Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl>CCOCC.[Zn]>[CH3:18][C:12]([C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])([CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Agent: [Zn]
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)C(=O)c1ccccc1Cl
Yield: 54.2 %

Procedure:
2-Chlorobenzoyl chloride (17.5 g, 0.1 mol) and ethyl 2-bromo-2,2-dimethylacetate (19.5 g, 0.1 mol) were diluted with ether (200 ml) and added dropwise into a 300 ml four-necked flask containing a zinc powder (13.0 g, 0.2 mol). After adding dropwise about 30 ml, the mixture was heated and the remaining solution was added dropwise over 2 h under reflux. After the completion of the dropwise addition, the mixture was refluxed for 4 h and allowed to cool, and 1N-hydrochloric acid (100 ml) was added dropwise. After partitioning, the aqueous layer was extracted with ether (100 ml), and the organic layer was combined. The mixture was dried over sodium sulfate and concentrated. The concentrated dry solid was purified by silica gel column chromatography (silica gel 1 kg, hexane:ethyl acetate=9:1) to give the title compound (13.8 g, 54%) as a colorless oil.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([O:4][CH2:1][CH:2]=[CH2:3])=[O:16]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: C=CCO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)c1ccccc1Cl

Procedure:
Sixty parts of allyl alcohol were dissolved in 240 parts of chloroform, followed by an addition of 105 parts of triethylamine. While stirring the resultant mixture at 10°-15° C., 175 parts of o-chlorobenzoyl chloride were added dropwise over 2 hours. After the resultant mixture was heated at 45°-50° C. for 3 hours, the liquid reaction mixture was poured in a separation funnel and washed first with dilute hydrochloric acid and then with water. The thus-formed light-yellowish organic layer was dried with calcium chloride and then treated with activated carbon. After driving chloroform off, the residue was distilled under reduced pressures to obtain 153 parts of allyl o-chlorobenzoate (hereinafter called "Compound A"; b.p. 101° C./3.5 mmHg).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[C:9]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:8][C:7]=12.[CH2:37]([OH:40])[CH2:38][OH:39].CC(C)([O-])C.[K+]>CN(C=O)C>[OH:39][CH2:38][CH2:37][O:40][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[C:9]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:8][C:7]=12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(OCCO)nccc4c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To a solution of tert-butyl 1-(4-(8-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutylcarbamate (50 mg, 0.099 mmol) in DMF (1 mL) were added ethane-1,2-diol (30.8 mg, 0.497 mmol) and potassium tert-butoxide (33.5 mg, 0.298 mmol) under nitrogen. The reaction mixture was stirred at RT overnight, followed by heating at 50° C. for 4 h. The product was extracted with ethyl acetate, washed with water, dried, and purified by chromatography to give the title compound (20 mg, 38%). LCMS (Method J): RT=1.493 min, [M+H]+=529.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([OH:17])[CH:9]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.4 %

Procedure:
A solution of 5-bromo-2-methoxybenzaldehyde (100 g, 0.46 mol) in chloroform(250 ml) was cooled with an ice bath and 3-chloroperoxybenzoic acid (50-60%purity) (146 g, 0.51 mol) in chloroform (1000 ml) added. The reaction mixture was allowed to warm slowly to room temperature and stirred for 72 h. The white solid was filtered off and the filtrate concentrated in vacuo. The residue was dissolved in ether (200 ml) and washed with 1M sodium sulphite solution (2×200 ml) then sodium hydrogen carbonate [half saturated] (3×200 ml). The ether layer was washed with 10% aqueous sodium hydroxide (3×100 ml) and the combined basic extract was acidified with concentrated hydrochloric acid and extracted with Et2O (3×100 ml). The combined organic extract was dried (MgSO4) and florisil (10 g) filtered and the solvent removed under reduced pressure to give the title compound (90 g) as a pale brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH:13]([C@H:16]1[NH:21][CH2:20][CH2:19][N:18]2[C:22]3[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[C:26]([C:33]([O:35][CH3:36])=[O:34])=[CH:25][C:23]=3[N:24]=[C:17]12)([CH3:15])[CH3:14]>ClCCCl.CC(O)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([N:21]2[CH2:20][CH2:19][N:18]3[C:22]4[CH:28]=[C:27]([S:29]([CH3:32])(=[O:30])=[O:31])[C:26]([C:33]([O:35][CH3:36])=[O:34])=[CH:25][C:23]=4[N:24]=[C:17]3[C@H:16]2[CH:13]([CH3:15])[CH3:14])[N:7]=1
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(F)(F)F)c(Cl)n1)[C@@H]3C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (20.0 mg, 0.092 mmol) in DCE (1 mL) and t-BuOH (1 mL) was added ZnCl2 (1M in diethyl ether, 0.2 mL, 0.2 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. Then a solution of (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (31 mg, 0.09 mmol) in DCE (1 mL) and t-BuOH (1 mL) was added to the reaction mixture via syringe over 1 min at 0° C. After addition, the resulting mixture was stirred at rt overnight. The reaction mixture was concentrated under vacuum. Water (5 mL) and EtOAc (5 mL) were added to the mixture. The aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 2-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (20 mg, 42.6% yield) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][NH:12]2)=[CH:8][CH:7]=1)=[O:4].[F:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1>C(OCC)C>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:2][C:3]([NH:5][C:6]3[CH:14]=[C:13]4[C:9]([CH:10]=[N:11][NH:12]4)=[CH:8][CH:7]=3)=[O:4])[CH2:25][CH2:26]2)=[CH:27][CH:28]=1
Reactant: O=C(CCl)Nc1ccc2cn[nH]c2c1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc2cn[nH]c2c1

Procedure:
The title compound is prepared from 2-chloro-N-(1H-indazol-6-yl)-acetamide and 4-(4-fluoro-benzyl)-piperidine according to the method described in Example 142b. Melting Point: 135-137° C. (diethylether)
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][N:13]([CH:54]([CH2:57][CH3:58])[CH2:55][CH3:56])[CH2:14][C:15]1[CH:16]=[C:17]([CH:51]=[CH:52][CH:53]=1)[C:18]([NH:20][C:21]1[S:22][C:23]2[CH2:50][CH2:49][CH2:48][CH2:47][C:24]=2[C:25]=1[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]2[CH:46]=[CH:45][C:40]([C:41]([O:43]C)=[O:42])=[CH:39][CH:38]=2)=[CH:31][CH:30]=1)=[O:27])=[O:19])[C:3](=[O:10])[O:4][CH2:5][C:6](=[O:9])[O:7]C.CO.[OH-].[Na+].[ClH:63]>C1COCC1>[ClH:63].[C:6]([CH2:5][O:4][C:3]([N:2]([CH3:1])[CH2:11][CH2:12][N:13]([CH2:14][C:15]1[CH:16]=[C:17]([CH:51]=[CH:52][CH:53]=1)[C:18]([NH:20][C:21]1[S:22][C:23]2[CH2:50][CH2:49][CH2:48][CH2:47][C:24]=2[C:25]=1[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][C:40]([C:41]([OH:43])=[O:42])=[CH:45][CH:46]=2)=[CH:33][CH:34]=1)=[O:27])=[O:19])[CH:54]([CH2:55][CH3:56])[CH2:57][CH3:58])=[O:10])([OH:9])=[O:7]
Reactant: CCC(CC)N(CCN(C)C(=O)OCC(=O)OC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)N(CCN(C)C(=O)OCC(=O)O)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To a mixture of 203 mg of methyl 4-{2-[4-({[2-({3-[7-methyl-3,6-dioxo-10-(pentan-3-yl)-2,5-dioxa-7,10-diazaundecan-11-yl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate, 4.0 mL of methanol and 4.0 mL of THF was added 1.5 mL of a 1.0 M aqueous sodium hydroxide solution at room temperature, followed by stirring for 14 hours at 60° C. 1.5 mL of 1.0 M hydrochloric acid was added to the reaction mixture under ice cooling, followed by concentration under reduced pressure. A mixed solvent (methanol/chloroform=15/85) was added to the residue, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% methanol/chloroform). A mixed solvent (acetonitrile/water=90/10) was added to the obtained product, 0.5 mL of 1.0 M hydrochloric acid was added thereto under ice cooling, and the solvent was removed under reduced pressure. The residue was subjected to lyophilization, thereby obtaining 186 mg of 4-(2-{4-[({2-[(3-{[(2-{[(carboxymethoxy)carbonyl](methyl)amino}ethyl)(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoic acid hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4](Br)[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([S:15][CH3:16])[CH:6]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=1)([O-:21])=[O:20]>>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([S:15][CH3:16])[CH:6]=1)[S:28][C:25]1[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][C:24]=1[C:29]([F:30])([F:31])[F:32]
Reactant: COC(=O)C(Br)c1cc(SC)cc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(S)c(C(F)(F)F)c1
Product: COC(=O)C(Sc1ccc([N+](=O)[O-])cc1C(F)(F)F)c1cc(SC)cc(C(F)(F)F)c1

Procedure:
Using the procedures of Example 1, bromo-(3-methylsulfanyl-5-trifluoromethyl-phenyl)-acetic acid methyl ester 106 and 4-nitro-2-trifluoromethyl-benzenethiol 107, prepared as described in Preparation 7 were combined to form (3-methylsulfanyl-5-trifluoromethyl-phenyl)-(4-nitro-2-trifluoromethyl-phenylsulfanyl)-acetic acid methyl ester, 108, which was then hydrolyzed under basic conditions to afford the title compound 109.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([O:7][CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)=O)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[O:7][C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[CH:4]=1
Reactant: CCOC(=O)N1CCN(C(=O)C(Oc2ccc(OC)cc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(c2c(-c3ccccc3)oc3ccc(OC)cc23)CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
The mixture of 4,070 g of 1-[α-(4-methoxyphenoxy)-phenylacetyl]-4-ethoxycarbonyl piperazine, 20,000 ml of toluene and 2,850 ml of phosphorus oxychloride is stirred under nitrogen at 98° for 24 hours. It is poured hot onto 100 kg of crushed ice, followed by 10,000 ml of 50% aqueous sodium hydroxide. After stirring for 30 minutes the organic phase is separated and the aqueous layer extracted with 10,000 ml of toluene. The combined toluene solutions are washed with 10,000 ml of 2 N aqueous sodium hydroxide and 4 times with 10,000 ml of water, dried, filtered and evaporated at about 60°, to yield the 1-(5-methoxy-2-phenyl-3-benzofuryl)-4-ethoxycarbonylpiperazine showing in the NMR-spectrum peaks centered at 8.09, 3.72 and 3.12 ppm.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH2:14][CH:13]3[CH:10]([C:11](=[O:15])[CH2:12]3)[C:9]=2[C:16]([O:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:40])C=1>C(Cl)Cl>[C:1]1([S:7]([C:8]2[CH2:14][CH:13]3[CH:10]([C:11](=[O:15])[CH2:12]3)[C:9]=2[C:16]([O:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])=[O:40])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(Sc2ccccc2)CC2CC(=O)C12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(S(=O)c2ccccc2)CC2CC(=O)C12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 150 mg of 3-phenylthio-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester in 7 mL of methylene chloride at -50° under argon was added 75 mg of 85% m-chloroperbenzoic acid in methylene chloride solution. The resulting solution was stirred between -40° and -35° for 30 min and then allowed to warm to room temperature over approximately 30 min. The solution was diluted with methylene chloride, washed successively with aqueous sodium sulfite and aqueous sodium bicarbonate, and then dried over sodium sulfate. Evaporation of the solvent afforded a crude product mixture which was purified by preparative thin layer chromatography on a 20×20×0.2 cm silica gel plate eluted with ether. The most prominent band, which was in the center of the plate, contained 115 mg (73.9%) of 3-phenylsulfinyl-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, as a colorless solid [an approximately 3:1 mixture of diastereoisomers at sulfur (by NMR)]. IR (neat): 1785, 1710, 1720, 1605 cm-1 : NMR (220 MHz; CDCl3): δ 2.32 (1H, m), 2.55 (1H, dd, J=18, 4), 2.7-3.0 (1H, m), 3.0-3.3 (1H, m), 3.36 (1H, m), 4.57 (1/4H, m, from minor isomer), 4.70 (3/4H, m, from major isomer), 6.86 (1H, broad s), and 7.1-7.6 (15H, m).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=3[OH:17])=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].[CH3:20][O:21][C:22]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:23]=1[CH2:24][N:25]([C:38]1[S:42][N:41]=[CH:40][N:39]=1)[S:26]([C:29]1[CH:34]=[C:33]([F:35])[C:32](F)=[CH:31][C:30]=1[F:37])(=[O:28])=[O:27]>CN(C)C=O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=3[O:17][C:32]3[C:33]([F:35])=[CH:34][C:29]([S:26]([N:25]([CH2:24][C:23]4[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:22]=4[O:21][CH3:20])[C:38]4[S:42][N:41]=[CH:40][N:39]=4)(=[O:27])=[O:28])=[C:30]([F:37])[CH:31]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Oc1ccc(Cl)cc1-c1ccc2[nH]cnc2c1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4[nH]cnc4c3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a mixture of 2-(1H-benzo[d]imidazol-5-yl)-4-chlorophenol (0.110 g, 0.45 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (0.020 g of a 60% w/w dispersion in mineral oil, 0.50 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. N-(2,4-Dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.210 g, 0.47 mmol) was added and the reaction mixture was stirred for 16 h at ambient temperature. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (10 mL). The organic phase was washed with water (2 10 mL) and brine (2 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-100% gradient of ethyl acetate in hexanes to afford 4-(2-(1H-benzo[d]imidazol-5-yl)-4-chlorophenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as an off-white solid in 34% yield (0.102 g): MS (ES+) m/z 669.7 (M+1), 671.7 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:14]=[CH:13][C:12]3=[N:15][C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][N:11]3[C:10]2=[O:26])=[N:6][C:7]=1[CH3:8].[H][H]>CN(C=O)C.CO.[Ni]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][C:12]3=[N:15][C:16]([CH2:18][O:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:17][N:11]3[C:10]2=[O:26])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(-n2ccc3nc(COc4ccccc4)cn3c2=O)ccc1F
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3nc(COc4ccccc4)cn3C2=O)ccc1F
Yield: 40.8 %

Procedure:
A solution of 6-(5-fluoro-6-methyl-pyridin-2-yl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (20 mg, 0.057 mmol) in a mixture of DMF (0.6 mL) and MeOH (0.6 mL) was hydrogenated in a H-cube reactor (1 mL/min, 30 mm Raney nickel cartridge, 80° C., full hydrogen mode, 1 cycle). The solvents were evaporated in vacuo and the crude product was purified by RP HPLC (C18 XBridge 19×100 5 um, gradient from 80% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 20% CH3CN to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% ACN) to yield 6-(5-fluoro-6-methyl-pyridin-2-yl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (8.2 mg, 41% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.49 (d, J=3.0 Hz, 3H), 3.24 (t, J=6.7 Hz, 2H), 4.35 (t, J=6.7 Hz, 2H), 5.02 (s, 2H), 6.97 (br. t, J=7.4, 7.4 Hz, 1H), 7.00-7.05 (m, 2H), 7.27-7.33 (m, 2H), 7.39 (t, J=8.6 Hz, 1H), 7.59 (s, 1H), 7.65 (dd, J=8.8, 3.2 Hz, 1H).
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH2:7][CH2:8]Cl)[CH3:6].[CH3:10][N:11]1[C:17]2[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:16]=2[NH:15][C:14](=[O:24])[C:13]2=[CH:25][S:26][CH:27]=[C:12]12>CN(C)C=O>[CH3:4][N:5]([CH3:6])[CH2:7][CH2:8][N:15]1[C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=2[N:11]([CH3:10])[C:12]2=[CH:27][S:26][CH:25]=[C:13]2[C:14]1=[O:24]
Reactant: Cc1cc2c(cc1C)N(C)c1cscc1C(=O)N2
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C)N(C)c1cscc1C(=O)N2CCN(C)C
Reaction time: 18 h

Procedure:
A mixture of 0.36 g. of 55% sodium hydride-mineral oil dispersion and 0.58 g. of dimethylaminoethylchloride hydrochloride in 25 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.52 g. of 4,9-dihydro-4,6,7-trimethyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water, and extracted with chloroform. The dried chloroform extracts are concentrated to an oil, which is purified by preparative thin layer chromatography (tlc) on silica gel with 10:1 benzene:methanol as eluent. The oil obtained is crystallized from hexane to give white crystals, m.p. 119°-120° C.
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:19])=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[C:17]=1[CH3:18])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH3:18][C:17]1[C:13]2[CH2:14][CH2:15][O:16][C:12]=2[CH:11]=[C:10]([CH3:19])[C:9]=1[NH2:8]
Reactant: Cc1cc2c(c(C)c1NCc1ccccc1)CCO2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc2c(c(C)c1N)CCO2
Yield: 86 %

Procedure:
Using N-benzyl-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 270, the title compound was synthesized in the same manner as in Reference Example 30. Yield 86%. Melting point: 85-86° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:41])[O:37][CH:38]([CH3:40])[CH3:39])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:41])[O:37][CH:38]([CH3:39])[CH3:40])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CC(C)OC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: Cc1ccc(C(C(=O)O)c2ccc(C)cc2)cc1
Product: Cc1ccc(C(C(=O)NCCCN2CCC(c3cccc(NC(=O)OC(C)C)c3)CC2)c2ccc(C)cc2)cc1

Procedure:
Example 145 was prepared from bis(4-methylphenyl)acetic acid and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.18–7.06 (m, 4H), 7.06–7.00 (m, 6H), 6.82–6.78 (m, 2H), 6.62 (s, 1H), 4.92 (septet, 1H, J=6.7 Hz), 4.72 (s, 1H), 4.04 (q, 1H, J=6.8 Hz), 3.32–3.26 (m, 2H), 2.88–2.81 (m, 2H), 2.41–2.27 (m, 3H), 2.21 (s, 6H), 1.92–1.83 (m, 2H), 1.74–1.66 (m, 2H), 1.62–1.46 (m, 3H), 1.21 (d, 6H, J=6.7 Hz); ESMS m/e: 542.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.O[C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:18]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Br)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and methyl 4-hydroxybenzoate: ESMS m/e: 593.0 (M+H)+.