Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[Cl:8][CH2:9][CH2:10]O>>[OH:1][C:2]([CH3:7])([CH3:6])[C:3]([O:5][CH2:10][CH2:9][Cl:8])=[O:4]
Reactant: OCCCl
Reactant: CC(C)(O)C(=O)O
Product: CC(C)(O)C(=O)OCCCl

Procedure:
2-Chloroethyl 2-hydroxy-2-methylpropionate was prepared from 2-hydroxy-2-methylpropionic acid and excess 2-chloroethanol essentially by the method described in Step 1 of Example 1: b.p. 75°-77° C./6 mm Hg; 1H NMR δ1.47 (s, 6H), δ3.18 (s, 1H), δ3.72 (t, 2H, J= 5.6 Hz), δ4.43 (t, 2H, J=5.6 Hz); 13C NMR 27.1, 41.2, 64.8, 72.1, 176.8 ppm; HRMS calcd for C5H7ClO3Tms (M-CH3) 223.0557, obsd 223.0577.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH2:18][CH2:19][CH2:20][O:21]C3CCCCO3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:58][S:59](Cl)(=[O:61])=[O:60].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH:11]=2)[O:17][CH2:18][CH2:19][CH2:20][O:21][S:59]([CH3:58])(=[O:61])=[O:60])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(OCCCOC3CCCCO3)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(OCCCOS(C)(=O)=O)c2)n1
Yield: 100.2 %

Procedure:
A mixture of Example 75 (193 mg, 0.27 mmol), methanesulfonyl chloride (63 μL, 0.81 mmol) and DIPEA (200 μL, 1.08 mmol) in DCM (10 mL) was stirred at RT for 1 h. The volatiles were evaporated under reduced pressure to afford the title compound (214 mg, Quantitative). LCMS (Method 4): Rt 3.57 min, m/z 791 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].[C:21](Cl)(=[O:26])[CH2:22][C:23](Cl)=[O:24]>O1CCCC1>[C:16]([C:15]1[CH:14]=[C:13]([N:12]2[C:23](=[O:24])[CH2:22][C:21](=[O:26])[NH:1][C:2]3[C:11]4[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=4[CH:5]=[CH:4][C:3]2=3)[CH:20]=[CH:19][CH:18]=1)#[N:17]
Reactant: O=C(Cl)CC(=O)Cl
Reactant: N#Cc1cccc(Nc2ccc3c(c2N)CCCC3)c1
Solvent: C1CCOC1
Product: N#Cc1cccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)c1
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
To an anhydrous tetrahydrofuran (30 mL) solution of 3-(1-amino-5,6,7,8-tetrahydronaphthalen-2-ylamino)benzonitrile (747 mg, 2.84 mmol) was added an anhydrous tetrahydrofuran (5 mL) solution of malonyl chloride (276 μL, 2.84 mmol) under cooling in ice-bath. The mixture was stirred for 30 minutes under cooling in ice-bath, and for 2 hours at room temperature. To the mixture was added purified water. The mixture was extracted with ethyl acetate, washed with purified water, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=1/1) to give the titled compound as white powder (333 mg, yield 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][CH2:15][CH:16]=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[OH:18][C:19]1([CH2:25][CH2:26][N:27]2[C:31](=[O:32])[CH2:30][S:29]C2CCCC2C=CC(C(O)=O)=CC=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[OH:18][C:19]1([CH2:25][CH2:26][N:27]2[C:31](=[O:32])[CH2:30][S:29][CH:16]2[CH2:15][CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=2[Cl:1])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reactant: CCOC(=O)c1ccc(CCCC=O)c(Cl)c1
Product: CCOC(=O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)c(Cl)c1

Procedure:
This compound is prepared by the method described in Example 2, Step B, except that an equivalent quantity of ethyl 3-chloro-4-(4-oxobutyl)benzoate is substituted for the ethyl 4-(4-oxobutyl)benzoate of Example 2, Step B. The title compound is obtained as a viscous, brownish oil.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=2)[CH:10]=[C:9]([Cl:24])[CH:8]=1)[CH3:6].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([CH2:48][OH:49])[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1>ClCCl.C1CCCCC1>[Cl:24][C:9]1[CH:8]=[C:7]([CH:5]([O:49][CH2:48][C:35]2([C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=3)[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:39][CH2:40]2)[CH3:6])[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:14]=2)[CH:10]=1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-1-(5-Chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate (1.1 g, 2.33 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.79 g, 2.57 mmol) were combined in a dichloromethane/cyclohexane mixture (1:1, 10 mL) and cooled to 0° C. The reaction was treated with tetrafluoroboric acid-diethyl ether complex (64 μL, 0.47 mmol), stirred at 0° C. for 1 h, quenched by addition of saturated sodium bicarbonate, and diluted with diethyl ether. The layers were separated. The ethereal was washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 0.81 g (56%) as a clear film. 1H-NMR (CDCl3, 500 MHz) δ 8.00 (s, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.30-7.33 (m, 2H), 7.01-7.05 (m, 2H), 6.77 (m, 1H), 5.62-5.68 (s, 2H), 4.93 (q, J=6.4 Hz, 1H), 3.72 (m, 2H), 3.58-3.61 (m, 2H), 3.33-3.39 (m, 2H), 3.03-3.08 (m, 2H), 2.08-2.22 (m, 2H), 1.87-1.97 (m, 2H), 1.44 (s, 9H), 1.43 (d, J=6.4 Hz, 3H), 0.91-0.92 (m, 2H), 0.05 (s, 9H). Mass spec.: 618.86 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][CH:31]=[CH:30]3)=[CH:23][C:13]=1[CH2:14][NH:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]([CH2:14][C:13]2[CH:23]=[C:24]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[NH:32][CH:31]=[CH:30]4)[CH:25]=[CH:26][C:12]=2[F:11])[CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2ccc3[nH]ccc3c2)cc1CNCCN1CCCC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N(CCN1CCCC1)Cc1cc(-c2ccc3[nH]ccc3c2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 145.9 %

Procedure:
4-Fluorobenzoyl chloride (93 mg, 0.59 mmol) was added to a solution of [2-fluoro-5-(1H-indol-5-yl)-benzyl]-(2-pyrrolidin-1-yl-ethyl)-amine (90 mg, 0.27 mmol) and triethyl amine (81 mg, 0.8 mmol) in 10 ml of dichloromethane at room temperature. The resulting mixture was stirred at ambient temperature for 2 h, and then the volatiles were removed in vacuo and the residue was dissolved in ethyl acetate and washed with 1 M HCl solution and water. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with methanol/dichloromethane) provided 181 mg of product. This was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated to afford 92 mg of the title compound. LC/MS: Retention time, 2.55 min; (M+H)=460.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)C)(C)(C)C.C(OCC)C.Cl>CO>[F:17][C:15]1[CH:14]=[CH:13][C:12]([S:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[C:11]([CH2:10][CH2:9][NH:7][CH3:6])[CH:16]=1
Reactant: CN(CCc1cc(F)ccc1Sc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CNCCc1cc(F)ccc1Sc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
{2-[5-Fluoro-2-(1H-indol-3-ylsulfanyl)-phenyl]-ethyl}-methyl-carbamic acid tert-butyl ester (99 mg, 0.24 mmol) is dissolved in methanol (1.5 mL) and diethyl ether saturated with hydrochloric acid (0.5 mL) is added. The mixture is stirred at ambient temperature for 2 hours and concentrated in vacuo. Water (5 mL) is added to the remanence and the mixture is basified by addition of aqueous ammonia (25%). The aqueous fraction is extracted with ethyl acetate (3×10 mL). The combined organic fractions are dried (MgSO4) and concentrated in vacuo. The product is purified by preparative HPLC or silica gel chromatography eluting with ethyl acetate-ethanol-triethyl amine (100:5:5) to give 62 mg (83%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:5])=[CH2:4].[C:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])(=[O:8])[CH3:7]>>[CH3:5][C:3](=[CH2:4])[CH2:2][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:6](=[O:8])[CH3:7]
Reactant: C=C(C)CCl
Reactant: CC(=O)Nc1ccccc1O
Product: C=C(C)COc1ccccc1NC(C)=O
Yield: 85.5 %

Procedure:
The compound (1.74 g, 85%) was prepared from 3-chloro-2-methylpropene (1.09 g, 11.9 mmol) and 2-acetamidophenol (1.50 g, 9.92 mmol) analogously to that described in Example 8(i).
Reaction SMILES: [CH:1]([C:4]1[C:12]([C:13]([O:19][CH2:20][CH:21]=[CH2:22])([CH2:17][CH3:18])[CH:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[CH:1]([C:4]1[C:12]([C:13]([CH2:17][CH3:18])([O:19][CH2:20][CH2:21][CH3:22])[CH:14]([CH3:15])[CH3:16])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: C=CCOC(CC)(c1c(C(C)C)nn2ccccc12)C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCOC(CC)(c1c(C(C)C)nn2ccccc12)C(C)C
Yield: 70 %

Procedure:
A solution of 500 ml of 2-isopropyl-3-(1-allyloxy-1-ethyl-2-methylpropyl)pyrazolo[1,5-a]pyridine (Example 31) in 20 ml of ethanol was stirred in a hydrogen atmosphere at atmospheric pressure and room temperature in the presence of 20 mg of 10% palladium-on-charcoal. Absorption ceased after an hour. The solution was filtered and concentrated to dryness in vacuo. The residue was applied to silica gel column chromatography, eluted with dichloromethane, to give 350 mg (70%) of the desired compound as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:6]=2[N:7]=1.[N:21]1([CH2:27][CH2:28][OH:29])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([N:24]3[CH2:25][CH2:26][N:21]([CH2:27][CH2:28][OH:29])[CH2:22][CH2:23]3)=[N:8][C:6]=2[N:7]=1
Reactant: OCCN1CCNCC1
Reactant: CS(=O)(=O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Product: OCCN1CCN(c2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
5-Chloro-2-(methylsulfonyl)-7-morpholinothiazolo[4,5-d]pyrimidine was reacted with 2-(piperazin-1-yl)ethanol, via General Procedure C, to give crude 2-(4-(5-chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)piperazin-1-yl)ethanol, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure C again to give 134 after purification by reverse HPLC. MS (Q1) 444 (M+)
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:9]=2)[CH:5]=[C:4]([CH:19]=O)[CH:3]=1.[CH3:21][O:22][C:23](=[O:38])[CH:24]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])P(OC)(OC)=O.CN(C)C(=N)N(C)C>O1CCCC1>[CH3:21][O:22][C:23](=[O:38])[C:24]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])=[CH:19][C:4]1[CH:3]=[C:2]([CH3:1])[C:10]2[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[N:9]=2)[CH:5]=1
Reactant: COC(=O)C(C(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: Cc1cc(C=O)cc2cn(COCC[Si](C)(C)C)nc12
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2-H-indazole-5-carbaldehyde (8.5 g, 29.3 mmol) and methyl-2-(tert-butoxycarbonyl)-2-(dimethoxyphosphoryl)acetate (10 g, 32.2 mmol, 1.1 equiv) in tetrahydrofuran (30 mL) at 0° C. was added tetramethylguanidine (5.9 mL, 49.8 mmol, 1.7 equiv). After 10 min, the ice bath was removed and the reaction stirred at room temperature overnight. The solvent was evaporated and the residue purified by flash chromatography on silica gel to afford 11.2 g (83%). 1H-NMR (CD3OD, 300 MHz) δ −0.05 (s, 9H), 0.84-0.96 (m, 2H), 1.14 (bs, 9H), 2.56 (s, 3H), 3.58-3.70 (m, 2H), 3.82 (s, 3H), 5.73 (s, 2H), 7.41 (s, 1H), 7.45 (s, 1H), 7.84 (s, 1H), 8.41 (s, 1H). Mass spec.: 462.5 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([OH:16])=[C:5]([C:13]([OH:15])=O)[CH:6]=[N:7]2.CN(C)C=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>O>[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:13]([C:5]2[CH:6]=[N:7][C:8]3[C:3]([C:4]=2[OH:16])=[C:2]([F:1])[CH:11]=[CH:10][C:9]=3[F:12])=[O:15])=[CH:37][CH:36]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cnc2c(F)ccc(F)c2c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)ccc(F)c2c1O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a mixture of 0.25 g of 5,8-difluoro-4-hydroxy-3-quinolinecarboxylic acid and 10 mL of dimethyformamide is added 0.20 g of carbonyldiimidazole. The mixture is stirred 18 h at 50° C. and then it is cooled to 25° C. The mixture is treated with 0.10 mL of distilled water and stirred for 5 min. To the resulting solution is added 0. 15 mL of 4-chlorobenzylamine. After stirring for 18 hours the solvent is evaporated at reduced pressure and the residue is dissolved in 10 mL of refluxing glacial acetic acid. Hot (100° C.) water is added dropwise until the solution becomes cloudy, and the mixture is allowed to cool to 25° C. The precipitate is collected by filtration and it is washed with two successive 5 mL portions of 50% aqueous acetic acid. It is dried for 18 h at 20 torr and 90° C. This procedure yields the title compound as 173 mg of a white powder.
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7](F)[CH:8]=2)[N:3]1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>CN(C=O)C>[O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7]([N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)[CH:8]=2)[N:3]1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(F)c([N+](=O)[O-])cc21
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(-n3ccnc3)c([N+](=O)[O-])cc21
Yield: 96.1 %

Procedure:
By using 2.02 g of ethyl 2-(2,3-dioxo-6-fluoro-7-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl)acetate, 1.33 g of imidazole and 15 ml of DMF, 2.24 g (96%) of ethyl 2-[2,3-dioxo-6-(1H-imidazol-1-yl)-7-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][O:10][CH3:11])=[CH:4][CH:3]=1.[CH:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH3:11][O:10][CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]([OH:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:3][CH:4]=1
Reactant: COC=Cc1ccc(Br)cc1
Reactant: CCCCCCCC=O
Product: CCCCCCCC(O)c1ccc(C=COC)cc1

Procedure:
By the method of example 28, 1-bromo-4-(2-methoxyethenyl)benzene is prepared, lithiated, and reacted with octanal to provide 1-(4-(2-methoxyethenyl)phenyl)-1-octanol as a yellow oil after chromatography. The hydroxyl group is protected as the t-butyldimethylsilyl ether in the usual fashion, and the enol ether is then cleaved with chlorotrimethylsilane and sodium iodide as described in example 33. The resulting aryl acetaldehyde is obtained as an oil, and is immediately condensed with glyoxylic acid, by the method described in example 1(C). Under the reaction conditions, the silyl ether is simultaneously eliminated, and chromatography provides the title compound as a tan solid, mp 98°-99° after trituration with hot hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:33][CH2:34][CH3:35])=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:38][S:39]([CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:41])=[O:40]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:49][CH2:48]3)=[O:21])[C:10]([C:23]3[C:24]([O:33][CH2:34][CH3:35])=[N:25][C:26]([C:29]([F:31])([F:30])[F:32])=[N:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1nc(C(F)(F)F)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CCOc1nc(C(F)(F)F)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 5) was reacted with 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 3) to give cis-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C30H32N6O4SF3Cl2 [(M+H)+] 699.1530, observed 699.1533.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]#[N:21])=[CH:17][CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[O:22]=[C:11]1[CH:12]=[N:13][C:14]2[C:19](=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[N:10]1[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:32]2[CH:31]=[CH:30][C:27]3[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=3[N:33]=2)[CH2:3][CH2:4]1
Reactant: N#Cc1ccc2c(c1)ncc(=O)n2CCN1CCC(N)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: N#Cc1ccc2c(c1)ncc(=O)n2CCN1CCC(NCc2ccc3c(n2)NC(=O)CO3)CC1
Yield: 65.7 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoxaline-6-carbonitrile (Intermediate 197, 0.125 g) was reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (0.17 g) and NaBH(OAc)3 (0.27 g) as described for Example 107. The residue was purified by reverse phase HPLC with acetonitrile in water containing 0.1% TFA. Fractions containing product were concentrated to remove acetonitrile, neutralized with Na2CO3 solid, extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated. The residue was suspended in diethyl ether and filtered to yield 127 mg of a colorless solid.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:9][CH:10]=[C:11]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[C:4]=2[N:3]=1.[Br:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[OH:30].C(=O)([O-])[O-].[K+].[K+]>O>[Br:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[O:30][C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:9][CH:10]=[C:11]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[C:4]=2[N:3]=1
Reactant: Oc1ccc(Cl)cc1Br
Reactant: CCC(CC)c1ccc(-c2ccco2)c2nc(Cl)n(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCC(CC)c1ccc(-c2ccco2)c2nc(Oc3ccc(Cl)cc3Br)n(C)c12
Temperature: 120 °C
Yield: 68.3 %

Procedure:
A mixture of 2-chloro-7-(1-ethylpropyl)-4-(2-furyl)-1-methyl-1H-benzimidazole (42 mg, 0.139 mmol), 2-bromo-4-chlorophenol (87 mg, 0.417 mmol) and potassium carbonate (58 mg, 0.417 mmol) was heated at 120° C. for 18 h under an argon atmosphere. The mixture was diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 1-20% ethyl acetate/n-hexane gradient mixture to give 45 mg (0.0950 mmol, 68%) of the title compound) as a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH:12]2[C:16]([F:18])([F:17])[C:15]([C:19]3[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+].CO>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH:12]2[C:16]([F:18])([F:17])[CH:15]([C:19]3[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:14][CH2:13]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CN=C(c3cccnc3F)C2(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC2CNC(c3cccnc3F)C2(F)F)cc1
Reaction time: 3 h

Procedure:
To a solution of 4,4-difluoro-5-(2-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-3-yl 4-methylbenzenesulfonate (18.0 g) in tetrahydrofuran (180 mL) was added sodium borohydride (3.68 g) under ice-cooling, methanol (90 mL) was further added, and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed with water. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4,4-difluoro-5-(2-fluoropyridin-3-yl)pyrrolidin-3-yl 4-methylbenzenesulfonate. To a suspension of sodium hydride (9.74 g) in tetrahydrofuran (100 mL) was added dropwise a solution of 4,4-difluoro-5-(2-fluoropyridin-3-yl)pyrrolidin-3-yl 4-methylbenzenesulfonate in tetrahydrofuran (100 mL) under ice-cooling, 15-crown-5 (32.2 g) was added, and the mixture was stirred for 3 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and washed with 1 mol/L hydrochloric acid. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→3:1) to give the title compound as a colorless solid (yield 6.35 g, 72%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]([NH:13][C:14]([C:16]1[S:20][C:19]([NH2:21])=[N:18][C:17]=1[CH3:22])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([NH:13][C:14]([C:16]1[S:20][C:19]([NH:21][C:1](=[O:4])[CH2:2][CH3:3])=[N:18][C:17]=1[CH3:22])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCC(=O)Cl
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: CCC(=O)Nc1nc(C)c(C(=O)NCc2ccccc2)s1
Yield: 31 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use propionyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 31% yield; m. p. 175-176° C.; 1H NMR (DMSO-d6, 300 MHz) δ 12.15, (s, 1H), 8.51 (t, J=6.0 Hz, 1H), 7.32-7.16 (m, 5H), 4.34 (d, J=6.0 Hz, 2H), 2.65-2.22 (m, 5H), 1.07 (t, J=7.5 Hz, 3H); MS (ES+) m/z 304.3 (M+1).