Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]([NH2:16])([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:17][CH:18]([CH:22]([CH3:24])[CH3:23])[C:19](Cl)=[O:20]>C(N(CC)CC)C>[CH3:7][C:8]([NH:16][C:19](=[O:20])[CH:18]([Br:17])[CH:22]([CH3:24])[CH3:23])([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(C)C(Br)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)C(Br)C(=O)NC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
Into a 200 ml four necked flask, there were charged benzene (100 ml), α,α-dimethylbenzylamine (9 g) and triethylamine (7.4 g), and α-bromo-isovaleryl chloride (13.3 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. The reaction mixture was washed with water to remove triethylamine hydrochloride. After the benzene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give 16.9 g of N-(α,α-dimethylbenzyl)-α-bromo-isovaleramide. M.P., 128°-129.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([CH2:18]Cl)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[C:20]([C:23]1[NH:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])[CH3:21].[I-].[Na+].[OH-].[Na+]>O.CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([CH2:18][N:24]3[CH:25]=[CH:26][CH:27]=[C:23]3[C:20](=[O:22])[CH3:21])[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CC(=O)c1ccc[nH]1
Reactant: CCOc1ccc(-c2nc(CCl)cs2)cc1OCC
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(-c2nc(Cn3cccc3C(C)=O)cs2)cc1OCC
Temperature: 80 °C
Reaction time: 4 h
Yield: 24.2 %

Procedure:
In a mixed solvent consisting of 2 ml of dimethylformamide and 0.2 ml of water were dissolved 200 mg of 2-(3,4-diethoxyphenyl)-4-chloromethylthiazole, 73 mg of 2-acetylpyrrole, 200 mg of sodium iodide and 200 mg of sodium hydroxide. The solution was stirred at 80° C. for 4 hours. The reaction mixture was subjected to distillation to remove the solvent. To the residue were added 30 ml of dichloromethane and 20 ml of water, and phase separation was conducted. The organic layer was washed with 15 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was recrystallized from methanol to obtain 60 mg of 2-(3,4-diethoxyphenyl)-4-(2-acetyl-1-pyrrolyl)methylthiazole as white acicular crystals.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[F:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[CH:19][CH:20]=1>[Pd]>[F:14][C:15]1[CH:20]=[C:19]([CH:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH2:3]2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: Fc1cccc([Mg]Br)c1
Agent: [Pd]
Product: COC(=O)c1cc2c([nH]1)CCC2c1cccc(F)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.5 g, 2.79 mmol) was reacted with (3-fluorophenyl)magnesium bromide (14 mL, 6.97 mmol, 0.5 M in THF, 2.5 equiv) according to General Procedure 3. The resulting endo-olefin (methyl 4-(3-fluorophenyl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate) was converted to the title compound by hydrogenation according to General Procedure 6 (with 5% Pd/C). The crude product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford the title compound: 150 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.24-2.35 (m, 1H), 2.73-3.01 (m, 3H), 3.84 (s, 3H) 4.22 (t, J=7.13 Hz, 1H), 6.65 (d, J=1.46 Hz, 1H), 6.86-6.93 (m, 2H) 7.00 (d, J=7.66 Hz, 1H), 7.19-7.30 (m, 1H) 9.07-9.28 (m, 1H).
Reaction SMILES: C([O:4][C@@H:5]1[C@:9]([CH2:18][CH:19]=[CH2:20])([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:7][C@H:6]1[N:30]1[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]1=[O:32])(=O)C.C[O-].[Na+].Cl>CO>[CH2:18]([C@@:9]1([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([CH2:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:7][C@@H:6]([N:30]2[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[C@@H:5]1[OH:4])[CH:19]=[CH2:20]
Reactant: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1O

Procedure:
To a stirred solution of nucleoside 1 (11.6 g, 22.3 mmol) in methanol (110 cm3) was added sodium methoxide (3.03 9, 55.5 mmol). The reaction mixture was stirred at room temperature for 16 h and neutralised with dilute hydrochloric acid. The solvent was partly evaporated and the residue was dissolved in dichloromethane (2×400 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogen-carbonate (3×250 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure to give 2 as a white solid material (10.1 g, 95%). δH (CDCl3) 8.77 (1H, br s, NH), 7.58 (1H , d, J 1.2, 6-H), 7.41-7.25 (10 H, m, Bn), 6.14 (1H, m, 2″-H), 6.12 (1H, d, J7.8, 1′-H), 5.23 (1H, m, 3″-Ha), 5.17 (1H, br s, 3″-Hb), 4.68 (1H, d, J 10.8, Bn), 4.59 (2 H, s, Bn), 4.55 (1H, d, J 10.9, Bn), 4.39 (1H, br s, 4′-H), 4.26 (1H, dd J 7.8, 10.7, 2′-H), 3.84 (1H, dd, J 3.1, 11.0, 5′-Ha), 3.58 (1H, dd, J 1.4, 11.0, 5′-15 Hb), 3.04 (1H, d, J 10.8, 2′-OH), 2.82-2.78 (2 H, m, 1″-Ha, 1″-Hb), 1.51 (3 H, d, J 1.0, CH3). δC (CDCl3) 163.5 (C-4), 151.1 (C-2), 137.3, 136.7 (Bn), 136.0 (C-6), 132.1 (C-2″), 128.8, 128.5, 128.3, 127.9, 127.6 (Bn), 118.4 (C-3″), 111.1 (C-5), 87.4, 82.6, 81.1, 79.3 (C-1′, C-2′, C-3′, C-4′), 73.7, 69.8 (Bn), 64.7 (C-5′), 35.1 (C-1″), 11.9 (CH3). (Found: C, 67.8; H, 6.1; N, 5.5. C27 H30N2O6 requires C, 67.8; H, 6.3; N, 20 5.9%).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:21])[NH:10][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:28]([O:34][C@@H:35]1[C@@H:40]([O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[C@H:39]([O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:38]([CH2:55][O:56][C:57](=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])[O:37][C@@H:36]1Br)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].O>C(#N)C>[CH2:1]([C:8]1[C:9]([O:21][C@@H:36]2[O:37][C@H:38]([CH2:55][O:56][C:57](=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])[C@@H:39]([O:48][C:49](=[O:54])[C:50]([CH3:51])([CH3:52])[CH3:53])[C@H:40]([O:41][C:42](=[O:47])[C:43]([CH3:44])([CH3:45])[CH3:46])[C@H:35]2[O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:30])[CH3:31])=[N:10][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: CCOC(=O)n1[nH]c(=O)c(Cc2ccccc2)c1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccccc2)c1C(C)C
Temperature: 25 °C
Yield: 55 %

Procedure:
To a solution of 4-benzyl-1-ethoxycarbonyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (0.100 g) in acetonitrile (3 mL) were added potassium carbonate (0.0575 g) and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (0.211 g) successively under stirring at room temperature. In addition, the mixture was stirred at 50° C. for 2.5 hours. The mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/8 to 1/5 to 1/4) to give 4-benzyl-1-ethoxycarbonyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.15 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:14]([N:15]=1)=[CH:13][C:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=1[CH:5]=2.[Cl:16][CH2:17][CH2:18][CH2:19][S:20][C:21]1[N:25]([CH3:26])[C:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=2)=[N:23][N:22]=1>>[ClH:16].[F:34][C:29]1[CH:28]=[C:27]([C:24]2[N:25]([CH3:26])[C:21]([S:20][CH2:19][CH2:18][CH2:17][N:10]3[CH2:9][CH2:8][C:7]4[CH:13]=[C:14]5[N:15]=[C:2]([CH3:1])[O:3][C:4]5=[CH:5][C:6]=4[CH2:12][CH2:11]3)=[N:22][N:23]=2)[CH:32]=[CH:31][C:30]=1[F:33]
Reactant: Cn1c(SCCCCl)nnc1-c1ccc(F)c(F)c1
Reactant: Cc1nc2cc3c(cc2o1)CCNCC3
Product: Cc1nc2cc3c(cc2o1)CCN(CCCSc1nnc(-c2ccc(F)c(F)c2)n1C)CC3
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-methyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (0.25 mmol) and 3-[(3-chloropropyl)thio]-5-(3,4-difluorophenyl)-4-methyl-4H-1,2,4-triazole and was obtained as a faint yellow slightly hygroscopic solid (0.11 mmol).
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[CH3:18][NH2:19]>C1COCC1.O>[C:4]1(=[O:12])[N:5]([CH2:6][CH3:7])[C:1](=[O:17])[C:2]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:3]12.[CH3:18][NH:19][SH:8](=[O:9])=[O:10]
Reactant: CN
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CCN1C(=O)c2ccccc2C1=O
Product: CN[SH](=O)=O
Temperature: 25 °C

Procedure:
2-Phthalimidoethanesulfonyl chloride (2.0 g) was added portion wise to a solution of 2.0 M methylamine in THF (15 ml) and the solution obtained this way was stirred at room temperature. After 48 hours the reaction mixture was poured in water (50 ml) causing the title compound to precipitate. The product was collected by filtration and recrystallized from EtOH:water, 50:1 to yield: 1.04 g (48%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][C:36]2[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=2[F:43])=[O:34])=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH:19]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:20]([OH:22])=O)=[O:17])[CH:12]=2)[CH:6]=1.CN(C(O[N:52]1N=N[C:54]2C=CC=N[C:53]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl>O1CCCC1.O>[CH2:53]([NH:52][C:20](=[O:22])[CH:19]([NH:18][C:16]([C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]([O:4][C:3]3[CH:29]=[C:30]([C:33]([NH:35][C:36]4[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=4[F:43])=[O:34])[CH:31]=[CH:32][C:2]=3[F:1])[CH:10]=[CH:9][N:8]=2)[NH:15][CH:14]=1)=[O:17])[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:54]
Reactant: COC(=O)CCC(NC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)C(CCC(=O)OC)NC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5-methoxy-5-oxopentanoic acid (260 mg, 0.44 mmol) in 20 ml of anhydrous tetrahydrofuran were added HATU (200 mg, 0.53 mmol) and N,N-diisopropylethylamine (170 mg, 1.32 mmol). The mixture was heated at 60° C. for 15 minutes and cooled to room temperature, followed by addition of 2-Methylamine solution in THF (0.44 ml, 0.88 mmol). The mixture was stirred for another 5 minutes, and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 2˜5% methanol in chloroform to give methyl 5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5-oxopentanoate as white solid. Yield: 127 mg, 47%.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:26][O:27][Si](C(C)(C)C)(C)C)[C@@H:10]([NH:19][S@](C(C)(C)C)=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.COC1C=CC(C=O)=CC=1.[O:46](C(OC(C)(C)C)=O)[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=O>C(OCC)C.CCO>[Si:1]([O:8][C@H:9]([CH2:26][OH:27])[C@@H:10]([NH:19][C:47](=[O:46])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[S@](=O)N[C@@H](Cc1cccc(F)c1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: COc1ccc(C=O)cc1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(F)c1)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 500 mL RBF containing (S)—N-((2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)butan-2-yl)-2-methylpropane-2-sulfinamide (2.600 g, 4.9 mmol) was added EtOH (25 ml) and the mixture was allowed to stir at 0° C. for 15 min. At this time, HCl (4N in dioxane) (3.7 ml, 15 mmol) was added via syringe. The reaction was monitored at 1 h by LC/MS 76877-2-1 and tlc (100% EtOAC amino bis TBS; Rf=0.80 UV active stains orange to anisaldehyde amine with primary alcohol deprotected Rf=0.45 to 0.1 streak, UV active and stains white to anisaldehyde). The reaction was allowed to stir for 3 h at 0° C. and then TEA (4.1 ml, 29 mmol) was added fast dropwise and a white solid formed. An LC/Ms was obtained to confirm that the secondary TBS ether was not removed during the TEA neutralization process. Approximately 15 mL of EtOH were removed by rotary evaporator and then DCM (10 mL) was added and the solid went into solution. At this time, (BOC)2O (2.3 ml, 9.8 mmol) was added in one portion and the reaction was allowed to stir for 1 h and then poured into diethyl ether (300 ml). The organic layer was washed with ammonium chloride (3×150 mL, sat) and brine. The organic layer was dried with magnesium sulfate, filtered and concentrated to give a colorless crude oil. The desired product has an Rf=0.40 in 35% EtOAc in hexanes, UV active, stains white to anisaldehyde and purple to moly stain. The crude oil was purified on a 120 g Isco column (10 to 35% EtOAc in hexanes) to give the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:26].C(=O)([O-])[O-].[Na+].[Na+].[CH2:33]([N:35]([CH2:39][CH3:40])[C:36]([Cl:38])=[O:37])[CH3:34]>CC(C)=O>[ClH:38].[ClH:38].[CH2:33]([N:35]([CH2:39][CH3:40])[C:36]([N:23]1[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]2[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]3[C:10]=2[N:9]=[CH:8][CH:7]=[C:6]3[CH3:26])[CH2:25][CH2:24]1)=[O:37])[CH3:34]
Reactant: COc1cc(NCCCCCCN2CCNCC2)c2nccc(C)c2c1
Reactant: CCN(CC)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCN(CC)C(=O)N1CCN(CCCCCCNc2cc(OC)cc3c(C)ccnc23)CC1
Product: Cl
Yield: 108.1 %

Procedure:
To a mixture of 2.4 g (0.00673 mole) of 6-methoxy-4-methyl-N-[6-(1-piperazinyl)hexyl]-8-quinolinamine and 1.7 g (0.016 mole) of sodium carbonate in 50 ml of acetone was added a solution of 1.8 g (0.007 mole) of diethylcarbamoylchloride in 20 ml of acetone. The mixture was stirred under gentle reflux for 2 hr, allowed to cool, filtered and concentrated to dryness in vacuo. A solution of the residue in dichloromethane was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Chromatography of the residue over 70 g of silica with 10% methanol in ethyl acetate afforded 2 g of product, Rf=0.3. The material was triturated with 2-propanol containing excess hydrogen chloride. The resulting yellow precipitate was collected, washed with 2-propanol and then ether, dried in vacuo at 52° overnight and air-equilibrated to afford 1.8 g (50%) of the title compound, mp 226°-228° (dec).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:10]=[C:9]1[C:22]([O:24]C(C)(C)C)=[O:23])=O)(C)(C)C>Cl.O1CCOCC1>[F:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][CH2:13][C@@H:11]1[CH2:12][NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10]1
Reactant: CC(C)(C)OC(=O)C1=CC(COc2cccc(F)c2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1C[C@H](COc2cccc(F)c2)CN1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4-(3-fluoro-phenoxymethyl)-pyrroline-1,2-dicarboxylic acid di-tert-butyl ester (Preparation 44, 475 mg, 1.2 mmol) was dissolved in a solution of anhydrous hydrogen chloride in dioxane (4M, 15 ml) and stirred at 50° C. under a nitrogen atmosphere for 1 hour. The solvent was removed under reduced pressure and the resulting semi-solid triturated with ethyl acetate to give a white solid which was recrystallised from ethyl acetate/isopropyl alcohol to give the title compound as a mixture of diastereomers (˜5:1 2S,4S:2S,4R) as a white solid hydrochloride salt (90 mg, 35%)
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:18]12([CH2:28][NH2:29])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[C:18]12([CH2:28][NH:29][C:9](=[O:11])[CH2:8][S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:25][CH:24]3[CH2:23][CH:22]([CH2:21][CH:20]([CH2:26]3)[CH2:19]1)[CH2:27]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)CSc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CSc1ccccc1)NCC12CC3CC(CC(C3)C1)C2
Reaction time: 2 h

Procedure:
A room temperature solution of (phenylsulfanyl)acetic acid (1.68 g, 10.0 mmol) in dichloromethane (10 mL) was treated with 2M oxalyl chloride in dichloromethane (8 mL, 16.0 mmol) and DMF (1 drop), stirred for 2 hours, concentrated, dissolved in dichloromethane (10 mL), treated with 1-adamantylmethylamine (1.65 g, 10.0 mmol) and N,N-diisopropylethylamine (2.1 mL, 12.0 mmol), and stirred for 1 hour. The mixture was filtered through a pad of silica gel (20 g) and concentrated to provide the desired product of sufficient purity for subsequent use.
Reaction SMILES: N1C=CC=CC=1.[OH-].[K+].[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18].[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([CH3:36])[C:28]=1[S:29]([CH2:32][N+:33]([O-:35])=[O:34])(=[O:31])=[O:30])[NH2:25].Cl>O1CCCC1.O>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[S:17]([NH:25][C:24]1[CH:23]=[C:22]([CH3:21])[C:28]([S:29]([CH2:32][N+:33]([O-:35])=[O:34])(=[O:31])=[O:30])=[C:27]([CH3:36])[CH:26]=1)(=[O:19])=[O:18]
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2ccc(F)cc2F)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 2 h
Yield: 22.1 %

Procedure:
0.65 g (8.22 mmol) of pyridine, dried over potassium hydroxide, and 1.3 g (6.11 mmol) of 2,4-difluorobenzenesulphonyl chloride are successively added to a solution, cooled to about 10° C., of 1.0 g (4.09 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 20 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for 2 h at 10° C. and then for 20 h at room temperature, after which it is poured into 100 ml of water. The mixture is brought to pH 3 by addition of concentrated hydrochloric acid and then extracted with methylene chloride. The combined organic extracts are washed with water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The oily residue obtained is purified by chromatography on a column of silica (eluent: methylene chloride) and by recrystallization from toluene, to give 0.38 g (22%) of 2,4-difluoro-N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]benzenesulphonamide.
Reaction SMILES: [C:1]1([N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:31](OC)[N:32]([CH3:34])[CH3:33]>>[C:1]1([N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH:21]=[CH:31][N:32]([CH3:34])[CH3:33])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Product: CN(C)C=CC(=O)c1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Yield: 95.6 %

Procedure:
1-(4′-Diphenylaminobiphenyl-4-yl)ethanone (1.0 g, 2.75 mmol) was reacted with N,N-dimethylformamide dimethylacetal (1.0 g, 8.25 mmol) for 12 hours at 100° C. Non-reacted N,N-dimethylformamide dimethylacetal was removed using a vacuum pump, and water (50 mL) and dichloromethane (100 mL×2) added. The organic layer was separated, filtered, dried and evaporated to obtain the title compound (1.1 g).
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[C:12]1([C:17]2[C:26]([CH:27]([OH:38])[C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[C:25]([CH:39]([CH3:41])[CH3:40])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:44])[CH2:20][C:21]([CH3:43])([CH3:42])[O:22]3)[CH2:16][CH2:15][CH2:14][CH:13]=1.CO>O1CCCC1>[CH:12]1([C:17]2[C:26]([CH:27]([OH:38])[C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=3)=[C:25]([CH:39]([CH3:40])[CH3:41])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:44])[CH2:20][C:21]([CH3:42])([CH3:43])[O:22]3)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)c1cc2c(c(C3=CCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(C3CCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 0.5 h

Procedure:
155 μl (872 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 4.9 mg (33 μmol) of (1R,2S)-1-aminoindan-2-ol in 5.0 ml of tetrahydrofuran, and the mixture is stirred for 30 min. A solution of 100 mg (218 μmol) of 5-cyclopent-1-en-1-yl-6-{hydroxy[4-(trifluoromethyl)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 36A) in 5.0 ml of tetrahydrofuran is then, very slowly, added dropwise, and the mixture is stirred for 4 h. Methanol is then added, and the mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. The crude product is purified by preparative HPLC (method 1). In addition to the title compound, the compounds described as Preparation Examples 22 and 23 are also isolated (for yield and analytical data see there).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH2:9][CH2:10][CH2:11][CH3:12])[N:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([O:29]C(C)(C)C)=[O:28])=[CH:17][CH:16]=1.[NH+]1C=CC=NC=1.[OH-].[Na+].FC(F)(F)C(O)=[O:45]>CN(C=O)C.CO>[CH2:9]([CH:4]1[NH:3][C:2](=[O:45])[CH:7]=[C:6]([CH3:8])[N:5]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([OH:29])=[O:28])=[CH:17][CH:16]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1nc(C)cc(N)n1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Agent: c1cnc[nH+]c1
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCC1NC(=O)C=C(C)N1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Heating 4-amino-2-n-butyl-6-methylpyrimidine (from Example 27) with 4-bromomethyl-2'-t-butoxycarbonylbiphenyl in an appropriate solvent such as methanol or DMF, followed by treatment of the intermediate pyrimidinium species with aqueous base such as 0.1N sodium hydroxide as described by Brown, Hoerger, and Mason (J. Chem. Soc., 1955, 4035), followed by treatment with neat trifluoroacetic acid to achieve final deprotection of the carboxyl group, provides the title compound.