Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)=[O:12].CCCCCC.C(OCC)(=O)C>ClCCl.[Cu]>[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)(=[O:12])[CH3:10]
Reactant: COc1ccc(I)cc1
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: [Cu]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(C(C)=O)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 120 h
Yield: 36 %

Procedure:
A stirred mixture of 4-iodoanisole (43.65 g, 0.187 mole), 4-bromo-3-nitro acetophenone (40.6 g, 0.166 mole) and copper powder (copper bronze, 36 g, 0.567 mole) kept under nitrogen is placed in an oil bath heated at 80° C. The temperature is slowly raised to 110° C. and the mixture is kept at this temperature for 5 days (TLC, 8:2 hexane-ethyl acetate). Upon cooling the mixture is dissolved in dichloromethane and filtered through a Celite pad. The filtrate and washings are evaporated and the residual thick, dark brown oil (58.4 g) is flash chromatographed (on silica Merck 60, preabsorbed in dichloromethane, eluted with 9:1 hexane-ethyl acetate to remove the impurities and 8:2 hexane-ethyl acetate to recover the main product) to provide 16.2 g (32%) of the title compound (yellow solid, m.p. 124°-126° C.).
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Si](C)(C)C)=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:22]([CH3:23])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].[K+].[Br-:25].C1C(=O)N(Cl)C(=O)C1.O>C(O)(=O)C.CO.CCOCC>[C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Br:25])=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:22]([CH3:23])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc([Si](C)(C)C)cc2)C[C@@H]2CC[C@H]1N2C
Reactant: [Br-]
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H]1[C@@H](c2ccc(Br)cc2)C[C@@H]2CC[C@H]1N2C
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 100.3 %

Procedure:
A mixture of 2β-Carbomethoxy-3β-(4′-trimethylsilylphenyl)tropane (594 mg, 1.79 mmol) and KBr (320 mg, 2.68 mmol) in 15 mL of acetic acid and 2 mL of MeOH was stirred at 60° C. for 20 min. 285 mg of NCS (2.15 mmol) was added at one time and the resulting mixture was stirred at the same temperature for 4 hrs. After cooling to rt 100 mL of H2O and 50 mL of Et2O were added. The aqueous phase was separated and the organic phase was extracted with 3N HCl (20 mL). The combined aqueous phase was washed with 20 mL of Et2O, basified with concentrated NH4OH and extracted with CH2Cl2 (2×50 mL). The solution was then dried and the removal of the solvent in vacuo gave the pure product as a white solid (607 mg, 100%). m.p. 114-116° C. 1H NMR (CDCl3, 400 MHz) δ 7.38 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 1H), 3.58-3.55 (m, 1H), 3.51 (s, 3H), 3.38-3.36 (m, 1H), 2.98-2.86 (m, 2H), 2.56 (dt, J−12.8, 2.8 Hz, 1H), 2.23 (s, 3H), 2.26.2.05 (m, 2H), 1.75-1.58 (m, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:27].[OH-].[Na+]>C(O)CO.O1CCOCC1.[Cu-]=O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:10]1[C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:12][C:8]([C:6]2[N:7]=[C:2]([NH2:27])[CH:3]=[CH:4][CH:5]=2)=[N:9]1
Reactant: [NH4+]
Reactant: Fc1ccccc1Cn1nc(-c2cccc(Br)n2)nc1-c1nccs1
Agent: O=[Cu-]
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: C1COCCO1
Product: Nc1cccc(-c2nc(-c3nccs3)n(Cc3ccccc3F)n2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 2-(3-(6-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiazole (I-19) and copper(I) oxide (e.g., about 0.2 eq) in ethylene glycol-dioxane (e.g., about 4:1) in a sealed tube is added ammonium hydroxide solution (e.g., ˜29% in water, ˜30 eq). The resultant mixture is warmed to about 100° C. and stirred at that temperature for about 24 h. The reaction solution is cooled to room temperature, poured into 1N NaOH solution and then extracted with EtOAc. The organic phases are dried, e.g., over Na2SO4 or MgSO4, filtered and concentrated. The crude product is purified using SiO2 chromatography and an appropriate gradient (EtOAc/hexanes) to give 6-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-2-amine (I-14) as a solid.
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][CH2:16][NH2:17].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CS(C)=O>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:13]([C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:3]=2)[CH2:14][CH2:15][CH2:16][NH2:17])=[CH:21][CH:20]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: NCCCNc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: NCCCN(Cc1ccc(Br)cc1)c1ccc2ccccc2n1
Temperature: 0 °C
Yield: 97.3 %

Procedure:
To a mixture of sodium hydride (2.64 g, 60% dispersion in mineral oil, 63.79 mmol) in dry dimethylsulfoxide (100 ml) was slowly added a solution of N-(quinolin-2-yl)propane-1,3-diamine (12 g, 56.62 mmol) in dry dimethylsulfoxide (25 ml) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred until gas evolution was ceased. To the resulting mixture a solution of 4-bromobenzylbromide (16.27 g, 63.79 mmol) in dry dimethylsulfoxide (50 ml) was slowly added at room temperature. The reaction mixture was stirred for 4 days at room temperature poured on to ice water (800 ml) and extracted with ethyl acetate (5×150 ml). The combined organic extracts were washed with water (4×150 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue (22.27 g) was washed with n-heptane (30 ml) which afforded 20.41 g of crude N-(4-bromobenzyl)-N-(quinolin-2-yl)propane-1,3-diamine which was purified by column chromatography on silica gel (900 ml) using a mixture of dichloromethane/methanol/triethylamine 9:0.5:0.5 as eluent affording 13.9 g (63%) of N-(4-bromobenzyl)-N-(quinolin-2-yl)propane-1,3-diamine as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:14]P(Br)Br>O>[Br:1][C:2]1[C:3]([Br:14])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cnc(O)c(Br)c1
Reactant: BrP(Br)Br
Solvent: O
Product: CCOC(=O)c1cnc(Br)c(Br)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
A mixture of ethyl 5-bromo-6-hydroxynicotinate (preparation 47a, 6.35 g, 25.8 mmol), tribromophosphine (2.50 mL, 26 mmol) and phosphorus oxytribromide (7.50 g, 26.2 mmol) was stirred at 120° C. After 3 hours, the mixture was cooled, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to yield the title compound (6.88 g, 86%) as a white solid.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18].[CH:24](O)=[O:25]>ClCCl>[CH:24]([NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:25]
Reactant: O=CO
Reactant: COC(=O)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(NC=O)c1
Temperature: 0 °C

Procedure:
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.47 g) was added to a mixture of methyl 3-aminobenzoate (1.50 g), formic acid (748 μL) and dichloromethane (15 mL) under cooling with ice-water, and the mixture was stirred at the same temperature for ten minutes under nitrogen atmosphere and stirred at room temperature for fourteen hours. The reaction mixture was poured into ice-water (30 mL) to be separated and the aqueous layer was extracted with dichloromethane. The organic layer was washed with water and an aqueous sodium hydrogencarbonate solution successively, and dried over anhydrous sodium sulfate. After the solvent was removed under reduced pressure, the residue obtained was washed with ether and dried to obtain the titled compound (1.61 g) as crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[CH:11]([CH3:17])[C:12]([CH:14]1[CH2:16][CH2:15]1)=O.[Cl-].[Cl-].[Ca+2]>CN(C=O)C>[CH:14]1([C:12]2[N:8]=[C:5]3[C:4]([CH3:9])=[CH:3][C:2]([I:1])=[CH:7][N:6]3[C:11]=2[CH3:17])[CH2:16][CH2:15]1
Reactant: CC(Br)C(=O)C1CC1
Reactant: Cc1cc(I)cnc1N
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1cc(I)cn2c(C)c(C3CC3)nc12
Yield: 52 %

Procedure:
A mixture of 5-iodo-3-methylpyridin-2-amine (100 mg), 2-bromo-1-cyclopropylpropan-1-one (113 mg) and DMF (1 ml) was stirred at 80° C. under a dry atmosphere (CaCl2 tube) overnight. The mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (69.3 mg) as a pale yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@H:16]([C:32]([N:34]1[C@H:39]([C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[CH:38]2[CH2:50][CH2:51][CH:35]1[CH2:36][CH2:37]2)=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=O)(C)(C)C>C(Cl)Cl>[CH2:25]([O:24][C:22]([NH:21][CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]([C:32]([N:34]1[C@H:39]([C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[CH:38]2[CH2:50][CH2:51][CH:35]1[CH2:36][CH2:37]2)=[O:33])[NH2:15])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1C2CCC(CC2)[C@H]1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1C2CCC(CC2)[C@H]1C(=O)OCc1ccccc1

Procedure:
Using the method of deprotection with trifluoroacetic acid in anhydrous methylene chloride, described by B. GUTTE and K. B. MERRIFIELD (J. Am. Chem. Soc. 1969, 91, 501), a quantitative yield of (3S)-2-[(S)-Nε -benzyloxycarbonyllysyl]-3-benzyloxycarbonyl-2-azabicyclo[2.2.2]octane is obtained from the (3S)-2-[(S)-Nα -tert-butoxycarbonyl-Nε -benzyloxycarbonyllysyl]-3-benzyloxycarbonyl-2-azabicyclo[2.2.2]octane prepared in the preceding stage.
Reaction SMILES: [OH:1][CH:2]1[CH2:8][C@H:7]2[N:9]([CH3:10])[CH:3]1[CH2:4][C:5](=[O:11])[CH2:6]2.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:10][N:9]1[CH:3]2[CH:2]([O:1][C:19](=[O:21])[CH3:20])[CH2:8][C@@H:7]1[CH2:6][C:5](=[O:11])[CH2:4]2
Reactant: CC(=O)OC(C)=O
Reactant: CN1C2CC(=O)C[C@H]1CC2O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1C[C@@H]2CC(=O)CC1N2C
Reaction time: 12 h

Procedure:
To an ice bath cooled, stirred solution of (R)-6-hydroxy-8-methyl-8-aza-bicyclo[3.2.1]octan-3-one (4.08 mmol, 0.634 g), triethylamine (20.4 mmol, 2.86 mL), and DMAP (0.245 mmol, 0.03 g) in dry DCM (3.5 mL) was added acetic anhydride (6.12 mmol, 0.58 mL). The reaction mixture was allowed to come to room temperature and was stirred for 12 hours. The reaction was evaporated and the resulting residue was purified on a 12 g SiO2 cartridge using 0-3% (2N NH3 in MeOH) in DCM to give acetic acid (R)-8-methyl-3-oxo-8-aza-bicyclo[3.2.1]oct-6-yl ester.
Reaction SMILES: [N:1]([C:4]1[C:13]([Cl:14])=[C:12]2[C:7]([C:8](=[O:36])[C:9]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:10][N:11]2[C:15]2[CH:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18]([F:29])=[CH:17][C:16]=2[F:30])=[C:6]([CH3:37])[C:5]=1[F:38])=[N+]=[N-].[H][H]>CO.[OH-].[Pd+2].[OH-].[C]>[NH2:1][C:4]1[C:13]([Cl:14])=[C:12]2[C:7]([C:8](=[O:36])[C:9]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:10][N:11]2[C:15]2[CH:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:18]([F:29])=[CH:17][C:16]=2[F:30])=[C:6]([CH3:37])[C:5]=1[F:38]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(N=[N+]=[N-])c(F)c(C)c2c1=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(N)c(F)c(C)c2c1=O
Yield: 104.9 %

Procedure:
Palladium hydroxide-carbon (180 mg) was added to a solution of ethyl 7-azido-1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-8-chloro-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.75 g) in methanol (9 ml), and the mixture was stirred at room temperature for 2.5 hours in a hydrogen atmosphere. The catalyst was removed by filtration through a membrane filter, and the solvent in the filtrate was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel to conduct elution with chloroform, thereby obtaining the title compound (1.75 g) as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([SH:12])[N:7]=1)=[O:5])[CH3:2].CN(C=O)C.[H-].[Na+].I[CH:21]([CH2:23][CH3:24])[CH3:22]>O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH:21]([CH2:23][CH3:24])[CH3:22])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCC(C)I
Reactant: CCOC(=O)c1cccc(S)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(SC(C)CC)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
6-Mercapto-pyridine-2-carboxylic acid ethyl ester (0.25 g, 1.3 mmol) was added with DMF (7 mL), and the mixture was cooled to 0° C. NaH (0.065 g, 1.56 mmol) was added thereto, and the mixture was stirred for 30 minutes. 2-Iodobutane (0.2 mL, 1.56 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. The reactant was added with water and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, and purified by column chromatography to obtain the title compound (0.17 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=O)[NH:5][C:6]1[N:7]2[CH:12]=[N:13][C:14]=1[C:15]1[O:19][N:18]=[C:17]([CH:20]2[CH2:22][CH2:21]2)[N:16]=1.C(N(CCC)CCC)CC.P(Cl)(Cl)([Cl:36])=O>ClCCl>[Cl:36][C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]2[CH:12]=[N:13][C:14]([C:15]3[O:19][N:18]=[C:17]([CH:20]4[CH2:22][CH2:21]4)[N:16]=3)=[C:6]2[N:5]=1
Reactant: O=c1[nH]c2c(-c3nc(C4CC4)no3)ncn2c2cccc(Cl)c12
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCN(CCC)CCC
Solvent: ClCCl
Product: Clc1cccc2c1c(Cl)nc1c(-c3nc(C4CC4)no3)ncn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred mixture of 6-chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydro-5-oxo-imidazo[1,5-a]quinazoline (1.0 g), tripropylamine (0.5 ml) and phosphorus oxychloride (5 ml) was heated at 140°-150° C. After 1 hour, more POCI3 (5 ml) and tripropylamine (0.5 ml) was added, and heating was continued for 11/2 hours. Then the warm mixture was poured into 200 ml of ice water with vigorous stirring. After 15 min. 100 ml of dichloromethane was added. Undissolved material was collected by filtration, rinsed with diethyl ether and dried to give the title compound as tan crystals, m.p. 238°-240° C. Yield 0.47 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]2[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=2)[CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([CH3:34])([CH3:33])[CH2:28][CH2:27][C:26]2([CH3:36])[CH3:35].C(=O)([O-])[O-].[Cs+].[Cs+].[Li+].[OH-]>CN(C=O)C.O>[CH3:20][N:19]1[C:15]([C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:29]([CH3:34])([CH3:33])[CH2:28][CH2:27][C:26]([CH3:36])([CH3:35])[C:25]=4[CH:24]=3)=[CH:7][CH:6]=2)[CH2:9][C:10]([OH:12])=[O:11])=[CH:16][N:17]=[CH:18]1
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)ccc21
Reactant: CCOC(=O)C[C@@H](c1ccc(O)cc1)c1cncn1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cncc1[C@@H](CC(=O)O)c1ccc(OCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
A mixture of 74.5 (0.15 mmol), 6-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (0.18 mmol) and cesium carbonate (0.2 mmol) in DMF (2 mL), was stirred at room temperature for 16 hours. To the reaction mixture was added LiOH in water (1 mL, 1N solution), and the reaction was stirred at 50° C. for 3 hours. The mixture was filtered and purified by reverse phase HPLC to give 74 (35 mg, 0.08 mmol) after lyophilization. MS ESI (pos.) m/e 447.3 (M+H). 1H NMR (500 MHz) (CDCl3) δ 8.64 (1H, s), 7.59 (1H, s), 7.33-7.36 (2H, m), 7.20 (1H, dd, J=7.9, 1.8 Hz), 7.08 (2H, d, J=8.5 Hz), 6.98 (2H, d, J=8.5 Hz), 4.98 (2 H, s), 4.53 (1H, m), 3.57 (3H, s), 2.96-3.06 (2H, m), 1.71 (4H, s), 1.31 (6H, s), 1.30 (6H, s).
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:15](O)[CH2:16]CCO>>[C:6]1(=[O:7])[O:8][CH2:9][CH2:16][CH2:15][CH2:14][O:13][C:1](=[O:12])[C:2]2[CH:11]=[CH:10][C:5]1=[CH:4][CH:3]=2
Reactant: OCCCCO
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Product: O=C1OCCCCOC(=O)c2ccc1cc2
Temperature: 160 °C
Reaction time: 1 h

Procedure:
474 g of dimethyl terephthalate and 660 g of 1,4-butanediol were placed into a 2 liter round bottomed flack fitted with a condenser, vigreux distillation column, nitrogen inlet and mechanical stirrer. The reactor was placed inside an isomantle and slowly heated to a temperature of 160° C. At this point 248 mg of tetrabutyl titanate catalyst pre-mixed with a small amount of pure 1,4-butanediol was injected, whilst the reactor contents were being stirred. The reaction was allowed to continue for 1 hour at 200° C. Methanol vapor which is produced during the reaction, was removed via the vigreux distillation column and combined condenser. The composition of the product was 82% by weight of butylene terephthalate (as confirmed by NMR) and 18% by weight of 1,4-butanediol.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[C:18]4[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=4[S:20][C:21]=3[C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=3)=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C(O)=O>C1COCC1>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[S:20][C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[C:17]=2[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:10][CH:11]=2)=[CH:23][CH:24]=1
Reactant: Nc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Product: Nc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Yield: 85 %

Procedure:
By essentially following the conditions described in Preparation 2, Part D, the free base of the title compound was prepared as an oil from 2-(4-aminophenyl)benzo[b]thiophene-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part C) in 85% yield following MPLC (SiO2; 30% then 40% THF with 5% TEA in hexanes). The product was converted to the dioxalate salt using two molar equivalents of oxalic acid and a similar procedure to that of Preparation 2-H, above.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[O:13]1[C@@H:23]2[C:14]31[C@H:19]([CH2:20][CH2:21][CH2:22]2)[CH2:18][O:17][CH2:16][CH2:15]3.[OH-].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C@@H:23]2[CH2:22][CH2:21][CH2:20][C@@H:19]3[C@:14]2([OH:13])[CH2:15][CH2:16][O:17][CH2:18]3)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: C1C[C@@H]2COCCC23O[C@H]3C1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O[C@]12CCOC[C@@H]1CCC[C@H]2Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-fluoroaniline (0.119 g, 1.07 mmol) in CH2Cl2 (1 mL) at 0° C. was added trimethylaluminum (2M in toluene, 0.535 mL) dropwise. The mixture was warmed to rt and stirred for 30 min. A mixture of cis and trans octahydrooxireno[e]isochromene (0.033 g, 0.214 mmol) in CH2Cl2 (1 mL) was then added and the mixture was stirred at rt overnight. The reaction mixture was cooled to 0° C. and treated with 50% NaOH (1 mL) then water (1 mL). It was diluted with more water and extracted 3× with CH2Cl2. The combined organics were dried, filtered and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 6.92 (t, 2H, J=8.8 Hz), 6.71 (dd, 2H, J=4.2 Hz, 8.8 Hz), 3.81-3.87 (m, 1H), 3.61 (dd, 1H, J=4.6 Hz, 11.2 Hz), 3.50 (t, 1H, J=11.0 Hz), 3.32 (s, 1H), 2.15-2.26 (m, 1H), 1.89-2.07 (m, 2H), 1.59-1.69 (m, 2H), 1.45-1.58 (m, 1H), 1.20-1.37 (m, 4H). HRMS (ES) m/z M+H calc'd.: 266.1551. found: 266.1549
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2CCC3(CCCC3)CC2)[CH2:9][CH2:8]1.N1C=CC=NC=1N1CCNCC1.ClCCCC#N.C([O-])([O-])=O.[Na+].[Na+]>C(O)CCC>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:9][CH2:8]1
Reactant: c1cnc(N2CCN(CCCCN3CCC4(CCCC4)CC3)CC2)nc1
Agent: N#CCCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: N#CCCCN1CCN(c2ncccn2)CC1

Procedure:
For example, 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane is prepared by the condensation of 1-(2-pyrimidinyl)piperazine with 3-chloro-1-cyanopropane by means of Na2CO3 in n-butanol gives 4-(2-pyrimidinyl)-1-(3-cyanopropyl)piperazine which is redued with LiA1H4 or with H2 and Raney nickel (RaNi) yielding 4-(2-pyrimidinyl)-1-(4-aminobutyl)piperazine, which is finally condensed with 8-oxaspiro [4,5]-decane-7,9-dione (3,3-tetramethyleneglutaric anhydride) in pyridine.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20].[Cl-].[NH4+]>CN(C)C=O>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[C:19]([F:20])([F:21])[F:22]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: CN(C)CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
In 6 mL of dimethylformamide, 256 mg (2.87 mmol) of 2-dimethylaminoethanol was dissolved, and 42 mg (1.05 mmol) of sodium hydride was added thereto, and the mixture solution was stirred at room temperature for 10 minutes, and then 200 mg (0.96 mmol) of 2-fluoro-5-nitrobenzotrifluoride was added thereto and the mixture solution was heated at 50° C. for two hours. The reaction solution was poured into a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, and the extract was washed with a saturated sodium chloride solution. To the organic layer, 20 mg of 10% palladium carbon and 2 mL of methanol were added, and the mixture solution was stirred at room temperature in a hydrogen atmosphere at normal pressures for 16 hours. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography to obtain 230 mg (97%) of a yellow oily target product.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.[K]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:14]2[C:13](=[O:15])[C:12]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]3[C:10]2=[O:20])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1c1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
18.5 Grams cyanuric chloride, 18.5 grams potassium phthalimide and 200 ml. acetone were combined and stirred at 0°-5°C. for 7 hours. The reaction mixture was then allowed to warm to room temperature and stirred an additional 15 hours. The white slurry was filtered, washed with cold acetone, reslurried in 250 ml. cold water, filtered, washed with water and dried. On recrystallization from benzene, there was obtained 17 grams of product, m.p. 175°-179°C.