Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]([CH3:20])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][N:6]2[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[CH3:19].C([Li])CCC.CCCCCC.[CH3:32][CH2:33][O:34]CC.C(Cl)(=O)C.[Cl-].[NH4+]>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[CH3:20][N:3]1[C:2]([C:33](=[O:34])[CH3:32])=[C:10]2[C:5]([N:6]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[CH2:7][CH2:8][CH2:9]2)=[N:4]1
Reactant: CCOCC
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3Br)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: CC(=O)c1c2c(nn1C)N(c1c(C)cc(C)cc1C)CCC2
Temperature: 25 °C
Yield: 6.4 %

Procedure:
A solution of 3-bromo-2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (1-3; 0.040 g, 1.2 mmol) in 6 mL of dry THF was cooled to −78° C. in a dry ice-acetone bath under an argon atmosphere and treated with n-butyllithium in hexane (0.83 mL, 1.32 mmol). After 10 m a solution of 1 M zinc chloride in ether (3.59 mL, 3.59 mmol) was added. The cooling bath was removed and the reaction stirred at room temperature. After 10 m acetyl chloride (0.113 g, 1.44 mmol) and tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol) were added and the brown solution was stirred for 2 hrs. The mixture was poured into 25 mL of saturated ammonium chloride solution, extracted twice with 25 mL portions of ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, and evaporated to dryness. The residue was purified on flash chromatography on silica gel eluting with ethyl acetate/hexane (15:85) giving 23 mg (6% yield) of 1-[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-yl]ethanone as a colorless oil: ms (M+H)+=298.
Reaction SMILES: [K+].[C:2]1(=[O:18])[N:6]([CH2:7][CH2:8][S:9]([O-])(=[O:11])=[O:10])[C:5](=[O:13])[C:4]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:3]12.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C1(C)C=CC=CC=1>[C:2]1(=[O:18])[N:6]([CH2:7][CH2:8][S:9]([Cl:20])(=[O:11])=[O:10])[C:5](=[O:13])[C:4]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Temperature: 0 °C
Yield: 79.3 %

Procedure:
60 g of the compound obtained in step A in 300 ml of toluene are heated to reflux for 1 hour in the presence of 30.7 g of phosphorus pentachloride. 30.7 g of phosphorus pentachloride are added again and refluxing is maintained for 90 minutes. 280 g of ice are added to the reaction medium, the mixture is stirred, and the insoluble matter is filtered off and then washed with ice-cold water. The residue is dried over P2O5 and then recrystallized in dichloroethane to obtain 32 g of the expected product, m.p.=160° C.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:6]1[CH:7]=[C:8]([S:13](Cl)(=[O:15])=[O:14])[CH:9]=[CH:10][C:11]=1[OH:12])(=[O:5])[CH3:4]>C(#N)C>[CH3:1][NH:2][S:13]([C:8]1[CH:9]=[CH:10][C:11]([OH:12])=[C:6]([C:3](=[O:5])[CH3:4])[CH:7]=1)(=[O:15])=[O:14]
Reactant: CN
Reactant: CC(=O)c1cc(S(=O)(=O)Cl)ccc1O
Solvent: CC#N
Product: CNS(=O)(=O)c1ccc(O)c(C(C)=O)c1
Reaction time: 0.08 h

Procedure:
A saturated solution of monomethyl amine in acetonitrile cooled to 0° C. was treated with 3-acetyl-4-hydroxy-benzenesulfonyl chloride. The mixture was stirred 5 min, concentrated in vacuo to an oil, disolved in ethyl acetate and treated with 1N aqueous HCl. The organic portion was separated, concentrated, filtered through silica gel (eluted with ethyl acetate) to provide N-methyl-3-acetyl-4-hydroxy-benzenesulfonic acid amide after concentration.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][C:9]=3[C:8]([N+:24]([O-:26])=[O:25])=[CH:7][C:6]=2[N:5](C(=O)C(F)(F)F)[CH2:4]1.C([O-])([O-])=O.[Cs+].[Cs+].CC(O)=O>O1CCOCC1.O.CO>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])=[CH:15][C:9]=3[C:8]([N+:24]([O-:26])=[O:25])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c3c(cc([N+](=O)[O-])c2c1)N(C(=O)C(F)(F)F)CC3CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.4 %

Procedure:
A suspension of 221(218 mg, 0.46 mmol) in dioxane (5 mL) was treated at room temperature with a solution of Cs2CO3 (0.33 g, 1.0 mmol) in water (1 mL) and MeOH (9 mL). The mixture was stirred at room temperature for 5 min and then treated with AcOH (0.15 mL) and diluted with water. The precipitate was collected and crystallised from CH2Cl2/hexane to give tert-butyl 1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indole-7-carbamate (222) (164 mg, 94%) as a red solid: mp 162-163° C. (dec.); 1H NMR [(CD3)2SO] δ 9.57 (s, 1H), 8.46 (d, J=1.7 Hz, 1H), 7.81 (d, J=9.1 Hz, 1H), 7.65-7.57 (m, 2H), 6.09 (d, J=2.1 Hz, 1H), 4.19-4.10 (m, 1H), 3.88 (dd, J=10.9, 3.7 Hz, 1H), 3.81-3.63 (m, 3H), 1.50 (s, 9H). Anal. (C18H20ClN3O4) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:9][CH2:8][C:7]=2[N:20]=1.C1C(=O)N([Cl:29])C(=O)C1>CC#N>[Cl:29][C:5]1[C:6]2[CH:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])[CH2:9][CH2:8][C:7]=2[N:20]=[C:3]([O:2][CH3:1])[C:4]=1[NH2:21]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1nc2c(cc1N)C(C)CN(C(=O)C(F)(F)F)CC2
Solvent: CC#N
Product: COc1nc2c(c(Cl)c1N)C(C)CN(C(=O)C(F)(F)F)CC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
To a solution of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (303 mg, 1.00 mmol) in MeCN (6 ml) was added a solution of NCS (134 mg, 1.00 mmol) in MeCN (6 ml). The resulting mixture was stirred for 2 h at 50° C. and then quenched with excess of sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 165 mg (49%) of 4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 4.28 (0.5H), 3.95 (2.5H), 3.88 (3H), 3.71 (2H), 3.61 (1H), 3.34 (1H), 3.16 (1H), 2.99 (1H), 1.13 (3H) ppm. To a solution of CuBr2 (43.0 mg, 0.19 mmol) and nBuNO2 (28.0 μl, 0.24 mmol) in MeCN (2.7 ml) was added a solution of 4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (54.0 mg, 0.16 mmol) in MeCN (2 ml) at room temperature. After leaving the mixture for 16 h at room temperature, it was heated at 50° C. for 4 h. After removal of MeCN under reduced pressure, the reaction was quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 45 mg (70%) of 3-bromo-4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H NMR (CDCl3) δ 4.29 (0.5H), 4.00 (0.5H), 3.90 (3H), 3.85 (1H), 3.75 (1H), 3.40 (1H), 3.30 (1H), 3.20 (1H), 3.10 (1H), 1.16 (3H) ppm. A mixture of 3-bromo-4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (60 mg, 0.15 mmol), K2CO3 (62 mg, 0.45 mmol), MeOH (2.4 ml) and H2O (0.5 ml) was heated at 55-60° C. for 1 h. After removal of solvent under reduced pressure, the mixture was taken into aq. NaHCO3 and extracted with EtOAc. The organic layer was dried and concentrated in vacuo to give 45 mg (98%) of 3-bromo-4-chloro-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 3.89 (s, 3H), 3.58 (m, 1H), 3.22 (m, 2H), 3.09 (dd, 1H), 2.93 (m, 2H), 2.71 (dd, 1H), 1.24 (d, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27](F)[N:26]=1.CC(C)([O-])C.[Na+]>C1COCC1>[Br:24][C:25]1[N:26]=[C:27]([O:22][C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]([C:10]4[S:9][C:5]5[C:6](=[O:8])[NH:7][C:2]([CH3:23])([CH3:1])[CH2:3][C:4]=5[N:11]=4)[C:17]=3[CH:18]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Fc1cccc(Br)n1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(O)cc43)sc2C(=O)N1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(N3CCOc4ccc(Oc5cccc(Br)n5)cc43)sc2C(=O)N1
Temperature: 150 °C
Yield: 13.6 %

Procedure:
To a solution of Example 57 (50 mg, 0.151 mmol) in THF (4 mL) was added 2-bromo-6-fluoropyridine (53 mg, 0.302 mmol) and sodium tert-butoxide (58 mg, 0.604 mmol). The mixture was heated to 150° C. under microwave irradiation for 30 minutes then cooled to r.t. The resulting mixture was partitioned between DCM (50 mL) and water (50 mL); the organic phase was washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The residue was triturated with Et2O to yield the title compound (10 mg, 14%) as an off-white solid. δH (CDCl3) 7.95 (1H, d, J 2.6 Hz), 7.52 (1H, t, J 7.9 Hz), 7.19 (1H, d, J 7.5 Hz), 6.97 (1H, d, J 8.9 Hz), 6.85 (1H, dd, J 8.9 and 2.6 Hz), 6.80 (1H, d, J 8.1 Hz), 5.32 (1H, s), 4.39-4.32 (2H, m), 4.16-4.10 (2H, m), 2.86 (2H, s), 1.38 (6H, s). LCMS (ES+) 487.0 (M+H)+, RT 3.73 minutes (Method 1).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:29][C:30]1[CH:35]=[C:34]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:33]=[C:32]([F:40])[C:31]=1[C:41]1[N:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[CH:43][C:42]=1[F:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:47]([C:45]3[CH:44]=[CH:43][C:42]([F:50])=[C:41]([C:31]4[C:32]([F:40])=[CH:33][C:34]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:35][C:30]=4[F:29])[N:46]=3)=[O:48])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(S(C)(=O)=O)cc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.7 %

Procedure:
A mixture of 3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (15.0 mg, 0.0384 mmol), 6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridine-2-carboxylic acid (15.3 mg, 0.0461 mmol), HATU (36.5 mg, 0.0960 mmol) in DMF (0.09 mL) and DIPEA (14.9 mg, 0.115 mmol) was stirred at room temperature for 16 h. The mixture was filtered, concentrated under reduced pressure and purified by preparative LC-MS (method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a colorless gum (11.0 mg, 41%). LCMS calc. for C33H37F3N5O7S (M+H)+: m/z=704.2. Found: 704.2.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:23])[CH:7]2[CH:12]([C:13](=[O:15])[CH:14]=1)[C:11]1([Cl:19])[C:16]([Cl:18])([Cl:17])[C:8]2([Cl:22])[C:9]([Cl:21])=[C:10]1[Cl:20])([CH3:4])([CH3:3])[CH3:2]>N1C=CC=CC=1.CO>[C:1]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:11]3([Cl:19])[C:16]([Cl:17])([Cl:18])[C:8]([Cl:22])([C:9]([Cl:21])=[C:10]3[Cl:20])[C:7]=2[C:6]=1[OH:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1=CC(=O)C2C(C1=O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(O)c2c(c1O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl

Procedure:
10 g. of 6-tert-butyl-1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-1,4-methanonaphthalene-5,8-dione, prepared according to Example 8, were dissolved in 50 ml. of methanol. A few drops of pyridine were added and the solution was refluxed strongly for three hours. Evaporation of the methanol yielded an oily material which upon recrystallization twice from Skelly B gave white needle crystals melting at 96° C-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[SH:26].C[O-].[Na+]>C(O)C.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>[Cl:1][C:2]1[CH:7]=[C:6]([S:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13]
Reactant: C[C@@](O)(C(=O)Nc1ccc(I)cc1Cl)C(F)(F)F
Reactant: Fc1ccccc1S
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@](O)(C(=O)Nc1ccc(Sc2ccccc2F)cc1Cl)C(F)(F)F
Reaction time: 18 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.147 g) was added to a deoxygenated mixture of (R)-N-(2-chloro-4-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 197) (1.0 g), 2-fluorothiophenol (0.263 ml) and sodium methoxide (0.288 g) in ethanol (50 ml). The mixture was then further deoxygenated by evacuation and refilling with argon (3 cycles), and then heated under reflux with stirring under argon for 18 hours. The mixture was treated with a further portion of tetrakis(triphenylphosphine)palladium(0) (0.147 g), heated for a further 24 hours then cooled and filtered. Volatile material was removed by evaporation and the residue was purified by flash chromatography eluting with 20% ethyl acetate/hexane to give the title compound (0.906 g) as an oil. NMR (CDCl3): 1.75 (s, 3H), 3.58 (s, 1H), 7.1 (t, 2H), 7.2-7.35 (m, 3H), 7.37 (d, 1H), 8.3 (d, 1H), 8.82 (brs, 1H); MS (ESP−): 392.
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[F:28])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:29][CH3:30])C1C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:27][C:23]1[C:22]([F:28])=[C:21]([NH:20][C:14]2[C:13]3[C:18](=[CH:19][C:10]([OH:9])=[C:11]([O:29][CH3:30])[CH:12]=3)[N:17]=[CH:16][N:15]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O

Procedure:
A solution of 7-(benzyloxy)-N-(3-chloro-2-fluorophenyl)-6-methoxyquinazolin-4-amine hydrochloride 2 (85.45 g, 0.192 mol) in trifluoroacetic acid (300 mL) was heated at 80° C. for 1 hour. The reaction mixture was the evaporated to dryness and the residues re-dissolved in methanol (200 mL). This solution was then added dropwise to a stirred aqueous solution of saturated sodium bicarbonate (500 mL). The resulting precipitate was collected by filtration, washed with acetonitrile and dried under vacuum. The crude solids were then purified by hot (100° C.) trituration with a mixture of butanone (500 mL) and MeOH (100 mL), filtered and dried to 4-[(3-chloro-2-fluorophenyl)amino]-6-methoxyquinazolin-7-ol 3 as a cream solid (45 g, 73%); 1H NMR Spectrum: (DMSO d6): 3.98 (s, 3H), 7.10 (s, 1H), 7.25-7.30 (m, 1H), 7.40-7.50 (m, 1H), 7.50-7.60 (m, 1H), 7.80 (s, 1H), 8.30 (s, 1H), 9.55 (s, 1H), 10.32 (s, 1H); Mass Spectrum: (M+H)+ 319.98
Reaction SMILES: [F:1][CH2:2][CH:3]([CH2:7][CH:8]([F:10])[F:9])[CH:4]([F:6])[F:5].FCC(O)CO>>[F:1][CH2:2][C:3]([CH:7]=[C:8]([F:10])[F:9])=[C:4]([F:6])[F:5]
Reactant: FCC(CC(F)F)C(F)F
Agent: OCC(O)CF
Product: FCC(C=C(F)F)=C(F)F

Procedure:
As another example, 2-fluoromethyl-1,1,4,4-tetrafluorobutane may be prepared by oxidizing commercially available 3-fluoro-1,2-propanediol to form a product which may then be reacted with CF2 carbene to form 2-fluoromethyl-1,1,4,4-tetrafluoro-1,3-butadiene which may then be hydrogenated to form 2-fluoromethyl-1,1,4,4-tetrafluorobutane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH:23]([C:27](=[O:35])[NH:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH2:22]2)[NH:12][C:11]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)=[N:10]1.[OH-].[Na+]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)[NH:12][C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH:23]([C:27]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:35])[CH2:22]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CNC(=O)C1CN(CC2=C(C(=O)OCC)C(c3ccc(F)cc3Br)N=C(c3nccs3)N2)CCO1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)NCC(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 88 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-((2-((2-ethoxy-2-oxoethyl)carbamoyl)morpholino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.5 g, 0.8 mmol) was reacted with sodium hydroxide (0.32 g, 8 mmol) according to the procedure as described in Example 58, Step B to give the title compound as a yellow solid (0.43 g, 88%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:11][C:10]([CH:7]1[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]1)=[O:12]
Reactant: OCCCCBr
Reactant: CCCC1CCC(C(=O)O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC1CCC(C(=O)OCCCCBr)CC1
Temperature: 25 °C

Procedure:
4-Propyl-cyclohexanecarboxylic acid (10.0 g, 58.0 mmol), 4-bromobutan-1-ol (9.2 g, 60.0 mmol) and a catalytic amount of para-toluene sulphonic acid are stirred under reflux in toluene (300 ml) in a flask equipped with Dean-Stark apparatus over night. The solution is allowed to cool to room temperature, is washed with aqueous sodium carbonate and water, dried and evaporated to dryness. Purification is achieved by flash column chromatography using petrol as eluant. Evaporation of the appropriate fractions gives 4-propyl-cyclohexanecarboxylic acid 4-bromo-butyl ester as the product. The structure is confirmed by 1H NMR spectroscopy and GCMS.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[OH:21])=[O:12].C(=O)([O-])[O-].[K+].[K+]>>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]2[NH:13][C:11](=[O:12])[C:3]3[C:4]4[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]=3[O:21][C:15]=2[CH:16]=1
Reactant: Cc1ccc(NC(=O)c2c(Br)sc3c2CCCC3)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc2c(c1)Oc1sc3c(c1C(=O)N2)CCCC3
Yield: 41.4 %

Procedure:
In the same manner as in Example 18 and using 2-bromo-4,5,6,7-tetrahydro-N-(2-hydroxy4-methylphenyl)-benzo[b]thiophene-3-carboxamide (5.8 g), dimethyl sufoxide (80 ml) and potassium carbonate (4.7 g), 1,2,3,4-tetrahydro-8-methyl[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one (1.87 g) was obtained.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](NCC3C=CC=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:32][CH2:31][C:30]3[CH:33]=[CH:34][C:27]([C:26]([F:35])([F:36])[F:25])=[CH:28][CH:29]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: Cc1nc(NCc2ccc(C(F)(F)F)cc2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [4-(trifluoromethyl)benzyl]amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.12-1.21 (m, 5H), 1.44-1.59 (m, 5H), 1.86 (s, 3H), 2.24 (s, 3H), 3.71 (d, J=10.74 Hz, 1H), 4.62 (d, J=4.82 Hz, 2H), 7.50-7.58 (m, 3H), 7.67 (d, J=8.11 Hz, 2H), 8.20 (t, J=5.15 Hz, 1H), 12.99 (bs, 1H); MS (ESI) m/z 379.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:13]1[CH2:18][CH2:17][CH:16]2[S:19][C:20](=[O:22])[CH:21]=[C:15]2[CH2:14]1)[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[C:30]([O:33][C:34]1[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:36](Cl)=[O:37])(=[O:32])[CH3:31].C([O-])(O)=O.[Na+]>O1CCCC1>[C:30]([O:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([O:22][C:20]1[S:19][C:16]2[CH2:17][CH2:18][N:13]([C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]([O:11][CH3:12])=[O:10])[CH2:14][C:15]=2[CH:21]=1)=[O:37])(=[O:32])[CH3:31]
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1CCC2SC(=O)C=C2C1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sc(OC(=O)c3ccccc3OC(C)=O)cc2C1
Reaction time: 0.17 h
Yield: 56 %

Procedure:
338 mg of (2S)-methyl 2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridin-5(2H,4H,6H)-yl)-acetate (IV-1) was dissolved in 15 ml of tetrahydrofuran, 0.83 ml of triethylamine was added dropwise and stirred for 10 minutes, and then 600 mg of acetylsalicylic chloride was added and stirred at room temperature for 24 hrs. The reaction solution was poured into saturated aqueous NaHCO3 solution (20 ml), extracted with ethyl acetate (50 ml×3), concentrated, evaporated, and subjected to flash column chromatography (petroleum ether:ethyl acetate=5:1), to obtain (S)-methyl 2-(2-(2-acetoxybenzoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5 (4H)-yl)-2-(2-chlorophenyl)-acetate (I-5) (280 mg). Yield: 56%, ee=96.1% (chiral HPLC analysis conditions: Chiralpak IC 4.6 mm×250 mm; column temperature: 25° C.; mobile phase: 85% n-hexane/15% tetrahydrofuran/0.1% diethylamine; flow rate: 0.5 ml/min; and detection wavelength: UV 254 nm), [α]D20=+14.00° (c 0.50, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 2.34 (s, 3H), 2.79-2.81 (m, 2H), 2.90-2.93 (m, 2H), 3.54-3.66 (m, 2H), 3.72 (s, 3H), 4.93 (s, 1H), 6.37 (s, 1H), 7.14-7.36 (m, 4H), 7.39-8.15 (m, 4H); 13C-NMR (75 MHz, CDCl3) δ 20.93, 24.93, 48.04, 50.12, 52.12, 67.65, 112.61, 117.34, 118.97, 121.66, 124.09, 126.14, 127.12, 129.35, 129.45, 129.79, 129.92, 130.71, 132.12, 133.54, 134.71, 135.73, 149.32, 151.12, 161.32, 169.47, 171.17; ESI-MS m/z 500 [M+H]+, 522 [M+Na]+; HRMS Calcd for C25H23NO6SCl [M+H]+ m/z 500.0931. found 500.0935.
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:7][CH2:6][CH2:5][C:4](Cl)([Cl:8])[C:3]1=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:10]
Reactant: O=C1C(Cl)(Cl)CCCC1(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Oc1c(Cl)cccc1Cl
Yield: 84.4 %

Procedure:
236 g (1 mol) of 2,2,6,6-tetrachlorocyclohexanone and 2.5 g (0.01 mol) of triphenylphosphine were introduced into a reactor equipped with a stirrer and a condenser. The mixture was heated at 150°-180° C. under stirring; the reaction was terminated when the evolution of hydrogen chloride from the reaction mixture ceased. The reaction mixture was then distilled under reduced pressure (boiling point (20 mm Hg)=100° C.) to yield 137.5 g of 2,6-dichlorophenol.