CCc1ccnc(C)c1
Agent: CCc1ccc(CC(O)c2n[nH]c3cc(Cl)ccc23)nc1
Agent: NC1CC1
Product: Cc1ccnc(/C=C/c2n[nH]c3cc(Nc4ccccc4C(=O)NC4CC4)ccc23)c1

Procedure:
The title compound was prepared analogously to 2-{3-[2-(5-Ethyl-pyridin-2-yl)-vinyl]-1H-indazol-6-ylamino}-N-prop-2-ynyl-benzamide described above, substituting 2,4-dimethyl-pyridine for 4-ethyl-2-methyl-pyridine in the step where 1-(6-Chloro-1H-indazol-3-yl)-2-(5-ethyl-pyridin-2-yl)-ethanol was prepared, and substituting cyclopropyl amine in place of propargyl amine in the final step of the sequence. 1H NMR (DMSO-d6): δ 9.85 (1H, s), 8.56 (2H, m), 8.20 (3H, m), 7.53 (5H, m), 7.35 (1H, s), 7.2 (1H, d, J=6.5 Hz), 7.0 (1H, s), 2.83 (1H, m), 0.70 (2H, m), 0.56 (2H, m). ESIMS (M+H+): 410.3.