Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:8]([CH3:10])[CH3:9])[N:5]([CH3:7])[N:6]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].C(N(CC)CC)C>C(OCC)(=O)C.[Cu]I>[NH2:13][CH2:12][CH2:11][NH:14][C:2]1[N:3]=[C:4]([N:8]([CH3:10])[CH3:9])[N:5]([CH3:7])[N:6]=1
Reactant: NCCN
Reactant: CN(C)c1nc(Br)nn1C
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)c1nc(NCCN)nn1C
Temperature: 80 °C

Procedure:
5-Bromo-N,N,2-trimethyl-1,2,4-triazol-3-amine (103 mg, 0.5 mmol) and copper (I) iodide (4.8 mg, 0.025 mmol) were placed in a sealed microwave vial and flushed with argon. Then ethane-1,2-diamine (1.5 ml, 22 mmol) and triethylamine (140 μL, 1 mmol) were added via siringe. The reaction mixture was heated in a microwave oven at 80° C. for 1 h. The reaction mixture was diluted with ethyl acetate, filtered through kieselguhr and the filtrate was concentrated under reduced pressure to give 97 mg (quantitative) MS(ESI) m/z=185.1 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[C:10](Cl)(=[O:13])[CH:11]=[CH2:12].[OH-].[Na+].Cl>>[C:10]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)(=[O:13])[CH:11]=[CH2:12]
Reactant: O=C(O)C1CCNCC1
Reactant: C=CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CC(=O)N1CCC(C(=O)O)CC1
Yield: 61.5 %

Procedure:
The procedure of Example A is used with 43 g (0.3 mol) of isonipecotic acid, 31 g (0.3 mol) of acryloyl chloride, 26.6 g (0.66 mol) of sodium hydroxide at 0° C. (ice-salt bath). The reaction mixture is acidified with 2N HCl to pH 3.0 and extracted with ethyl acetate. The organic layer is washed with a sodium chloride solution, dried over magnesium sulfate to dryness to leave a crystalline material which is crystallized from ethyl acetate n-hexane to yield 33.8 g (60%) product. Melting point 109°-110° C. NMR (CDCl3), 5.4-6.9 gamma (br m, 3H, CH2 =CH), 4.0 gamma (br, 2H), 2.1-3.4 gamma (br m, 3H), 1.2-2.1 gamma m, 4H).
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][N:23]([CH3:41])[C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:32]2[CH:37]=[CH:36][C:35]([N:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=O)=[CH:26][CH:25]=1.O>C1COCC1>[CH3:22][N:23]([CH3:41])[C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:32]2[CH:37]=[CH:36][C:35]([N:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:9][C:10]#[N:11])=[CH:26][CH:25]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ccc(C(=CC#N)c2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (1.4 mL, 8.9 mmol) in anhydrous THF (15 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 8.9 mL, 8.9 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of bis-(4-dimethylamino-phenyl)-methanone (1.19 g, 4.4 mmol) in THF (20 mL) and refluxed overnight. The reaction mixture was poured into water (20 mL), extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc/Hexane) to give 3,3-bis-(4-dimethylamino-phenyl)-acrylonitrile as a light yellow needle-like solid (0.75 g, 58% yield): mp, 181-183° C.; 1H NMR (DMSO-d6) δ 2.96 and 2.98 (2s, 6H, 2N(CH3)2), 5.70 (s, 1H, CH), 6.67-6.80 (m, 4H, Ar), 7.15-7.23 (m, 4H, Ar); 13C NMR (DMSO-d6) δ 39.7, 39.8, 87.0, 111.3, 111.4, 120.0, 124.2, 125.6, 129.8, 130.7, 151.0, 151.5, 162.2. Anal. Calcd for C19H21N3: C, 78.32; H, 7.26; N, 14.42. Found: C, 78.33; H, 7.29; N, 14.38.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:42]([NH2:44])=[O:43])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH:35][CH2:36][C:37]5S[CH:39]=[CH:40][CH:41]=5)[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].S1C=CC=C1CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:42]([NH2:44])=[O:43])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH:35][CH2:36][C@H:37]5[CH2:41][CH2:40][CH2:39][O:4]5)[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNCc5cccs5)c4)cc23)CC1
Agent: NCc1cccs1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC[C@H]5CCCO5)c4)cc23)CC1
Yield: 70.3 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-1H-indole-7-carboxamide trifluoroacetate, substituting 1-[(2R)-tetrahydro-2-furanyl]methanamine (31.5 mg, 0.6 mmol) for 1-(2-thienyl)methanamine to afford 36.9 mg of the title compound (70.3%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[CH3:28][SiH:29]([CH3:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.Cl>C(OCC)C>[CH3:28][Si:29]([CH3:36])([CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: C#CCCCCCC
Reactant: C[SiH](C)c1ccccn1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CCCCCCC=C[Si](C)(C)c1ccccn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To 1.0 ml of diethyl ether were added 10 mg (0.25 μmol) of bis(cyclooctadiene)platinum, 13 mg (0.50 μmol) of triphenylphosphine and 165 mg (1.5 mmol) of 1-octyne, and 69 mg (0.5 mmol) of dimethyl(2-pyridyl)silane was added dropwise thereto at room temperature over 1 hour. Further, the mixture was continued to be stirred for 6 hours at an inner temperature of 40° C., followed by the addition of 6 ml of 1N hydrochloric acid and 5 ml of diethyl ether. After the mixture was stirred for 30 minutes, it was left stand and separated into the organic and aqueous layers. The organic layer was extracted with five portions of 6 ml of 1N hydrochloric acid, and the resulting aqueous layers were combined together and turned basic with the addition of sodium hydroxide pellets. This aqueous layer was extracted with three portions of 10 ml of diethyl ether. The resulting organic layer was dried over magnesium sulfate and the solvent was evaporated off under reduced pressure to give 112 mg of dimethyl(1-octenyl)(2-pyridyl)silane. Yield: 90%.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([F:12])=[CH:5][C:6]([S:10][CH3:11])=[C:7]([CH3:9])[CH:8]=1.[C-:13]#[N:14].[Na+].[Cl-].[Na+]>>[C:13]([CH2:2][C:3]1[C:4]([F:12])=[CH:5][C:6]([S:10][CH3:11])=[C:7]([CH3:9])[CH:8]=1)#[N:14]
Reactant: CSc1cc(F)c(CCl)cc1C
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Product: CSc1cc(F)c(CC#N)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-Chloromethyl-4-fluoro-2-methylthiotoluene (21 g) is dissolved in N,N-dimemthylformamide (90 ml), and thereto is added finely divided sodium cyanide (6.03 g), and the mixture is stirred at room temperature for 18 hours. To the reaction mixture are added saturated aqueous sodium chloride solution (300 ml) and ice water (300 ml), and the mixture is extracted with ethyl acetate (300 ml×3). The combined extracts are washed with saturated aqueous sodium chloride solution (200 ml×3), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5-cyanomethyl-4-fluoro-2-methylthiotoluene.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])[CH:10]=[CH:11][C:12]=1[F:13].N1C=CC=CC=1>ClCCl>[CH2:18]([S:15]([NH:14][C:9]1[CH:10]=[CH:11][C:12]([F:13])=[C:7]([CH:8]=1)[NH:6][C:2](=[O:3])[O:4][CH3:5])(=[O:17])=[O:16])[CH3:19]
Reactant: COC(=O)Cl
Reactant: CCS(=O)(=O)Nc1ccc(F)c(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(F)c(NC(=O)OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.4 %

Procedure:
22.1 g (229 mmol) of methyl chloroformate was added dropwise to a mixture of 50.0 g (229 mmol) of N-(3-amino-4-fluorophenyl)ethanesulfonamide, 18.1 g (229 mmol) of pyridine and 500 ml of dichloromethane at a temperature of not higher than 5° C. Thereafter the temperature was raised to room temperature and the reaction was continued for 5 hours. After the dichloromethane layer was separated out by adding water to the resultant mixture, the dichloromethane layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. Thereafter the dichloromethane was distilled off to obtain the crude product (crystals). The crude product was washed with diisopropyl ether, thereby obtaining 61.0 g of the objective product (yield: 96%) in the form of light brown crystals.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([NH2:28])[N:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]>C(O)=O>[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[N:21]=[C:20]([NH:28][CH:5]=[O:7])[N:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(N)n2)cc1
Solvent: O=CO
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NC=O)n2)cc1
Reaction time: 1 h

Procedure:
A mixture of formic acid (7 ml) and acetic anhydride (2 ml) was stirred at 20 C for 1 h. 4-[4-(Methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-amine (0.5 g, 1.576 mmol) was then added and stirring was continued at ambient temperature for 18 h. This gave the title compound as a colourless precipitate which was collected by filtration and dried (0.32 g).
Reaction SMILES: [N:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][C:2]=1[C:15]#[N:16].[NH4+].[Cl-].[N-:19]=[N+:20]=[N-:21].[Na+]>[Li+].[Cl-].CN(C=O)C>[NH:19]1[C:15]([C:2]2[CH:3]=[CH:4][C:5]3[C:14](=[C:13]4[C:8](=[CH:7][CH:6]=3)[CH:9]=[CH:10][CH:11]=[N:12]4)[N:1]=2)=[N:16][N:21]=[N:20]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2ccc3cccnc3c2n1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: c1cnc2c(c1)ccc1ccc(-c3nnn[nH]3)nc12
Temperature: 125 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a flask was added a mixture of 6 g [1,10]phenanthroline-2-carbonitrile, 3.1 g NH4Cl, 3.8 g NaN3, 0.01 g LiCl and 60 ml DMF, and the mixture was then heated to 120-130° C. and stirred overnight. After completion of reaction, the reaction mixture was cooled to room temperature, filtered to remove solids, and vacuum distallated to remove DMF, and then 300 ml water was added. Next, HCl(aq) was added to adjust pH value to about 4, and stirred for 30 minutes. Finally, the solution was filtered to give solids, and then the solids were washed by water and dried to obtain products 2-(1H-tetrazol-5-yl)-[1,10]phenanthroline 6.1 g. (yield=84.0%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[CH2:6][CH2:5]2.C([O:18][N:19]=O)CC(C)C.Cl.O>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[C:6](=[N:19][OH:18])[CH2:5]2
Reactant: O=C1CCc2cc(F)c(F)cc21
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1C(=NO)Cc2cc(F)c(F)cc21
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5,6-difluoroindan-1-one (Preparation 76) (3.1 g, 18.4 mmol) in MeOH at 40° C. was added isoamylnitrite (3.22 mL, 23.9 mmol) followed by conc. HCl (1.8 mL). The reaction was stirred at 40° C. for 45 min, cooled to rt and poured into water (50 mL). The precipitate was collected by filtration and air-dried to give the title compound: δH(DMSO-d6) 3.77 (2H, s), 7.72-7.85 (2H, m), 12.79 (1H, s).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[CH2:5].[F-].[Cs+].[CH:15]1([CH:21]=[CH:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CS(C)=O>[CH:15]1([CH:21]([CH2:3][C:4]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)=[O:5])[CH2:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C=C(O[Si](C)(C)C)c1ccco1
Reactant: O=C(C=CC1CCCCC1)c1cccc(O)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1ccco1)C1CCCCC1)c1cccc(O)c1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(furan-2-yl) ethylene (1.66 g, 9.1 mmol; prepared according to J. Chem. Soc.,Perkin Trans. I 1989, 1585) and CsF (0.41 g, 2.7 mmol) were added to a suspension of 3-cyclohexyl-1-(3-hydroxyphenyl)-2-propen-1-one on Wang resin (2.6 g, 1.82 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% AcOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 2.7 g of 3-cyclohexyl-1-(3-hydroxyphenyl)-5-(furan-2-yl)-1,5-pentanedione on Wang resin.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C:10](=O)[C:9]2[CH:15]=[CH:16][C:17]([Cl:20])=[C:18]([CH3:19])[C:8]1=2)=[O:6])([CH3:3])[CH3:2].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26][NH2:27].[BH4-].[Na+].[OH-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:27][CH2:26][C:25]2[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:23]([C:22]([F:21])([F:35])[F:36])[CH:24]=2)[C:9]2[CH:15]=[CH:16][C:17]([Cl:20])=[C:18]([CH3:19])[C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)ccc2c1N(C(=O)OC(C)C)CCCC2=O
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: Cc1c(Cl)ccc2c1N(C(=O)OC(C)C)CCCC2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 14 h
Yield: 57.4 %

Procedure:
Inject titanium isopropoxide (0.176 mL, 0.60 mmol) to a mixture of 8-chloro-9-methyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (90 mg, 0.30 mmol) and 3,5-bis(trifluoromethyl)benzylamine (137 mg, 0.45 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Add methanol (1.3 mL) and sodium borohydride (28 mg, 0.75 mmol) and stir the mixture under nitrogen at room temperature for 2 h. Add 0.1M NaOH, stir for 30 min. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford (+/−)-5-(3,5-Bis-trifluoromethyl-benzylamino)-8-chloro-9-methyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (90 mg, 57%). Add acetyl chloride (0.025 mL, 0.34 mmol) dropwise to a solution of the amine (90 mg, 0.17 mmol) and pyridine (0.025 mL, 0.34 mmol) in dichloromethane (1.2 mL) at 0° C. Stir under nitrogen at room temperature for 1 h 30 min. Add water and extract with dichloromethane. Dry the organic layer over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (40 mg, 42%); MS (ES+): 565 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:5]=[CH:4][C:3]=1[C:16]1[NH:17][CH2:18][C:19]([CH3:25])([C:21]([O:23]C)=[O:22])[N:20]=1.[OH-].[Na+]>CO.O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:5]=[CH:4][C:3]=1[C:16]1[NH:17][CH2:18][C:19]([CH3:25])([C:21]([OH:23])=[O:22])[N:20]=1
Reactant: COCCOCCOc1ccc(C2=NC(C)(C(=O)OC)CN2)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCOCCOc1ccc(C2=NC(C)(C(=O)O)CN2)c(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of methyl 2-(2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-4-methyl-4,5-dihydro-1H-imidazole-4-carboxylate (0.17 g, 0.5 mmol) in MeOH (5 mL) was added NaOH (40 mg, 1.0 mmol) and water (one drop). The resulting solution was stirred for 2 h at room temperature. The solvent was evaporated under vacuum and the residue was purified by Combi Flash to obtain the title compound as colorless oil (100 mg, 60%). 1H NMR (300 MHz, CD3OD, n=2): δ 7.65-7.85 (m, 1H), 6.55-6.75 (m, 2H), 4.30-4.40 (m, 1H), 4.10-4.30 (m, 2H), 3.70-3.95 (m, 2H), 3.65-3.70 (m, 2H), 3.55-3.65 (m, 2H), 3.33 (s, 3H), 1.74 (s, 3H). LC-MS (ES, m/z): 339 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=2)[CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][C:16]([CH3:22])([CH3:23])[C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(Br)cn2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(Br)cn2)cc1)C(=O)O
Yield: 52 %

Procedure:
Hydrolysis of ethyl 2-[4-(2-{(5-bromopyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate with NaOH as per general procedure H provided after chromatography and crystallization from dichloromethane-hexane, the title compound as a white solid (56 mg; 52% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]3[C:17]([C:18]=2[CH:19]=[O:20])=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:6][CH2:5]1.[P:27](Cl)([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28]>>[CH:19]([C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]=1[N:7]1[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][O:1][P:27](=[O:28])([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])[CH2:9][CH2:8]1)=[O:20]
Reactant: CCOP(=O)(Cl)OCC
Reactant: O=Cc1c(N2CCN(CCO)CC2)n(-c2ccccc2)c2ccccc12
Product: CCOP(=O)(OCC)OCCN1CCN(c2c(C=O)c3ccccc3n2-c2ccccc2)CC1
Yield: 71 %

Procedure:
2-[4-(2-Hydroxyethyl)piperazin-1-yl]-1-phenyl-1H-indole-3-carboxaldehyde is reacted with diethyl chlorophosphate as described in Step 1 of Example 31 to afford phosphoric acid diethyl ester 2-[4-(3-formyl-1-phenyl-1H-indol-2-yl)piperazin-1-yl]ethyl ester (71% yield) as a yellow solid. ESI/MS 486 (M+H); RT 2.94 min; NMR 10.15 (1H, s); 8.13 (1H, d, J=9 Hz); 7.68 (5H, m); 7.20 (2H, m); 6.91 (1H, d, J=6 Hz), 4.04 (6H, m); 3.28 (6H, m); 2.49 (4H, br s); 1.23 (6H, t).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1(=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1>[Ti](Cl)(Cl)(Cl)Cl.CCCCC>[C:8]1([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH:7]=1
Reactant: C1CCNC1
Reactant: O=C1CCc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCC
Product: C1=C(N2CCCC2)c2ccccc2C1
Reaction time: 2 h

Procedure:
To a 100 ml reaction tube equipped with a stirrer bar, Suba.Seal™ stopper, and a nitrogen balloon, was added pyrrolidine (1.3 ml) and pentane (8 ml). Titanium tetrachloride (0.2 ml) was added slowly to each tube. 1-Indanone (0.2 g, 1.33 mmol) was added as a solid and the reaction stirred vigorously for 2 h. The reaction mixture was filtered through Celite and the solvent removed in vacuo to give the title compound as a dark solid. m/z (ES+) 186 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:23]3[CH:24]=[CH:25][C:26]4[C:30]([CH:31]=3)=[N:29][N:28]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:27]=4)[CH:9]=[C:10]([C:11]([C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][NH:19][CH2:20]4)=[CH:15][CH:14]=3)=O)[N:6]2[N:5]=[CH:4][N:3]=1.CS(O)(=O)=O>ClCCl>[CH2:32]([N:28]1[CH:27]=[C:26]2[C:30]([CH:31]=[C:23]([C:8]3[CH:9]=[C:10]([CH2:11][C:13]4[CH:22]=[C:21]5[C:16]([CH2:17][CH2:18][NH:19][CH2:20]5)=[CH:15][CH:14]=4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:24]=[CH:25]2)=[N:29]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Nc1ncnn2c(C(=O)c3ccc4c(c3)CNCC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: Nc1ncnn2c(Cc3ccc4c(c3)CNCC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 617.8 %

Procedure:
[4-Amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-methanone (0.050 g, 0.01 mmol) was dissolved in dichloromethane (1 mL) and methanesulfonic acid (0.104 mL, 1.61 mmol) was added followed by Et3SIH (0.128 mL, 0.80 mmol). The resulting mixture was stirred at rt overnight. The mixture was diluted with dichloromethane and washed with saturated aqueous NaHCO3, water and brine. The organic layer was concentrated, suspended in MeOH and filtered to give a desired product as white solid (30 mg, 62%). 1H-NMR (CD3OD-d4) 8.28-8.24 (m, 1 H), 7.78 (s, 1 H), 7.70 (dd, 1H), 7.59-7.56 (m, 1 H), 7.33-7.23 (m, 5 H), 7.11 (dd, 1 H), 7.07-6.89 (m, 3 H), 6.39 (s, 1 H), 5.57 (s, 2 H), 4.16 (s, 2 H), 3.82 (s, 2 H), 2.96 (t, 2 H), 2.71 (t, 2 H); LC-MS [M+H]+=486.3, RT=2.30 min.
Reaction SMILES: C(=O)([O-])O.[K+].F[C:7]1[CH:8]=[C:9]([O:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14].O.[CH2:24]([OH:26])[CH3:25]>>[CH2:24]([O:26][C:7]1[CH:8]=[C:9]([O:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH3:25]
Reactant: CCO
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])c(F)c2)n[nH]1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: CCOc1cc(Oc2cc(C)[nH]n2)ccc1[N+](=O)[O-]
Yield: 42.3 %

Procedure:
Potassium hydrogencarbonate (0.15 g, 1.5 mmol) was added to a solution of 3-(3-fluoro-4-nitrophenyloxy)-5-methylpyrazole (0.36 g, 1.5 mmol) in ethanol (5 ml), and the mixture was refluxed under heating for 10 hours. After completion of the reaction, the reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove magnesium sulfate, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a yellow solid of 3-(3-ethoxy-4-nitrophenyloxy)-5-methylpyrazole (0.17 g, yield: 42.3%). mp: 123-124° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.47 (t, J=7.0 Hz, 3H), 2.33 (d, J=0.5 Hz, 3H), 4.13 (q, J=7.0 Hz, 2H), 5.73 (d, J=0.5 Hz, 1H), 6.68 (dd, J=2.5 and 9.1 Hz, 1H), 6.81 (d, J=2.5 Hz, 1H), 7.91 (d, J=9.1 Hz, 1H), 9.53 (br s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][C:7]=1[OH:10])([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 79.8 %

Procedure:
5.00 g (36.7 ml) of 4-acetylphenol was dissolved in 50 ml of sulfuric acid. To the solution, 3.10 ml (40.7 mM) of nitric acid (60%, density=1.38) was gradually added dropwise under stirring at 2°-10° C. on an ice bath, followed by stirring at 2°-10° C. after the addition. After the reaction, the reaction mixture was poured into ice water to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by recrystallization from methanol to obtain 5.84 g of 2-nitro-4-acetylphenol (Yield: 79.8%).