Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:11]=[C:10]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[N:9]=1.C(=O)(O)[O-].[Na+].Cl[C:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:38]>O1CCOCC1>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[N:11]=[C:10]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:37](=[O:38])[O:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:28][CH:29]=2)[N:9]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccc2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
(4-{4-[(3S)-3-Methylmorpholin-4-yl]-6-[(phenylsulfonyl)methyl]pyrimidin-2-yl}phenyl)amine (2 g, 4.71 mmol) was dissolved in dioxane (20 mL). Sodium bicarbonate (594 mg, 7.07 mmol) was added, followed by phenyl chloroformate (0.593 mL, 4.71 mmol) and the reaction stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resultant oil partitioned between 20 mL DCM and 20 mL water. The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The cream solid obtained was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM, to give the desired material as a white solid (1.1 g).
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][O:8][C:9]1[C:26]([O:27][CH3:28])=[CH:25][C:12]2[CH:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][NH:15][CH2:16][CH2:17][C:11]=2[CH:10]=1.[O:29]([CH2:36][CH2:37][CH2:38]Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:7][O:8][C:9]1[C:26]([O:27][CH3:28])=[CH:25][C:12]2[CH:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][N:15]([CH2:38][CH2:37][CH2:36][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH2:17][C:11]=2[CH:10]=1
Reactant: COc1cc2c(cc1OC)C(Oc1ccccc1)CNCC2
Reactant: BrCCCOc1ccccc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)C(Oc1ccccc1)CN(CCCOc1ccccc1)CC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
A mixture of 7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine of Example 35 (4.8 g, 16 mmole) and 3-phenoxypropyl bromide (4 g, 18 mmole) in 25 ml DMF containing potassium carbonate (milled, 4.4 g, 32 mmole) was stirred at 80° C. for two hours. After cooling, the mixture was stirred with 300 ml water and was extracted with ethyl acetate-ether. The organic extract was washed with water, saturated NaCl and was dried (anhydrous MgSO4), filtered and evaporated to 9 g of an oil. This oil was purified by HPLC (silica gel, 10% ethyl acetate/ dichloromethane) to give 4.7 g (68%) of 7,8-dimethoxy-3-(3-phenoxypropyl)-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine solid, m.p. 95°-100° C.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[C:2]=[O:3].[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24]>C(Cl)Cl>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]([NH:1][C:4]2[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=2)=[O:3])=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH2Cl2 (30 mL) was added 4-chloro-3-(trifluoromethyl)aniline (3.21 g, 16.4 mmol), and the solution was stirred at room temp. overnight. The resulting slurry was diluted with CH2Cl2 (50 mL) and filtered to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-ethoxycarbonylphenyl)urea as a white solid (5.93 g, 97%): TLC (40% EtOAc/60% hexane) Rf 0.44.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].I[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].[OH-].[K+]>[Cu].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: COc1ccccc1S
Reactant: O=C(O)c1ccccc1I
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1Sc1ccccc1C(=O)O

Procedure:
Stir under reflux for 3 hours a mixture of 70 g (0.5 mole) of o-methoxythiophenol, 120.5 g (0.486 mole) of o-iodobenzoic acid 81.7 g (1.46 mole) of potassium hydroxide, 85 g (1.34 mole) of copper powder and 800 ml of water. Filter the reaction mixture hot and again filter the filtrate through celite. Acidify the filtrate with concentrated hydrochloric acid. Separate the precipitate, wash well with water and dry in vacuo at 70° C. to obtain the title product. (m.p. 198°-200° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]([CH3:33])[C@@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[CH3:26][N:27]([CH3:33])[C@@H:28]1[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:29]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CC[C@@H](N(C)C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)—N,N-dimethylpyrrolidin-3-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 2.07-2.22 (m, 1 H) 2.33 (s, 4 H) 2.70-2.95 (m, 6 H) 3.71 (d, J=5.05 Hz, 3 H) 3.83-4.01 (m, 2 H) 7.64 (br. s., 1 H) 7.68-7.80 (m, 1 H) 8.05-8.61 (m, 3 H) 8.67 (s, 1 H). ESI-MS m/z [M+H]+ 435.3.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:27][CH:28]([NH2:30])[CH3:29].C(N(CC)C(C)C)(C)C>ClCCl>[CH:28]([NH:30][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3])([CH3:29])[CH3:27]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Cl)c1)=N2
Reactant: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)NC(C)C)c1)=N2
Yield: 59.1 %

Procedure:
To a stirred solution of methyl 2-(3-(chlorosulfonyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (393 mg, 1.0 mmol) in dichloromethane (4 mL) was added propan-2-amine (60 mg, 1.0 mmol) and N,N-diisopropylethylamine (258 mg, 2.0 mmol). The resultant mixture was stirred overnight. The mixture was purified on preparative Thin layer chromatography to afford 245 mg of methyl 2-(3-(N-isopropylsulfamoyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate, which was used directly.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:41])[C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:23]([OH:33])=[C:22]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[CH:21]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:48]([O:50][C:51](=[O:57])[CH2:52][CH2:53][CH2:54][CH2:55]Br)[CH3:49].O>CN(C=O)C>[Cl:32][C:28]1[CH:27]=[C:26]([C:24]2[CH:25]=[C:20]([C:19](=[O:41])[NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)[CH:21]=[C:22]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:23]=2[O:33][CH2:55][CH2:54][CH2:53][CH2:52][C:51]([O:50][CH2:48][CH3:49])=[O:57])[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)CCCCBr
Reactant: O=C(NCCCCCCCCn1ccc2ccccc21)c1cc(-c2cccc(Cl)c2)c(O)c(-c2cccc(Cl)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCCCn2ccc3ccccc32)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
A mixture of N-(8-indol-1-yl-octyl)-3,5-bis(3-chlorophenyl)-4-hydroxybenzamide (0.399 g, 0.68 mmol), K2CO3 (0.116 g, 0.84 mmol), and ethyl-5-bromovalerate (0.176 g, 0.84 mmol) in DMF was stirred at room temperature under nitrogen. After ˜48 h, the reaction mixture was poured into water (40 ml) and extracted with EtOAc (1×20 ml, 4×10 ml). The combined extracts were washed with water (3×10 ml), brine (2×10 ml), dried over Na2SO4, filtered and the filtrate concentrated in vac and dried. The crude product was purified by flash chromatography (alumina, hexane, 10% and 60% EtOAc/Hex) to give the desired product as a light yellow oil (0.432 g, 86%); (400 MHz, DMSO-d6) δ 1.12-1.30 (m, 15H), 1.44-1.55 (m, 2H), 1.67-1.76 (m, 2H), 1.92 (t, J=7 Hz, 2H), 3.16-3.27 (m, 4H), 3.98 (q, J=7 Hz, 2H), 4.12 (t, J=7.2 Hz, 2H), 6.38 (d, J=3.1 Hz, 1H), 6.95-6.99 (m, 1H), 7.06-7.10 (m, 1H), 7.32 (d, J=3.3 Hz, 1H), 7.40-7.52 (m, 6H), 7.56-7.59 (m, 2H), 7.68 (t, J=1.8 Hz, 2H), 7.87 (s, 2H), 8.53 (t, J=5.7 Hz, 1H); IR (film) 3320, 2940, 2950, 1730, 1630, 1540, cm−1; mass spectrum [(+)APCI], m/z 713 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C:7]([CH2:28][C:29]#[C:30][CH3:31])([S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][C:9]#[C:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[NH2:33][CH2:34][C@@H:35]([C:37]1[CH:38]=[CH:39][C:40]([OH:48])=[C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH:42]=1)[OH:36]>>[C:1]([O:5][C:6](=[O:32])[C:7]([CH2:8][C:9]#[C:10][CH3:11])([S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][CH:24]([NH:33][CH2:34][C@H:35]([OH:36])[C:37]3[CH:38]=[CH:39][C:40]([OH:48])=[C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH:42]=3)[CH2:25][CH2:26]2)=[CH:17][CH:16]=1)(=[O:13])=[O:14])[CH2:28][C:29]#[C:30][CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CC#CCC(CC#CC)(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: CC#CCC(CC#CC)(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1 from 0.37 g (0.8 mmol) of Reference Example 27, 2-But-2-ynyl-2-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-hex-4-ynoic acid tert-butyl ester, and 0.24 g (1.0 mmol) of (R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide, yielding 0.54 g of an off-white solid; m.p. 93-95° C.; MS (ES) m/z 688.2 (MH+); HRMS (ES) Calcd. for C34H46N3O8S2 (MH+): 688.2721, Found: 688.2722.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][C@H:33]([NH:36][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2cc(F)ccc2OC)c(N)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Product: COc1ccc(F)cc1C(=O)c1cnc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)nc1N

Procedure:
The same procedure was used as described in Example 9 starting from (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone, Example 48, and (S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (Astatech), to give (S)-3-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester. MS (M+H)+, 432.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].C([O:8][C:9]([C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:34])[F:33])[CH2:21][CH2:20]3)=[N:15][N:14]2[CH:37]=1)=O)C>>[CH2:1]([NH:5][C:9]([C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:33])([F:35])[F:34])[CH2:23][CH2:24]3)=[N:15][N:14]2[CH:37]=1)=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Reactant: CCCCN
Product: CCCCNC(=O)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Yield: 72 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use n-butylamine in place of isoamylamine to react with 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid in 72% yield (0.077 g). m.p. 187-189° C. 1H NMR (300 MHz, CDCl3) δ 8.1 (s, 1H), 7.75-7.66 (m, 2H), 7.65-7.5 (m, 2H), 7.48-7.38 (m, 1H), 7.37-7.3 (m, 1H), 6.92 (d, J=9.6 Hz, 1H), 4.05-3.94 (m, 1H), 3.93-3.82 (m, 1H), 3.69-3.54 (m, 2H), 3.5-3.38 (m, 4H), 3.35-3.28 (m, 2H), 1.65-1.53 (m 2H), 1.47-1.33 (m, 2H), 0.92 (t, J=7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.5, 161.9, 154.9, 137.7, 135.3, 134.2, 132.4, 129.5, 127.2, 126.8, 126.7, 126.2, 125.4, 121.8, 118.3, 112.3, 46.2, 46.1, 45.6, 41.1, 38.9, 31.7, 20.1, 13.8. MS (ES+) m/z 475.2 (M+1).
Reaction SMILES: [CH3:1][C:2]12[C:7]([CH2:9]CC=C(C)CO)([CH3:8])[CH:6]3[CH2:16][CH:3]1[CH:4]2[CH2:5]3.CN/C(/NCCSCC1OC(CN(C)C)=CC=1)=C\[N+]([O-])=[O:22].Cl>>[CH3:1][C:2]1[C:7]([CH3:8])([CH3:9])[CH:6]([CH2:16][CH2:3][OH:22])[CH2:5][CH:4]=1
Reactant: CC(=CCCC1(C)C2CC3C(C2)C31C)CO
Reactant: CN/C(=C\[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Agent: Cl
Product: CC1=CCC(CCO)C1(C)C

Procedure:
5-(2,3-dimethyltricyclo[2.2.1.0(2,6)]-hept-3-yl)-2-methyl-2-penten-1-ol, or santanol.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1.C(N(CC)CC)C>C(O)CCC>[F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cccc(Nc2nc(F)nc3nc[nH]c23)c1
Temperature: 25 °C

Procedure:
This compound was prepared by the reaction of 2-fluoro-6-chloropurine (1.7 g; 0.01 mol), m-anisidine (1.23 g; 0.01 mol) and triethylamine (3.5 ml; 0.025 mol) in n-butanol (20 ml) at 90° C. for 4 hours. The reaction mixture was then cooled to the room temperature. The white precipitate was filtered off, rinsed with n-butanol (3×10 ml) and water (3×10 ml) and dried in the drying oven into constant weight. Yield: 5.55 g (61%) of yellowish crystalline powder. TLC (chloroform-methanol; 85:15): one single spot. HPLC purity: 99+%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20](=[O:21])[CH2:19][CH:18]([C:22]([OH:24])=O)[CH2:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:25][NH2:26]>>[CH3:25][NH:26][C:22]([CH:18]1[CH2:19][C:20](=[O:21])[N:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:11][CH:12]=2)[CH2:17]1)=[O:24]
Reactant: CN
Reactant: O=C(O)C1CC(=O)N(c2ccc(CCc3cccc(F)c3)cc2)C1
Product: CNC(=O)C1CC(=O)N(c2ccc(CCc3cccc(F)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 36 d), the esterification of (RS)-1-{4-[2-(3-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid and reaction of the intermediate acid chloride with methylamine yields the (RS)-1-{4-[2-(3-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methylamide as a light yellow solid; MS: m/e=341 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:10]=1[C:11]#[N:12]>CS(C)=O>[F:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:9]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[C:11]#[N:12]
Reactant: N#Cc1c(F)cccc1F
Reactant: Nc1ccccc1
Solvent: CS(C)=O
Product: N#Cc1c(F)cccc1Nc1ccccc1
Temperature: 25 °C

Procedure:
Aniline (4.66 g, 50 mmol) was dissolved in dimethyl sulfoxide (20 mL) and stirred under argon at room temperature. Sodium hydride, dry, 95% (1.51 g, 60 mmol) was added in portions and a deep purple color developed while the mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0° C. in an ice bath and 2,6-difluorobenzonitrile (7.15 g, 50 mmol) dissolved in dimethyl sulfoxide (5 mL) was added and the mixture stirred at room temperature for 1.5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic phase was washed with water (5×), brine (1×) dried over anhydrous Na2SO4 filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 0–25% CH2Cl2 in hexane to give the title compound as a white amorphous solid. ES (+) MS m/e=213 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][N:12]=[C:13]3[C:18]=2[N:17]=[C:16]([O:19][CH3:20])[CH:15]=[CH:14]3)=[N:7][CH:8]=1.[C-:21]#[N:22].[K+]>CCO.O>[CH3:20][O:19][C:16]1[N:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[C:9]2[C:6]1[N:7]=[CH:8][C:3]([CH2:2][C:21]#[N:22])=[CH:4][CH:5]=1
Reactant: [C-]#N
Reactant: COc1ccc2nccc(-c3ccc(CBr)cn3)c2n1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc2nccc(-c3ccc(CC#N)cn3)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.9 %

Procedure:
To a stirred solution of 8-(5-bromomethylpyridin-2-yl)-2-methoxy[1,5]naphthyridine (0.70 g, 2.12 mmole), in EtOH (50 mL) at 60° C. was added KCN (0.21 g, 3.18 mmole) in H2O (3 mL). After 1.5 h, the reaction contents were cooled to RT and concentrated under vacuum. The aqueous residue was dissolved in EtOAc and washed with H2O, and dried over Na2SO4. Concentration under vacuum and purification on silica (EtOAc) afforded the title compound (0.38 g, 65%) as light yellow solid: LC-MS (ES) m/e 277 (M+H)+.
Reaction SMILES: NO.[C:3]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][CH2:15][S:14][CH:13]2[C:17]([NH:19][CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][CH2:22]O)=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:36]([NH2:47])(=[O:46])[C:37]1[C:38](=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:39](N)=[O:40].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:3]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][CH2:15][S:14][CH:13]2[C:17]([NH:19][CH:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:21][CH2:22][N:47]2[C:36](=[O:46])[C:37]3[C:38](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:39]2=[O:40])=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(NC(CCO)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: NC(=O)c1ccccc1C(N)=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: NO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NC(CCN1C(=O)c2ccccc2C1=O)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57 %

Procedure:
Intermediates of general structure (XXVI), e.g., 3-([1,1′-biphenyl]-4-ylsulfonyl)-N-(3-hydroxy-1-phenylpropyl)-1,3-thiazolidine-2-carboxamide (1.0 g, 1.0 eq, 2.07 mmol) were dissolved in 20 ml dry THF under nitrogen. Phthalamide (395 mg, 1.5 eq, 2.69 mmol), diethylazodicarboxylate (470 mg, 1.5 eq, 2.69 mmol) and polymer bound triphenyl phosphine (1.0 g, 1.5 eq, 2.70 mmol) were then added and the reaction mixture was shaken for 12 hours at RT. The triphenyl phosphine resin was filtered off and the THF solution evaporated in vacuo. The residue was taken up in DCM and washed twice with a saturated sodium carbonate solution and then water. The organic layer was dried with magnesium sulfate and concentrated in vacuo to give a crude product which was purified on silica gel using cyclohexane/ethyl acetate(7/3) as eluent, to obtain the desired products, e.g., 3-([1,1′-biphenyl]-4-ylsulfonyl)-N-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide in 57% yield as a white oil in 96% purity by HPLC.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:25](OC1C=CC(C2C=CC(C#N)=CC=2)=CC=1)CCCCCCCC>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:25]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CCCCCCCCCOc1ccc(-c2ccc(C#N)cc2)cc1
Product: CCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In the synthesis of 4'-octyloxybiphenyl-4-caboxylic acid of Example 12, the same hydrolysis as in Example 12 was repeated except that 4'-nonyloxy-4-cyanobiphenyl was used instead of 4'-octyloxy-4-cyanobiphenyl to obtain 4'-nonyloxybiphenyl-4-carboxylic acid. This 4'-nonyloxybiphenyl-4-carboxylic acid was condensed with 4-(2-methylnonanoyl) phenol in the same manner as in the synthesis of 4-(2-methylnonanoyl) phenyl, 4'-octyloxybiphenyl-4-carboxylic acid ester of Example 13 to synthesize 4-(2-methylnonanoyl)phenyl, 4'-nonyloxybiphenyl-4-carboxylic acid ester having the aforementioned physical and chemical properties.
Reaction SMILES: O=S1(=O)[CH2:7][CH:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[CH2:9][CH2:10][NH:11][C@:12]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:45])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH2:39][CH:38]4[CH:36]([CH:37]4[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1.Cl.C12CC(NC1)C[O:55]2>>[C@H:3]12[CH2:8][CH:6]([N:5]([CH2:9][CH2:10][NH:11][C@:12]34[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:13]3[C@@H:14]3[C@@:27]([CH3:30])([CH2:28][CH2:29]4)[C@@:26]4([CH3:31])[C@@H:17]([C@:18]5([CH3:45])[C@@H:23]([CH2:24][CH2:25]4)[C:22]([CH3:32])([CH3:33])[C:21]([C:34]4[CH2:39][CH:38]6[CH:36]([CH:37]6[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:35]=4)=[CH:20][CH2:19]5)[CH2:16][CH2:15]3)[CH2:4]1)[CH2:7][O:55]2
Reactant: C1OC2CNC1C2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4CC3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4CC3CO4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared quantitative yield following the method described above for the preparation of ethyl 3-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S)-2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)bicyclo[3.1.0]hex-2-ene-6-carboxylate, using racemic (1S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride as the reactant. MS: m/e 685.6 (M+H)+, 2.83 min (method 6). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.80 (br. s., 1H), 5.51-5.37 (m, 1H), 4.73 (d, J=2.0 Hz, 1H), 4.59 (dd, J=2.3, 1.5 Hz, 1H), 4.42 (s, 1H), 4.18-4.10 (m, 2H), 4.07 (d, J=7.8 Hz, 1H), 3.65 (dd, J=7.7, 1.6 Hz, 1H), 3.50 (s, 1H), 2.95 (dd, J=9.8, 1.5 Hz, 1H), 2.95-2.40 (m, 8H), 2.18 (dt, J=6.5, 3.3 Hz, 1H), 2.09-1.96 (m, 3H), 1.92-1.72 (m, 6H), 1.71 (s, 3H), 1.68-1.31 (m, 9H), 1.30-1.10 (m, 10H), 1.08-0.8 (m, 16).