Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:17][C:16]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=2[NH:14][C:13](=[O:24])[CH2:12]1)=O)C1C=CC=CC=1>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:15]2[NH:14][C:13](=[O:24])[CH2:12][NH:11][CH2:17][C:16]=2[CH:18]=1
Reactant: COc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC(=O)N2
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CNCC(=O)N2
Reaction time: 2 h
Yield: 98.4 %

Procedure:
A solution of 7-methoxy-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid benzyl ester (1.26 g, 3.86 mmol) in ethyl acetate (25 mL) and ethanol (25 mL) was treated with 10% Pd—C (125 mg) and hydrogenated under 40 psi H2 on a Paar apparatus. After two hours LCMS indicated completion of the reaction. The mixture was filtered and concentrated to afford 7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (730 mg, 96%) as a white solid, used without further purification; NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 7.00 (d, J=8 Hz, 1H), 6.80 (d, J=8 Hz, 1H), 6.78 (s, 1H), 3.80 (s, 2H), 3.72 (s, 3H), 3.38 (s, 2H), 3.00 (br, 1H); MS (m/e) 193 (M+1); mp 148° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[CH2:7][NH:6][CH2:5]2.[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[C:23]([CH:27]=1)[C:24](O)=[O:25])(=[O:18])=[O:17]>>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:12])([F:14])[F:13])[CH2:7][N:6]([C:24]([C:23]1[CH:27]=[C:19]([S:16]([CH3:15])(=[O:17])=[O:18])[CH:20]=[CH:21][C:22]=1[O:28][C@@H:29]([CH3:34])[C:30]([F:32])([F:33])[F:31])=[O:25])[CH2:5]2
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)c1cc2c(cc1I)CNC2
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2cc(I)c(C(F)(F)F)cc2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example 1 from 5-Iodo-6-trifluoromethyl-2,3-dihydro-1H-isoindole and 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example B3). Yellow foam. MS (m/e): 607.0 (M+, 100%).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].C1C(=O)N([Cl:18])C(=O)C1>C(#N)C.C(OCC)(=O)C>[Cl:18][C:7]1[CH:8]=[C:9]2[O:1][C:2](=[O:10])[NH:3][C:4]2=[N:5][CH:6]=1
Reactant: O=c1[nH]c2ncccc2o1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=c1[nH]c2ncc(Cl)cc2o1
Temperature: 85 °C

Procedure:
A mixture of 3H-oxazolo[4,5-b]pyridin-2-one (36) (300 mg, 2.2 mmol, 1 equiv) and NCS (352 mg, 2.65 mmol, 1.2 equiv) in 5 mL of acetonitrile was heated at 85° C. overnight. The reaction solution was diluted with ethyl acetate (EtOAc), and washed with water. The organic solution was concentrated and purified by flash chromatography, to provide 6-Chloro-3H-oxazolo[4,5-b]pyridin-2-one (37): LCMS Retention time, 0.69 min; LCMS observed (M+H)+: 171.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:28][CH3:29].CCOC(C)=O>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH2:28][CH3:29])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1
Reactant: CCI
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Reaction time: 0.25 h
Yield: 77.8 %

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (490 mg, 1.4 mmol) in Acetone (5 mL) was added Cesium Carbonate (706 mg, 2.17 mmol); after 15 min, Iodoethane (122 uL, 1.53 mmol) was added and the mixture stirred at room temperature 5d. Conc. in vacuo onto Celite and chromatography (0-20% EtOAc:Hex, ISCO silica gel) afforded N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-ethyl-methanesulfonamide as a clear oil (400 mg, 75%). 1H-NMR (CDCl3): 8.01 (s, 1H), 6.32 (d, 1H, J=6.8 Hz), 4.03 (m, 1H), 3.76 (m, 1H), 3.33 (m, 1H), 3.20 (m, 1H), 2.91 (s, 3H), 2.41 (m, 1H), 1.92 (m, 2H), 1.72 (m, 2H), 1.40 (m, 2H), 1.21 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.C(N(CC)C(C)C)(C)C.[F:49][C:50]([F:60])([F:59])[C:51]1[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:56][CH2:55][C:54]2[CH:53]=[CH:52][C:51]([C:50]([F:49])([F:59])[F:60])=[CH:58][CH:57]=2)=[O:8])=[CH:4][N:3]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
To a mixture of 6-chloronicotinic acid (2.0 g, 13 mmol) and HBTU (4.8 g, 13 mmol) in DMF (20 mL, 200 mmol) at 0° C. were added N,N-diisopropylethylamine (6.6 mL, 38 mmol) and 4-(trifluoromethyl)benzylamine (2.2 mL, 15 mmol). The reaction mixture was slowly warmed to ambient temperature. The reaction mixture was quenched with an equal volume of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were washed successively with water, aqueous lithium chloride, and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on the Isco (120 g cartridge, chloroform to 12% MeOH in chloroform). The product was not thoroughly dried proceeding to the next reaction. Assumed 100% conversion.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][CH:10]1[C:15](=[O:16])[N:14]2[CH:17]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:18](=[O:24])[N:19]([CH:21]([CH3:23])[CH3:22])[CH2:20][CH:13]2[N:12]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=2[Cl:43])(=[O:35])=[O:34])[CH2:11]1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH:17]2[N:14]3[C:15](=[O:16])[CH:10]([NH:9][C:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:7])[CH2:11][N:12]([S:33]([C:36]4[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=4[Cl:43])(=[O:35])=[O:34])[CH:13]3[CH2:20][N:19]([CH:21]([CH3:23])[CH3:22])[C:18]2=[O:24])=[CH:27][CH:28]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Product: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCCC3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O

Procedure:
Synthesis took place in analogy to Example 22 using cyclopentanecarbonyl chloride and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW=654.12 (calculated, monoisotopic); measured value (M+H)+: 655.1
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:13]=[C:14]([CH:21]=[CH:22][CH:23]=2)[O:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[N:30][NH:31]2)=[CH:27][CH:26]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:31]1[C:32]2[C:28](=[CH:27][CH:26]=[C:25]([NH:24][C:2]3[N:3]=[C:4]([NH:11][C:12]4[CH:13]=[C:14]([CH:21]=[CH:22][CH:23]=4)[O:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18])[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:33]=2)[CH:29]=[N:30]1
Reactant: CNC(=O)COc1cccc(Nc2nc(Cl)nc3[nH]ccc23)c1
Reactant: Nc1ccc2cn[nH]c2c1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CNC(=O)COc1cccc(Nc2nc(Nc3ccc4cn[nH]c4c3)nc3[nH]ccc23)c1
Temperature: 115 °C
Yield: 8.7 %

Procedure:
To a mixture of 2-(3-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)phenoxy-N-methylacetamide (0.062 g) in nBuOH (0.6 mL) was added 6-aminoindazole (0.028 g) and TMSCl (0.013 mL). After heating at 115° C. for 15 h, the mixture was purified by prep HPLC to give 2-(3-(2-(1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)phenoxy-N-methylacetamide (0.007 g, MS calcd for C22H20N8O2 428.4. found [MH] 429.1; UV 238.1, 311.6 nm).
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:21][NH:22][C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1.[CH3:41][N:42]1[CH:46]=[CH:45][N:44]=[C:43]1[S:47](Cl)(=[O:49])=[O:48]>O1CCCC1.O>[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:21][N:22]([S:47]([C:43]2[N:42]([CH3:41])[CH:46]=[CH:45][N:44]=2)(=[O:49])=[O:48])[C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: Cn1ccnc1S(=O)(=O)Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2nccn2C)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26 mg) in tetrahydrofuran (4 mL) were added dropwise 15-crown-5 (0.13 mL), a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (162 mg) in tetrahydrofuran (1 mL) and 1-methyl-1H-imidazole-2-sulfonyl chloride (136 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→ethyl acetate) to give the title compound as a pale-yellow oil (yield 229 mg, 98%).
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:10][C:11]#[N:12].C(=O)([O-])[O-].[K+].[K+].[CH2:24](B(CC)CC)[CH3:25]>O>[CH2:24]([C:7]1[CH:8]=[C:9]([CH2:10][C:11]#[N:12])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH3:25]
Reactant: CCB(CC)CC
Reactant: COc1ccc(CC#N)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(CC#N)ccc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 37.1 %

Procedure:
N,N-Dimethylformamide (75 ml) was added to 3-bromo-4-methoxybenzyl cyanide (9.0 g, 40 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)-dichloromethane adduct (400 mg, 0.49 mmol) and potassium carbonate (24.0 g, 174 mmol) at room temperature. Further, triethylborane (1M n-hexane solution, 50 ml, 50 mmol) was added dropwise thereto and the reaction mixture was stirred at 70° C. for 5 hours. After the temperature of the reaction mixture was returned to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=8/1-5/1) to give (3-ethyl-4-methoxyphenyl)acetonitrile (2.6 g, yield: 38%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18](N(C)OC)=[O:19])=[CH:14][CH:13]=1.[Cl-].[NH4+]>C1COCC1.[Li]CCCC.CCCCCC>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([C:18]([C:15]2[CH:16]=[N:17][C:12]([Cl:11])=[CH:13][CH:14]=2)=[O:19])=[C:3]([F:10])[CH:4]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Reactant: Fc1cc(Br)c(F)cc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)nc1)c1cc(F)c(Br)cc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 35.9 %

Procedure:
A mixture of 1,4-dibromo-2,5-difluorobenzene (1.36 g) in anhydrous THF (20 ml) and 1.6M n-BuLi in hexane (3.43 ml) was stirred at −78° C. under nitrogen for 20 min. The reaction mixture was added to 6-chloro-N-methyl-N-(methyloxy)-3-pyridinecarboxamide (0.921 g) in THF (20 ml) and stirred at −78° C. The mixture was then stirred at −70° C. for 30 min allowed to warm to room temperature then cooled again to −70° C. and treated with 10% aqueous ammonium chloride. The reaction mixture was warmed to room temperature and partitioned between ethyl acetate and 10% aqueous ammonium chloride. The organic layer was separated using a hydrophobic filter tube and the solvent was removed under vacuum. The residue was purified using a silica SPE cartridge eluting with petroleum ether/ethyl acetate (9:1 to 1:3) to give impure title compound (0.548 g).
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[C:52]([F:53])=[CH:51][C:35]3[N:36]=[C:37]([C:39]4[C:43]([NH2:44])=[CH:42][N:41]([CH:45]5[CH2:50][CH2:49][CH2:48][CH2:47][O:46]5)[N:40]=4)[NH:38][C:34]=3[CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)(O)[O-].[Na+]>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[C:52]([F:53])=[CH:51][C:35]3[N:36]=[C:37]([C:39]4[C:43]([NH:44][C:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:8])=[CH:42][N:41]([CH:45]5[CH2:50][CH2:49][CH2:48][CH2:47][O:46]5)[N:40]=4)[NH:38][C:34]=3[CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(Cl)N1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4N)nc3cc2F)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4NC(=O)N4CCCCC4)nc3cc2F)CC1
Temperature: 80 °C

Procedure:
1.2 mL of 1-piperidinecarbonyl chloride and 1.7 mL of N,N-diisopropylethylamine are added to a solution of 480 mg of 4-{2-[4-amino-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-6-fluoro-3H-benzimidazol-5-yl}piperazine-1-carboxylic acid tert-butyl ester in 10 mL of THF. The reaction mixture is heated at 80° C. for 16 hours. The reaction medium is cooled to ambient temperature and 20 mL of a saturated solution of sodium bicarbonate are added. The aqueous phases are extracted with 3 times 10 mL of EtOAc. The organic phases are dried over MgSO4, filtered and concentrated under vacuum in a rotary evaporator. The reaction crude is purified by flash chromatography, elution being carried out with a mixture of cyclohexane/ethyl acetate. 350 mg of 4-{6-fluoro-2-[4-[(piperidine-1-carbonyl)amino]-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-3H-benzimidazol-5-yl}piperazine-1-carboxylic acid tert-butyl ester are obtained in the form of a brown foam. 1H NMR (400 MHz, DMSO-d6, δ in ppm): from 1.37 to 2.22 (m, 12H); 1.42 (s, 9H); 3.04 (m, 4H); 3.44 (m, 4H); 3.53 (m, 4H); 3.67 (m, 1H); 3.96 (m, 1H); 5.52 (dd, J=2.0 and 10.0 Hz, 1H); 7.29 (d, J=7.5 Hz, 1H); 7.56 (d, J=11.5 Hz, 1H); 8.15 (s, 1H). ES mass spectrum: m/z=597 MH+ (base peak).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.[CH2:10]([OH:15])[CH2:11][CH2:12][C:13]#[CH:14]>C(NCC)C.ClCCl.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:14]#[C:13][CH2:12][CH2:11][CH2:10][OH:15]
Reactant: Clc1ccc(Cl)c(I)c1
Reactant: C#CCCCO
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: OCCCC#Cc1cc(Cl)ccc1Cl

Procedure:
A solution of 1,4-dichloro-2-iodobenzene (20.0 g, 73.3 mmol), 4-pentyn-1-ol (6.17 g, 73.3 mmol), bistriphenylphosphine(Pd II) chloride (1.03 g, 1.47 mmol), and copper(I) iodide (0.14 g, 0.733 mmol) in 400 ml of diethylamine was stirred under nitrogen for three days. This was diluted with dichloromethane and the oily layer was adsorbed onto silica gel and eluted with hexanes-ethyl acetate (5:1) to give 5-(2,5-dichlorophenyl)pent-4-yn-1-ol, 13.7 g (82%); NMR (CDCl3) δ 1.9 (m, 2H), 2.6 (t, 2H), 3.85 (t, 2H), 7.2 (dd, 1H), 7.28 (m, 1H), 7.4 (d, 2H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[OH:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>CO>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([OH:16])=[CH:18][CH:19]=2)[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: Nc1ccc(O)cc1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(O)cc2)C(=O)OC1=O

Procedure:
To a boiling solution of 4.24 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 200 ml. of methanol is added 2.18 g. (0.02 m.) of p-hydroxyaniline. The resulting mixture is refluxed overnight and filtered to yield 5-acetyl-4-hydroxy-3-[1-(p-hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 223°-225° C. Both the mono-and di-sodium salts are prepared upon treatment of the dione with sodium methoxide in methanol.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[C:18]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(OCCCOc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1ccccc1)c1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1

Procedure:
1,3-Diphenoxypropane (22.8 g), benzoyl chloride (31 g) and anhydrous aluminum chloride (33 g) are reacted in 1,2-dichloroethane (300 ml) for eighteen hours at 70° to yield 33.4 g (77% of theory) of colorless crystals mp 146°-8°.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28](N(CC)C(C)C)(C)[CH3:29].BrCC>C1COCC1>[CH2:28]([N:13]1[CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])=[CH:17][CH:16]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ccccc1-c1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Solvent: CCBr
Solvent: C1CCOC1
Product: CCN1CCN(Cc2ccc(-c3ccccc3Cl)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound was made in the following manner: 100 mg of 3-(S)-benzyl-1-(2′-chloro-biphenyl-4-ylmethyl)-piperazine was dissolved in THF, 3 equiv. of N,N-diisopropylethylamine were added followed by 2 equiv. of bromoethane. The reaction was be shaken at room temperature overnight. The reaction was concentrated in vacuo. The residue was diluted with DCM and washed with 1N aqueous NaOH solution. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as free base. Treatment with 1 equiv. 2M HCl in dioxane and concentration in vacuo gave 16 mg of its hydrochloride salt. Yield 27%, ES MS (+) m/z 405
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:38][CH2:37][C:36]5[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=5[Cl:34])[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1
Reactant: NCc1ccccc1Cl
Product: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4ccnc(NCc5ccccc5Cl)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 48 supra) (100 mg, 0.21 mmol) and 2-chlorobenzylamine (120 mg, 0.84 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford crude (4-{3-[2-(2-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 60 mg).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([O:8][C@H:9]1[O:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O.[CH2:37]1COCC1.C1(C)C=CC=CC=1>C[C-]1C=CC=C1.[C-]1(C)C=CC=C1.[Ti+2]>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:6]([O:8][C@H:9]2[O:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:10]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH2:37])[CH:28]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:30]=1
Reactant: C1CCOC1
Reactant: O=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Ti+2]
Agent: C[c-]1cccc1
Solvent: Cc1ccccc1
Product: C=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 69 %

Procedure:
A solution of 2.50 g (4.9 mmol) of 2-(R)-(3,5-bis(trifluoro-methyl)benzoyloxy)-3-(S)-phenyl-4-benzyl morpholine (from Example 67) and 2.50 g (12.0 mmol) of dimethyl titanocene (from Example 68, Step A) in 35 mL of 1:1 v/v THF/toluene was stirred in an oil bath at 80° C. for 16 hours. The reaction mixture was cooled and concentrated in vacuo. Flash chromatography on 150 g of silica gel using 3:1 v/v hexanes/methylene chloride as the eluant afforded 1.71 g (69%) of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>>[Cl:27][CH2:28][C:29]([NH:1][C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:25])([F:26])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1)=[O:30]
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3N)C2=O)cnc1OCC(F)(F)F
Reactant: O=C(Cl)CCl
Product: Cc1cc(C(C)N2Cc3c(ccnc3NC(=O)CCl)C2=O)cnc1OCC(F)(F)F
Yield: 96 %

Procedure:
The title compound is prepared in 96% yield (270 mg, pale brown solid) from 4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (230 mg, 0.63 mmol, Example-17, single enantiomer) and 2-chloroacetyl chloride (90 mg, 0.79 mmol) in a similar manner to Example-18 (Method-D).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])=[C:12](Br)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:24][S:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])=[C:12]([C:29]3[CH:30]=[CH:31][C:26]([S:25][CH3:24])=[CH:27][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(O)CCOc1c(Br)cnn(-c2ccc(F)c(F)c2)c1=O
Reactant: CSc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CSc1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCCC(C)(C)O)cc1
Yield: 64.5 %

Procedure:
The product from Example 471C (12.79 g, 32.86 mmol) was coupled to 4-(methyl-thio)phenylboronic acid (6.07 g, 36.15 mmol) with K2CO3 (10 g, 72.3 mmol) and PdCl2(PPh3)2 (1.15 g, 1.64 mmol) in ethanol (200 mL) at 60–65° C. for 40–70 minutes to provide the title intermediate (yield: 9.16 g, 64.5%).