Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[CH:18]=[O:19])[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]1=2.[BH4-].[Na+]>CO>[S:1]1[C:5]([C:6]2[CH:7]=[C:8]([C:15]3[CH:16]=[C:17]([CH2:18][OH:19])[CH:20]=[CH:21][CH:22]=3)[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]1=2
Reactant: O=Cc1cccc(-c2cc(-c3cc4ccccc4s3)c3[nH]ncc3c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(-c2cc(-c3cc4ccccc4s3)c3[nH]ncc3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
A mixture of 3-(7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-benzaldehyde (Preparation #25, F (using 3-bromobenzaldehyde), 50 mg, 0.14 mmol), and NaBH4 (0.01 g, 0.26 mmol) in MeOH (2 mL) was stirred at ambient temperature for about 1 hour. The reaction mixture was concentrated under reduced pressure then the residue was purified by reverse phase preparative HPLC (Thermo Hypersil-Keystone 250×21.2 mm 8μ Hypersil® HS C18 column; 5% CH3CN/50 mM aqueous ammonium acetate hold for 5 min; 5-50% CH3CN/50 mM aqueous ammonium acetate over 20 min; 50-100% CH3CN/50 mM aqueous ammonium acetate over 1 min; hold at 100% CH3CN for 5 minutes, 21 mL/min) to yield [3-(7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-phenyl]-methanol (6 mg, 12%); (DMSO-d6, 400 MHz) 8.8 (d, 1H), 8.55 (d, 1H), 8.37 (s, 1H), 8.19 (d, 1H), 8.18 (s, 1H), 8.10 (t, 1H), 8.04 (dd, 1H), 7.93 (dd, 1H), 7.89 (d, 1H, 7.45 (m, 2H), 5.40 (t, 1H), 4.6 (d, 2H); RP-HPLC (Table 1, Method e) Rt=1.85 min; m/z: (M−H)− 355.8.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([NH:19][CH2:20][CH3:21])=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH:22]1(C2CCCCCCCCCC2)[CH2:32]CCCCC=CCC[CH2:23]1.C(Br)C=C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([N:19]([CH2:32][CH:22]=[CH2:23])[CH2:20][CH3:21])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCNc1ccc2[nH]c3cnc(C(=O)OCC)cc3c2c1
Reactant: C1=CCCCC(C2CCCCCCCCCC2)CCCCC1
Solvent: CCO
Solvent: C=CCBr
Product: C=CCN(CC)c1ccc2[nH]c3cnc(C(=O)OCC)cc3c2c1

Procedure:
93 mg of 6-(N-ethylamino)-beta-carboline-3-carboxylic-acid-ethylester in 8 ml of absolute ethanol is heated together with 49 mg of 1,5-diaza-[5.4.0]bicycloundec-5-ene and 50 mg of allyl bromide under nitrogen for 2 h at 70° C. After evaporation, the substance is distributed in ethyl acetate and saturated sodium bicarbonate solution. The organic phase is dried, filtered and concentrated. The residue is chromatographed by means of 80 g of silica gel with methylene-chloride/ethanol (12/1) as the eluant, and, after recrystallizing out of ethyl-acetate/ether, 56 mg of 6-(N-allyl-N-ethylamino)-beta-carboline-3-carboxylic-acid-ethylester is obtained (m.p. 190°-192° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:14](C)([O:16]C3C=CC(C4NN=NN=4)=CC=3)C)[C:11]3[CH:35]=[C:36]([F:40])[C:37]([F:39])=[CH:38][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[OH2:41].[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[C:14]([OH:41])=[O:16])[C:11]3[CH:35]=[C:36]([F:40])[C:37]([F:39])=[CH:38][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccc(-c2nnn[nH]2)cc1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C

Procedure:
To the solution of 0.17 g (0.469 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid ethyl ester (Example 1, intermediate b) in 4 ml dioxan and 2 ml water, 34 mg (1.42 mmol) lithium hydroxide monohydrate were added and the reaction was stirred at reflux temperature for 2 h. After cooling to room temperature the solution was partially evaporated, diluted with 2 ml water and the pH was adjusted to 1-2 with 1M aqueous hydrochloric acid. The resulting suspension was stirred for 30 min. and then filtered. The filter cake was thoroughly washed with water and dried under high vacuum. Colorless solid (83%). MS (Turbo Spray): m/z=333.3 [M−H].
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)(=[O:22])=[O:21])=[CH:16][C:15]=2[O:30][CH2:31][CH2:32][OH:33])[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[F:29][C:25]1[CH:24]=[C:23]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:11]3[CH2:12][CH2:13][NH:9][CH2:10]3)=[C:15]([CH:16]=2)[O:30][CH2:31][CH2:32][OH:33])(=[O:21])=[O:22])[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2OCCO)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(c1cccc(F)c1)c1ccc(C2CCNC2)c(OCCO)c1
Reaction time: 4 h
Yield: 94.9 %

Procedure:
A solution of HCl (4 M in 1,4-dioxane, 0.3 mL, 1.2 mmol) was added to a solution of 3-[4-(3-fluoro-benzenesulfonyl)-2-(2-hydroxy-ethoxy)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.215 mmol) in 1,4-dioxane (1 mL) under nitrogen atmosphere. The reaction mixture was stirred for 4 hours The solvent was then evaporated under reduced pressure to give 82 mg of 2-[5-(3-fluoro-benzenesulfonyl)-2-pyrrolidin-3-yl-phenoxy]-ethanol hydrochloride as a foam. MS (M+H)=366.
Reaction SMILES: C(N(CC)CC)C.[F:8]N1N=C(F)C=C(F)N1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[N:19]=1>ClCCl>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([F:8])=[O:23])=[C:20]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[N:19]=1
Reactant: FC1=CC(F)=NN(F)N1
Reactant: O=C(O)c1ccc(Cl)nc1NCc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(F)c1ccc(Cl)nc1NCc1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
2.27 ml of triethylamine (16.31 mmol) and 1.65 ml of 2,4,6-trifluorotriazine (19.57 mmol) are added successively to a suspension of 4.3 g of 6-chloro-2-[(pyridin-2-ylmethyl)amino]nicotinic acid (16.31 mmol) in 90 ml of dichloromethane. The mixture is stirred for 1 hour at ambient temperature and then a dichloromethane/ice-cold water mixture is added. The organic phase is washed 3 times with ice-cold NaHCO3aq and then dried over Na2SO4, filtered, and concentrated under vacuum. 3.97 g of expected product are obtained in the form of an orange solid. Yield=92%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][NH2:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27]>O1CCCC1>[Cl:1][C:2]1[C:3]([CH2:12][NH:13][C:26]([C:22]2[O:21][CH:25]=[CH:24][CH:23]=2)=[O:27])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(Cl)c1ccco1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ncc(C(F)(F)F)cc1Cl)c1ccco1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine (1 mmol) in tetrahydrofuran (5 ml) was added triethylamine (1 mmol) at room temperature and the mixture was stirred at room temperature for 1.5 hour. The mixture was added to a solution of 2-furoyl chloride (1 mmol) in tetrahydrofuran (5 ml) at room temperature and left to stir at room temperature overnight. The mixture was evaporated to dryness and the residue washed with water. The solid was filtered, washed with diethyl ether/light petroleum (b.p. 60-80° C.) and dried to give the title product, 1H N.M.R. (CDCl3) δ (ppm) 4.9 (2H, d), 6.55 (1H, m), 7.2 (1H, m), 7.5 (1H, s), 7.8 (1H, br.s), 8.0 (1H, s) and 8,8 (1H, s).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:17]=[O:18])=[CH:5][C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1)#[CH:2].Br[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(N(CC)CC)C>CN(C)C=O.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>[CH3:14][C:10]1([CH3:13])[CH2:9][CH2:8][C:7]([CH3:16])([CH3:15])[C:6]2[CH:5]=[C:4]([CH:17]=[O:18])[C:3]([C:1]#[C:2][C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:12][C:11]1=2
Reactant: C#Cc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Reactant: Brc1ncccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2cc(C=O)c(C#Cc3ncccn3)cc21
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A solution of 0.400 g (1.66 mmol) of 3-ethynyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde, 0.278 g (1.75 mmol) of 2-bromopyrimidine, 0.053 g (0.075 mmol) of dichlorobis(triphenylphosphine)palladium(II), 0.026 g (0.14 mmol) of cuprous iodide, and 0.253 g (2.50 mmol) of triethylamine in 12 mL of dimethylformamide was heated to 45° C. for 3 hours, cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The product was purified by flash chromatography on silica gel (25% ethyl acetate/hexane) to afford 0.372 g (70%) of 5,5,8,8-tetramethyl-3-pyrimidin-2-ylethynyl-5,6,7,8-tetrahydro-2-naphthaldehyde.(M+=318).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][C:6]([CH2:7][N:8]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:31](O)[CH3:32])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:57][S:58]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)(=[O:60])=[O:59]>ClCCl.O>[CH3:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][N:8]([CH2:7][C:6]2[CH:43]=[CH:44][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[C:11]([C:16]3[C:21]([NH:22][C:23]4[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)=[N:20][CH:19]=[C:18]([CH:31]([N:64]4[CH2:65][CH2:66][N:61]([S:58]([CH3:57])(=[O:60])=[O:59])[CH2:62][CH2:63]4)[CH3:32])[CH:17]=3)[N:12]=[C:13]([CH3:15])[N:14]=2)=[CH:36][CH:37]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Yield: 55 %

Procedure:
1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol (732.1 mg, 1.233 mmol) was dissolved in dichloromethane (22 mL) and the reaction flask was cooled in an ice water bath. The reaction was stirred under nitrogen, and triethylamine (0.77 mL, 5.5 mmol) and methanesulfonylchloride (0.37 mL, 4.8 mmol) were added via syringe. The reaction was stirred at 0° C. under nitrogen for 15 min and then was diluted with dichloromethane (125 mL) and treated with water (20 mL). The layers were separated, and the aqueous phase was extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and dissolved in dichloromethane (13 mL). To this solution were added triethylamine (0.77 ml, 5.5 mmol) and 1-methanesulfonylpiperazine (648 mg, 3.95 mmol). The reaction was stirred under nitrogen at room temperature overnight and then concentrated and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; 100:1 DCM/MeOH to elute impurities to 50:1 DCM/MeOH to elute product). The fractions with product were collected, concentrated, and washed with hexanes. The material dried under high vacuum at room temperature to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (501.6 mg,). 1H NMR (CDCl3, 400 MHz) δ 11.63 (s, 1H), 8.70 (d, J=2.54 Hz, 1H), 8.28 (d, J=2.54 Hz, 1H), 8.22 (d, J=2.54 Hz, 1H), 7.92 (dd, J=9.00 Hz, 2.74 Hz, 1H), 7.22 (t, J=9.29 Hz, 4H), 6.86 (dd, J=18.58 Hz, 8.61 Hz, 4H), 6.72 (d, J=8.80 Hz, 1H), 4.93-4.76 (m, 4H), 3.93 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.54 (quartet, J=6.78 Hz, 1H), 3.16 (t, J=4.40 Hz, 4H), 2.68 (s, 3H), 2.61-2.49 (m, 7H), 1.38 (d, J=6.65 Hz, 3H). m/z (ESI, +ve ion) 740 (M+H)+.
Reaction SMILES: C[Al](C)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[Si:12]([O:19][CH:20]1[CH2:23][N:22]([CH2:24][C@H:25]([OH:30])[C:26](OC)=[O:27])[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O>[Si:12]([O:19][CH:20]1[CH2:23][N:22]([CH2:24][C@H:25]([OH:30])[C:26]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=2)=[O:27])[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: Nc1ccccn1
Reactant: COC(=O)[C@@H](O)CN1CC(O[Si](C)(C)C(C)(C)C)C1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CN(C[C@H](O)C(=O)Nc2ccccn2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
Trimethylaluminium (2.384 mL, 4.77 mmol) was added to pyridin-2-amine (0.390 g, 4.15 mmol) in toluene (30 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate (Intermediate AD3) (1.2 g, 4.15 mmol) in toluene (10 mL) was added and the reaction was allowed to warm to room temperature and then heated at 80° C. for 4 hours. The reaction mixture was cooled, 20% Rochelle salt in water (75 mL) added and stirred for 2 hours. The mixture was extracted with ethyl acetate (2×5 mL) and the combined organic extracts washed with water (50 mL) and brine (50 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in EtOAc to afford the product (1.25 g).
Reaction SMILES: [CH:1]1([CH:4]=[C:5]2[C:9](=[O:10])[C:8]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:7]([O:20]C)[CH2:6]2)[CH2:3][CH2:2]1>N1CCOCC1>[CH:1]1([CH:4]=[C:5]2[CH2:6][C:7](=[O:20])[CH:8]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[C:9]2=[O:10])[CH2:2][CH2:3]1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(=CC2CC2)C1
Solvent: C1COCCN1
Product: Cc1cc(C)c(C2C(=O)CC(=CC3CC3)C2=O)c(C)c1
Temperature: 25 °C
Yield: 266.2 %

Procedure:
A solution of 5-[1-Cyclopropyl-methylidene]-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (83 mg, 0.28 mmol) in morpholine (3 ml) was heated at 10° C. for 17 hours. The reaction was allowed to cool to room temperature and then evaporated to dryness under reduced pressure. The crude material was dissolved in EtOAc (15 ml) and then washed with 2M HCl (3×15 ml) and brine (15 ml). The organic phase was dried over Na2SO4, filtered and evaporated to dryness under reduced pressure to give a colourless oil (200 mg). The crude material was purified by flash chromatography over SiO2 using a 100% hexane to 100% EtOAc gradient to give the desired compound as a white solid (45 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:35]1([N:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)N)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:41]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:22]=3[C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc([N+](=O)[O-])cc4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 601.6 (M+H)+.
Reaction SMILES: C(OC(C1NN=C(COC2C=CC=CC=2)C=1)=O)C.C(OC(=O)N[C@H](C)CO)(C)(C)C.C(OC([C:36]1[N:37]([CH2:49][CH:50]([NH:52][C:53](OC(C)(C)C)=O)[CH3:51])[N:38]=[C:39]([CH2:41][O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:40]=1)=O)C.CC1CN2N=C(COC3C=CC=CC=3)C=C2C(=O)N1.CC1CN2N=C(COC3C=CC=CC=3)C=C2CN1>>[CH3:51][C@@H:50]1[CH2:49][N:37]2[N:38]=[C:39]([CH2:41][O:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:40]=[C:36]2[CH2:53][NH:52]1
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Agent: CC1Cn2nc(COc3ccccc3)cc2C(=O)N1
Agent: CC1Cn2nc(COc3ccccc3)cc2CN1
Agent: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Product: C[C@@H]1Cn2nc(COc3ccccc3)cc2CN1

Procedure:
The compound was prepared from 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester and (1R)-2-hydroxy-1-methyl-ethyl-carbamic acid tert-butyl ester using the methods described in the preceding examples 11 (rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 12 (rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one), and 13 (rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([O:20][Si](CC)(CC)CC)([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:8]=2)[NH:3]1.[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37]Cl)[CH:32]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.C1COCC1>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:11]([OH:20])([C:16]([F:17])([F:18])[F:19])[C:12]([F:14])([F:15])[F:13])=[CH:6][CH:5]=3)[CH2:10][CH:2]2[CH3:1])[CH:32]=1
Reactant: COC(=O)c1cccc(CCl)c1
Reactant: CC[Si](CC)(CC)OC(c1ccc2c(c1)CC(C)N2)(C(F)(F)F)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN2c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3CC2C)c1
Temperature: 80 °C
Reaction time: 10 h
Yield: 56.4 %

Procedure:
To a solution of 94 mg (0.23 mmol) of 2-methyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-2,3-dihydro-1H-indole in 0.5 mL of DMF were added 104 mg (0.45 mmol) of 3-chloromethyl-benzoic acid methyl ester and the mixture was stirred at 80° C. for 10 hrs. After cooling to RT the mixture was treated with 0.5 mL of a 1M solution of TBAF in THF and stirred for an hour at 60° C. Evaporation of the solvent and chromatography on silica gel with EtOAc/n-heptane gave 58 mg (99%) of 3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-benzoic acid methyl ester, light red oil, MS: 448 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCl>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(NCc2ccccc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1)N(Cc1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Yield: 47.4 %

Procedure:
A solution of benzyl-(3-bromo-phenyl)-amine (2 g, 7.6 mmol), benzenesulphonyl chloride (3.2 ml, 25 mmol) and pyridine (2.2 ml, 27.5 mmol) in dry dichloromethane (50 ml) were heated to reflux for 15 hrs. The reaction mixture was cooled to room temperature, quenched with water and extracted with dichloromethane (3×75 ml). The organics were combined, dried (magnesium sulphate) and concentrated in vacuo. The crude residue was then purified by column chromatography eluting with dichloromethane to afford the title compound as a white solid (1.45 g, 47%). HPLC retention time 4.93 mins. Mass spectrum (ES+) m/z 402 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][CH2:7][O:8][CH2:9][C:4]=2[C:3]([C:10]([OH:12])=O)=[N:2]1.[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:3]3[C:4]4[CH2:9][O:8][CH2:7][CH2:6][C:5]=4[O:1][N:2]=3)=[O:12])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1noc2c1COCC2
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1noc2c1COCC2
Yield: 9.5 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 6,7-dihydro-4H-pyrano[3,4-d]isoxazole-3-carboxylic acid (0.101 g, 0.598 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.12 g, 0.460 mmol). The product was purified by reverse phase flash chromatography. Yield 9.50%. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 2.93 (t, 2H), 3.90 (t, 2H), 4.26 (dd, 1H), 4.42 (dd, 1H), 4.50-4.62 (m, 1H), 4.86-4.90 (m, 2H), 6.64 (d, 1H), 7.50 (d, 1H), 7.64 (d, 1H), 7.71 (d, 1H), 7.87 (dd, 1H), 7.95 (d, 1H).
Reaction SMILES: [CH2:1](OCC)C.[N:6]1([C:12]2[C:17]([CH:18]=[O:19])=[CH:16][CH:15]=[C:14]([C:20]([F:23])([F:22])[F:21])[N:13]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C[Mg]Cl>C1COCC1>[N:6]1([C:12]2[C:17]([CH:18]([OH:19])[CH3:1])=[CH:16][CH:15]=[C:14]([C:20]([F:23])([F:21])[F:22])[N:13]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: O=Cc1ccc(C(F)(F)F)nc1N1CCOCC1
Reactant: CCOCC
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)c1ccc(C(F)(F)F)nc1N1CCOCC1
Reaction time: 0.5 h

Procedure:
To a diethylether (7.0 ml) solution of 2-morpholin-4-yl-6-(trifluoromethyl)pyridine-3-carbaldehyde (Journal of Medicinal Chemistry, 2005, 48, p 71-90, 0.88 g, 3.4 mmol) was added THF solution of methylmagnesiumchloride (3.0M, 1.36 ml) at 0° C. and the mixture was stirred for 0.5 h. The same procedure as described in Example 9C was performed to give the title compound as a colorless oil (quant. 0.9 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]#[N:15])[CH2:9][CH2:8]1>C1COCC1.O>[O:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]1
Reactant: N#CCN1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCCN1CCOCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 71.9 %

Procedure:
To anhydrous THF (35 mL) was added LiAlH4 (3.19 g, 84 mmol) in one portion in an ice bath. The mixture was stirred at 0° C. for 20 min, and a solution of 2-morpholinoacetonitrile (3.50 g, 28 mmol) in anhydrous THF (10 mL) was added dropwise. Upon the end of addition the mixture was refluxed for 3 h, then cooled to rt, diluted with water (20 mL), filtered and concentrated in vacuo to give the title compound as yellow oil (2.62 g, 72%).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:25]1([NH:31][NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[C:25]1([N:31]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(C(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: O=c1ccn(-c2ccc(C(F)(F)F)cc2)nc1-c1ccnn1-c1ccccc1
Yield: 12 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[4-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (crude 718 mg, 2.13 mmol) in 20 mL of methanol was added phenylhydrazine (345 mg, 3.20 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 3-(1-phenyl-1H-pyrazol-5-yl)-1-[4-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 12% for two steps) as a yellow solid.