Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[NH:10][C:9]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:8]=2[S:7](=[O:19])(=[O:18])[N:6]=1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:15][C:13]1[CH:12]=[CH:11][C:9]2[NH:10][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][S:7](=[O:18])(=[O:19])[C:8]=2[CH:14]=1
Reactant: [H][H]
Reactant: CC(C)NC1=NS(=O)(=O)c2cc([N+](=O)[O-])ccc2N1
Agent: [Pd]
Solvent: CO
Product: CC(C)NC1=NS(=O)(=O)c2cc(N)ccc2N1

Procedure:
A solution of 3-isopropylamino-7-nitro-4H-1,2,4-benzothiadiazine 1,1-dioxide (0.6 g) in hot methanol (25 mL) was supplemented with 10% Pd/C (0.06 g) and submitted to hydrogen under pressure (4 bars) for 1 h at 40° C. The insoluble material was removed by filtration and the filtrate was concentrated to dryness by evaporation under reduced pressure. The residue of the crude title compound was recrystallized from methanol-water (yield: 0.45 g); m.p.: 278-283° C.; IR (KBr): 3455, 3363, 3216, 2972, 1618, 1575, 1510, 1298, 1255, 1174, 1146, 1113 cm−1; 1H-NMR (DMSO-d6, HMDS; d ppm): 1.10 (d, 6H, 2×CH3), 3.85 (m, 1H, NH—CH), 5.15 (bs, 2H, NH2), 6.50-6.95 (bm, 4H, 5-H+6-H+8-H+NH—CH), 9.75 (bs, 1H, NH).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]#[C:4][C:5]([F:8])([F:7])[F:6].[CH3:11][NH:12][N:13]=[C:14](Br)[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2[C:3]([C:2]([F:10])([F:9])[F:1])=[C:4]([C:5]([F:8])([F:7])[F:6])[N:12]([CH3:11])[N:13]=2)=[CH:20][CH:19]=1
Reactant: CNN=C(Br)c1ccc(Cl)cc1
Reactant: FC(F)(F)C#CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1nc(-c2ccc(Cl)cc2)c(C(F)(F)F)c1C(F)(F)F
Temperature: 20 °C
Reaction time: 16 h

Procedure:
5.7 g (41 nmol) of gaseous hexafluoro-2-butyne were passed at below (-50)° C. into a suspension, cooled to (-70)° C., of 9 g (36 mmol) of α-bromo-4-chlorobenzaldehyde methylhydrazone in 100 ml of toluene. The mixture was subsequently heated to (-25)° C., and 8.4 g (83 mmol) of triethylamine were added dropwise at this temperature. After the mixture had been stirred for 2 hours at this temperature and for a further 16 hours at approx. 20° C., it as washed with water, dried over magnesium sulfate and finally concentrated.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:15]2[N:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:17]=[C:18]3[C:23]=2[CH:22]=[CH:21][CH:20]=[CH:19]3)=[O:13])=[CH:7][CH:6]=1)C.[OH-].[Li+]>C1COCC1.CO>[CH:30]1([N:14]([C:15]2[N:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:17]=[C:18]3[C:23]=2[CH:22]=[CH:21][CH:20]=[CH:19]3)[C:12](=[O:13])[NH:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:36])=[O:3])=[CH:10][CH:9]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCOC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-[3-cyclohexyl-3-(2-phenyl-2H-indazol-3-yl)-ureido]-benzoic acid ethyl ester (10 mg, 21 μmol in THF/MeOH 2/1 (150 μl) was a added a 1 N aqueous lithium hydroxide solution (120 μl, 120 μmmol) at ambient temperature under an argon atmosphere. The reaction mixture was stirred for 12 h at ambient temperature, poured onto ice water/1 N aqueous HCl solution 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give the title compound (10 mg, 22 umol; quant.) as yellow solid. MS: m/e=455.4 [M+H+].
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[N:21]1[NH:22][C:23](=[O:27])[CH:24]=[CH:25][CH:26]=1.O>CN(C=O)C>[O:27]=[C:23]1[N:22]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[N:21]=[CH:26][CH:25]=[CH:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: O=c1cccn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2ncccc2=O)CC1
Temperature: 45 °C
Yield: 17 %

Procedure:
tert-Butyl 4-bromo-1-piperidinecarboxylate (1.00 g, 3.78 mmol) in DMF (20 mL) was treated with K2CO3 (523 mg, 3.78 mmol) and 3(2H)-pyridazinone (340 mg, 3.78 mmol) and then heated at 45° C. for 60 hours. The reaction mixture was allowed to cool to room temperature, poured into water (80 mL) and extracted with ethyl acetate (80 mL). The organic layer was washed with brine (3×50 mL), dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution with hexanes:ethyl acetate, 3:1) to provide the title compound (180 mg, 17% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.41 (s, 9H), 1.66 (m, 4H), 2.91 (m, 2H), 4.05 (m, 2H), 4.96 (m, 1H), 6.93 (dd, 1H, J=1.5, 9.0 Hz), 7.39 (dd, 1H, J=3.0, 9.0 Hz), 7.95 (dd, 1H, J=3.0, 9.0 Hz); (MS (DCI/NH3) m/e 280 (M+H)+.
Reaction SMILES: [CH:1]([CH2:14][C:15](O)=[S:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>C1C=CC=CC=1>[CH:1]([CH2:14][C:15]([Cl:20])=[S:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OC(=S)CC(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: S=C(Cl)CC(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
19.5 g (0.076 mol) of benzhydrylthioacetic acid in 114 ml of benzene are placed in a three-necked flask provided with a condenser and a dropping funnel. The mixture is heated and 19 ml of thionyl chloride are added drop by drop. Once the addition is complete, the reflux is continued for about 1 hour, cooling and filtering are carried out and the benzene and the excess thionyl chloride and then evaporated. In this way, a clear orange oil is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@@H:27]1[CH2:31][CH2:30][C@@H:29]([NH2:32])[CH2:28]1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:32][C@@H:29]2[CH2:30][CH2:31][C@@H:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: N[C@@H]1CC[C@@H](c2ccccn2)C1
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H]1COc2c(N[C@@H]3CC[C@@H](c4ccccn4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 100 °C
Reaction time: 7 h
Yield: 15.3 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (1.40 g, 5.05 mmol), (1R,3R)-3-(2-pyridyl)cyclopentylamine (985 mg, 6.07 mmol) and triethylamine (1.40 mL, 10.0 mmol) in anhydrous DMSO (8 mL) was stirred at 100° C. for 7 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (EtOAc) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[(1R,3R)-3-(2-pyridyl)cyclopentylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (325 mg, 15%) as a yellow powder.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:28]=3[Cl:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(Cl)cc1Cl

Procedure:
The title compound, light yellow solid (88 mg, 70%), MS (ISP) m/z=499.3 [(M+H)+], mp 187° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2,4-dichloro-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:27](=[O:28])[C:11]3=[CH:12][NH:13][C:14]([CH3:26])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH2:24]O)=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Cl-].[Li+].CS([Cl:43])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:27](=[O:28])[C:11]3=[CH:12][NH:13][C:14]([CH3:26])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH2:24][Cl:43])=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1ccc(C#CCO)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1ccc(C#CCCl)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 75.6 %

Procedure:
To a solution of the product of Example 68 (0.6 g, 1.5 mmol), 2,6-lutidine (0.72 ml, 6.2 mmol) and lithium chloride (0.262 g, 6.2 mmol) in N,N-dimethylformamide (6 ml) at 0° C. was added methanesulphonyl chloride (0.36 ml, 4.6 mmol) dropwise and the solution allowed to warm to ambient temperature with stirring for 7 hours. The solvent was removed in vacuo and the crude product purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) to give the product as a yellow solid (0.463 g, 74%). 1H NMR (360 MHz, DMSO-d6) δ12.49 (1H, br s), 8.59 (1H, s), 8.13 (2H, d, J 9.0 Hz), 7.59 (4H, m), 7.41 (2H, d, J 9.0 Hz), 4.75 (2H, s), 2.26 (3H, s); MS (ES+) m/z 408/410/412 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:17][O:16][C:15](=[O:18])[C@H:14]([CH2:19]C(O)=O)[C@@H:13]([O:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[C@H:12]([CH3:29])[O:11][C:10]1=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[SH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N+:48]=1[O-].[Al]>C1COCC1>[C:24]([O:23][C@@H:13]1[C@@H:14]([CH2:19][S:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[C:15](=[O:18])[O:16][CH2:17][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:10](=[O:30])[O:11][C@H:12]1[CH3:29])(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CC(=O)O
Reactant: [O-][n+]1ccccc1S
Agent: CC(C)COC(=O)Cl
Agent: [Al]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CSc1ccccn1
Reaction time: 0.08 h
Yield: 28.4 %

Procedure:
To a solution of 2-((3S,7R,8R,9S)-3-(tert-butoxycarbonylamino)-8-(isobutyryloxy)-9-methyl-2,6-dioxo-1,5-dioxonan-7-yl)acetic acid (500 mg, 1.2 mmol) in anhydrous THF (7 mL) at −15° C. was added N-methylmorpholine (127 μL, 1.2 mmol) and isobutylchloroformate (152 μL, 1.2 mmol). The mixture was stirred for 5 min and then treated with a solution of 2-mercaptopyridine N-oxide (177 mg, 1.4 mmol) and TEA (162 μL, 1.2 mmol) in THF (2 mL). The reaction was stirred at −15° C. in the dark (covered with aluminum foil) for 1 h. The reaction was then filtered, concentrated, and the resulting bright yellow residue dissolved in CH2Cl2 (5 mL) and irradiated for 1 hr. The crude reaction mixture was concentrated and purified by flash chromatography (SiO2, 10% EtOAc/hexanes) to furnish the title compound (169 mg, 29%) as a fluffy white solid: mp 54-58° C.; IR (neat) 3370, 2980, 2939, 2878, 1753, 1718 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=4.9 Hz, 1H), 7.48-7.41 (m, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.00-6.94 (m, 1H), 5.32 (bs, J=12.9 Hz, 1H), 5.21-5.07 (m, 2H), 4.87 (dt, J=16.1, 6.4 Hz, 2H), 3.66-3.60 (m, 1H), 3.59 (bs, 1H), 3.15-3.00 (m, 2H), 2.68 (dq, J=14.2, 7.1 Hz, 1H), 1.43 (s, 9H), 1.33-1.25 (m, 9H); 13C NMR (101 MHz, CDCl3) δ 176.11, 171.91, 171.33, 157.67, 155.07, 149.73, 136.35, 122.89, 120.10, 81.00, 75.34, 74.76, 66.22, 51.66, 51.26, 34.68, 28.74, 28.64 (3), 19.38, 19.23, 18.14; ESIMS m/z 519 ([M+Na]+).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:28])[C:5]1[CH:10]=[C:9]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([C:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=4)=[N:16][NH:17]3)=[CH:13][CH:12]=2)[C:8]([CH3:26])=[C:7]([F:27])[CH:6]=1)[CH3:2].C([O-])=O.[NH4+]>[Pd].C(O)C>[CH2:1]([NH:3][C:4](=[O:28])[C:5]1[CH:10]=[C:9]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)=[N:16][NH:17]3)=[CH:13][CH:12]=2)[C:8]([CH3:26])=[C:7]([F:27])[CH:6]=1)[CH3:2]
Reactant: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(C4=CCNCC4)n[nH]c3c2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(C4CCNCC4)n[nH]c3c2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
A mixture of N-ethyl-3-fluoro-4-methyl-5-[3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indazol-6-yl]benzamide (Intermediate 21, 100 mg), 10% palladium on carbon (20 mg) and ammonium formate (50 mg) in ethanol (10 mL) was stirred at 90° C. for 1 h under nitrogen. The catalyst was removed by filtration and the filtrate was concentrated under vacuum. The product was dissolved in methanol and eluted through an SCX ion exchange cartridge. Elution with a solution of ammonia (0.88) in methanol gave the title compound as a white solid (89 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.I[C:17]1[CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:21][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(I)c1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
To a vial containing ethyl 5-chloroindole-2-carboxylate (1.50 g, 6.70 mmol), were added 3-iodobenzotrifluoride (1.16 mL, 8.10 mmol), potassium phosphate (2.98 g, 14.1 mmol), copper iodide (64.0 mg, 0.34 mmol), and 1,2-trans-N,N′-dimethylcyclohexane diamine (0.211 mL, 1.33 mmol), and the mixture was purged with N2. Anhydrous toluene (degassed via N2-sparge, 6.7 mL) was added, and the reaction vial was capped and placed in a pre-heated (110° C.) oil bath. The mixture was stirred vigorously for 18 h, then was allowed to cool to room temperature. The reaction mixture was filtered, rinsing with ethyl acetate, and the filtrate was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30%, then 30 to 100% hexanes in ethyl acetate) afforded the title compound: LCMS C, tr=2.86 min, m/z 368.1 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J=8.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.60 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.25 (dd, J=9.0, 2.0 Hz, 1H), 6.97 (d, J=9.0 Hz, 1H), 4.22 (q, J=7.0 Hz, 2H), 1.22 (t, J=7.0 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:4]=2[CH:3]=1.O.[NH2:24][NH2:25]>O1CCOCC1>[NH:24]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:4]=2[CH:3]=1)[NH2:25]
Reactant: NN
Reactant: O=C(CCCc1ccccc1)N1CCc2nnc(Cl)cc2C1
Solvent: O
Solvent: C1COCCO1
Product: NNc1cc2c(nn1)CCN(C(=O)CCCc1ccccc1)C2

Procedure:
11.8 g of 3-chloro-5,6,7,8-tetrahydro-6-(4-phenylbutyryl)pyrido[4,3-c]pyridazine and 60 cc of hydrazine hydrate are stirred at a bath temperature of 50° for 53 hours with the addition of 50 cc of dioxane. The mixture is worked up as described in Example 10. The qentisinate of the title compound has a M.P. of 203°-205° (decomp., from methanol/water 2:1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[C:21]([B-](F)(F)F)([CH3:23])=[CH2:22].[K+]>C(O)CC>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:21]([CH3:23])=[CH2:22])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: C=C(C)[B-](F)(F)F
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: [K+]
Solvent: CCCO
Product: C=C(C)c1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 120 °C
Yield: 38.3 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.41 g, 1.153 mmol) was combined with potassium isopropenyltrifluoroborate (0.189 g, 1.268 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (0.034 g, 0.046 mmol) and TEA (0.241 mL, 1.730 mmol) in n-propanol (10 mL) and heated in a microwave reactor at 120° C. for 90 min. Additional potassium isopropenyltrifluoroborate (0.086 g, 0.577 mmol) was added to the reaction mixture which was heated in a microwave reactor at 120° C. for an additional 30 min. The reaction mixture was filtered through celite and concentrated to dryness. The residue was dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified on 40 g silica gel eluted with 0 to 10% CH3OH/DCM to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(1-methylethenyl)benzonitrile (0.140 g, 0.442 mmol, 38.3% yield) as a brown oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.74 (s, 1H), 7.46-7.54 (m, 2 H), 7.43 (s, 1H), 7.21 (s, 1H), 5.57 (s, 1H), 5.25 (s, 1H), 3.77 (s, 2H), 2.10 (s, 3H), 1.99 (br. s., 2H). LC-MS (ES+) m/z 317.19, 319.17 [M+H].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:10]=[C:11]([CH:15]([OH:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7].C(N(CC)CC)C>ClCCl>[S:2]([O:17][CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=1)[CH3:16])(=[O:4])(=[O:3])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)c1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Yield: 71 %

Procedure:
A solution of 4.63 ml (59.8 mmol) of methane sulphonyl chloride diluted with 20 ml of dichloromethane is added dropwise to a solution of 10 g (59.8 mmol) of 3-nitrophenylethanol and 8.31 ml (59.8 mmol) of triethylamine in 120 ml of dichloromethane, cooled down with an ice bath. Agitation is maintained for 1 hour at 0° C. and for 2 hours at 20° C. The reaction mixture is then concentrated under vacuum and the residue is taken up in 125 ml of ethyl acetate and 100 ml of water. After agitation and decantation, the organic phase is washed successively with 100 ml of water and 100 ml of salt water. The organic solution is dried over magnesium sulphate, filtered and concentrated under vacuum. The evaporation residue is purified on a silica column (eluent heptane/ethyl acetate 6/4) and the pure fractions are collected and evaporated in order to produce a yellow oil with a yield of 71%.
Reaction SMILES: [CH:1](=[N:10][NH2:11])[C@H:2]([C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3].[H][H]>C(O)C.O.[Pt]=O>[NH:10]([CH2:1][C@H:2]([C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3])[NH2:11]
Reactant: NN=C[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: O
Product: NNC[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A 1.5 portion of D-arabinose hydrazone in 40 ml of ethanol and 20 ml of water was reduced with 200 mg of platinum oxide and hydrogen for 4 hours. The mixture was then filtered and the filtrate evaporated to dryness. The residue was dissolved in 40 ml of methanol and then evaporated to dryness, giving 1.24 g of 1-deoxy-1-hydrazino-D-arabinitol.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1.I[CH3:31]>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]([N:18]([CH3:31])[C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2N(Cc2ccc(Cl)c(Cl)c2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1Cc2ccccc2N(Cc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (0.1 g, 4.16 mmol) was added to a 0° C. solution of tert-butyl 1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (0.85 g, 2.09 mmol) and iodomethane (95%, 2.97, 10 eq) in anhydrous tetrahydrofuran (10 mL). The mixture was stirred at room temperature for 1 hour. The mixture was quenched by slowly adding few drops of water. The resulting mixture was dried over anhydrous sodium sulfate and the solvent evaporated. The residue was purified by flash chromatography (eluted with 5% EtOAc in hexane) to give tert-butyl 1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydroquinolin-3-yl(methyl)carbamate as white solid (789 mg). 1H NMR (DMSO) 400 MHz δ 7.57 (d, J=4 Hz, 1H), 7.61 (brd, J=6.4 Hz, 1H), 7.47 (d, J=1.6, 1H), 7.23 (dd, J=2.0 Hz and 8.4 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.91 (m, 1H), 6.53 (m, 1H), 6.45 (d, 8.4 Hz, 1H), 4.45 (brd, J=10.4 Hz, 1H), 4.29 (br, 1H), 3.40 (t, 10.4 Hz, 1H), 3.21 (m, 1H), 3.02 (m, 1H), 2.74 (m, 1H), 2.72 (s, 3H), 1.36 (m, 9H). LCMS m/e 422 (M+H).
Reaction SMILES: Cl.[CH2:2]1[C@H:6]2[CH2:7][CH:8]([CH2:10][OH:11])[CH2:9][C@H:5]2[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].F[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30].O>CN(C=O)C>[F:26][C:25]([F:27])([F:28])[C:22]1[CH:21]=[C:20]([C:29]([F:30])([F:31])[F:32])[CH:19]=[CH:24][C:23]=1[N:3]1[CH2:4][C@@H:5]2[CH2:9][CH:8]([CH:10]=[O:11])[CH2:7][C@@H:6]2[CH2:2]1
Reactant: Fc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: OCC1C[C@H]2CNC[C@H]2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=CC1C[C@@H]2CN(c3ccc(C(F)(F)F)cc3C(F)(F)F)C[C@@H]2C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 12.6 %

Procedure:
To a solution of (3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-ylmethanol hydrochloride (862 mg) and potassium carbonate (1.68 g) in DMF (10 mL) was added 1-fluoro-2,4-bis(trifluoromethyl)benzene (1.24 g). The reaction mixture was stirred at 80° C. for 3 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane). To a solution of the obtained oil (1.71 g) and triethylamine (2.03 mL) in DMSO (10 mL) and ethyl acetate (10 mL) was added sulfur trioxide pyridine complex (2.32 g) under cooling to 0° C. The reaction mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (215 mg).