Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[NH:15][NH2:16].CCN(CC)CC.[CH2:28]([O:31][CH:32]([CH2:35][O:36][CH2:37][C:38]#[CH:39])[CH2:33][NH2:34])[C:29]#[CH:30]>C1COCC1.O>[CH2:28]([O:31][CH:32]([CH2:35][O:36][CH2:37][C:38]#[CH:39])[CH2:33][NH:34][C:2]([NH:16][NH:15][C:14]([O:18][CH2:19][CH3:20])=[O:17])=[O:3])[C:29]#[CH:30]
Reactant: C#CCOCC(CN)OCC#C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCOCC(CNC(=O)NNC(=O)OCC)OCC#C
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
To 4-nitrophenyl chloroformate (1084 mg, 5.38 mmol) in THF (18 mL) at 0° C. was added ethyl carbazate (560 mg, 5.38 mmol) and Et3N (2.98 mL, 21.52 mmol). The mixture was stirred at 0° C. for 1 h. Then more Et3N (2.98 mL, 21.52 mmol) was added, followed by a solution of 2,3-bis(prop-2-ynyloxy)propan-1-amine (I-13b: 5.92 mmol) in 5 mL THF, and the mixture was stirred at room temperature for 30 min. Water was added, extracted twice with AcOEt, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (40-100% AcOEt/heptane), giving ethyl 2-(2,3-bis(prop-2-ynyloxy)propylcarbamoyl)hydrazinecarboxylate (I-13c: 855 mg, 54%) as a light yellow oil. LC-MS (M+1) 298.2, t=0.75 minute.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:43]=[CH:42][C:25]([CH2:26][N:27]3[CH2:32][C@@H:31]([CH3:33])[N:30](C(OC(C)(C)C)=O)[C@H:29]([CH3:41])[CH2:28]3)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1>Cl.CC#N>[CH3:33][CH:31]1[NH:30][CH:29]([CH3:41])[CH2:28][N:27]([CH2:26][C:25]2[CH:42]=[CH:43][C:22]([CH:9]3[NH:10][C:11]4[C:12]5[C:13](=[N:14][NH:15][C:16](=[O:21])[C:17]=5[CH:18]=[CH:19][CH:20]=4)[CH:8]3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:23][CH:24]=2)[CH2:32]1
Reactant: C[C@@H]1CN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)C[C@@H](C)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Product: CC1CN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CC(C)N1
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A mixture of (2R,6R)-tert-butyl 4-(4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzyl)-2,6-dimethylpiperazine-1-carboxylate (72 mg, 0.12 mmol) in HCl—CH3CN (2 mL) was stirred for 2 hours. After removal of solvents, the residue was purified by prep-HPLC to afford the title product as a white solid (33 mg, 53%). LC-MS (ESI) m/z: 497 (M+1)+. 1H-NMR (400 MHz, DMSO) δ (ppm): 1.02-1.03 (d, J=6.4 Hz, 6H), 1.58 (t, J=10 Hz, 1H), 2.66 (d, J=10 Hz, 1H), 2.91 (t, J=6.8 Hz, 2H), 3.41 (s, 2H), 4.20 (d, J=10 Hz, 1H), 4.58 (d, J=10 Hz, 1H), 4.98 (s, 1 H), 6.97 (t, J=2.4 Hz, 2H), 7.04 (d, J=8.0 Hz, 1H), 7.09 (d, J=2.4 Hz, 2H), 7.16 (d, J=2.4 Hz, 2H), 7.58 (t, J=7.6 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 10.34 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:35]=[CH:36][CH:37]=3)[C:21]([N:23]3[CH2:34][CH2:33][CH2:32][C@H:24]3[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:22])=[CH:12][CH:11]=2)[CH:5]=[C:6]([OH:9])[C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][C:46](=[O:48])[CH3:47]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:35]=[CH:36][CH:37]=3)[C:21]([N:23]3[CH2:34][CH2:33][CH2:32][C@H:24]3[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:22])=[CH:12][CH:11]=2)[CH:5]=[C:6]([O:9][CH2:45][C:46](=[O:48])[CH3:47])[C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)c1cccc(COc2ccc(-c3cc(O)c(F)c(F)c3)cc2)c1
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1cc(-c2ccc(OCc3cccc(C(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)c3)cc2)cc(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
The compound (106 mg, 0.208 mmol) of Step 1 of Example 47 was dissolved in DMF (2 mL), and potassium carbonate (57.5 mg, 0.416 mmol) and bromoacetone (0.0192 mL, 0.229 mmol) were added thereto, and stirred at room temperature for 5 hours. The solvent was distilled away under reduced pressure. The resulting residue was diluted with ethyl acetate, washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The resultant was purified by silica gel chromatography to thus obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:21]=1.C(N(CC)CC)C>C(Cl)Cl.N1C=CC=CC=1>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([N:29]1[CH2:30][CH2:31][N:26]([C:22]2[N:21]=[C:20]([O:19][CH3:18])[CH:25]=[CH:24][N:23]=2)[CH2:27][CH2:28]1)=[O:7])#[N:2]
Reactant: N#Cc1ccccc1C(=O)O
Reactant: COc1ccnc(N2CCNCC2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccnc(N2CCN(C(=O)c3ccccc3C#N)CC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
To a suspension of 2.0 g (14 mmol) of 2-cyanobenzoic acid in 100 mL of CH2Cl2 are added 1.5 mL (17.5 mmol) of oxalyl chloride and a catalytic amount of pyridine. The suspension is left stirred at room temperature for 3 hours. The solvent is evaporated at reduced pressure, giving a crude which is suspended in 100 mL of CH2Cl2 and which is slowly added on a solution of 2.45 g (12.6 mmol) of 4-methoxy-2-(1-piperazinyl)pyrimidine and 4 mL (28 mmol) of triethylamine in 50 mL of CH2Cl2 cooled to 0° C. in an ice bath. The solution is kept at 0° C. for one hour and is allowed to reach room temperature. The reaction mixture is washed with H2O, dried with Na2SO4 and the solvent eliminated at reduced pressure. The resulting crude is purified by chromatography on silica gel, using ethyl acetate as eluent, providing 2.06 g (6.4 mmol) of 2-[4-(2-cyanobenzoyl)-1-piperazinyl]-4-methoxipyrimidine with m.p.=166-168° C.
Reaction SMILES: [Li][C:2]1[C:3]2[C:8]([C:9]([Li])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.Cl[Si:18]([Cl:21])([CH3:20])[CH3:19]>C(OCC)C>[Cl:21][Si:18]([CH3:20])([CH3:19])[C:2]1[C:3]2[C:8]([C:9]([Si:18]([Cl:21])([CH3:20])[CH3:19])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: C[Si](C)(Cl)Cl
Reactant: [Li]c1c2ccccc2c([Li])c2ccccc12
Solvent: CCOCC
Product: C[Si](C)(Cl)c1c2ccccc2c([Si](C)(C)Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 44 h
Yield: 13 %

Procedure:
The obtained solution of 9,10-dilithioanthracene was dropped into a solution prepared from 61.4 g (0.476 mol) of dichlorodimethylsilane and 40 ml of dried diethyl ether as a solvent, in a 1L-volume flask for 2 hours using a separating funnel. After the solution was stirred for 44 hours at room temperature and salt yielded by reaction was removed by means of filtration, the remaining filtrate was concentrated to remove the solvent of the filtrate using an evaporator. The residue was recrystallized in n-pentane to obtain 5.6 g (yield: 13%) of yellow 9,10-bis(chlorodimethylsilyl)anthracene.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:17])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.[CH2:18]([C:22]1[S:26][C:25]([S:27]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])=[O:28])=[C:24](B(O)O)[CH:23]=1)[CH:19]([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([C:11]1[N:10]([CH2:9][C:8]([C:4]2[CH:3]=[C:2]([C:24]3[CH:23]=[C:22]([CH2:18][CH:19]([CH3:20])[CH3:21])[S:26][C:25]=3[S:27]([NH:30][C:31]([CH3:33])([CH3:32])[CH3:34])(=[O:29])=[O:28])[CH:7]=[CH:6][CH:5]=2)=[O:17])[CH:14]=[CH:13][N:12]=1)[CH3:16]
Reactant: CCc1nccn1CC(=O)c1cccc(Br)c1
Reactant: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCc1nccn1CC(=O)c1cccc(-c2cc(CC(C)C)sc2S(=O)(=O)NC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of 1-(3-bromophenyl)-2-(2-ethylimidazol-1-yl)ethanone (54.6 mg, 0.186 mmol; see step (a)) in toluene (10 mL) and ethanol (1 mL) was added 5-isobutyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (101 mg, 0.317 mmol; see Example 1(c)), Pd(PPh3)4 (12.9 mg, 0.0112 mmol), Na2CO3 (373 μL, 0.745 mmol, 2.0 M aq) and the reaction mixture was stirred for 4 h at 80° C. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc. The combined organic phase was dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the sub-title compound as a colourless syrup in 94% yield (85.5 mg, 0.175 mmol).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:17])([CH2:14][NH:15][CH3:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[C:21](Cl)(Cl)=[O:22].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:16][N:15]1[CH2:14][C:11]2([CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)[O:17][C:21]1=[O:22]
Reactant: CNCC1(O)CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN1CC2(CCN(Cc3ccccc3)CC2)OC1=O

Procedure:
A solution of 23 g 1-benzyl-4-hydroxy-4-methylaminomethylpiperidine and 250 ml dichloromethane is mixed with 100 ml of a 15% solution of phosgene in toluene. Evaporation of solvent gives a residue which is treated with 300 ml dichloromethane and 300 ml aqueous sodium bicarbonate. Separation of the dichloromethane layer followed by evaporation gives 20 g 3-methyl-8-benzyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 137°-138°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5]Cl.[C-:12]#[N:13].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(CCl)cc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CC#N)cc1Cl
Reaction time: 6 h
Yield: 99 %

Procedure:
145 grams of 3-chloro-4-methoxybenzyl chloride was added to a solution comprising 40.6 grams of sodium cyanide in 230 ml of dimethylsulfoxide over a 40 minute time period at a temperature within the range of 40°-45° C. The reaction mixture was then stirred at this temperature for 6 hours and poured into 800 ml of water, the separated oil being extracted with 3 200 ml portions of ether. The ethereal solution was next washed with a dilute (1:1) hydrochloric acid solution in two 100 ml portions, with two 100 ml portions of water and dried over magnesium sulfate. The ether was then driven off, yielding 136.5 grams of crystalline 3-chloro-4-methoxy-phenylacetonitrile, m.p. 54°-56° C., which was refluxed for 16 hours with 420 ml of 48% hydrobromic acid. Following, the reaction mixture was cooled to -5° C. and, after two hours at this temperature, the precipitate filtered, triturated with ether in three 400 ml portions, dried over magnesium sulfate and boiled down to yield 137 grams (97.7%) of 3-chloro-4-hydroxyphenyl acetic acid, m.p. 101°-104° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1.[OH-].[Na+]>C1COCC1.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:17])[CH3:18])=[O:15])[C:11]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1
Reactant: COC(=O)CCC1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1C(=O)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(CCC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 350 mg (0.85 mmol) of ester 19-1 in a 1:1:1 mixture of THF/MeOH/H2O was added 170 mg (4.25 mmol) of NaOH. After stirring overnight at room temperature, the reaction was quenched with 1M HCl and then extracted three times with EtOAc. The combined organic phase was washed with brine, dried over MgSO4, and concentrated to provide 24-1 as a white solid. Data for 24-1: 1HNMR (500 MHz, d6-DMSO) δ 12.0 (s, 1H), 7.5-7.1 (m, 8H), 6.2 (s, 1H), 4.95 (m, 1H), 4.7 (m, 1H), 3.0 (m, 1H), 2.75 (s, 6H), 2.45 (m, 1H), 2.2 (m, 2H) ppm. HRMS (ES) calc'd M+H for C22H22F2N2O3: 401.1671. Found: 401.1695.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[C:6]2[CH2:15][C:16]1[NH:24][C:23]2[C:22](=[O:25])[N:21]([CH3:26])[C:20](=[O:27])[N:19]([CH2:28][C:29]([CH3:31])=[CH2:30])[C:18]=2[N:17]=1.[CH2:32]([Zn]CC)C.ClCI>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[C:6]2[CH2:15][C:16]1[NH:17][C:18]2[N:19]([CH2:28][C:29]3([CH3:32])[CH2:31][CH2:30]3)[C:20](=[O:27])[N:21]([CH3:26])[C:22](=[O:25])[C:23]=2[N:24]=1
Reactant: C=C(C)Cn1c(=O)n(C)c(=O)c2[nH]c(Cc3cncc4cc(OC)c(OC)cc34)nc21
Reactant: CC[Zn]CC
Agent: ClCI
Solvent: ClCCCl
Product: COc1cc2cncc(Cc3nc4c(=O)n(C)c(=O)n(CC5(C)CC5)c4[nH]3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 18, 8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-3-(2-methyl-allyl)-3,7-dihydro-purine-2,6-dione (100 mg, 0.24 mmol) is suspended in 1,2-dichloroethane (30 ml). Diethyl zinc (1M hexane solution, 1.2 ml, 1.20 mmol) is added, followed by chloroiodomethane (0.174 ml, 0.24 mmol) and the reaction is stirred at ambient temperature for 1 hour, prior to quenching with saturated aqueous NH4Cl. After extraction with chloroform, the organic phase is washed with water, dried over MgSO4 and evaporated. Purification by preparative HPLC affords 8-(6,7-dimethoxyisoquinolin-4-ylmethyl)-1-methyl-3-(l -methyl-cyclopropylmethyl)-3,9-dihydro-purine-2,6-dione, [MH]+ 436.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[C:6]([NH2:8])[CH:7]=1.CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([N:9]2[CH:12]=[CH:16][CH:15]=[CH:14]2)[CH:3]=1)[NH2:8]
Reactant: Nc1cc(N)cc(Cl)c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: Nc1cc(Cl)cc(-n2cccc2)c1

Procedure:
To a solution of 5-chloro-1,3-phenylenediamine (2.00 g) in acetic acid (20 mL) was added 2,5-dimethoxytetrahydrofuran (1.8 mL). After 4 hours at reflux, the reaction mixture was concentrated. The residue was suspended in satd. NaHCO3 and EtOAc. The reaction mixture was filtered and the organic layer was collected, washed with satd. NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by chromatography (silica gel: EtOAc/hexane: 1/4) afforded 0.54 g of 3-chloro-5-(1-pyrrolyl)aniline. MS (m/z) 193 (MH+). (2) To a solution of the compound obtained above (0.35 g) in CH2Cl2 (15 mL) was added a solution of trichloroacetyl chloride (0.17 g) dissolved in CH2Cl2 (2 mL). After 45 minutes at room temperature, 2-(4-cyanobenzyl)proline methyl ester (0.38 g) (prepared in a similar fashion to Example 1 (1) and (2)) dissolved in CH2Cl2 (10 mL) and triethylamine (2 mL) were added. After stirring overnight, the mixture was concentrated. The residue was dissolved in EtOAc, washed with satd. NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. Purification by chromatography (silica gel: EtOAc/hexane: 1/4, Chromatotron) afforded 0.51 g of N-[[3-chloro-5-(1-pyrrolyl)phenyl]carbamoyl]-2-(4-bromobenzyl)proline methyl. MS (m/z) 463 (MH+). (3) The titled compound was prepared from the above compound in a fashion similar to Example 1 (4): MS (m/z) 431 (MH+). mp 266.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][N:8]([S:40]([C:37]3[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=3)(=[O:42])=[O:41])[CH2:7][CH2:6]2)(=[O:13])=[O:12])=[CH:19][CH:18]=1)[C:22]#[C:23][CH3:24]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.7 %

Procedure:
To a solution of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in methylene chloride (10 ml) was added triethylamine (261 mg, 2.58 mmol), 4-methoxyphenylsulfonyl chloride (320 mg, 1.55 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 590 mg (88%) of the product as a solid. HR-MS: m/z Calculated for C24H72N8O8S2 522.1251; Found 522.1252.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C[C:29]([CH2:31][CH:32]([CH3:34])[CH3:33])=O.CC[O:37][CH2:38][CH3:39]>>[OH:37][C@@H:38]1[CH2:39][CH2:33][C@H:32]([CH2:34][N:19]2[CH2:20][CH2:21][C:16](=[C:5]3[C:4]4[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:13]=4[S:12][C:11]4[C:6]3=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH2:17][CH2:18]2)[CH2:31][CH2:29]1
Reactant: CC(=O)CC(C)C
Reactant: Clc1ccc2c(c1)C(=C1CCNCC1)c1ccccc1S2
Reactant: CCOCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O[C@H]1CC[C@@H](CN2CCC(=C3c4ccccc4Sc4ccc(Cl)cc43)CC2)CC1

Procedure:
A mixture of 6 grams of 4-(2-chloro-9-thioxanthenylidene)piperidine, 4 grams of cis-(1-mesyloxymethyl-4-hydroxy)cyclohexane, 1.5 grams of finely crushed potassium carbonate and 25 milliliters of methylisobutylketone was heated under reflux for 5 hours while stirring. After cooling were added 200 milliliters of ether, and the organic phase was extracted with 5% aqueous methane sulphonic acid. The aqueous phase was made alkaline with aqueous ammonia, and the base which precipitated was extracted with ether. The etherphase was dried over anhydrous potassium carbonate, treated with active carbon and evaporated. The residue was crystallized from cyclohexane. Yield: 1.5 grams of 1-(cis-4-hydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)piperidine, which melted at 100-103 degrees Centigrade.
Reaction SMILES: [NH2:1][CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][C@@H:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)=[O:4].C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[C:27]([NH:1][CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][C@@H:6]1[CH:11]2[CH2:10][CH2:9][N:8]([CH2:13][CH2:12]2)[CH2:7]1)=[O:4])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.5 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate (I30) (100 mg, 0.38 mmol) in DCM (4 ml) and triethylamine (0.08 ml, 0.58 mmol), was added benzoyl chloride (58.0 μl, 0.50 mmol). The reaction was stirred at RT for 1.5 hours, and then the volatiles were evaporated. The crude was purified by flash chromatography (DCM/MeOH/NH4OH=95/5/0.3) to obtain (R)-quinuclidin-3-yl 2-benzamido-2-phenylacetate (70 mg; 50% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.C1C=CC=CC=1.C1([Li])C=CC=CC=1.[CH2:23]([N:26]=[C:27]=[S:28])[CH:24]=[CH2:25]>O>[CH2:23]([NH:26][C:27](=[S:28])[CH:3]([O:2][CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH:24]=[CH2:25]
Reactant: COCc1ccccn1
Reactant: C=CCN=C=S
Agent: [Li]c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: C=CCNC(=S)C(OC)c1ccccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 9.95 g. (0.081 mole) of 2-(methoxymethyl)pyridine in 80 ml. of dry benzene is added dropwise to a chilled solution of 40 ml. (0.084 mole) of phenyl lithium in 80 ml. of dry benzene. The mixture is stirred at 0°C. for 1 hour after the addition is complete. Then 8.02 g. of allyl isothiocyanate in 50 ml. of benzene is added dropwise and the mixture is allowed to come to room temperature gradually. The mixture is then diluted with 500 ml. of water and acidified with 10% hydrochloric fractions The layers are separated and the organic layer is washed several times with water. The aqueous layers are combined, neutralized with 10% aqueous sodium hydroxide solution and then brought to pH 9 5% aqueous sodium bicarbonate solution, then extracted with chloroform. The chloroform extracts are washed once with brine and dried over magnesium sulfate. The solvent is removed and the residue is chromatographed on a silica gel column, eluting with ethyl acetate. The fraction, containing the product are combined and evaporated and the residue is recrystallized from ethyl acetate/hexane to give N-allyl-2-methoxy-2-(2-pyridyl)thioacetamide, m.p. 59.5°-60°C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1>[NH:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[CH2:12][C@@H:9]1[CH2:10][CH2:11][C@H:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCC(Cc2nc3ccccc3[nH]2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC[C@@H](Cc2nc3ccccc3[nH]2)CC1
Temperature: 65 °C

Procedure:
The cis/trans mixture of 4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid ethyl esters (D) (600 mg, 2.1 mmol) was dissolved in a minimal amount of THF (5mL) and mixed with concentrated aqueous LiOH (2 mL). The reaction was stirred vigorously and heated at 65° C. for 3 h. After cooling and concentration, the crude material was dissolved in 1:1 water/CH3CN and subjected to preparative reverse-phase HPLC to yield (E) cis-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid (200 mg, 37%): 1H No (400 MHz, CD3OD) δ 7.77 (m, 2 H), 7.60 (m, 2 H), 3.11 (d, 2 H), 2.62 (m, 1 H), 2.10 (m, 3 H), 1.65 (m, 4 H), 1.43 (m, 2 H); mass spectrum m/z 259 [(M+H)+; calcd for C15H19N2O2: 259].
Reaction SMILES: [NH2:1][C@@H:2]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.[BH4-].ClCCl>CO>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][NH:1][C@@H:2]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[CH:26][CH:27]=1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Reactant: COc1ccc(C=O)cc1
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN[C@H](Cc2c[nH]c3ccccc23)c2nc(-c3ccccc3)c[nH]2)cc1
Reaction time: 8 h
Yield: 76.2 %

Procedure:
2-{(1R)-1-Amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (36.3 mg, 0.12 mmol) and p-anisaldehyde (12 μL, 0.1 mmol) in 1 mL of methanol were shaken for about 2 hours at about 22° C. Borohydride resin (76 mg, 2.5 mmol/g, AMBERLITE® IRA-400) was then added and the slury was stirred overnight before addition of dichloromethane (1 mL) and aldehyde Wang resin (31 mg, 3.22 mmol/g, Novabiochem). After about 8 hours of stirring, the slurry was then filtered and evaporated in vacuo to give a yellow solid (32.2 mg, 76%). 1H-NMR (CDCl3, 100 MHz) δ: 8.86 (br s, 1H); 7.73-6.68 (m, 15H); 4.62 (s, 1H); 4.33 (dd, J=4.7 and 8.5 Hz, 1H); 3.81 (s, 2H); 3.74 (s, 3H); 3.27 (ABX system, 2H) 2.26 (s, 1H). LC/MS: m/z=423 (M+H).