Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[S:10])=[CH:4][CH:3]=1.BrBr.S(=O)(O)O.[OH-].[NH4+]>C(Cl)(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:17]3[CH:16]=[C:15]([CH3:18])[CH:14]=[CH:13][C:12]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=S)Nc2ccc(I)cc2)cc1
Agent: BrBr
Agent: O=S(O)O
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc2nc(Nc3ccc(I)cc3)sc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 35 %

Procedure:
A suspension of N-(4-iodophenyl)-N′-(4-methylphenyl)thiourea (0.62 g, 4.68 mmol) in chloroform (23 mL) was treated with a solution of bromine (2.65 g, 16.59 mmol) in chloroform (1 mL). The reaction mixture was stirred at rt for 5 minutes and then heated at 50° C. for 5 minutes. Then the reaction mixture was allowed to cool, and was treated with sulphurous acid until the orange color disappeared. The reaction mixture was neutralized by treatment with conc. ammonium hydroxide. More chloroform was then added to dissolve the precipitate. The layers was separated, and the organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to give N-(4-iodophenyl)-6-methyl-1,3-benzothiazol-2-amine (0.6 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ 2.36 (s, 3H), 7.12 (m, 1H), 7.48 (d, 1H), 7.60 (m, 3H), 7.65 (m, 2H), 10.50 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH:44]3[CH2:46][CH2:45]3)[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH:44]3[CH2:45][CH2:46]3)[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C3CC3)c2)c1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C4CC4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K60) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous off-white substance (337 mg, 77%).
Reaction SMILES: Br[C:2]1[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1.[C:19]1(OB(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.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>[CH3:18][S:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[O:6][C:2]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:13]=1
Reactant: CSc1ccc(-c2c(Br)oc3ccccc23)cc1
Reactant: OB(O)Oc1ccccc1
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: Cc1ccccc1
Product: CSc1ccc(-c2c(-c3ccccc3)oc3ccccc23)cc1
Yield: 67.3 %

Procedure:
A mixture of the product of Step 3 (450 mg), phenylboric acid (750 mg), Pd (PPh3)4 (80 mg) and NaOH (3 mL, 1N) in toluene (8 ml) and EtOH (10 mL) was refluxed for 20 h. A saturated solution of NaHCO3 (50 ml) was added and the mixture was extracted with Et2O (200 mL). The extract was dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluted with 30:1 hexane/EtOAc to give the title compound (300 mg).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH:16]=2)=[N:6][C:5]1=[O:23])([CH3:3])[CH3:2].Br>O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[N:6][C:5]1=[O:23])([CH3:3])[CH3:2]
Reactant: COc1cccc(-c2nc(=O)n(C(C)C)c3cc(C)ccc23)c1
Agent: Br
Solvent: O
Product: Cc1ccc2c(-c3cccc(O)c3)nc(=O)n(C(C)C)c2c1
Temperature: 25 °C

Procedure:
To 0.5 g of 1-isopropyl-4-(3-methoxyphenyl)-7-methyl-2(1H)-quinazolinone is added 5 ml of 48% (aqueous) hydrobromic acid (heat evolves and the solution turns yellow). The mixture is then refluxed for 6 hours. The mixture is cooled to room temperature, then 95 ml of water added, and the resulting mixture extracted thrice with 100 ml portions of a benzene: n-butanol (4:1) mixture each extract is retained separately. Each extract is washed 4 times with 75 ml portions of water (the pH of the last wash should be neutral). The extracts are combined and evaporated to dryness to obtain a residue which is then crystallized from methanol and ethyl acetate (1:1) to obtain 1-isopropyl-4-(3-hydroxyphenyl)-7-methyl-2(1H)-quinazolinone; m.p. 270°-272°, which yields refined product upon recrystallization from methanol; m.p. 274°-275° C.
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[CH2:14][CH3:15].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:12])=[CH:7][C:6]=1[CH2:14][CH3:15]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CCc1cc(C(C)=O)cnc1OCC(F)F
Product: CCc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)F
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (240 mg, clear colorless oil) from 1-(6-(2,2-difluoroethoxy)-5-ethylpyridin-3-yl)ethanone (220 mg, 0.94 mmol, Step-6) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16]C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CO.[CH3:20][NH2:21]>>[CH3:20][NH:21][C:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[O:16]
Reactant: CN
Reactant: COC(=O)C1CCN(c2ccc(Br)cc2)CC1
Solvent: CO
Product: CNC(=O)C1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 1-(4-bromophenyl)piperidine-4-carboxylate (950 mg) was added methylamine methanol solution (25%, 20 mL) at room temperature. The reaction mixture was stirred overnight at room temperature, and concentrated under reduced pressure. To a solution of the residue in acetonitrile (15 mL) were successively added tetraethylammonium bromide (1.05 g), isoamyl nitrite (1.05 g) and copper(I) bromide (0.09 g) at room temperature. The reaction mixture was stirred at room temperature for 40 min, and then at 60° C. for 2 hr. The reaction mixture was added to water, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (800 mg).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]1[CH2:22][C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[O:21]1[C:20]2[CH:22]=[CH:12][CH:13]=[CH:14][C:19]=2[CH:18]=[CH:17][CH2:16][C:15]1=[O:9]
Reactant: O=C1CCCc2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1CC=Cc2ccccc2O1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To 100 g of m-chloroperbenzoic acid in 1 l of chloroform at 0° C. is added dropwise 100 g of α-tetralone in 250 ml chloroform. After 5 days of stirring at room temperature the reaction mixture is treated carefully with 1 l sat. NaHCO3 and stirred for 1/2 hour. The organic layer is separated, washed with 500 ml of water and solid NaHCO3 until no evolution of gas. The organic layer is separated washed with sat. NaHCO3 and water and dried (MgSO4) After filtering and concentrating to dryness it is vaccum distilled to obtain low melting material which is used directly in the next step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:34][CH2:35][OH:36])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15](=[C:21]3[C:26](=[O:27])[N:25]([CH2:28][CH3:29])[C:24](=S)[N:23]([CH2:31][CH3:32])[C:22]3=[O:33])[CH:14]=2)=[CH:7][CH:6]=1.N1C=CC=CC=1.[O:43]1CCCC1>>[OH:1][CH2:2][CH2:3][N:4]([CH2:34][CH2:35][OH:36])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15](=[C:21]3[C:26](=[O:27])[N:25]([CH2:28][CH3:29])[C:24](=[O:43])[N:23]([CH2:31][CH3:32])[C:22]3=[O:33])[CH:14]=2)=[CH:7][CH:6]=1
Reactant: CCN1C(=O)C(=C2C=C(C=Cc3ccc(N(CCO)CCO)cc3)CC(C)(C)C2)C(=O)N(CC)C1=S
Reactant: C1CCOC1
Solvent: c1ccncc1
Product: CCN1C(=O)C(=C2C=C(C=Cc3ccc(N(CCO)CCO)cc3)CC(C)(C)C2)C(=O)N(CC)C1=O
Temperature: 20 °C

Procedure:
To 3.24 g of [3-[2-[4-[bis (2-hydroxyethyl) amino]phenyl]ethenyl] 5,5-dimethyl-2-cyclohexene-1-ylidene]-N,N'diethylthiobarbiturate and 2.93 g of hexafluorobisphenol A bischloroformate in 100 ml of THF (tetrahydrofuran) there was added dropwise in one hour 1.02 ml of pyridine, at 0° C. The reaction mixture was allowed to heat up to 20° C. After eighteen hours of stirring, the reaction product was precipitated in methanol. M.W.: 9,900, the Tg was measured to be 142°-148° C.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([S:15](Cl)(=[O:17])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[NH2:19][CH2:20][CH2:21][O:22]/[N:23]=[C:24](/[C:30]1[N:31]=[C:32]([NH:35]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:33][CH:34]=1)\[C:25]([O:27]CC)=[O:26].[OH-].[Na+].Cl>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[OH:4][C:5]1[CH:6]=[C:7]([S:15]([NH:19][CH2:20][CH2:21][O:22]/[N:23]=[C:24](/[C:30]2[N:31]=[C:32]([NH2:35])[S:33][CH:34]=2)\[C:25]([OH:27])=[O:26])(=[O:16])=[O:17])[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: CC(=O)Oc1ccc(S(=O)(=O)Cl)cc1OC(C)=O
Reactant: CCOC(=O)/C(=N\OCCN)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(/C(=N/OCCNS(=O)(=O)c2ccc(O)c(O)c2)C(=O)O)cs1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
1.17 g of 3,4-diacetoxy-benzenesulphonyl chloride were added to a solution of 6.0 g of 2-(tritylamino)-4-thiazoleglyoxylic acid ethyl ester (Z)-O-(2-aminoethyl) oxime and 0.49 g of 4-dimethylamino-pyridine in 50 ml of N,N-dimethylformamide. The reaction solution was stirred at 20° C. for 3 hours, 10 ml of 2N sodium hydroxide solution were then added, and the solution was stirred at 20° C. for an additional hour. Then, 20 ml of water were added and the pH of the reaction mixture was lowered to 3 by the addition of 3N hydrochloric acid. The resulting precipitate was filtered off under suction, washed with a small amount of water and then heated to 50° C. for 40 minutes in 60 ml of 80% aqueous acetic acid. The mixture was cooled to 20° C. and evaporated completely in a vacuum. The residue was dissolved in 30 ml of methanol and treated in an ice bath with a total of 180 ml of diethyl ether. The precipitate was filtered off under suction, suspended in a small amount of water and brought into solution by the dropwise addition of 2N sodium hydroxide solution. The solution of pH 7.5 was applied to a MCI gel column (CHP2OP) conditioned with 1% aqeuous acetic acid and chromatographed according to the procedure described in the first paragraph of this Example. The product was eluted with a 9:1 (v/v) water/acetonitrile mixture. The pure fractions were concentrated completely in a vacuum and the solid residue was crystallized from methanol/diethyl ether. There was obtained 2-amino-4-thiazoleglyoxylic acid (Z)-O-[2-[(3,4-dihydroxyphenyl)sulphonamido]ethyl] oxime as white crystals of melting point 92-94° C. (decomposition).
Reaction SMILES: C(N(CC)CC)C.Cl.[N:9]1[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1.[NH2:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:29])[C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1>C(Cl)Cl>[CH2:33]([O:32][C:30]([C:23]1([CH3:29])[C:22]2[C:26](=[CH:27][C:19]([NH:18][C:15]([C:12]3[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=3)=[O:16])=[CH:20][CH:21]=2)[NH:25][C:24]1=[O:28])=[O:31])[CH3:34]
Reactant: CCOC(=O)C1(C)C(=O)Nc2cc(N)ccc21
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(C)C(=O)Nc2cc(NC(=O)c3ccncc3)ccc21

Procedure:
22.1 ml. Triethylamine and 9.4 g. (0.053 mol) pyridine-4-carboxylic acid chloride hydrochloride are added to a cooled solution of 13 g. (0.048 mol) 6-amino-3-ethoxycarbonyl-3-methylindolin-2-one in 500 ml. methylene chloride and the reaction mixture then stirred at ambient temperature for about 2 hours. Subsequently, the reaction mixture is evaporated to dryness and the residue is stirred with water, filtered with suction and the product obtained is recrystallised from ethanol/methylene chloride. Yield: 11.9 g. (73% of theory); m.p. 222°-224° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH:13]2[CH2:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: NC1CCC1
Solvent: ClCCl
Product: O=S(=O)(NC1CCC1)c1ccc(Br)cc1F
Yield: 42.7 %

Procedure:
According to general procedure C, 4-Bromo-2-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and cyclobutylamine (0.31 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-cyclobutyl-2-fluorobenzenesulfonamide (192 mg, 43%) was provided after purification. MS (ESI) m/z 308. HPLC purity 90.7% at 210-370 nm, 11.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH2:16])=[O:15].Br[C:18]1[CH:19]=[CH:20][C:21]([C:24]2([C:34]#[N:35])[CH2:33][CH2:32][C:27]3([O:31][CH2:30][CH2:29][O:28]3)[CH2:26][CH2:25]2)=[N:22][CH:23]=1.CN(CC)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]I.O>[C:34]([C:24]1([C:21]2[N:22]=[CH:23][C:18]([NH:16][C:14]([C:3]3[CH:4]=[N:5][N:6]([C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=4)[C:2]=3[CH3:1])=[O:15])=[CH:19][CH:20]=2)[CH2:25][CH2:26][C:27]2([O:28][CH2:29][CH2:30][O:31]2)[CH2:32][CH2:33]1)#[N:35]
Reactant: Cc1ccc(-n2ncc(C(N)=O)c2C)cc1
Reactant: N#CC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Agent: [Cu]I
Agent: CCN(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-n2ncc(C(=O)Nc3ccc(C4(C#N)CCC5(CC4)OCCO5)nc3)c2C)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 2.6 %

Procedure:
5-Methyl-1-(4-methylphenyl)-1H-pyrazole-4-carboxamide (786 mg) and 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (1.12 g) described in Reference Example 82, copper (I) iodide (35 mg), N,N-dimethylethylamine (33 mg) and potassium carbonate in 1,4-dioxane (5 ml) was stirred at 100° C. for six hours. After the reaction, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified with a silica gel column chromatography to give the titled compound (42 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10]CC)=O)[CH2:4][CH2:3]1.C1(C)C=CC=CC=1>O>[CH:2]12[CH2:7][CH2:6][CH:5]([CH2:4][CH2:3]1)[C:8](=[O:10])[NH:1]2
Reactant: CCOC(=O)C1CCC(N)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NC2CCC1CC2
Temperature: 25 °C
Yield: 68.7 %

Procedure:
A solution of ethyl 4-aminocyclohexanecarboxylate (0.6 g, 3.49 mmol), toluene (1 mL) in oil bath (170° C.) was heated for 2-3 h to dryness. After cooling to rt, the reaction mixture was diluted with water and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, 300 mg of the desired product was obtained by column chromatography purification. MS (ESI): 126 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH3:23])[N:14]=2)[CH3:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:24]I.[H-].[Na+]>CN(C=O)C>[CH3:23][C:15]1[N:14]=[C:13]([N:11]([C:8]2[CH:9]=[CH:10][C:5]([N:4]([CH3:24])[C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[CH3:12])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: CC(=O)Nc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 600 %

Procedure:
To a solution of (4-acetamido-phenyl)-(2-methyl-quinazolin-4-yl)-methylamine (231 mg, 0.075 mmol) in 5 mL of DMF was added methyl iodide (0.9 g, 6.3 mmol) and the mixture was cooled to 0° C. Sodium hydride (60% oil suspension, 75 mg, 1.9 mmol) was added, and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched by adding 50 uL of water, diluted with 25 mL of ethyl acetate, washed with water (25 mL×3) and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by chromatography (90% ethyl acetate/hexanes) to give the title compound (143 mg, 0.45 mmol, 59%). 1H NMR (CDCl3): 7.19 (d, J=8.1, 1H), 7.54 (ddd, J=8.4, 6.6, 1.8, 1H), 7.16 (s, broad, 4H), 6.97-7.09 (m, 2H), 3.66 (s, 3H), 3.28 (s, 3H), 2.76 (s, 3H), 1.92 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4]>C1COCC1.C(O)C.[Pt](=O)=O>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:2]([CH3:5])([CH3:1])[CH2:3][OH:4])=[CH:11][CH:10]=1
Reactant: CC(C)(CO)c1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(N)cc1
Temperature: 25 °C
Yield: 134.2 %

Procedure:
The product from Example 194B (0.321 g, 1.644 mmole) was dissolved in a mixture of THF (10 mL) and ethanol (2 mL). To this was added platinum(IV)oxide (0.030 g, 0.131 mmole). The flask was capped with a septum and the contents vacuum degassed three times. Hydrogen was introduced via a balloon and the mixture stirred at room temperature. An additional 38.2 mg (0.167 mmole) of catalyst was added in two aliquots before chromatographic analysis indicated that the starting material was consumed. After stirring overnight under hydrogen the mixture was filtered through a sand/celite plug followed by an ethyl acetate rinse. The filtrate was concentrated to dryness and the residue purified by chromatography on amine modified silica gel eluting with ethyl acetate-hexane beginning at 8% and advancing to 66% ethyl acetate to provide the title compound (0.3645 g, 68% yield) as a clear oil. MS (DCI+) m/z@183.1 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([S:30][CH3:31])[C:24]([C:26]([F:29])([F:28])[F:27])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].CO.[OH:34]OS([O-])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+]>O.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([S:30]([CH3:31])=[O:34])[C:24]([C:26]([F:29])([F:27])[F:28])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C(F)(F)F)c(SC)cc3n2COCCOC)c1
Reactant: O=S([O-])OO
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cnn(-c2nc3cc(C(F)(F)F)c(S(C)=O)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a mixture of 1-[1-(2-methoxy-ethoxymethyl)-6-methylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from EXAMPLE 71, product from Step B) (0.300 g, 0.654 mmol) and methanol (3.3 mL) was added a solution of OXONE®/potassium peroxymonosulfate (0.402 g, 0.654 mmol) in water (3.3 mL). The mixture was allowed to stir for 4 h at 23° C. EtOAc (40 mL) and water (20 mL) were added and the biphasic mixture was stirred. The layers were separated and the aqueous layer was further extracted with EtOAc (30 mL). The combined organic layers were washed with brine (15 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (20-100% EtOAc/hexanes) to yield the titled compound (0.249 g, 80% yield) as a 10:9 mixture of regioisomers. MS (ESI/CI): mass calcd. for C19H21F3N4O5S, 474.1; m/z found, 475.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.94 (d, J=0.6 Hz, 1H), 8.58 (s, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 6.34-6.23 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 3.74-3.66 (m, 2H), 3.51-3.41 (m, 2H), 3.28 (s, 3H), 2.81 (s, 3H), 1.40 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:6]([CH:32]=1)[O:7][CH2:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([O:15]C(=O)N(C)C)[CH2:12][N:11]1[C:21](OCCCCCCCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[C:6]([CH:32]=1)[O:7][CH2:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]1[CH3:21]
Reactant: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCOc1cc(Cl)ccc1CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C[C@H](O)C[C@H]1CCOc1cc(Cl)ccc1CCc1ccccc1
Yield: 29.5 %

Procedure:
1380 mg of (2R,4R)-2-{2-[5-chloro-2-(2-phenylethyl)phenoxy]ethyl}-4-dimethylcarbamoyloxy-1-octyloxycarbonylpyrrolidine [prepared as described in step (a) above], 20 ml of tetrahydrofuran and 450 mg of lithium aluminum hydride were allowed to react together and subsequently treated in the same manner as described in step (b) of Example 1. The concentrated substance thus obtained was purified by silica gel column chromatography, using a 5:1 by volume mixture of methylene chloride and methanol as the eluent, to give 256 mg (yield 30%) of the title compound as a colorless solid substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH2:39]([S:41]([NH2:44])(=[O:43])=[O:42])[CH3:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:44][S:41]([CH2:39][CH3:40])(=[O:43])=[O:42])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][C:27]2([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:28][CH2:29]1)=[O:23]
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 47.6 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-(6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.109 g, 0.210 mmol) obtained in step 2 and ethanesulfonamide (0.114 g, 1.05 mmol), the title compound (0.061 g, 48%) was obtained.