Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.CC(C)([O-])C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>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]>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([NH:8][C:5]2[C:4]([C:17]3[N:25]=[C:24]([CH3:26])[N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[CH:3][C:2]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:7][N:6]=2)=[CH:14][CH:13]=1
Reactant: C1COCCN1
Reactant: COc1ccc(Nc2ncc(Br)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(Nc2ncc(N3CCOCC3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Temperature: 97.5 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
A mixture of 5-bromo-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6yl)pyridin-2-amine (0.310 g, 0.625 mmol) (Example 64 intermediate), morpholine (0.054 g, 0.625 mmol) (Aldrich, St. Louis, Mo.), sodium tert-butoxide (0.090 g, 0.937 mmol) (Aldrich, St. Louis, Mo.), tris(dibenzylideneacetone)dipalladium (0) (0.011 g, 0.012 mmol) (Aldrich, St. Louis, Mo.) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.022 g, 0.037 mmol) (Strem Chemicals, Inc., Newburyport, Mass.) in dioxane (100 mL, 941 mmol) was deoxygenated and stirred at 95-100° C. under N2 for three hours. The reaction mixture was diluted with ethyl acetate and washed with water (3×). The organic layer was concentrated, adsorbed onto a plug of silica gel and chromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (120 g), eluting with a gradient of 10% to 50% ethyl acetate in hexane to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6yl)-5-morpholinopyridin-2amine (0.105 g, 33% yield). The residue was treated with trifluoroacetic acid (Aldrich, St. Louis, Mo.) and dichloromethane to give N-(3-(2-methyl-9H-purin-6-yl)-5-morpholinopyridin-2-yl)-1H-indazol-4-amine MS (ESI pos. ion) m/z 419 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.46 ((br. s., 1H); 9.56 ((br. s., 1H); 8.56 (d, J=0.39 Hz, 1H); 8.51-8.53 (m, 1H); 8.12 (d, J=1.37 Hz, 2H); 6.82 (d, J=9.00 Hz, 1H); 3.78-3.86 (m, 7H); 3.11 (br. s., 2H); 3.12 (t, J=4.89 Hz, 2H); 2.84 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:13])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2[CH:33]([CH2:36][CH3:37])[CH2:34][OH:35].C(O)CCC.O>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][CH:15]3[CH2:16][CH2:17][N:18]([C:24]4[N:32]=[CH:31][N:30]=[C:29]5[C:25]=4[N:26]=[CH:27][N:28]5[CH:33]([CH2:34][OH:35])[CH2:36][CH3:37])[CH2:19][CH2:20]3)=[O:13])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CO)n1cnc2c(Cl)ncnc21
Reactant: O=C(NC1CCNCC1)c1ccc(-c2cccc(F)c2)nc1
Solvent: O
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCC(CO)n1cnc2c(N3CCC(NC(=O)c4ccc(-c5cccc(F)c5)nc4)CC3)ncnc21
Temperature: 85 °C

Procedure:
6-(3-fluorophenyl)-N-(piperidin-4-yl)nicotinamide (2.0 g, 5.37 mmol) and 2-(6-chloro-9H-purin-9-yl)butan-1-ol (1.58 g, 6.98 mmol) were placed in a flask along with 10 mL of butanol, 10 mL of water and 10 mL of triethylamine. The mixture was heated to 85° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and brine. The ethyl acetate was washed 3× with brine and then dried over MgSO4, filtered and concentrated. The residue was purified by chromatography (silica, 1.5% EtOH/EtOAc) to give the desired racemic product (Example 88, 1.34 g, 57%). The material was purified by chiral chromatography-SFC (50% iPrOH in CO2, AD-H 30×250 mm col) to give the two peaks (enantiomeric pair)
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@H:12]2[O:16][C@@H:15]([N:17]3[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]3=[O:19])[CH2:14][C@@H:13]2[OH:26])(=O)=O)=CC=1.[CH3:28][NH2:29].[K+].[Br-]>O>[CH3:28][NH:29][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:14][C@@H:13]1[OH:26]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)cc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: CNC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Reaction time: 72 h

Procedure:
5'-O-(p-toluenesulfonyl)thymidine (19.8 g, 50 mmol) was placed in a pressure vessel into which monomethylamine (250 g) was condensed. The vessel was sealed and allowed to stand at room temperature for 3 days. The vessel was cooled, opened, and the monomethylamine allowed to evaporate. The remaining contents of the vessel were removed by rinsing with water. The aqueous solution was passed through a column (6.5×20 cm) of AG50Wx8 ion-exchange resin (H+ form). The column was washed with water until the washings were neutral. The product was then eluted with 1N aqueous ammonium hydroxide. The eluent was stripped down and the resulting solid chromatographed on a column (6.5×20 cm) of silica gel with methylene chloride/methanol/concentrated aqueous ammonium hydroxide (85:13:2) as the eluting solvent. The product containing fractions were stripped down, then taken up in water and lyophilized. The product was a pale-yellow, amorphous solid (8.81 g, 69%). A satisfactory combustion analysis could not be obtained for this material.) [α]D25 (c=1.0 in water): +25.9 deg. ir (KBr): cm-1 1693, 1472, 1273, 1076. NMR (DMSO-d6): δ1.790 (s, 3H), 2.051 (ddd, 13.4, 6.3, 3.5 hz, 1H), 2.142 (dt, 13.4, 6.9 hz, 1H), 2.314 (s, 3H), 2.658 (d, 5.5 hz, 2H), 3.775 (td, 5.3, 3.2 hz, 1H), 4.171 (dt, 6.3, 3.2 hz, 1H), 6.134 (t, 6.9 hz, 1H) and 7.639 (s, 1H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[F:5][C:6]1[CH:7]=[C:8]([C:22]2[N:23]=[C:24]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]3[CH3:42])[C:25]3[CH2:30][N:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[NH:12][C:13](OC1C=CC=CC=1)=[O:14]>>[CH:1]1([NH:4][C:13](=[O:14])[NH:12][C:11]2[CH:10]=[CH:9][C:8]([C:22]3[N:23]=[C:24]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]4[CH3:42])[C:25]4[CH2:30][N:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][C:26]=4[N:27]=3)=[CH:7][C:6]=2[F:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)Oc4ccccc4)c(F)c3)nc(N3CCOC[C@@H]3C)c2C1
Reactant: NC1CC1
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)c(F)c3)nc(N3CCOC[C@@H]3C)c2C1
Yield: 40 %

Procedure:
Method as described for example 51, using cyclopropylamine and (S)-ethyl 2-(3-fluoro-4-((phenoxycarbonyl)amino)phenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate as starting materials. The mixture was reduced in vacuo and purified by flash SCX2 chromatography affording the title compound (11 mg, 0.023 mmol, 40%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][CH:46]([CH2:49][N:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:37]=1[NH2:38].Cl>C(O)C(F)(F)F>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:48][CH2:47][CH:46]([CH2:49][N:50]5[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]5)[CH2:45][CH2:44]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCC(CN3CCCCC3)CC2)ccc1N
Agent: Cl
Solvent: OCC(F)(F)F
Product: COc1cc(N2CCC(CN3CCCCC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 170 °C
Yield: 44 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.11 g, 0.25 mmol) and 2-(methyloxy)-4-[4-(1-piperidinylmethyl)-1-piperidinyl]aniline (0.076 g, 0.25 mmol) in trifluoroethanol (1.5 mL) was added HCl (0.13 mL, 4M in dioxane, 0.50 mmol). The reaction was heated at 170° C. for 80 min in the microwave. When complete by MS, the reaction mixture was quenched with sodium methoxide (0.5M in MeOH) and concentrated. Purification by flash chromatography, followed by prep-HPLC, and recrystallization with DCM/hexanes provided the title compound (0.082 g, 0.11 mmol, 46%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.26 (m, 2H), 1.36 (br. s., 2H), 1.43-1.53 (m, 4H), 1.63 (br. s., 1H), 1.77 (d, J=11.7 Hz, 2H), 2.09 (d, J=7.0 Hz, 2H), 2.27 (s, 4H), 2.63 (t, J=12.1 Hz, 2H), 3.67 (d, J=11.4 Hz, 2H), 3.78 (s, 3H), 6.40-6.51 (m, 2H), 6.65 (d, J=2.2 Hz, 1H), 6.97 (t, J=7.0 Hz, 1H), 7.20 (t, J=8.1 Hz, 2H), 7.35-7.42 (m, 2H), 7.44-7.48 (m, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.81 (d, J=7.7 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 8.19 (d, J=5.1 Hz, 1H), 8.33 (s, 1H), 8.46 (s, 1H), 9.40 (br. s., 1H), 10.24 (s, 1H). MS (M+H, ES+) 729.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[Ca+2].[Cl-].Cl>C(OCC)(=O)C.O>[OH:27][C:21]1[CH:26]=[CH:25][C:24]([C:17]2([C:24]3[CH:25]=[CH:26][C:21]([OH:27])=[CH:22][CH:23]=3)[CH2:18][CH2:19][CH:14]([CH2:13][CH2:12][C@H:9]3[CH2:8][CH2:7][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]3)[CH2:15][CH2:16]2)=[CH:23][CH:22]=1
Reactant: CCCCC[C@H]1CC[C@H](CCC2CCC(=O)CC2)CC1
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCC[C@H]1CC[C@H](CCC2CCC(c3ccc(O)cc3)(c3ccc(O)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.5 %

Procedure:
4-[2-(Trans-4-n-pentylcyclohexyl)ethyl]cyclohexanone (112.4 g), phenol (152.7 g) and calcium chloride (90.1 g) were mixed, followed by gradually dropwise adding conc. hydrochloric acid (68 ml) with vigorous stirring at room temperature, agitating the mixture for 30 minutes after completion of the dropwise addition, further allowing the resulting material to stand at room temperature for 24 hours, adding hot water (0.5 l) and ethyl acetate (2 l) to dissolve it on heating, washing with saturated NaCl aqueous solution using hot water at 40° to 50° C., drying over Na2SO4, filtering, concentrating and recrystallizing the resulting concentrate from a mixed solvent of ethyl alcohol and methyl alcohol (87:13) (SOLMIX® made by Nihon Kasei Co., Ltd.) to obtain white crystals of 1,1-bis(4-hydroxyphenyl)-4-[2-(trans-4-n-pentylcyclohexyl)ethyl]cyclohexane (78.8 g) as a diol compound of the present invention. M.P.: 203.4-204.4° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:28])=[CH:4][C:5]([F:27])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:20]([O-:22])=[O:21])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:23])[C:10]([C:24]([OH:26])=[O:25])=[CH:9]2)[CH:7]=1.[CH3:29][NH2:30].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:28])=[CH:4][C:5]([F:27])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:20]([O-:22])=[O:21])=[C:15]([NH:30][CH3:29])[C:16]=3[F:18])[C:11](=[O:23])[C:10]([C:24]([OH:26])=[O:25])=[CH:9]2)[CH:7]=1
Reactant: CN
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc([N+](=O)[O-])c(F)c(F)c32)c(F)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CNc1c([N+](=O)[O-])cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(5-Amino-2,4-difluorophenyl)-7,8-difluoro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (70 mg) was added to a mixed liquid of a 40% aqueous solution (80 mg) of methylamine and pyridine (2 ml), and the mixture was stirred at room temperature for 1 hour. The solution was acidified with 3% citric acid (10 ml), and solids formed were collected by filtration. The solids were washed with water, ethanol and hexane to obtain the title compound (56 mg) as a yellow powder.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([CH3:21])[CH3:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[CH:19]([O:18][C:14]1[C:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[O:9][C:10]=2[CH:17]=[CH:16][CH:15]=1)([CH3:21])[CH3:20]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OC(C)C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)O)oc2cccc(OC(C)C)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 118.3 %

Procedure:
To 220 mg of 4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 3 mL of TFA/dichloromethane (1:1). The solution was stirred at room temperature for 3 h. The solvents were removed under vacuum and the residue was triturated with acetonitrile. Filtration of the precipitate gave 210 mg of 4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].S(Cl)(Cl)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH2:32])(=[O:31])=[O:30]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](=[O:31])(=[O:30])[NH2:32])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CCCCCCCOc1cccc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCOc1cccc(C(=O)Nc2ccccc2S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
A benzene (30 ml) solution containing 3 g (12.5 mmol) of 3-heptyloxybenzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.50 g (14.5 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained crude crystals were recrystallized from acetonitrile to obtain 3.00 g (yield: 60.0%) of the title compound. NMR (DMS-d6) δ: 0.87 (3 H, t, J=7 Hz), 1.22-1.50 (8 H, m), 1.70-1.80 (2 H, M), 4.41 (2 H, t, J=7 Hz), 7.17-7.23 (1 H, m), 7.33 (1 H, ddd, J=8 Hz, 8 Hz, 2 Hz), 7.77 (2 H, s), 7.90 (1 H, dd, J=8 Hz, 2 Hz), 8.48 (1 H, d, J=8 Hz), 10.38 (1 H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH:12]1([CH2:18][O:19][C:20]2[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=2[O:22][CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][N:27]2[CH2:26][CH2:25][CH:24]([CH2:23][O:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[O:19][CH2:18][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:29][CH2:28]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: c1ccc(OCC2CCNCC2)c(OCC2CCCCC2)c1
Reactant: COc1ncc(Cl)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ncc(Cl)cc1CN1CCC(COc2ccccc2OCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
150 mg of 5-chloro-2-methoxy-3-pyridinecarboxaldehyde and 291 mg of 4-[2-(cyclohexylmethyloxy)phenoxymethyl]piperidine were dissolved in 5 ml of 1,2-dichloroethane. To the mixture were added 0.06 ml of acetic acid and 214 mg of sodium triacetoxyborohydride, followed by stirring at room temperature overnight. An aqueous saturated sodium bicarbonate was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to give 285 mg of the title compound as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16](B(O)O)=[C:15]([CH3:23])[CH:14]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C3C(C4C=CC=CC=4C=2)=CC=CC=3)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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]>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([C:2]2[C:7]([CH3:8])=[CH:6][N:5]([OH:9])[CH2:4][C:3]=2[CH3:10])=[C:15]([CH3:23])[CH:14]=1
Reactant: COc1cc(C)c(B(O)O)c(C)c1
Reactant: Cc1c[n+]([O-])cc(C)c1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: COc1cc(C)c(C2=C(C)CN(O)C=C2C)c(C)c1
Temperature: 120 °C
Reaction time: 48 h
Yield: 1.8 %

Procedure:
A flame-dried sealable Schlenk tube was charged with 4-bromo-3,5-dimethyl-pyridine 1-oxide (1; 10.1 g, 50.0 mmol), 2 (18.0 g, 100 mmol), Pd2(dba)3 (0.915 g, 1.00 mmol), dicyclohexyl-(2-phenanthren-9-yl-phenyl)-phosphane (1.8 g, 4.0 mmol), and K3PO4 (31.9 g, 150 mmol). The Schlenk tube was next evacuated and backfilled with N2. Then, degassed dry toluene (100 mL) was added via syringe under N2. The Schlenk tube was sealed, and the mixture was stirred at 120° C. for 48 h. The reaction mixture was subsequently cooled to room temperature, diluted with methylene chloride (500 mL), filtered, and concentrated in vacuo. The resulting dark brown oil was allowed to stand at room temperature until the colorless crystalline product separated from the liquid. The solid was then collected by filtration and identified as the pure title compound (6.55 g). The filtrate was purified by flash chromatography eluting with 95:5 CHCl3: methanol to afford an additional 0.23 g of the title compound. The combined yield was 6.78 g (53%): mp 194-195° C.; 1H NMR (400 MHz, CD2Cl2): δ 7.990 (s, 2H), 6.705 (s, 2H), 3.798 (s, 3H), 1.892 (s, 6H), 1.842 (s, 6H); 13C NMR (125 MHz, CD2Cl2): δ 159.771, 139.578, 137.663, 137.187, 135.775, 128.289, 113.709, 55.605, 20.198, 17.087; MS (ESI): m/z 258.4 [(M+H)+, 100]; Anal. Calcd. For C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found: C, 74.54; H, 7.40; N, 5.51.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18]C(C(O)=O)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C(Cl)Cl.CN(C=O)C>[Cl:4][C:2]([CH:1]1[CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:13])[CH2:15][CH2:16]1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of oxalyl chloride (8.72 ml, 17.45 mmol) in DCM (150 ml) was added 1-(tert-butoxy-carbonyl)piperidine-4-carboxylic acid (2 g, 8.72 mmol) at 0° C. Then a few drops of DMF were added. The mixture was stirred at room temperature for 2 h, washed with NH4Cl aqueous and brine. The organic layer was separated, dried (MgSO4) and concentrated. The resulting crude product was directly used in the next step.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8](Br)=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.C(CC(=O)C)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[NH3:27].[Cl-].[NH4+]>C(CC(=O)C)(=O)C.[Cu+2].CN1C(=O)CCC1>[CH3:1][NH:2][C:3]1[C:8]([NH2:27])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1
Reactant: CNc1ncc(C(F)(F)F)cc1Br
Reactant: N
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)CC(C)=O
Solvent: CN1CCCC1=O
Product: CNc1ncc(C(F)(F)F)cc1N
Temperature: 120 °C
Reaction time: 7 h

Procedure:
To a pressure-resistant reaction container, N-methyl-(3-bromo-5-trifluoromethyl-pyridin-2-yl)-amine (0.51 g), copper (II) acetylacetone (0.11 g), acetylacetone (0.20 g), cesium carbonate (1.30 g), NMP (2 ml), and 28% of aqueous ammonia (1 ml) were added, and stirred at 120° C. for 7 hours, then at 130° C. for 3 hours. The mixture was allowed to cool to room temperature, and then saturated aqueous ammonium chloride solution was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.28 g of N2-methyl-5-trifluoromethylpyridin-2,3-diamin.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=[O:9]>[Pd].C(OCC)(=O)C>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=[O:9]
Reactant: O=C(O)C1CC2C=CC1C2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)C1CC2CCC1C2

Procedure:
A solution of 5-norbornene-2-carboxylic acid (0.25 mole) in 100 ml. of ethyl acetate is hydrogenated over 5% palladium on carbon catalyst at 40 psi and 30°-50° C. The theoretical amount of hydrogen is absorbed exothermically within 0.5 hour. Removal of catalyst and solvent affords a residue of essentially pure norbornane-2-carboxylic acid, as indicated by infrared, NMR, and glpc analyses. The substituted acids are reduced readily in the same way.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C=O)s2)cc1
Temperature: 60 °C

Procedure:
To a stirred solution of 5-bromothiophene-2-carbaldehyde (1 g, 5.2 mmol) in toluene (40 mL) and ethanol (20 mL) was added (4-methoxyphenyl)boronic acid (1.59 g, 10.4 mmol), 2M Na2CO3 (14.7 mL), and Pd(PPh3)4 (60 mg, 0.05 mmol). The reaction was purged with argon and heated at 60° C. for about 5 h. The reaction mixture was concentrated, diluted with water (100 mL), and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with brine solution (20 mL), the organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120μ) using 10% ethyl acetate in hexane eluent to afford 5-(4-methoxyphenyl)thiophene-2-carbaldehyde as off white solid (1 g, 87.7% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.85 (s, 1H), 7.97 (d, 1H), 7.73 (d, 2H), 7.61 (d, 1H), 7.02 (d, 2H), 3.98 (s, 3H); LC-MS m/z calcd for [M+H]+ 219.04. found 219.3.