Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([CH:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH2:14]2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.Br[CH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(O)C.O>[C:36]1([CH2:35][CH2:34][CH2:33][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([CH:13]3[S:23][C:22]4[N:24]5[C:15](=[CH:16][N:17]=[C:18]5[CH:19]=[CH:20][CH:21]=4)[CH2:14]3)=[O:12])[CH2:5][CH2:4]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C(NCC1CCNCC1)C1Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCC1CCN(CCCc2ccccc2)CC1)C1Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 746.4 mg (1.91 mM) of N-(4-piperidyl)methyl-3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.4 ml (10.0 mM) of triethylamine in ethanol (5 ml) was added 0.35 ml (2.30 mM) of 1-bromo-3-phenylpropane at room temperature and the mixture was refluxed under nitrogen for 64 hours. This reaction mixture was diluted with water and extracted with chloroform, and the organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The residue was purified by column chromatography (methanol/ethyl acetate 20-30-50%) to provide the title compound as red amorphous substance.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([NH:27][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([NH:20][CH2:19][C:17]2[O:18][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH:11]=[CH:10]3)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: NC1CCCCC1
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3cc(NC4CCCCC4)ccc3n2)o1

Procedure:
The title compound, MS: m/e=336.5 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and cyclohexylamine.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[C:11]1([NH2:18])[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1.C(N(CC)CC)C>C(O)(C)C>[NH2:17][C:13]1[CH:12]=[C:11]([NH:18][C:2]2[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc(N)c1
Reactant: Cn1cc(Br)nc(Br)c1=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1cc(Br)nc(Nc2cccc(N)c2)c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 3,5-dibromo-1-methylpyrazin-2(1H)-one (536 mg, 2.0 mmol) and benzene-1,3-diamine (324 mg, 3.0 mmol) in isopropanol (18 mL) was added triethylamine (2.8 mL). The reaction mixture was stirred at 80° C. overnight. Then the mixture was evaporated under reduced pressure to afford 219a (480 mg, 81%) as a white solid. MS-ESI: [M+H]+ 295.0
Reaction SMILES: [C:1]([C:4]1([CH2:14][S:15][C:16]([CH3:19])(C)C)[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=[O:2].S.C(OC(=O)C)(=[O:23])C>FC(F)(F)C(O)=O.C(OCC)C>[C:1]([C:4]1([CH2:14][S:15][C:16](=[O:23])[CH3:19])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)SCC1(C(=O)O)CCc2ccccc2C1
Agent: S
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCC1(C(=O)O)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (5.36 g, 20.0 mmol) in trifluoroacetic acid (40 mL) and add mercuric acetate (6.36 g, 20.0 mmol). Stir at ambient temperature under an atmosphere of argon for 4.5 hours, then treat with gaseous hydrogen sulfide. Remove the resulting black solid by filtration and dilute the filtrate to 100 mL with methylene chloride. Wash with water, then with brine and dry (MgSO4). Evaporate the solvent in vacuo to a residue. Mix the residue with sulfuric acid (0.3 mL of 10% solution in acetic acid) and add acetic anhydride (2.04 g, 20.0 mmol). Stir the mixture for 2 hours under an atmosphere of argon at ambient temperature, then dilute with 100 mL ethyl ether. Wash with water, brine then dry (MgSO4). Concentrate the filtrate in vacuo to give the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[C:7]([OH:13])(=O)[CH2:8][C:9]([OH:11])=O.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][N:2]1[C:7](=[O:13])[CH2:8][C:9](=[O:11])[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: CNC(=O)NC
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CN1C(=O)CC(=O)N(C)C1=O
Temperature: 90 °C
Reaction time: 6 h
Yield: 73.4 %

Procedure:
276 g (3.14 mol) of 1,3-dimethylurea and 376 g (3.62 mol) of malonic acid were dissolved in 600 ml of glacial acetic acid at 60° to 70° C. To the solution was added 1250 ml of acetic anhydride and the temperature was gradually raised to 90° C. After stirring for 6 hours, the reaction mixture was allowed to stand at room temperature overnight and then the glacial acetic acid and acetic anhydride were distilled off under reduced pressure. The residue was poured into 500 ml of ethanol while it was still hot, the crystals thus-deposited were collected by filtration and refluxed by heating in a mixture of 380 ml of concentrated hydrochloric acid and 400 ml of water for 2 hours. The mixture was allowed to stand under cooling with ice for 6 hours, the crystals thus-deposited were collected by filtration and washed with a small amount of ethanol to obtain 360 g of 1,3-dimethylbarbituric acid.
Reaction SMILES: C(N1C(C(OCC)=O)=NNN1)C1C=CC=CC=1.[CH2:18]([N:25]1[N:29]=[N:28][C:27]([C:30]([O:32]CC)=[O:31])=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.S1(CCCC1)(=O)=O.[OH-].[K+:43]>C(O)C.O>[CH2:18]([N:25]1[N:29]=[N:28][C:27]([C:30]([O-:32])=[O:31])=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[K+:43]
Reactant: CCOC(=O)c1nnn(Cc2ccccc2)n1
Agent: CCOC(=O)C1=NNNN1Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Solvent: O
Solvent: CCO
Product: O=C([O-])c1nnn(Cc2ccccc2)n1

Procedure:
A mixture of ethyl 1-benzyl-2H-tetrazole-5-carboxylate and ethyl 2-benzyl-2H-tetrazole-5-carboxylate (7 g; prepared as described below and still containing a little sulpholane) was dissolved in hot ethanol (100 ml) and the hot solution was treated with a solution of potassium hydroxide (2.7 g) in water (8 ml). The white solid which separated was filtered off from the hot solution and washed with ethanol to give potassium 2-benzyl-2H-tetrazole-5-carboxylate (4.64 g), m.p. 264°-267° C. [The pure salt, obtained as a hemihydrate after recrystallisation from water, had a melting point of 272°-273° C.]
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.[OH:12][C:13]([CH3:46])([CH3:45])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH3:23])[CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.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>[OH:12][C:13]([CH3:45])([CH3:46])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:25]=[CH:26][C:27]([C:2]3[CH:3]=[N:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=3)=[CH:28][CH:29]=2)[CH3:23])[CH2:17][CH2:16]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)(O)c1ncc(Br)cn1
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: CCO
Solvent: COCCOC
Product: C[C@@H](c1ccc(-c2cnc(C(C)(C)O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To a solution of 2-(5-bromopyrimidin-2-yl)propan-2-ol (30 mg, 0.14 mmol) in DME (6 mL) was added Pd(PPh3)4 (10 mg, 0.01 mmol) under nitrogen. The mixture was stirred at room temperature for 1 h. (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (60 mg, 0.125 mmol) in EtOH (2 mL) was added, followed by addition of satd aq NaHCO3 (2 mL). The mixture was stirred at 100° C. for 2 h, quenched with water, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (17 mg, yield 25.12%). LC-MS Method 2 tR=1.00 min, m/z=490; 1H NMR (CD3OD): δ0.95 (s, 3H), 1.27 (s, 3H), 1.57 (d, 3H), 1.61 (s, 6H), 2.22 (s, 2H), 2.25 (m, 1H), 2.50 (m, 2H), 3.06 (m, 1H), 5.61 (m, 1H), 7.10 (m, 2H), 7.34 (m, 5H), 7.45 (m, 2H), 8.92 (s, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-].[CH3:5][CH:6]([CH3:8])[O-].CC(C)[O-].[Al+3].C(O)CCCCCO.[CH:22]([OH:25])([CH3:24])C>>[CH2:22]([OH:25])[CH2:24][CH2:1][CH2:2][CH2:4][CH:6]([CH3:8])[CH3:5]
Reactant: CC(C)[O-]
Reactant: CC(C)O
Agent: OCCCCCCO
Agent: [Al+3]
Product: CC(C)CCCCCO
Temperature: 125 °C

Procedure:
With the apparatus of Example 1, 174.2 grams aluminum tri-isopropoxide was charged, followed by 94.4 grams of isooctyl acohol and 108.4 grams of hexylene glycol. The mixture was heated with agitation to 90° C. where isopropyl alcohol began distilling off. A high boiling petroleum solvent was added and the material was heated to 125° C. where vacuum was applied to remove the remaining isopropyl alcohol. The material was cooled and adjusted to a final active solids content of 48% by addition of more petroleum solvent.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][C:21]3[O:24][CH:25]=[CH:26][C:20]=3[CH2:19]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:27][NH:28][CH3:29].[CH2:30]=O>C(O)(=O)C>[CH3:27][N:28]([CH2:30][C:25]1[O:24][C:21]2[CH2:22][CH2:23][N:18]([S:15]([C:12]3[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:14][CH:13]=3)(=[O:17])=[O:16])[CH2:19][C:20]=2[CH:26]=1)[CH3:29]
Reactant: CNC
Reactant: C=O
Reactant: O=S(=O)(c1ccc(CCc2ccccc2)cc1)N1CCc2occc2C1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(S(=O)(=O)c1ccc(CCc3ccccc3)cc1)C2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.240 g (0.653 mmol) of 5-(4-phenethylbenzenesulfonyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 10 ml of acetic acid, 0.09 g (1.0 mmol) of 50% aqueous dimethylamine and 0.08 g (1.0 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: CI.[C:3]([O-])([O-])=O.[K+].[K+].[CH:9]1([CH2:14][CH:15]([C:24]2[CH:25]=[N:26][C:27]([SH:30])=[CH:28][CH:29]=2)[C:16]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10]1>CN(C=O)C>[CH:9]1([CH2:14][CH:15]([C:24]2[CH:25]=[N:26][C:27]([S:30][CH3:3])=[CH:28][CH:29]=2)[C:16]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(S)nc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cn1
Reaction time: 16 h

Procedure:
MeI (44 μL of a 2.3M solution in anhydrous DMF, 102 μmol) and K2CO3 (14 mg, 102 μmol) were added to a stirred solution of 3-cyclopentyl-2-(6-mercaptopyridin-3-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 66, 34 mg, 102 μmol) in anhydrous DMF (1 mL). After 16 h, the solvents were evaporated off under reduced pressure, then the residue was partitioned between EtOAc (12 mL) and H2O (5 mL). The organic layer was washed with H2O (5 mL) and brine (5 mL), before being dried (MgSO4). The solution was filtered, passed through a short SiO2 plug, and evaporated to give 3-cyclopentyl-2-(6-methylsulfanylpyridin-3-yl)-N-thiazol-2-ylpropionamide: m/z (ES+)=348.2 [M+H]+. Step 2: Oxidation of this thioether (52 mg, 150 μmol), by the protocol described in EXAMPLE 55, gave the title compound: RTA=3.17 min; m/z (ES+)=364.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[N:10][C:9]=2[N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:29][O:30][C:31](=[O:36])[C:32]([NH2:35])([CH3:34])[CH3:33].C(N(CC)C(C)C)(C)C.[N-]=C=O>ClCCl>[CH3:29][O:30][C:31](=[O:36])[C:32]([NH:35][C:14]([C:12]1[CH:11]=[N:10][C:9]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:13]=1)=[O:15])([CH3:34])[CH3:33]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1cnc(N2CCCCC2)c(-c2ccc(F)cc2)n1
Agent: O=C(Cl)C(=O)Cl
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1cnc(N2CCCCC2)c(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a dichloromethane (1 ml) solution of 6-(4-Fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carboxylic acid (0.107 g, 0.358 mmol, 1.0 eq) was added oxalyl chloride (0.136 g, 1.07 mmol, 3.0 eq). The reaction was stirred at room temperature for 3 hours after which time the solvent was removed in vacuo. The residue was re-dissolved in dichloromethane (3 ml) and added portion-wise to a dichloromethane (1 ml) solution of aminoisobutyric acid methyl ester (0.066 g, 0.429 mmol, 1.2 eq). PS-N,N-diisopropyl-ethylamine (0.31 g, 1.04 mmol, 3.0 eq) resin was added to the reaction and the mixture stirred overnight at room temperature. PS-isocyanate (0.15 g, 0.358 mmol, 1.0 eq) and PS-aminomethyl (0.15 g, 0.358 mmol, 1.0 eq) resin were added to the reaction and the mixture stirred for a further 12 hrs at room temperature. The reaction was filtered and resin washed successfully with dichloromethane (2×3 ml). The combined filtrates were concentrated in vacuo and the residue purified by chromatography on silica gel with heptane:ethyl acetate (1:1) to afford 2-{[6-(4-fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester. Yield=0.030 g (21%). HPLC-MS=100%; 2.52 min (MW=400; M+1=401.2).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH2:17]>C(O)(C)C>[ClH:1].[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Fc1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: CC(C)O
Product: Cl
Product: Fc1ccc2ncnc(Nc3ccc(Cl)c(Cl)c3)c2c1
Yield: 84.8 %

Procedure:
A mixture of 4-chloro-6-fluoroquinazoline (2 g), 3,4-dichloroaniline (1.78 g) and isopropanol (30 ml) was heated at reflux for 2 hours. The resulting solid was filtered off, washed with isopropanol and with diethyl ether to give 4-(3,4-dichloroanilino)-6-fluoroquinazoline hydrochloride (3.2 g), m.p. >300° C.; NMR Spectrum: (CD3SOCD3) 7.74 (d, 1H), 7.88 (m, 1H), 8.07 (m, 2H), 8.24 (d, 1H), 8.97 (m, 1H), 8.98 (s, 1H);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]#[CH:18])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([CH:14]1[CH2:16][CH2:15]1)[CH3:13])[CH2:7]2.C(=O)([O-])O.[K+].O.Cl[C:26](=[N:32][OH:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[O:33][N:32]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:18]=2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([CH:14]1[CH2:16][CH2:15]1)[CH3:13])[CH2:7]2
Reactant: C#Cc1cc(Cl)c2c(c1)CN([C@@H](C)C1CC1)C2=O
Reactant: CCOC(=O)C(Cl)=NO
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(-c2cc(Cl)c3c(c2)CN([C@@H](C)C2CC2)C3=O)on1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.2 %

Procedure:
7-chloro-2-((S)-1-cyclopropylethyl)-5-ethynylisoindolin-1-one (28.66 g, 110.35 mmol) and potassium hydrogen carbonate (110.0 g, 1103.45 mmol) were dissolved in a solution consisting of 1200 mL of ethyl acetate and 400 mL of water. To this solution was added ethyl 2-chloro-2-(hydroxyimino)acetate (66.9 g, 441.38 mmol). The ethyl 2-chloro-2-(hydroxyimino)acetate was added at room temperature as a solution in 160 mL of ethyl acetate via syringe pump at a rate of 5 mL/Hr. Following the addition of the ethyl 2-chloro-2 (hydroxyimino)acetate, the reaction was allowed to continue stirring at room temperature for an additional 12 hours. The ethyl acetate layer was extracted in a separatory funnel, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel eluting with a gradient of 0 to 25% ethyl acetate in hexane to afford the title compound as a white solid (17.05 g, 41.2%). 1H NMR (300 MHz, CDCl3) δ ppm 0.36-0.53 (m, 3H) 0.63-0.73 (m, 1H) 0.98-1.12 (m, 1H) 1.38 (d, 3H) 1.47 (t, 3H) 3.80 (dq, 1H) 4.43-4.65 (m, 4H) 7.05 (s, 1H) 7.83 (s, 2H). MS ESI, m/z=375 (M+H). HPLC Method B: 0.82 min
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[S:31][C:32]5[CH:38]=[C:37](C(OCC)=O)[CH:36]=[CH:35][C:33]=5[N:34]=4)[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1.C[Mg]Cl.[CH3:47]O.[CH2:49]1[CH2:53][O:52]CC1>C(OCC)(=O)C>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:19])([F:17])[F:18])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[S:31][C:32]5[CH:38]=[C:37]([C:53]([OH:52])([CH3:49])[CH3:47])[CH:36]=[CH:35][C:33]=5[N:34]=4)[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc2nc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)sc2c1
Reactant: CO
Agent: C[Mg]Cl
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc2nc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)sc2c1
Temperature: 0 °C

Procedure:
The ethyl ester Example 3-A, ethyl 2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylate (20 mg, 0.033 mmol) was dissolved in THF (1.0 mL), and at RT was charged with a solution of methyl magnesium chloride (0.4 mL, 3.0 M THF, 1.2 mmol) in a dropwise fashion over a few minutes slowly enough so as not to allow the internal temperature of the reaction to exceed 30° C. After 1 hr the reaction was cooled to 0° C. and treated with MeOH (3 mL) in a dropwise fashion (rapid evolution of gas, internal temperature did not exceed 10° C.). The reaction was allowed to warm on its own accord to RT and diluted with ethyl acetate (9 mL) and the cloudy suspension was washed with 2×1 mL of 1 N HCl. The organic extracts were dried in vacuo and the resulting residue was purified using mass-directed reverse phase HPLC using gradient of 30 to 90% acetonitrile/water with 0.05% TFA as modifier. The resulting product was cold vacuum concentrated and free based using an SPE polymer support cartridge and MeOH (2 mL) mobilizing solvent (product SPE PLHCO3 MP part no PL3540-C603). All resulting methanol effluent was concentrated to furnish the title compound as a white powder.
Reaction SMILES: [CH3:1][C:2](C)([CH3:6])[C:3](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].[Cl:12][C:13]1[CH:48]=[CH:47][C:16]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)=[CH:24][CH:25]=3)[CH:20]=[C:19]2[CH2:39][C:40]([CH3:46])([CH3:45])[C:41]([O:43][CH3:44])=[O:42])=[CH:15][CH:14]=1.C(C(C(C([O-])=O)O)O)([O-])=O>C(Cl)Cl.CCOC(C)=O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)=[CH:24][CH:25]=3)[C:20]([C:2]([CH3:6])([CH3:3])[CH3:1])=[C:19]2[CH2:39][C:40]([CH3:45])([CH3:46])[C:41]([O:43][CH3:44])=[O:42])=[CH:47][CH:48]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)Cc1c(C(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Trimethylacetyl chloride (4.23 g, 4.32 mL, 35.09 mmol) was added to a cold suspension (0° C.) of AlCl3 (11.7 g, 87.7 mmol) in dry CH2Cl2 (60 mL) under Ar. The yellow mixture was stirred at 0° C. for 15 minutes, and a solution of 9.00 g (17.54 mmol) of methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A) in CH2Cl2 (40 mL) was added dropwise (over 10 minutes) at 0° C. The reaction mixture was stirred for 10 minutes and slowly poured onto an ice-cold and vigourously stirred mixture of 0.5M aqueous Na, K tartrate (500 mL) and EtOAc (400 mL). After 20 minutes, the aqueous layer was extracted with EtOAc (2×) and the combined organic extracts were washed with H2O (2×), with 1N aqueous NaOH (2×), with H2O (2×) and dried (MgSO4). Filtration and removal of solvents provided a yellow oily residue which was chromatographed on silica gel using EtOAc-hexane (1:4) to give the title compound.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[S:22][C:10]2[N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12](=[O:15])[CH:13]=[CH:14][C:9]=2[C:8]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:6])[CH:2]=C.C[N+]1([O-])CC[O:33]CC1.[C:37]([O-:40])(O)=O.[Na+]>O=[Os](=O)(=O)=O.CC(C)=O.O>[OH:33][CH:2]([CH2:37][OH:40])[CH2:1][NH:4][C:5]([C:7]1[S:22][C:10]2[N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12](=[O:15])[CH:13]=[CH:14][C:9]=2[C:8]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:6]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCNC(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Reactant: O=C([O-])O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NCC(O)CO)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Reaction time: 16 h

Procedure:
To a stirred solution of the compound of Example 95 (50 mg) in 8:1 acetone-water (10 mL) was added 4-methylmorpholine N-oxide (100 mg) followed by a catalytic amount of OsO4. The reaction mixture was stirred for 16 h and then poured into saturated NaHCO3 solution (20 mL). The product was extracted with DCM (2×20 mL) and the combined organic fractions dried over MgSO4, filtered and solvent removed in vacuo. The crude product was purified by column chromatography (silica, 10% EtOH in DCM) to give the title compound as a solid (32 mg). δH (CDCl3) 7.8–7.1 (11H, m), 6.44 (1H, d, J 10 Hz), 5.62 (1H, bs), 3.7–3.1 (5H, m). LCMS (ES+) 421 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:13][C:14]1[C:27]2[CH2:26][CH2:25][C@H:24]3[C@@H:19]([CH2:20][CH2:21][CH2:22][NH:23]3)[C:18]=2[CH:17]=[C:16]([F:28])[CH:15]=1>C(Cl)Cl.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:23]3[C@@H:24]4[C@H:19]([C:18]5[CH:17]=[C:16]([F:28])[CH:15]=[C:14]([F:13])[C:27]=5[CH2:26][CH2:25]4)[CH2:20][CH2:21][CH2:22]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: Fc1cc(F)c2c(c1)[C@@H]1CCCN[C@H]1CC2
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@H]2c3cc(F)cc(F)c3CC[C@@H]21
Yield: 70 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-7,9-difluoro-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 70% of theory; TLC: rf=0.43 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=368 [M+H]+.