Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.[CH:34]1([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CS(C)=O>[CH:34]1([NH:40][C:7]2[C:8]3[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:24][CH:23]=[N:22][CH:21]=4)=[CH:16][CH:15]=3)[N:12]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: NC1CCCCC1
Solvent: CS(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NC3CCCCC3)c2C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (35 mg, 0.07 mmol) in DMSO (1 mL) was dispensed in a library plate. Cyclohexanamine (6.94 mg, 0.07 mmol) was added and the reaction mixture was stirred overnight at 80° C. before it was filtered and purified by preparative HPLC to give 1-(4-(cyclohexylamino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (11.2 mg, 36%).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[C:20]([C:28]3[N:29]=[C:30]4[C:36]([C:37](O)=[O:38])=[CH:35][N:34]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:31]4=[N:32][CH:33]=3)=[N:19]2)[CH2:15]1)([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.CN(C(ON1N=[N:63][C:58]2[CH:59]=CC=N[C:57]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>CN(C=O)C>[CH:58]([NH:63][C:37]([C:36]1[C:30]2[C:31](=[N:32][CH:33]=[C:28]([C:20]3[C:21]4[C:26](=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[N:18]([CH:16]4[CH2:17][N:14]([CH:1]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH2:15]4)[N:19]=3)[N:29]=2)[N:34]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:46])([CH3:47])[CH3:45])[CH:35]=1)=[O:38])([CH3:59])[CH3:57]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(-c3nn(C4CN(C(c5ccccc5)c5ccccc5)C4)c4cc(F)ccc34)cnc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CN(C(c5ccccc5)c5ccccc5)C4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of 2-[1-(1-benzhydryl-azetidin-3-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (130 mg, 0.20 mmol) in DMF (2 mL) were added HATU (84 mg, 0.22 mmol) and isopropylamine (86 μL, 1.00 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 50% EtOAc/hexanes to isolate 74 mg (54%) of 2-[1-(1-benzhydryl-azetidin-3-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as an off-white foamy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:4]2[CH:3]=1.C([Li])CCC.[CH2:35]([S:37]SCC)[CH3:36].O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:37][CH2:35][CH3:36])[N:5]2[N:8]=[C:9]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)[N:12]=3)=[C:4]2[CH:3]=1
Reactant: CCSSCC
Reactant: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCSc1cc(Cl)cc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (150 mg, 0.37 mmol) in anhydrous tetrahydrofuran (5 mL) at −78° C. was added n-butyllithium (0.7 mL, 1.1 mmol of 1.6 M solution in hexane). The resulting solution was stirred for 10 minutes at −78° C., followed by addition of diethyldisulfide (0.14 mL, 1.1 mmol). The reaction was stirred at −78° C. for 20 minutes and then allowed to warm to room temperature. Water and ethyl acetate were added to the reaction mixture The phases were separated, the aqueous phase washed with ethyl acetate and the combined organic phase dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting solid was purified by flash chromatography (1:1 ethyl acetate-hexane) to give, after recrystallization from ethyl acetate N-{4-[5-chloro-7-(ethylsulfanyl)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine (90 mg, 52%) as a solid. 1H-NMR (CDCl3): δ 8.42(broad s, 1H), 8.08 (d, 1H), 7.66 (q, 2H), 7.17 (t, 2H), 6.73 (d, 1H), 6.31 (d, 1H), 5.18 (d, 1H), 4.20 (m, 1H), 3.22 (q, 2H), 2.0–2.1 (m, 2H), 1.4–1.9 (m, 9H); 19F-NMR (CDCl3): δ112.8; MS m/z 468(M+1).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:22](Cl)(=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C(Cl)(Cl)Cl>[CH2:38]([C:39]1[N:13]([CH2:12][CH2:11][CH2:10][N:9]([CH3:8])[CH3:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=1)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CN(C)CCCNc1ccccc1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCc1nc2ccccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Triethylamine (0.62 ml) was added to a solution containing N-[3-(dimethylamino)propyl]-1,2-benzenediamine (0.78 g) in chloroform (4 ml) and then stearoyl chloride (1.22 g) was added thereto while being cooled with ice. After being stirred for 2 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (3.33 ml) was added to a solution containing the residue (1.93 g) in n ethanol (20 ml). After being stirred for 5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (1.73 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1), thereby yielding the entitled compound (1.53 g) as pale brown wax.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][C:5]2([CH2:12][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8]2)[CH2:4][CH2:3]1.[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[CH2:19].C([O-])(O)=O.[Na+].O>C(O)C.C(O)(=O)C>[ClH:1].[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:18][CH2:19][N:2]1[CH2:7][CH2:6][C:5]2([CH2:12][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8]2)[CH2:4][CH2:3]1
Reactant: C=Cc1ccccn1
Reactant: O=C1CC2(CCNCC2)Sc2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC2(CCN(CCc3ccccn3)CC2)Sc2ccccc21
Reaction time: 24 h
Yield: 82.7 %

Procedure:
Under N2, a mixture of product from Step D (0.54 g, 0.002 mol), 2-vinylpyridine (0.62 g, 0.0059 mol), NaHCO3 (0.6 g, 0.0071 mol) in absolute ethanol (20 ml) was heated at reflux. After 24 hours, acetic acid (4 drops) was added and refluxing was continued. After 24 hours, H2O (20 ml), and 2-vinylpyridine (2 ml) were added. After another 72 hours at reflux, the reaction was concentrated to dryness. The residue was chromatographed on silica gel (Still column, 50 mm) and the product eluted with 5% CH3OH--CHCl3. The compound was crystallized as the hydrochloride salt from ethanol to yield 0.62 g (80%) of product.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:16])[CH3:15])[CH3:6].C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.C(OC(=O)C)(=O)C.O>[CH2:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:1]([O-:4])=[O:2])[C:8]=1[NH:13][C:14](=[O:16])[CH3:15])[CH3:6]
Reactant: CCc1ccccc1NC(C)=O
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCc1cccc([N+](=O)[O-])c1NC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of nitric acid (4.2 mL) in glacial acetic acid (5.2 mL)) was added drop wise to solution of N-(2-ethylphenyl)acetamide (Example 139f)(1.00 g, 6.13 mmol) in AcOH (22 mL) and acetic anhydride (18 mL) at 0° C. The reaction was stirred at 0° C. for 1 h, diluted with water (50 mL) and neutralized with Na2CO3 (pH˜8). The neutralized mixture was extracted with EtOAc (3×50 mL), the combined extract was washed with water and brine, and dried with anhydrous MgSO4. The filtrate was evaporated and the residue was purified on HPLC to give 0.62 g (48%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.81 (broad s, 1H), 7.68-7.73 (m, 1H), 7.57-7.62 (m, 1H), 7.39 (t, J=8.0 Hz, 1H), 2.64 (q, J=8.0 Hz, 2H), 2.00 (s, 3H), 1.10 (t, J=8.0 Hz, 3H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([OH:42])[C@@H:14]1[O:18][C@@H:17]([C@H:19]([OH:41])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C@@H:31]([OH:40])[CH2:32][C:33]2[C:37](=[O:38])[O:36][C@@H:35]([CH3:39])[CH:34]=2)=[O:25])[CH2:16][CH2:15]1.[CH3:43][O:44][CH2:45]Cl>C(N(C(C)C)CC)(C)C>[CH3:43][O:44][CH2:45][O:40][CH:31]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]([O:41][CH2:35][O:36][CH3:37])[CH:17]1[CH2:16][CH2:15][CH:14]([CH:13]([O:42][CH2:17][O:18][CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[O:18]1)[CH2:32][C:33]1[C:37](=[O:38])[O:36][CH:35]([CH3:39])[CH:34]=1
Reactant: COCCl
Reactant: CCCCCCCCCCCC[C@@H](O)[C@H]1CC[C@H]([C@H](O)CCCCC(=O)CCCCC[C@@H](O)CC2=C[C@H](C)OC2=O)O1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCC(OCOC)C1CCC(C(CCCCC(=O)CCCCCC(CC2=CC(C)OC2=O)OCOC)OCOC)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of annonacinone (595 mg, 1.0 mmol) in diisopropylethylamine (7 mL) is stirred at room temperature while chloromethyl methyl ether (360 mg, 4.5 mmol) is added. The mixture is stirred at room temperature for eight hours, concentrated in vacuo, and the residue is partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous phase is separated and extracted with ethyl acetate (2×50 mL) and the combined organic fractions are washed (1× water), dried (saturated aqueous NaCl, sodium sulfate), filtered, and concentrated. Chromatography (hexane-2:1 hexane:ethyl acetate gradient over silica gel 230-400 mesh) affords 3-{2,13-bis(methoxymethyloxy)-13-[tetrahydro-5-(1-methoxymethyloxytridecyl) furan-2-yl]tridecan-8-on-1-yl}-5-methyl-2-(5H)-furanone.
Reaction SMILES: CC1[C:6](=O)[O:5][C@@H:4]([O:8]/C=C2\[C@@H]3[C@H](OC\2=O)C2C(C)(C)CC[C@H](O)C=2C3)[CH:3]=1.[CH3:26][C:27]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]([CH3:35])([CH3:34])[C:28]=1[C:36]([OH:38])=O.[Na]C(C(OC)=O)C(OC)=O>>[O:38]=[C:36]1[C:28]2[C:29]([CH3:34])([CH3:35])[CH2:30][CH2:31][C:32](=[O:33])[C:27]=2[CH2:26][CH:3]1[C:4]([O:5][CH3:6])=[O:8]
Reactant: CC1=C(C(=O)O)C(C)(C)CCC1=O
Reactant: CC1=C[C@H](O/C=C2/C(=O)O[C@@H]3C4=C(C[C@H]23)[C@@H](O)CCC4(C)C)OC1=O
Agent: COC(=O)C([Na])C(=O)OC
Product: COC(=O)C1CC2=C(C1=O)C(C)(C)CCC2=O

Procedure:
A process for preparing dl-strigol, a potent seed germination agent, which comprises preparing the 2-bromomethyl-substituted methyl ester of 2,6,6-trimethylcyclohex-1-en-3-one-1-carboxylic acid, alkylating and cyclizing the said compound with an excess of dimethyl sodiomalonate to obtain methyl 1,4-diketo-7,7-dimethyl-4,5,6,7-tetrahydroindane-2-carboxylate and its enol, subjecting the said keto and enol forms of the compound, in admixture, to alkylation with methyl bromoacetate followed by acidic hydrolysis and spontaneous decarboxylation to obtain methyl 1,4-diketo-7,7-dimethyl-4,5,6,7-tetrahydroindane-2-acetic acid, reducing the said acetic with a hydride reducing agent and recovering and separating the resulting 1,4-cis and trans-dihydroxy-7,7-dimethyl-4,5,6,7-tetrahydroindane-2-acetic acid lactones, formylating each of the cis and trans γ lactones, alkylating the respective resulting hydroxy methylene lactones with bromobutenolide and recovering dl-strigol, dl-4'-epi-strigol, dl-4-epi-strigol and dl-4,4'-diepi-strigol.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:18]=[C:17]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[N:34]=[C:35]=[O:36].C(N(CC)C(C)C)(C)C>C1COCC1>[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[NH:34][C:35]([NH:23][C:22]1[CH:24]=[CH:25][C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:9]3[NH:8][CH:12]=[CH:11][CH:10]=3)[CH:18]=2)=[CH:20][CH:21]=1)=[O:36]
Reactant: Nc1ccc(-c2ccnc(-c3ccc[nH]3)c2)cc1
Reactant: Cc1ccc(F)c(N=C=O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3ccnc(-c4ccc[nH]4)c3)cc2)c1
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-(2-(1H-pyrrol-2-yl)pyridin-4-yl)aniline TFA salt (60 mg, 0.17 mmol) in anhydrous THF (10 ml) was added 2-fluoro-5-methyl-phenylisocyanate (48 mg, 0.32 mmol) and N,N-diisopropylethylamine (40 mg, 0.31 mmol). After 1 hour, the reaction mixture was evaporated and purified by silica gel chromatography with 2-3% MeOH/CHCl3 to give 1-(2-fluoro-5-methylphenyl)-3-{4-[2-(1H-pyrrol-2-yl)pyridin-4-yl]phenyl}urea as off-white solid. Yield: 28 mg.
Reaction SMILES: [Cl:1]C1C=CC(B(O)O)=CC=1.[C:11]1(C)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:21][N:20]=[C:19]([C:22]([F:25])([F:24])[F:23])[C:18]=1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[C:30]([Cl:41])[CH:29]=1>>[Cl:41][C:30]1[CH:29]=[C:28]([O:27][CH2:26][C:18]2[C:19]([C:22]([F:24])([F:25])[F:23])=[N:20][S:21][C:17]=2[C:12]2[CH:13]=[CH:14][C:15]([Cl:1])=[CH:16][CH:11]=2)[CH:33]=[CH:32][C:31]=1[CH2:34][CH2:35][C:36]([OH:38])=[O:37]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCc1ccc(OCc2c(C(F)(F)F)nsc2-c2ccccc2C)cc1Cl
Product: O=C(O)CCc1ccc(OCc2c(C(F)(F)F)nsc2-c2ccc(Cl)cc2)cc1Cl

Procedure:
The title compound was prepared according to the procedure described in Example 172 following Step 1-6 using (4-chloro-phenyl)boronic acid for coupling and then hydrolysis of ethyl 3-(4-((5-(o-tolyl)-3-(trifluoromethyl)isothiazol-4-yl)methoxy)-2-chloro-phenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ7.53-7.59 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 6.97 (s, 1H), 6.81-6.85 (m, 1H), 5.06 (s, 2H), 2.99 (t, J=8.1 Hz, 2H), 2.60 (t, J=8.1 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C20H14Cl2F3NO3S, 474.0 (M−H). found 474.0.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][C@@H:30]([CH2:34][OH:35])[C:31](O)=[O:32])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:29][C@@H:30]([CH2:34][O:35][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[C:31]([NH:7][C:8]2[CH:18]=[CH:17][CH:16]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)=[O:32])(=[O:27])=[O:28])=[CH:24][CH:25]=1
Reactant: C1=COCCC1
Reactant: O=C(O)[C@H](CO)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1cccc(N)c1
Product: CCOC(=O)c1cccc(NC(=O)[C@H](COC2CCCCO2)NS(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The procedure described in Example 1 was repeated, except that dihydropyran (1.46 ml) and ethyl m-aminobenzoate (2.13 g) were successively reacted with (S)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (3 g) to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (2.3 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:11][OH:12])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1.[H-].[Na+].[CH2:15](I)[CH3:16].O>CN(C)C=O>[CH3:10][C:6]1([CH3:9])[O:5][CH2:4][C:3]([CH2:11][O:12][CH2:15][CH3:16])([CH2:2][OH:1])[CH2:8][O:7]1
Reactant: CC1(C)OCC(CO)(CO)CO1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCC1(CO)COC(C)(C)OC1
Reaction time: 2 h

Procedure:
To a stirred solution of 5,5-di-(hydroxymethyl)-2,2-dimethyl-1,3dioxane (5.09) (Bellstein 19, II, 93) in dry dimethylformamide (50 ml) under nitrogen, at 20°, was added sodium hydride (0.689g, 80% dispersion in oil). The mixture was stirred at 80° for 2 hours and cooled. Ethyl iodide (4.49g) in dry dimethylformamide (40 ml) was added and the mixture was heated at 110° for 3 hours. The mixture was cooled and poured into water. The aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with brine, dried over anhydrous magnesium sulphate and evaporated in vacuo. 2,2-Dimethyl-5-ethoxymethyl-5- hydroxymethyl-1,3-dioxane was obtained as a pale yellow oil (1.2 g) and was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH:10](OC1C=CC([N+]([O-])=O)=CC=1)=[O:11]>C(Cl)Cl>[CH:10]([NH:1][CH2:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])=[O:11]
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccccc1N
Solvent: ClCCl
Product: Nc1ccccc1CNC=O

Procedure:
The amine component employed is prepared by reaction of 2.6 g of 2.6 g of 2-(aminomethyl)aniline, dissolved in 50 ml of methylene chloride, with 3.91 g of 4-nitrophenyl formate at room temperature for 4 h. Purification over 250 g of silica gel (mobile phase N) gives 2-(formylaminomethyl)aniline: Rf (N)=0.22.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]1=O)C.[CH3:13][NH:14]N>CO>[CH3:13][N:14]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:5]=2[CH:4]=[N:2]1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: CNN
Solvent: CO
Product: Cn1ncc2c1CCCC2=O
Temperature: 0 °C

Procedure:
To an ice-cold solution of 67 grams of 2-dimethylaminomethylene-1,3-cyclohexanedione in 600 ml of methanol was added slowly a solution of 21.3 ml of methylhydrazine in 200 ml of methanol and the resulting solution was heated at reflux for 2 hours. The solvent was removed under reduced pressure and the residue was triturated with ethyl ether to give 1,5,6,7-tetrahydro-1-methyl-4H-indazol-4-one as a tan crystalline solid melting at about 88°-91° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH:23][C:24]([C:26]5[C:27]([Cl:32])=[N:28][CH:29]=[CH:30][CH:31]=5)=[O:25])[CH:21]=[CH:22][C:16]=4[CH2:15][CH2:14][C:13]=3[C:12]([C:33]([NH2:35])=[O:34])=[N:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O>[Cl:32][C:27]1[C:26]([C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:16]3[CH2:15][CH2:14][C:13]4[C:12]([C:33]([NH2:35])=[O:34])=[N:11][N:10]([C:7]5[CH:8]=[CH:9][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][CH:6]=5)[C:18]=4[C:17]=3[CH:19]=2)=[O:25])=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: CC(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4cccnc4Cl)ccc2CC3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4cccnc4Cl)ccc2CC3)cc1
Reaction time: 14 h
Yield: 50 %

Procedure:
A mixture of 1-(4-acetylphenyl)-8-{[(2-chloropyridin-3-yl)carbonyl]amino}-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (200 mg, 0.41 mmol) in MeOH (3 mL) and water (0.3 mL) was added NaBH4 (10 mg, 0.25 mmol) at RT and stirred for 14 h. The mixture was separated on silica gel column (EtOAc) to give product (100 mg, 50%). 1H NMR was consistent with its structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:23])=[CH:4][N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc(Sc2ccccc2)cn1
Solvent: ClCCl
Product: O=S(c1ccccc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-chloro-5-(phenylthio) pyridine (2.21 g., .01 moles) in 50 ml. of methylene chloride is treated with a methylene chloride solution of 2.02 g. of 85% m-chloroperbenzoic acid. The solution is stirred at room temperature for 1 hour and washed with 50 ml. of aqueous saturated sodium bicarbonate solution. The organic layer is separated dried and evaporated in vacuo to yield 2-chloro-5-(phenylsulfinyl)pyridine.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)(C1C=CC(C)=CC=1)(=O)=O.[NH:35]1[CH:39]=[N:38][CH:37]=[N:36]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.CN(C=O)C>[N:35]1([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:23][CH2:22]3)=[CH:19][CH:20]=2)[CH:39]=[N:38][CH:37]=[N:36]1
Reactant: c1nc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(CCCn3cncn3)cc2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The N-(4-(3-tosyloxypropyl)phenyl)-4-tert-butoxycarbonylaminopiperidine (330 mg, 0.68 mmol) obtained in Example 8(4) was dissolved in a mixed solvent of acetonitrile (5 ml) and DMF (5 ml), and 1,2,4-triazole (54 mg, 0.81 mmol) and potassium carbonate (187 mg, 1.35 mmol) were added thereto, followed by stirring at 60° C. for 1 hour. After the reaction mixture was cooled to room temperature, water was added thereto, and the precipitate was collected by filtration, thereby obtaining N-(4-(3-(1,2,4-triazol-1-yl)-propyl)-phenyl)-4-tert-butoxycarbonylaminopiperidine (192 mg, 74%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:12]=2[OH:13])=[CH:3][N:2]=1.[C:20]([C:22]1[CH:23]=[C:24]([S:29]([NH:32][C:33]2[S:37][N:36]=[CH:35][N:34]=2)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1F)#[N:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:20]([C:22]1[CH:23]=[C:24]([S:29]([NH:32][C:33]2[S:37][N:36]=[CH:35][N:34]=2)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)#[N:21]
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Reactant: Oc1ccc(-c2ccccc2)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(-c2ccccc2)cc1-c1ccnnc1
Temperature: 90 °C

Procedure:
3-Pyridazin-4-ylbiphenyl-4-ol (Preparation 4, 50 mg, 0.2 mmol) and 3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 47, 50 mg, 0.2 mmol) were dissolved in dimethylsulfoxide (2 mL). Potassium carbonate (83 mg, 0.6 mmol) was added and the reaction heated to 90° C. for 16 hours. The crude material was then purified by reverse phase column chromatography (ISCO™, 4 g, C18, 20:1 water:acetonitrile to 3:2 water acetonitrile). The appropriate fractions were combined and concentrated in vacuo to afford the title compound as an off white solid (25 mg, 24%).