Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH:20]=[C:19]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[C:18]=3[CH:17]=2)=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>CCO.C1COCC1>[F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH:20]=[C:19]([C:28]4[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=4)[C:18]=3[CH:17]=2)=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)Nc4ccc(C(=O)O)c(F)c4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 41.6 mg (0.091 mmol) ethyl 2- fluoro-4-[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoate (Compound 40) in 2.0 ml EtOH and 2.0 ml of THF was added 40.0 mg NaOH (1.00 mmol, 1.0 ml of a 1M aqueous solution). After stirring at room temperature for overnight, the reaction was quenched by the addition of 10% HCl. Extraction with EtOAc, and drying of the organic layers over MgSO4, provided a solid after removal of the solvent under reduced pressure. Crystallization from CH3CN afforded the title compound as a pale-yellow solid. 1H NMR (d6-acetone): δ 9.84 (1H, s), 7.94-7.83 (3H, m), 7.64 (1H, dd, J=2.0 Hz), 7.53 (2H, d, J=8.1 Hz), 7.23 (4H, s), 6.04 (1H, t, J=4.7 Hz), 2.38 (2H, d, J=4.7 Hz), 2.36 (3H, s), 1.35 (6H, s).
Reaction SMILES: C([O:3][CH3:4])#N.N1[C:13]2[C:8](=[CH:9]C=CC=2)[CH2:7]C1.[C:14]([N:17]1[C:25]2[C:20](=[C:21]([CH3:31])[C:22](Br)=[C:23]([CH3:29])[C:24]=2[N+:26]([O-])=O)[CH:19]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:18]1)(=[O:16])[CH3:15]>C1C=CC=CC=1.[Pd]>[C:14]([N:17]1[C:25]2[C:20](=[C:21]([CH3:31])[CH:22]=[C:23]([CH3:29])[C:24]=2[NH:26][C:4](=[O:3])[C:8]([CH3:13])([CH3:9])[CH3:7])[CH:19]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:18]1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)CCC1CN(C(C)=O)c2c1c(C)c(Br)c(C)c2[N+](=O)[O-]
Reactant: COC#N
Reactant: c1ccc2c(c1)CCN2
Agent: [Pd]
Solvent: c1ccccc1
Product: CCOC(=O)CCC1CN(C(C)=O)c2c(NC(=O)C(C)(C)C)c(C)cc(C)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.26 (3H, t, J=7.1 Hz, CH2 CH3), 1.60˜2.20 (2H, m, —CH2 CH2 CO2—), 2.00·2.20 (2H, m, —CH2 CH2 CO2—), 2.23 (3H, s, >NCOCH3), 2.44, 2.47 (6H, s×2, —CH3x2), 3.10·3.60 (1H, m, Indoline C3—H), 4.00 (2H, m, Indoline C2—H), 4.10 (2H, q, J=7.1 Hz, —CH2 CH3). (8) 1-Acetyl-5-bromo-3-(2-ethoxycarbonylethyl)-4,6-dimethyl-7-nitro-indoline (2.7 g) was dissolved in benzene (100 ml), and 5% Pd—C. (500 mg) was added, which was followed by catalytic hydrogenation at room temperature under atmospheric pressure. Pd—C. was filtered off and benzene was evaporated under reduced pressure. CHCl3 (100 ml) was added to the residue, and the mixture was washed successively with saturated aqueous solution of sodium hydrogencarbonate and saturated brine and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was dissolved in CHCl3 (20 ml) and pivaloyl chloride (790 mg) and Et3N (80 mg) were added, which was followed by stirring at room temperature for 30 min. CHCl3 (100 ml) was added, and the mixture was washed successively with 5% aqueous citric acid and saturated brine and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=50/1−10/1) to give 2.6 g of N-[1-acetyl-3-(2-ethoxycarbonylethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]2[C:10]([CH3:29])=[CH:11][N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:28])[C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)[C:6]=2[N:5]=[C:4]1SC)[CH3:2].C(O)(=O)C>COCCOC.C(O)C.[Ni]>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]2[C:10]([CH3:29])=[CH:11][N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20](=[O:28])[C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)=[CH:18][CH:19]=3)[C:6]=2[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1c(SC)nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c1=O
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CCO
Solvent: COCCOC
Product: CCn1cnc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c1=O
Temperature: 40 °C
Yield: 74.8 %

Procedure:
In a mixture of DME (50 ml) and ethanol (2 ml) was dissolved 3-ethyl-7-[4-(4-fluorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (344 mg) followed by addition of acetic acid (224 mg), and the mixture was warmed to 40° C. Then, Raney nickel was added until disappearance of the starting compound had been verified by TLC. The catalyst was then filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution in that order, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was allowed to stand, whereupon crystals separated out. This crystal crop was harvested by filtration, rinsed with ethanol and hexane, and dried to provide the title compound (230 mg).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C@@H:27]([CH:34]3[CH2:36][CH2:35]3)[CH2:28][S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[C:17](=[O:37])[C@:16]([CH2:39]C(O)=O)([CH3:38])[CH2:15]2)[CH:11]=[CH:12][CH:13]=1.C[Si](C)(C)OC=C(O[Si](C)(C)C)O[Si](C)(C)C.Cl>ClCCl.O.C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C@@H:27]([CH:34]3[CH2:36][CH2:35]3)[CH2:28][S:29]([CH2:32][CH3:33])(=[O:30])=[O:31])[C:17](=[O:37])[C@:16]([CH2:38][C:1](=[O:5])[CH2:2][OH:3])([CH3:39])[CH2:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CCS(=O)(=O)C[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: C[Si](C)(C)OC=C(O[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)C[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)CO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (0.063 ml, 0.715 mmol) was added to a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 349, 0.316 g, 0.572 mmol) in dichloromethane (1.9 ml). The reaction was stirred for 3 h at room temperature. The solvents were removed in vacuo. To the solids was added tris(trimethylsiloxy)ethylene (0.42 ml, 1.26 mmol) and the reaction was stirred at 90° C. After 2 h, the reaction was cooled, charged with THF (1 mL) and HCl (1.4 M, 0.982 ml, 1.375 mmol), and brought to reflux for 30 min. After cooling, the reaction was poured into water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo. Silica gel chromatography (step gradient elution 1 to 5% 2 M ammonia in MeOH in dichloromethane) afforded the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2C([NH:9][C:10](=[O:11])[C:5]=12)=O.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].[C:20](=[O:23])([O-])[O-].[K+].[K+]>CN(C)C=O>[C:15]([NH:19][CH2:2][CH2:3][C:4]12[CH:14]=[CH:13][CH:12]=[CH:6][CH:5]1[C:10]([NH:9][C:20]2=[O:23])=[O:11])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)N
Reactant: O=C1NC(=O)c2c(CCBr)cccc21
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)NCCC12C=CC=CC1C(=O)NC2=O
Temperature: 50 °C

Procedure:
A mixture of 2-bromoethyl phthalimide (20 g, 2 equiv), tert-butylamine (41 ml, 1 equiv) and potassium carbonate (10.86 g, 2 equiv) in dimethylformamide (200 ml) was heated to 50° C. for 48 hours. Solvent was evaporated and the residue partitioned between dichloromethane and water. The organic phase was dried (K2CO3) and solvent removed to afford the title compound as an orange solid (18.93 g). 1H-NMR (CDCl3), δ 1.05 (9H, s), 2.85 (2H, t), 3.77 (2H, t), 7.72 (2H, m), 7.85 (2H, m)
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=[CH:7][N:6]=1)[C:2]#[CH:3].[OH-].[Na+].[I:20]I>C(O)C>[I:20][C:3]#[C:2][CH2:1][O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=[CH:7][N:6]=1
Reactant: C#CCOc1cc(Oc2ccccc2)ncn1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: IC#CCOc1cc(Oc2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 25.7 %

Procedure:
To a solution of 0.3 g of 4-(2-propynyloxy)-6-phenoxypyrimidine dissolved in 3 ml of ethanol were added 1.87 ml of 10% sodium hydroxide and 0.51 g of iodine at 0° C. The mixture was stirred at room temperature for 5 hours, and the alcohol was distilled out under reduced pressure. A saturated sodium thiosulfate solution was added to the residue, which was extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.12 g of 4-(3-iodo-2-propynyloxy)-6-phenoxypyrimidine (the present compound (171)).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=O)=[CH:10][CH:9]=1.O=S(Cl)Cl.[OH-].[Na+]>ClCCl.C(OCC)C>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([CH:12]2[NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4]2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(N)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)COC(c2ccc(Cl)cc2)N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.4 %

Procedure:
To a solution of 2-amino-2-methyl-propan-1-ol (59 g, 0.66 mol) in dichloromethane (120 mL) at 0° C. was added dropwise a solution of 4-chloro-benzoyl chloride (53 g, 0.3 mol) in dichloromethane (75 mL). The resulting mixture was stirred at r.t. for 2.5 h, then filtered and the filtrate was concentrated. Then SOCl2 (120 g, 1 mol) was added dropwise. The mixture was stirred at room temperature for overnight, then diluted with ethyl ether (150 mL). The resulting mixture was cooled in an ice bath, neutralized with aqueous NaOH (20%). The organic layer was separated, and aqueous layer was extracted with ethyl ether for 3 times. The organic lays were combined and washed with water twice, dried over anhydrous Na2SO4 and concentrated. The residue was distilled in vacuo to give the title product (25 g) as oil.
Reaction SMILES: [CH:1]1([N:11]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29]>C1COCC1>[CH:1]1([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCC2N1CCCNCC1
Reactant: CC(C)CCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CCN1CCCN(C2CCCc3ccccc32)CC1
Yield: 74.2 %

Procedure:
A 250 mL flask was charged with a solution of 1-(1,2,3,4-tetrahydronaphthyl)homopiperazine (2.68 g, 11.6 mmol) in THF (105 mL). Triethylamine (2.20 ml, 3.03 g, 29.9 mmol) and 1-bromo-3-methylbutane (2.00 ml, 1.59 g, 10.5 mmol) were added. The solution was immersed in a 60° C. oil bath for 16 hours during which time a precipitate formed. The resulting mixture was filtered and the filtrate was concentrated to give an orange oil. This crude product was purified by column chromatography using diethyl ether:hexane:methanol (5:5:1) to obtain the title compound as a yellow oil (2.34 g). 1H NMR (CDCl3, 300 MHz) δ 0.89 (d, 6H), 1.39 (m, 2H), 1.54-1.79 (m, 5H), 1.92-2.15 (m, 2H), 2.50 (m, 2H), 2.60-2.80 (m, 10H), 3.90 (m, 1H), 7.02-7.18 (m, 3H), 7.77 (d, 2H); m/s: M+H+ 301.
Reaction SMILES: [CH3:1][N:2]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][O:24][CH2:25]/[CH:26]=[CH:27]/[CH2:28][NH:29][CH3:30])[CH2:19][CH2:18]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:1][N:2]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][O:24][CH2:25]/[CH:26]=[CH:27]/[CH2:28][N:29]([CH3:30])[C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=2)[CH2:19][CH2:18]1)[S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:13])[F:14])=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: CNC/C=C/COC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reactant: Cc1nccc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nccc(N(C)C/C=C/COC[C@H]2CC[C@H](CN(C)S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)n1
Temperature: 25 °C

Procedure:
A solution of 77 mg (0.17 mmol) trans-N-methyl-N-[4-(4-methylamino-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide (example 20.6), 0.044 g (0.34 mmol) of 4-chloro-2-methyl-pyrimidine [Ger. Offen. (1990), DE3905364 A1] and 0.06 ml (0.34 mmol) N-ethyl-diisopropylamine in 1 ml of N,N-dimethylformamide was stirred for 2 hours at 80° C. The reaction mixture was then cooled to room temperature, poured into 30 ml of ice-water and extracted 3 times with 10 ml of ether. The combined ether phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 95:5:1 v/v/v mixture of dichloromethane, methanol and saturated aqueous ammonia as the eluent giving 55 mg (59%) trans-N-methyl-N-(4-{4-[methyl-(2-methyl-pyrimidin-4-yl)-amino]-(E)-but-2-enyloxymethyl}-cyclohexylmethyl)-4-trifluoromethyl-benzenesulfonamide as yellowish viscous oil, MS: 541 (MH+).
Reaction SMILES: C1C(=O)N(O[C:9]([O:11][N:12]2[C:17](=[O:18])[CH2:16][CH2:15][C:13]2=[O:14])=[O:10])C(=O)C1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:28])=[CH:22][CH:21]=1>CC#N>[C:36]([O:35][C:33]([NH:32][CH2:31][CH2:30][NH:29][C:27]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:9]([O:11][N:12]2[C:13](=[O:14])[CH2:15][CH2:16][C:17]2=[O:18])=[O:10])=[CH:21][CH:22]=1)=[O:28])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)NCCNC(=O)Nc1ccc(N)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNC(=O)Nc1ccc(NC(=O)ON2C(=O)CCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.3 %

Procedure:
N,N′-Disuccinimidylcarbonate (5.49 g, 21.44 mmol, 1.1 eq) was added at room temperature to a stirred solution of N-(4-aminophenyl)({2-[(tert-butoxy)carbonylamino]ethyl}amino)carboxamide (6.75 g, 19.49 mmol, 1.0 eq) in CH3CN (350 mL). After stirring overnight at room temperature, the reaction mixture was filtered and to afford 9.70 g of the expected crude product as a light brown solid.
Reaction SMILES: C([N:4]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([O:22]C)[CH:15]=2)[C:11]2[C:6](=[C:7]([O:26]C)[C:8]([O:24]C)=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])C.[ClH:28]>C(O)C>[OH2:3].[ClH:28].[OH:24][C:8]1[C:7]([OH:26])=[C:6]2[C:11]([C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:22])[CH:15]=3)[CH2:13][NH:4][CH2:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccc([C@H]2CN(C(C)=O)Cc3c2ccc(OC)c3OC)cc1OC
Agent: Cl
Solvent: CCO
Product: O
Product: Oc1ccc([C@H]2CNCc3c2ccc(O)c3O)cc1O

Procedure:
(i) To 1.15 g of (R)-(+)-N-acetyl-7,8-dihydroxy-4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline 1/4 hydrate were added 9 ml of 3N hydrochloric acid and 9 ml of ethanol, and the mixture was heated under an argon gas stream for 24 hours. After the reaction solution was cooled, the crystals which separated out were collected by filtration, affording 1.09 g of (R)-(+)-7,8-dihydroxy-4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride monohydrate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9]2)=[N:6][CH:7]=1.Cl.[F:19][C@@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([N:22]3[CH2:23][CH2:24][C@@H:20]([F:19])[CH2:21]3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: F[C@@H]1CCNC1
Reactant: CS(=O)(=O)O[C@@H]1CCN(c2ccc(Br)cn2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: F[C@@H]1CCN([C@H]2CCN(c3ccc(Br)cn3)C2)C1
Temperature: 70 °C
Yield: 98.6 %

Procedure:
Dissolve methanesulfonic acid (R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl ester (0.23 g, 0.71 mmol) and (R)-3-fluoro-pyrrolidine hydrochloride (107 mg, 0.85 mmol) in DMF (5 mL) and add Cs2CO3 (0.69 g, 2.13 mmol). Warm to 70° C. overnight. Dilute with EtOAc (100 mL) and wash with H2O (3×100 mL). Dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 75-100% EtOAc/hexane to give 0.22g (100%) of the title compound. 1H-NMR (CDCl3), δ 1.87-2.00 (m, 1H), 2.00-2.09 (m, 1H), 2.18-2.30 (m, 2H), 3.40-3.80 (m, 9H), 5.10-5.28 (m, 1H), 5.34-5.40 (m, 1H), 6.28 (d, J=9.0 Hz, 1H), 7.51 (dd, J=9.0, 2.4 Hz, 1H), 8.18 (d, J=2.4 Hz, 1H).
Reaction SMILES: [OH:1][C@H:2]([CH3:16])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[C:11]=2[N:13]=O)[CH:6]=[N:5]1.N1C=CC=CC=1.[CH3:23][O:24][CH2:25][C:26](Cl)=O>O1CCCC1.CN(C)C1C=CN=CC=1.[Pd]>[CH3:23][O:24][CH2:25][C:26]1[O:15][C:10]2[CH:9]=[CH:8][C:7]3[CH:6]=[N:5][N:4]([CH2:3][C@H:2]([OH:1])[CH3:16])[C:12]=3[C:11]=2[N:13]=1
Reactant: COCC(=O)Cl
Reactant: C[C@@H](O)Cn1ncc2ccc(O)c(N=O)c21
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCc1nc2c(ccc3cnn(C[C@@H](C)O)c32)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0 %

Procedure:
A solution of the product from Step A (1.05 g, 4.75 mol) in tetrahydrofuran (50 mL) containing 10% palladium-on-carbon (0.1 g) was stirred under an atmosphere of hydrogen at room temperature for 18 hours. The reaction mixture was filtered, pyridine (1.0 mL, 12.3 mol) and methoxy acetyl chloride (0.43 mL, 4.75 mol) were added, and this mixture was stirred at room temperature. More pyridine (5.0 mL) was added and the reaction mixture was stirred at room temperature for 20 minutes followed by the addition of 4-dimethylaminopyridine (0.1 g); this mixture was heated at 60° C. for 3 hours followed by removal of solvents by heating at 220° C. for 30 minutes. The resulting dark liquid was purified by chromatography (silica gel, hexane/ethyl acetate gradient) to give a yellow oil (200 mg, 16%): LC/MS m/z 262.
Reaction SMILES: N1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[C:7]1=O)[CH2:13]2.[CH:17]1CC=C[CH:18]=1>CO>[C:6]12([C:2]3[C:17](=[CH2:18])[CH:5]=[CH:4][CH:3]=3)[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2
Reactant: C1=CCC=C1
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: C1CCNC1
Solvent: CO
Product: C=C1C=CC=C1C12CC3CC(CC(C3)C1)C2
Reaction time: 92 h
Yield: 104.4 %

Procedure:
Pyrrolidine (10.0 mL, 0.116 mol) was syringed into a solution of 2-adamantanone (25.00 g, 0.1664 mol) and cyclopentadiene (30.0 mL, 0.364 mol) in 250 mL of methanol. The reaction was stirred for 92 hours before the yellow precipitate was collected by suction filtration, rinsed with a small volume of methanol and dried in vacuo. 25.71 grams (77.9%) of adamantyl fulvene were isolated. 6.00 grams (0.0303 mol) of this product were dissolved in 30 mL of tetrahydrofuran and this solution added over 30 minutes to at stirred slurry of LiAlH4 (1.40 g, 0.0369 mol) at 0° C. After 5 hours of stirring at room temperature, the reaction was cooled to 0° C. and quenched by slow addition of 20 mL of saturated NH4Cl solution. Then 300 mL H2O, 25 mL concentrated HCl, and 50 mL diethyl ether were added, the organic layer isolated, and the aqueous layer extracted with addition diethyl ether (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and rotavapped to give the product, (2-adamantyl)cyclopentadiene, in quantitative yield as a light yellow oil. To this material was added 50 mL methanol, 50 mL ethanol, 20 mL tetrahydrofuran, 36 mL acetone (0.49 mol) and 0.5 mL pyrrolidine (0.006 mol). After stirring for 48 hours, 5 mL of acetic acid were injected, followed by 200 mL H2O and 200 mL diethyl ether. The organic layer was isolated and the aqueous layer extracted with diethyl ether (3×40 mL). The combined organic layers were extracted with H2O (3×25 mL) and with 10% aqueous NaOH (3×25 mL), dried over MgSO4, filtered and rotavapped. The obtained yellow solid was further purified by overnight soxlet extraction by 150 mL methanol. The precipitate in the filtrate was isolated by filtration at 0° C., and in vacuo drying: 4.54 g (62.5%) of 3-(2-adamantyl)-6,6-dimethylfulvene, as a yellow powder.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11](Cl)[CH:10]=1>CN1C(=O)CCC1.O>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([NH2:8])=[CH:10][C:11]=1[O:7][CH2:6][CH2:5][O:4][CH3:3])#[N:14]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COCCOc1cc(N)ccc1C#N
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 39.5 %

Procedure:
Sodium hydride (300 mg of an 80% suspension in mineral oil, 10 mmol) was added to 2-methoxyethanol (0.76 g, 10 mmol) in NMP (5 ml) and the mixture stirred for 15 minutes. 4-Amino-2-chlorobenzonitrile (1.5 g, 10 mmol) was added and the mixture heated at 100° C. for 5 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate (3×50 ml). The combined extracts were dried (MgSO4) and the solvent removed by evaporation. The residue was purified by chromatography eluting with increasingly polar mixtures of methylene chloride/ethyl acetate to give 4-cyano-3-(2-methoxyethoxy)aniline (760 mg, 40%) as a dark yellow oil.
Reaction SMILES: [CH3:1][S:2]CCl.[CH2:5]([S:8][C:9]1[NH:10][C:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)C=C>>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:11]2[N:10]=[C:9]([S:8][CH2:5][S:2][CH3:1])[NH:13][C:12]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:27][CH:26]=1
Reactant: CSCCl
Reactant: C=CCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)[nH]1
Product: COc1ccc(-c2nc(SCSC)[nH]c2-c2ccc(OC)cc2)cc1

Procedure:
By substituting chloromethyl methyl sulfide for the allyl bromide of Example 11 one obtains as product 4,5-bis-(4-methoxyphenyl)-2-(methylthiomethylthio)imidazole, m.p. 171°-172°.