Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([C:8]1[CH:13]=[CH:12]N=CC=1)=[O:7].[C:19]([C:21]1C=CC=CN=1)#[N:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([C:8]1[CH:13]=[CH:12][CH:21]=[CH:19][N:20]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccncc2)cc1OC
Reactant: N#Cc1ccccn1
Product: COc1ccc(C(=O)c2ccccn2)cc1OC

Procedure:
2-(3,4-Dimethoxybenzoyl)pyridine was prepared analogously to 4-(3,4-dimethoxybenzoyl)pyridine using 2-cyanopyridine. The crude mixture was purified by flash column chromatography (silica gel, 1% methanol/methylene chloride) to afford after drying in vacuo (60° C., 1 mm) 1.67 g (34%) of the product: mp 91.5-93° C.; 1H NMR (CDCl3) δ 8.76-8.70 (m, 1H), 8.05-7.71 (m, 4H), 7.55-7.45 (m, 1H), 7.00-6.89 (m, 1H), 3.96 (s, 3H), 3.96 (s, 3H); 13C NMR (CDCl3) δ 192.1, 155.7, 153.3, 148.7, 148.2, 136.9, 128.9, 126.7, 125.7, 124.4, 112.6, 109.8, 56.0, 55.9; Anal. Calcd for C14H13NO3. Theoretical: C, 69.12; H, 5.39; N, 5.76. Found: C, 68.96; H, 5.47; N, 5.66.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([N:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=1[C:42]1[N:43]=[C:44]([CH2:61][CH3:62])[C:45]([NH:50][C@@H:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][C@@H:52]2[OH:60])=[N:46][C:47]=1[CH2:48][CH3:49].Br[CH2:64][CH2:65][F:66]>>[Cl:32][C:33]1[CH:38]=[C:37]([N:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=1[C:42]1[N:43]=[C:44]([CH2:61][CH3:62])[C:45]([NH:50][C@@H:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][C@@H:52]2[O:60][CH2:64][CH2:65][F:66])=[N:46][C:47]=1[CH2:48][CH3:49]
Reactant: CCc1nc(-c2ccc(N(C)C)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: FCCBr
Agent: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(N(C)C)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-({5-[2-chloro-4-(dimethylamino)phenyl]-3,6-diethylpyrazin-2-yl}amino)-2,3-dihydro-1H-inden-2-ol and 1-bromo-2-fluoroethane and making non-critical variations provided the title compound as a light yellow amorphous solid. IR (diffuse reflectance) 2969, 2932, 2907, 2877, 1608, 1563, 1545, 1483, 1447, 1392, 1353, 1207, 1177, 1123, 1042 cm−1; OAMS supporting ions at: ESI+ 483.2; MS (EI) m/z 482 (M+); HRMS (FAB) calcd for C27H32CLFN4O+H1 483.2327, found 483.2324. [α]25D=−79 (c 0.52, methylene chloride); Anal. Calcd for C27H32ClFN4O: C, 67.14; H, 6.68; N, 11.60. Found: C, 67.19; H, 6.90; N, 11.63.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([N:14]2[CH2:19][CH:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)(=[O:13])=[O:12])[C@@H:7]([C:27]([OH:29])=[O:28])[CH2:6]1)=[O:4]>O1CCCC1.C(O)C.[Pd]>[CH3:1][N:2]([CH3:30])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)(=[O:13])=[O:12])[C@@H:7]([C:27]([OH:29])=[O:28])[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CCN(S(=O)(=O)N2CC=C(c3ccc(F)cc3)CC2)[C@@H](C(=O)O)C1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CCN(S(=O)(=O)N2CCC(c3ccc(F)cc3)CC2)[C@@H](C(=O)O)C1
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(R)-carboxylic acid (1.39 g, 3.16 mmol) [prepared as described in Example 28, Steps 1-4] and 10% Pd/C (0.7g) in 10 % tetrahydrofuran/ethanol (45 ml) was stirred under an atmosphere of hydrogen (1 atm) overnight. The reaction mixture was filtered through Celite with excess ethanol and the filtrate was concentrated in vacuo to give 4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxylic acid (88%) as a white solid. This material was converted to N-hydroxy-4-dimethylaminocarbonyl-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide by following the procedure described in Example 28, Step 5 above.
Reaction SMILES: [C:1]([CH:4]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:5][CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2].[N+:23](/[CH:26]=[CH:27]/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O-:25])=[O:24]>C(OCC)C>[CH2:11]([O:10][C:8]([CH2:7][C@@H:6]1[CH2:5][C@@:4]([C:1](=[O:3])[CH3:2])([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C@@H:27]([CH:28]=[CH:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@@H:26]1[N+:23]([O-:25])=[O:24])=[O:9])[CH3:12]
Reactant: O=[N+]([O-])/C=C/C=C/c1ccccc1
Reactant: CCOC(=O)C=CCC(C(C)=O)C(=O)OCc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C[C@@H]1C[C@@](C(C)=O)(C(=O)OCc2ccccc2)[C@@H](C=Cc2ccccc2)[C@@H]1[N+](=O)[O-]
Reaction time: 24 h
Yield: 83 %

Procedure:
To a solution of 6-benzyl 1-ethyl 5-acetylhex-2-enedioate (4b, 0.3 mmol, 1.0 eq) and 1-((1E,3E)-4-nitrobuta-1,3-dienyl)benzene (0.6 mmol, 2.0 eq) in diethyl ether (0.4 mL) was added catalyst VI (Q-NH2) (0.03 mmol, 0.2 eq) at room temperature (22° C.). The resulting mixture was stirred vigorously for 24 hours, and then the reaction was continued for about 6 hours after removal of the solvent. After the reaction was completed (monitored by TLC and crude NMR), the title product was afforded by flash chromatography over silica gel (Et2O:Hexane=1:10 to 1:4) in 83% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:23])[C:5]([N:12]2C(=O)C3=CC=CC=C3C2=O)=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2.O.NN>CS(C)=O>[NH2:12][C:5]1[C:4]([F:23])=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][O:10]2
Reactant: O=C1c2ccccc2C(=O)N1c1c(F)cc(Cl)c2c1CCCO2
Agent: NN
Solvent: O
Solvent: CS(C)=O
Product: Nc1c(F)cc(Cl)c2c1CCCO2
Temperature: 0 °C

Procedure:
To a solution of 10.05 g of 41D in 60 mL of DMSO was added 7.58 g of hydrazine hydrate. The mixture was heated to 65°-75° C. for 3 hours, cooled, and poured into ice-water. The mixture was extracted with 3 portions of ether. The ether layer was extracted with water, brine, and dried over MgSO4 to afford 5-amino-8-chloro-6-fluorochromane (41E) as a yellow oil which solidified on standing, m.p.: 47°-50° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:15])[C:11]=2[O:13][CH3:14])[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+]>O1CCCC1>[NH2:15][C:10]1[C:11]([O:13][CH3:14])=[C:12]2[C:7]([CH2:6][CH2:5][C:4]2=[CH:3][CH2:2][NH:1][C:23](=[O:25])[CH3:24])=[CH:8][CH:9]=1
Reactant: COc1c(N)ccc2c1C(=CCN)CC2
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(N)ccc2c1C(=CCNC(C)=O)CC2
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
3-(2-Aminoethylidene)-4-methoxyindan-5-amine (15.3 mg, 0.076 mmol) and triethylamine (21.2 μL, 0.152 mmol) were dissolved in tetrahydrofuran (0.9 mL), a solution of acetic anhydride (7.18 μL, 0.076 mmol) in tetrahydrofuran (0.1 mL) was added under ice-cooling, and the mixture was stirred for 15 min. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) to give the title compound (16.2 mg, yield 87%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.Cl[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:17][C:16]1[C:11]([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Clc1cccnc1Cl
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccn(-c2ncccc2Cl)n1
Temperature: 130 °C
Reaction time: 14 h
Yield: 82.2 %

Procedure:
A mixture of 15.30 g of 3-trifluoromethyl-1H-pyrazole, 16.64 g of 2,3-dichloropyridine, 26.42 g of potassium carbonate and 100 ml of N,N-dimethylformamide was stirred at 130° C. for 14 hours. The reaction mixture was allowed to cool to room temperature and then water was poured thereto. The mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 22.88 g of 3-chloro-2-(3-trifluoromethyl-1H-pyrazol-1-yl)pyridine of the formula:
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.Cl.[N:37]1[CH:42]=[CH:41][C:40]([CH2:43]Cl)=[CH:39][CH:38]=1>CN(C=O)C>[C:1]1([C:7](=[N:8][C:9]([CH3:10])([CH2:43][C:40]2[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=2)[C:11]([O:13][CH3:14])=[O:12])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCc1ccncc1
Reactant: COC(=O)[C@H](C)N=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C(C)(Cc1ccncc1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of methyl N-(diphenylmethylene)alaninate from Step A (9.78 g, 36.6 mmol) in 60 ml DMF at 0° C. was added a 1M solution of sodium bis(trimethylsilyl)amide in THF (45.72 ml, 45.72 mmol) over a 20 min period. After 30 min, a solution of 4-picolyl chloride hydrochloride (3.00 g, 18.29 mmol) in 40 ml DMF was added to the reaction via cannula over a 25 min period. The reaction was warmed to rt and stirred for 5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3×). The combined organic layers were washed with 3M LiCl (2×) and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (0-40% EtOAc/hexanes) afforded methyl 2-[(diphenylmethylene)amino]-2-methyl-3-pyridin-4-ylpropanoate as a white solid (5.28 g, 81%). LCMS [M+H]=359.2. 1H NMR (d4-MeOH) δ 8.51 (dd, J=4.5, 1.5 Hz, 2H), 7.56 (dd, J=8.4, 1.4 Hz, 2H), 7.40-7.37 (m, 4H), 7.34-7.30 (m, 2H), 7.26-7.23 (m, 2H), 7.10-7.07 (m, 2H), 3.33 (A of AB, d, J=13.0 Hz, 1H), 3.27 (s, 3H), 3.18 (B of AB, d, J=12.9 Hz, 1H), 1.32 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.Cl.[NH2:16][C@H:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[OH:22].CCN(C(C)C)C(C)C>C(O)C>[OH:22][C@H:18]1[CH2:19][CH2:20][CH2:21][C@@H:17]1[NH:16][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: N[C@H]1CCC[C@@H]1O
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1N[C@H]1CCC[C@@H]1O
Temperature: 60 °C
Yield: 72.8 %

Procedure:
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1.4 g, 6.0 mmol), (1S,2S)-2-aminocyclopentanol hydrochloride (0.7 g, 6.9 mmol) and DIEA (1.0 g) in ethanol (20 mL) was heated at 60° C. for 15 h. After being cooled to room temperature, the reaction solution was concentrated and the residue was purified on silica gel column (eluting with 0-10% ethyl acetate in petroleum ether) to give ethyl 4-((1S,2S)-2-hydroxycyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylate (1.3 g, 4.37 mmol, yield 73%) as a white solid. MS (ESI): m/z 298.5 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([CH:17]=O)=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.[NH2:27][OH:28]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([CH:17]=[N:27][OH:28])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1ccccc1-c1cc(-c2cnc3nc(C=O)ccn23)ccc1F
Reactant: NO
Solvent: CO
Solvent: O
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(C=NO)ccn23)ccc1F
Temperature: 60 °C

Procedure:
A suspension of 2′-fluoro-5′-(7-formylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile (260 mg, 0.8 mmol) in methanol (3 ml) was treated with hydroxylamine (0.13 ml of a 50 wt. % solution in water) then heated at 60° C. for 3 h. The reaction was cooled to 0° C., the solid collected by filtration and washed with a little cold methanol to afford 2′-fluoro-5′-[7-(hydroxyiminomethyl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as a yellow solid. This solid was suspended in dichloromethane (5 ml), treated with 1,1′-carbonyldiimidazole (180 mg, 1.1 mmol) and triethylamine (0.31 ml, 2.3 mmol) then heated at reflux for 2 h. The reaction was cooled, diluted with dichloromethane then washed with water, brine, dried over anhydrous sodium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with dichloromethane/methanol/conc. ammonia (99:0.9:0.1) afforded a solid which was recrystallised from acetonitrile to furnish 3-(2′-cyano-6-fluorobiphenyl-3-yl)imidazo[1,2-α]pyrimidine-7-carbonitrile as a yellow powder (160 mg, 63% over 2 steps): δH (400 MHz, DMSO) 7.64-7.72 (3H, m), 7.78-7.81 (1H, m), 7.89 (1H, ddd, J 7, 7 and 1), 7.94-7.99 (2H, m), 8.05 (1H dd, J 8 and 2), 8.43 (1H, s), 9.36 (1H, d, J 7); m/z (ES+) 340 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([N:43]=[C:44]=[O:45])=[CH:39][N:38]=1)=[O:36]>ClCCl>[CH3:33][O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:45])=[CH:39][N:38]=1)=[O:36]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: COC(=O)c1ccc(N=C=O)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (67.8 mg, 0.67 mmol) (Aldrich), followed by the addition of solution of 5-isocyanato-pyridine-2-carboxylic acid methyl ester in toluene (from Example 83c supra). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-5-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-pyridine-2-carboxylic acid methyl ester as a white solid. (Yield 83 mg, 56.1%).
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][CH2:8][CH3:9].[CH:15]1([CH2:21][C@H:22]2[C@H:26]([C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[O:25][C:24]([CH3:34])([CH3:33])[N:23]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C1(CC2COC(C)(C)N2C(OC(C)(C)C)=O)CCCCC1>O1CCCC1.CO>[CH2:6]([NH:10][S:11]([CH2:14][C:27]([C@@H:26]1[O:25][C:24]([CH3:34])([CH3:33])[N:23]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[C@H:22]1[CH2:21][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH2:28][CH2:29][CH2:30][CH3:31])[OH:32])(=[O:13])=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Reactant: CCCCNS(C)(=O)=O
Agent: CC(C)(C)OC(=O)N1C(CC2CCCCC2)COC1(C)C
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: CCCCNS(=O)(=O)CC(O)(CCCC)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (4.48 ml., 11.2 mmole, 2.8 eq., 2.5M in hexane) was added to a solution of N-butylmethanesulfonamide [846 mg., 5.6 mmole, 1.4 eq., prepared as described in Example 1(a)] in tetrahydrofuran (16 ml., 0.35M) at -40° and stirred for 10 minutes. The reaction was then warmed to 0°, stirred for 30 minutes and cooled to -40°. (4S-trans)-4-(Cyclohexylmethyl)-2,2-dimethyl-5-(1-oxopentyl)-3-oxazolidinecarboxylic acid, 1,1-dimethylethyl ester (1.5 g., 3.93 mmole, 1 eq.) in tetrahydrofuran (4 ml., 1.0M) was then added. After 90 minutes at -40°, the reaction was quenched with aqueous saturated NH4Cl, warmed to room temperature and extracted three times with ether. The organic extracts were dried (Na2SO4), filtered through MgSO4, and concentrated. The residue was chromatographed on silica gel (Merck, 80 g.) eluting with hexane:acetone (10:1) to provide 237 mg. of (4S-trans)-5-[2-[butylamino)sulfonyl]-1-butyl-1-hydroxyethyl]-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylic acid, 1,1-dimethylethyl ester, isomer A; [α]D =+4.2° (c=1.0, methanol) and 101 mg. of isomer B; m.p. 138°-140°; [α]D =+5.5° (c=1.0, methanol) and 1.518 g. of a mixture of isomer A and isomer B.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)[S:11][C:12]=1[S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.NN.C(=O)([O-])O.[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:20][NH2:21])[S:11][C:12]=1[S:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc(-c2ccccc2F)c(Sc2ccccc2)s1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NCc1nc(-c2ccccc2F)c(Sc2ccccc2)s1
Temperature: 70 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
To a solution of 2-{[4-(2-fluorophenyl)-5-(phenylthio)-1,3-thiazol-2-yl]methyl}-1H-isoindole-1,3(2H)-dione (345 mg) in ethanol (5 mL) was added hydrazine monohydrate (0.05 mL) and the mixture was stirred at 70° C. for 3 hr. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 209 mg, yield 86%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:19]2[CH2:21][CH2:20]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:22]([O:24][C:25](=[O:28])[NH:26][CH3:27])[CH3:23].[H-].[Na+].Cl.O>CN(C=O)C>[CH2:22]([O:24][C:25](=[O:28])[N:26]([CH2:2][C:3]1[C:4]([CH:19]2[CH2:21][CH2:20]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1)[CH3:27])[CH3:23]
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Reactant: CCOC(=O)NC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N(C)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
1.00 g (3.2 mmol) of 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) was dissolved in 20 ml of DMF. Then, the reaction mixture was cooled down to 0° C. 0.36 ml=0.366 g (3.52 mmol) of methyl-carbamic acid ethyl ester was added to the stirred solution, followed by 0.14 g (3.2 mmol) of sodium hydride (55%). After 18 hours, the reaction mixture was poured into crashed ice, the pH was adjusted to <3 with HCl/H2O and it was then extracted twice with Et2O. The combined organic phases were washed with water, dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by flash chromatography (SiO2, gradient of EtOAc, n-heptane) to give 0.87 g of the title compound as light yellow solid.
Reaction SMILES: [C:1](#[N:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(C#N)CCCCCCCCCC.[CH2:21]([CH2:23]N)[OH:22]>O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:2]([C:1]1[O:22][CH2:21][CH2:23][N:7]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NCCO
Reactant: CCCCCC#N
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCCC#N
Agent: [Zn+2]
Solvent: O
Product: CCCCCC1=NCCO1
Yield: 58.1 %

Procedure:
9.72 g (100 mmoles) of hexanenitrile was substituted for undecyl cyanide in Example 1 and the reaction was repeated with 6.11 g (100 mmoles) of ethanolamine and 549 mg (2.5 mmoles) of zinc acetate dihydrate under identical conditions. At the end of the reaction the product was worked up as before and distilled at 73° C./10 mm to give 8.2 g (60%) of 2-pentyl-2-oxazoline.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Br:35])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:26]=2[Br:35])=[CH:20][C:16]=1[C:17]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:18]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Br)ccc1Cl
Reactant: OC1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCOC1)c1cc(Oc2ccc(C(F)(F)F)cc2Br)ccc1Cl
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-chloro-5-(2-bromo-4-trifluoromethylphenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-chloro-5-(2-bromo-4-trifluoromethylphenoxy)benzoate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[C:4]([CH3:20])[N:3]=1.CCN(C(C)C)C(C)C.[NH2:30][C@H:31]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[CH2:32][OH:33]>CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[C:4]([CH3:20])[N:3]=[C:2]([NH:30][C@H:31]([C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)[CH2:32][OH:33])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Reactant: Cc1nc(Cl)nc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1nc(N[C@@H](CO)c2ccc(F)cc2)nc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92.5 %

Procedure:
A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-5-nitropyrimidin-4-amine (Method 75; 1.0 g, 3.4 mmol), DIEA (0.57 g, 4.4 mmol), and (R)-2-amino-2-(4-fluorophenyl)ethanol (0.58 g, 3.7 mmol) in n-BuOH (15 ml) was heated to 60° C. for 2 hours. The reaction was then cooled to 25° C., concentrated, and treated with hexane. The resulting solid was collected by filtration to give the title compound (1.3 g, 93%). MS: Calcd.: 413; Found: [M+H]+ 414.