Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:27]=1[O: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][CH2:45][CH3:46])[CH2:23]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CN(C)C=O.S(Cl)([Cl:73])=O>ClCCl>[CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:27]=1[O: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][CH2:45][CH3:46])[CH2:23][Cl:73])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(CO)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
Under an argon atmosphere, 3,4,5-tris(octadecyloxy)benzyl alcohol (10.0 g, 11.0 mmol) was dissolved in dichloromethane (100 mL), N,N-dimethylformamide (84.0 μL, 1.10 mmol) and thionyl chloride (1.20 ml, 16.4 mmol) were added, and the mixture was stirred at 30° C. for 90 min. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, acetonitrile was added, and the precipitated solid was filtered. The obtained solid was dried under reduced pressure to give the title compound (10.0 g, 98.2%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:28])[C:8]1=[O:29])=[O:5])[CH3:2].[Cl-].[CH2:31]([O:38][NH3+:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])(=O)C.[Na+]>CCO.O>[CH2:31]([O:38][N:39]=[CH:22][C:19]1[CH:20]=[CH:21][N:17]([C:14]2[CH:15]=[C:16]3[C:11]([NH:10][C:9](=[O:28])[C:8](=[O:29])[N:7]3[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][C:13]=2[C:24]([F:26])([F:27])[F:25])[CH:18]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: [NH3+]OCc1ccccc1
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=O)c3)cc21
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=NOCc4ccccc4)c3)cc21
Yield: 82.8 %

Procedure:
1.1 g (2.7 mmol) of the compound of Example 70, 0.86 g (5.4 mmol) of O-benzylhydroxylammonium chloride and 0.44 g (5.4 mmol) of sodium acetate in 4.5 ml of EtOH/H2O (1:2) were refluxed for 30 minutes. The ethanol was then removed under reduced pressure, and the precipitate was filtered off with suction and recrystallized from ethanol to yield 1.15 g (84%) of the product. The 1H-NMR shows that an E/Z mixture is present. Melting point 142°-147° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: CCOP(OCC)OCC
Reactant: ClCc1cccc(Br)c1
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1cccc(Br)c1)OCC
Reaction time: 8 h

Procedure:
3-bromobenzyl chloride shown by the formula (vi) and triethyl phosphite were put in a three-necked flask equipped with a reflux condenser, to which toluene was added and heated with stirring for 8 hours under reflux. The mixture was purified by common method, to obtain diethyl 3-bromobenzylphosphonate shown-by the formula (vii).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[C:29]([CH2:30][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)[CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:26]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cccc(-c2ccc(F)cc2)c1
Product: Fc1ccc(-c2cccc(CN3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(4-fluorophenyl)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[3-(4-fluorophenyl)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH2:15]([O:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(C=O)c(F)cc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)c(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Fluoro-4-hydroxy-5-methoxy-benzaldehyde (653, 1.62 g, 9.52 mmol) was dissolved in N,N-dimethylformamide (50 mL) and sodium hydride (60% dispersion in mineral oil, 530 mg, 13 mmol) was added. After 20 minutes, benzyl bromide (1.5 mL, 12 mmol) was added to the reaction mixture. The reaction was stirred at room temperature under an atmosphere of nitrogen for 5.5 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 0-50% ethyl acetate in hexane to provide compound as a white solid, consistent with the desired structure by 1H-NMR (654, 2.0 g, 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.C(OCC)(=O)C.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][CH:14]([C:18]([OH:20])=[O:19])[CH2:13][C:12]=3[CH:21]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc3c(c2)CC(C(=O)O)CCO3)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
Into a suspension of 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (280 mg) in methanol (20 ml)/ethyl acetate (10 ml) was added 10% palladium on charcoal (50% water content, 70 mg). Hydrogen gas was introduced, and the resulting mixture was stirred at room temperature for 17 hours and at 50° C. for 3 hours, and was then filtered to remove the catalyst. The filtrate was concentrated, and the residue was recrystallized from ethyl acetate/hexane to obtain 7-(4-methylphenyl)-2,3,4,5-tetrahydro-1-benzooxepine-4-carboxylic acid (187 mg) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.[NH2:8][C:9]1C=C(C)[N:12]=[C:11]([CH3:16])[C:10]=1[Br:17]>>[NH2:7][C:4]1[CH:5]=[CH:6][N:1]=[N:2][C:3]=1[Br:17].[NH2:16][C:11]1[C:10]([Br:17])=[CH:9][N:8]=[N:1][CH:12]=1
Reactant: Nc1ccnnc1
Reactant: Cc1cc(N)c(Br)c(C)n1
Product: Nc1ccnnc1Br
Product: Nc1cnncc1Br
Yield: 5 %
Yield: 15 %

Procedure:
Bromination of pyridazin-4-ylamine was performed in the same manner as for the preparation of 4-amino-3-bromo-2,6-dimethylpyridine. Chromatography on SiO2 (20% ethyl acetate in hexanes to 100% ethyl acetate, gradient, followed by 2% methanol in ethyl acetate) yielded 4-amino-3-bromopyridazine (first eluting: 15% yield) and 4-amino-5-bromopyridazine (second eluting: 5% yield) as tan solids.
Reaction SMILES: [N+:1]([C:4]1[C:8]([C:9]2[CH:14]=[C:13]([O:15][C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:11][C:10]=2[OH:20])=[CH:7][N:6]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[N:5]=1)([O-:3])=[O:2].[C:27]([O:31][C:32](=[O:51])[N:33]([S:39]([C:42]1[CH:47]=[C:46]([Cl:48])[C:45](F)=[CH:44][C:43]=1[F:50])(=[O:41])=[O:40])[C:34]1[N:35]=[CH:36][S:37][CH:38]=1)([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[C:27]([O:31][C:32](=[O:51])[N:33]([S:39]([C:42]1[CH:47]=[C:46]([Cl:48])[C:45]([O:20][C:10]2[CH:11]=[CH:12][C:13]([O:15][C:16]([F:18])([F:19])[F:17])=[CH:14][C:9]=2[C:8]2[C:4]([N+:1]([O-:3])=[O:2])=[N:5][N:6]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH:7]=2)=[CH:44][C:43]=1[F:50])(=[O:40])=[O:41])[C:34]1[N:35]=[CH:36][S:37][CH:38]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Reactant: O=[N+]([O-])c1nn(C2CCCCO2)cc1-c1cc(OC(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(OC(F)(F)F)cc2-c2cn(C3CCCCO3)nc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethoxy)phenol (Preparation 24, 2.00 g, 5.36 mmol) and tert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 4, 2.20 g, 5.36 mmol) in dimethylsulfoxide (30 mL) was added potassium carbonate (1.5 g, 11 mmol). The reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was then diluted with water and extracted with ethyl acetate (×3). The combined organic phase was washed with water (×2) then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was triturated with ether and the solid collected by filtration and dried in vacuo to afford the title compound with a 5% de-boc impurity (3.70 g). The compound was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.Cl[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=3)[CH:30]=[N:29][CH:28]=2)[CH2:20]1>>[OH2:2].[CH3:38][O:37][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][C:33]=1[O:39][CH3:40])[CH:30]=[N:29][CH:28]=[C:27]2[CH2:26][CH2:25][N:21]1[CH2:22][CH2:23][CH2:24][CH:19]([CH2:18][N:9]2[C:8](=[O:12])[CH2:7][C:6]3[CH:13]=[C:14]([O:15][CH3:16])[C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH:11]=[CH:10]2)[CH2:20]1
Reactant: COc1cc2cncc(CCN3CCCC(CCl)C3)c2cc1OC
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(CCc3cncc4cc(OC)c(OC)cc34)C1)C=C2
Product: O

Procedure:
Prepared from 7,8-dimethoxy-2-oxo-1,3-dihydro-2H-3-benzazepine and 3-chloromethyl-N-[2-(6,7-dimethoxy-isoquinol-4-yl)-ethyl]piperidine analogously to Example 2.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4].Cl[CH2:9][C:10](Cl)=[O:11]>C(O)C>[CH3:4][CH:3]([CH:2]1[NH:1][C:10](=[O:11])[CH2:9][O:7][CH2:6]1)[CH3:5]
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(Cl)CCl
Solvent: CCO
Product: CC(C)C1COCC(=O)N1

Procedure:
Treatment of valinol in basic ethanol with chloroacetyl chloride using the procedure of Surry, et. al., J. Am. Chem. Soc. (1955) 77, 633, gives 5-(2-propyl)-3-morpholinone. Deprotonation of the latter with NaH in DMF solution and reaction with methyl iodide gives the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].Cl[CH2:15][C:16]([CH2:18]Cl)=[CH2:17]>CN(C=O)C>[C:7]([O:6][C:5]([N:4]1[CH2:18][C:16](=[CH2:15])[CH2:17][O:1][CH2:2][CH2:3]1)=[O:11])([CH3:8])([CH3:10])[CH3:9]
Reactant: C=C(CCl)CCl
Reactant: CC(C)(C)OC(=O)NCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C1COCCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 37 %

Procedure:
A solution of tert-butyl 2-hydroxyethylcarbamate 38.1 (9.00 mL, 58.2 mmol) in DMF (50.0 mL) was cooled in a ice bath and treated portion wise with sodium hydride (60% in mineral, 5.12 g, 128 mmol). The mixture was stirred in ice bath for 15 minutes and then treated with 3-chloro-2-(chloromethyl)prop-1-ene (7.07 mL, 61.1 mmol). After addition was complete, the ice bath was removed and the reaction mixture was stirred was stirred at room temperature overnight. The mixture was diluted with water and extracted with ether. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford an oil which purified by flash chromatography (gradient EtAOAc/hexane 5%-40%) to afford the desired product (4.6, 37% yield) clear oil. LCMS 114.10 [M-tBuCO2]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][NH2:23].C1COCC1>>[CH3:22][NH:23][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cn1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(N(C)c2ccc(OC)nc2)c2ccccc2n1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine (69 mg, 0.23 mmol) and 2.0 M methylamine in THF (4 ml, 8 mmol) by a procedure similar to Example 122 to give 20 mg (30%) of yellow solids. 1H NMR (CDCl3): 8.02-8.01 (m, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.42-7.34 (m, 2H), 6.97-6.94 (m, 1H), 6.76-6.70 (m, 2H), 5.01 (brs, 1H), 3.95 (s, 3H), 3.50 (s, 3H), 3.12 (d, J=5.1 Hz, 3H).
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][C:16](=O)[C:15]([CH3:21])([CH3:20])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C([BH3-])#[N:23].[Na+]>CO>[NH2:23][CH:16]1[CH2:17][CH2:18][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:14][C:15]1([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N)C(C)(C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (700 g, 9.09 mol) was added to a stirred solution of 1-t-butyloxy carbonyl-3,3-dimethyl-4-piperidone (352 g, 1.55 mol) in methanol (1.0 L). The suspension was stirred for 3 hr at 20-30° C. The reaction mixture was cooled to 0° C. and sodiumcyanoborohydride (45 g, 0.71 mol) was added portion wise over 30 minutes. Cooling was removed and the suspension was stirred for 12 hr at 20-30° C. The reaction mixture was concentrated to dryness, stirred with water (2.0 L) and extracted with 1.0 L×3 dichloromethane. Combined organic extract was washed with water and dried over sodium sulfate. Evaporation of organic solvent afforded the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([Li])[CH2:19][CH2:20][CH3:21].[CH:23]1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:38])[C:27]=2[CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>CCCCCC.C1COCC1.C1(C)C=CC=CC=1>[CH:18]1[C:10]2[CH:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:35]4([OH:37])[C:34]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[C:28]([C:6]5[CH:7]=[CH:2][CH:3]=[C:4]([C:8]6[C:17]7[C:12]([C:11]8[CH:3]=[CH:2][CH:7]=[CH:6][C:10]=8[CH:9]=6)=[CH:13][CH:14]=[CH:15][CH:16]=7)[CH:5]=5)([OH:38])[C:27]5[C:36]4=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:7]=[CH:6][CH:5]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:21]=[CH:20][CH:19]=1
Reactant: [Li]CCCC
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: Brc1cccc(-c2cccc3ccccc23)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: OC1(c2cccc(-c3cc4ccccc4c4ccccc34)c2)c2ccccc2C(O)(c2cccc(-c3cc4ccccc4c4ccccc34)c2)c2ccccc21

Procedure:
Under an atmosphere of argon, 1-(3-bromophenyl)naphthalene (6.5 g, 20 mmole, 2.8 eq) was dissolved into a mixed solvent composed of anhydrous toluene (25 ml) and anhydrous THF (25 ml) and the resultant solution was cooled at −25° C. in a dry ice/methanol bath. To the cooled solution, a hexane solution of n-butyllithium (1.50 mole/liter, 15 ml, 23 mmole, 1.1 eq) was added and the resultant solution was stirred at −20° C. for 1 hour. To the obtained mixture, anthraquinone (1.5 g, 7.2 mmole) was added and the resultant mixture was stirred at −20° C. for 1 hour and at the room temperature for 3 hours and left standing for one night. To the obtained reaction mixture, a saturated aqueous solution of ammonium chloride (20 ml) was added. The formed solid was separated by filtration and washed with water, methanol and acetone and a white solid (5.9 g, quant.) was obtained.
Reaction SMILES: [CH:1]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)=[CH:15][CH:16]=2)[N:11]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[CH:1]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:20]=[C:21]([NH:25][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:16]=2)[N:11]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[N:10]=1)=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(Nc3cccc(N)c3)cc21
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(Nc3cccc(NC(=O)c4ccccc4)c3)cc21
Yield: 96.3 %

Procedure:
To a solution of N-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine (91 mg, 0.2 mmol) and pyridine (0.081 mL, 1.0 mmol) in CH2Cl2 (0.5 mL) cooled to −5° C. under an atmosphere of argon was added benzoyl chloride (0.028 mL, 0.24 mmol). After 0.5 h the reaction was quenched with saturated NaHCO3(aq) then extracted 2×5 mL CH2Cl2. The pooled organic material was washed with brine (5 mL), dried with Na2SO4, decanted and concentrated under reduced pressure to give an oil. The crude material was purified by silica gel chromatography (eluting with hexane:EtOAc 3:2) to give N-(3-{3-Styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamino}-phenyl)-benzamide (108 mg, 96% yield). Rf sm 0.35, Rf p 0.44 (ethyl acetate:hexane 1:1); FTIR (thin film) 3320, 2951, 2893, 1657, 1604, 1537, 1493, 1409, 1303, 1248, 1074 cm−1; LCMS (ESI) [M+H]/z Calc'd 561, Found 561. Anal. Calc'd: C, 72.82; H, 6.47; N, 9.99. Found: C, 72.33; H, 6.39; N, 9.81.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[N:14][NH:15][CH:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]1[N:28]=[CH:27][CH:26]=[CH:25][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[N:14][N:15]([C:18]3[N:28]=[CH:27][CH:26]=[CH:25][C:19]=3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[C:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: c1ccc(CN2CCc3n[nH]cc3C2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1-n1cc2c(n1)CCN(Cc1ccccc1)C2
Temperature: 140 °C
Yield: 130 %

Procedure:
The mixture of 5-benzyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (1.0 g, 4.69 mmol), ethyl 2-chloronicotinate (1.55 g, 8.35 mmol), K2CO3 (1.7 g, 12.30 mmol), 18-CROWN-6 (0.2 g, 0.757 mmol) and KI (0.13 g, 0.783 mmol) in N,N-dimethylformamide (15 mL) was heated to 140° C. under stirring. After completion of the reaction the mixture was concentrated, the remainder dissolved in 250 mL of dichloromethane, washed subsequently with water (3×30 mL) and brine, dried (MgSO4), filtered and concentrated to give 2.21 g of a brown oil, which was purified by chromatography over silica gel (eluent CH2Cl2/methanol). 200 mg of the title compound was obtained as a white amorphous solid; ESI-MS [M+H]+: 363.2.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]([S:21][CH3:22])[NH:19][CH:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[C:12]([C:9]1[CH:8]=[C:7]([C:16]2[N:17]=[C:18]([S:21]([CH3:22])=[O:31])[NH:19][CH:20]=2)[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: CSc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c[nH]1
Yield: 38.7 %

Procedure:
To a solution of 0.32 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthioimidazole in 5 ml of chloroform was added 0.18 g of m-chloroperbenzoic acid at room temperature and the mixture was stirred for a day. The reaction mixture was washed with a diluted alkali solution, dried, concentrated under reduced pressure, and the residue thus formed was recrystallized from cyclohexane to provide 0.13 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylsulfinylimidazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.[CH3:27][CH:28]([NH2:30])[CH3:29].CCN(C(C)C)C(C)C>O1CCOCC1>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[O:18][CH:15]1[CH2:16][CH2:17][N:12]([C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]=[CH:8][C:6]3=[N:7][C:2]=2[NH:30][CH:28]([CH3:29])[CH3:27])[CH2:13][CH2:14]1
Reactant: CC(C)N
Reactant: Fc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)Nc1nc2cnccc2nc1N1CCC(Oc2ccc(F)cc2F)CC1
Yield: 70.7 %

Procedure:
A solution of 3-chloro-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)pyrido[3,4-b]pyrazine (2 g, 5.31 mmol), propan-2-amine (1.36 mL, 15.92 mmol) and DIPEA (1.85 mL, 10.62 mmol) in dioxane (10.62 mL) was heated at 95° C. overnight. After concentration, the residue was purified with silica gel column chromatography using a gradient of 0% to 100% EtOAc in heptanes to give the title compound (1.5 g, 71%) as an off-white solid. ESI-MS m/z [M+H]+ 400.00.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH2:29][CH3:30])[C:16]3[C:21]([C:22]=2[C:23]#[N:24])=[CH:20][CH:19]=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:29]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([C:25]([F:27])([F:28])[F:26])[CH:17]=2)[C:22]([C:23]#[N:24])=[C:14]1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH3:30]
Reactant: CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)c(C#N)c2ccc(C(F)(F)F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(N2CCNCC2)c(C#N)c2ccc(C(F)(F)F)cc21
Yield: 10.2 %

Procedure:
4-(3-cyano-1-ethyl-6-trifluoromethyl-1H-indol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.26 g, 6.1 mmol) is treated with TFA (5 mL) in dichloromethane (5 mL) for 1 h at room temperature. After the removal of the volatiles, the residue is treated with saturated NaHCO3 and the precipitate is collected via filtration, washed with water thoroughly and dried in air to furnish essentially pure 1-ethyl-2-piperazin-1-yl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (0.20 g, 100%).