Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[N:7]([CH3:13])[C:8](=[O:12])[NH:9][C:10]=1[CH3:11])=[O:4].[OH-].[Na+]>CO>[F:21][C:16]1[CH:15]=[C:14]([CH:6]2[C:5]([C:3]([OH:4])=[O:2])=[C:10]([CH3:11])[NH:9][C:8](=[O:12])[N:7]2[CH3:13])[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: COC(=O)C1=C(C)NC(=O)N(C)C1c1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=C(C(=O)O)C(c2ccc(F)c(F)c2)N(C)C(=O)N1
Temperature: 500 °C

Procedure:
(−)-4-(3,4-Difluorophenyl)-3,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester (650 mg, 2.19 mmol) was dissolved in methanol (10 ml), treated with 2.5N sodium hydroxide (10 ml), and warmed to 500° C. for 8hr. The solvent was removed in vacuo, the remaining aqueous phase treated with 10% KHSO4 (aq), and extracted with ethyl acetate (3X). The extracts were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness in vacuo to give a crude oil. Crystallization from diethyl ether gave the product as a white solid [αD]=−128°, c=0.20 MeOH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=[O:23])=[C:17]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[C:17]([O:26][CH2:27][C:28]([F:31])([F:29])[F:30])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC(=O)O)c(OCC(F)(F)F)c2)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetate (3.0 g, MW=435, 6.90 mmol) from Step 7 above in MeOH (25 mL) was added a solution of aqueous NaOH (6.9 mL of a 2.0 N solution, 13.8 mmol). The mixture was refluxed for 3 h and then cooled to ambient temperature. The solvents were removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and 0.25 M aqueous citric acid (75 mL). The organic phase was separated and washed with H2O (25 mL) and brine (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetic acid was obtained as an amorphous solid (HPLC retention time=9.4 min (method A)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](S(C)(=O)=O)[N:28]=3)=[CH:23][C:22]2=[O:37])[C@@H:9]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[CH:4][C:3]=1[F:38].[O:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1>CC(N(C)C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C@@H:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)[N:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:45][CH:42]4[CH2:43][CH2:44][O:39][CH2:40][CH2:41]4)[N:28]=3)=[CH:23][C:22]2=[O:37])=[CH:4][C:3]=1[F:38]
Reactant: NC1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@H](c2ccc(Cl)c(F)c2)n2ccc(-c3ccnc(S(C)(=O)=O)n3)cc2=O)C1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1[C@@H](c1ccc(Cl)c(F)c1)[C@@H]1CCNC1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
(R)-tert-Butyl 3-((R)-(4-chloro-3-fluorophenyl)(4-(2-(methylsulfonyl)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate (45.1 mg, 0.0801 mmol) was dissolved in DMA (1.0 mL, 0.1M) at room temperature under nitrogen and treated with tetrahydro-2H-pyran-4-amine (40.5 mg, 0.401 mmol). The solution was heated to 120° C. for 1 hour in the microwave. The reaction was then diluted with EtOAc (15 mL) and washed with water (3×15 mL) and brine (15 mL). The organics were isolated, dried over sodium sulfate, filtered and concentrated. The crude product was loaded onto an SP1 samplet and purified by silica gel chromatography using a 10% to 80% gradient of acetone in hexanes. Product containing fractions were pooled, concentrated and then redissolved in dichloromethane (2 mL) and treated with 1:1 TFA/DCM (1.0 mL) and stirred at room temperature for 1 hour. The reaction was diluted to 15 mL with additional DCM and washed with NaHCO3 (2×15 mL). The organics were isolated, dried over sodium sulfate, filtered and concentrated to afford 1-((R)-(4-chloro-3-fluorophenyl)((R)-pyrrolidin-3-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one as an oil. 1H NMR (400 MHz, ((CD3)2SO) δ 8.40 (d, 1H), 8.04 (d, 1H), 7.62 (m, 2H), 7.37 (d, 1H), 7.34 (br s, 1H), 7.13 (d, 1H), 7.08 (s, 1H), 6.86 (d, 1H), 5.84 (br s, 1H), 3.97 (m, 1H), 3.87 (m, 2H), 3.38 (m, 2H), 2.86 (m, 1H), 2.79 (m, 2H), 2.34 (m, 1H), 1.84 (br d, 2H), 1.74 (m, 1H), 1.52 (m, 3H), 1.27 (m, 2H); LCMS (ESI) m/z 484.1 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15]>CO.[Cu]I>[CH3:16][Si:14]([CH3:15])([CH3:17])[C:13]1[O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH:12]=1
Reactant: COC(=O)c1ccc(O)c(C#C[Si](C)(C)C)c1
Agent: [Cu]I
Solvent: CO
Product: COC(=O)c1ccc2oc([Si](C)(C)C)cc2c1
Temperature: 60 °C

Procedure:
Methyl 4-hydroxy-3-[(trimethylsilyl)ethynyl]benzoate (11 g, 44.5 mmol) is combined with CuI (423 mg, 2.2 mmol) and DIA (7.1 ml, 50 mmol) in MeOH (110 mL) in a flask under nitrogen. The reaction is warmed to 60° C. for 6 h, the volatiles are removed in vacuo, and the brown-green residue is chromatographed over 500 g silica gel (230-400 mesh) eluting with 20% EtOAc/hexane. Two pools are isolated to provide 3.43 g (31%) of the early eluting methyl 2-trimethylsilylbenzofuran-5-carboxylate and 2.63 g (33%) of the later eluting methyl benzofuran-5-carboxylate. The pools are combined in MeOH (130 mL). The solution is treated with 2N NaOH (46.8 ml, 93.6 mmol), is warmed to 50° C., and is stirred for 2 h. The mixture is cooled, the volatiles are removed in vacuo, and the residue is dissolved in water (50 mL). The pH of the mixture is adjusted to 2 with 12N HCl, is diluted with water (40 mL), and the mixture is cooled to 0° C. The off-white solid is collected, washed with water, and is dried to give 6.0 g. The solid is dried in vacuo over P2O5 for 18 h to give 4.6 g (99%) of benzofuran-5-carboxylic acid as an off-white solid. MS for C9H6O3, (EI) m/z: 162 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.[NH2:20][CH:21]1[CH2:27][CH:26]2[N:28]([CH3:29])[CH:23]([CH2:24][CH2:25]2)[CH2:22]1>>[CH3:29][N:28]1[CH:23]2[CH2:24][CH2:25][CH:26]1[CH2:27][CH:21]([NH:20][C:17]([C:15]1[CH:16]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:19])[CH2:22]2
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3ccccc3)nc12
Reactant: CN1C2CCC1CC(N)C2
Product: CN1C2CCC1CC(NC(=O)c1cc(Cl)cc3oc(-c4ccccc4)nc13)C2
Yield: 20 %

Procedure:
N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamide was prepared from 6-chloro-2-phenyl-benzoxazole-4-carboxylic acid and 3-amino-8-methyl-8-azabicyclo[3.2.1]octane using the method outlined in Step C of Example 7. This compound was obtained in 20% yield as a white solid: mp 187-190° C.; 1H NMR (500 MHz, CDCl3) δ 9.44 (d, J=7.5 Hz, 1H), 8.26 (d, J=7.1 Hz, 2H), 8.21 (d, J=2.0 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.65-7.47 (m, 3H), 4.46 (q, J=7.2 Hz, 1H), 3.25 (br s, 1H), 2.38 (m, 5H), 2.26 (m, 4H), 1.84 (d, J=14.3 Hz, 2H), 2.15 (m, 1H), 2.04 (m, 1H), 1.78-1.60 (m, 3H); MS (APCI) m/z 397 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH2:30])[N:17]=[CH:16]2.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>ClCCl>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30][C:40](=[O:43])[CH:41]=[CH2:42])[N:17]=[CH:16]2
Reactant: C=CC(=O)Cl
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3c2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1CCCC[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of (1R,2S)—N1-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)cyclohexane-1,2-diamine (0.94 g, 2.1 mmol) in dichloromethane (25 mL) at 0° C. was added DIEA (0.37 mL, 2.1 mmol) and acryloyl chloride (0.17 mL, 2.1 mmol) and the reaction was stirred for 3 h. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((1S,2R)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)cyclohexyl)acrylamide (0.8 g, 76%). MS (ES+) C25H26Cl2N4O3 requires: 500, found: 501.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:28][CH2:27]2)[CH:21]=1)=[O:18]
Reactant: O=C(CCCCCCl)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 6-chloro-1-phenyl-1-hexanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: Anal. Calcd for C27H36N2O2+0.1CHCl3: C, 75.3; H, 8.39; N, 6.46. Found: C, 75.4; H, 7.89; N, 6.18; ESMS m/e: 421.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)=[O:4].Cl.[NH2:15][OH:16].C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([N:5]1[CH2:10][CH2:9][C:8](=[N:15][OH:16])[CH2:7][CH2:6]1)=[O:4]
Reactant: NO
Reactant: CC(C)(C)C(=O)N1CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)C(=O)N1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
3.0 g (16 mmol) of the N-trimethylacetyl-4-piperidone obtained according to the procedure above and 1.2 g (17 mmol) of hydroxylamine hydrochloride were placed into a 50 mL flask with 20 mL of ethanol. To the resulting mixture was added 1.9 g (18 mmol) of Na2CO3, and the resulting mixture was allowed to stir at room temperature overnight. The ethanol was removed in vacuo, and the resulting solid was triturated with ethyl acetate (2×50 mL). Combined ethyl acetate washings were washed with water (30 mL) and brine (30 mL), and dried (Na2SO4). The ethyl acetate solution was concentrated to yield 2.4 g (74%) of N-trimethylacetyl-4-hydroxyiminopiperidine as a white solid: 1H NMR (300 MHz, CDCl3) δ3.75 (dd, 4H, J=12.3, 6.2 Hz), 2.68 (dd, 2H, J=6.2, 6.2 Hz), 2.39 (dd, 2H, J=6.2, 6.1 Hz), 1.36 (s, 9H); 13C NMR (75 MHz, CDCl3) δ176.66, 156.34, 45.02, 43.51, 38.77, 31.13, 28.31, 24.93.
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH2:14][C:15]#[N:16].[CH3:17][O:18][CH2:19][C:20](OCC)=[O:21].C(O)(=O)C>C(O)C.COCCOC>[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH:14]([C:20](=[O:21])[CH2:19][O:18][CH3:17])[C:15]#[N:16]
Reactant: CCOC(=O)COC
Reactant: N#CCc1cc(Cl)cc(Cl)c1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)O
Solvent: CCO
Product: COCC(=O)C(C#N)c1cc(Cl)cc(Cl)c1Cl
Temperature: 0 °C

Procedure:
To a stirred refluxing solution of sodium ethoxide (from 1.38 g sodium) in ethanol (25 ml) was added over 5 minutes a mixture of 2,3,5-trichlorophenylacetonitrile (11 g) and ethyl methoxyacetate (8.85 g) in dry DME (25 ml). After 4 hours the mixture was cooled on ice and acidified by dropwise addition of acetic acid (ca. 6 ml), diluted with ice-water (150 ml) and extracted with dichloromethane (2×100 ml). The dichloromethane extract was washed with water, dried over MgSO4 and concentrated giving a yellow solid, which was triturated with a little ether and filtered. 8.6 g Homogeneous by TLC (19:1 CH2Cl2 :MeOH).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([NH:12][C:13](=[NH:16])SC)[CH2:7][CH2:6]2.[CH:17]1([NH2:20])[CH2:19][CH2:18]1>CO>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([NH:12][C:13]([NH:20][CH:17]1[CH2:19][CH2:18]1)=[NH:16])[CH2:7][CH2:6]2
Reactant: NC1CC1
Reactant: CSC(=N)NN1CCc2cc(Cl)ccc21
Agent: Cl
Solvent: CO
Product: N=C(NC1CC1)NN1CCc2cc(Cl)ccc21

Procedure:
12 g of 1-(5-chloroindolin-1-yl)-2-methylisothiourea hydrochloride in 60 ml of methanol were heated for 5 hours at 100° with 15 ml of cyclopropylamine. The reaction mixture was concentrated to dryness. The residue was partitioned between ethyl acetate and dilute aqueous sodium hydroxide. The ethyl acetate phase was concentrated, and dried over magnesium sulphate to give the title compound. M.Pt. 146° - 149° (on recrystallization from ethyl acetate).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13]CC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O.O1CCOCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 3-phenoxybenzoate (0.220 g; 0.725 mmol) was added to a mixture of NaOH in water (1.5 mL; 2M) and dioxane (1.5 mL) and stirred vigorously at room temperature overnight. The resulting mixture was concentrated in vacuo and extracted with dichloromethane. The aqueous layer was acidified with a 6N solution of hydrochloric acid in water. The precipitated product was collected by filtration to yield 0.200 g (quantitative) of the title compound as a white solid which was used without further purifications.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[C:12]([F:42])=[CH:13][C:14]([F:41])=[C:15]([C:17]2[C:18](=[O:40])[N:19]([CH2:38][CH3:39])[C:20]3[C:25]([CH:26]=2)=[CH:24][N:23]=[C:22]([N:27]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[CH3:28])[CH:21]=3)[CH:16]=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O.O>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:27]([CH3:28])[C:22]2[CH:21]=[C:20]3[C:25]([CH:26]=[C:17]([C:15]4[C:14]([F:41])=[CH:13][C:12]([F:42])=[C:11]([NH:10][C:8]([NH:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[O:9])[CH:16]=4)[C:18](=[O:40])[N:19]3[CH2:38][CH3:39])=[CH:24][N:23]=2)=[CH:31][CH:32]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2F)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
Phenyl isocyanate (58 mg, 0.488 mmol) was added to a solution of Example A7 (200 mg, 0.444 mmol) and pyridine (140 mg, 1.776 mmol) in THF (5 mL) and the mixture was stirred at RT overnight. The mixture was diluted with EtOAc, water and satd. NaHCO3; the resulting precipitate was collected by filtration, washed with EtOAc and dried in vacuo to give 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea (219 mg, 87% yield). MS (ES-API) m/z: 570.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[F-].[Cs+].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:10][O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1nc(Br)cnc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: CO
Product: COc1nc(-c2ccccc2)cnc1N
Yield: 81.8 %

Procedure:
5-Bromo-3-methoxy-2-pyrazinamine (0.31 g), cesium fluoride (0.8 g), benzeneboronic acid (0.36 g) and [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride (0.08 g) in methanol (7 mL) was heated at reflux for 2 hours. The solvent was evaporated and the residue purified by chromatography on silica eluting with toluene/ethyl acetate mixtures to give the sub-title compound (0.25 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][CH2:11][Si:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=1)([CH3:14])[CH3:13])(=O)C.[OH-].[Na+].S(=O)(=O)(O)O>C(OCC)C.O>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([Si:12]([CH3:13])([CH3:14])[CH2:11][OH:10])=[CH:16][CH:17]=1)[CH3:23]
Reactant: CCOc1ccc([Si](C)(C)COC(C)=O)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CCOc1ccc([Si](C)(C)CO)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 86.4 %

Procedure:
To 48 ml of a 1M diethyl ether solution of lithium aluminum hydride (1.82 g, 0.048 mole) that had been cooled to 0° C. was added dropwise a solution of 11.0 g (0.044 mole) of 2-(4-ethoxyphenyl)-2-methyl-2-silapropyl acetate in 50 ml of diethyl ether. Fifteen minutes after the addition was complete, the reaction mixture was allowed to warm to room temperature, and it was stirred for 4.5 hours. To the reaction mixture were then added sequentially 1.8 ml of water, 1.8 ml of an aqueous 15% solution of sodium hydroxide, and 5.4 ml of water. Sufficient aqueous 10% sulfuric acid was added to dissolve the undissolved salts, and this mixture was extracted twice with diethyl ether. The combined extracts were washed with water and then with a saturated aqueous sodium carbonate solution that had been diluted with water (50:50). After being dried over anhydrous potassium carbonate and filtered, the solvent was evaporated under reduced pressure, leaving 8.0 g of 2-(4-ethoxyphenyl)-2-methyl-2-silapropanol as an orange oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH:27]([O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH2:33])([CH3:29])[CH3:28]>>[CH:27]([O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[NH:33][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:19])=[CH:7][CH:6]=1)(=[O:9])=[O:10])([CH3:29])[CH3:28]
Reactant: CC(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(=O)OC(C)C)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to phenylalanine isopropyl ester trifluoroacetate using the procedure described in Method 3 to give the title compound as an oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH:19]=C)[CH2:3][C@@H:4]1[CH2:8][N:7]([C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:6](=[O:17])[CH2:5]1.I([O-])(=O)(=O)=[O:22].[Na+]>CC(O)(C)C.C1COCC1.O.O=[Os](=O)(=O)=O>[OH:22][CH2:19][CH2:18][CH:2]([CH3:1])[CH2:3][C@@H:4]1[CH2:8][N:7]([C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:6](=[O:17])[CH2:5]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC(C)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: CC(CCO)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
OsO4 (2 mL of a 4% wt solution in t-BuOH) was added to the alkene 88 (5.8 g, 0.021 mol) in THF/H2O (3:1, 100 mL). After 1 hour, sodium periodate (11.4 g, 0.053 mol) was added. After 2 hours, the suspension was filtered and the solids washed with dichloromethane. The filtrate was concentrated and the residue azeotroped with toluene. The residue was dissolved in ethanol and sodium borohydride (2.5 g) added. The suspension was stirred at room temperature overnight. 1N citric acid was added and the mixture diluted with ether. The resultant two layers were separated and the aqueous phase was extracted with ether and the combined organic dried (MgSO4) and concentrated. Flash chromatography (1:1 hexane/EtOAc) of the residue gave an oil. 4.2 g, 73%. MS, m/z (relative intensity): 276 [M+H, 100%].
Reaction SMILES: [F:1][CH:2]([F:37])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][N:12]([C:25](OC3C=CC([N+]([O-])=O)=CC=3)=[O:26])[CH2:11]2)=[CH:6][CH:5]=1.[NH:38]1[CH2:43][CH2:42][S:41][CH2:40][CH2:39]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[F:1][CH:2]([F:37])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][N:12]([C:25]([N:38]3[CH2:43][CH2:42][S:41][CH2:40][CH2:39]3)=[O:26])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: C1CSCCN1
Reactant: COCCc1noc(C2CC(c3ccc(CC(F)F)cc3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCc1noc(C2CC(c3ccc(CC(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Temperature: 150 °C

Procedure:
A solution of 56.0 mg (0.065 mmol, purity 60%) of the compound from Example 62A in 1-methyl-2-pyrrolidone (2.0 ml) was admixed with 37.0 μl (40.0 mg, 0.390 mmol) of thiomorpholine and 34.0 μl (25.0 mg, 0.195 mmol) of N,N-diisopropylethylamine and then heated in a single-mode microwave (Emrys Optimizer) at 150° C. for 30 min. For workup, the reaction solutions were combined and purified directly by means of preparative HPLC. Yield: 14.7 mg (47% of theory)
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCC(=O)CC>[CH2:1]([C:2]([CH2:3][CH3:4])=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]#[N:9])[CH3:8]
Reactant: N#CCc1ccccc1
Solvent: CCC(=O)CC
Product: CCC(CC)=C(C#N)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in Example 1, by reacting benzyl cyanide with 3-pentanone in the presence of a base.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[F:46][C:47]([F:60])([F:59])[CH2:48][CH2:49][O:50][C:51]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)=[O:52]>C(OCC)(=O)C>[F:60][C:47]([F:46])([F:59])[CH2:48][CH2:49][O:50][C:51]([N:53]1[CH2:54][CH2:55][N:56]([C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:57][CH2:58]1)=[O:52]
Reactant: O=C(OCCC(F)(F)F)N1CCNCC1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: O=C(NCC(=O)N1CCN(C(=O)OCCC(F)(F)F)CC1)OCc1ccccc1
Reaction time: 48 h

Procedure:
To a solution of 842 mg N-Benzyloxycarbonyl glycine were added 2.0 ml N-ethylmorpholine, 1.32 g TOTU and 910 mg Piperazine-1-carboxylic acid 3,3,3-trifluoro-propyl ester. After stirring for 48 h the reaction mixture was diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl, saturated aqueous NaHCO3 and brine. The crude product obtained was used without further purification. Yield: 1.63 g.