Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:5]([CH3:34])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([Cl:32])[CH:23]=3)[CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=2)[N:8]=1)(=O)[CH3:2].[CH3:35][O:36][NH3+:37].[Cl-]>N1C=CC=CC=1>[Cl:32][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[O:28][CH:29]([CH3:30])[CH3:31])[C:21]([NH:20][C@H:16]([CH2:17][CH2:18][OH:19])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[N:8]=[C:4]([C:1](=[N:37][O:36][CH3:35])[CH3:2])[N:5]([CH3:34])[CH:6]=2)=[CH:10][CH:11]=1)=[O:33]
Reactant: CC(=O)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Reactant: CO[NH3+]
Agent: [Cl-]
Solvent: c1ccncc1
Product: CON=C(C)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
80 mg (0.031 mmol) of (S)-N-(1-(4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-3-chloro-4-isopropoxybenzamide in 2 mL of pyridine was treated with 27.6 mg (0.033 mmol) of hydroxylamine methyl ether hydrochloride. The reaction was stirred overnight after which the solvents were evaporated and the residue purified via reverse phase HPLC (acetonitrile/water). 11.2 mg (70% yield) of 2 was obtained and characterized by LCMS and HNMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: COc1cc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc2ccccc2cc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Phenyl N-(2-methoxynaphth-3-yl)carbamate (375 mg, 1.28 mmol) and 1-(3,5-dimethylphenyl)piperazine (208 mg, 1.28 mmol) were dissolved in anhydrous tetrahydrofuran (25 ml) and thereto DBU (195 mg, 1.28 mmol) was added, and then stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].Br[C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][N:31]=1)[C:9]([NH:11][C:12]1[S:13][C:14]2[C:20]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][CH:18]=[C:17]([O:27][CH3:28])[C:15]=2[N:16]=1)=[O:10]>O1CCOCC1>[CH3:1][O:2][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][N:31]=1)[C:9]([NH:11][C:12]1[S:13][C:14]2[C:20]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][CH:18]=[C:17]([O:27][CH3:28])[C:15]=2[N:16]=1)=[O:10]
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3s2)ccn1
Temperature: 50 °C
Yield: 68.3 %

Procedure:
To a stirred solution of 0.09 ml (2.23 mmol) methanol in 5 ml dioxane at room temperature was added 49 mg (1.12 mmol) sodium hydride (55% dispersion in mineral oil) and the mixture heated at 50° C. for 1 hour. 100 mg (0.22 mmol) 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide was then added and the mixture heated at 50° C. for 16 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with dichloromethane, and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate) followed by trituration in ether and hexane afforded 60 mg (67%) 2-methoxy-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide as a white crystalline solid. ES-MS m/e (%): 398 ([M−H]−, 100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Br[CH2:24][CH:25]1[O:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[O:27]1[CH2:26][CH:25]1[CH2:24][O:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: BrCC1CO1
Reactant: Cc1cccc(Nc2cc(Nc3cccc(O)c3)ncn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc(Nc2cc(Nc3cccc(OCC4CO4)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A mixture of 4-[3'-hydroxyanilino]6-(3'-methylanilino)pyrimidine (1 g), 1-bromo-2,3-epoxypropane (0.44 ml) and potassium carbonate (0.95 g) in DMSO (12 ml) was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with water, dried (MgSO4) and evaporated to give 4-[3'-(2,3-epoxypropoxy)anilino]6-(3'-methylanilino)pyrimidine in 38% yield, m.p. 143°-145° C.;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[OH-].[NH4+:14]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([NH2:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1ccc(Br)cc1S(N)(=O)=O
Yield: 55 %

Procedure:
Prepared by general procedure III from 5-Bromo-2-methyl-benzenesulfonyl chloride (1.89 g, 7 mmol) and ammonium hydroxide (20 mL) to give the title compound (0.96 g, 55%) as a white solid. MS (ISN) 248.0 [(M−H)−], 250.0 [(M+2−H)−].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=2)=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Nc1cc(C2=C(c3ccc(F)cc3)CCCC2)ccn1
Agent: [Pd]
Solvent: CO
Product: Nc1cc([C@@H]2CCCC[C@@H]2c2ccc(F)cc2)ccn1
Reaction time: 48 h
Yield: 54.1 %

Procedure:
A solution of 4-[2-(4-Fluoro-phenyl)-cyclohex-1-enyl]-pyridin-2-ylamine (220 mg, 0.82 mmol, synthesis described in example 56) in methanol (10 mL) is passed through H-Cube® Continuous-flow Hydrogenation Reactor at 60° C. and under 60 psi hydrogen pressure. The 10% Pd/C cartridge is used and the reaction is run for 48 hours. The solvent is removed to give 120 mg of the desired product.
Reaction SMILES: [CH3:1][C@H:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[NH:3]1.C([Li])CCC.[C:15](Cl)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[CH3:17][C:16]([CH3:19])([CH3:18])[C:15]([N:3]1[C@@H:2]([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5][C:4]1=[O:9])=[O:20]
Reactant: C[C@@H]1NC(=O)OC1(C)C
Reactant: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@H]1N(C(=O)C(C)(C)C)C(=O)OC1(C)C
Yield: 92.4 %

Procedure:
Reaction of the auxiliary (5) (0.180 g, 1.40 mmol) in solution in tetrahydrofuran (3 ml) at -78° C. with butyllithium (1.4M, 1 ml, 1.41 mmol) and pivaloyl chloride (0.190 ml, 1.55 mmol) for 30 minutes and then at room temperature for 1 hour with work-up and recrystallisation at ca -10° C. from 60-80 petroleum ether furnished the title compound (16) as a solid (0.276 g, 93%); νmax (CH2Cl2) 1683 and 1775 cm-1 ; [α]D24 (c 1 in CHCl3)=+51.3; (Found: C, 62.25; H, 9.09; N, 6.45. C11H19NO3 requires C, 61.95; H, 8.98; N, 6.57%); δH (CDCl3 ; 300 MHz) 1.20 (3H, d, J=6.5, CH3CH), 1.31 (9H, s, C(CH3)3), 1.33 (3H, s, C(CH3)2), 1.37 (3H, s, C(CH3)2), 4.11 (1H, q, J=6.5, CHCH3) ; δC (125 MHz; CDCl3) 14.33 (CH3), 21.41 (CH3), 26.31 (CH3), 27.22 (CH3), 41.60 (CH3), 60.92 (CH), 81.01 (C), 151.75 (CO), 179.08 (CO); m/z (CI+, NH3) 214 (M+ +1).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[Cl:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:9][C:10]1[CH:15]=[C:14]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCN(c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 72.6 %

Procedure:
N-Ethylpiperazine (4.3 mL, 34.3 mmol, 1.2 equiv) is added to a mixture of 2-chloro-4-fluoronitrobenzene (5 g, 28.6 mmol) and potassium carbonate (7.9 g, 57.1 mmol, 2 equiv) in DMF (50 mL). The reaction mixture is stirred at 100° C. for 6 h, allowed to cool to RT, diluted with H2O and extracted with EtOAc. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by trituration in diethyl ether to provide 5.6 g of the title compound as a yellow solid: ES-MS: 270.0 [MH]+; tR=2.90 min (system 1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][CH2:6][CH2:7][NH:8][CH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)[CH3:2].[C:21]([BH3-])#N.[Na+].C=O.C(O)(=O)C>CO>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH2:7][N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=1)[CH3:21])[CH3:20]
Reactant: CCOC(CCCNCc1ccc(C#N)cc1)OCC
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(CCCN(C)Cc1ccc(C#N)cc1)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
The compound (1.16 g) obtained in Example 44-1 was dissolved in methanol (34.8 ml) and added with sodium cyanoborohydride (1.21 g) and a 36% formaldehyde aqueous solution (0.648 ml). The solution was adjusted to pH 4 with acetic acid and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (1.22 g) as a yellow oily substance.
Reaction SMILES: [C:1]([CH:5]([CH:8]=O)[CH:6]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:10][NH:11][C:12](=[O:17])[CH2:13][N+:14]([O-:16])=[O:15].N1CCCC1>C(O)C>[C:1]([C:5]1[CH:6]=[C:13]([N+:14]([O-:16])=[O:15])[C:12](=[O:17])[N:11]([CH3:10])[CH:8]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)C[N+](=O)[O-]
Reactant: CC(C)(C)C(C=O)C=O
Solvent: CCO
Solvent: C1CCNC1
Product: Cn1cc(C(C)(C)C)cc([N+](=O)[O-])c1=O
Yield: 29.5 %

Procedure:
To a solution of 2-tert-butyl-malonaldehyde (385 mg, 3.00 mmol) and the above amide (355 mg, 3.00 mmol) dissolved in ethanol (6.0 mL) was added pyrrolidine (63 microL, 0.750 mmol). The mixture was heated at reflux for 18 h and concentrated in vacuo. Purification by silica-gel chromatography (75% ethyl acetate in hexanes) provided 5-tert-butyl-1-methyl-3-nitro-1H-pyridin-2-one (186 mg, 30%) as an orange solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH2:38]>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27]([NH:38][CH2:37][CH2:36][CH2:35][N:34]([CH3:39])[CH3:33])=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Reactant: CN(C)CCCN
Product: CN(C)CCCNc1ncccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1

Procedure:
Using the conditions of Example 334 and N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-chloropyridine-3-carboxamide and 3-(dimethylamino)propylamine gives 900 mg of the desired product:M+ =508.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)=[C:8]([C:10](OC)=[O:11])[N:9]=1)(=[O:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:10]([C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:14]1[CH:15]=[CH:16][C:17]([S:20][CH3:21])=[CH:18][CH:19]=1)=[O:11]
Reactant: COC(=O)c1nc(NC(C)=O)sc1-c1ccc(SC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc(-c2sc(NC(C)=O)nc2C=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
Methyl 2-(acetylamino)-5-[4-(methylthio)phenyl]-1,3-thiazole-4-carboxylate (200 mg) was dissolved in tetrahydrofuran (2 ml), and then lithium aluminium hydride (35.3 mg) was added portionwise to the solution at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature for 30 minutes, and quenched with methanol. Ethyl acetate and 1N hydrochloric acid were added to the mixture, and extracted. The aqueous layer was extracted with ethyl acetate (twice). The combined organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual solid was dissolved in methanol (0.4 ml) and chloroform (7 ml). Then manganase (IV) oxide (1.08 g) was added to the solution under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 13 hours, and filtered through a celite pad. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with chloroform/methanol (20:1) as an eluent to give N-{4-formyl-5-[4-(methylthio)phenyl]-1,3-thiazol-2-yl}acetamide (153.6 mg) as a pale brown amorphous substance.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CCN(CC)CC.[F:27][C:28]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C(Cl)Cl>[F:27][C:28]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[CH:33][C:29]=1[C:30]([NH:2][C@H:3]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])=[O:31]
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(F)c(F)c(F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To an ice-cold solution of di-tert-butyl L-glutamate hydrochloride (6.6 g, 22.4 mmol) and Et3N (6.9 ml, 50 mmol) in dry CH2Cl2 (70 ml) was added, over a period of 1.5 hr, 2,3,4,5-tetrafluorobenzoyl chloride (5.0 g, 23.5 mmol) in dry CH2Cl2 (20 ml) and thirty minutes later the solution was allowed to warm to room temperature. Sixteen hours later the solution was washed with H2O, dried (MgSO4) and evaporated to dryness. 1H NMR δ 1.40+1.42 (2s, 18H, t-butyl), 1.85+1.95 (2m, 2H, CH2CH), 2.34 (t, 2H, CH2CO, J=7.5 Hz), 4.3 (m, 1H, CH), 7.57 (m, 1H, H6), 8.80 (d, 1H, NH, J=7.5 Hz); 19F NMR δ −138.6+139.0 (2m, 2F, F2+5), −152.4 (m, 1H, F4), −154.9 (t, 1F, F3, J=20 Hz).
Reaction SMILES: [ClH:1].[C:2]1([S:8]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]4[CH2:20][CH2:21][NH:22][CH2:23][C:13]([C:14]=34)=[CH:12]2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:25].[Na+].C(O)(=O)C.C(=O)C.Cl>C1COCC1>[ClH:1].[CH2:24]([N:22]1[CH2:21][CH2:20][C:15]2[C:14]3[C:13](=[CH:12][N:11]([S:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)(=[O:10])=[O:9])[C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:23]1)[CH3:25]
Reactant: O=S(=O)(c1ccccc1)n1cc2c3c(cccc31)CCNC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN1CCc2cccc3c2c(cn3S(=O)(=O)c2ccccc2)C1
Temperature: 70 °C

Procedure:
1-(Phenylsulfonyl)-3,4,5,6-tetrahydro-1H-azepino[3,4,5-cd]indole hydrochloride, Example 12 (70 mg, 0.2 mmol) was dissolved in THF (4 mL) before sodium triacetoxyborohydride (142 mg, 0.7 mmol) and acetic acid (134 mg, 2.2 mmol) was added. acetaldehyde (14.7 mg, 0.3 mmol) was added and the reaction mixture was heated in MW at 70° C. for 600 s. The reaction mixture was evaporated and the crude product was purified by preparative HPLC (33-63), using Xterra column. The product was isolated and transformed to the hydrochloride. 12.9 mg of the pure product was isolated as a clear oil. MS m/z 341 [M+H]+.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([OH:45])=[C:39]([S:41]([OH:44])(=[O:43])=[O:42])[CH:40]=1>C(Cl)Cl.C1COCC1>[OH:45][C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:5](=[O:7])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])=[CH:40][C:39]=1[S:41]([OH:44])(=[O:42])=[O:43]
Reactant: Nc1ccc(O)c(S(=O)(=O)O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: N[C@@H](CCC(=O)Nc1ccc(O)c(S(=O)(=O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boc-Glu-OtBu (100 mg, 0.33 mmol) was dissolved in methylene chloride (1 mL) and THF (1 mL). CDI (65 mg, 1.1 mmol) was added thereto and stirred at room temperature for 30 minutes. Then, 5-amino-2-hydroxybenzene sulfonic acid salt (77 mg, 0.33 mmol) was added thereto and stirred overnight at room temperature. After removing a solvent, purification was conducted in accordance with the purification process A. The obtained intermediate was dissolved in 2 mL of TFA and stirred at room temperature for 3 hours, and a solvent was removed therefrom. The obtained product was purified in accordance with the purification process A to obtain a title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:23][C:24](=[O:47])[CH:25]([CH2:44][CH2:45]O)[N:26]([CH3:43])[S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:21]=[CH2:22].C(Br)(Br)(Br)[Br:49].O>O1CCCC1>[CH2:20]([O:23][C:24](=[O:47])[CH:25]([CH2:44][CH2:45][Br:49])[N:26]([CH3:43])[S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:21]=[CH2:22]
Reactant: C=CCOC(=O)C(CCO)N(C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)C(CCBr)N(C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Yield: 86.1 %

Procedure:
After triphenylphosphine (4.72 g, 18.0 mmol) was added to a solution of (±)-2-(2-hydroxyethyl)-N-methyl-N-(4-phenoxybenzenesulfonyl)glycine allyl ester (6.08 g, 15.0 mmol), the product of Example 41(2), in tetrahydrofuran (45 ml), a solution of carbon tetrabromide (5.97 g, 18.0 mmol) in tetrahydrofuran (20 ml) was added over 20 minutes to the solution with ice-cooling and with stirring. The mixture was stirred at room temperature for 1 hour. To the reaction mixture, water was added and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=5/1 as the eluant to afford the desired compound (6.05 g, yield 86%) as a colorless oil.
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.[CH2:20]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)[CH:21]=[CH2:22]>>[CH2:20]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:30][CH:31]=1)[CH:21]=[CH2:22]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: C=CCOc1ccc(C=O)cc1
Product: C=CCOc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-prop-2-enoxybenzaldehyde 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-[(4-prop-2-enoxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]([F:29])([C:25]([F:28])([F:27])[F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:30]1([C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]([F:29])([C:25]([F:28])([F:27])[F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:33]2[CH2:34][CH2:35][N:30]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)[CH2:31][CH2:32]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(NCC(F)(F)C(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)C(F)(F)F)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,3,3,3-pentafluoro-propyl)-amide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([NH:13][C:14]3[N:19]4[C:20]([CH3:26])=[C:21]([C:23](O)=[O:24])[CH:22]=[C:18]4[CH:17]=[N:16][N:15]=3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:49]([NH2:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C.CCN(CC)CC>[CH2:49]([NH:56][C:23]([C:21]1[CH:22]=[C:18]2[CH:17]=[N:16][N:15]=[C:14]([NH:13][C:11]3[CH:12]=[C:7]([C:5](=[O:6])[NH:4][CH:1]4[CH2:3][CH2:2]4)[CH:8]=[CH:9][C:10]=3[CH3:27])[N:19]2[C:20]=1[CH3:26])=[O:24])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1Nc1nncc2cc(C(=O)O)c(C)n12
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1Nc1nncc2cc(C(=O)NCc3ccccc3)c(C)n12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-6-methyl-pyrrolo[1,2-d][1,2,4]triazine-7-carboxylic acid (37, 0.13 mmol) in DMF (1 mL) was added EDCI (37 mg, 0.20 mmol), HOBt (30 mg, 0.20 mmol), Et3N (45 μL) and benzylamine (29 μl, 0.27 mmol). The reaction mixture was stirred for 3 h at rt. The crude material was purified by preparative HPLC to give the titled product, 3.3 mg as an off white solid. HPLC (condition A) tR 4.40 min. MS m/z 455 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[CH2:13]=[O:14]>C(O)(C)(C)C.CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][CH2:13][OH:14]
Reactant: Cc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Reactant: C=O
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
A solution of potassium tertiary-butylate (90 mg, 0.8 mmol) in tert.-butanol (1 ml, synthesis quality, 99%) was added to a mixture of 2,4-dichloro-6-nitrotoluene (1.03 g, 5 mmol) and paraformaldehyde (150 mg, 5 mmol) in DMSO (2.5 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å). After the addition of the potassium tertiary-butylate solution, a color change from yellow to deep violet occurred. It was stirred for 5 min at room temperature and for 30 min at 70° to 80° C. (oil bath temperature). The mixture was then allowed to cool to room temperature and neutralized with a few drops of conc. HCl. The mixture was diluted with EtOAc (30 ml) and washed with H2O (30 ml). The aqueous phase was post-extracted with EtOAc (2×30 ml). Drying the organic phases over Na2SO4, filtering and evaporating the solvent under reduced pressure yielded the crude product which was purified by column chromatography (20 g SiO2, 12×2 cm, solvent: PE 30 ml, PE/EtOAc 10:1 110 ml, 9:1 100 ml, 8:1 360 ml, 7:1 80 ml). 2-(2,4-dichloro-6-nitrophenyl)ethanol (769 mg, 65%) was obtained as a yellow solid.