Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH:7]([NH2:10])([CH3:9])[CH3:8]>CCOCC>[CH3:8][CH:7]([NH:10][C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH3:9]
Reactant: CCOC(=O)Cl
Reactant: CC(C)N
Solvent: CCOCC
Product: CCOC(=O)NC(C)C

Procedure:
To a solution of ethyl chloroformate (21.7 g, 0.2 mol) in 200 ml ether cooled to 0° C. was added dropwise 35.7 ml of isopropylamine with stirring and cooling. After complete addition of the amine, the reaction mixture was stirred at room temperature for an additional 0.5 hour. The reaction mixture was filtered, and the ether solution was washed with water, and dried over magnesium sulfate. Evaporation of the ether and distillation of the residue in a Kugelrohr apparatus resulted in 22.6 g of the title compound B.p.: 50°-66° C. (bath temperature) at 1.5 mm Hg.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[NH:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[C:30]1[N:35]([CH3:36])[C:34](=[O:37])[CH:33]=[C:32]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][C:39]=2[F:44])[N:31]=1>O1CCCC1>[F:44][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][C:38]=1[C:32]1[N:31]=[C:30]([N:18]2[CH2:19][CH2:20][NH:21][C@@H:16]([C:13]3[CH:12]=[CH:11][C:10]([N:4]4[CH2:5][CH2:6][O:7][CH2:8][CH2:9]4)=[CH:15][CH:14]=3)[CH2:17]2)[N:35]([CH3:36])[C:34](=[O:37])[CH:33]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Reactant: c1cc(N2CCOCC2)ccc1[C@@H]1CNCCN1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN[C@@H](c3ccc(N4CCOCC4)cc3)C2)nc(-c2ccncc2F)cc1=O
Reaction time: 12 h
Yield: 72.8 %

Procedure:
To a solution of the above prepared (3R)-3-(4-(morpholin-4-yl)phenyl)piperazine trihydrochloride (0.5 g, 1.40 mmol) and triethylamine (0.8 g, 7.91 mmol) in tetrahydrofuran (10 ml) was added 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-(3H)-pyrimidin-4-one (0.3 g, 1.25 mmol) which was prepared by Reference Example 2 portionwise. After stirring for 12 hours, the resulting suspension was partitioned between chloroform and 1N sodium hydroxide and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish 6-(3-fluoro-pyridin-4-yl)-3-methyl-2-((3S)-3-(4-morpholin-4-yl-phenyl)-piperazin-l-yl)-3H-pyrimidin-4-one (0.41 g, 0.91 mmol, 73%) as white crystals.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[F:13][C:14]1[CH:15]=[C:16]([CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:22]1[CH2:23][CH2:24][CH2:25][CH:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=2)[CH2:21]1
Reactant: BrCC1COc2ccccc2O1
Reactant: Fc1cccc(C2CCCNC2)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Fc1cccc(C2CCCN(CC3COc4ccccc4O3)C2)c1
Temperature: 140 °C
Yield: 135.5 %

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (340 mg, 0.48 mmol), 3-(3-fluorophenyl)piperidine (323 mg, 2.50 mmol) and triethylamine (455 mg, 4.50 mmol) in acetonitrile (3 mL) was heated in a microwave reactor at 140° C. for 60 min. The mixture was absorbed on silica and purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 213 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>C1COCC1>[CH3:11][C:12]([S@:15](/[N:17]=[C:8](/[C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=1)\[CH3:9])=[O:16])([CH3:14])[CH3:13]
Reactant: CC(=O)c1cccc(C)c1
Reactant: CC(C)(C)[S@](N)=O
Solvent: C1CCOC1
Product: C/C(=N\[S@](=O)C(C)(C)C)c1cccc(C)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a stirred solution of 1-(3-methylphenyl)ethanone (1.61 g, 12.0 mmol, 1.00 equiv.) and (R)-(+)-2-methyl-2-propanesulfinamide (1.94 g, 14 mmol, 1.33 equiv.) in THF (50 mL) was added Ti(OEt)4 (3.19 g, 14 mmol, 1.17 equiv.) dropwise. The reaction mixture was stirred for 16 h at 60° C., cooled to room temperature, and quenched with a saturated aqueous NaHCO3 solution (50 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×100 mL). The combined organics were concentrated and the resulting residue was purified by flash chromatography (silica gel, eluting with 0-5% CH3OH in CH2Cl2) to afford 1.51 g (53%) of the title compound as a white solid. LC/MS: m/z (ES+) 238 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[C:31]1([O:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(C)C=CC=CC=1>CCCCCC>[O:37]([C:38]([N:8]1[CH2:9][CH2:10][C:11]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(OC2(c3ccccc3)CCN(Cc3ccccc3)CC2)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C(Oc1ccccc1)N1CCC(Oc2ccc(C(F)(F)F)cc2)(c2ccccc2)CC1

Procedure:
A solution of 10.0 g of 1-benzyl-4-phenyl-4-(p-trifluoromethylphenoxy)piperidine and 4.1 g of phenylchloroformate in 100 ml. of toluene was refluxed for 17 hours. The toluene was removed under reduced pressure to give a colorless oil which when rubbed with a glass rod in the presence of hexane gave a white solid of 1-phenoxycarbonyl-4-phenyl-4-(p-trifluoromethylphenoxy)piperidine.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][C:7]1[C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:9][CH:10]=[CH:11][CH:12]=1.CI>C1COCC1>[CH2:6]([C:7]1[C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:1]
Reactant: [Li]CCCC
Reactant: Cc1cccnc1NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CI
Product: CCc1cccnc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Normal-butyllithium (2.69 M, 157.1 mL) was dropwise added to a solution of tert-butyl 3-methylpyridin-2-ylcarbamate (40.0 g) in THF (550 mL) at an internal temperature of −40 to −20° C., followed by stirring at 0° C. for 1 hr. Subsequently, a solution of methyl iodide (28.6 g) in THF (50 mL) was dropwise added to the reaction solution at an internal temperature of −70 to −60° C., followed by stirring at −78° C. for 30 min. The reaction solution was poured into ice water, followed by extraction with ethyl acetate twice. The organic layers were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled away. Hexane (300 mL) was added to the resulting residue, and the precipitate was collected by filtration and dried under reduced pressure to obtain compound (40a) (32.4 g, 76%) as a white solid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][CH:9]1[S:13](=[O:15])(=[O:14])[O:12][CH2:11][CH2:10]1>O1CCCC1>[CH:1]1([NH:7][CH2:11][CH2:10][CH:9]([S:13]([OH:15])(=[O:14])=[O:12])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CC1CCOS1(=O)=O
Solvent: C1CCOC1
Product: CC(CCNC1CCCCC1)S(=O)(=O)O
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of cyclohexylamine (1.50 g, 15.1 mmol) in tetrahydrofuran (15 mL) was added 2,4-butane sultone (2.04 g, 14.4 mmol). The solution stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and dried in vacuo. Yield: 59%. 1H NMR (DMSO, 500 MHz) δ ppm 8.50 (s (broad), 1H), 3.02 (m, 2H), 2.93 (m, 1H), 2.60 (m, 1H), 1.93 (m, 3H), 1.75 (m, 3H), 1.57 (m, 1H), 1.21 (m, 4H), 1.11 (m, 4H). 13C (DMSO, 125 MHz) δ ppm 56.23, 53.20, 43.09, 29.54, 29.41, 29.39, 25.40, 24.42, 17.23. ES-MS 234 (M−1).
Reaction SMILES: C(O)C.[CH3:4][C:5]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:6]=1[N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[S:17]([CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]2)=[O:18]>[C].[Pd].C(N(CC)CC)C>[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[S@:17]([CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]2)=[O:18]
Reactant: Cc1cc(Br)ccc1-n1ccnc1S(=O)CCCOc1ccc2c(c1)CCC(=O)N2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccccc1-n1ccnc1[S@@](=O)CCCOc1ccc2c(c1)CCC(=O)N2
Yield: 131.2 %

Procedure:
In a pressure glass reactor containing ethanol was placed 12 g of 6-{3-[1-(2-methyl-4-bromophenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril. To the resulting solution were added 18 ml of triethylamine and 6 g of a 10% palladium carbon powder. The reactor inside was purged with hydrogen gas and the reactor contents were subjected to a reaction at a pressure of 3 kg/cm2 at 70° C. for 16 hours. The reaction was repeated on the same scale. The reaction mixture obtained from two times of the reaction was filtered to remove the catalyst. The filtrate was extracted with chloroform, washed with 1 N aqueous hydrochloric acid solution thoroughly, washed with an aqueous solution saturated with sodium chloride, dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent. The resulting white oil was purified by a silica gel column chromatography (eluant: dichloromethane/ethyl acetate/methanol=30/10/1) to obtain crude crystals. The crude crystals were recrystallized from ethanol to obtain 13.2 g of (S)-(+)-6-{3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[N:33]1[C:40]2[N:36]([N:37]=[C:38]([C:41]3[S:45][CH:44]=[N:43][CH:42]=3)[CH:39]=2)[CH:35]=[CH:34]1.[CH3:46][S:47]([C:50]1[CH:51]=[C:52]([CH:56]=[C:57]([S:59]([F:64])([F:63])([F:62])([F:61])[F:60])[CH:58]=1)[C:53](O)=[O:54])(=[O:49])=[O:48]>CN(C=O)C>[CH3:46][S:47]([C:50]1[CH:51]=[C:52]([CH:56]=[C:57]([S:59]([F:64])([F:60])([F:61])([F:62])[F:63])[CH:58]=1)[C:53]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([CH3:25])=[C:27]([N:33]2[C:40]3[N:36]([N:37]=[C:38]([C:41]4[S:45][CH:44]=[N:43][CH:42]=4)[CH:39]=3)[CH:35]=[CH:34]2)[CH:28]=1)=[O:54])(=[O:49])=[O:48]
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cncs3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(S(C)(=O)=O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cncs3)cc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
193 mg (0.51 mmol) of HATU and 62 mg (0.51 mmol) of 4-N,N-dimethylaminopyridine (DMAP) were added to a solution of 100 mg (0.34 mmol) of the compound of Example 89A and 122 mg (0.37 mmol) of the compound of Example 32A in 2 ml of DMF. The reaction was stirred at RT for 20 h. The reaction mixture was then purified directly by preparative HPLC (Method 16). This gave 86.4 mg (42% of theory) of the title compound.
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.CCCCCCC.S(=O)(=O)(O)O.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>C(O)C>[C:5]12([C:32]3[CH:33]=[C:28]([Br:27])[CH:29]=[CH:30][C:31]=3[OH:34])[CH2:12][CH:11]3[CH2:10][CH:9]([CH2:8][CH:7]([CH2:13]3)[CH2:6]1)[CH2:14]2
Reactant: Oc1ccc(Br)cc1
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCCCCCC
Product: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 20 °C

Procedure:
In a 100 ml three-necked flask, and under a nitrogen environment, is placed 1 g of 1-acetoxyadamantane and 10 ml of n-heptane. After total dissolution, 0.25 g of concentrated sulfuric acid is added drop by drop while keeping the temperature at 20° C., then 0.886 g of 4bromophenol is poured in slowly. After leaving 24 hours in vigorous agitation, 20 ml of denatured ethanol are added while maintaining the temperature at 20° C. Next, the solvent is evaporated to dryness under reduced pressure and a whitish raw product is obtained. The product is redissolved in water at approximately 60° C., it is washed to pH 6 and dried in a vacuum oven for 24 hours at 25° C. One collected 1.24 g of expected raw product (Melting point: 140°-141° C.).
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:1][C:2]2[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[O:19])=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc(O)c1N
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(O)c1NC(=O)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
A solution of 1.0 g (4.9 mmol) of methyl 2-amino-3-hydroxybenzoate 9a, 1.03 g (7.4 mmol) of 4-fluorobenzoic acid 9b, 10 mL DMF and 2.9 mL (20.6 mmol) of TEA were placed into a flask and stirred for 10 min. HATU (7.4 mmol, 2.8 g) was added and the reaction was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organics were washed with water and brine and the solvent was evaporated to give 1.2 g of crude product, methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9c, which was used without purification. MS m/z (M+H+) 290.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:6][C:5](=[O:7])[N:4]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[C@H:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:27])[O:6][C:5](=[O:7])[N:4]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[C@H:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)OC(C)(C)[C@@H]2c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)OC(=O)N(C2CCNCC2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 250-mL round-bottomed flask were added (S)-tert-butyl 4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)piperidine-1-carboxylate (4530 mg, 12.10 mmol) and 2,2,2-trifluoroacetic acid (23.16 mL, 302 mmol) in DCM (24.200 mL). The mixture was then stirred at rt overnight. The reaction mixture was concentrated in vacuo. The material thus obtained was dissolved in DCM, and extracted with water (3×). The aqueous layers were combined and the pH of the solution was adjusted to above 8 by adding 35% NH4OH water solution. The solution was then extracted with EtOAc (3×). The organic extract was dried over MgSO4. The solution was filtered and concentrated in vacuo to give the residual material as a yellow solid. The material was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8]([O:11][CH3:12])([O:9][CH3:10])[CH2:7][CH2:6][NH:5][CH2:4]1.C(Cl)Cl.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C>>[CH3:1][O:2][CH:3]1[C:8]([O:11][CH3:12])([O:9][CH3:10])[CH2:7][CH2:6][N:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:4]1
Reactant: CCOC(=O)Cl
Reactant: COC1CNCCC1(OC)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(OC)(OC)C(OC)C1
Reaction time: 8 h

Procedure:
The title compound was prepared by taking 3,4,4-trimethoxypiperidine (150 mg, 0.00086 mol) in Methylene chloride (10 mL, 0.2 mol) and adding Ethyl chloroformate (0.098 mL, 0.0010 mol) and Triethylamine (0.24 mL, 0.0017 mol). The reaction was stirred overnight and then quenched with NaHCO3. The crude was obtained by evaporating the organic layer and was taken to the next step as-is (210 mg, 99%). MS calculated for C11H21NO5: (M+H) 248; found 248.1.
Reaction SMILES: [Cl:1]Cl.Cl.N[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([I:12])=[CH:7][N:6]=1.N([O-])=O.[Na+]>O>[Cl:1][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([I:12])=[CH:7][N:6]=1
Reactant: ClCl
Reactant: Cc1cc(I)cnc1N
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(I)cnc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 14.2 %

Procedure:
At −10° C., 21.3 g of chlorine gas were introduced into a suspension of 146 g of 10% strength by weight hydrochloric acid and 23.4 g of 2-amino-3-methyl-5-iodopyridine [J. Org. Chem. (1995), p. 5356]. At about −50° C., a solution of 48.3 g of sodium nitrite in 120 ml of water was subsequently added dropwise. After about 2 hours of stirring at 0° C., the mixture was diluted with 1 l of water and extracted with methyl tert-butyl ether (MtBE). The organic phases were washed with NaHCO3 solution and water and then dried. Distillative removal of the solvent under reduced pressure and silica gel chromatography (cyclohexane/MtBE=1:10) gave 3.6 g of the product in the form of dark crystals.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([CH:11]=[CH2:12])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH:31][C@H:32]([C:36]([O:38][CH3:39])=[O:37])[CH:33]([CH3:35])[CH3:34])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=[O:14].[C:40](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:40][N:31]([S:28]([C:25]1[CH:26]=[CH:27][C:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13]([C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[CH2:12])[C:6]=4[C:2]=3[CH3:1])=[O:14])=[CH:21][CH:20]=2)=[CH:23][CH:24]=1)(=[O:30])=[O:29])[C@H:32]([C:36]([O:38][CH3:39])=[O:37])[CH:33]([CH3:35])[CH3:34]
Reactant: O=C([O-])[O-]
Reactant: C=Cc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=Cc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N(C)[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of 0.077 g (0.14 mmol) of the product of Example 96, Step 2, methyl N-[(4′-{[(3-methyl-4-vinyl-1-benzofuran-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valinate, in 1 mL of DMF, 0.05 g of potassium carbonate were added, followed by 0.018 mL of iodomethane. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was extracted with dichloromethane. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to provide 0.1 g of methyl N-methyl-N-[(4′-{[(3-methyl-4-vinyl-1-benzofuran-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valinate. Yield 63.4%. MS: 561 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[O:6][N:5]=1.Cl[CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20].O>CN(C)C=O>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:16][C:15]=1[CH2:14][O:3][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[O:6][N:5]=1
Reactant: COC(=O)c1cc(O)no1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCc2nc(-c3ccccc3)oc2C)no1
Reaction time: 0.25 h
Yield: 72.4 %

Procedure:
Sodium hydride (60%, oily, 1.40 g) was added to a solution of methyl 3-hydroxyisoxazole-5-carboxylate (5.01 g) in N,N-dimethylformamide (70 ml) at 0° C., which was stirred for 15 minutes. 4-Chloromethyl-5-methyl-2-phenyloxazole (7.26 g) was added to the mixture. After being stirred at 60° C. for 2 hours, the reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolecarboxylate (7.96 g, yield 72%) as colorless crystals. This was recrystallized from tetrahydrofuran-hexane. Melting point: 123–124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:19][CH2:20]O>>[CH2:19]([O:12][C:11]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)=[O:13])[CH3:20]
Reactant: O=C(O)c1cc2ccc(Cl)cc2[nH]1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Temperature: 120 °C

Procedure:
6-Chloro-1H-indole-2-carboxylic acid (2.59 g, 13.4 mmol) was dissolved in EtOH (75 mL) and conc. H2SO4 (1 mL) was added. The reaction was heated to 120° C. overnight then submitted to aqueous workup to give the title compound.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]#[N:18])[C:10]([C:19]3[N:23]=[C:22]([CH2:24][OH:25])[S:21][N:20]=3)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[C:17]([C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[N:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:9]=[C:10]2[C:19]1[N:23]=[C:22]([CH2:24][O:25][S:27]([CH3:26])(=[O:29])=[O:28])[S:21][N:20]=1)#[N:18]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cccc2c(-c3nsc(CO)n3)cn(CC3CCCCC3)c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1nc(-c2cn(CC3CCCCC3)c3c(C#N)cccc23)ns1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 1-cyclohexylmethyl-3-(5-hydroxymethyl-[1,2,4]thiadiazol-3-yl)-1H-indole-7-carbonitrile (416 mg, 1.18 mmol) in dichloromethane (40 ml) was added methanesulfonyl chloride (0.110 ml, 1.42 mmol) and triethylamine (0.214 ml, 1.53 mmol) sequentially. The reaction was allowed to stir for 1 h and then poured into a separating funnel. The organics were washed with 2M aqueous sodium carbonate solution (20 ml), brine (20 ml), dried over magnesium sulfate, filtered, and the solvent removed in vacuo to afford methanesulfonic acid 3-(7-cyano-1-cyclohexylmethyl-1H-indol-3-yl)-[1,2,4]thiadiazol-5-ylmethyl ester (503 mg, 1.17 mmol) which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[N:11]([N:13]=[CH:14][C:15]=3[C:16]3[CH:17]=[C:18]([C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[S:19][CH:20]=3)[CH:12]=2)[CH:4]=[N:3]1.S(Cl)([Cl:31])=O>CN(C=O)C>[Cl:31][C:20]1[S:19][C:18]([C:21]([NH:23][CH2:24][C:25]([F:27])([F:28])[F:26])=[O:22])=[CH:17][C:16]=1[C:15]1[CH:14]=[N:13][N:11]2[CH:12]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=[N:9][C:10]=12
Reactant: Cn1cc(-c2cnc3c(-c4csc(C(=O)NCC(F)(F)F)c4)cnn3c2)cn1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3c(-c4cc(C(=O)NCC(F)(F)F)sc4Cl)cnn3c2)cn1
Temperature: 80 °C
Yield: 51.8 %

Procedure:
4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide (107 mg, 0.263 mmol) was taken up in thionyl chloride (2 ml, 27.4 mmol) and heated at 80° C. overnight. Evaporated solvent under vacuum and took up in 3 ml DMF, purified reverse-phase 30-100% ACN/H2O w/0.1% TFA. Evaporated solvent under vacuum to yield 60 mgs pale yellow solid (51.7%). LRMS [M+H]=441.0
Reaction SMILES: [I:1][C:2]1[C:3](=O)[NH:4][C:5]([S:12][CH3:13])=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O>[Cl:16][C:3]1[C:2]([I:1])=[C:7]([C:8]([F:11])([F:10])[F:9])[N:6]=[C:5]([S:12][CH3:13])[N:4]=1
Reactant: CSc1nc(C(F)(F)F)c(I)c(=O)[nH]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1nc(Cl)c(I)c(C(F)(F)F)n1
Yield: 98 %

Procedure:
5-Iodo-2-methylthio-6-trifluoromethyl-3H-pyrimidin-4-one (11.8 g) was dissolved in phosphoryl chloride (40 ml) and phosphorous pentachloride (7.9 g) was added at room temperature with stirring. The mixture was refluxed for 3 hr and the phosphoryl chloride was removed under reduced pressure. The residue was poured onto icy water and extracted with chloroform. The chloroform layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 4-chloro-5-iodo-2-methylthio-6-trifluoromethylpyrimidine (12.2 g) as pale brown crystalline solid, mp 55-56° C.