Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[CH:7][CH:8]=2)[O:3]1.[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C)([O-])=O.CCOCC.O>[CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[C:7]([C:16](=[O:18])[CH3:17])[CH:8]=2)[O:3]1
Reactant: Cc1ccc2c(c1)OC(C)(C)CC2(C)C
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CC(=O)c1cc2c(cc1C)OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To an ice-bath cooled solution of 1.96 g (9.6 mmol) of 2,2,4,4,7-pentamethyl-chroman (Compound 46) in 30 ml of nitromethane was added under argon 1.059 g (13.5 mmol) of acetyl chloride followed by 1.9 g (14.3 mmol) of aluminum chloride. The reaction mixture was stirred at room temperature for 14 h and then cooled in an ice-bath and treated with 25 ml of conc. HCl. The mixture was warmed to room temperature and diluted with ether and water. The organic layer was separated and the aqueous layer extracted with ether. The organic extracts were combined and washed successively with water, saturated NaHCO3 solution, water again, and saturated NaCl solution, and then dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (silica; 5% ethyl acetate in hexanes) to give the title compound as a pale yellow oil. PMR (CDCl3): & 1.36 (6H, s), 1.37 (6H, s), 1.86 (2H, s), 2.49 (3H, s), 2.56 (3H, s), 6.65 (1H, s), 7.74 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Cl[C:37]1[CH:38]=[CH:39][C:40]2[O:52][CH:51]([C:53]3[S:54][CH:55]=[CH:56][CH:57]=3)[C:50]3[C:49]4[C:44](=[CH:45][CH:46]=[CH:47][C:48]=4[F:58])[NH:43][C:42]=3[C:41]=2[N:59]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:58][C:48]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:49]=1[C:50]1[CH:51]([C:53]3[S:54][CH:55]=[CH:56][CH:57]=3)[O:52][C:40]3[CH:39]=[CH:38][C:37]([C:18]4[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:23])=[O:24])=[CH:20][C:10]5[O:9][C:8]([C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)=[C:12]([C:13]([NH:15][CH3:16])=[O:14])[C:11]=5[CH:17]=4)=[N:59][C:41]=3[C:42]=1[NH:43]2
Reactant: Fc1cccc2[nH]c3c(c12)C(c1cccs1)Oc1ccc(Cl)nc1-3
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3[nH]c5cccc(F)c5c3C(c3cccs3)O4)cc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (110 mg, 0.22 mmol), 2-chloro-7-fluoro-6-(thiophen-2-yl)-6,11-dihydropyrido[2′,3′:5,6]pyrano[4,3-b]indole (78 mg, 0.22 mmol) and K3PO4 (176 mg, 0.66 mmol) in dioxane/H2O (0.8 mL/0.2 mL) was added Pd2(dba)3 (10 mg, 0.011 mmol) and X-Phos (10 mg, 0.022 mmol) under N2. The mixture was heated to 80° C. and then stirred for 1 hour. The reaction mixture was cooled to RT, diluted with EtOAc and filtered. The filtrate was washed with H2O, brine, dried over Na2SO4. After concentrated, the resulting residue was purified using Prep-TLC (petroleum ether:EtOAc=1:1) to provide the desired product of compound 66 (65 mg, yield 42.7%). 1H-NMR (CDCl3, 400 MHz) δ 9.94 (s, 1H), 7.96 (s, 1H), 7.89˜7.91 (m, 2H), 7.51 (s, 1H), 7.04˜7.34 (m, 8H), 6.91 (s, 1H), 6.85 (t, J=4.0 Hz, 1H), 6.68 (t, J=9.2 Hz, 1H), 5.81 (br s, J=3.6 Hz, 1H), 3.02 (s, 3H), 2.93 (s, 6H). MS (M+H)+: 697.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([S:23](Cl)(=[O:25])=[O:24])[CH2:19][CH2:18]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([S:23]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)(=[O:25])=[O:24])[CH2:19][CH2:18]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CCN(CC1CCN(S(=O)(=O)Cl)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC1CCN(S(=O)(=O)N2CCOCC2)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(1-chlorosulfonylpiperidin-4-ylmethyl)amine (0.18 grams, 0.45 mmole), morpholine (0.04 grams, 0.45 mmol) and diisopropylethylamine (0.12 grams, 0.93 mmole) in tetrahydrofuran (10 ml) was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and water. The organic layer was dried over potassium carbonate and evaporated to give a residue, which was purified by flash chromatography on silica gel using 40% ethyl acetate in hexane. Appropriate fractions were combined and evaporated to give (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-[1-(morpholine-4-sulfonyl)-piperidin-4-ylmethyl]amine as an oil, (0.17 g, 85%), M+H 452. Analysis % of the hydrochloride salt: Found: C, 54.06; H, 7.62; N, 8.24. Requires: C, 54.01; H, 8.00; N, 8.22.
Reaction SMILES: S(O)(=O)(=O)C.S(O)(=O)(=O)C.O[C@@H:12]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@H:14]([C@@H:15](O)[CH2:16][C@@H:17]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:30])[CH2:23][CH2:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:13]1.[Cl-:41].[K+].[Cl-].[Na+].[Cl-].[Li+]>>[Cl:41][CH:12]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:30])[CH2:23][CH2:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:13]1
Reactant: [Cl-]
Reactant: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CS(=O)(=O)O
Agent: [K+]
Agent: [Li+]
Product: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CC(Cl)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
3α,6α-Dihydroxy-5β-cholestan-24-one (I) is mesylated in a conventional manner to form 3α,6α-dihydroxy-5β-cholestan-24-one dimesylate (VI). Then the compound (VI) is reacted with an inorganic salt such as potassium chloride, sodium chloride or lithium chloride to give 3-chlorocholest-5-en-24-one (VII).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][C:11]([F:17])([F:16])[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:27])[C@H:9]([CH2:18][O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][C:11]([F:17])([F:16])[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: COC(=O)C(F)(F)C[C@@H](COC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(F)(F)C[C@@H](COC(=O)OC(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
To a mixture of (S)-methyl 4-(tert-butoxycarbonylamino)-5-(tert-butoxycarbonyloxy)-2,2-difluoropentanoate (46.0 g, 0.12 mol) and MeI (15.0 mL, 0.24 mol) in DMF (300 mL) was added sodium hydride (60%, 7.2 g, 0.18 mol) at 0° C. The reaction mixture was stirred at 0° C. for 3 h and LC-MS showed the reaction was completed. The reaction was quenched with saturated NH4Cl solution and filtered. The filtrate was concentrated to remove most of DMF and the residue was dissolved in EtOAc (1.5 L). The organic layer was washed with water and brine, dried over Na2SO4. The organic layers were combined and concentrated. The resulting residue was purified on silica gel column (hexanes/EtOAc) to give (S)-methyl 4-(tert-butoxycarbonyl(methyl)amino)-5-(tert-butoxycarbonyloxy)-2,2-difluoropentanoate (42 g, 88%). LRMS (M+Na+) m/z 420.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[C:17]([N:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)[C:10]=23)[CH:5]=[CH:6][CH:7]=1>O1CCOCC1.Cl.O1CCOCC1>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[C:17]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[C:10]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1cccc(Nc2ncnc3[nH]nc(N4CCNCC4)c23)c1

Procedure:
Under a nitrogen atmosphere, 2.0 g (4.65 mmol) of 4-(3-chloro-phenylamino)-3-(4-tert-butyloxycarbonyl-piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine (see Example 24) in 80 ml of dioxane and 80 ml of HCl/dioxane (4N) are stirred at 60° C. for 2 hours. Cooling and filtering yield 4-(3-chloro-phenylamino)-3-(piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine dihydrochloride; analysis calc. for C15H16N7Cl.2HCl (+0.14 H2O+5% dioxane): C44.93%, H 4.78%, N 22.97%, Cl 24.91%, H2O 0.68%; found C45.12%, H 4.73%, N 23.16%, Cl 24.67%, H2O 0.68%; HPLC: tRet(grad20-100/20)=8.0.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:22])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30]>ClCCl>[CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:29](=[O:31])[CH3:30])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cncn1C1CCCc2ccc(N)cc21
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)C(n1cncc1C(=O)OC(C)C)CCC2
Reaction time: 2.5 h

Procedure:
To a solution of 3-(7-amino-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester (0.180 g, 0.602 mmol) and pyridine (0.052 g, 0.662 mmol) in dichloromethane (2 mL) is added acetyl chloride (0.052 g, 0.662 mmol) at 0° C. and the reaction is stirred for 2.5 hours. The solution is then washed with 10% aqueous HCl and water and the combined aqueous phases are extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered, and concentrated to give a residue, which is purified by silica gel chromatography (dichloromethane-methanol mixtures) to give 3-(7-acetylamino-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 342.2 (M+H)+; 1H NMR (400 MHz, MeOD) δ ppm 1.39 (d, J=6.3 Hz, 3 H), 1.40 (d, J=6.3 Hz, 3 H), 1.78-1.92 (m, 2 H), 2.08 (s, 3 H), 2.16-2.31 (m, 2 H), 2.81-2.89 (m, 1 H), 2.98 (dt, J=16.9, 6.1 Hz, 1 H), 5.25 (sept, J=6.3 Hz, 1 H), 6.32 (t, J=5.4 Hz, 1 H), 7.17 (br. s, 1 H), 7.22 (d, J=8.3 Hz, 1 H), 7.43 (s, 1 H), 7.50 (dd, J=8.3, 2.1 Hz, 1 H), 7.74 (d, J=1.0 Hz, 1 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[NH:19][CH2:18]1.[CH2:25](Br)[CH:26]=[CH2:27]>C(#N)C>[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[N:19]([CH2:27][CH:26]=[CH2:25])[CH2:18]1
Reactant: O=[N+]([O-])c1ccc(C2CCS(=O)(=O)NC2)c(F)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CC(c2ccc([N+](=O)[O-])cc2F)CCS1(=O)=O

Procedure:
Anhydrous potassium carbonate (3.6 g, 26.1 mmol) is added to a solution of 4-(2-fluoro-4-nitrophenyl)tetrahydro-2 H-1,2-thiazine 1,1-dioxide (1.795 g, 6.54 mmol) and allyl bromide (2.0 ml, 23.1 mmol) in dry acetonitrile (25 ml). The mixture is heated to reflux for 5 min then cooled. After filtration and evaporation the residue is chromatographed over silica gel (150 g) eluting with 0-1% methanol-chloroform. The title compound is obtained as flakes (1.70 g, 83%) mp 121°.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:31])[CH2:4][CH2:5][N:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:7](=[O:16])[C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[BH4-].[Na+]>CO>[ClH:1].[CH3:2][N:3]([CH3:31])[CH2:4][CH2:5][N:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:7](=[O:16])[CH:8]([OH:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)CCN(C(=O)C(=O)c1ccccc1)c1ccccc1SCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)CCN(C(=O)C(O)c1ccccc1)c1ccccc1SCc1ccccc1

Procedure:
A solution of Example 19 in methanol was treated with sodium borohydride at room temperature in the usual manner. This product was converted to the hydrochloride salt and crystallized from methanol-ether, m.p. 213°-215° (dec.).
Reaction SMILES: [C:1]1([C:7]23[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:16])[CH2:12][CH:11]2[CH2:10][O:9][NH:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C>C(O)(=O)C.[Zn]>[NH2:8][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]([CH2:10][OH:9])[CH2:12][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:14]1
Reactant: O=C(OCc1ccccc1)N1CC2CONC2(c2ccccc2)C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC1(c2ccccc2)CN(C(=O)OCc2ccccc2)CC1CO
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Powdered zinc (43.7 g, 669 mmol) is added to a solution of benzyl 6a-phenyl-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (31 g, 96 mmol) in acetic acid (310 mL) and the mixture is stirred for 30 minutes. Ethyl acetate (500 mL) is added and the mixture is filtered through diatomaceous earth. The solvent is removed under vacuum and the crude product is re-dissolved in ethyl acetate. Water is added to the solution and the pH is adjusted to 10 with 2 M NaOH. The solution is filtered through diatomaceous earth, the layers are separated, and the organic layer is dried over magnesium sulfate, and concentrated to give the title compound (31 g, 99%). ES/MS (m/e): 327 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[N:10]=[C:4]2[CH:3]=1.[C:16](=[O:23])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[NH2:17].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:19]([O:18][C:16](=[O:23])[NH:17][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[N:10]=[C:4]2[CH:3]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Brc1ccn2nc(N3CCCC3)nc2c1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
To an argon purged solution of 7-bromo-2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine (383 g, 1.43 mol) in dioxane (14.4 ml) were added tert-butyl carbamate (202 g, 1.72 mol), cesium carbonate (654 g, 2.01 mol), tris(dibenzylideneacetone) dipalladium(0) (26.3 g, 28.7 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (33.2 g, 57.4 mmol). The resulting mixture was heated to 100° C. and stirred for 18 hours under argon atmosphere. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using heptane/ethyl acetate 10-70% as eluent affording (2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-carbamic acid tert-butyl ester (346 mg, 79.5%) as an off-white solid. mp: 216-219° C., MS: m/z=304.1 (M+H+)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[OH:11][C:4]1[CH:3]=[C:2]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:5]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: CN1CCNCC1
Product: CC(=O)c1ccc(N2CCN(C)CC2)cc1O

Procedure:
1-(4-Fluoro-2-hydroxy-phenyl)-ethanone (4.5 g, 29.22 mmol) was treated with N-methylpiperazine (5 mL) at 130° C. for 3 h to give 1-[2-hydroxy-4-(4-methyl-piperazin-1-yl)-phenyl]-ethanone in quantitative yield.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:11][C:4]1[N:3]=[C:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 73.6 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (772 mg, 4 mmol), aniline (364 μL, 4 mmol) and DIEA (838 μL, 24.8 mmol) in 10 mL THF was stirred at r.t. for 70 h. After removal of the solvent, the residue was dissolved in DCM, and subjected to silica gel column purification to give 735 mg (yield 74%) of the title compound. LC-MS: Calculated mass=249. Observed mass=250.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH:18]1[C:26]2[C:21](=[CH:22][N:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:18]1[C:26]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[CH:20]=[CH:19]1)=[O:6]
Reactant: c1cc2[nH]ccc2cn1
Reactant: O=C(O)c1c(F)cccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1c(F)cccc1Cl)n1ccc2cnccc21
Reaction time: 0.25 h
Yield: 39.7 %

Procedure:
To a stirred solution of 2-chloro-6-fluorobenzoic acid (2.5 g, 14.32 mmol) in dichloromethane (20 mL), oxalyl chloride (3.029 ml, 28.64 mmol) was added at 0° C. After stirring at the same temperature for 15 min, dimethylfromamide (2-3 drops) was added, and the reaction was allowed to stir at room temperature for 1.5 hours. The reaction mixture was cooled and concentrated on rotary evaporator. The residue was taken up in dichloromethane (20 mL) and treated with 5-azaindole (1.72 g, 14.51 mmol) and triethylamine (6.1 mL, 43.52 mmol). The resulting reaction mixture was allowed to stir at room temperature for 20 hours. The reaction mixture was concentrated under vacuum, diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under rotary evaporator. The product was isolated by silica gel column chromatography using ethyl acetate (25%) in hexanes as eluent to yield (2-chloro-6-fluorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (1.56 g, 39.5%).
Reaction SMILES: [Na].O.[CH2:3]([O:5][CH2:6][N:7]1[C:12]([CH3:13])=[C:11]([C:14]([O:16]C)=[O:15])[CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[C:9]([C:27]([O:29][CH3:30])=[O:28])=[C:8]1[CH3:31])[CH3:4]>CN(C)CC(O)C.C1C=CC=CC=1>[CH2:3]([O:5][CH2:6][N:7]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[C:9]([C:27]([O:29][CH3:30])=[O:28])=[C:8]1[CH3:31])[CH3:4]
Reactant: CCOCN1C(C)=C(C(=O)OC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC)=C1C
Agent: CC(O)CN(C)C
Agent: [Na]
Solvent: c1ccccc1
Solvent: O
Product: CCOCN1C(C)=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC)=C1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Optically active dihydropyridine acid derivatives are prepared as described by T. Shibanuma, et al., Chem. Pharm. Bull., 28, 2809-2812 (1980). 2,6-Dimethyl-3,5-di(carbomethoxy)-4-(3-nitrophenyl)-1,4-dihydropyridine is prepared by the Hantzsch method (Ann. Chim., 215, 1 (1882)), then reacted with chloromethoxyethane and NaH to produce 1-ethoxymethyl-2,6-dimethyl-3,5-di(carbomethoxy)-4-(3-nitrophenyl)-1,4-dihydropyridine. Sodium (13.3 g) is added to 1-dimethylamino-2-propanol (150 mL) and the mixture stirred for 1 h. A solution of H2O (3.8 mL) in 1-dimethylamino-2-propanol (40 mL) is added dropwise, and the solution heated to dissolve any remaining sodium. A solution of 1-ethoxymethyl-2,6-dimethyl-3,5-di(carbomethoxy)-4-(3-nitrophenyl)-1,4-dihydropyridine (38 g) in benzene (190 mL) is then added with cooling to 0° C., and the mixture stirred for 3 h. The solvent is then removed by evaporation and the residue acidified to pH 2 by adding 3N HCl in a dry ice-acetone bath. The aqueous solution is then extracted with CHCl3, and the extract washed with water, dried, and concentrated to yield racemic 1-ethoxymethyl-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine. The product is then dissolved in methanol (200 mL) and cinchonidine and the solvent removed. The resulting salt is then dissolved in hot ethanol (150 mL) and allowed to stand at room temperature overnight. The crystals formed are recrystallized from EtOH, treated with 0.1N HCl, and extracted with CHCl3 to produce (-)-1-ethoxymethyl-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine (mp=134°-135°, αD22 =-16.00°). The other isomer may be recovered from the original crystallization solvent.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:8])[OH:7])([CH3:4])([CH3:3])[CH3:2].C[O:10][CH2:11][C:12]1([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]1.[CH2:19]([N:22]=C=O)[CH2:20][CH3:21]>>[C:1]([NH:5][C:6](=[O:7])[OH:8])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH:22][C:11]([C:12]1([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]1)=[O:10])[CH2:20][CH3:21]
Reactant: COCC1(S(N)(=O)=O)CC1
Reactant: CCCN=C=O
Agent: CC(C)(C)NC(=O)O
Product: CCCNC(=O)C1(S(N)(=O)=O)CC1
Yield: 100 %

Procedure:
This compound was obtained in a crude 100% yield according to the procedure described for the synthesis of 1-methoxymethylcyclopropylsulfonylamine tert-butyl-carbamate except that 1.10 equivalents of n-propyl isocyanate was used as the electrophile. The compound was taken directly into the next reaction without purification: 1H NMR (CDCl3) δ 0.10 (m, 2H), 0.51 (m, 2H), 0.67 (m, 1H), 1.10 (m, 2H), 1.49 (s, 9H), 1.62 (m, 2H), 1.87 (d, J=7.0Hz, 2H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2)=[O:4].[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][NH:18]1>>[CH3:16][C@@H:17]1[NH:18][CH2:19][CH2:20][N:21]([CH2:2][C:3]([NH:5][C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH:8]=[CH:9][CH:10]=[N:11]3)=[O:4])[CH2:22]1
Reactant: C[C@H]1CNCCN1
Reactant: O=C(CCl)Nc1cccc2ncccc12
Product: C[C@H]1CN(CC(=O)Nc2cccc3ncccc23)CCN1

Procedure:
to The subtitle compound was prepared from 2-chloro-N-(quinolin-5-yl)acetamide (1 g) (J Indian Chem Soc, 1940, 17, 619-621) and (S)-2-methylpiperazine (0.5 g) by the method of Example 58 step (i) as a white solid. Yield: 1.4 g