Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@@:8]([NH2:34])([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10])(OC(C)(C)C)=O.[ClH:35].O1CCOCC1>O1CCOCC1>[ClH:33].[ClH:35].[NH2:34][C@H:8]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)[C@@](N)(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3[nH]ccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a solution of (2R)-2-Boc-amino-3-(4-chlorophenyl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one in 1 mL dioxane was added 1 mL 4M HCl/dioxane. The resulting suspension was stirred at room temperature overnight, after which it was concentrated to dryness. The solids were dissolved in minimal MeOH and then triturated with ether. The resulting solids were isolated by filtration through a flitted funnel with nitrogen pressure, rinsed with ether, and dried in vacuo to give (2R)-2-amino-3-(4-chlorophenyl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride (19 mg, 38%) as a pink powder. 1H NMR (D2O, 400 MHz) δ 8.16 (1H, s), 7.27 (1H, s), 7.18-7.11 (4H, m), 6.68 (1H, s), 4.60-4.56 (1H, m), 3.98-3.69 (4H, m), 3.61-3.52 (2H, m), 3.45-3.37 (1H, m), 3.20-3.12 (1H, m), 3.00-2.91 (2H, m). LCMS (APCI+) m/z 385 [M+H]+. HPLC Rt 1.68 min.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[Na].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>C(O)C>[CH2:11]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCBr
Reactant: Oc1ccccc1O
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCCCCOc1ccccc1O
Reaction time: 1 h
Yield: 87.1 %

Procedure:
110 g (1 mole) of catechol was added to a solution of 23 g (1 mole) of metallic sodium in 1 liter of absolute ethanol and the mixture was stirred under nitrogen for 1 hour. Then, 166 g ((1.1 mole) of 1-bromopentane were added dropwise to the mixture over 15 minutes and the mixture was refluxed with stirring for 3 hours, was cooled and poured into 3 liters of water. The mixture was extracted with 1000 ml of ether and the ether extracts were washed with 20% sodium carbonate solution and then water, dried over magnesium sulfate and evporated to dryness under reduced pressure to obtain 157 g of 2-(n-pentyloxy)-phenol as a yellow oil. IR spectrum showed OH at 3540cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([OH:31])=[CH:23][N:22]=1.[O-]CC.[Na+]>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[CH:23]=[N:22]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: Oc1cnnc2ccccc12
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1ncc(=O)c2ccccc21)C(F)(F)F
Temperature: 85 °C

Procedure:
To a suspension of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (216 mg) and cinnolin-4-ol (V. G. Chapoulaud et al., Tetrahedron, 2000, 56, pp. 5499-5507) (216 mg) in anhydrous ethanol (1.2 mL) was added sodium ethoxide (21 wt. % solution in ethanol, 276 μL). After heating at 85° C. for 16 hours, the reaction mixture was diluted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (eluted with 40% ethyl acetate-hexanes) to give the title compound as a pale yellow solid (26 mg), m.p. 122° C.-123° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19]CC2C=CC=CC=2)=[C:4]([O:11]CC2C=CC=CC=2)[CH:5]=[C:6]([CH:10]=1)[CH:7]1[O:9][CH2:8]1.[CH:27]1([CH2:30][NH2:31])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[C:3]([OH:19])=[C:4]([OH:11])[CH:5]=[C:6]([CH:10]=1)[CH:7]([OH:9])[CH2:8][NH:31][CH2:30][CH:27]1[CH2:29][CH2:28]1
Reactant: Clc1cc(C2CO2)cc(OCc2ccccc2)c1OCc1ccccc1
Reactant: NCC1CC1
Product: Oc1cc(C(O)CNCC2CC2)cc(Cl)c1O

Procedure:
By reacting 5-chloro-3,4-dibenzyloxystyrene oxide with cyclopropylmethylamine followed by hydrogenation there is obtained 5-chloro-α-(cyclopropylmethylaminomethyl)-3,4-dihydroxybenzyl alcohol.
Reaction SMILES: [ClH:1].[N:2]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:18]=[C:19]([NH:26][C@@H:27]4[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]=[N:21][C:22]=3[C:23]([NH2:25])=[O:24])=[CH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:33][N:34]([CH3:41])[CH2:35]/[CH:36]=[CH:37]/[C:38](O)=[O:39].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[CH3:33][N:34]([CH3:41])[CH2:35]/[CH:36]=[CH:37]/[C:38]([N:29]1[CH2:30][CH2:31][CH2:32][C@@H:27]([NH:26][C:19]2[N:20]=[N:21][C:22]([C:23]([NH2:25])=[O:24])=[C:17]([NH:16][C:13]3[CH:14]=[CH:15][C:10]([C:8]([N:2]4[CH2:3][CH2:4][O:5][CH2:6][CH2:7]4)=[O:9])=[CH:11][CH:12]=3)[N:18]=2)[CH2:28]1)=[O:39].[ClH:1]
Reactant: NC(=O)c1nnc(N[C@@H]2CCCNC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)C/C=C/C(=O)N1CCC[C@@H](Nc2nnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(piperidin-3-ylamino)-1,2,4-triazine-6-carboxamide HCl salt (47 mg, 0.10 mmol) in NMP (4 mL) was added (E)-4-(dimethylamino)but-2-enoic acid (50 mg, 0.30 mmol), DIEA (180 μL, 1.0 mmol) and then PyBOP (104 mg, 0.20 mmol). The mixture was stirred at RT for 2 h, quenched with TFA (0.2 mL), diluted with 2 mL water, and subjected to reverse phase preparative HPLC to isolate the title compound (80) as an HCl salt (32 mg). MS found for C26H35N9O4 as (M+H)+ 538.2, (M−H)− 536.3. UV: λ=246 nm.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[N:24][CH:23]=[CH:22]3)(=[O:18])=[O:17])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:29]I>CN(C)C=O>[C:3]([O:7][C:8]([N:10]([C@H:11]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[N:24][CH:23]=[CH:22]3)(=[O:18])=[O:17])[CH2:12]1)[CH3:29])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2ccc3cnccc3c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCN(S(=O)(=O)c2ccc3cnccc3c2)C1
Reaction time: 0.5 h

Procedure:
265 mg of sodium hydride was added with stirring under ice cooling to an N,N-dimethylformamide (10 mL) solution of 500 mg of (S)-6-{3-(tert-butoxycarbonylamino)pyrrolidin-1-ylsulfonyl}isoquinoline obtained in Step 1. After stirring in this state for 30 minutes, 0.8 mL of methyl iodide was added dropwise to the reaction solution, and the mixture was further stirred for 30 minutes for reaction. The reaction was terminated by the dropwise addition of water in small portions under ice cooling to the reaction solution. Then, 50 mL of water was added thereto, followed by three extractions with 50 mL of ether. The combined organic layer was washed with 100 mL of saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (acetone:hexane=1:1) to obtain 100 mg of the compound of interest as a colorless oil (19%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30]([O:32]C(C)(C)C)=[O:31].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30]([OH:32])=[O:31]
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)OC(C)(C)C)c(Cl)c3)CC2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(Cl)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A solution of tert-butyl (2-chloro-4-{2-[(1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl]ethoxy}phenyl)acetate (0.96 g, 1.86 mmol) in DCM (10 ml) was treated with TFA (10.0 ml, 130 mmol) and the mixture stirred at RT for 50 min. The volatiles were removed and the residue purified by column chromatography using a Biotage RP C18 cartridge (30 g) using a gradient eluant of 0-100% water:acetonitrile+0.05% formic acid. to afford the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[N:36]1([CH:32]2[CH2:31][CH2:30][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:34][CH2:33]2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: C1COCCN1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(N3CCOCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a solution (5 mL) of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.5 g) and morpholine (0.14 mL) in acetic acid was added sodium cyanoborohydride (0.34 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The obtained extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.2 g, 35%).
Reaction SMILES: [N:1]1([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>ClCCl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:14][C:13]2[CH:15]=[CH:16][C:10]([N:1]3[C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[N:3]=[CH:2]3)=[CH:11][CH:12]=2)=[O:26])=[CH:20][C:19]=1[C:27]([F:28])([F:29])[F:30]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(-n2cnc3cnccc32)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(-n2cnc3cnccc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
The 4-(imidazo[4,5-c]pyridin-1-yl)aniline prepared in Step B was dissolved in 10 mL of dichloromethane, and 30 mg (0.137 mmol) of 4-chloro-3-(trifluoromethyl)phenyl isocyanate was added thereto and the mixture solution was stirred at room temperature for three hours. The solvent was distilled under reduce pressure, and the obtained crude product was recrystallized from ethyl acetate to obtain 35.0 mg (51%) of 1-(4-chloro-3-(trifluoromethyl)-phenyl)-3-(4-imidazo[4,5-c]pyridin-1-ylphenyl)urea (Table 1, Compound No. 1) as a colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[N:9]=2)=[C:4]([O:32][CH3:33])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[NH:10][N:9]=2)=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1nn(S(=O)(=O)c2ccc(C)cc2)c2nccc(-c3ccsc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(F)ccc1-c1n[nH]c2nccc(-c3ccsc3)c12
Temperature: 60 °C

Procedure:
To a stirred solution of 3-(4-fluoro-2-methoxyphenyl)-4-(thiophen-3-yl)-1-tosyl-1H-pyrazolo[3,4-b]pyridine 27 (50 mg 0.102 mmol) in methanol (10 mL) and water (5 mL) was added potassium carbonate (0.204 mmol) and the RM was heated to 60° C. overnight. After completion of the SM the solvents was completely distilled off, diluted with water and extracted with chloroform twice. The organic layer was dried over sodium sulphate. The crude product was passed through 100-200 mesh silica gel eluting the pre compound at 28-30% ethyl acetate in hexane as eluent to get the pale yellow colored solid of compound 3-(4-fluoro-2-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine 28. 1H NMR (CDCl3) δ: 8.56(d,1H), 7.44(m,1H), 7.23(m,1H), 7.16(m,1H), 7.02(m,1H), 6.95(m,1H), 6.73(m,1H), 6.34(m,1H) and MS m/z=325.8.
Reaction SMILES: O=C1CCC2C(=CC(OCCCC[N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:38]=[CH:37][CH:36]=[CH:35][C:24]=4[O:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH:32](C)[CH3:33])=[O:30])[CH2:19][CH2:18]3)=CC=2)N1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:20]1([C:23]2[CH:38]=[CH:37][CH:36]=[CH:35][C:24]=2[O:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:19][CH2:18][NH:17][CH2:22][CH2:21]1
Reactant: CC(C)OC(=O)CCCOc1ccccc1N1CCN(CCCCOc2ccc3c(c2)NC(=O)CC3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCOc1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(2-(4-ethoxy-4-oxobutoxy)phenyl)piperazine-1-carboxylate 13c (0.5 g) in 1 mL DCM was added 1 mL trifluoroacetic acid. The resulting mixture was stirred at rt for 1 h. The color of the reaction mixture darkened and a gas was evolved. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was concentrated on rotavapor and the residue was poured onto a mixture of crushed ice and sodium bicarbonate (NaHCO3). The aqueous layer was extracted with DCM, dried over magnesium sulfate and evaporated the solvent to give ethyl 4-(2-(piperazin-1-yl)phenoxy)butanoate 25. The compound 25 was carried to next step without any further purification. Brown oil, 0.37 g (99%). 1H NMR (400 MHz, CDCl3): δ 1.22 (t, J=7.2 Hz, 3H); 2.13 (quintet, J=6.8 Hz, 2H); 2.51 (t, J=7.2 Hz, 2H); 3.08 (broad s, 8H); 4.02 (t, J=6.0 Hz, 2H); 4.11 (q, J=7.2 Hz, 2H); 6.82-6.97 (m, 4H). MS (ESI): m/z=293.50 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[CH:24]=[CH:25][C:26]2[C:27](=[N:29][O:30][N:31]=2)[N:28]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]3[C:27](=[N:29][O:30][N:31]=3)[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Clc1ccc2nonc2n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc4nonc4n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1, Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (125 mg, 0.40 mmol) and 5-chloro[1,2,5]oxadiazolo[3,4-b]pyridine (62.2 mg, 0.40 mmol) as starting materials. LRMS (APCI) calc'd for (C19H16F2N5O3S) [M+H]+, 432. found 432.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][CH2:16][CH2:17][OH:18])([O-])=O.[H][H]>[Ni].CO>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCCO
Agent: [Ni]
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1NCCCO
Yield: 100 %

Procedure:
A mixture of 141 parts of 3-{[2-nitro-4-(trifluoromethyl)phenyl]amino}-1-propanol and 1200 parts of methanol is hydrogenated at normal pressure and at room temperature with 15 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 110 parts (100%) of 3-{[2-amino-4-(trifluoromethyl)phenyl]amino}-1-propanol.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([CH2:22][O:23][CH2:24][CH3:25])([OH:21])[CH:6]([N+:18]([O-])=O)[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH3:2].[H][H]>[Ni].C(O)(C)C>[CH2:24]([O:23][CH2:22][C:5]([CH2:4][O:3][CH2:1][CH3:2])([OH:21])[CH:6]([NH2:18])[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH3:25]
Reactant: CCOCC(O)(COCC)C(Cc1cccc2ccccc12)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(C)O
Product: CCOCC(O)(COCC)C(N)Cc1cccc2ccccc12
Yield: 90 %

Procedure:
A mixture of α,α-diethoxymethyl-β-nitro-1-naphthalenepropanol (7.75 g) and Raney nickel (0.8 g) in isopropanol (100 ml) was stirred under hydrogen at atmospheric pressure until hydrogen absorption stopped. The mixture was then degased for 15 minutes in vacuo and filtered through celite. The filtrate was evaporated in vacuo to yield α,α-diethoxymethyl-β-amino-1-naphthalenepropanol (6.37 g) as an oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:5][CH2:6][CH:7]([OH:9])[CH3:8])[CH3:4].Cl[C:11]1([N:36]=[N:37][C:38]2[N:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:16]=[CH:15][C:14]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:13][NH:12]1>O1CCCC1>[CH2:3]([N:5]([CH2:6][CH:7]([OH:9])[CH3:8])[C:11]1([N:36]=[N:37][C:38]2[N:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:16]=[CH:15][C:14]([C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:13][NH:12]1)[CH3:4]
Reactant: ClC1(N=Nc2cccnn2)C=CC(C(c2ccccc2)(c2ccccc2)c2ccccc2)=NN1
Reactant: CCNCC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC(C)O)C1(N=Nc2cccnn2)C=CC(C(c2ccccc2)(c2ccccc2)c2ccccc2)=NN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
To a 50% suspension of 1.5 g sodium hydride in 100 ml tetrahydrofuran, 3 g ethyl-(2-hydroxypropyl)amine are added; this is stirred at room temperature for 30 minutes, thereafter 4.5 g of 3-chloro-6-triphenylmethylazopyridazine are added. Stirring is maintained for 5 minutes, the organic phase is washed with a saturated solution of sodium chloride, rendered anhydrous and evaporated to dryness under a vacuum. The residue is taken up with ethyl alcohol, diluted with water, and the precipitate is collected under a vacuum which is then triturated with diisopropyl ether to yield 4 g of 3-[ethyl-(2-hydroxypropyl)amino]-6-triphenylmethylazopyridazine melting at 137° C. (with decomposition). A solution of 3 g of 3-[ethyl-(2-hydroxypropyl)amino]-6-triphenylmethylazopyridazine in 300 ml ethyl alcohol and 50 ml tetrahydrofuran containing 300 mg 5% palladium on carbon is hydrogenated at room temperature and pressure. The catalyst is filtered out, then the residue is evaporated and triturated with diethyl ether to yield 2.5 g of 3-[ethyl-(2-hydroxypropyl)amino]-6-(2-triphenylmethylhydrazino)pyridazine melting at 122° C. (with decomposition). A solution of 2 g of 3-[ethyl-(2-hydroxypropyl)amino]-6-(2-triphenylmethylhydrazino)pyridazine in 100 ml absolute ethyl alcohol is mixed with 2.5 ml concentrated hydrochloric acid and stirred for 15 minutes at room temperature. This is evaporated under a vacuum and the residue taken up with isopropyl alcohol. This is diluted with diisopropyl ether to yield 1.2 g of 3-[ethyl-(2-hydroxypropyl)amino]-6-hydrazinopyridazine dihydrochloride melting at 208°-212° C. (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]([N:16]=[C:17]=S)([CH3:15])[CH3:14]>>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:17]([NH:16][CH:13]([CH3:15])[CH3:14])=[N:12][S:9](=[O:11])(=[O:10])[C:3]=2[CH:4]=1
Reactant: Nc1ccc(I)cc1S(N)(=O)=O
Reactant: CC(C)N=C=S
Product: CC(C)NC1=NS(=O)(=O)c2cc(I)ccc2N1

Procedure:
The title compound was prepared from 2-amino-5-iodobenzenesulfonamide and isopropyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 305-307° C. dec; 1H-NMR (DMSO-d6): δ 1.17 (d, 6H, CH(CH3)2), 3.91 (m, 1H, CH(CH3)2), 7.02 (d, 1H, ArH), 7.15 (br., 1H, NH), 7.8-7.9 (m, 2H, ArH), 10.43 (br.s, 1H, NH); MS: m/e 365 (M+, 27%); (C10H12N3I1O2S1) calc. C, 32.89; H, 3.31; N, 11.51, found C, 32.79; H, 3.41; N, 11.27.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:11]=[C:10]([O:12][CH:13]([F:15])[F:14])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].S(Cl)([Cl:22])(=O)=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:11]([Cl:22])=[C:10]([O:12][CH:13]([F:14])[F:15])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18]
Reactant: Cn1nc(-n2ncc(C#N)c2N)cc1OC(F)F
Reactant: O=S(=O)(Cl)Cl
Solvent: CC#N
Product: Cn1nc(-n2ncc(C#N)c2N)c(Cl)c1OC(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.0 g (19.7 mmol) 5-Amino-1-(5-difluoromethoxy-1-methyl-3-pyrazolyl)-4-pyrazolecarbonitrile was dissolved in 180 ml acetonitrile and 2.65 g (19.7 mmol) sulfuryl chloride added dropwise. The mixture was stirred for one hour at room temperature and concentrated.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[S:36](Cl)(=[O:38])=[O:37]>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[S:36]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1cc(Cl)ccc1Cl)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 28 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 2,5-dichlorobenzenesulfonyl chloride under the conditions used in example 2 giving 28% of the title compound.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:16]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[N:1]1([CH2:10][CH2:11][CH2:12][C:13]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=2)=[O:15])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)CCCn1cnc2ccccc21
Reactant: CC(C)(C)c1ccc(N)cc1
Product: CC(C)(C)c1ccc(NC(=O)CCCn2cnc3ccccc32)cc1

Procedure:
Part C. The title compound was synthesized according to a procedure described in Example 98 starting from 4-benzoimidazol-1-yl-butyric acid and 4-tert-butyl-aniline. Calculated for C16H23N3O m/z: 335.20, found 336.1 [M+H]+.