Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18](N(C(C)C)CC)(C)C.CI>C(#N)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]([N:15]([CH3:18])[C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#CNc1cccc(SCc2ccccc2)c1
Solvent: CI
Solvent: CC#N
Product: CN(C#N)c1cccc(SCc2ccccc2)c1
Temperature: 82.5 °C
Yield: 80 %

Procedure:
To a solution of 3-(benzylthio)phenylcyanamide (0.80 g, 3.33 mmol) dissolved in acetonitrile (8 mL) was added diisopropylethylamine (0.65 g, 5.0 mmol), followed by addition of methyl iodide (0.94 g, 6.66 mmol). The reaction mixture was refluxed at 80-85° C. for 3 hours. After removal of solvents the residue was taken by dichloromethane (40 ml) and the organic solution was washed by water (40 ml). After dried over MgSO4 and filtered, dichloromethane solution was then concentrated in vacuo to afford yellow oil as crude product. Purification by column chromatography (SiO2, Hexane/CH2Cl2, 50% to 100%) to afford 3-(benzylthio)phenyl-N-methylcyanamide as a pale yellow oil (0.67, 80% yield): CH2Cl2 Rf=0.45; 1H-NMR (CDCl3) δ (ppm) 7.3-6.8 (m, 9H, Ar—H), 4.06 (s, S—CH2, 2H), 3.57 (s, 3H, N—CH3).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[C:25]([OH:30])[CH:24]=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:44][C:45]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=1[CH2:52][CH2:53]O>C1COCC1>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[C:25]([O:30][CH2:53][CH2:52][C:46]2[CH:47]=[CH:48][C:49]([Cl:51])=[CH:50][C:45]=2[Cl:44])[CH:24]=1
Reactant: COC(=O)c1ccc(Br)c(O)c1
Reactant: OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1.6 g of triphenylphosphine and 1 g of 4-Bromo-3-hydroxy-benzoic acid methyl ester were dissolved in 15 ml of anhydrous THF. The solution was cooled to 0° C. to 10° C. and a solution of 0.88 ml DEAD in 5 ml anhydrous THF was added dropwise over 20 min. The reaction was warmed to RT and stirred for 45 min. A solution of 0.69 ml 2-(2,4-Dichlorophenyl)-ethanol in 2 ml anhydrous THF was added with cooling. The reaction was stirred at RT for 3 h, then the solvents were removed under reduced pressure. The residue was treated with n-heptane:ethyl acetate/1:1. The filtrate was dried under reduced pressure. The product was purified by silica gel chromatography, eluting with n-heptane:ethyl acetate/4:1 to n-heptane:ethyl acetate/1:1. Yield 2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:35][CH2:34]1>>[CH2:39]([N:36]1[CH2:37][CH2:38][CH:33]([NH:32][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:30])[F:29])[C:9]=4[CH:17]=3)=[CH:19][CH:20]=2)[CH2:34][CH2:35]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-amino-1-benzylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=619.99 (M+H+); retention time=0.61 minutes.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[N:8]=[CH:7][N:6]=1>C(O)C>[CH:17]1([N:14]2[CH2:15][CH2:16][N:11]([C:9]3[CH:10]=[C:5]([NH:2][NH2:3])[N:6]=[CH:7][N:8]=3)[CH2:12][CH2:13]2)[CH2:20][CH2:19][CH2:18]1
Reactant: NN
Reactant: Clc1cc(N2CCN(C3CCC3)CC2)ncn1
Solvent: O
Solvent: CCO
Product: NNc1cc(N2CCN(C3CCC3)CC2)ncn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
At RT, 4.4 ml (4.5 g, 89.7 mmol) of hydrazine hydrate are added dropwise with stirring to a solution of 1.9 g (7.5 mmol) of 4-chloro-6-(4-cyclobutylpiperazin-1-yl)pyrimidine in 28 ml of ethanol. The reaction solution is stirred at 80° C. for 16 h. For work-up, the mixture is concentrated under reduced pressure, the residue is triturated repeatedly with diethyl ether, and the precipitated solid is filtered off and dried under reduced pressure. The residue is then purified by column chromatography on silica gel (mobile phase dichloromethane/methanol 10/2). Yield: 1.5 g (80% of theory)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N1CCC(=O)CC1)=O)C1C=CC=CC=1.Cl[C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46]=[CH:45][N:44]=1.[Cl-].[Li+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]=[C:14]([C:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[N:46]=[CH:45][N:44]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: Clc1ncnc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Cl-]
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CC=C(c2ncnc3ccccc23)CC1
Yield: 73 %

Procedure:
To a 25 mL flask was charged 4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (prepared from 4-Oxo-piperidine-1-carboxylic acid benzyl ester according to the literature: Wustrow, D. J. et. al. (1991), Synthesis, 993-995. 1.14 g, 3.12 mmol), 4-chloroquinazoline (0.512 g, 3.12 mmol), lithium chloride (0.397 g, 9.36 mmol), Pd(PPh3)4 (0.180 g, 0.156 mmol) and hexamethyl ditin (1.02 g, 3.12 mmol). 1,4-Dioxane (20 mL) was added and the reaction was degassed with N2 for 15 minutes. The mixture was stirred at reflux overnight. After cooling, the black suspension was poured into saturated aqueous potassium fluoride solution. The mixture was diluted with EtOAc and stirred for 2 hours. The organic phase was separated. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 2:3) to give 4-Quinazolin-4-yl-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (0.790 g, 73%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 9.27 (s, 1H), 8.19 (d, J=7.2 Hz, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.91 (m, 1H), 7.62 (t, J=7.2 Hz, 1H), 7.41 (m, 6H), 6.18 (m, 1H), 5.23 (s, 2H), 4.32 (s, 2H), 3.85 (t, J=5.6 Hz, 1H), 2.80 (br s, 2H). LCMS (APCI+) m/z 346 [M+H]+; Rt=3.16 min.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH:4]([CH3:6])[CH3:5].[NH2:8][C:9]([NH2:11])=[S:10]>CCO>[CH:4]([C:3]1[N:8]=[C:9]([NH2:11])[S:10][CH:2]=1)([CH3:6])[CH3:5]
Reactant: NC(N)=S
Reactant: CC(C)C(=O)CBr
Solvent: CCO
Product: CC(C)c1csc(N)n1
Yield: 91.4 %

Procedure:
1-Bromo-3-methyl-butan-2-one (10.5 g, 64 mmol, prepared as described in Org. Syn. Coll. Vol. 6, p. 193 (1988)) was added to a stirring slurry of thiourea (4.601 g, 60 mmol) in 20 mL EtOH. The reaction mixture was heated to reflux for 90 minutes, then cooled and concentrated under reduced pressure. The residue was dissolved in water, and the resulting solution was diluted with concentrated aqueous NaOH until pH was adjusted to about 12. The mixture was extracted with diethyl ether, and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to give 4-isopropyl-thiazol-2-ylamine (7.8 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5](Br)=[CH:4][C:3]=1[F:10].C(=O)=O.CC(C)=O.[Li]CCCC.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25].[Cl-].[NH4+]>CCOCC>[Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Si:24]([CH3:26])([CH3:25])[CH3:23])=[C:6]([F:8])[CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: Fc1cc(Br)c(F)cc1Br
Agent: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CCOCC
Product: C[Si](C)(C)c1cc(F)c(Br)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To a solution of 1,4-dibromo-2,5-difluorobenzene (5 g, 18.4 mmol) in anhydrous Et2O (60 mL) at −78° C. (dry ice/acetone bath) was added n-BuLi (7.72 mL, 19.31 mmol) dropwise. The reaction mixture was stirred at −78° C. for 30 minutes (min) (light yellow color), then TMSCl (2.59 mL, 20.23 mmol) was added. The reaction mixture was allowed to slowly warm to 20° C. and was stirred for 12 h. The reaction mixture was poured into a saturated (satd) aqueous (aq) ammonium chloride solution (NH4Cl; 150 mL), and the crude product was extracted with Et2O (3×). The combined organic layers were washed with satd aq NaCl, dried over MgSO4, filtered and concentrated (orange/brown oil). The residue was purified by column chromatography (silica gel (SiO2), eluting with hexanes) to afford the title compound as a colorless oil (4.17 g, 86%): 1H NMR (400 MHz, CDCl3) δ 7.20 (dd, J=7.1, 5.1 Hz, 1H), 7.09 (dd, J=8.0, 4.4 Hz, 1H), 0.31 (d, J=0.9 Hz, 9H); 19F NMR (376 MHz, CDCl3) δ −105.42, −115.48; EIMS m/z 266.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].[Br:11]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:11][CH:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[C:5]#[N:6]
Reactant: N#CCc1ccccc1Cl
Reactant: NC(=O)CCC(=O)NBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(Br)c1ccccc1Cl
Yield: 65.7 %

Procedure:
To a solution of 2-chlorobenzylcyanide (1.0 g, 6.60 mmol) in CCl4 (25 mL) was added N-bromosuccinamide (1.29 g, 7.26 mmol) and 2,2′-azobis-(2-methylpropionitrile) (0.05 g, 0.33 mmol). The reaction mixture was allowed to reflux for 48 h. The reaction mixture was then diluted with EtOAc (50 mL) and washed with 0.1 M NaOH (50 mL). The organic phase was concentrated to dryness yielding 1.0 g (66%) product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5].C1(CC(O)=O)C=CC=CC=1.[C:22]1([NH:28][C:29](=[O:52])[CH:30]([CH:36]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:37]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=O)[C:31](=O)[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[C:22]1([NH:28][C:29]([C:30]2[C:36]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)=[C:37]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[N:1]([CH2:2][CH2:3][C:4]([N:6]3[CH2:11][CH2:10][O:9][CH2:8][CH2:7]3)=[O:5])[C:31]=2[CH:32]([CH3:34])[CH3:33])=[O:52])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: NCCC(=O)N1CCOCC1
Agent: O=C(O)Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC(=O)N1CCOCC1

Procedure:
A nitrogen inerted reactor, equipped with a suitable reflux condenser and soxhlet extractor containing freshly activated 3A molecular sieves (4-8 mesh; 97.2 g), is charged with 3-amino-1-morpholin-4-yl-propan-1-one, compound with phenylacetic acid (765 mmol) and 2-[2-(4-fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoic acid phenylamide (450 mmol). THF (360 mL) is added, and the resulting solution is stirred vigorously as the reaction is heated at reflux temperature for ca. 24 hours, during which time the product begins to precipitate. Half-saturated aqueous NaHCO3 (100 mL) is added, and the reaction mixture is cooled with continued stirring to ca. 0° C. MtBE (100 mL) is added, and the solids are collected via filtration. The solid is washed with distilled water (100 mL) and MtBE (2×100 mL), collected, and dried under vacuum at ≦50° C. to afford 5-(4-fluorophenyl)-2-isopropyl-1-(3-morpholin-4-yl-3-oxo-propyl)-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide as a white solid (194 g). This material is carried on to subsequent steps without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[C:19]1([CH3:32])[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH:26][CH:27]=[CH:28][C:29](=[O:31])[CH3:30])[CH:20]=1>>[C:29]([C:28]1[CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:26]([CH2:25][C:21]2[CH:20]=[C:19]([CH3:32])[CH:24]=[CH:23][CH:22]=2)[CH:27]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)C=CNCc1cccc(C)c1
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3cccc(C)c3)C=C1C(C)=O)C2=O

Procedure:
The title compound 61 is prepared according to the procedure reported in step D of Example 8 with aldehyde 54 (100 mg, 0.41 mmol) and enamine 62 (80 mg, 0.42 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=2:1) afford the title compound 61 as a yellow solid. (Yield 115 mg, 68%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH:11][C:12]2[N:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)=[CH:2]1.[NH2:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([CH3:34])([CH3:33])[CH2:27][C:28](=[O:32])[NH:29]2)=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>O.CN(C=O)C>[CH3:33][C:26]1([CH3:34])[C:25]2[C:30](=[CH:31][C:22]([NH:21][C:14]([C:13]3[C:12]([NH:11][CH2:10][C:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:1][CH:2]=4)=[N:20][CH:19]=[CH:18][CH:17]=3)=[O:16])=[CH:23][CH:24]=2)[NH:29][C:28](=[O:32])[CH2:27]1
Reactant: CC1(C)CC(=O)Nc2cc(N)ccc21
Reactant: O=C(O)c1cccnc1NCc1c[nH]c2ncccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(=O)Nc2cc(NC(=O)c3cccnc3NCc3c[nH]c4ncccc34)ccc21
Reaction time: 24 h

Procedure:
2-((1H-Pyrrolo[2,3-b]pyridin-3-yl)methylamino)nicotinic acid (100 mg, 0.37 mmol), 7-amino-4,4-dimethyl-3,4-dihydroquinolin-2(1H)-one (65 mg, 0.37 mmol), TBTU (133 mg, 0.41 mmol) and DIEA (0.07 mL, 0.41 mmol) was added to DMF (1 mL). The reaction was run at RT for 24 h. The reaction was then diluted with water and the resultant precipitate was filtered and purified using flash column to afford product. MS (ES+): 441.5 (M+H). Calc'd. for C25H24N6O2—440.20.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:19][C:20]([CH:22]2[CH:26]=[CH:25][C:24](=NO)[O:23]2)=[O:21])[S:9][C:10]=1[C:11]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12].[CH2:29]([N:31](CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.C(=O)([O-])O.[Na+]>ClCCl>[C:29]([C:24]1[O:23][C:22]([C:20]([NH:19][C:8]2[S:9][C:10]([C:11]([CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[O:12])=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:7]=2)=[O:21])=[CH:26][CH:25]=1)#[N:31]
Reactant: O=C(c1sc(NC(=O)C2C=CC(=NO)O2)nc1-c1ccco1)C1CCOCC1
Reactant: CCN(CC)CC
Agent: CN1CC[NH+](C)C1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
Compound 514 (2.08 g, 5.00 mmol) and triethylamine (0.836 mL, 6.00 mmol) were suspended in dichloromethane (20 mL), and 2-chloro-1,3-dimethylimidazolinium chloride (2.03 g, 12.0 mmol) was added thereto at 0° C. This was stirred at 0° C. for 30 minutes, and then triethylamine (0.836 mL, 6.00 mmol) was added thereto, followed by stirring at 0° C. for 5 minutes. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=49:1), followed by recrystallizing from a mixed solvent (3:1) of ethanol and water to afford the entitled Compound 515 (1.26 g, 63%) as a pale brown solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[N:11]=[C:12](SC)[NH:13][CH:14]=2)=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:35]([F:38])([F:37])[F:36]>C(O)C>[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:12]3[NH:13][CH:14]=[C:9]([CH2:8][C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=4)[C:10](=[O:17])[N:11]=3)=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:35]([F:36])([F:37])[F:38]
Reactant: CSc1nc(=O)c(Cc2cnc(C)nc2)c[nH]1
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: CCO
Product: Cc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Yield: 69.5 %

Procedure:
5-(2-Methyl-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (30 mg, 248.31 gmol−1, 0.12 mmol, 1 eq) and 2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (57 mg, 315.73 gmol−1 0.18 mmol, 1.5 eq) were stirred in 300 μl of absolute ethanol at 125° C. for 50 hours. Solvent from the reaction mixture was evaporated and the resulting crude was purified by preparative HPLC-MS. The gathered fractions of appropriate composition were lyophilized and the resulting oily product was triturated with DCM and diethyl ether to afford 2-{2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-5-(2-methyl-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (43 mg, yield=65.5%, purity=95%) MS: [M+H]+=516.38. 1H NMR (300 MHz; CDCl3) δ/ppm 2.64 (s, 3H), 2.89 (t, J=7.0 Hz, 2H), 3.52 (s, 2H), 3.57-3.66 (m, 2H), 5.20 (br.s., 1H), 6.94 (d, J=7.75 Hz, 2H), 7.02 (d, J=9.26 Hz, 1H), 7.17-7.30 (m, 3H), 7.39 (d, J=8.70 Hz, 1H), 7.67 (s, 1H), 8.49 (s, 2H), 12.18 (br.s., 1H).
Reaction SMILES: C1COCC1.[H-].[Na+:7].[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)[CH2:9][CH3:10].Cl[CH2:19][C:20](=[O:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23]>O.CCOCC>[CH2:16]([O:15][C:13]([C:12]1[CH2:19][C:20]([O-:26])=[C:21]([C:22]([O:24][CH3:25])=[O:23])[C:8]=1[CH2:9][CH3:10])=[O:14])[CH3:17].[Na+:7]
Reactant: CCOC(=O)CC(=O)CC
Reactant: COC(=O)CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1=C(CC)C(C(=O)OC)=C([O-])C1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
A round bottom flask was charged with THF (1.5 L) followed by the portionwise addition of NaH (60% dispersion in mineral oil, 70.0 g, 1.75 mol). Additional THF (500 mL) was added and the resulting mixture was cooled to about −10° C. Ethyl propionylacetate (250 mL, 1.80 mol) was added dropwise over about 1 h in order to keep internal temperature below about 10° C. The resulting mixture was stirred at ambient temperature for about 0.5 h to give a clear yellow solution and then methyl 4-chloroacetoacetate (100 mL, 0.88 mol) was added dropwise over about 5 min. The resulting mixture was heated at about 50° C. for about 19 h to give a reddish orange suspension. The reaction mixture was cooled to ambient temperature, concd under reduced pressure and the resulting liquid was transferred to a beaker and diluted with water (350 mL). The mixture was stirred in an ice bath for about 2 h. The solid was collected by vacuum filtration and the filter cake was rinsed with water (150 mL) and dried under vacuum for about 1 h. The solid was suspended in Et2O (1.5 L), filtered, washed with Et2O (1.5 L), and dried under vacuum. The resulting solid was azeotroped with toluene (1 L) to give a solid that was re-suspended in Et2O (1 L) and collected by vacuum filtration. The filter cake was washed with Et2O (500 mL) and dried under vacuum to give sodium 4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate (204.2 g, 89%) as beige solid: 1H NMR (DMSO-d6) δ 3.94 (q, J=7.1 Hz, 2H), 3.46 (s, 3H), 3.04 (q, J=7.2 Hz, 2H), 2.66 (s, 2H), 1.13 (t, J=7.1 Hz, 3H), 0.99 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([O:16]C)=O)=[CH:10][CH:9]=1)=[O:6])[CH:2]=[CH2:3].N1([C:24]2[N:29]=[CH:28][C:27]([C:30](OC)=O)=[CH:26][CH:25]=2)CCOCC1>>[CH3:5][O:4][C:1]1[CH:30]=[C:27]([CH2:26][CH2:25][C:24]2[CH:9]=[C:8]([NH:13][C:14]([C:11]3[CH:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[O:4][CH2:1][CH:2]=[CH2:3])=[N:13][CH:12]=3)=[O:16])[NH:7][N:29]=2)[CH:28]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(N2CCOCC2)nc1
Reactant: C=CCOC(=O)Nc1ccc(C(=O)OC)cn1
Product: C=CCOC(=O)Nc1ccc(C(=O)Nc2cc(CCc3cccc(OC)c3)n[nH]2)cn1
Yield: 37 %

Procedure:
Methyl 6-(prop-2-enoxycarbonylamino)pyridine-3-carboxylate, used as starting material was prepared in an analogous manner to the synthesis of methyl 6-morpholin-4-ylpyridine-3-carboxylate in Example 32, but starting with 6-(prop-2-enoxycarbonylamino)pyridine-3-carboxylic acid carboxylate (880 mg, 3.96 mmol) to give the title compound (0.35 g, 37%); 1H NMR (400.132 MHz, CDCl3) 3.93 (s, 3H), 4.75 (dt, 2H), 5.32 (dq, 1H), 5.41 (dq, 1H), 6.09-5.99 (m, 1H), 8.07 (d, 1H), 8.30 (dd, 1H), 8.97 (d, 1H), 9.45 (brs, 1H); MH+237.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[N:22]([CH3:23])[C:21](=[O:24])[CH2:20][CH2:19][N:18]([CH:25]3[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26]3)[C:17]=2[N:31]=1)[C:6]([OH:8])=O.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:65][CH:66]1[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[N:22]([CH3:23])[C:21](=[O:24])[CH2:20][CH2:19][N:18]([CH:25]3[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26]3)[C:17]=2[N:31]=1)[C:6]([NH:65][CH:66]1[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]1)=[O:8]
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCC(C)C1)CCC(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCC(C)C1)CCC(=O)N2C
Reaction time: 0.08 h
Yield: 93.9 %

Procedure:
A mixture of 0.043 g (0.0001 mole) of (rac)-3-methoxy-4-[5-methyl-9-(3-methyl-cyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-benzoic acid (I-58a), 0.042 g (0.00011 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.044 mL (0.00025 mole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.017 g (0.00015 mole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (20:80-100:0) to give 0.049 g of (rac)-3-methoxy-4-[5-methyl-9-(3-methyl-cyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-N-(1-methyl-piperidin-4-yl)-benzamide (I-58) as a white solid.