Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-:3])=O.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N12CCN(CC1)CC2>C(O)C>[C:12]1([CH:11]2[O:3][N:1]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=Cc1ccccc1
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: CCOC(=O)C1=NOC(c2ccccc2)C1
Temperature: 80 °C
Reaction time: 60 h
Yield: 24.5 %

Procedure:
A mixture of ethyl 2-nitroacetate (0.96 mL; 8.70 mmol), styrene (0.5 mL; 4.35 mmol) and 1,4-diazabicyclo[2.2.2]octane (DABCO) (0.050 mg, 0.438 mmol) in ethanol (2 mL) was stirred at 80° C. for 60 hrs. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to afford ethyl 5-phenyl-4,5-dihydroisoxazole-3-carboxylate 0.234 g (25%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].Br[C:14]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[S:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[N:16]([CH3:43])[CH:15]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([S:23]([NH:26][C:27]4[S:31][N:30]=[CH:29][N:28]=4)(=[O:24])=[O:25])=[CH:20][CH:21]=3)[N:16]([CH3:43])[CH:15]=2)=[CH:5][C:4]=1[F:12])#[N:2]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Product: Cn1cc(-c2ccc(C#N)c(F)c2)c2ccc(S(=O)(=O)Nc3ncns3)cc21

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (4-cyano-3-fluorophenyl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 3-(4-cyano-3-fluorophenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.92 (s, 3 H) 7.60 (dd, J=8.53, 1.55 Hz, 1 H) 7.73-7.80 (m, 2 H) 7.87-7.97 (m, 2 H) 8.02-8.10 (m, 2 H) 8.23 (s, 1 H). m/z (ESI) 413.0 (M+H)+.
Reaction SMILES: C([O:4][C@@:5]1([CH2:41][CH3:42])[C:38]2[CH:37]=[C:36]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:20]([CH2:26][O:27]C(=O)C)=[N:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:39])[C:9]=2[CH2:8][O:7][C:6]1=[O:40])(=O)C.NN.Cl>CO>[CH2:41]([C@:5]1([OH:4])[C:38]2[CH:37]=[C:36]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:20]([CH2:26][OH:27])=[N:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:39])[C:9]=2[CH2:8][O:7][C:6]1=[O:40])[CH3:42]
Reactant: CCCCCN1C(COC(C)=O)=Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@@]2(CC)OC(C)=O
Agent: Cl
Agent: NN
Solvent: CO
Product: CCCCCN1C(CO)=Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@]2(O)CC
Reaction time: 2 h
Yield: 65.9 %

Procedure:
To a solution of (9S)-9-acetoxy-2-acetoxymethyl-9-ethyl-1-pentyl-1H,12H-pyrano[3″,4″:6′7′]indolizino[1′2′:6,5]pyrido[4,3,2-de]quinazoline-10,13(9H,15H)-dione (34 mg, 0.059 mmol) in methanol (3 ml) cooled in an ice-bath was added anhydrous hydrazine (100 μl) and the mixture was stirred for 2 hr. at room temperature. Aqueous 1 N hydrochloric acid solution (5 ml) was added dropwise to acidify the reaction mixture, and the mixture was stirred for 1 hr. at room temperature. The mixture was extracted with dichloromethane (50 ml) and the dichloromethane layer was washed with brine, dried over MgSO4 and evaporated. The residue was purified by column chromatography (dichloromethane/methanol=25/1) to give pure product (19 mg, 65%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].[F:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[C:36]1[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=1>>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH:24]=[CH:23][C:22]=1[C:36]1[CH:41]=[N:40][C:39]([NH2:42])=[N:38][CH:37]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=C(c1cc(C(F)(F)F)ccc1Br)N1CCOCC1
Product: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3C(=O)N3CCOCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using (2-bromo-5-(trifluoromethyl)phenyl)(morpholino)methanone and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C22H18F4N4O2, 446.14; m/z found, 447.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.65-8.58 (d, J=1.3, 2H), 7.91-7.85 (dd, J=8.3, 1.9, 1H), 7.78-7.76 (m, 1H), 7.76-7.73 (d, J=8.1, 1H), 7.71-7.63 (m, 1H), 7.46-7.43 (dd, J=2.7, 1.8, 1H), 7.43-7.41 (dd, J=6.2, 1.7, 1H), 3.72-3.60 (m, 2H), 3.60-3.52 (m, 1H), 3.46-3.39 (m, 1H), 3.37-3.33 (m, 1H), 3.16-3.09 (m, 1H), 2.92-2.77 (m, 2H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C@@H:8]([CH2:20][CH2:21][C:22](=[O:31])[C:23]([F:30])([F:29])[CH2:24][C@@H:25]([CH3:28])[CH2:26][CH3:27])[C@H:7]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:6]1)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[C:1]([O:4][C@@H:5]1[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C@@H:8]([CH2:20][CH2:21][CH:22]([OH:31])[C:23]([F:29])([F:30])[CH2:24][C@@H:25]([CH3:28])[CH2:26][CH3:27])[C@H:7]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC[C@H](C)CC(F)(F)C(=O)CC[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@H](C)CC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Reaction time: 0.58 h
Yield: 100.3 %

Procedure:
A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((6S)-4,4-difluoro-6-methyl-3-oxooctyl)-3-(2-tetrahydro pyranyloxy)cyclopentyl]heptanate (D) (72.56 g, 132.7=1) in methanol (290 ml) was cooled to approximately −20° C., and sodium borohydride (5.00 g, 132.2 mmol) was added thereto. After stirring for approximately 35 minutes, acetic acid (7.5 ml, 131=1) was added dropwise, and the reaction mixture was concentrated under reduced pressure. The residue was supplemented with water (326 ml) and extracted three times with ethyl acetate (226 ml). The organic layers were combined, washed with 3% aqueous sodium chloride (323 ml) and saturated aqueous sodium chloride (323 ml), and dried with anhydrous magnesium sulfate (40.6 g). The solution was concentrated under reduced pressure to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((6S)-4,4-difluoro-6-methyl-3-hydroxyoctyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (E) (73.01 g; quantitative yield) as a colorless oil.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[CH2:17]([N:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:12][CH2:13]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
1.14 ml (10.5 mmol) of phenyl isocyanate are slowly added dropwise to a solution of 1.90 g (10.0 mmol) of 4-amino-1-benzylpiperidine and 1.46 ml (10.5 mmol) of triethylamine in 40 ml of dichloromethane. The reaction mixture may subsequently be stirred at room temperature for 1 h, and is then evaporated to dryness in vacuo. The residue is mixed with 50 ml of diethyl ether, stirred well, separated off by filtration, washed with 5 ml of diethyl ether and dried in a high vacuum. 2.62 g (85%) of the title compound are obtained as colourless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])=[CH:4][CH:3]=1.Cl[C:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=[O:21]>N1C=CC=CC=1>[CH3:29][O:28][C:26]([C:25]1[CH:30]=[CH:31][C:22]([C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])=[CH:17][CH:18]=2)=[O:21])=[CH:23][CH:24]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(N)cc1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2ccc(C(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 85.7 %

Procedure:
To a solution of tert-butyl 2-(4-aminobenzoyl)hydrazinecarboxylate (1.0 g, 3.98 mmol) in anhydrous pyridine (20 mL) was added dropwise methyl 4-(chlorocarbonyl)benzoate (TCI) (948 mg, 4.78 mmol) at rt. After 50 min, aminomethyl resin (Polymers Laboratories PL-AMS, 1.96 mmol/g, 960 mg) was added and the resulting mixture was stirred for 22 hrs at rt After filtration and rinsing the resin, water (160 mL) was added into the filtrate and a white solid precipitated out. Filtration and washing with water gave a white solid, which was dried under vacuo at 60° C. for 15 hrs. The title compound (1.41 g) was obtained as a white solid (85%) in 98.7% purity by HPLC (MaxPlot detection between 230 and 400 mn).
Reaction SMILES: [C:1]1([C:7]([N:9]=[C:10]=[S:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=1[CH3:34].C1(C)C=CC=CC=1>C(O)C>[C:7]([NH:9][C:10]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[N:20]=[CH:19][CH:18]=2)=[C:28]([CH3:34])[CH:29]=1)=[S:11])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (61 mg, yield 80%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[C:20]([CH:21]3[CH2:23][CH2:22]3)=[N:19][N:18]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:7]=2[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[OH-].[Na+].C(O)(=O)C>C(O)(C)C>[CH:21]1([C:20]2[C:6]3[C:5]([C:3]([OH:4])=[O:2])=[CH:10][C:9]([C:11]4[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=4)=[N:8][C:7]=3[N:18]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[N:19]=2)[CH2:22][CH2:23]1
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)nc2c1c(C1CC1)nn2C1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: O=C(O)c1cc(-c2ccc(O)cc2)nc2c1c(C1CC1)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A mixture of 3-cyclopropyl-6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid methyl ester (11.3 g) and sodium hydroxide solution (1N, 100 mL) in isopropanol (100 mL) was stirred at r.t. for 5 h. The mixture was poured onto ice-water and the pH was adjusted to 5 with acetic acid. The mixture was extracted with dichloromethane three times and the combined organic layers were dried over magnesium sulphate, filtrated and concentrated in vacuo. 10.35 g (95%) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@:13]([F:15])([CH3:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:29](O)=[O:30])=[N:22][N:23]([CH2:25][CH:26]([F:28])[F:27])[CH:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C@@:13]([F:15])([CH3:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:21]3[C:20]([Cl:19])=[CH:24][N:23]([CH2:25][CH:26]([F:28])[F:27])[N:22]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1nn(CC(F)F)cc1Cl
Reactant: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(N)ccc1F
Product: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(NC(=O)c2nn(CC(F)F)cc2Cl)ccc1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.3) and 4-chloro-1-(2,2-difluoro-ethyl)-1H-pyrazole-3-carboxylic acid (CAS 1006486-42-5) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=448.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3](O)=[O:4].[C:11]1([C@@H:17]([NH2:19])[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C1C=CN=CC=1)C>[F:8][C:7]([F:10])([F:9])[CH2:6][CH:2]([CH3:1])[C:3]([NH:19][C@H:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:18])=[O:4]
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(CC(F)(F)F)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(CC(F)(F)F)C(=O)N[C@@H](C)c1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 2-methyl-4,4,4-trifluorobutanoic acid (10.0 g, 0.064 mole) in dichloromethane (150 mL) was treated with 4-(N,N-dimethylamino)-pyridine (7.8 g, 0.064 mole), and the mixture was stirred for 15 min. A solution containing (S)-1-phenylethylamine (7.8 g, 0.064 mole) in dichloromethane (50 mL) was added, the mixture was stirred for a further 15 min, and then a solution of dicyclohexylcarbodiimide (15.9 g, 0.077 mole) in dichloromethane (100 mL) was added. Stirring was continued for 15 hours, then the precipitated dicyclohexylurea was removed by filtration, and the filtrate was concentrated to an oil under reduced pressure. The oil was partitioned between 2N hydrochloric acid (100 mL) and ether (100 mL), and the two phase mixture was filtered to remove a further quantity of dicyclohexylurea. The layers were separated; and the ether fraction was washed with 2N hydrochloric acid (100 mL), 2N aqueous sodium hydroxide solution (100 mL) and saturated brine (100 mL); dried (MgSO4); and evaporated to an oil, which solidified on standing. The solid, which comprised a mixture of the two diastereomeric butyramides was used directly in the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:12][C:13]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:14]=1[CH2:15]Cl.O>CS(C)=O>[CH3:12][C:13]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:14]=1[CH2:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)c(Cn2ccc3ccccc32)c(C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A solution of indole (1.185 g) in dry DMSO (3 ml) is dropped into a suspension of sodium hydride (60% mineral oil suspension; 0.44 g) in dry DMSO (10 ml). After two hours, the resulting solution is added with a solution of 2,4,6-trimethylbenzyl chloride (1.9 g) in dry DMSO (2 ml) heating at 60° C. for 6 h. The reaction mixture is kept at room temperature overnight, then poured into water (250 ml) extracted with ethyl acetate and dried (Na2SO4). The drying agent is filtered off, the solvent is evaporated off under reduced pressure and the resulting residue is purified by column chromatography (silica gel; eluent n-hexane/AcOEt 9/1) to obtain 2.2 g of 1-(2,4,6-trimethylbenzyl)indole.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:3].F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.CNC.[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[CH:45]=[N:46][C:47]([N:50]2[C:58]3[C:53](=[CH:54][CH:55]=[C:56]([C:59](O)=[O:60])[CH:57]=3)[C:52]([S:62]([CH3:64])=[O:63])=[CH:51]2)=[N:48][CH:49]=1>ClCCl>[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[CH:49]=[N:48][C:47]([N:50]2[C:58]3[C:53](=[CH:54][CH:55]=[C:56]([C:59]([N:2]([CH3:3])[CH3:1])=[O:60])[CH:57]=3)[C:52]([S:62]([CH3:64])=[O:63])=[CH:51]2)=[N:46][CH:45]=1
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4ccccc4F)cn3)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
HATU (158 mg, 0.41 mmol), diisopropylethylamine (0.32 ml, 0.41 mmol) and dimethylamine (2M in THF) (0.95 mL, 1.89 mmol) were added to an ice-cooled suspension of 51e) (150 mg, 0.38 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with dichloromethane (40 mL) and washed with saturated ammonium chloride solution (2×30 mL), saturated sodium hydrogen carbonate solution (2×30 mL), water (30 mL), and brine (30 mL). The organic phase was dried over sodium sulfate and evaporated. The remnant was purified by column chromatography [100-200 mesh silica; 2% methanol in dichloromethane]. White solid. Yield: 62 mg (38% of theory). LC-MS (method 5): Rt=2.99 min; m/z [M+H]+=423.2
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[CH:25][C:24]([C:27]([O:29]CC)=[O:28])=[N:23][N:22]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[N:23][N:22]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(C(=O)O)nn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
To a solution of ethyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate that was prepared in a manner analgous to that described for Intermediate Example Int-4 (2.00 g, 3.90 mmol) in MeOH (50 mL) was added an aqueous NaOH solution (10%, 10 mL). The resulting mixture was stirred at room temperature for 24 h, then was diluted with water (100 mL). The resulting mixture was adjusted to pH 4 using an aqueous HCl solution (2 N). The resulting crystals were collected, washed with water, and dried at 40° C. to give 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid (1.50 g, 79%) which was used without further purification:
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=2)[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][CH:14]=1.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[C:36]([F:42])[CH:35]=1>>[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][N:11]([CH2:12][C:13]2[CH:32]=[CH:31][C:16]([O:17][C:18]3[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=3)[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][CH:14]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[CH3:1])=[C:36]([F:42])[CH:35]=1
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: CCOC(=O)COc1cccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)c1
Product: CCOC(=O)COc1cccc(Oc2ccc(CN(Cc3ccc(Cl)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 83B and 4-chloro-2-fluorobenzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([CH:11]([NH2:16])[CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>CO>[N:1]1[C:10]2[CH:9]([CH:11]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1
Reactant: NCCCC(N)C1CCCc2cccnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NCCCC(NCc1ccccc1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of N′-(1-(2-trimethylsilyl)-ethan-lyloxymethyl)-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-1,4-butanediamine (70 mg, 0.15 mmol) in methanol (4 mL) was added benzaldehyde (0.015 mL, 0.15 mmol). The mixture was stirred overnight at room temperature, then cooled to 0° C. Sodium borohydride (38 mg, 1.0 mmol) was then added, and the reaction was stirred for one hour, gradually warming to room temperature. The solution was then concentrated. The residue was taken up in dichloromethane and washed with 1N sodium hydroxide (3 mL), then dried over anhydrous sodium sulfate, concentrated and purified by chromatography on silica gel (10:1 dichloromethane:methanol) to afford N′-(1-(2-trimethylsilyl)-ethan-lyloxymethyl)-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-N-benzyl-1,4-butanediamine (39 mg, 49%). 1H NMR (CDCl3) δ 0.10(s, 9H), 0.80 (t, 2H, J=7.0 Hz), 1.41 (m, 3H), 1.76-2.21 (m, 5H), 2.44 (m, 2H), 2.46-2.26 (m, 2H), 3.35 (t, 2H, J=7.0 Hz), 3.67 (s, 2H), 4.06 (m, 1H), 4.08 (d, 1H, J=15.8 Hz), 4.22 (d, 1H, J=15.8 Hz), 5.80 (d, 1H, J=14.6 Hz), 6.02 (d, 1H, J=14.6 Hz), 7.00 (m, 1H), 7.27 (m, 8H), 7.42 (m, 1H), 7.80 (m, 1H), 8.44 (d, 1H, J=4.8 Hz).
Reaction SMILES: OC1C(O)CCN(C(C)[CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]4[C:27]([CH:28]=3)=[C:26]([O:29][CH2:30][C:31]3[C:35]5[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:34]=5[O:33][CH:32]=3)[CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:13][CH2:12]2)C1.[CH2:42]1[CH:47]2[CH:48](CO)[CH2:49][CH2:50][CH2:51][N:46]2[CH2:45][CH2:44][O:43]1>>[CH2:42]1[C@@H:47]2[C@H:48]([CH2:10][N:11]3[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]4[NH:21][C:22]5[C:27]([CH:28]=4)=[C:26]([O:29][CH2:30][C:31]4[C:35]6[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:34]=6[O:33][CH:32]=4)[CH:25]=[CH:24][CH:23]=5)=[O:19])[CH2:13][CH2:12]3)[CH2:49][CH2:50][CH2:51][N:46]2[CH2:45][CH2:44][O:43]1
Reactant: OCC1CCCN2CCOCC12
Reactant: CC(CN1CCC(NC(=O)c2cc3c(OCc4coc5ccc(Cl)cc45)cccc3[nH]2)CC1)N1CCC(O)C(O)C1
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCOC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1

Procedure:
This compound is synthesized from the compound 176 (see example 138) and (9RS,9aSR)-1-(octahydro-pyrido[2,1-c][1,4]oxazin-9-yl)-methanol (63) analogously to the method described in example 127.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9]2[N+:10]([O-])=[CH:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][N:10]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CNc2cc([N+](=O)[O-])cc[n+]2[O-])cc1
Solvent: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2cc([N+](=O)[O-])ccn2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 108.4 %

Procedure:
To a 2 L 3 neck round bottom flask fitted with a mechanical stirrer, was added N-(4-methoxybenzyl)-4-nitropyridin-2-amine 1-oxide (38.72 g, 0.14 mol) and chloroform (580 mL). The reaction mixture was cooled to 0° C. and phosphorus trichloride (36.8 mL, 0.42 mol) was added dropwise. The reaction mixture was allowed to warm to rt and stir overnight. The reaction mixture was filtered and the resulting solid was slurried with hexanes and filtered (repeated several times) to afford N-(4-methoxybenzyl)-4-nitropyridin-2-amine (39.34 g, 102%) as a yellow solid. LCMS: (FA) ES+ 260.3.