Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:19])=O>CN(C=O)C>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([Cl:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(CC1CCCC1)c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)C(CC1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the title B compound, 3-cyclopentyl-2-phenylpropionic acid (3.1 g, 14.2 mmol) is added 10 mL of thionyl chloride and one drop of DMF. The reaction mixture is stirred at ambient temperature for 2 h. The excess thionyl chloride is evaporated and the residue is twice treated with toluene and evaporated to yield 3-cyclopentyl-2-phenylpropionyl chloride as an orange-yellow oil which is selected as such without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5](Br)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5]([P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: FC(F)(F)c1ccccc1C(Br)c1ccccc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C(c1ccccc1)c1ccccc1C(F)(F)F

Procedure:
A solution of 2-(trifluoromethyl)benzhydryl bromide (25.2 g, 79.8 mmol) in triethyl phosphite (20.5 mL, 120 mmol), under N2, was heated at 155° C. for 16 hours. Excess triethyl phosphite was removed by distillation to give a yellow oil, 28.8 g. The crude product was chromatographed on a silica gel column. Elution with ethyl acetate/hexane (1:1) afforded analytically pure O,O-diethyl 2-trifluoromethylphenyl(phenyl)methylphosphonate as a pale yellow oil. 300 MHz 1H NMR (CDCl3): δ4.86 (d, 1H, J-26.18 Hz, PCH). MS: 373 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[NH2:27]>>[F:23][C:24]1[CH:25]=[C:26]([NH:27][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Cl)cc3)c2)o1
Reactant: COc1ccc(N)cc1F
Product: COc1ccc(NC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1F

Procedure:
N-(3-Fluoro-4-methoxyphenyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carbonyl chloride and 3-fluoro-4-methoxyaniline using method K. NMR; δH [2H6]—DMSO 10.35,(1H, b), 8.04,(2H, d), 7.90,(1H, dd), 7.78-7.75,(2H, m)7.59-7.51,(4H, m), 7.17,(1H, t), 3.82,(3H, s), 2.57,(3H, s), 2.33,(3H, s). LCMS; retention time 3.50 min, MH+ 418.
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:6]=[C:7]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([Cl:19])[CH:12]=3)[CH:8]=[N:9][CH:10]=2)[CH2:4][CH2:3]1.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21]>C(Cl)Cl>[Cl:19][C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]([C:2]3([NH:1][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[CH2:3][CH2:4]3)[CH:10]=[N:9][CH:8]=2)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1ccc(-c2cncc(C3(N)CC3)c2)cc1Cl
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCS(=O)(=O)NC1(c2cncc(-c3ccc(C#N)c(Cl)c3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-(1-aminocyclopropyl)pyridin-3-yl)-2-chlorobenzonitrile (70 mg, 0.26 mmol) in DCM (3 mL) at room temperature was added TEA (0.109 mL, 0.779 mmol) and EtSO2Cl (74 μL, 0.779 mmol) dropwise, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, re-dissolved in DMF (3 mL) and filtered. The filtrate was purified by Xbridge Phenyl followed by Xbridge C18 eluting with 20-80% ACN-water gradient to give N-(1-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)cyclopropyl)ethanesulfonamide. HRMS: (ESI) m/z 362.0712 [(M+H)+ Calcd for C97H96ClN3O2S 362.0725]. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.3 Hz, 3H), 1.32-1.38 (m, 2H), 1.49-1.54 (m, 2H), 2.90 (q, J=7.4 Hz, 2H), 7.60 (dd, J=8.1, 1.8 Hz, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H), 8.01 (t, J=2.3 Hz, 1H), 8.67 (d, J=2.3 Hz, 1H), 8.72 (d, J=2.3 Hz, 1H).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][C:9]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)(=O)=O.[NH:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20]1>>[OH:18][C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:10][CH2:11][CH:6]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20]2)[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CS(=O)(=O)OC1CCC(O)(c2ccccn2)CC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C2CCC(O)(c3ccccn3)CC2)C1
Reaction time: 0.25 h

Procedure:
The 4-hydroxy-4-pyridin-2-ylcyclohexyl methanesulfonate (0.245 g, 0.9 mmol) and tert-butyl (3R)-pyrrolidine-3-ylcarbamate (1.6 g, 8.59 mmol) were weighed into a microwave oven tube. The neat reaction mixture was placed into the microwave oven for 15 minutes at 71° C. The mixture was chromatographed on silica gel, eluting with 1% NH4OH in ethyl acetate/methanol (100/0 to 10/90), providing tert-butyl [(3R)-1-(4-hydroxy-4-pyridin-2-ylcyclohexyl)pyrrolidin-3-yl]carbamate. LC/MS: 362.2 (M+H, 100%). 1H NMR (CDCl3) δ 8.52 (m, 1H), 7.70 (m, 1H), 7.43 (d, 1H), 7.19 (m, 1H), 4.86 (bs, 2H), 4.20 (bs, 1H), 2.82 (m, 1H), 2.68 (s, 1H), 2.56 (m, 1H), 2.40 (m, 1H), 2.31 (s, 1H), 2.27-2.17 (m, 3H), 2.04-1.98 (m, 2H), 1.78-1.74 (m, 3H), 1.61 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1[NH:8][C:9](=[O:17])[C:10]2[CH2:16][O:15][CH2:14][CH2:13][C:11]=2[N:12]=1.[F:23][C:24]1[CH:41]=[CH:40][C:27]([C:28]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37](O)=[O:38])[CH2:32][CH2:31]2)=[O:29])=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]([CH2:6][C:7]1[NH:8][C:9](=[O:17])[C:10]2[CH2:16][O:15][CH2:14][CH2:13][C:11]=2[N:12]=1)[C:37](=[O:38])[CH2:36][N:33]1[CH2:34][CH2:35][CH:30]([C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([F:23])=[CH:41][CH:40]=2)[CH2:31][CH2:32]1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: O=c1[nH]c(CNCc2ccc(F)cc2F)nc2c1COCC2
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)Cc2ccc(F)cc2F)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (33 mg) from 2-((2,4-difluorobenzylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C29H29F3N4O4 554.7. found 555.4 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.26-7.43 (m, 1H) 7.20 (t, J=8.59 Hz, 2H) 6.80-6.99 (m, 1H) 4.54-4.75 (m, 4H) 4.49 (d, J=10.61 Hz, 4H) 3.86-4.00 (m, 3H) 3.74 (br. s., 3H) 3.43 (br. s., 5H) 2.63-2.79 (m, 2H) 2.44 (br. s., 1H) 2.24 (br. s., 2H) 2.12 (s, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=O)C.[CH:14]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]=[C:28]3[C:34]([NH2:35])=[CH:33][N:32]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:29]3=[N:30][CH:31]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>C(Cl)Cl>[OH:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:35][C:34]1[C:28]2[C:29](=[N:30][CH:31]=[C:26]([C:23]3[CH:24]=[CH:25][C:20]([S:17]([CH:14]([CH3:16])[CH3:15])(=[O:19])=[O:18])=[CH:21][CH:22]=3)[N:27]=2)[N:32]([C:36]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=1)=[O:9]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(NC(=O)c2ccccc2O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 5 mL microwave vial was charged with 2-acetoxybenzoic acid (33.87 mg, 0.1880 mmol) To this was added a solution of 2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-amine (100 mg, 0.1790 mmol), TBTU in DCM (1 mL) followed by PS-NMM. The reaction was shaken for 3 hours at ambient temperature then filtered and the resin washed with DCM (1 mL). This crude mixture was taken onto the next step as is.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([N:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[CH2:28]=[C:29]([CH3:31])[CH3:30]>C(#N)C>[CH3:28][C:29]1([CH3:31])[C:4]2[C:5](=[CH:17][CH:18]=[C:2]([CH3:1])[CH:3]=2)[NH:6][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:30]1
Reactant: C=C(C)C
Reactant: Cc1ccc(N=Cc2ccccc2[N+](=O)[O-])cc1
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Product: Cc1ccc2c(c1)C(C)(C)CC(c1ccccc1[N+](=O)[O-])N2
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a suspension of 4-methyl-N-(2-nitrobenzylidene)aniline (10 g) and boron trifluoride etherate (3 mL) in anhydrous acetonitrile was added isobutene (70 mL, pre-cooled to −78° C.) at ice-bath. After addition, the resulting mixture was stirred at 90° C. in sealed tube overnight. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give 4,4,6-trimethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline (10.5 g, yield 85.4%). LC/MS m/e obsd. (ESI+) [(M+H)+] 297.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N)[CH2:27][NH2:28].Cl>CN(C)C=O>[C:27]([C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])#[N:28]
Reactant: NCCN
Reactant: CCCCCCC(C)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1Br
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCCCC(C)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1C#N
Temperature: 25 °C

Procedure:
A mixture of S 3'-bromo-4'-(1-methylheptyloxy)-4-biphenylcarboxylic acid (56.7 g), cuprous cyanide (16.3 g) and dimethylformamide (140 ml) was heated for 12 hours under reflux, followed by cooling the resulting material to room temperature, treating with 10 wt. % ethylenediamine aqueous solution (700 ml), acidifying with 6N hydrochloric acid, collecting the precipitates by filtration, washing with boiling water, dry-sucking and recrystallizing from acetic acid to obtain S 3'-cyano-4'-(1-methylheptyloxy)-4-biphenylcarboxylic acid (40.8 g) (C-S, 100.0° C., S-I, 138.7° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:22](Cl)=[O:23]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:22]([C:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[S:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:23]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: COc1ccc(-c2cc3ccccc3s2)cc1
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2cc(C)cc(C)c2)cc1

Procedure:
When 2-p-methoxyphenylbenzothiophene was acylated with 3,5-dimethylbenzoyl chloride as described in the procedure of Example 1, 3-(3',5'-dimethylbenzoyl)-2-(4'-methoxyphenyl)benzothiophene was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH2:16][O:17][CH3:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]2[N:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30](OC)=[O:31])=[N:28][CH:29]=3)[O:21][N:20]=2)[N:3]=1.[BH4-].[Na+]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH2:16][O:17][CH3:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]2[N:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][OH:31])=[N:28][CH:29]=3)[O:21][N:20]=2)[N:3]=1
Reactant: COCCN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(=O)OC)nc3)n2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(CO)nc3)n2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
To a solution of methyl 5-(3-{4-amino-6-[(2-methoxyethyl)(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridine-2-carboxylate (Example 311, 212 mg, 0.472 mmol) in anhydrous THF (50 mL) at 0 C, under nitrogen, was added sodium borohydride (45 mg, 1.18 mmol) portion-wise. The resulting reaction mixture was stirred at room temperature for 16 h and then quenched with a saturated ammonium chloride aq. solution (10 mL). The solution was extracted into EtOAc (3×25 mL) and combined organics washed with brine, dried over magnesium sulfate and evaporated to dryness to afford the title compound as a yellow solid (186 mg, 94%). Method C HPLC-MS: MH+ requires m/z=421. Found: m/z=421, Rt=1.19 min (73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[F:17][C:18]([F:29])([F:28])[CH2:19]OS(C(Cl)(Cl)Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]2[CH2:7][CH2:8][N:9]([CH2:19][C:18]([F:29])([F:28])[F:17])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(CC(F)(F)F)CC2
Yield: 46.3 %

Procedure:
Into a 1-neck round-bottom flask was added 7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.500 g, 2.2 mmol), trichloro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (0.45 mL, 2.9 mmol), and potassium carbonate (0.91 g, 6.61 mmol), in N,N-dimethylformamide (5 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was partitioned between saturated aqueous Na2CO3 and dichloromethane. Extraction with another portion of dichloromethane, drying (MgSO4), concentration and flash chromatography isolation (on SiO2, MeOH/dichloromethane 0-3%) provided 7-methoxy-8-nitro-3-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (310 mg, 46%) as a yellow oil. 1H-NMR (CDCl3) δ 7.65 (s, 1H), 6.83 (s, 1H), 3.74 (s, 3H), 3.19 (q, J=9.6 Hz, 2H), 2.95 (m, 4H), 2.88 (s, 4H); LC/MS (ESI+): 305.05 (M+H).
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:17]3[CH2:23][CH2:22][NH:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([N:21]2[CH2:22][CH2:23][C:17]3[C:16]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[N:15][C:14]([C:11]4[CH:10]=[CH:9][C:8]([NH:7][C:5]([NH:4][CH2:2][CH3:3])=[O:6])=[CH:13][CH:12]=4)=[N:19][C:18]=3[CH2:20]2)=[O:36])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Agent: Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2ccc(Cl)cc2)C3)cc1

Procedure:
The compound pa was prepared following the general procedure described in Example 5 by reacting 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt with 4-Chlorobenzoic acid chloride: LC-MS m/z=521 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](O)=[O:31]>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[O:31])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)c1ccccn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Product: C[C@@]1(c2cc(NC(=O)c3ccccn3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound. MS (ESI): m/z=329.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=1.Cl.O1CCOCC1.O>>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:13]=[CH:12][C:5]3[C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)OCCNC2=O
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)OCCNC3=O)ncc1Cl
Temperature: 100 °C
Yield: 73.2 %

Procedure:
A mixture of 8-amino-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.092 g, 0.0003 mol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (0.05 g, 0.00028 mol), 4 N HCl in dioxane/water (0.07 mL, 0.00028 mol) was heated at 100° C. for 4 hrs. The slurry was evaporated and the residue treated with ethyl acetate and a 10% sodium carbonate solution. The insoluble solid was collected, washed, dried to give 2-[5-chloro-2-(5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (0.09 g, 74%) as a yellow solid. MP: 293-5° C.; 1H-NMR (DMSO-d6) δ 11.62 (s, 1H), 9.74 (s, 1H), 8.72-6 (d, 1H), 8.70 (d, 1H) 8.29 (s, 1H) 8.11 (s, 1H), 7.77 (m, 2H), 7.51-3 (d, 2H), 7.33-5 (d, 1H), 7.15-9 (t, 1H), 4.27 (s, 1H); LC/MS (ESI+): 439 (M+H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[N:31]1([CH2:38][CH2:39][O:40][C:41]2[CH:42]=[CH:43][C:44]([C:47]([O-])=O)=[N:45][CH:46]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.[Na+]>>[N:31]1([CH2:38][CH2:39][O:40][C:41]2[CH:42]=[CH:43][C:44]([CH2:47][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[CH:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[N:45][CH:46]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CCNc1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C([O-])c1ccc(OCCN2CCCCCC2)cn1
Agent: [Na+]
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cn1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 47.1 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and sodium 5-(2-azepan-1-ylethoxy)pyridine-2-carboxylate (60 mg) according to an analogous synthetic method to Example 152, the title compound (16 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1>CN(C=O)C>[CH3:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])[CH:18]=1
Reactant: CN1CC(=O)NC1=NC(=O)O
Reactant: Cc1ccnc(N)c1
Solvent: CN(C)C=O
Product: Cc1ccnc(NC(=O)N=C2NC(=O)CN2C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 12.7 %

Procedure:
A mixture of 3.0 g (12.8 mM) of the phenyl carbamate 8 and 2.8 g (25.7 mM) of 2-amino-4-methylpyridine in 25 ml of anhydrous DMF was stirred at 25° C. for 5 hrs., filtered and the filtrate diluted with 150 ml of water. The resulting precipitate was collected and recrystallized from ethanol to give 0.6 g of the above urea as a pale yellow solid, m.p. 231°-232° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:35]=[N:34][C:33]([Br:36])=[CH:32][N:31]=1.N1C=CC=CC=1>CN(C)C=O.C(Cl)Cl>[Br:36][C:33]1[N:34]=[CH:35][C:30]([NH:29][C:13](=[O:15])[CH:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]2)=[N:31][CH:32]=1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)O)cc1Cl
Reactant: Nc1cnc(Br)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionic acid (prepared as in Example 45, 1.05 g, 3.04 mmol) and N,N-dimethylformamide (5 drops) in methylene chloride (10 mL) cooled to 0° C. was treated with oxalyl chloride (0.39 mL, 4.57 mmol). The reaction mixture was stirred at 0° C. for 1 h and then at 25° C. for 1 h. The solution was then concentrated in vacuo, and the orange-brown gel was dissolved in methylene chloride (5 mL). The resulting solution was added dropwise via an addition funnel at 0° C. to a solution of 2-amino-5-bromopyrazine (0.79 g, 4.57 mmol, prepared according to Tetrahedron 1988, 44, 2977–2983) in methylene chloride (5 mL) and pyridine (0.37 mL, 4.57 mmol). The reaction mixture was stirred at 0° C. for 30 min and then at 25° C. for 3 h. The reaction mixture was quenched with a 1N aqueous citric acid solution (10 mL) and stirred for 15 min. The reaction was then diluted with a 1N aqueous citric acid solution (50 mL) and ethyl acetate (75 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL), and a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 50% ethyl acetate/hexanes) afforded N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionamide (0.622 g, 41%) as a yellow-orange foam: mp 97–103° C. (foam to gel); (ES)+-HRMS m/e calcd for C19H19BrClN3O4S (M+H)+ 500.0041 found 500.0048.
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH2:22].C1(N)C(F)=C(F)C(F)=[C:25]([NH2:32])C=1F.Cl.Cl>CO>[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH:22][C:3]1[C:7]([NH:32][CH3:25])=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: Cc1[nH]cnc1CSCCN
Reactant: COC1=NS(=O)(=O)N=C1OC
Agent: Cl
Solvent: CO
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1nc[nH]c1C
Reaction time: 0.5 h

Procedure:
To a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.5 g; 14.0 mmoles) in 250 ml of dry methanol that had been cooled to 2° in an ice-water bath was added dropwise over a period of 25 minutes a solution of 2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamine (from the dihydrochloride, 3.42 g; 14.0 mmoles) in 25 ml of methanol. After stirring at 2° for 20 minutes, anhydrous methylamine was bubbled into the solution for 6 minutes and stirring was continued at ambient temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure and the residue was placed on 50 g of silica gel and chromatographed by gradient elution using methylene chloride-methanol. The appropriate fractions were combined to give 3.2 g of the title compound. Additional purification of the product using column chromatography gave an analytical sample of the title compound as an amorphous solid, mp 98°-110°. The NMR spectrum (100 MHz) in d6 dimethyl sulfoxide gave the following resonances δ: 7.46 (s, 1H); 3.70 (s, 2H); 2.53 (t, 2H); 2.86 (s, 3H); 2.72 (t, 2H); 2.15 (s, 3H).