Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[S:7][C:8]2[C:13]([NH:14][C@H:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:16][OH:17])=[N:12][C:11]([SH:22])=[N:10][C:9]=2[N:23]=1.[ClH:24]>O.CC#N>[Cl:24][C:6]1[S:7][C:8]2[C:13]([NH:14][C@H:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:16][OH:17])=[N:12][C:11]([S:22][S:22][C:11]3[N:12]=[C:13]([NH:14][C@@H:15]([CH2:16][OH:17])[CH2:18][CH:19]([CH3:20])[CH3:21])[C:8]4[S:7][C:6]([Cl:24])=[N:23][C:9]=4[N:10]=3)=[N:10][C:9]=2[N:23]=1
Reactant: Cl
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)C[C@H](CO)Nc1nc(SSc2nc(N[C@@H](CO)CC(C)C)c3sc(Cl)nc3n2)nc2nc(Cl)sc12
Temperature: 2.5 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
Sodium nitrite (5.19 g, 75 mmol) in water (25 mL) was added dropwise at 0° C. to (2R)-2-[[2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl]amino]-4-methylpentan-1-ol (7.50 g, 25 mmol) in conc. HCl (150 mL) and CH3CN (150 mL). The reaction mixture was stirred for 18 h at 0-5° C., and then poured onto ice (500 mL), and extracted with EtOAc. Any remaining solid was filtered off. The combined organic phases were washed sequentially with saturated NaCl solution and saturated aqueous NaHCO3 solution. The organic phase was dried and evaporated and the solid previously filtered off was added to this. The total solid was slurried in EtOAc, which after filtration provided the title compound (6.3 g, 80% yield) as a solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]([O:26]C)=[O:25])[CH:19]=[CH:20][CH:21]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:1][C:2]1[C:11]2[C:10]([CH3:12])([CH3:13])[CH2:9][CH2:8][C:7]([CH3:14])([CH3:15])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:20][CH:21]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)C=Cc1cccc(-c2ccc3c(c2O)C(C)(C)CCC3(C)C)c1
Reactant: BrCc1ccccc1
Product: CC1(C)CCC(C)(C)c2c1ccc(-c1cccc(C=CC(=O)O)c1)c2OCc1ccccc1
Yield: 91.1 %

Procedure:
In a manner similar to that of Example 1(a), by reaction of 500 mg (1.37 mmol) of methyl 3-[3-(1-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylate with 180 μl (1.5 mmol) of benzyl bromide, 550 mg (88%) of the expected compound were obtained in the form of a yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][P:23]([C:26]1[N:31]=[C:30]([O:32][CH3:33])[C:29]([NH2:34])=[CH:28][CH:27]=1)([CH3:25])=[O:24].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:34][C:29]2[C:30]([O:32][CH3:33])=[N:31][C:26]([P:23]([CH3:22])([CH3:25])=[O:24])=[CH:27][CH:28]=2)=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: COc1nc(P(C)(C)=O)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1nc(P(C)(C)=O)ccc1Nc1nnc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 6-(Dimethylphosphoryl)-2-methoxypyridin-3-ylamine (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]([NH:24]CC4C=CC(OC)=CC=4)=[CH:21][C:22]=3[CH3:23])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:24][C:20]1[N:19]=[CH:18][C:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=3)[CH2:10][CH2:11]2)=[O:16])=[C:22]([CH3:23])[CH:21]=1
Reactant: COc1ccc(CNc2cc(C)c(C(=O)N3CCN(c4ncc(C)cc4C)CC3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N)cc3C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (840 mg) described in Preparation Example 146 was added 4-methoxybenzylamine (2 mL), and the mixture was stirred at 160° C. for 2.5 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. To the obtained residue was added diethyl ether, and the insoluble material was collected by filtration to give [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl][6-(4-methoxybenzylamino)-4-methylpyridin-3-yl)methanone (790 mg). The obtained [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl][6-(4-methoxybenzylamino)-4-methylpyridin-3-yl)methanone (790 mg) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (13 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give (6-amino-4-methylpyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone. The obtained (6-amino-4-methylpyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone and triethylamine (0.75 mL) were dissolved in dichloromethane (10 mL), 3-chloropropane-1-sulfonyl chloride (0.49 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (7 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.32 mL) was added, and the mixture was stirred at room temperature for 4.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl][6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-methylpyridin-3-yl]methanone. The obtained [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl][6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-methylpyridin-3-yl]methanone was dissolved in dichloromethane, 1N hydrogen chloride/diethyl ether was added, and the precipitate was collected by filtration to give the title compound (385 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[CH:12]1(I)[CH2:16][CH2:15][CH2:14][CH2:13]1>CC#N.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH:8][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1cccc(CCN)c1
Reactant: IC1CCCC1
Solvent: CC#N
Solvent: ClCCl
Product: COc1cccc(CCNC2CCCC2)c1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
3-Methoxyphenethylamine (4.5 mL, 30 mmol), and cyclopentyl iodide (1.15 mL, 10 mmol) in CH3CN (15 mL) were irradiated for 10 min in a microwave at 110° C. After cooling to room temperature the mixture was diluted with CH2Cl2 and washed with NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude product was purified by silica gel chromatography using hexane as eluent and the product N-(3-methoxyphenethyl)cyclopentanamine (1.45 g, 66%) was obtained as a colorless liquid which solidified upon standing. 1H NMR (400 MHz, CDCl3): δ 8.48 (s, 1H), 7.20 (t, 1H, J=8.0 Hz), 6.79-6.73 (overlapping doublets and singlet, 3H), 3.74 (s, 3H), 3.44-3.39 (m, 1H), 3.38-3.11 (m, 4H), 1.84-1.83 (m, 2H), 1.82-1.81 (m, 4H), 1.66-1.56 (m, 2H). LC-MS (ESI) Calcd for: C14H21NO [M+H]+: 220.16. Found: 220.00.
Reaction SMILES: [F:1][CH2:2][C:3]([CH3:10])([CH3:9])[C:4](=[O:8])[C:5]([OH:7])=[O:6].I[CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:1][CH2:2][C:3]([CH3:10])([CH3:9])[C:4](=[O:8])[C:5]([O:7][CH2:12][CH3:13])=[O:6]
Reactant: CC(C)(CF)C(=O)C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)C(C)(C)CF
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
To a solution of 4-fluoro-3,3-dimethyl-2-oxobutanoic acid (2.3 g, 15.53 mmol) in DMF (30 mL) was added iodoethane (1.880 mL, 23.29 mmol) and K2CO3 (5.36 g, 38.8 mmol). The reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with EtOAc and stirred for 10 min. The solid was filtered. The filtration was partitioned between EtOAc and water. The organic phase was washed water, sat. NaCl, and concentrated. The residue was diluted with hexane (˜100 mL) and washed with water (2×30 mL), dried over MgSO4, filtered and concentrated to yield ethyl 4-fluoro-3,3-dimethyl-2-oxobutanoate (2.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[CH3:7].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:47][C:48]1[CH:53]=[CH:52][C:51]([N:54]2[C:62]3[CH2:61][CH2:60][CH:59]([C:63]([O:65][CH3:66])=[O:64])[NH:58][C:57]=3[CH:56]=[N:55]2)=[CH:50][CH:49]=1>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([N:58]2[CH:59]([C:63]([O:65][CH3:66])=[O:64])[CH2:60][CH2:61][C:62]3[N:54]([C:51]4[CH:50]=[CH:49][C:48]([F:47])=[CH:53][CH:52]=4)[N:55]=[CH:56][C:57]2=3)=[O:11])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: COC(=O)C1CCc2c(cnn2-c2ccc(F)cc2)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C1CCc2c(cnn2-c2ccc(F)cc2)N1C(=O)Cn1nc(C(F)(F)F)c(Cl)c1C
Temperature: 80 °C
Reaction time: 5 h
Yield: 11 %

Procedure:
To a solution of 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]acetic acid (20 mg, 0.073 mmol) in DMF (2 mL) was added Et3N (50 μL, 0.219 mmol), HATU (55 mg, 0.145 mmol) followed by methyl 1-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine-5-carboxylate (20 mg, 0.073 mmol) at room temperature. The resulting solution was then stirred at 80° C. for 5 h. The reaction mixture was then cooled to room temperature, H2O (10 mL) was added and the mixture was extracted with EtOAc (2×15 mL). The combined EtOAc layers were dried (MgSO4), filtered, concentrated in vacuo and the resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as white powder (0.004 g, 0.008 mmol, 7%). 1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), 7.52 (2H, dd, J=5, 9 Hz), 7.26 (2H, t, 8.6, J=17.2 Hz), 5.3 (2H, dd, J=17.2, 69.2 Hz), 3.83 (s, 3H), 2.80-2.82 (m, 2H), 2.29 (s, 3H), 2.15-2.17 (m, 2H); MS: (ES) m/z calculated for C21H18ClF4N5O3 [M+H]+ 500.1, found 500.1.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH:20]=O)[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>CO.O>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH:20]=[N:24][OH:25])[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1c(=O)c(C=O)c(OC)c2cc(C)ccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCn1c(=O)c(C=NO)c(OC)c2cc(C)ccc21

Procedure:
A solution of 1-hexyl-3-formyl-4-methoxy-6-methyl-2(1H)-quinolinone (Step (2) of Example 1, 1 g), hydroxylamine hydrochloride (0.3 g) and sodium acetate (0.3 g) in methanol (20 ml) was stirred for 3hrs. The mixture was then diluted with water and extracted with methylene chloride. The extracts were dried, evaporated and the resulting solid was crystallized from ether-hexane to give 1-hexyl-3-oximinomethyl-4-methoxy-6-methyl-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS: m/e 316 (M.+); NMR (CDCl3): δ3.98 (s, 3H, OCH3), 8.54 (s, 1H, CH=N).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9](OC3C=CC=CC=3)[C:8]=2[N:22]=1)[CH3:2].C([O-])(=O)C.[NH4+:39]>C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:39])[C:8]=2[N:22]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCOCCCc1cccnc1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCOCCCc1cccnc1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
Under a nitrogen atmosphere, 2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]pyridine (4.6 g) from Part A and ammonium acetate (46 g) were heated in a sealed tube to 150° C. After 65 hours, NMR analysis indicated that the reaction was complete. The reaction mixture was cooled to ambient temperature, dissolved in ethyl acetate, and washed 3 times with 1N potassium hydroxide and once with water. The organic layers were dried with magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in 10% hydrochloric acid and washed 3 times with dichloromethane (DCM). Potassium hydroxide was added to the aqueous layer to bring the pH to 14, and this was subsequently washed 4 times with DCM. The combined organic layers were washed twice with water, twice with brine, dried with magnesium sulfate, and concentrated under reduced pressure. The oil was purified by column chromatography over silica using 98/2 DCM/methanol as the eluant. The oil was then triturated with ethyl acetate/hexane and the resulting solid was recrystallized from ethyl acetate/hexane to yield 2-(ethoxymethyl)-6,7-dimethyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]pyridin-4-amine as a white solid, m.p. 78.0–78.5° C.
Reaction SMILES: [C:1]([Si:5]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[CH:28][CH:27]=4)=[CH:21][C:20]=3[Cl:35])[C:14]2=[O:36])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[F:62][C:63]([F:71])([F:70])[CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)(=O)C>[C:1]([Si:5]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[O:6][CH:7]1[CH2:8][CH2:9][CH:10]([CH:13]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[C:20]([Cl:35])=[CH:21][C:22]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([N:67]5[CH2:68][CH2:69][CH:64]([C:63]([F:71])([F:70])[F:62])[CH2:65][CH2:66]5)=[O:34])=[CH:28][CH:27]=4)=[CH:23][C:24]=3[Cl:25])[C:14]2=[O:36])[CH2:11][CH2:12]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: FC(F)(F)C1CCNCC1
Reactant: CC(C)(C)[Si](OC1CCC(C2CCN(Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC1CCC(C2CCN(Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50.2 %

Procedure:
Treat a solution of 4′-{3-[4-(tert-Butyl-diphenyl-silanyloxy)-cyclohexyl]-2-oxo-pyrrolidin-1-ylmethyl}-3′,5′-dichloro-biphenyl-4-carboxylic acid (0.35 g, 0.5 mmol) in CH2Cl2 (20 mL) with 1,1′-carbonyldiimidazole (0.162 g, 1.0 mmol) and stir for 45 minutes at room temperature. Treat the reaction with 4-trifluoromethylpiperidine hydrochloride (0.142 g, 0.75 mmol) and diisopropylethylamine (0.097 g, 0.75 mmol), and stir for 12 hours at room temperature. Load the mixture on silica gel column and flash with 25% to 50% ethyl acetate in hexanes to afford 0.21 g (50%) of the title compound. MS (m/z): 835 (M+).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][C:7]#[N:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:1][CH2:2][C:3]1([CH2:6][C:7]#[N:8])[CH2:5][CH2:4]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: N#CCC1(CO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(CC#N)CC1
Temperature: -10 °C

Procedure:
To a solution of [1-(hydroxymethyl)cyclopropyl]acetonitrile (prepared according to the procedure described in WO2005/105749 Example 2/Step 4, incorporated by reference) (1 eq.) in DCM at −40° C. was added triethylamine (3 eq.) and then methanesulfonyl chloride (1.5 eq.). The reaction was warmed to −10° C. over 1 h, and it was diluted with DCM and quenched with saturated aqueous NaHCO3. The aqueous phase was extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 0%→50% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].C([Li])CCC.[C:17]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1.[OH-].[Na+]>[OH:22][C:17]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[CH3:11])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: O=C1CCCC1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1C1(O)CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
4-Bromo-3-methyl-benzoic acid (4.00 g, 18.6 mmol) was dissolved in tetrahydrofuran (80 mL) and the solution was cooled to −78° C. n-Butyllithium (16.4 mL of 2.5 M in hexanes, 40.9 mmol) was added dropwise over 20 min while maintaining the internal temperature below −65° C. resulting in a thin, light yellow slurry. The reaction mixture was allowed to stir for 30 min at −78° C. Cyclopentanone (1.57 g, 1.65 mL, 18.6 mmol) was then added in a dropwise manner. The mixture was stirred at −78° C. for 30 min, warmed to room temperature and stirred for 2 h. The reaction mixture was then diluted with 1 M NaOH (100 mL) and washed with diethyl ether. The organic layer was discarded and the aqueous layer was acidified with 4 M HCl to <pH 3. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined extracts were dried over Na2SO4 and concentrated in vacuo. The crude product was filtered through silica gel eluting with 0-10% methanol/dichloromethane, and all product containing fraction concentrated in vacuo. The resulting solid was slurried in dichloromethane and filtered to provide 4-(1-hydroxycyclopentyl)-3-methylbenzoic acid (1.10 g, 26%) as a white solid. ESI-MS m/z calc. 220.10994. found 221.5 (M+1)+; Retention time: 1.16 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 7.70 (d, J=1.4 Hz, 1H), 7.67 (dd, J=8.1, 1.7 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 4.77 (s, 1H), 2.54 (s, 3H), 2.07-1.98 (m, 2H), 1.98-1.89 (m, 2H), 1.87-1.77 (m, 2H), 1.72-1.59 (m, 2H).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:14]2[S:15][CH:16]([CH3:18])[CH2:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[Si:25]([CH3:28])([CH3:27])[CH3:26].Cl>O1CCCC1.CCCCCC>[C:1]([NH:5][S:6]([C:9]1[C:14]2[S:15][CH:16]([CH3:18])[CH2:17][C:13]=2[CH:12]=[CH:11][C:10]=1[Si:25]([CH3:28])([CH3:27])[CH3:26])(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1Cc2cccc(S(=O)(=O)NC(C)(C)C)c2S1
Reactant: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1Cc2ccc([Si](C)(C)C)c(S(=O)(=O)NC(C)(C)C)c2S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.0 g of N-t-butyl-2,3-dihydro-2-methylbenzo[b]thiophene-7-sulfonamide in 175 ml of dry tetrahydrofuran was added 20 ml of a 1.6M hexane solution of n-butyl lithium at -40° C. to -30° C. under an inert atmosphere. The mixture was allowed to warm and was stirred at room temperature for 30 minutes. It was recooled to -30° C. and was contacted with 3.0 ml of chlorotrimethylsilane. The mixture was stirred at room temperature for 2 hours and was acidified with 10 ml of 6N hydrochloric acid. The organic layer was separated, was dried over magnesium sulfate, and was concentrated to a crude solid which was suspended in chlorobutane/hexane and filtered to give 2.0 g of the title compound as a beige solid, m.p. 119°-124° C.
Reaction SMILES: [F:1][C:2]1[C:10]([CH2:11][S:12][CH3:13])=[C:9]2[C:5]([C:6]([CH:14]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH2:15][C:16](OCC)=[O:17])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.ClC1C=CC(C(C2C3C(=C(CSC)C(F)=CC=3)NC=2)CCO)=CC=1>>[F:1][C:2]1[C:10]([CH2:11][S:12][CH3:13])=[C:9]2[C:5]([C:6]([CH:14]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=3)[CH2:15][CH2:16][OH:17])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(c1ccc(C(F)(F)F)cc1)c1c[nH]c2c(CSC)c(F)ccc12
Agent: CSCc1c(F)ccc2c(C(CCO)c3ccc(Cl)cc3)c[nH]c12
Product: CSCc1c(F)ccc2c(C(CCO)c3ccc(C(F)(F)F)cc3)c[nH]c12

Procedure:
The title compound was prepared starting from 2.98 g (6.78 mmol) of the compound from Example 48A in analogy to the synthesis of the compound from Example 16. 2.47 g (92% of theory) of the title compound were obtained.
Reaction SMILES: [CH:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:20])C(=O)C1.O>CN(C=O)C>[Br:20][C:11]1[CH:12]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: Nc1ccc(C2CCCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(C2CCCC2)cc1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
4-Cyclopentylaniline (210 mg, 1.30 mmol) was dissolved in cold (0° C.) DMF (8 mL) and treated with NBS (232 mg, 1.30 mmol). The reaction was stirred at 0° C. for 5 min and then warmed to room temperature for 1 h. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (0-50% ethyl acetate/hexanes) yielded 2-bromo-4-cyclopentylaniline (251 mg, 80% yield). LC/MS m/z 242.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH2:22][F:21])=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ccc(OCF)cn1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(OCF)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-fluoromethoxy-pyridine-2-carboxylic acid (CAS1174321-03-9, WO2009091016) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=441.3 [M+H]+.