Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([NH2:12])=[C:7]([CH3:13])[CH:6]=1.[CH2:15]([S:17](Cl)(=[O:19])=[O:18])[CH3:16]>N1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:14])[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([NH:12][S:17]([CH2:15][CH3:16])(=[O:19])=[O:18])=[C:7]([CH3:13])[CH:6]=1
Reactant: CNC(=O)Oc1cc(C)c(N)c(C)c1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1c(C)cc(OC(=O)NC)cc1C
Temperature: 42 °C
Reaction time: 0.33 h

Procedure:
3,5-Dimethyl-4-aminophenyl N-methylcarbamate (1.0g., 0.0052 mole), prepared according to the general directions of A. T. Shulgin, U.S. Pat. No. 3,084,098 was dissolved in 5 ml. of pyridine. To this solution was added ethanesulfonyl chloride (0.68g., and 0.0053 mole) and after being stirred for about 20 minutes the reaction solution was warmed briefly at 42° C. Quenching the reaction solution in excess water yielded brown solids which upon being recrystallized from ethanol/water melted at 171°-73° C. (0.85g.).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH2:48][C@H:49]2[O:51][CH2:50]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1>CN(C=O)C>[CH2:1]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[CH:19][CH:18]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:48][C@@H:49]3[CH2:50][O:51]3)=[CH:14][CH:15]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(O)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: CCCCc1nc(-c2ccc(OC[C@@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenol (0.42 g, 1.0 mmol, 1.0 eq.) and Cs2CO3 (1.0 g, 3.0 mmol, 3.0 eq.) in DMF (3 mL) was stirred and preheated to 80° C. The reaction mixture was then treated with a solution of (2S)-(+)-glycidyl tosylate (0.27 g, 1.2 mmol, 1.2 eq.) in 1 mL of DMF dropwise, and further stirred at 80° C. for ˜30-60 min following completion of the addition. Analysis of the reaction by TLC and LC/MS showed that the starting phenol had been consumed and the desired alkylated-phenol was the major product. The reaction was then cooled and diluted with EtOAc and washed with brine. The organic phase was dried with Na2SO4 and evaporated in vacuo. The crude alkylated-phenol was then purified by flash column chromatography over silica gel (EtOAc/hexanes ˜1:3).
Reaction SMILES: BrC1C=CC(S([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14](=[O:26])[CH:13]=2)(=O)=O)=CC=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]O.[OH-].[Na+].Cl>CN(C=O)C>[CH2:19]([N:15]1[C:16]([CH3:18])=[CH:17][C:12]([O:11][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([Cl:27])[CH:29]=2)=[CH:13][C:14]1=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OCc1cccc(Cl)c1
Reactant: Cc1cc(OS(=O)(=O)c2ccc(Br)cc2)cc(=O)n1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2cccc(Cl)c2)cc(=O)n1Cc1ccccc1

Procedure:
1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl 4-bromobenzenesulfonate (3.0 mmol, 1.3 g), N,N′-dimethylformamide (30 mL), 3-chlorobenzyl alcohol (3.0 mmol, 0.43 g), and sodium hydroxide (60%, 3.3 mmol, 0.13 g) were stirred at room temperature under nitrogen for 4 hours. Hydrochloric acid (1 N, 10 mL) was added and the mixture extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate and concentrating, the mixture was purified by flash column chromatography eluting with ethyl acetate:hexanes (1:1) to obtain a light yellow oil. (14.3 g, 64%): 1H NMR (DMSO-d6/300 MHz) δ: 7.4-7.0 (m, 10H), 6.0-5.8 (m, 2H), 5.2 (s, 2H), 5.0 (s, 2H), 2.1 (s, 3H). ES HRMS m/z 340.110 (M+H, C20H18NO2Cl requires 340.110).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:18]1([N:24]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:25](=[O:34])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([N:24]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:25](=[O:34])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCCCNC(=O)N(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCCCNC(=O)N(c1ccccc1)c1ccccc1

Procedure:
Batch size: 2.6 g (17.6 mmol) 3-(3-pyridyl)-acrylic acid, 1.8 ml (20.8 mmol) oxalyl chloride and 5.0 g (16.0 mmol) 6-(3,3-diphenyl-ureido)-hexylamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:16]([CH3:18])[CH3:17].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(Br)cc1
Temperature: 60 °C
Yield: 78.6 %

Procedure:
A mixture of 4-bromophenol (16-2, 7.02 g, 39.4 mmol) and potassium carbonate (12.6 g, 90.9 mmol) in DMSO (20.0 mL) was added with 2-iodopropane (16-1, 5.2 mL, 49.0 mmol). The mixture was heated at 60° C. overnight. The solution was cooled to room temperature and added with water (200 mL). The reaction was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc:hexanes=1:100 as eluant) to give 1-bromo-4-isopropoxybenzene (6.66 g) as colorless oil in 79% yield: 1H NMR (CDCl3) δ 7.34 (m, 2 H), 6.77 (dd, J=8.9, 3.1 Hz, 2 H), 4.49 (m, 1 H), 1.33 (s, 3 H), 1.31 (m, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([SH:9])[N:3]=1.CC(C)([O-])C.[K+].[F:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br>CS(C)=O>[F:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][S:9][C:4]1[N:5]=[C:6]([NH2:8])[CH:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: Nc1cc(N)nc(S)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1cc(N)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
4,6-diamino-2-pyrimidinethiol (7.3 g) was dissolved in DMSO (100 ml) at room temperature under an atmosphere of nitrogen. Potassium tert-butoxide (1M in THF, 48.3 ml) was added followed by 2,3-difluorobenzyl-bromide (10.0 g). The mixture was stirred for 2 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate and ammonium chloride. The organic phase was washed with ammonium chloride (3×) and brine, then dried over magnesium sulphate and evaporated to give the subtitled product as a white solid (12.2 g)
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([OH:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[Cl:29][C:30]([Cl:34])([Cl:33])[C:31]#[N:32]>ClC(Cl)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([O:19][C:31](=[NH:32])[C:30]([Cl:34])([Cl:33])[Cl:29])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Reactant: N#CC(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: COC(=O)[C@@H]1C[C@H](OC(=N)C(Cl)(Cl)Cl)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 28.8 %

Procedure:
A solution of 8a (0.05 g, 0.13 mmol), trichloroacetonitrile (0.1 mL, 1.0 mmol), 1,8-Diazobicylo[5.4.0]undec-7-ene (0.05 mL, 0.3 mmol) in dichloroethane (20 mL) was stirred at 0° C. for 24 h. The reaction mixture was then washed with saturated NaHCO3 (10 mL) and H2O (10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure to give a crude oil. The oil was purified by column chromatography (eluent: ethyl acetate/n-hexanes) to afford 21 (0.02 g, 37%) as a white solid, mp 120-123° C.; 1H NMR (CDCl3): δ 1.18 (s, 3H); 1.50 (s, 3H); 1.52-1.76 (m, 4H); 1.85 (dd, Ja=2.6, Jb=10.1, 1H); 2.10 (dd, Ja=2.9, Jb=11.6, 1H); 2.20 (m, 1H); 2.24 (s, 1H); 2.35-2.58 (m, 3H); 2.80 (dd, Ja=4.1, Jb=12.5, 1H); 3.75 (s, 3H); 5.34 (dd, Ja=7.7, Jb=12.2, 1H); 6.40 (dd, Ja=0.9, Jb=1.5, 1H); 7.41 (dd, 1H, 1.5, 1.5, 1H); 7.43 (dd, Ja=0.9, Jb=1.5, 1H); 8.38 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:20]>>[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:23][CH2:22]1)[CH3:20]
Reactant: Clc1ccc(OCCOc2nccnc2Cl)cc1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2nccnc2OCCOc2ccc(Cl)cc2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 4. Step 2, starting from 2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine*(150 mg, 0.53 mmol) and N-ethylpiperazine (221 mg, 1.93 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 138 mg (72%) of the title product. HRMS m/z calcd for C18H23CIN4O2(M)+362.1510, found 362.1526. Anal. (C18H23CIN4O2)C, H, N.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[C:22]=2[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:28][C:24]3[C:22]4[N:23]=[C:19]([NH2:18])[S:20][C:21]=4[CH:27]=[CH:26][CH:25]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Nc1nc2c(O)cccc2s1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Temperature: 80 °C

Procedure:
To a solution of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), ((0.13 g, 0.5 mmol) and 2-amino-4-hydroxybenzothiazole (83 mg, 0.5 mmol, Astatech) in DMF (1 mL) was added potassium carbonate (0.14 g, 1 mmol) and the mixture was heated at 80° C. for 16 h with sirring. The reaction mixture was allowed to cool to room temperature and partitioned between EtOAc and brine. The layers were separated and the aq. layer was extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. Purification of the residue by silica gel chromatography (2:1 hexanes:EtOAc) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 389 (M+1). Mp: 232.0–233.5° C. Anal. Calcd for C18H11F3N4OS: C, 55.67; H, 2.85; N, 14.43; S, 8.26. Found: C, 55.52; H, 3.08; N, 14.23; S, 8.36.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][C:8](Cl)=[O:9].Cl.[CH2:12]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(Cl)Cl>[Cl:5][CH2:6][CH2:7][C:8]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)=[O:9]
Reactant: c1ccc(Cc2cccnc2)cc1
Reactant: O=C(Cl)CCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(CCCl)c1ccc(Cc2cccnc2)cc1
Yield: 86.6 %

Procedure:
In 15 ml of methylene chloride was suspended 8.1 g of anhydrous aluminum chloride, and 3.0 ml of 3-chloropropionyl chloride was added to the suspension with ice-cooling, after which 5.0 g of 3-benzylpyridine hydrochloride was added in small portions to the resulting mixture over 30 minutes. The resulting mixture was subjected to reaction at room temperature for one hour, and then the reaction mixture was added to 30 ml of iced water. The crystals thus precipitated were collected by filtration, and suspended in a mixture of 50 ml of ethyl acetate and 30 ml of water, after which the resulting suspension was neutralized with sodium hydrogen-carbonate with ice-cooling. Insolubles were removed by filtration, and the organic layer of the filtrate was separated, washed with 10 ml of a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure to obtain 5.5 g (yield 86.6%) of pale yellow, oily 3-[p-(3-chloropropionyl)benzyl]pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=[CH:6][N:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:18][CH:17]=2)[N:4]=1.[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH3:1][O:2][C:3]1[C:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][N:5]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:20][CH:21]=2)[N:4]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A mixture of ethyl 3-[3-methoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazole-4-yl]propionate (380 mg), 1 N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for 2 hours, diluted with 1 N hydrochloric acid (2 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-methoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid was obtained (319 mg, yield: 89%). This was recrystallized from ethanol-hexane. Melting point: 127–128° C.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:8][CH:7]=1.[NH3:20].C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[NH2:20][CH2:2][C@@H:3]([OH:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:8][CH:7]=1
Reactant: O=C1COCCN1c1ccc(NC[C@@H](O)CCl)cc1
Reactant: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: NC[C@@H](O)CNc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.4 %

Procedure:
30.00 g of 4-[4-((R)-3-chloro-2-hydroxy-propylamino)-phenyl]-morpholin-3-one (MW=284.75; 1 eq.) were added to 1298 g of conc. aqueous ammonia (MW=17.03; 88 eq.). The reaction mixture was stirred for 2.5 h at room temperature. Then 3.0 g of charcoal were added and after 10 min of stirring, the suspension was filtered and the cake was washed with 90 mL of water. Filtrate and wash water were combined and concentrated in vacuo to a mass of 100 g. The concentrate was alkalized by addition of 21.84 g of potassium carbonate (MW=138.21; 1.5 eq.) and to the alkaline solution were added 200 mL of methylenechloride. After 10 min of stirring, the layers were separated and the aqueous layer was extracted once more with 100 mL of methylenechloride. The organic layers were combined and concentrated in vacuo. To the residue were added 150 mL of methyl tert-butyl ether and the resulting suspension was stirred for at least one hour at ambient temperature. Then the crystalline product was isolated by filtration and the filter cake was washed with 75 mL of methyl tert-butyl ether. After drying in vacuo at 30° C., 21.08 g of the crystalline title compound (MW 265.31) were isolated. Yield=75.4%.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]([F:23])[F:22])=[C:15]([Cl:24])[CH:14]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>>[Cl:24][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][CH2:20][CH:21]([F:23])[F:22])[CH2:12][N:9]1[C:10](=[O:11])[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[C:7]=2[CH2:8]1
Reactant: O=COc1ccccc1
Reactant: O=C1c2ccnc(Cl)c2CN1Cc1ccc(OCC(F)F)c(Cl)c1
Product: O=C(Oc1ccccc1)c1nccc2c1CN(Cc1ccc(OCC(F)F)c(Cl)c1)C2=O
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (220 mg, yellow solid) from 4-chloro-2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (230 mg, 0.62 mmol, Intermediate-39) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([O:19][CH2:20][CH2:21][OH:22])=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[CH:6]=1)C.[CH3:32][NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH3:32][N:33]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:4](=[O:3])[C:5]1[CH:6]=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[C:8]([O:19][CH2:20][CH2:21][OH:22])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)[CH:10]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(Cl)c2)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Reactant: CNCCCCCCCCc1ccccc1
Product: CN(CCCCCCCCc1ccccc1)C(=O)c1cc(-c2ccc(F)c(Cl)c2)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1

Procedure:
N-Methyl-N-(8-phenyloctyl)-3,5-bis[m-chloro-p-fluoro-phenyl)-4-(2-hydroxyethoxy)-benzamide was prepared as a white solid (0.313 g, 78%) from 3,5-bis[(m-chloro)-(p-fluoro)-phenyl)-4-(2-hydroxyethoxy)-benzoic acid ethyl ester and N-methyl-N-(8-phenyloctyl)amine using a procedure similar to step 2 of Example 175. 1H NMR (CDCl3) δ7.71-7.66 (dd, 2H); 7.52-7.45 (m, 2H); 7.36 (m, 2H); 7.30-7.12 (m, 7H); 3.52 and 3.28 (2bt, 2H); 3.27 (m, 4H); 3.04 (2s, 3H); 2.58 (m, 2H); 1.60 (m, 4H); 1.42-1.10 (m, 9H).
Reaction SMILES: CN(C=O)C.[F:6][C:7]([F:20])([F:19])[C:8]1[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:28][C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[O:31][N:30]=1>O>[F:20][C:7]([F:19])([F:6])[C:8]1[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[CH2:28][C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:41])[F:42])[CH:35]=2)[O:31][N:30]=1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 90 °C

Procedure:
A DMF solution (25 mL) of 4-(trifluoromethyl)-1H-indole-5-carbonitrile (2.66 mmol max) was treated with Cs2CO3 (1.73 g, 5.32 mmol) followed by 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.699 g, 2.66 mmol). The resulting suspension was heated to 90° C. for 30 min. The cooled reaction mixture was diluted with H2O (25 mL) and then extracted with EtOAc (3×25 mL). The pooled organic portions were washed with H2O and brine. Drying (Na2SO4) and filtration were followed by concentration. Column chromatography (SiO2, EtOAc/hexanes) afforded the title compound in excellent purity as a pale yellow solid (900 g, 75% over two stages): 1H NMR (DMSO-d6) δ 8.32 (d, J=6.0 Hz, 1H), 8.25 (bs, 1H), 8.11-8.06 (m, 2H), 7.98 (d, J=3.0 Hz, 1H), 8.86-8.81 (m, 2H), 6.82-6.81 (m, 1H), 5.95 (s, 2H).
Reaction SMILES: II.[Mg].Br[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([Cl:17])[CH:6]=1.[C:18](=[O:20])=[O:19].Cl>O1CCCC1>[Cl:17][C:7]1[CH:6]=[C:5]([C:18]([OH:20])=[O:19])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C=O
Reactant: Clc1cc(Br)ccc1-c1ccccc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2)c(Cl)c1
Temperature: 65 °C

Procedure:
Few crystals of iodine are added to tetrahydrofuran (200 mL) containing magnesium turnings (2.8 g, 0.117 mol). The mixture is heated at 60-70° C. A solution of 4-bromo-2-chlorobiphenyl (26 g, 0.097 mol) in tetrahydrofuran (50 mL) is added dropwise to the reaction mixture and refluxed for 1 hr. Reaction mixture is brought to room temperature and then cooled to −20° C. Carbon dioxide gas is passed through the reaction mixture for 45 minutes. The reaction mixture is treated with 3N HCl (125 mL) and extracted with ethyl acetate (2×200 mL). Combined organic layer is dried over sodium sulphate. Removal of solvent under reduced pressure gives a solid which is washed with diethyl ether (2×100 mL) and then dried to furnish 2-chlorobiphenyl-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.O.[OH-].[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O>[C:20]1([NH:19][C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[O:9])[CH:5]=[N:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1nnn[nH]1)c1cncc(Nc2ccccc2)n1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 5 ml of dimethylsulfoxide, 4.55 ml of aniline was added, and the mixture was heated for 17 hours at 80°-90 ° C. Water and 10%-sodium hydroxide aqueous solution were added to the reaction mixture, and the aqueous alkaline solution was washed with chloroform. The aqueous layer was filtered, and the filtrate was adjusted with 10%-hydrochloric acid to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and ethanol affording 0.80 g of the desired compound as yellow needles, m.p. 290°-293.5° C. (decomp.).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[F:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[N:61]=[C:62]=[O:63]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:62]([NH:61][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=2[F:54])=[O:63])[CH2:48]1
Reactant: O=C=Nc1ccccc1F
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)Nc2ccccc2F)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 87 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1-fluoro-2-isocyanatobenzene as the starting materials in 87% yield. LCMS for C30H29ClFN8O2 (M+H)+: m/z=587.0.