Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:15][C:16]1[C:24]2[N:23]=[C:22](Cl)[NH:21][C:20]=2[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1>>[Br:15][C:16]1[C:24]2[N:23]=[C:22]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=4)[CH2:10][CH2:11]3)[NH:21][C:20]=2[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1
Reactant: Clc1cnc(N2CCNCC2)c(Cl)c1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Product: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncc(Cl)cc4Cl)CC3)[nH]c2c1

Procedure:
The piperazine from step (a) above (162 mg, 0.7 mmol) and 4-bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (168 mg, 0.56 mmol, Example 6b) reacted under the conditions of Example 3c to give the title compound as a white solid. M.p. 176-179° C. MS (ESI, pos. ion) m/z: 495 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>Cl>[CH3:13][C:12]([NH:6][C:5]1[CH:4]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:9]=[CH:8][CH:7]=1)=[O:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: Cl
Product: CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a solution of 161.0 g of α, α, α-trifluoro-m-toluidine in 500 ml of 2N hydrochloric acid, at room temperature, with vigorous agitation, is added rapidly 102.0 g of acetic anhydride. An exothermic reaction occurs and the temperature is allowed to rise spontaneously to about 50°. Subsequently, the mixture is allowed to cool to room temperature, and then cooled in ice. The crystalline solid is filtered to give 189.3 g of α,α,α-trifluoro-m-acetotoluidide.
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])[N:9]=[CH:8][NH:7][C:6]2=[O:15].C1C=CC2N=CNC(=O)C=2C=1.[Cl:27][CH2:28][CH2:29][CH2:30]I.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:27][CH2:28][CH2:29][CH2:30][N:7]1[C:6](=[O:15])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8]1
Reactant: ClCCCI
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: O=c1[nH]cnc2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncn(CCCCl)c(=O)c2cc1OC

Procedure:
3-(3-chloropropyl)-6,7-dimethoxy-4(3H)-quinazolinone was prepared starting from 6,7-dimethoxy-4-(3H)quinazolinone (1.61 g, 8 mmol). The quinazolinone was combined with 1-chloro-3-iodopropane (1.9 mL, 8 mmol), an excess of potassium carbonate (10 g) and stirred in 30 mL DMF overnight. The salts were filtered off and the reaction mixture dilluted with water. The solid that formed was collected via vacuum filtration, washed with water and dried, 0.70 g (31%); brown solid; m.p. 143° C., MS: 282.8 (M+H)+
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[NH2:20]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: CCOCCn1ccc2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOCCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 140 °C
Reaction time: 7 h
Yield: 51.2 %

Procedure:
To a solution of 4-chloro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (90 mg) in 1-methyl-2-pyrrolidone (0.7 mL), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (151 mg) was added, and the mixture was heated to 140° C. and stirred for 7 hrs. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with ethyl acetate (25 mL×3). The organic layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=10/0→8/2). The object fraction was concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether, collected by filtration and dried under reduced pressure to give the title compound (90 mg) as pale-yellow needle crystals.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=[O:18])[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][OH:20])[C@H:10]1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1.[NH4+].[Cl-]>[CH3:29][S:30]([O:20][CH2:19][C@@H:11]1[C@@H:10]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:14]2[NH:15][C:16](=[O:18])[O:17][C@H:13]2[CH2:12]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CO)C[C@@H]2O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.3 %

Procedure:
To a solution of (3aS,4R,5R,6R,7aS)-4,5-bis(benzyloxy)-6-(hydroxymethyl)hexahydrobenzo[d]oxazol-2(3H)-one (1.86 g, 4.86 mmol) in pyridine (11 mL) at −20° C. was added MeSO2Cl (0.723 g, 6.31 mmol). The mixture was slowly warmed to room temperature and stirred for 4 h. The reaction was diluted with aqueous saturated NH4Cl (100 mL) and extracted with EtOAc (2×60 mL). The extracts were washed with 0.5 N HCl (3×60 mL), dried with MgSO4. The solvent was evaporated to give ((3aS,4R,5R,6R,7aS)-4,5-bis(benzyloxy)-2-oxooctahydrobenzo[d]oxazol-6-yl)methyl methanesulfonate as a white solid (2.25 g, 100%) which was pure enough for next reaction. MS m/z 484.1 (M+23, 100%); 1H NMR (400 MHz, CDCl3) δ 7.30-7.44 (m, 10H), 4.92 (d, J=11.9 Hz, 1H), 4.87 (d, J=11.1 Hz, 1H), 4.66-4.70 (m, 2H), 4.65 (d, J=11.0 Hz, 1H), 4.57 (d, J=11.9 Hz, 1H), 4.43 (dd, J=9.7 Hz, 4.2 Hz, 1H), 4.21 (dd, J=9.7 Hz, 3.0 Hz, 1H), 3.59 (t, J=6.8 Hz, 1H), 3.51 (t, J=7.6 Hz, 1H), 3.41 (t, J=8.9 Hz, 1H), 2.12-2.26 (m, 2H), 1.79-1.87 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[S:11][C:12]([CH3:14])=[CH:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Br:15]Br>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]2[S:11][C:12]([CH3:14])=[C:13]([Br:15])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: BrBr
Reactant: COC(=O)c1cccc2cc(C)sc12
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc2c(Br)c(C)sc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
A solution of 2-methyl-benzo[b]thiophene-7-carboxylic acid methyl ester (0.50 g, 2.44 mmol) in CHCl3 (10 mL) is cooled to 0° C., treated with a solution of Br2 (0.13 mL, 2.44 mmol) in CHCl3 (5 mL). The reaction is stirred at 0° C. for 30 min, then at RT overnight. The reaction is diluted with CH2Cl2 (50 mL), washed with 10% Na2S2O3 (2×20 mL); dried with Na2SO4, filtered and concentrated to give the title compound (0.69 g, 2.43 mmol, 100%). 1H NMR (CDCl3): δ 2.58 (s, 3H), 4.02 (s, 3H), 7.50 (t, J=7.9 Hz, 1H), 7.92 (d, J=7.9 Hz, 1H), 8.08 (d, J=7.5 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:8]=1)([CH3:5])[CH3:4].[CH3:25][O:26][CH2:27][CH2:28]Br>CN(C=O)C>[CH:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:28][CH2:27][O:26][CH3:25])=[CH:14][CH:15]=2)[CH:10]=[C:9]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:8]=1)([CH3:5])[CH3:4]
Reactant: COCCBr
Reactant: Cc1cc(Nc2cc3cc(O)ccc3c(OC(C)C)n2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.5 %

Procedure:
NaH (6 mg) was added to 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (50 mg) in DMF (2 ml) and stirred at room temperature for 30 minutes. Then 2-bromoethyl methyl ether (23 mg) was added and stirred at room temperature overnight. The mixture was sent to preparative LC-MS and 5 mg of [1-Isopropoxy-6-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine was produced. LC-MS m/e 357(MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH:9]1(Br)[CH2:11][CH2:10]1.C(O[Na])(C)(C)C.O>CS(C)=O>[CH:9]1([S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: BrC1CC1
Reactant: Fc1ccc(S)cc1
Agent: CC(C)(C)O[Na]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc(SC2CC2)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
To a stirred solution of 4-fluorobenzenethiol (134 g, 1.05 mol) in DMSO (3 L) under nitrogen atmosphere were added cyclopropyl bromide (140 g, 1.15 mol) and t-BuONa (138.7 g, 1.44 mol). Then the reaction mixture was heated to 80° C. and stirred for 2 days. TLC (petroleum ether) indicated the reaction was complete. After cooled to room temperature, the mixture was poured into water (2 L), extracted with diethyl ether (1.5 L×3). The combined organic phases were washed with water (1 L), then brine (1 L), dried over Na2SO4 and concentrated in vacuum to give cyclopropyl(4-fluorophenyl)sulfane (129 g, 73.1%) as a colorless oil. To a mixture of cyclopropyl(4-fluorophenyl)sulfane (129 g, 0.77 mol) and acetic acid (1.9 L) was added 30% H2O2 (1.2 L), and the mixture was heated to reflux and stirred overnight. TLC (petroleum ether:ethyl acetate=4:1) indicated the reaction was complete. After cooled to room temperature, the mixture was poured into water (1 L), then Na2S2O3 (200 g) was added to consume excess H2O2, then Na2CO3 was added to adjust pH=7. The mixture was extracted with ethyl acetate (1.5 L×2). The combined organic layers were washed with water (1 L), dried over Na2SO4 and concentrated in vacuum to give 69 g of crude product, which was purified by column chromatography (25% ethyl acetate in petroleum ether) to give the title compound (42 g, 27.3%) as a white solid.
Reaction SMILES: [Br:1]Br.C(Cl)(Cl)(Cl)Cl.[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12](=[O:26])[CH2:11][C:10]1=[O:27]>C(Cl)Cl>[Br:1][CH:11]1[C:10](=[O:27])[N:9]([CH3:8])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:12]1=[O:26]
Reactant: BrBr
Reactant: CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CN1C(=O)C(Br)C(=O)N(c2ccccc2)c2ccccc21

Procedure:
While irradiating with a 500 watt lamp at about 40° C., a solution of 5 ml of bromine and 30 ml of carbon tetrachloride was introduced dropwise into a solution of 25 g of the product of Step A and 750 ml of carbon tetrachloride. At the end of the introduction, the lamp was extinguished, the mixture was cooled and 500 ml of methylene chloride were added. The organic phase was washed with a saturated sodium carbonate solution, then with water and the product obtained was chromatographed on silica. Elution with an ethyl acetate-methylene chloride mixture 7-3-yielded 10.5 g of the sought product melting at 132° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([C@:14]34[CH2:22][NH:21][CH2:20][C@H:19]3[CH2:18][S:17][C:16]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15]4)[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:21]2[CH2:20][C@@H:19]3[C@@:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([C:7]5[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=5)[CH:9]=4)([N:15]=[C:16]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[S:17][CH2:18]3)[CH2:22]2)=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(-c4cccnc4F)c3)CNC[C@H]2CS1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(-c4cccnc4F)c3)CN(c3ccc(F)cc3)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl(±)-{(4aR*,7aS*)-7a-[3-(2-fluoropyridin-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl}carbamate obtained in Preparation Example 18-(9) (72 mg) was mixed with 4-fluorobenzeneboronic acid (24.7 mg), copper (II)acetate (6.1 mg), triethylamine (93.2 μL, specific gravity: 0.73 g/cm3) and molecular sieves 4 A (powder) (57.6 mg) in dichloromethane (3 mL), and the mixture was stirred under a nitrogen atmosphere at room temperature for 11 hours and 30 minutes. 4-Fluorobenzeneboronic acid (23.5 mg) and copper (II) acetate (12 mg) were further added. The atmosphere was changed to an open system, followed by further stirring. After 23 hours and 45 minutes, the reaction suspension was purified by NH-silica gel column chromatography. The resulting product was purified again by pTLC to obtain the title compound (15 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][C:32]([OH:34])=O)(=[O:30])=[O:29])=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[CH3:35][N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:37].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][C:32]([N:36]([CH3:37])[CH3:35])=[O:34])(=[O:29])=[O:30])=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@H]4NS(=O)(=O)CC(=O)O)s2)cc1C#N
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@H]4NS(=O)(=O)CC(=O)N(C)C)s2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
Prepared using General Procedure 16: To (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid (20 mg, 0.04 mmol) in DCM (0.4 mL) was added HATU (45 mg, 0.12 mmol) and DIEA (10.3 mg, 0.08 mmol). After 30 min, dimethylamine (2M solution in THF, 200 μL, 0.4 mmol) was added and the reaction stirred for 18 h at room temperature. The reaction was quenched with water (100 μL) and the solvent evaporated. The crude material was purified by preparative HPLC to afford 14 mg (66%) of (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)-N,N-dimethylacetamide 43 as white solid. LCMS-ESI (m/z) calculated for C25H27N5O4S2: 525.2; found 526.2 [M+H]+, tR=3.42 min. 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J=8.9, 2.3 Hz, 1H), 8.14 (d, J=2.3 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 5.50 (d, J=8.2 Hz, 1H), 5.07 (q, J=7.7 Hz, 1H), 4.76 (hept, J=6.1 Hz, 1H), 4.28 (d, J=14.6 Hz, 1H), 4.09 (d, J=14.6 Hz, 1H), 3.50 (ddd, J=17.0, 8.8, 3.4 Hz, 1H), 3.20 (dt, J=9.7, 7.1 Hz, 1H), 3.15 (s, 3H), 3.02 (s, 3H), 2.72 (dtd, J=11.4, 8.0, 3.5 Hz, 1H), 2.20 (dq, J=13.1, 8.4 Hz, 1H), 1.46 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 166.99, 165.73, 163.22, 161.71, 144.17, 141.92, 133.44, 133.34, 129.31, 127.92, 127.33, 126.37, 122.70, 115.57, 113.91, 103.71, 72.56, 59.23, 54.92, 38.30, 35.99, 31.36, 21.74. Chiral HPLC: (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)-N,N-dimethylacetamide was eluted in 40% IPA in hexanes, 100% ee, tR=22.87 min.
Reaction SMILES: C(OC([NH:8][C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20](Cl)[N:19]=2)=[CH:14][CH:13]=1)([CH3:11])[CH3:10])=O)(C)(C)C.[NH2:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][OH:33])=[CH:29][CH:28]=1.FC(F)(F)C(O)=O>C(OCCO)C>[NH2:8][C:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][OH:33])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][CH:17]=1)([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Cl)ncc2Cl)cc1
Reactant: Nc1ccc(CCO)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCCO
Product: CC(C)(N)c1ccc(-c2nc(Nc3ccc(CCO)cc3)ncc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-[4-(1-tertbutoxycarbonylamino-1-methylethyl)phenyl]-2,5-dichloropyrimidine (1.53 g, 4.0 mmol) and 4-aminophenethyl alcohol (1.10 g, 8.0 mmol) in 2-ethoxyethanol (15 ml) was heated to reflux for 18 h. The reaction was cooled to room temperature, trifluoroacetic acid (2 ml) added and the reaction stirred for 30 min. Solvent was removed in vacuo and the residue partitioned between CH2Cl2 (100 ml) and saturated, aqueous Na2CO3 (80 ml). The aqueous layer was re-extracted with CH2Cl2 (2×80 ml) and the combined CH2Cl2 layer washed with aqueous Na2CO3 (80 ml), brine (80 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 10-15% methanol in CH2Cl2) to give the title compound as a buff solid (1.30 g) m.p. 162-163°. δH (d6DMSO) 9.74 (1H, s), 8.55 (1H, s), 7.76 (2H, d, J 8.5 Hz), 7.68 (2H, d, J 8.5 Hz), 7.62 (2H, d, J 8.5 Hz), 7.12 (2H, d, J 8.5 Hz), 4.57 (1H, bs), 3.55 (2H, m), 2.65 (2H, t, J 7.2 Hz), 1.41 (6H, s); MS (ESI) 383 (MH+, 35Cl, 100%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Cl:17][CH2:18][C:19]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])=[O:20]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a cooled (0° C.) solution of 2,4-difluoroaniline, (1.5 g, 11.6 mmol) in DCM (50 mL) was added triethylamine (1.9 mL, 13.9 mmol) followed by 2-chloroacetyl chloride (1.0 mL, 12.8 mmol). The reaction was warmed to RT and stirred for 2 h. The reaction mixture was concentrated, redissolved in EtOAc (50 mL) and washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to yield 2.2 g of crude product which was further purified by flash column chromatography using 1:1 EtOAc:hexanes as the eluent. 2.0 g of 2-chloro-N-(2,4-difluorophenyl)acetamide, (yield: 84%) was isolated.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([OH:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(O)c1
Reactant: BrCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 64.5 %

Procedure:
A mixture of ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-hydroxybenzyl)oxy]-1H-pyrazole-4-carboxylate (2.00 g), benzyl bromide (0.97 g) potassium carbonate (0.53 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give ethyl 1-benzyl-3-[(3-benzyloxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (1.51 g, yield 64%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([C:21]2[S:29][C:28]3[C:23](=[N:24][CH:25]=[CH:26][C:27]=3Cl)[CH:22]=2)=[O:20])[CH:13]=1>>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([C:21]2[S:29][C:28]3[C:23](=[N:24][CH:25]=[CH:26][C:27]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:22]=2)=[O:20])[CH:13]=1
Reactant: O=C(Nc1cccnc1)c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)Nc5cccnc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid pyridin-3-ylamide by a procedure analogous to Example 1C. MS: 400 (MH+), HPLC Rf: 4.58 min.; HPLC purity 99%.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C([C:15]([O-:17])=[O:16])=CC=CC=1O.[K+].C(C1C(CC2C=CC=CC=2)=C(C)C=CC=1)C1C=CC=CC=1.C(=O)=O>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:15]([OH:17])=[O:16])=[CH:3][CH:2]=1
Reactant: Cc1c(O)cccc1C(=O)[O-]
Reactant: Oc1ccccc1
Agent: Cc1cccc(Cc2ccccc2)c1Cc1ccccc1
Agent: O=C=O
Agent: [K+]
Product: O=C(O)c1ccc(O)cc1
Yield: 81.1 %

Procedure:
A pressure vessel was charged with 4.71 g of phenol, 17.56 g of potassium ortho-cresolate being in a dry powder form and 43 ml of NeoSK 1400 (a dibenzyltoluen mixture medium produced by Soken Chemical K.K.). With stirring, reaction was carried out at a carbon dioxide pressure of 3 kg/cm2 (G) and at 270° C. for one hour. An analysis of the reaction mixture after conversion to acid form showed a para-hydroxybenzoic acid yield of 81.1% on the basis of phenol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.C(N(CC)C(C)C)(C)C.[NH:22]1[CH2:27][CH2:26][S:25][CH2:24][CH2:23]1>C(#N)C>[F:9][C:6]1[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=[C:2]([F:1])[C:7]=1[N:22]1[CH2:27][CH2:26][S:25][CH2:24][CH2:23]1
Reactant: C1CSCCN1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(F)c(N2CCSCC2)c(F)c1

Procedure:
A solution of 3,4,5-trifluoronitrobenzene (5.00 g, 28.24 mmol) in acetonitrile (60 mL) is cooled to 0° C. and treated with N,N-diisopropylethylamine (7.38 mL, 42.35 mmol) followed by thiomorpholine (2.98 mL, 29.65 mmol). The ice bath is removed and the reaction mixture stirred at room temperature under nitrogen for approximately 24 h, during which additional thiomorpholine (0.1 eq) is added. The solvent is removed under reduced pressure, and the residue is diluted with ethyl acetate, washed with 1N hydrochloric acid (until the washings are acidic), saturated aqueous sodium bicarbonate and saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound, mp 104-105° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([OH:16])[C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][CH2:18][CH2:19][C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)[C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: Cc1cccc(CCBr)c1
Reactant: COC(=O)c1cc(O)c2c(c1)OC(F)(F)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCCc2cccc(C)c2)c2c(c1)OC(F)(F)O2
Temperature: 80 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
1.8 g of 2,2-difluoro-7-hydroxy-benzo[1,3]dioxole-5-carboxylic acid methyl ester, 4.6 g of 1-(bromo-ethyl)-3-methyl-benzene, and 3.2 g of K2CO3 were added to 70 ml of anhydrous DMF and the reaction mixture stirred at 80° C. for 3 h. The reaction mixture was then allowed to cool to room temperature, 300 ml of water added and extracted three times using 100 ml of EA each. The organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP 1:4 yielded 2.4 g of the title compound, colorless oil. Rf (EA/HEP 1:4)=0.32