Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1[N:3]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C@H:12]([CH3:27])[CH2:11]3)C(C)=CC=1.C(N(CC)CC)C.Cl.NO>O.C(O)C>[NH2:3][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:12]([CH3:27])[CH2:11]2
Reactant: Cc1ccc(C)n1-c1ccc2c(c1)C[C@@H](C)N2C(=O)OCc1ccccc1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H]1Cc2cc(N)ccc2N1C(=O)OCc1ccccc1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
To a stirred solution of phenylmethyl (2R)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-2,3-dihydro-2-methyl-1H-indole-1-carboxylate (Step 3, 2.11 g, 5.84 mmol) in water/ethanol (1:9, 60 mL) is added triethylamine (6.5 mL, 46.7 mmol) and hydroxylamine hydrochloride (6.49 g, 93.4 mmol). The reaction mixture is stirred at 90° C. for 20 h and is then concentrated under reduced pressure. The residue is taken up in CH2Cl2 (60 mL) and washed with H2O (2×20 mL) and saline (2×20 mL), and the combined aqueous layer is extracted with CH2Cl2 (2×20 mL). The combined organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is purified by chromatography on a Biotage Flash 40M 90 g silica gel cartridge (30-50% EtOAc/Hexanes eluent) to give the title compound, MS (ESI+) for C17H18N2O2 m/z 283 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:15]([OH:21])([CH3:20])[CH2:16][C:17](=[NH:19])[NH2:18].C(=O)(O)[O-].[K+].Br[CH2:28][C:29](=O)[C:30]([CH3:33])([CH3:32])[CH3:31]>O1CCCC1.O>[C:30]([C:29]1[N:19]=[C:17]([CH2:16][C:15]([C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=3)=[CH:7][C:2]=2[F:1])([OH:21])[CH3:20])[NH:18][CH:28]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(O)(CC(=N)N)c1ccc(-c2ccc(F)cn2)cc1F
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1c[nH]c(CC(C)(O)c2ccc(-c3ccc(F)cn3)cc2F)n1

Procedure:
A solution of the di(trifluoroacetate) salt of (±)-3-[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]-3-hydroxybutanimidamide (50 mg, 0.10 mmol), potassium bicarbonate (19 mg, 0.19 mmol) and 1-bromo-3,3-dimethylbutan-2-one (52 mg, 0.29 mmol) in tetrahydrofuran (1 mL) and water (0.25 mL) were stirred at ambient temperature overnight. Volatiles were removed in vacuo and the residue was purified by HPLC (Gilson; KR100-5C18 100×21.2 mm column; 10-100% MeCN/H2O) over 12 min to afford the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.51 (d, J=2.8 Hz, 1H), 7.90 (dd, J=4.3, 8.8 Hz, 1H), 7.76-7.58 (m, 4H), 6.99 (s, 1H), 3.45 (AB, J=14.9 Hz, 2H), 3.30 (bs, 1H), 1.732 (s, 3H), 1.23 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([O:4][C:5]([N:7]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:16]=[CH:17][C:18]([C:20]([O:22]C)=[O:21])=[CH:19][C:11]=3[O:10][C:9]=2[CH2:8]1)=[O:6])[CH3:3].C1COCC1.CO.[Li+].[OH-]>O>[CH3:3][C:2]([CH3:24])([O:4][C:5]([N:7]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:16]=[CH:17][C:18]([C:20]([OH:22])=[O:21])=[CH:19][C:11]=3[O:10][C:9]=2[CH2:8]1)=[O:6])[CH3:1]
Reactant: COC(=O)c1ccc2c3c(oc2c1)CN(C(=O)OC(C)(C)C)CC3
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(oc3cc(C(=O)O)ccc23)C1
Temperature: 30 °C

Procedure:
A solution of 11-11 (0.79 g, 2.38 mmol) in 1:1 THF/MeOH (30 mL) was treated with LiOH (0.95 g, 23.8 mmol) in 10 mL of H2O and heated to 30° C. overnight. The solvents were removed under vacuum and the residue was dissolved in H2O and acidified with 10% KHSO4 and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and evaporated to give 11-12 as an off-white solid.
Reaction SMILES: C(C1CN([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([O:33][CH3:34])=[O:32])[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)N(C2C=CC=CC=2)C=1)=O.[CH2:42]([P:51](=[O:58])([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])P(=O)(OCC)OCC.[CH3:59][N:60]([CH3:63])C=O.[H-].[Na+]>O>[CH2:56]([O:55][P:51](/[CH:42]=[CH:27]\[C:26]1[C:22]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([O:33][CH3:34])=[O:32])[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:23][N:60]([C:63]2[CH:38]=[CH:39][CH:16]=[CH:17][CH:18]=2)[CH:59]=1)([O:52][CH2:53][CH3:54])=[O:58])[CH3:57]
Reactant: COC(=O)c1cccc(-c2nc(COc3ccc(CON4CC(C=O)=CN4c4ccccc4)cc3OC)c(C)o2)c1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOP(=O)(/C=C\c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C(=O)OC)c3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 4.4 %

Procedure:
To a mixture of methyl 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol2-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (33.0 g), tetraethyl methylenediphosphonate (18.91 g) and N,N-dimethylformamide (300 mL) was added sodium hydride (60% in oil, 2.86 g) at 0° C., and the mixture was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 3-[4-({4-[({4-[(Z)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate as colorless crystals (1.82 g, yield 4.4%) from a fraction eluted with acetone-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 112-113° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F>CS(C)=O.O>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(-n2cccn2)c(F)c1
Temperature: 90 °C
Yield: 87.1 %

Procedure:
A solution of 2.0 g(29.37 mmol) of pyrazol and 8.12 g(58.75 mmol) of potassium carbonate in 70 mL of DMSO was treated with 4.67 g(3.25 mL, 29.37 mmol) of 3, 4-difluoronitrobenzene followed by warming at 90° C. for 18 h. The solution was cooled and diluted with 100 mL water and was extracted with ethyl acetate (2×100 mL). The organic layers were extracted with water (5×100 mL) and with saturated NaCl solution (75 mL). Drying (Na2SO4) and concentration in vacuo afforded an off-white solid which was recrystallized from hot hexanes to afford 5.3 g(87%) of the title pyrazol derivative as an off- white solid, mp 128-129° C.
Reaction SMILES: [C:1]([Si:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C@@H:7]1[CH2:11][C@H:10]([C:12]#[N:13])[C@@H:9]([OH:14])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:27]I>[Ag-]=O>[C:1]([Si:5]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C@@H:7]1[CH2:11][C@H:10]([C:12]#[N:13])[C@@H:9]([O:14][CH3:27])[CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)[Si](O[C@H]1C[C@H](O)[C@@H](C#N)C1)(c1ccccc1)c1ccccc1
Agent: O=[Ag-]
Product: CO[C@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H]1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
A mixture of (1S,2R,4S) and (1R,2S,4R)-4-(tert-butyl-diphenyl-silanyloxy)-2-hydroxy-cyclopentanecarbonitrile (2 g, 5.47 mmol), methyliodide (15 ml; 246 mmol) and silver(I) oxide (2.54 g, 10.94 mmol) was stirred at room temperature overnight. The excess of methyliodide was removed under reduced pressure and the remaining residue was suspended in DCM and filtered through a pad of celite. The filtrate was evaporated and the remaining yellow gum was purified by silica gel column chromatography (heptane/EtOAc 90:10-80:20) to obtain 1.62 g (4 mmol, 78%) of the title compound as colorless gum. MS (EI): 380.2 (M+H)+.
Reaction SMILES: [Mg].BrCCBr.Cl[CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1.C[N:15]1CCC([Mg]Cl)CC1.[S:23](Cl)(Cl)(=[O:25])=[O:24].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:13][N:10]1[CH2:11][CH2:12][CH:7]([S:23]([NH2:15])(=[O:25])=[O:24])[CH2:8][CH2:9]1
Reactant: O=S(=O)(Cl)Cl
Reactant: CN1CCC([Mg]Cl)CC1
Reactant: CN1CCC(Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CN1CCC(S(N)(=O)=O)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a suspension of magnesium (0.426 g, 17.51 mmol) in THF (50 mL) was added 1,2-dibromoethane (0.058 mL, 0.674 mmol) and stirred for 10 min and then 4-chloro-1-methylpiperidine (1.8 g, 13.47 mmol) in THF (4 mL) was added and the mixture was refluxed under nitrogen overnight. Cooled solution of the (1-methylpiperidin-4-yl)magnesium chloride was canulated into a cold (−78° C.) solution of sulfuryl chloride (1.3 mL, 16 mmol) in THF (10 mL). The mixture was stirred at 0° C. for 1.5 h and cooled to −78° C. and bubbled ammonia gas for 10 min and stirred at −78° C. for 10 min and allowed to warm to r.t. maintained under balloon pressure of NH3 for 2 h. Diluted with 100 mL ether, filtered off the solids and the filtrate was concentrated to afford a brown solid. Brown solid in THF was stirred with K2CO3 for 1h and filtered and concentrated to afford 1-methylpiperidine-4-sulfonamide as a beige solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.59 (2 H, m), 1.84 (2 H, m), 1.93 (2 H, m), 2.15 (3 H, s), 2.71 (1 H, ddd, J=12.13, 8.32, 3.66 Hz), 2.84 (2 H, m), 6.69 (2 H, brs).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([S:24]([C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:19][CH2:18]2.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[CH:5][C:6]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([S:24]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:19][CH2:18]3)=[CH:7][CH:8]=1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: N#Cc1ccc(S(=O)(=O)N2CCc3cc(Br)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)nc4)ccc32)cc1
Temperature: 90 °C
Yield: 62.9 %

Procedure:
236.5 mg 2-(Trifluormethyl)pyridin-5-ylboronic acid, 300.0 mg 4-(5-Bromo-2,3-dihydro-indole-1-sulfonyl)-benzonitrile and 807.4 mg cesium carbonate were dissolved in a mixture of 3 ml water and 10 ml dimethylformamide. The reaction mixture was degassed with argon and then 47.7 mg tetrakis(triphenylphosphine)palladium(0) were added and the mixture heated to 90° C. for two hours. The cooled reaction mixture was diluted with 100 ml ethyl acetate and washed with 50 ml water and brine. The organic layer was dried over MgSO4 and the solvent removed in vacuo. The resulting crude material was purified by purified by chromatography on silica gel to obtain 223 mg 4-[5-(6-Trifluoromethyl-pyridin-3-yl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=3)[CH:11]=2)[N:6]=[C:5]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:4]=1.Br[CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[Cl:29][CH2:28][CH2:27][O:19][C:15]1[CH:14]=[C:13]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:4]=[C:3]3[NH:2][CH3:1])[CH:18]=[CH:17][CH:16]=1
Reactant: ClCCBr
Reactant: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(O)c3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(OCCCl)c3)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
A suspension of 3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenol (0.30 g, 0.914 mmol), 1-bromo-2-chloroethane (0.38 ml, 4.57 mmol), and potassium carbonate (0.38 g, 2.74 mmol) in DMF (10 mL) was stirred for 2 days at room temperature. Water (10 mL) and ethyl acetate (10 mL) were added to the mixture and extracted. The organic layer was separated and concentrated in vacuo to leave a solid, which was collected by filtration and washed with hexane and dried to give 0.30 g of 6-(3-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine as brown solid (83%). The product was used without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl-].[CH3:14][O:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:36]([N:43]1[CH2:48][CH2:47][CH:46]([CH:49]=O)[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1.C(OCC)(=O)C>[CH2:36]([N:43]1[CH2:44][CH2:45][CH:46]([CH:49]=[CH:14][O:15][CH3:16])[CH2:47][CH2:48]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC=CC1CCN(Cc2ccccc2)CC1
Temperature: -40 °C

Procedure:
A solution of di-isopropylamine (4.38 g, 6.1 mL, 43.3 mmol) in anhydrous tetrahydrofuran (50 mL) was cooled to 0° C. with stirring. A solution of n-butyl lithium in hexanes (2.4 M, 17.3 mL, 43.3 mmol) was added dropwise; the resulting solution was stirred for 15 minutes. The reaction mixture was transferred via cannula to a suspension of methoxymethyl triphenyl phosphonium chloride (14.9 g, 43.3 mmol) in anhydrous tetrahydrofuran (100 mL), stirred at -20° C. The reaction mixture was stirred at -20° C. for 35 minutes, then it was cooled to -40° C. A solution of 1-benzyl-4-formylpiperidine (8 g, 39.4 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise. The reaction mixture was warmed gradually to ambient temperature over 21 hours, then it was poured onto water (500 mL) mixed and extracted three times with ethyl acetate (500 mL). The combined organic layers were dried over magnesium sulfate, treated with decolorizing charcoal and filtered through Celite®. Solvent was removed in vacuo to give an orange oil. Column chromatography (ethyl acetate) gave the product as a mixture of E- and Z- isomers (Rf=0.41, 5.06 g):1H-NMR:7.4-7.2(m,5H), 6.3(d,0.6H,J=13), 5.8(d,0.4H,J=6), 4.65(dd,0.6H,J=13,6), 4.2(dd,0.4H,J=6,5), 3.5(s,1.2H), 3.45(s,1.8H), 2.9-2.7(m,2H), 2.5-2.3(m,1H), 2.1-1.3(m,7H); HR-MS:Calcd for C15H21NO:231.1623; Found:231.1633.
Reaction SMILES: Cl.C(O[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH:14]([OH:26])[CH2:15][CH2:16][CH2:17][O:18]CC1C=CC=CC=1)=[O:8])(C)(C)C.[NH:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1C(O)=O.[CH2:35]([N:42]=[C:43]=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.C(N(CC)CC)C>[OH:18][CH2:17][CH2:16][CH2:15][C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:9]1[C:7]([C@@H:34]1[CH2:33][CH2:32][CH2:28][N:27]1[C:43]([NH:42][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:44])=[O:8])=[O:26]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)CCCOCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCCO)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
4N Hydrochloric acid (1,4-dioxane solution, 20 ml) was added to (S)-1-(tert-butoxycarbonyl)-2-[1-hydroxy-4(phenylmethyloxy)butyl]pyrrolidine (high polar isomer, 3.00 g) and the mixture was allowed to stand at room temperature for 30 minutes. The reaction mixture was concentrated and the residue was reacted with N-(benzylamincarbonyl)-L-proline obtained by stirring L-proline (0.99 g), benzyl isocyanate (0.97 g) and triethylamine (0.87 g) in DMF (10 ml) at room temperature for 1 hour, in the same manner as in Example 5-b), to give the title compound (2.20 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([CH:20]2[CH2:24][C:23](=[O:25])[N:22]([CH3:26])[CH2:21]2)[C:5]([O:18][CH3:19])=[C:6]([CH:8]([NH:10]C(=O)OC(C)(C)C)[CH3:9])[CH:7]=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>C(Cl)Cl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[NH2:10][CH:8]([C:6]1[C:5]([O:18][CH3:19])=[C:4]([CH:20]2[CH2:21][N:22]([CH3:26])[C:23](=[O:25])[CH2:24]2)[C:3]([CH3:27])=[C:2]([Cl:1])[CH:7]=1)[CH3:9]
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CC(=O)N(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C(C)N)cc(Cl)c(C)c1C1CC(=O)N(C)C1
Reaction time: 0.5 h

Procedure:
Solutions of the individual diastereoisomers of tert-butyl {1-[5-chloro-2-methoxy-4-methyl-3-(1-methyl-5-oxopyrrolidin-3-yl)phenyl]ethyl}carbamate (28 mg, 0.070 mmol [peak 1 from step 1]; 56 mg, 0.14 mmol [peak 2 from step 1]) in separate reaction flasks in methylene chloride (1 mL) were each treated individually with trifluoroacetic acid (1 mL) dropwise and stirred for 30 minutes. The reaction mixtures were individually concentrated to give diastereoisomer from peak 1 (38 mg, quantitative) and diastereoisomer from peak 2 (65 mg, quantitative) as residues that were used without further purification. Peak 1: LCMS for C15H19ClNO2 (M−NH2)+: m/z=280.1. Found: 280.1. Peak 2: LCMS for C15H22ClN2O2 (M+H)+: m/z=297.1. Found: 297.1.
Reaction SMILES: CN(C=O)C.C(Cl)(C([Cl:10])=O)=O.[CH3:12][O:13][C:14]1[C:19]2[C:20]3[N:21]=[CH:22][NH:23][C:24](=O)[C:25]=3[S:26][C:18]=2[CH:17]=[CH:16][CH:15]=1>ClCCCl>[Cl:10][C:24]1[C:25]2[S:26][C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([O:13][CH3:12])[C:19]=3[C:20]=2[N:21]=[CH:22][N:23]=1
Reactant: COc1cccc2sc3c(=O)[nH]cnc3c12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cccc2sc3c(Cl)ncnc3c12
Temperature: 25 °C
Yield: 66.1 %

Procedure:
DMF (0.125 mL, 1.7 mmol) is added dropwise to a solution of (COCl)2 (0.15 mL, 1.68 mmol) in 1,2-dichloroethane (4.5 mL) at r.t. After gas evolution ceases, 9-methoxy-4-oxo-3H-benzothieno[3,2-d]pyrimidine (73.2 mg, 0.32 mmol) is added. The resulting mixture is heated at reflux for 4hr. After the reaction is cooled to r.t., the black tar is filtered off. The filtrate is stripped to dryness and then mixed with water. A yellow solid forms and is collected via filtration. The solid is washed with water and air dried to give 4-chloro-9-methoxybenzothieno[3,2-d]pyrimidine (53 mg, 66%). 1H NMR (DMSO) δ9.17 (1H, s), 7.82-7.78 (2H, m), 7.3-7.2 (1H, m), 4.06 (3H, s).
Reaction SMILES: [C:1]([CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:13])([O:3][CH2:4][CH3:5])=[O:2].[I-].[Na+].[H-].[Na+].[H][H].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1.O>[C:1]([C:6]1([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:13])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1CCCCCC1=O
Reactant: [H][H]
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(C(=O)OCC)CCCCCC1=O
Temperature: 65 °C

Procedure:
For example, a solution of 2-carboethoxy-cycloheptanone (I) (92.2 g, 0.5 mole) in toluene (1.6 l) is treated with sodium iodide (1 g) and 60% sodium hydride in mineral oil (23.3 g, 0.58 mole). The mixture is heated at 110° C. until hydrogen gas evolution drops off. Ethyl bromoacetate (98.0 g, 0.58 mole) is added dropwise and the mixture is warmed to 65° C. for 18 hours. The mixture is cooled and water (500 ml) is added. The layers are separated and the aqueous layer is extracted with toluene (2×1 l). The extracts are dried (MgSO4) and filtered. The filtrate is concentrated at reduced pressure and distilled to yield pure 2-carboethoxy-2-carboethoxymethylcycloheptanone (II) with a bp 182°-185° C. at 13 mm.
Reaction SMILES: CO[C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH2:18][C@@H:19]3[CH2:22][CH2:21][N:20]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:16]=2)[O:8][N:7]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][C@H:19]1[CH2:18][O:17][C:15]1[CH:16]=[C:11]([C:9]2[O:8][N:7]=[C:6]([CH2:5][CH2:4][C:3]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH:10]=2)[CH:12]=[N:13][CH:14]=1)=[O:24])([CH3:27])([CH3:29])[CH3:28]
Reactant: COC(=O)CCc1cc(-c2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)on1
Reactant: C1CCNC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cc(CCC(=O)N3CCCC3)no2)c1
Temperature: 100 °C
Yield: 100.8 %

Procedure:
To 3-[5-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-3-isoxazolyl]propionic acid methyl ester (210 mg, 0.5 mmol) was added pyrrolidine (1.2 mL, 15 mmol). The mixture was heated at 100° C. for 12 h, cooled, and concentrated. The residue was dissolved in water and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by CC on SiO2 with EtOAc/hexane 1:1 to give 3-[5-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-3-isoxazolyl]-1-(1-pyrrolidinyl)-1-propanone (230 mg, 99%).
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][CH2:4][NH:3]1.[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][CH2:4][N:3]1[C:22]([C:21]1[CH:25]=[CH:26][N:27]=[CH:28][C:20]=1[NH:19][C:17]([C:15]1[C:14]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:13][CH:12]=[C:11]([CH:8]2[CH2:10][CH2:9]2)[N:16]=1)=[O:18])=[O:23]
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: CC1(C)CCCN1
Product: CC1(C)CCCN1C(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 23 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 2,2-dimethylpyrrolidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (23%) as sticky yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][N:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:13](=S)[C@H:12]([NH:22][C:23]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[C:39]4[C:34](=[N:35][CH:36]=[CH:37][CH:38]=4)[NH:33][C:32]3=[O:40])[CH2:27][CH2:26]2)=[O:24])[CH2:11][CH2:10]1.[CH3:41][NH2:42]>C(O)C.[Hg](Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][N:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:13](=[N:42][CH3:41])[C@H:12]([NH:22][C:23]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[C:39]4[C:34](=[N:35][CH:36]=[CH:37][CH:38]=4)[NH:33][C:32]3=[O:40])[CH2:27][CH2:26]2)=[O:24])[CH2:11][CH2:10]1
Reactant: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=S)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: CN
Agent: Cl[Hg]Cl
Solvent: CCO
Product: CN=C1[C@H](NC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@@H](c2cccc(F)c2F)CN1CC(F)(F)F
Reaction time: 2 h

Procedure:
Mercury(II) chloride (23 mg, 0.084 mmol) was added to a solution of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-thioxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (32 mg, 0.055 mmol) and methylamine (2.0 M in tetrahydrofuran; 274 μL, 0.547 mmol) in ethanol (1 mL). After 2 h, the mixture was filtered and concentrated. Purification by reverse phase HPLC(C-18, 95% water/acetonitrile→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound as a bis trifluoroacetate salt (33 mg). MS 580.2415 (M+1).