Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+].C(O)(C)C.[C:7]([NH:10][C:11]1[S:15][N:14]=[C:13]([CH2:16]C(=O)C2C=CC(Cl)=CC=2)[C:12]=1[N+:26]([O-:28])=[O:27])(=[O:9])[CH3:8]>O>[C:7]([NH:10][C:11]1[S:15][N:14]=[C:13]([CH3:16])[C:12]=1[N+:26]([O-:28])=[O:27])(=[O:9])[CH3:8]
Reactant: CC(=O)Nc1snc(CC(=O)c2ccc(Cl)cc2)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)Nc1snc(C)c1[N+](=O)[O-]
Yield: 70.3 %

Procedure:
Reduced iron (2.94 grams, 50.0 mmol) and 0.30 gram of ammonium chloride were introduced into 20 ml of isopropyl alcohol and 3 ml of water, and the mixture was heated under reflux for 20 minutes. 5-Acetylamino-3-(4-chlorobenzoylmethyl)-4-nitroisothiazole (2.04 grams, 6.00 mmol) was added little by little, and the mixture was heated under reflux for 2 hours. The iron was removed by suction filtration, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated salt water and then dried over anhydrous sodium sulfate. After filtration, the solvent was removed by distillation under reduced pressure. The residue was dissolved in 20 ml of acetic acid and heated under reflux for 2 hours. The mixture was then poured into water and extracted with ethyl acetate. The extract was washed with aqueous bicarbonate and then with saturated salt water, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed by distillation and the material was crystallized from ethyl acetate. Recovery was 1.23 gram (4.22 mmol); Yield was 70.3%; and Melting Point was 210° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10](Cl)(=[O:14])[CH2:11][CH2:12][CH3:13]>CCOCC>[C:10]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(=O)Cl
Reactant: Cc1cccc(C)c1N
Solvent: CCOCC
Product: CCCC(=O)Nc1c(C)cccc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 200 g. of 2,6-dimethylaniline in 2 l. of ether is cooled in an ice bath and to this 88 g. of butyryl chloride in 150 ml. of ether is added dropwise (over 21/2 hours). A white precipitate forms and the reaction mixture is allowed to stir at 0° C. for 1 hour longer and then 15 hours at room temperature. The reaction mixture is then evaporated in vacuo and the white solid residue is slurried in 1 l. of water, filtered and washed with water and dried to obtain N-butyryl-2,6-dimethylaniline (m.p. 134°-6° C.).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:20]1([C:30](Cl)=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:30]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:31])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1,3-bis(4-fluorophenyl)-1-propanol (450 mg, 1.71 mmol) in ethyl acetate (15 ml) were added 1-naphthoyl chloride (386 ml, 2.56 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:acetone=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (515 mg, 72%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][C:22](O)=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1>>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[C:16]([NH2:15])=[N:17][CH:18]=[CH:19]3)[CH2:12][CH2:13]1
Reactant: Nc1nccc2cc(O)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: Nc1nccc2cc(OC3CCNCC3)ccc12
Yield: 25.5 %

Procedure:
This compound was prepared from 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (455 mg, 2.26 mmol) and 1-amino-6-hydroxyisoquinoline (435 mg, 2.71 mmol) by the Mitsunobu procedure described in 3C. Subsequent Boc deprotection according to procedure described in 3D gave 6-(piperidin-4-yloxy)-isoquinolin-1-ylamine (140 mg), EIMS: m/z=244.6 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH:19]=[CH2:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:21])=[O:29]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 37.1 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethenylbenzonitrile (0.076 g, 0.251 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.069 g, 0.251 mmol) and DIPEA (0.088 mL, 0.502 mmol) were combined in THF (2 mL) and treated with HATU (0.105 g, 0.276 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness and partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified on an XTerra™ C-18 column eluted with 5 to 90% CH3CN/H2O (0.2% NH4OH buffer). Appropriate fractions were combined, concentrated to dryness, chased twice with ethanol and twice with toluene to remove residual water to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethenyl phenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.040 g, 0.093 mmol, 36.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.2 (br. s., 1H), 8.31 (br. s., 1H), 7.80 (s, 1H), 7.77 (s, 1H), 7.26-7.53 (m, 4H), 6.75 (dd, 1H), 6.04 (d, 1H), 5.44 (d, 1H), 4.53 (d, 2H). LC-MS (ES−) m/z 429.08, 431.11, 433.00 [M−1]. LC-MS (ES+) m/z 430.97, 432.95, 434.95 [M+H].
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([S:15]([NH:18][C:19]2[S:23][CH:22]=[CH:21][N:20]=2)(=[O:17])=[O:16])[CH:9]=1.C(N(CC)CC)C>O1CCCC1>[CH:12]1[C:13]([NH:14][C:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:7])=[CH:8][CH:9]=[C:10]([S:15]([NH:18][C:19]2[S:23][CH:22]=[CH:21][N:20]=2)(=[O:17])=[O:16])[CH:11]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)CCC(=O)Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Yield: 67 %

Procedure:
an Indo-Sulfathiazole Analog: Compound 27j was synthesized by the method outlined in FIG. 1. Briefly, Compound 27j was synthesized by first complexing succinic anhydride with sulfathiazole by reacting these compounds at room temperature for 6 hours in tetrahydrofuran (THF) in the presence of triethylamine (TEA) to produce succinylsulfathiazole as a white solid (67% yield). The succinylsulfathiazole was then reacted for 2 hours at room temperature with O—(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU) in dichloromethane in the presence of TEA to produce the corresponding succinimidyl ester, which was reacted with 1-(4-aminobutyl)-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide in dichloromethane in the presence of TEA at room temperature for 16 hours to produce Compound 27j as a yellow gummy mass (45% yield). Compound 27j was characterized by NMR, two-dimensional NMR, and mass spectroscopy.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>C(Cl)Cl.CN(C=O)C>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
The NaH 60% dispersion in oil (0.94 g, 23.4 mmol) was added to a solution of 4-bromoindole (3.07 g, 15.6 mmol) and triisopropylsilyl chloride (3.62 g, 18.8 mmol) in CH2Cl2 (50 mL) and DMF (2 mL). The reaction was stirred at room temperature for 1 h and quenched with water. The insoluble material was filtered off and the solvent was removed. Purification by column chromatography (SiO2, CH2Cl2/heptane 1:4) yielded 3.44 g (63%) of the title compound: 1H NMR (CDCl3) δ 7.42–6.63 (m, 5 H), 1.66 (sept, J=8 Hz, 3 H), 1.10 (d, J=8 Hz, 18H; MS (ESI) 354.4 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Li]CCCC.[C:17]([O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](=[O:33])N(OC)C)([CH3:20])([CH3:19])[CH3:18]>C(OCC)C>[C:17]([O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](=[O:33])[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)([CH3:20])([CH3:18])[CH3:19]
Reactant: CON(C)C(=O)CCCCNC(=O)OC(C)(C)C
Reactant: Brc1cnc2ccccc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCCCC(=O)c1cnc2ccccc2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-bromoquinoline (25 g, 120 mmol) in diethyl ether −78° C. was added nBuLi (2.5M THF, 48 ml, 120 mmol) dropwise over 30 minutes. After 30 minutes, 21-2 (3.9 g, 15 mmol), dissolved in 50 ml ether was added dropwise over 10 minutes. After 30 minutes, the cooling bath was removed. After 1.0 hour, the reaction was quenched with sat. NH4Cl. The organic portion was separated, washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed (silica gel, 20-50% ethyl acetate/hexanes) to give 21-3 as a yellow solid.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[C:25]1(=O)[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C(=O)C>[C:25]1(=[N:1][N:2]2[C:7](=[O:8])[C:6]([C:9]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[S:11](=[O:20])(=[O:19])[N:10]=3)=[C:5]([OH:21])[C:4]3[S:22][CH:23]=[CH:24][C:3]2=3)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: O=C1CCCC1
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=C1CCCC1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.054 g, 0.15 mmol) was reacted with cyclopentanone (0.95 g, 11.3 mmol) in N,N-dimethylacetamide (1 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C[Si]([C:17]([F:20])([F:19])[F:18])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]2[CH2:11][CH2:12]2)([OH:9])[C:17]([F:20])([F:19])[F:18])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C(c1ccc(Br)cc1)C1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1)(C1CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
To a solution of (4-bromophenyl)(cyclopropyl)methanone (587 mg, 2.60 mmol) in tetrahydrofuran (5.2 mL) were added molecular sieves 4 Å (500 mg), trimethylsilyl trifluoromethane (772 μL, 5.20 mmol) and tetrabutylammonium fluoride (tetrahydrofuran solution, 1 mol/L, 3.9 mL, 3.90 mmol) at 0° C., and the mixture was stirred at room temperature for 18 hours. The solution was filtered through diatomaceous earth, and then thereto was added 1 mol/L hydrochloric acid solution (10 mL), and the mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1→5:1) to give 1-(4-bromophenyl)-1-cyclopropyl-2,2,2-trifluoroethanol (747 mg, 97%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH:17]([NH2:21])[CH:18]([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]=[C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[N:24]1[CH2:33][CH2:34][CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH:17]([NH:21][CH2:35][CH2:34][CH2:33][N:24]1[C:25](=[O:32])[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]1=[O:22])[CH:18]([CH3:19])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)C(N)c1nc2ccccc2n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)C(NCCCN1C(=O)c2ccccc2C1=O)c1nc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(1-benzyl-1H-benzimidazol-2-yl)-2-methyl-propylamine (160 mg, 0.56 mmol) and 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde (114 mg, 0.56 mmol) in dry DCM (3 ml) at room temperature, was added sodium triacetoxyborohydride (119 mg, 0.56 mmol). After 10 minutes, acetic acid (34 μl, 0.56 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography to give material that was used in Example 5g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].Cl.[OH:13][CH:14]1[CH2:17][NH:16][CH2:15]1.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:16]1[CH2:17][CH:14]([OH:13])[CH2:15]1)=[S:11]
Reactant: S=C=Nc1ccc(Br)cc1Br
Reactant: OC1CNC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OC1CN(C(=S)Nc2ccc(Br)cc2Br)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2,4-Dibromophenylisothiocyanate (CAS #13037-63-3, 3.02 g, 0.0103 mole), and 3-hydroxyazetidine hydrochloride (CAS #18621-18-6, 1.18 g, 10.8 mmol) were suspended in acetonitrile (35 mL). Triethylamine (1.53 mL, 0.011 mole) was added dropwise to the stirred suspension. After 20 minutes of stirring at room temperature, the reaction mixture had become a light yellow solution. After another 10 minutes of stirring at room temperature, the isothiocyanate was consumed and the intermediate, N-(2,4-dibromophenyl)-3-hydroxyazetidine-1-carbothioamide had formed. Although not necessary, this intermediate thiourea was isolated and purified by partitioning between 1:1 hexane/ethyl acetate (150 mL) and 1 M aqueous KH2PO4 (35 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (10 mL) and dried (Na2SO4). The filtrate was partially concentrated at which point the thiourea crystallized. The crystals were collected by filtration and dried under vacuum to provide N-(2,4-dibromophenyl)-3-hydroxyazetidine-1-carbothioamide.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].S([CH2:21][N+:22]#[C-:23])(C1C=CC(C)=CC=1)(=O)=O.[C:24]([O:34][CH2:35][CH3:36])(=[O:33])/[CH:25]=[CH:26]/[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.C(OCC)(=O)C>[C:24]([C:25]1[C:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][NH:22][CH:21]=1)([O:34][CH2:35][CH3:36])=[O:33]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)/C=C/c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.5 %

Procedure:
To a 1.0 M solution of lithium hexamethyldisilazide in THF (41 mL, 41 mmol) at 78° C. was added dropwise over 45 min. a solution of tosylmethyl isocyanide (8.1 g, 41 mmol) in THF. After the reaction was stirred for an additional 45 min. a solution of trans-ethyl cinnamate (7.3 g, 41 mmol) in THF (40 mL) was added over 40 min. The reaction was warmed to 25° C. and stirred for 5 h. The reaction was diluted with ethyl acetate and washed with sat. aqueous NaHCO3. The aqueous layer was extracted three times with ethyl acetate, dried (Na2SO4), concentrated and purified by chromatography on silica gel eluting with a gradient of 20–30% ethyl acetate in hexanes to provide 3.4 g (41%) of 3-carboethoxy-4-phenylpyrrole as an off-white solid. 1HNMR (CDCl3): δ 8.62 (br s, 1H), 7.5 7–7.12 (m, 6H), 6.73 (s, 1H), 4.19 (q, J=7.1 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=3)[N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH3:14].[CH2:31]([S:34](Cl)(=[O:36])=[O:35])[CH2:32][CH3:33]>CCOC(C)=O>[CH2:31]([S:34]([NH:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=3)[N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH3:14])(=[O:36])=[O:35])[CH2:32][CH3:33]
Reactant: CCCS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(-c2noc(-c3ccc(N4CCCCC4C)c(N)c3)n2)cc1F
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1cc(-c2nc(-c3ccc(C(=O)OC)c(F)c3)no2)ccc1N1CCCCC1C

Procedure:
The title compound was obtained following procedure and work up described for example 67, step 1, but starting from methyl 4-{5-[3-amino-4-(2-methylpiperidin-1-yl)phenyl]-1,2,4-oxadiazol-3-yl}-2-fluorobenzoate, prepared as in example 67, Steps 1 and 2, (200 mg; 0.49 mmol) and 1-propanesulfonyl chloride (280 mg; 2 mmol). The title compound was obtained as a yellow powder after column chromatography (EtOAc:cHex from 10:90 to 100:0). LC/MS (Method B): 517.4 (M+H)+. HPLC (Method A) Rt. 6.37 min (purity: 96.5%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:32].[K+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:7][CH:8]([C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:32])=[O:24])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)=[O:30])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccc(C=O)cc2)cc1)NC(=O)OC(C)(C)C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 91.4 %

Procedure:
Amide compound 10 (2.0 g, 4.85 mmol) was dissolved in THF (50 mL) and the solution stirred at 70° C. Potassium permanganate (3.06 g, 19.4 mmol) dissolved in water (50 mL) was added slowly through a dropping funnel (5 mL/min) over 2 hours. After addition was complete, reaction mixture was stirred at 70° C. for 30 min and cooled to room temperature. The brown precipitate was filtered over a Celite® bed and the filtrate was concentrated under reduced pressure. The residual oil was taken up in EtOAc (100 mL) and acidified with 2.0 M HCl. The organic layer was separated and washed with water (1×50 mL) and brine (1×50 mL), dried, and concentrated under reduced pressure to yield the desired acid compound 11 (1.9 g, 91%). 1H NMR (DMSO-d6): 12.7 (br, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.4 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 4.56 (ddd, J=13.6, 9.2, and 6.0 Hz, 1H), 2.93 (s, 3H), 2.74-2.91 (m, 5H), 1.31 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=2)[C:33]([O:35][CH3:36])=[O:34])O1.C([O-])([O-])=O.[Na+].[Na+]>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:19][C:18]([F:21])([F:20])[C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:30]3[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=3)[C:33]([O:35][CH3:36])=[O:34])[N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: FC(F)(F)c1cccc(Nc2nc(Cl)nc3scnc23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2nc(Nc3cccc(C(F)(F)F)c3)c3ncsc3n2)c1
Temperature: 95 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a stirred solution of 5-chloro-N-(3-(trifluoromethyl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (330 mg, 1 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (314 mg, 1.2 mmol) and Na2CO3 (498 mg, 4.7 mmol) in 2 mL of water and 20 mL of dioxane was added Pd(PPh3)4 (93 mg, 0.075 mmol) in one portion at room temperature under nitrogen. Then the mixture was stirred at 95° C. for 16 hours under nitrogen. The solvent was evaporated at 40° C. at reduced pressure and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (4:1)) to give methyl 3-(7-(3-(trifluoromethyl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (365 mg, 84.8%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.18 (s, 1H), 8.93 (s, 1H), 8.74 (d, 1H, J=7.8 Hz), 8.61 (s, 1H), 8.21 (brs, 2H), 7.94 (d, 1H, J=7.8 Hz), 7.65-7.60 (m, 2H), 7.48-7.46 (m, 1H), 4.01 (s, 3H). LC-MS: 431 [M+H]+, 429 [M−H]−, tR=1.92 min. HPLC: 95.92% at 214 nm, 97.01% at 254 nm, tR=5.14 min.
Reaction SMILES: [OH:1][C:2]1([C:29]2[S:33][C:32](S(C)(=O)=O)=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1.[CH3:38][C:39]([O-:42])([CH3:41])[CH3:40].[K+]>>[C:39]([O:42][C:32]1[S:33][C:29]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([N:8]3[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=4)=[O:14])[CH2:9]3)[CH2:4][CH2:3]2)=[CH:30][N:31]=1)([CH3:41])([CH3:40])[CH3:38]
Reactant: CS(=O)(=O)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: CC(C)(C)Oc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compound was prepared as a white solid from N-({1-[4-hydroxy-4-(2-methanesulfonyl-thiazol-5-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (less polar isomer, 47a), and t-BuOK (Aldrich, 1.0 N in THF) using the procedure described in Example 52.