Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])C1C=CC=CC=1.CN(C)C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(Cl)Cl>[F:21][C:16]([F:22])([C:17]([F:18])([F:19])[F:20])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: FC(F)(F)C(F)(F)CCCCCCCOCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: OCCCCCCCC(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 74.4 %

Procedure:
16 g of 1-benzyloxy-8,8,9,9,9-pentafluorononane are dissolved in 700 ml of abs. methylene chloride, treated at 0° C. with 18.4 ml of N,N-dimethylaniline and stirred for 5 minutes. 26.4 g of aluminium trichloride are then added in portions and the reaction mixture is warmed to 50° C. for 45 minutes. For work-up, the mixture is allowed to come to room temperature, stirred into 2N hydrochloric acid, extracted 3 times with methylene chloride, dried over magnesium sulphate and concentrated in vacuo. The crude product is chromato-graphed on silica gel using a hexane-ethyl acetate gradient. 8.6 g of 8,8,9,9,9-pentafluorononan-1-ol are obtained as an oil.
Reaction SMILES: [C:1](=[O:9])([O:6][CH2:7][CH3:8])[O:2][CH:3](Cl)[CH3:4].[C:10]([NH:13][C:14]1[C:15]([I:30])=[C:16]([N:25]([C:27](=[O:29])[CH3:28])[CH3:26])[C:17]([I:24])=[C:18]([C:21]([O-:23])=[O:22])[C:19]=1[I:20])(=[O:12])[CH3:11].[K+].[I-].[Na+]>CN(C)C=O>[C:10]([NH:13][C:14]1[C:15]([I:30])=[C:16]([N:25]([C:27](=[O:29])[CH3:28])[CH3:26])[C:17]([I:24])=[C:18]([C:21]([O:23][CH:3]([O:2][C:1]([O:6][CH2:7][CH3:8])=[O:9])[CH3:4])=[O:22])[C:19]=1[I:20])(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: CCOC(=O)OC(C)Cl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)c1c(I)c(NC(C)=O)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1-Chloroethyl ethyl carbonate (10.00 g, 66.0 mmol) was added dropwise during 1.5 hour at room temperature to a solution of potassium 5-(N-acetylamino)3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (40.00 g, 60.0 mmol) and sodium iodide (0.89 g, 6.0 mmol) in dry dimethylformamide (200 ml). After stirring at 50° C. for 24 hours the solvent was removed at reduced pressure. The residue was dissolved in chloroform (120 ml) and washed four times with a saturated sodium hydrogen carbonate solution and twice with water. After drying with magnesium sulfate, treatment with activated charcoal and filtration, the title compound was crystallised by concentrating the solution at reduced pressure. Yield: (79%). Purity by HPLC: 99%. 1H-NMR (DMSO-d6): delta=1.25 (t, J=7 Hz, CH3); 1.64 (d, J=6 Hz, CH3); 1.67 (s, N(Me)COCH3); 2.05(s, NCOCH3); 2.96 (s, NCH3); 4.21 (q, J=7 Hz, CH2); 6.97 (q, J=6 Hz, CH); 10.10 ppm (s, NH).
Reaction SMILES: CO[C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:13]=[C:12]2[CH3:28])[CH:5]=1.[OH-].[Na+].[C:32](N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:45][N:46](C)[OH:47].C(N(CC)CC)C>O1CCCC1>[Cl:18][C:15]1[C:16](=[O:17])[N:11]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[CH3:10])[C:3]([N:46]([O:47][CH3:32])[CH3:45])=[O:29])[C:12]([CH3:28])=[N:13][C:14]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1
Reactant: CN(C)O
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3)c(Cl)c2=O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3)c(Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 3-[5-chloro-4-(4-fluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4-methyl-benzoic acid methyl ester from Step A (63 mg, 0.15 mmol) in tetrahydrofuran (1 mL) was added 1N sodium hydroxide (1 mL) and the solution was stirred at ambient temperature for eighteen hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH=2 using 1M HCl. The solution was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The slurry was filtered and concentrated to an orange oil used without any additional purification. To a solution of the crude acid in tetrahydrofuran (2 mL) was added 1,1′-carbonyldiimidazole (37 mg, 0.23 mmol). After stifling at ambient temperature for one hour, N,N-dimethylhydroxylamine HCl (22 mg, 0.23 mmol) and triethylamine (0.04 mL, 0.30 mmol) were added. The solution continued to stir for eighteen hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, water, and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the amide as a colorless oil (60 mg, 90%). MS (M+H): 446
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([CH3:12])[C:3]=1[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].F[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.O>[NH2:25][C:24]1[CH:26]=[CH:27][C:21]([O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[C:22]([N+:28]([O-:30])=[O:29])[CH:23]=1
Reactant: Cc1c(O)ccc(CC(=O)O)c1C
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(CC(=O)O)ccc(Oc2ccc(N)cc2[N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under an N2 atmosphere, 2-(4-hydroxy-2,3-dimethylphenyl)acetic acid (0.780 g, 4.33 mmol) was dissolved in DMSO (29 mL). Cesium carbonate (3.53 g, 10.8 mmol) was added and the reaction was allowed to stir at room temperature for 5 min. 4-Fluoro-3-nitroaniline (0.678 g, 4.33 mmol) was added and the reaction was heated to 80° C. for 2.25 h. The reaction was allowed to cool to room temperature and diluted with water. Citric acid was added to pH 4 and the reaction was extracted with ethyl acetate. The layers were separated and the aqueous layer was washed with additional ethyl acetate. The organics were combined, dried (Na2SO4), filtered, and concentrated in vacuo. Flash column chromatography of the residue, eluting with 0% to 8% methanol in dichloromethane, afforded the title compound. LC-MS ESI (pos.) m/z: 317.2 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)C.C(O)C.[OH-].[Na+]>O>[Br:21][C:17]1[CH:16]=[C:15]([C:7]2[N:6]([CH2:5][C:4]([OH:22])=[O:3])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Yield: 88.3 %

Procedure:
A solution of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester (4.8 g, 0.0133 mole), 95% ethanol (50 ml), sodium hydroxide pellets (0.6 g, 0.014 mole), and water (5 ml) was refluxed for 2 hrs. The ethanol was evaporated and water (50 ml) added. Glacial acetic acid was added dropwise until precipitation began (pH neutral). The precipitated solid was collected by filtration and recrystallized from ethanol-tetrahydrofuran, giving 3.9 g (88% yield) of white needles, mp 247°-249° C.
Reaction SMILES: [CH2:1]([C:6]1[CH2:7][CH2:8][C:9]2[CH2:10][NH:11][C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=3[C:18]=2[CH:19]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[C:17]1[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]1)=[N:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCCC1=CC2=C(CC1)CNC1=C2CCCC1
Product: CCCCCc1ccc2cnc3ccccc3c2c1
Yield: 92.9 %

Procedure:
A mixture of 20 grams of 9-pentyl 1,2,3,4,5,6,7,8-octahydrophenanthridine, prepared as described in example 3, 108 grams of an alkylated benzene solvent and 4 grams of a 5% Palladium/Al catalyst were refluxed for 19 hours. Hydrogen gas was evolved during the reaction. The solvent was removed under diminished pressure to yield after work-up 18 grams of 9-pentyl phenanthridine; infrared spectrum, 6.41; 6.65; and 6.72 μ; C13 nuclear magnetic resonance spectrum, solvent CDCl3, ref. T.M.S.; δ in ppm.: ##STR9##
Reaction SMILES: [Li]CCCC.N(C(C)C)C(C)C.[CH:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1.Br[CH2:23][CH2:24][CH2:25][CH2:26][Cl:27].[NH4+].[Cl-]>C1COCC1>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][C:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)C1CCC1
Reactant: ClCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(CCCCCl)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
Under an N2 atmosphere at ˜7° C., BuLi (2.5M in hexanes, 52.8 mL, 132 mmol) was added drop wise to a solution of iPr2NH (18.52 mL, 132 mmol, distilled from NaOH) in dry THF (70 mL) in 10 min. The reaction mixture was allowed to warm to rt, stirred for 0.5 h, cooled to −60° C. and then, ethyl 1-cyclobutanecarboxylate (prepared according to Török, B.; Molnár, Á., J. Chem. Soc. Perkin Trans. 1, 1993, 7, 801–804, 14.05 g, 110 mmol) in dry THF (30 mL) was added dropwise in 20 min. The resulting mixture was allowed to warm to 0° C. in 20 min., cooled again to −60° C. and then, a solution of 1-bromo-4-chlorobutane (19.1 mL, 165 mmol) in dry THF (30 mL) was added dropwise in 20 min, after which the temperature was raised to −20° C. in 15 min. After 1.5 h, the temperature was raised to −10° C. and stirring was continued for 1 h. The reaction mixture was allowed to reach rt, poured into a mixture of aqueous saturated NH4Cl (200 mL) and ice (50 mL) and extracted with Et2O (500 mL). The organic layer was washed with brine (250 mL), dried (Na2SO4) and evaporated in vacuo. The remaining oil was purified by fractional distillation under reduced pressure to give ethyl 1-(4-chlorobutyl)-1-cyclobutanecarboxylate (20.53 g, 86%) as a thin, colorless oil. 1H NMR (CDCl3): δ=4.13 (q, J=7.1 Hz, 2H), 3.51 (t, J=6.8 Hz, 2H), 2.50–2.32 (m, 2H), 1.96–1.70 (m, 8H), 1.40–1.20 (m, 2H), 1.26 (t, J=7.2 Hz, 3H). 13C NMR (CDCl3): δ=176.6, 60.3, 47.6, 44.8, 37.3, 32.8, 30.1 (2×), 22.4, 15.8, 14.4. HRMS calcd for C11H20(37Cl)O2 (MH+): 221.1122, found: 221.1116.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](C=O)=[CH:16]2)=[O:11].[CH3:24][O:25][C:26](=[O:47])[CH:27]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:48]1(C)C=CC=CC=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH:48]=[CH:27][C:26]([O:25][CH3:24])=[O:47])=[CH:16]2)=[O:11]
Reactant: Cc1ccccc1
Reactant: O=Cc1cc2cc(NC(=O)c3cc4ccccc4o3)ccc2[nH]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)C=Cc1cc2cc(NC(=O)c3cc4ccccc4o3)ccc2[nH]1
Temperature: 25 °C
Yield: 66 %

Procedure:
21 (100 mg, 0.33 mmol) was added to a solution of methyl(triphenylphosphoranylidene)acetate (120 mg, 0.36 mmol) in toluene (30 mL) and the reaction mixture was heated to reflux for 4 days. The solvent was removed after cooled to room temperature. The product was crystallized in a solution of acetone and ether. The mother liquid was then purified by flush column chromatography eluting with ethyl acetate and hexane (1/2, v/v). A total of 78 mg (66% yield) of yellow solid 22 was obtained. mp: 259°-260° C. 1H NMR (DMSO-d6, ppm): 11.57 (s, 1 H, NH), 10.38 (s, 1 H, NH), 8.07-7.35 (m, 9 H, Ar--H, CH=CH), 6.93 (s, 1 H, Ar--H), 6.57-6.53 (d, 1 H, J=15.8 Hz, CH=CH), 3.74 (s, 3 H, CH3). Anal. (C21H16N2 O4), C, H, N.
Reaction SMILES: NC(C)[CH2:3][CH2:4][N:5]1[C:26]2[C:27]3[C:7]([CH2:8][C@@H:9]4[C:21]([C:22]=3[CH:23]=[CH:24][CH:25]=2)=[CH:20][C@@H:12]([C:13](=[O:19])[N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:11][N:10]4[CH3:28])=[CH:6]1.[N:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)=[C:31]=[S:32].[CH2:42]([N:44](CC)CC)[CH3:43]>C1COCC1>[N:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:44][CH2:42][CH2:43][CH2:3][CH2:4][N:5]2[C:26]3[C:27]4[C:7]([CH2:8][C@@H:9]5[C:21]([C:22]=4[CH:23]=[CH:24][CH:25]=3)=[CH:20][C@@H:12]([C:13](=[O:19])[N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:11][N:10]5[CH3:28])=[CH:6]2)=[O:38])=[CH:35][CH:34]=1)=[C:31]=[S:32]
Reactant: O=C(Cl)c1ccc(N=C=S)cc1
Reactant: CCN(CC)C(=O)[C@@H]1C=C2c3cccc4c3c(cn4CCC(C)N)C[C@H]2N(C)C1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)[C@@H]1C=C2c3cccc4c3c(cn4CCCCNC(=O)c3ccc(N=C=S)cc3)C[C@H]2N(C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
A solution of 370 mg (0.94 mmol) of 5 in 15 mL of dry THF was cooled to 0° C. and treated with a solution of 190 mg (0.96 mmol) of 6 in 5 mL of dry THF, stirred at 0° C. for 30 minutes and then at room temperature overnight. The reaction mixture was treated with 0.14 mL (1.0 mmol) of triethylamine and stirred at room temperature for 2 hours The reaction mixture was concentrated at reduced pressure. The residue was dissolved in methylene chloride, washed with H2O, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue was chromatographed on 200 g of silica gel using 3% methanol in methylene chloride as eluent to yield 325 mg (62%) of 7 as a tan amorphous solid [α]D=+47.5° (c=0.91%; CHCl3).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([NH:28][C:29](=[O:37])[CH2:30][CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:20]([Cl:38])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:38][C:20]1[CH:19]=[C:18]([N:8]2[CH2:9][CH2:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7]2)[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]=1[NH:28][C:29](=[O:37])[CH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(CCC1CCCC1)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(CCC1CCCC1)Nc1c(Cl)cc(N2CCc3ccccc3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (150 mg, 1.34 mmol), 1,2,3,4-tetrahydroisoquinoline (107 mg, 0.8 mmol), and N-(4-bromo-2-chloro-6-trifluoromethyl phenyl)-3-cyclopentyl propionamide (200 mg, 0.5 mmol) were then added, and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane: methanol 5%) to afford the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12]NC(C)C)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:17][N:18]([CH3:35])[C:19]1[O:20][CH:21]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C:22](=[O:24])[N:23]=1.C(P(CCCC)CCCC)CCC.C(OCC)(=O)C>C(#N)C.C(OCC)C>[CH3:17][N:18]([CH3:35])[C:19]1[O:20][C:21]([CH:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)[CH3:12])([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C:22](=[O:24])[N:23]=1
Reactant: CN(C)C1=NC(=O)C(C(=O)OCc2ccccc2)O1
Reactant: CC(C)NCCc1c[nH]c2cc(F)ccc12
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CC#N
Product: CC(c1c[nH]c2cc(F)ccc12)C1(C(=O)OCc2ccccc2)OC(N(C)C)=NC1=O
Yield: 60.9 %

Procedure:
To a mixture of 6-fluoro-3-(1-isopropylamino)ethylindole (435 mg), benzyl 2-dimethylamino-4-oxo-2-oxazolin-5-carboxylate (518 mg) in acetonitrile (15 ml) was added tri-n-butylphosphine (492 μl). The mixture was refluxed for 2.5 hours. Removal of the solvent gave a residue, to which a mixture of ethyl acetate and ethyl ether in a ration of 10:1 was added to provide benzyl 2-dimethylamino-5-[1-(6-fluoroindol-3-yl)ethyl]-4-oxo-2-oxazolin-5-carboxylate (509 mg) as a crystal.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.O1[C:10](=O)[CH:9]=[NH+:8][N-]1.[CH:12]([C:14]1[C:18](=[O:19])O[N-][N+:15]=1[CH3:20])=O.[OH-].[Na+].[CH3:23][N:24](C=O)C>>[CH:18]([C:14]1[N:15]2[CH:20]=[CH:10][CH:9]=[N:8][C:23]2=[N:24][CH:12]=1)=[O:19]
Reactant: C[n+]1[n-]oc(=O)c1C=O
Reactant: CN(C)C=O
Reactant: O=c1c[nH+][n-]o1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnc2ncccn12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To 14 ml DMF cooled to 0° was added 6.0 g (0.039 mol) phosphorus oxychloride dropwise over 15 minutes, followed by 1.79 g (0.015 mol) imidazo[1,5-a]pyrimidine (1). The resulting mixture was heated at 120° for 0.5 hours and then at 90° for 5 hours. The cooled reaction mixture was then poured onto a mixture of ice water, made basic with 40% NaOH solution and then extracted with 4×100 ml portions of CH2Cl2. The combined organic extracts were dried and the solvent removed in vacuo to give crude (2). This was purified by chromatography on silica gel eluting with CH2Cl2 (97)-isopropanol (3) to give pure (2), m.p. 198°-200°.
Reaction SMILES: [CH2:1]([Br:4])[CH:2]=[CH2:3].[F:5][C:6]1[CH:11]=[C:10]([N:12]2[CH:16]=[N:15][C:14]([CH3:17])=[N:13]2)[C:9]([O:18][CH3:19])=[CH:8][C:7]=1[NH:20][C:21]([NH2:23])=[S:22]>C(O)C>[BrH:4].[F:5][C:6]1[CH:11]=[C:10]([N:12]2[CH:16]=[N:15][C:14]([CH3:17])=[N:13]2)[C:9]([O:18][CH3:19])=[CH:8][C:7]=1[NH:20][C:21]([S:22][CH2:3][CH:2]=[CH2:1])=[NH:23]
Reactant: COc1cc(NC(N)=S)c(F)cc1-n1cnc(C)n1
Reactant: C=CCBr
Solvent: CCO
Product: Br
Product: C=CCSC(=N)Nc1cc(OC)c(-n2cnc(C)n2)cc1F
Temperature: 70 °C
Yield: 101.4 %

Procedure:
Step U (1): Allyl bromide (0.308 mL, 3.55 mmol) was added to a solution of 1-(2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (1.0 g, 3.55 mmol, from Preparation B, Step B(4)) in absolute ethanol (25 mL). The resulting mixture was heated at 70° C. for 2 h. After cooling to rt, the reaction was concentrated in vacuo. The residual volatiles were removed under high vacuum to afford allyl 2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydrobromide (1.45 g, 3.60 mmol, 101% yield) as an off-white solid. LC-MS (M+H)+ 322.0.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](O)([CH3:9])[CH3:8])=[N:4][CH:3]=1.[SH:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]>ClCCCl.O.[I-].[Zn+2].[I-]>[Br:1][C:2]1[S:6][C:5]([C:7]([S:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])([CH3:9])[CH3:8])=[N:4][CH:3]=1
Reactant: CC(C)(O)c1ncc(Br)s1
Reactant: COC(=O)CCS
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)CCSC(C)(C)c1ncc(Br)s1
Yield: 95.8 %

Procedure:
The product of Step 2 (9.00 g, 40.5 mmol) was taken up in 1,2-DCE (400 mL) before adding methyl 3-mercaptopropionate (9.74 g, 81 mmol) and zinc iodide (38.8 g, 122 mmol). The reaction was stirred at reflux for 5 h. The suspension was diluted with water and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Flash chromatography (0-15% ethyl acetate in hexanes) provided methyl 3-{[2-(5-bromo-1,3-thiazol-2-yl)propan-2-yl]sulfanyl}propanoate (12.58 g, 96%) as a colorless oil. ESI: [M+H]+ m/z 323.9/326.0.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:13]4[CH:14]=[C:15]([NH:20][C@H:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[CH3:22])[C:16]([C:18]#[N:19])=[CH:17][C:12]=4[N:11]=[CH:10]3)[CH:5]=2)[CH2:3][CH2:2]1.[H][H]>[Pd].CO.Cl>[NH2:19][CH2:18][C:16]1[C:15]([NH:20][C@H:21]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH3:22])=[CH:14][C:13]2[N:9]([C:6]3[CH:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[NH:8][N:7]=3)[CH:10]=[N:11][C:12]=2[CH:17]=1
Reactant: C[C@H](Nc1cc2c(cc1C#N)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C[C@H](Nc1cc2c(cc1CN)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Reaction time: 30 h
Yield: 64.8 %

Procedure:
To 1-(5-cyclopropyl-1H-pyrazol-3-yl)-6-((S)-1-(4-fluorophenyl)ethylamino)-1H-benzo[d]imidazol-5-carbonitrile (Example 33, 1.25 g, 3.2 mmol) and 10% palladium on carbon (0.69 g, 0.65 mmol) in MeOH (40 ml) was added 15 drops of conc. HCl. The reaction was charged 45 psi hydrogen and shook for 30 hours. The solvent was removed. The residue was dissolved in EtOAc (200 ml), washed with saturated sodium bicarbonate (50 ml) and dried over sodium sulfate. After removal of solvent, the residue was purified by reverse-phase column chromatography (5-50% CH3CN in H2O) to give the title compound as an off-white solid (0.81 g, 61%). 1H NMR (400 MHz) 12.65 (s, 1H), 8.15 (s, 1H), 7.46 (m, 2H), 7.36 (s, 1H), 7.11 (m, 2H), 6.91 (d, J=5.6 Hz, 1H), 6.74 (s, 1H), 5.94 (s, 1H), 4.54 (m, 1H), 3.92 (s, 2H), 2.07-1.91 (m, 3H), 1.48 (d, J=6.4 Hz, 3H), 1.01 (m, 2H), 0.72 (m, 2H). MS: Calcd.: 390; Found: [M+H]+ 391.
Reaction SMILES: [OH-:1].[Na+].[NH2:3]O.C[O:6][C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[C:12]2[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=O>C1COCC1.CO.O>[OH:1][NH:3][C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[C:12]2[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:6]
Reactant: NO
Reactant: [OH-]
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(F)cc1)cn2C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cn1cc(Cc2ccc(F)cc2)c2cc(C(=O)NO)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of sodium hydroxide (64 mg, 1.6 mmol) and 50% aqueous hydroxylamine (0.65 mL) was added 3-(4-fluoro-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid methyl ester (58 mg, 0.2 mmol) dissolved in THF/MeOH (1 mL, 1:1). After stirring 4 hr at room temperature, the solution was diluted with water (4 mL) and the volatile solvents were removed in vacuo. The solution was then neutralized to pH=7-8 with 1N HCl and then subjected to HPLC purification to provide 3-(4-fluoro-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid hydroxyamide (32 mg, 50% yield). 1H NMR (400 MHz, DMSO) δ 11.05 (s, 1H), 8.83 (br s, 1H), 7.97 (s, 1H), 7.57 (dd, 1H, J=1.7, 8.6 Hz), 7.41 (d, 1H, J=8.6 Hz) 7.30 (m, 2H), 7.18 (s, 1H), 7.08 (m, 2H), 4.03 (s, 2H), 3.74 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:17]#[C:18][Si](C)(C)C)[CH:7]=[C:8]3[C:13]=2[C:12](=[O:14])[CH2:11][CH2:10][C:9]3([CH3:16])[CH3:15])[CH2:3][CH2:2]1.CO.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CCCCCC>[CH:1]1([C:4]2[CH:5]=[C:6]([C:17]#[CH:18])[CH:7]=[C:8]3[C:13]=2[C:12](=[O:14])[CH2:11][CH2:10][C:9]3([CH3:15])[CH3:16])[CH2:3][CH2:2]1
Reactant: CC1(C)CCC(=O)c2c(C3CC3)cc(C#C[Si](C)(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CCC2=O

Procedure:
Following General Procedure F and using 8-cyclopropyl-4,4-dimethyl-6-(trimethylsilanyl)ethynyl-1-tetralone (Intermediate 159, 1.05 g, 3.38 mmol), methanol (20 mL) and potassium carbonate (1 g, 14.5 mmol) followed by flash column chromatography using 7% ethyl acetate in hexane as the eluent, the title compound was obtained (0.57 g, 80%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[C:6]1([C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9])[OH:7].[OH-:14].[Na+]>O>[C:8]1([O:9][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[O:7][CH2:4][CH:3]([OH:14])[CH2:1][Cl:2]
Reactant: Oc1ccccc1O
Reactant: ClCC1CO1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: OC(CCl)COc1ccccc1OCC(O)CCl
Temperature: 40 °C
Reaction time: 48 h
Yield: 82.3 %

Procedure:
37.0 g. of epichlorohydrin are added under a nitrogen atmosphere to 11.0 g. of catechol. After the catechol is dissolved, a solution of 0.15 g of sodium hydroxide in a few drops of water is added dropwise and the temperature is raised to 40° C. At this temperature the reaction mixture is stirred for 48 hours, after which the remaining epichlorohydrin is distilled off under reduced pressure. The resulting oil is dissolved in chloroform, washed twice with water and distilled. 19.5 g. of 1,1'-(o-phenylenedioxy)-bis-(3-chloropropan-2-ol) are obtained with a boiling point of 153°-156° C./10-2 -10-3 mm.Hg. After crystallization from diethyl ether the melting point is 64°-66° C.