Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([CH2:12][C:13]1([N:34]2[CH:38]=[C:37]([C:39]3[C:40]4[CH:47]=[CH:46][N:45](COCC[Si](C)(C)C)[C:41]=4[N:42]=[CH:43][N:44]=3)[CH:36]=[N:35]2)[CH2:16][N:15]([C:17]2[N:18]=[CH:19][C:20]([C:23]([NH:25][C@@H:26]([CH:31]3[CH2:33][CH2:32]3)[C:27]([F:30])([F:29])[F:28])=[O:24])=[N:21][CH:22]=2)[CH2:14]1)#[N:11].[OH-].[NH4+].C([O-])(O)=O.[Na+]>C(#N)C.O>[C:10]([CH2:12][C:13]1([N:34]2[CH:38]=[C:37]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH:36]=[N:35]2)[CH2:16][N:15]([C:17]2[N:18]=[CH:19][C:20]([C:23]([NH:25][C@@H:26]([CH:31]3[CH2:33][CH2:32]3)[C:27]([F:29])([F:28])[F:30])=[O:24])=[N:21][CH:22]=2)[CH2:14]1)#[N:11]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5cnc(C(=O)N[C@@H](C6CC6)C(F)(F)F)cn5)C4)c3)ncnc21
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(c2cnc(C(=O)N[C@@H](C3CC3)C(F)(F)F)cn2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Boron trifluoride etherate (0.078 mL, 0.62 mmol) was added to a solution of 5-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]pyrazine-2-carboxamide in acetonitrile (4.0 mL) at 0° C. under N2. The reaction mixture was stirred at room temperature for 3 h. LCMS (M+H)+: m/z=553.2. The mixture was cooled to 0° C., then water (1.6 mL) was added. After 30 min, 5.0 M ammonium hydroxide in water (0.38 mL) was added slowly at 0° C. over 5 min. Then the reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with saturated aqueous NaHCO3, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-5%) to afford the desired product. LCMS (M+H)+: m/z=523.2. 1H NMR (400 MHz, DMSO-d6): δ 12.53 (br, 1H), 8.94 (s, 1H), 8.79 (d, J=9.3 Hz, 1H), 8.68 (s, 1H), 8.51 (d, J=1.4, 1H), 8.40 (s, 1H), 7.86 (d, J=1.4 Hz, 1H), 7.63 (dd, J=3.1, 2.3 Hz, 1H), 7.08 (dd, J=3.3, 1.4 Hz, 1H), 4.66 (d, J=9.9 Hz, 2H), 4.40 (d, J=10.0 Hz, 2H), 3.82 (m, 1H), 3.63 (s, 2H), 1.22 (m, 1H), 0.48 (m, 1H), 0.38 (m, 1H), 0.30 (m, 1H), 0.02 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([C:22]3[NH:23][C:24]([CH3:29])=[C:25]([Cl:28])[C:26]=3[Cl:27])=[O:21])[CH2:15][CH2:14]2)[S:6][C:7]=1[C:8]([O:10]CC)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[O:63]1[CH2:67][CH2:66][CH:65]([C:68](O)=[O:69])[CH2:64]1>CN(C=O)C.CCOC(C)=O>[Cl:27][C:26]1[C:25]([Cl:28])=[C:24]([CH3:29])[NH:23][C:22]=1[C:20]([NH:19][CH:16]1[CH2:17][CH2:18][N:13]([C:5]2[S:6][C:7]([C:8]([OH:10])=[O:9])=[C:3]([CH2:2][NH:1][C:68]([CH:65]3[CH2:66][CH2:67][O:63][CH2:64]3)=[O:69])[N:4]=2)[CH2:14][CH2:15]1)=[O:21]
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1CN
Reactant: O=C(O)C1CCOC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(CNC(=O)C4CCOC4)c(C(=O)O)s3)CC2)c(Cl)c1Cl
Reaction time: 0.17 h
Yield: 95.6 %

Procedure:
Ethyl 4-(aminomethyl)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylate (Example 246; 200 mg; 0.434 mmol) was dissolved in anhydrous DMF (2 ml). HATU 165 mg; 0.434 mmol) was added followed by diisopropylethylamine (149 μl, 0.868 mmol). The reaction mixture was stirred for 10 minutes and tetrahydrofuran-3-carboxylic acid (50 mg; 0.434 mmol) and reaction was stirred at room temperature for 2.5 h. The mixture was diluted with EtOAc, washed well with water, dried over Na2SO4 and concentrated in vacuo to give the title compound as an off-white solid (220 mg)-(LCMS (ES) MH+: 558, 561). The ethyl ester product was hydrolysed with lithium hydroxide/THF in a manner analogous to Example 31 to give the title compound (25 mg).
Reaction SMILES: [CH2:1]([C:3]1([C:9]([O:11]C)=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].[H-].[Na+].[C:15](#[N:17])[CH3:16]>>[CH2:1]([C:3]1([C:9](=[O:11])[CH2:16][C:15]#[N:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1)[CH3:2]
Reactant: CCC1(C(=O)OC)CCCCC1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Product: CCC1(C(=O)CC#N)CCCCC1

Procedure:
Acetonitrile was reacted with 1-ethyl-1-methoxycarbonylcyclohexane in the presence of sodium hydride to provide 1-ethyl-1-(2-cyanoacetyl)cyclohexane. A 55 g portion of the latter compound was dissolved in 200 ml of diethyl ether containing 20.5 g of absolute methanol, and the solution was stirred and cooled to about 5° C. Hydrogen chloride gas was next bubbled through the reaction mixture for forty-five minutes, after which time the reaction mixture was stored at 0° C. for twelve hours. Removal of the reaction solvent by evaporation under reduced pressure provided a yellow solid, which was dissolved in 300 ml of fresh absolute methanol and treated with 97 g of triethylamine and 22 g of hydroxylamine hydrochloride. The reaction mixture was heated at 50° C. for three hours, and then cooled to room temperature and diluted with 25 ml of concentrated hydrochloric acid. The acidic reaction mixture was heated at 50° C. for twelve hours, and then cooled to room temperature and concentrated to dryness by evaporation of the solvent under reduced pressure. The residue thus obtained was dissolved in water, and the aqueous mixture was made alkaline by the addition of 20% sodium hydroxide. The product was extracted into diethyl ether, which was then washed with water, dried, and the solvent was removed by evaporation. Distillation of the product afforded 14 g of 3-amino-5-(1-ethylcyclohexyl)isoxazole. B.P. 135°-140° C. at 0.1-0.05 torr.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12
Reactant: Oc1ncnc2[nH]ncc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Clc1ncnc2[nH]ncc12

Procedure:
To a mixture of commercially available 4-hydroxypyrazolo[3,4-d]pyrimidine (78) (Acros, 14.5 g, 106.5 mmol) stirred in POCl3 (375 mL) was added N,N-dimethylaniline (21 mL). The mixture was refluxed for 1.5 h. After cooling, excess POCl3 was removed by rotarty evaporation and pumped on high vacuum before pouring over 500 mL ice while stirring. The mixture was stirred for 10 min before extracting with ethyl ether (6×250 mL). The combined organic layer was washed with ice water (3×100 mL) and dried over MgSO4 and filtered. The ethyl ether was stripped and the resulting pale yellow solid (10 g, 61%) was pumped on high vacuum overnight. Compound 79: mp>300° C., dec. 125° C.; MS (ES+ calculated: 154.56; found: 156.21 M+H). HPLC (98% purity, retention time 6.033 minutes—method D) 1H NMR (400 MHz, DMSO-d6) δ 14.55 (bs, 1H), 8.84 (s, 1H), 8.46 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[CH:20]=[CH:21][C:22]([F:37])=[C:23]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH3:38]>>[NH2:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[CH:20]=[CH:21][C:22]([F:37])=[C:23]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)ccc1F)c1cc(F)ccc1F
Reactant: N
Product: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2ccc(F)c(NS(=O)(=O)c3cc(F)ccc3F)c2)n1

Procedure:
Following a procedure analogous to the procedure described in Example 51, Step B using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.120 g, 0.212 mmol) and ammonia (7 N solution in MeOH, 4.54 mL, 31.7 mmol) the title compound was obtained as a white solid (71 mg, 0.13 mmol, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1H), 8.06 (d, J=5.1 Hz, 1H), 7.45-7.71 (m, 3H), 7.34-7.45 (m, 2H), 7.23-7.34 (m, 1H), 6.80 (s, 2H), 6.19 (d, J=5.1 Hz, 1H), 3.88-4.03 (m, 2H), 3.40-3.56 (m, 2H), 3.21-3.31 (m, 1H), 1.92-2.07 (m, 2H), 1.63-1.82 (m, 2H). MS (ESI): 548.11 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][Si](C)(C)C)=[CH:16][N:15]=2)[CH2:10][CH2:9]1>CO>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([CH3:7])[CH2:9][CH2:10]2)=[N:15][CH:16]=1)#[CH:21]
Reactant: CN1CCN(c2ccc(C#C[Si](C)(C)C)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(N2CCN(C)CC2)nc1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
Potassium carbonate (1M aq., 1.5 mL, 1.5 mmol) was added in a drop-wise manner to a solution of 1-methyl-4-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)piperazine (325 mg, 1.19 mmol) in MeOH (5.0 mL) at room temperature, and the resulting mixture was stirred for 2 h. After removal of the solvent in vacuo, water (5 mL) and brine (10 mL) were added and the product was extracted with DCM (150 mL, then 3×10 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and filtered. Evaporation of the solvent gave 1-(5-ethynylpyridin-2-yl)-4-methylpiperazine (239 mg, quantitative yield), which was used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 8.32 (s, 1H), 7.55 (dd, J=8.9, 2.1 Hz, 1H), 6.58 (d, J=8.8 Hz, 1H), 3.54-3.67 (m, 4H), 3.08 (s, 1H), 2.46-2.58 (m, 4H), 2.35 (s, 3H); MS ESI [M+H]+ 201.9, calcd for [C12H15N3+H]+ 202.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C1N2CCN(CC2)C1.[O:25]1[CH2:30][CH2:29][N:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[N:14][C:13]([O:16][C:31]([N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:32])=[CH:12][CH:11]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1c(Cl)cc(-c2ccc(OC(=O)N3CCOCC3)nn2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
1.27 g of 6-(3,5-dichloro-4-methylphenyl)-3-pyridazone and 1.12 g of triethylenediamine were dissolved in 25 ml of hexamethylphosphoric triamide, and then 1.5 g of morpholinocarbonyl chloride were added dropwise thereto. When the addition was complete, the mixture was stirred at room temperature for 1 hour and then poured into about 200 g of ice-water. The precipitate thus produced was collected by filtration, washed with water and dried, giving 1.75 g (94%) of the desired Compound No. 10. The melting point and spectroscopic data of this product agreed completely with those of the product obtained in Example 2.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][CH:28]([CH3:33])[CH2:29][C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][CH:28]([CH3:33])[CH3:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CC(C)CC(=O)O
Agent: Cl
Product: CC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (74 mg, 72%), MS (ISP) m/z=411.5 [(M+H)+], mp 182° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 3-methyl-butyric acid.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].C(O)C.[Cl-].[NH4+]>[Fe].O>[CH3:1][N:2]([CH3:23])[C:3]([CH:5]1[CH2:6][CH2:7][N:8]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: CN(C)C(=O)C1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)C1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.3 %

Procedure:
1-(4-Nitro-benzenesulfonyl)-piperidine-4-carboxylic acid dimethylamide (0.17 g, 0.49 mmol) was suspended in a 5:1 mixture of ethanol and water (3 ml). To this solution was added iron powder (0.08 g, 0.98 mmol) followed by saturated ammonium chloride solution (0.1 ml) and the mixture was stirred at room temperature for 18 hours. After this time, the reaction mixture was filtered through a pad of celite, the celite was washed with ethanol (10 ml) and ethyl acetate (50 ml) and the solution was concentrated under vacuum. The resulting residue was partitioned between DCM (50 ml) and water (20 ml), the organic layer was separated, dried with MgSO4, filtered and concentrated to afford the title compound (0.15 g, 100% yield) as a yellow solid. Tr=1.71 min, m/z (ES+) (M+H)+ 312.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([NH2:19])[CH2:16][N:15]2[C:20](=[O:40])[NH:21][CH:22]([C:27](=[O:39])[NH:28][CH:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH:30]2[OH:38])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])C.CCN(C(C)C)C(C)C.Cl.[C:51](Cl)(=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[N:54][CH:53]=1.C(O)C(N)(CO)CO.[Li+].[OH-]>C(Cl)Cl.C(O)(=O)C>[OH:38][CH:30]1[CH2:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]1[NH:28][C:27]([CH:22]([NH:21][C:20]([N:15]1[CH2:16][CH:17]([NH:19][C:51]([C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)=[O:58])[CH2:18][CH:14]1[C:12]([NH:11][C:6]1([C:4]([OH:3])=[O:5])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:13])=[O:40])[C:23]([CH3:26])([CH3:24])[CH3:25])=[O:39]
Reactant: O=C(Cl)c1cccnc1
Reactant: C=CC1CC1(NC(=O)C1CC(N)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC(NC(=O)c2cccnc2)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.9 %

Procedure:
To a stirred solution of compound 151 (35 mg, 0.064 mmol) in DCM (1 ml), was added DIEA (0.12 mmol, 19 μl) and nicotinoyl chloride hydrochloride (0.12 mmol, 17 mg).The solution was stirred at RT for 18 h, PS-trisamine was added then stirred at RT for 4 h. After filtration, the solution was washed with citric acid (10% aq) and NaHCO3 (sat, aq), the organic phase was dried over Na2SO4 and concentrated. The residue was dissolved in THF:MeOH (2:1, 1.5 ml). LiOH (1N aq, 3.2 mmol, 320 μl) was added. The solution was stirred at 60° C. for 24 h. Acetic acid was added and then concentrated. The residue was dissolved in MeOH and subjected to purification by HPLC, affording the title compound (19.5 mg, 0.03 mmol). Purity by HPLC>98%, M+H+633.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[NH:13][NH2:14].[F:15][C:16]([F:20])([F:19])[C:17]#[N:18]>CO.CCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[NH:13][NH:14][C:17](=[NH:18])[C:16]([F:20])([F:19])[F:15]
Reactant: N#CC(F)(F)F
Reactant: CC(C)Oc1cc(NN)c(Cl)cc1Cl
Solvent: CO
Solvent: CCCCC
Product: CC(C)Oc1cc(NNC(=N)C(F)(F)F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
Under a dry nitrogen atmosphere a stirred solution of 2.4 g (0.01 mole) of 2,4-dichloro-5-(1-methylethoxy)phenylhydrazine in 140 mL of methanol was cooled to -60° C. in a dry ice-isopropanol bath. Trifluoroacetonitrile (23.2 g, 0.24 mole) was bubbled into the cold solution during a two minute period. After complete addition the cold solution was stirred for 30 minutes, then allowed to warm slowly to room temperature during the next three hours. A stream of nitrogen gas was bubbled into the room temperature solution to aid in the vaporization and removal of trifluoroacetonitrile, leaving a liquid residue. This residue was evaporated further under reduced pressure to leave a resinous material. This material was stirred in cold pentane to produce a solid. The pentane was decanted and the solid triturated in fresh cold pentane. The pentane was decanted and the solid dried under reduced pressure to yield 2.9 g of N-[2,4-dichloro-5-(1-methylethoxy)anilino]trifluoroacetamidine (mp 80.5°-81° C.).
Reaction SMILES: CC([O-])(C)C.[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH:24]=O.CO>C1COCC1.O>[F:20][C:21]1[CH:22]=[C:23]([CH2:24][C:17]#[N:18])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(C=O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(CC#N)cc1F
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a suspension of t-BuOK (25.3 g, 0.207 mol) in THF (150 mL) was added a solution of TosMIC (20.3 g, 0.104 mol) in THF (50 mL) at −78° C. The mixture was stirred for 15 minutes, treated with a solution of 3-fluoro-4-methoxy-benzaldehyde (8.00 g, 51.9 mmol) in THF (50 mL) dropwise, and continued to stir for 1.5 hours at −78° C. To the cooled reaction mixture was added methanol (50 mL). The mixture was heated at reflux for 30 minutes. Solvent of the reaction mixture was removed to give a crude product, which was dissolved in water (200 mL). The aqueous phase was extracted with EtOAc (100 mL×3). The combined organic layers were dried and evaporated under reduced pressure to give crude product, which was purified by column chromatography (Petroleum Ether/EtOAc 10:1) to afford 2-(3-fluoro-4-methoxyphenyl)acetonitrile (5.0 g, 58%). 1H NMR (400 MHz, CDCl3) δ 7.02-7.05 (m, 2 H), 6.94 (t, J=8.4 Hz, 1 H), 3.88 (s, 3 H), 3.67 (s, 2 H). 13C NMR (100 MHz, CDCl3) δ 152.3, 147.5, 123.7, 122.5, 117.7, 115.8, 113.8, 56.3, 22.6.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:43](=[O:45])[CH3:44])=[N:40][CH:41]=2)O1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:37]=[CH:38][C:39]([NH:42][C:43](=[O:45])[CH3:44])=[N:40][CH:41]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(=O)Nc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]-acetamide via General Procedure A. Purification on silica and ether trituration gave 233. NMR (CDCl3): 2.25 (3H, s), 2.67-2.71 (4H, m), 2.81 (3H, s), 3.29-3.33 (4H, m), 3.89 (2H, s), 3.89-3.93 (4H, m), 4.08-4.12 (4H, m), 7.35 (1H, s), 7.97 (1H, br. s), 8.28 (1H, d), 8.71 (1H, d), 9.30 (1H, s). MS (ESI+): MH+ 532.28 (100%)
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:46])[N:41]([CH:43]([F:45])[F:44])[CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[F:44][CH:43]([F:45])[N:41]1[C:40](=[O:46])[CH:39]=[CH:38][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:42]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1ccc(Br)cn1C(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C(F)F)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 110 °C
Yield: 50.6 %

Procedure:
A microwave vial equipped with a flea stirbar was charged with (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (20 mg, 0.047 mmol), 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one (25 mg, 0.113 mmol), Cs2CO3 (27 mg, 0.083 mmol), H2O (0.1 mL) and dry dioxane (1 mL). The mixture was sparged with N2 for 10 min and heated at 110° C. in the microwave for 0.5 h. The mixture was diluted with glacial HOAc (0.1 mL) and MeOH (0.5 mL) and filtered. The filtrate was directly purified by prep HPLC to afford (S)-3-((S)-1-(4-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (11.8 mg, 57%) as an oil. LC-MS Method 1 tR=1.55 min, m/z=497, 248; 1H NMR (CDCl3) 1.13 (s, 3H), 1.19 (s, 3H), 1.56 (d, 3H), 2.15-2.35 (s, 4H), 2.42 (m, 2H), 2.88 (m, 1H), 5.71 (q, 1H), 6.64 (d, 1H), 7.04 (d, 2H), 7.18 (d, 2H), 7.30-7.40 (5H), 7.52 (1H), 7.60 (m, 1H), 7.75 (t, 1H).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl[Si](C)(C)C.CN(P(N(C)C)(N(C)C)=O)C.[CH:23]([Mg]Br)([CH3:25])[CH3:24]>C1COCC1>[CH:23]([CH:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)([CH3:25])[CH3:24]
Reactant: O=C1C=CCC1
Reactant: CC(C)[Mg]Br
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)C1CCC(=O)C1
Temperature: -70 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of cyclopent-2-enone (1.5 mL, 18.27 mmol), CuBr—SMe2 (188 mg, 0.91 mmol), chlorotrimethylsilane (4.59 mL, 36.54 mmol) and HMPA (6.55 g, 36.54 mmol) in THF (30 mL) was added isopropylmagnesium bromide (36.54 mL, 1 M in THF) at −70° C. After stirring for 1 h at −70° C., the reaction mixture was quenched with HCl (10%). The mixture was extracted with Et2O. The organic layer was washed with aqueous NaHCO3 and brine. After dried over Na2SO4, the organic layer was concentrated to give 3-isopropylcyclopentanone (4 g, 100%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH2:7])=[O:6])[CH3:4].O=[C:9]([CH3:17])[CH2:10][CH2:11][C:12](OCC)=[O:13]>O>[CH3:4][C@@H:3]1[N:2]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2([CH3:17])[NH:7][C:5]1=[O:6]
Reactant: CCOC(=O)CCC(C)=O
Reactant: C[C@H](N)C(N)=O
Agent: Cl
Solvent: O
Product: C[C@H]1C(=O)NC2(C)CCC(=O)N12

Procedure:
L-Alaninamide hydrochloride (20.7 g, 0.166 mol) and ethyl 4-oxopentanoate (20 g, 0.13 mol) were reacted together according to the procedure of Example 2 to give the title compound, 4.5 g (19.1%), m.p. 228°-230° (with decomposition), [alpha]D =+50.7° (c=3, H2O). NMR (CDCl3): deltaH =7.95 (bs, 1H, NH); 4.30 (q, J=8 Hz, 1H, CHCH3); 3.00-2.10 (c.a., 4H, CH2CH2); 1.60 (s, 3H, C-CH3 ; 1.45 (d, J=8 Hz, 3H, CH3CH). MS (E.I., 70 eV, 1.5 mA) m/z=168 (M+), 153 (M-CH3)+, 125 (M-CHNO)+, 112 (M-C3H4O)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[F:8].[Mg].[CH3:11]I.[Cl-].[NH4+]>O1CCCC1.[Cu]I>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11]
Reactant: CI
Reactant: Fc1ccc(Br)cc1F
Agent: [Cu]I
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cccc(F)c1F

Procedure:
Under a nitrogen atmosphere, 82.5 g of 3,4-difluorobromobenzene (1) dissolved in 150 mL of tetrahydrofuran (THF) was added dropwise to 12.5 g of dried magnesium, and after completing the dropwise addition, the mixture was refluxed for 1 hour. The resulting solution was added dropwise to 15 mL of THF having 91.5 g of methyl iodide and 12.3 g of copper(I) iodide added thereto under cooling with an ice bath. After stirring over night, a saturated ammonium chloride aqueous solution was added thereto to terminate the reaction. The aqueous layer was extracted with diethyl ether, which was added to the organic layer, and the organic layer was washed with a saturated saline and then dried over anhydrous magnesium sulfate. The organic layer was distilled to obtain 37.6 g of 2,3-difluorotoluene (2)