Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])=[CH:4][N:3]=1.[Si:15]([O:22][C@H:23]1[CH2:28][CH2:27][C@@H:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][C@@H:24]1[F:34])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1>[Si:15]([O:22][C@H:23]1[CH2:28][CH2:27][C:26]([C:2]2[CH:7]=[N:6][C:5]([N:8]3[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]3[CH3:14])=[CH:4][N:3]=2)([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][C@@H:24]1[F:34])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CCOC(=O)[C@@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](F)C1
Reactant: Cc1ccc(C)n1-c1cnc(Br)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2cnc(-n3c(C)ccc3C)cn2)CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](F)C1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 150.6 %

Procedure:
To a 1 L flask was added 2-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyrazine (23 g, 67 mmol), (1R,3S,4S)-ethyl 4-((tert-butyldimethylsilyl)oxy)-3-fluorocyclohexanecarboxylate (28 g, 83 mmol), {[P(t-Bu)3]PdBr}2 (800 mg, 1 mmol) followed by toluene (250 mL). The reaction mixture was degassed three times by purging with nitrogen and then cooled to −35±5° C. To the reaction mixture was added NaHMDS (47 mL, 2 M in THF, 94 mmol), dropwise. The temperature was raised to room temeperature over a one hour period and stirred for a further 30 minutes. The reaction mixture was quenched with 8% aqueous ammonium chloride (200 mL), the phases separated, and the aqueous layer extracted with heptane (300 mL). The combined organic layer was washed with 10% brine (400 mL), concentrated under reduced pressure(45±5° C., 50˜100 mbar) to give 48 g of (1RS,3S,4S)-ethyl 4-((tert-butyldimethylsilyl)oxy)-1-(5-(2,5-dimethyl-1H-pyrrol-1-yl)pyrazin-2-yl)-3-fluorocyclohexanecarboxylate as a mixture of 1R and 1S diastereomers. This material was used for next step without further purification. HPLC retention time=8.274 min HPLC method d: Instrument: Agilent Technologies 1200 series. Column: Waters Xbridge C18, 150*3.0 mm, 3 um. Column temperature: 35° C. Flow rate: 0.70 mL/min. Detection: 210 nm/DAD. Mobile phase composition: A: 0.1% H3PO4 in water; B: acetonitrile. Gradient: 0 min: 90% A, 10% B; 5 min: 100% B; 11 min 100% B. LC-MS method: [M+H]+=476.2706, 1H NMR (400 MHz, DMSO-d6): 8.47 (s. 1H), 8.43 (s, 1H), 5.85 (s, 2H), 4.39˜4.52 (m, 1H), 4.14 (dd, J=12 Hz, J=8 Hz, 2H), 3.59˜3.66 (m, 1H), 2.28˜2.94 (m, 1H), 2.06 (s, 6H), 1.84˜1.97 (m, 3H), 1.46˜1.52 (m, 3H), 1.14˜1.17 (t, J=12 Hz, J=8 Hz, 2H), 0.81 (s, 9H), 0.01 (d, J=4 Hz, 6H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([C:16](=[O:22])[C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)[C:12]([Cl:15])=[C:13]([Cl:14])[C:7]=2[O:6]1)=O.COCCO[AlH2-]OCCOC.[Na+]>O1CCCC1>[Cl:15][C:12]1[C:11]([C:16](=[O:22])[C:17]2[S:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][C:8]2[CH2:9][CH:5]([CH:3]=[O:2])[O:6][C:7]=2[C:13]=1[Cl:14]
Reactant: COC(=O)C1Cc2cc(C(=O)c3cccs3)c(Cl)c(Cl)c2O1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CC1Cc2cc(C(=O)c3cccs3)c(Cl)c(Cl)c2O1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (±)methyl-6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylate (3.57 g., 0.01 mole) in tetrahydrofuran (50 ml.) at -70° C. is added a solution of "Red-Al" (1.5 g., 0.0107 mole) in tetrahydrofuran (10 ml.) over a ten minute period. The reaction solution is stirred one hour at -70° C. and then quenched with 20% sulfuric acid (10 ml.). The water layer is separated and extracted twice with tetrahydrofuran (10 ml.). The organic layers are combined, washed with brine (two 5 ml. portions), dried over magnesium sulfate and the tetrahydrofuran distilled at reduced pressure. The residue is dissolved in n-butyl chloride (50 ml.) and added to a solution of sodium bisulfite (6 g.) in warm water (10 ml.). The mixture is stirred overnight before the solid bisulfite addition product is added to a saturation sodium bicarbonate solution (25 ml.) and stirred for two hours at room temperature. The mixture is extracted with ether (2×50 ml.). The ether extracts are washed with brine (2×25 ml.), dried over MgSO4 and evaporated in vacuo to give the (±)-6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxaldehyde which melts at 162°-4° C.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]2[C:5]([C:6]([F:21])([F:20])[CH2:7][CH2:8][C@@:9]32[C:14]([F:16])([F:15])[CH2:13][O:12][C:11]([NH2:17])=[N:10]3)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[N:27][CH:28]=1>>[F:20][C:6]1([F:21])[C:5]2[C:18](=[CH:19][C:2]([C:25]3[CH:26]=[N:27][CH:28]=[C:23]([F:22])[CH:24]=3)=[CH:3][CH:4]=2)[C@@:9]2([C:14]([F:16])([F:15])[CH2:13][O:12][C:11]([NH2:17])=[N:10]2)[CH2:8][CH2:7]1
Reactant: NC1=N[C@@]2(CCC(F)(F)c3ccc(Br)cc32)C(F)(F)CO1
Reactant: OB(O)c1cncc(F)c1
Product: NC1=N[C@@]2(CCC(F)(F)c3ccc(-c4cncc(F)c4)cc32)C(F)(F)CO1
Yield: 32 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-7-bromo-4,4,5′,5′-tetrafluoro-3,4,5′,6′-tetrahydro-2H-spiro[naphthalene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.4) with 5-fluoropyridin-3-ylboronic acid yielded the title compound (32% yield) as a pale yellow solid. MS (ISP): m/z=384.0 [M+H]+.
Reaction SMILES: C(OC([CH:7]([NH2:17])[C@@H:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=O)(C)C.Cl.O.CN>C1(C)C=CC=CC=1>[NH2:17][CH2:7][C@@H:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][C:10]([OH:12])=[O:11]
Reactant: CC(C)C[C@@H](CC(=O)O)C(N)C(=O)OC(C)C
Agent: CN
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 90 °C
Reaction time: 0.21 h
Yield: 88 %

Procedure:
A 500 ml three-necked round-bottom flask, under nitrogen atmosphere, is added with (S)-3-(isopropoxycarbonyl-amino-methyl)-5-methyl-hexanoic acid salt of (S)-(−)-phenyl-ethyl-amine (70.0 g, 0.190 moles), 35% hydrochloric acid (29.7 g, 0.285 moles), water (200 ml) and toluene (100 ml) and the mixture is vigorously stirred for 10-15 minutes. The phases are separated and the aqueous phase is extracted with toluene (2×100 ml). The collected organic phases are concentrated to small volume to obtain an oil which is added with 30% hydrochloric acid (57.8 g, 0.475 moles). The mixture is heated at 90° C. for 24-48 h. At end-reaction 41% aqueous monomethylamine (26.7 ml) is added till pH of about 6 and left to cool to room temperature. The mixture is cooled to 0-5° C. for at least 1 h and then the solid is filtered off and washed with a 1:1 water/isopropanol mixture cooled to 0-5° C. (3×15 ml). The solid is dried in oven at 50-60° C. for 16-18 h. 26.6 g of a white solid are obtained having an enantiomer ratio 99.94:0.06, with a yield of 88%. The XRPD spectrum of the so obtained product has the most intense peaks at 9.4; 12.2; 14.4; 16.6; 18.2; 19.0; 19.7; 20.1; 22.1; 22.6; 23.1; 23.4; 24.6; 26.8; 27.5; 27.9; 29.8±2θ, as illustrated in FIG. 1. The product has a mean particle size D50 of about 50 micrometers.
Reaction SMILES: [ClH:1].CO[C:4](=[NH:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1.N([C:24]1[C:37]([NH:38]C2C=CC=CC=2)=[CH:36][CH:35]=[CH:34][C:25]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27])C1C=CC=CC=1>CO.C(OCC)C>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[O:12][CH3:13])[CH2:5][C:4]1[NH:16][C:36]2[CH:35]=[CH:34][C:25]([C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:24][C:37]=2[N:38]=1.[ClH:1]
Reactant: COC(=N)Cc1ccc(OC)c(OC)c1
Reactant: O=C(c1ccccc1)c1cccc(Nc2ccccc2)c1Nc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(Cc2nc3cc(C(=O)c4ccccc4)ccc3[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of methyl-(3,4dimethoxyphenyl)-acetimidate hydrochloride (2.5 g; 10 mmol) and 2,3-diamiinobenzophenone (2.1 g; 10 mmol) in methanol (70 mL) was stirred at ambient temperature for 72 hours. The reaction mixture was concentrated to dryness, and H2O was added. The solid (2.3 g) was subjected to flash chromatography on silica gel (CH2Cl2/MeOH; 9:1) to afford a gummy material. This was dissolved in diethyl ether, and Ether-HCl was added to obtain the title compound as a buff solid, hydrochloride, penta-hydrate (250 mg), m.p. 172-175° C. Anal. Calcd. for C23H20N2O3HCl.5H2O: C, 66.97; H, 5.23; N, 6.79. Found: C, 67.11, H, 4.84; N, 6.77. Mass Spectrum: (EI; M+) m/z 372. 1H-NMR (D)MSO-d6; 400 MHz) δ8.0 (s, 1H) 7.84-7.9 (m, 2H), 7.68-7.77 (m, 3H), 7.55-7.61 (m, 2H), 7.2 (s, 1H), 6.93-7.01 (m, 2H), 4.42 (s, 2H), 3.79 (s, 3H), 3.77 ppm (s, 3H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([CH3:16])([CH3:15])[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[CH3:17]>C(O)(=O)C.O.[Zn]>[CH3:16][C:7]([C:5]1[S:6][CH:2]=[C:3]([CH3:17])[CH:4]=1)([CH3:15])[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cc(C(C)(C)C(=O)N2CCCC2)sc1Br
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1csc(C(C)(C)C(=O)N2CCCC2)c1

Procedure:
To a solution of the 1-[2-(5-bromo-4-methyl-2-thienyl)-2-methylpropanoyl]pyrrolidine in acetic acid (8 ml) and water (5 ml) was added zinc dust (1.1 g, 15 mmol). The mixture was heated under reflux for 24 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate and then washed sequentially with 1N hydrochloric acid, 1N sodium hydroxide and a saturated brine solution. The ethyl acetate solution was dried over magnesium sulfate and then evaporated. The residue was purified by flash chromatography on silica eluting with a 20–75% mixture of ethyl acetate in iso-hexane to afford 1-[2-methyl-2-(4-methyl-2-thienyl)propanoyl]pyrrolidine (0.151 g) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[S:11][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:8][C:7]1[C:6]([O:9][CH3:10])=[CH:5][C:4]2[C:13](=[O:15])[CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:11][C:3]=2[C:2]=1[Cl:1]
Reactant: COc1ccc(SC(C(=O)O)c2ccccc2)c(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: S=C=S
Product: COc1cc2c(c(Cl)c1Cl)SC(c1ccccc1)C2=O
Temperature: 0 °C

Procedure:
A solution of 1.17 g of α-(2,3-dichloro-4-methoxyphenylthio)-α-phenylacetic acid in 25 ml of carbon disulfide is refluxed with 0.5 g of thionyl chloride until the solution becomes clear. The solution is cooled to 5° and to it is added, in small portions, 340 mg of aluminum chloride. The mixture is stirred at reflux for 3 additional hours. Ice-water (20 g) is added to quench the reaction mixture and the product is extracted into dichloromethane. The dichloromethane extract is washed with sodium bicarbonate solution, water, dried and concentrated to give a syrup. The oily residue is triturated with 2 ml of acetone and allowed to stand at room temperature. Crystals slowly deposit and are collected after 2 days. Recrystallization from chloroform gives 6,7-dichloro-5-methoxy-2-phenylbenzo[b]thiophen-3(2H)-one as a yellowish solid, mp 228°-229° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[CH:20]=[C:21]([NH:26][S:27]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=2[F:25])[CH:5]=[CH:4][N:3]=1.[NH4+:38].[OH-]>>[NH2:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[CH:20]=[C:21]([NH:26][S:27]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=2[F:25])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cc(NS(=O)(=O)c3c(F)cccc3F)ccc2F)n1
Temperature: 120 °C

Procedure:
Following a procedure analogous to the procedure described in Example 21 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-4-fluorophenyl}-2,6-difluorobenzenesulfonamide (150 mg, 0.264 mmol) and NH4OH (3 mL) heated at 120° C. in a microwave reactor for 15 min, the title compound was obtained as a yellow solid (67 mg, 0.122 mmol, 46.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.99 (s, 1H), 7.78 (d, J=5.3 Hz, 1H), 7.59-7.75 (m, 1H), 7.18-7.30 (m, 4H), 7.15 (d, J=5.8 Hz, 1H), 6.57 (s, 2H), 5.59 (d, J=5.2 Hz, 1H), 3.64-3.77 (m, 4H), 3.40-3.47 (m, 4H). m/z (ES+): 549 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][OH:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:29]([N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH2:27][OH:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCCc1nc(CO)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(CO)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 49 %

Procedure:
A solution of 4′-{[4-butyl-2-(hydroxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.4 g), benzyl bromide (0.49 mL) and cesium carbonate (1.3 g) in N,N-dimethylacetamide (14 mL) was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.86 g, 49%) as a colorless liquid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[N:2].[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1)#[N:11].O>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C:10]#[N:11])=[CH:13][CH:14]=2)=[O:20])[CH:7]=[CH:8][CH:9]=1)#[N:2]
Reactant: N#Cc1cccc(N)c1
Reactant: N#Cc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1ccc(NC(=O)Nc2cccc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 103.8 %

Procedure:
m-Cyanoaniline (0.5 g, 3.38 mmol) and p-cyanophenylisocyanate (0.49 g, 3.38 mmol) were dissolved in dimethylformaide (8 ml) and triethylamine (1 ml). The reaction was stirred at ambient temperature under a nitrogen atmosphere for 24 h. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with water (3×), brine, dried (MgSO4) and concentrated to give a amorphous solid. This was triturated to a crystalline white solid with ethyl ether. This solid was filtered and washed with ether to give N-(3-cyanophenyl)-N'-(4-cyanophenyl)urea as a white powder (0.92 g, mp 183-5° C.); LRMS (M+H)+ m/z 280, (M+NH4)+ m/z 297; 1H NMR (DMSO-d6): 9.32(s, 1H), 9.21(s, 1H), 7.97(s, 1H), 7.75-7.6(m, 5H), 7.55-7.4(m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][C@@H:29]1[CH2:33][S:32](=[O:35])(=[O:34])[NH:31][CH2:30]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:31]3[CH2:30][C@H:29]([CH3:28])[CH2:33][S:32]3(=[O:35])=[O:34])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 27.2 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (534 mg) described in Preparation Example 110 and (S)-4-methylisothiazolidine 1,1-dioxide (320 mg) described in Preparation Example 4 and by the reaction and treatment in the same manner as in Example 4, the title compound (163 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([N:25]5[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]5)=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:39])[O:4][N:3]=1.Cl>O1CCOCC1>[N:25]1([C:23]2[N:12]3[C@@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:14][O:15][C:16]4=[C:11]3[C:10](=[CH:9][CH:8]=[C:7]4[C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:39])[N:24]=2)[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: Cc1noc(C)c1-c1ccc2nc(N3CCCN(C(=O)OC(C)(C)C)CC3)n3c2c1OC[C@@H]3c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2nc(N3CCCNCC3)n3c2c1OC[C@@H]3c1ccccn1
Yield: 66.2 %

Procedure:
tert-Butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-1,4-diazepane-1-carboxylate (53 mg, 0.10 mmol) was treated with a solution of 4.0 M hydrogen chloride in 1,4-dioxane (2.0 mL) for 10 min. The mixture was concentrated and purified by preparative LCMS using pH 10 buffer to give the title compound (28.5 mg, 66%). LCMS calc. for C24H27N6O2 (M+H)+: m/z=431.2. found: 431.3.
Reaction SMILES: C([Mg]Cl)(C)C.[Li+].[Cl-].[S:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[CH:13]([CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14]>C1COCC1>[OH:14][CH:13]([C:9]1[S:8][CH:12]=[CH:11][N:10]=1)[CH:15]1[CH2:16][CH2:17][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20]1
Reactant: c1cscn1
Reactant: CCOC(=O)C1CCC(C=O)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(C(O)c2nccs2)CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a 500 mL round bottom flask was added iPrMgCl-LiCl (1.3 M in THF, 99 mL, 129 mmol) and the solution cooled in an ice bath. Thiazole (9.7 mL, 135 mmol) was then introduced at such a rate that the internal temperature did not exceed 5° C. and then the thick slurry was stirred for 1 h. 100 mL of THF was introduced and the reaction mixture cooled to −50° C. at which point ethyl 4-formylcyclohexanecarboxylate (23 g) was added as a solution in THF (100 mL) via cannula. When complete the reaction mixture was permitted to warm slowly to 5° C. where it was stirred for 30 min then quenched by the addition of water and EtOAc. The layers were separated, the organic mixture dried with MgSO4, filtered and concentrated in vacuo to afford ethyl 4-[hydroxy(1,3-thiazol-2-yl)methyl]cyclohexanecarboxylate as a 3:2 mixture of trans:cis isomers both of which are racemic mixtures. This brown oil was used directly in the subsequent step without further manipulation.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[C:19]([CH3:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=4[CH3:24])=[N:15][C:14]=3[C:27](O)=[O:28])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:30]([O:37][C:38](=[O:47])[C:39]1[CH:44]=[C:43]([NH2:45])[CH:42]=[CH:41][C:40]=1[CH3:46])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38](=[O:47])[C:39]1[CH:44]=[C:43]([NH:45][C:27]([C:14]2[N:15]=[C:16]([C:18]3[C:19]([CH3:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:2][CH:3]4[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]4)[CH2:8]2)[CH2:10]3)=[O:28])[CH:42]=[CH:41][C:40]=1[CH3:46])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cc(C)c(-c2nc(C(=O)O)c(CCC34CC5CC(CC(C5)C3)C4)[nH]2)c(C)n1
Reactant: Cc1ccc(N)cc1C(=O)OCc1ccccc1
Product: Cc1cc(C)c(-c2nc(C(=O)Nc3ccc(C)c(C(=O)OCc4ccccc4)c3)c(CCC34CC5CC(CC(C5)C3)C4)[nH]2)c(C)n1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-(2,4,6-trimethyl-pyridine-3-yl)-1H-imidazole-4-carboxylic acid (Example 182) was reacted with 5-amino-2-methyl-benzoic acid benzyl ester according to the procedure of Example 20, step d to afford 5-{[5-(2-adamantan-1-yl-ethyl)-2-(2,4,6-trimethyl-pyridine-3-yl)-1H-imidazole-4-carbonyl]-amino }-2-methyl-benzoic acid benzyl ester. The benzyl group was removed following the procedure of Example 1, step e, to afford the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) 12.40 (1H, br s), 9.69 (1H, s), 8.30 (1H, d), 7.76 (1H, d), 7.17 (1H, d), 7.05 (1H, s), 2.99 (2H, m), 2.44 (3H, s), 2.43 (3H, s), 2.25 (3H, s), 2.09 (3H, s), 1.92 (3H, br s), 1.64 (6H, m), 1.51 (6H, br s), 1.42 (2H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 54.92; H, 8.21; N, 8.30%. C39H55N5O8.7.0 mols H2O requires: C, 55.24; H, 8.20; N, 8.26%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11]([C:14]1[N:15]=[C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][N:27]3[C:31]([CH3:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[N:28]3)[CH2:21][CH2:20]2)[S:17][CH:18]=1)=[N:12][OH:13].[C:38](Cl)(=[O:40])[CH3:39].C(N(CC)CC)C.Cl>ClCCl>[C:38]([O:13][N:12]=[C:11]([C:14]1[N:15]=[C:16]([CH:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:37])[CH2:26][N:27]3[C:31]([CH3:32])=[CH:30][C:29]([C:33]([F:35])([F:36])[F:34])=[N:28]3)[CH2:23][CH2:24]2)[S:17][CH:18]=1)[CH:10]=[CH:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(C=Cc3c(F)cccc3F)=NO)cs2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)ON=C(C=Cc1c(F)cccc1F)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1

Procedure:
A solution of 3-(2,6-difluorophenyl)-1-[2-[1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolyl]-2-propen-1-one 1-oxime (i.e. the product of Example 2, Step B) (0.10 g, 0.189 mmol), acetyl chloride (0.017 g, 0.22 mmol) and triethylamine (0.022 g, 0.22 mmol) in dichloromethane (5 mL) was stirred for 2 hr and shaken with 1 mL of 1 N hydrochloric acid. The mixture was poured onto a Celite® extraction tube, eluted with dichloromethane and concentrated to give 0.11 g of crude material which was purified via silica gel chromatography (hexanes-ethyl acetate gradient) to provide 0.11 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]([NH:8][CH:9]([CH3:11])[CH3:10])=[N:4][CH:5]=[CH:6][N:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:9]([NH:8][C:3]1[C:2]([NH:12][C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)=[N:7][CH:6]=[CH:5][N:4]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Nc1nccnc1Cl
Reactant: Cc1cccc(N)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2nccnc2NC(C)C)c1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
3-chloro-N-isopropylpyrazin-2-amine (6 g, 35.0 mmol), m-toluidine (5.62 g, 52.4 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.435 g, 0.699 mmol), Pd2(dba)3 (0.320 g, 0.350 mmol), and sodium t-butoxide (5.04 g, 52.4 mmol) were mixed in 200 mL of toluene and degassed for 20 minutes. The mixture was heated to reflux for 5 h. The reaction was cooled to room temperature and water was added. The reaction mixture was extracted with dichloromethane and washed with water. The crude was columned with 10% ethyl acetate and dichloromethane to give N2-isopropyl-N3-(m-tolyl)pyrazine-2,3-diamine (7.4 g, 87%).