Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][CH2:10][CH2:11][CH3:12])=O)=[CH:3][CH:2]=1.[C:13]([NH:21][NH2:22])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7](=[N:22][NH:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:3][CH:2]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CCCCC(=O)c1ccncc1
Solvent: CCO
Product: CCCCC(=NNC(=O)c1ccccc1)c1ccncc1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A mixture of 5.97 gm (0.0366 mole) of n-butyl 4-pyridinyl ketone, 5.45 gm (0.04 mole) of benzoic acid hydrazide and 100 ml of absolute ethanol is refluxed 4.5 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point, cooled to room temperature and chilled. The solids which deposit are collected, washed with water and dried to yield 7.89 gm (77%) of the title compound having a melting point of 142.1° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:8]([O:29][CH3:30])=[C:9]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:28])=[C:18]([N:20]3[CH:24]=[C:23]([C:25]([OH:27])=O)[CH:22]=[N:21]3)[CH:19]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[N:40]1[CH:41]=[CH:42][CH:43]=[C:38]([CH2:37][NH:36][C:25]([C:23]2[CH:22]=[N:21][N:20]([C:18]3[CH:19]=[C:14]([C:12](=[O:13])[NH:11][C:9]4[CH:10]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=[C:7]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:8]=4[O:29][CH3:30])[CH:15]=[CH:16][C:17]=3[CH3:28])[CH:24]=2)=[O:27])[CH:39]=1
Reactant: NCc1cccnc1
Reactant: COc1c(NC(=O)c2ccc(C)c(-n3cc(C(=O)O)cn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(C(=O)NCc4cccnc4)cn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 8 h
Yield: 54.2 %

Procedure:
The above carboxylic acid (75 mg, 0.15 mmol), 3-(aminomethyl)pyridine (25 mg, 0.23 mmol) and HATU (85 mg, 0.23 mmol) were dissolved in DMF (1.5 mL). N,N-Diisopropylethylamine (78 μL, 0.45 mmol) was added and the reaction was stirred overnight. Water was added and the resulting solution was extracted with CH2Cl2 (4×30 mL). The combined organic extracts were washed with 5% LiCl solution, dried over MgSO4, filtered, and concentrated. The residue was purified by semi-prep HPLC. The product fractions were concentrated and sodium bicarbonate added. The resulting solid was collected by vacuum filtration, washed with water, and dried under vacuum at 55° C. to provide the title compound (48 mg, 54%) as white solid: mp 127-133° C.; ESI MS m/z 591 [C30H34N6O5S+H]+; HPLC>95%, tR=15.03 min.
Reaction SMILES: C([N:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[N:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:23])C1C=CC=CC=1>[Pd].C([O-])=O.[NH4+]>[CH2:16]([N:10]1[C:11](=[O:15])[C:12]([CH3:14])=[CH:13][NH:8][C:9]1=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cn(Cc2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: Cc1c[nH]c(=O)n(Cc2ccccc2)c1=O

Procedure:
A mixture of 1,3-dibenzyl-5-methyl-2,4(1H,3H)-pyrimidinedione (2 g, 6.5 mmol), 5% palladium on carbon (3 g) and 0.4N ammonium formate (250 mL in methanol) was heated 1.5 hours at reflux. The reaction mixture then was filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (95:5) to give 3-benzyl-5-methyl-2,4(1H,3H)-pyrimidinedione, m.p. 208°-210° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:36]([O:35][C:33]([CH2:32][CH2:31][CH2:30][NH:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28])=[O:34])[CH3:37]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 100 °C
Reaction time: 48 h
Yield: 54.1 %

Procedure:
1.03 g (2.64 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one obtained in Example 66 was dissolved in 30 mL of dimethylformamide under argon atmosphere, 11.5 mL (79.2 mmol) of ethyl 4-bromobutyrate, 1.83 g (13.3 mmol) of potassium carbonate and 3.96 g (26.4 mmol) of sodium iodide were added and the mixture was stirred at 100° C. for 48 hours. The reaction solution was cooled on ice, an aqueous saturated solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:acetonitrile=25:l) and recrystallized from ethyl acetate/n-hexane to give 720 mg of 5-(3-ethoxycarbonylpropylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one (yield: 54%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23]Br)=[CH:17][CH:16]=1.[C-]#N.[K+].[CH3:28][N:29](C)C=O>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][C:28]#[N:29])=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCBr)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCC#N)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of 3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl bromide (1.5 g), powdered potassium cyanide (1.52 g) and N,N-dimethylformamide (30 ml) was stirred for 3 hours at 80° C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), which was then concentrated to give 4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]butyronitrile (1.2 g, 92%). Recrystallization of the product from ethyl acetate--hexane gave colorless needles, m.p.73°-74° C.
Reaction SMILES: Cl[CH:2]([N:9]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[O:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[P:16]([S-:24])([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[S:17].[K+].C1C=CC=CC=1>CC(C)=O>[P:16]([S:24][CH:2]([N:9]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[O:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[S:17])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]
Reactant: Cc1cc(=O)n(C(Cl)c2ccccc2)o1
Reactant: CCOP(=S)([S-])OCC
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)SC(c1ccccc1)n1oc(C)cc1=O
Yield: 62.2 %

Procedure:
To a solution of 1.12 g of 2-(α-chlorobenzyl)-5-methyl-4-isoxazolin-3-one in 15 ml of acetone were added 1.12 g of potassium O,O-diethyl dithiophosphate, and the mixture was then shaken for several minutes. After this, 20 ml of benzene were added to the reaction mixture and then most of the acetone was distilled off. After filtering the solution, the solvent was distilled from the filtrate and the remaining yellowish-brown oil was purified by column chromatography through silica gel eluted with a 20:1 by volume mixture of benzene and acetone. There were obtained 1.16 g (62.0% of theory) of O,O-diethyl S-[α-(5-methyl-3-oxo-4-isoxazolin-2-yl)benzyl] phosphorodithioate, in the form of a pale yellow oil, n23D =1.5697.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([O:32]C)=[O:31])[C:18]([C:34]([F:37])([F:36])[F:35])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.O[Li].O.O.CO>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([OH:32])=[O:31])[C:18]([C:34]([F:36])([F:35])[F:37])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2cccc(N3CCN(C)CC3)c2)ncc1C(F)(F)F
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 2-(2-(2-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I67) (150 mg, 292 μmol) was dissolved in a THF (10 mL), then LiOH.H2O (36.7 mg, 876 μmol) was added. Water (2 mL) then MeOH (1 mL) was added. The resulting mixture was stirred at room temperature for 16 hours then the volatiles were removed by evaporation under reduced pressure. The residue was dissolved in MeOH (3 mL) then acidified with concentrated HCl to pH 2-3. The volatiles were evaporated under reduced pressure to give an orange residue. The residue was chromatographed on silica gel (0-20% MeOH/DCM) to give the title compound (I68) (120 mg, 82%) as a yellow crystalline solid; 1H NMR (400 MHz, d6-DMSO) δ 11.04 (bs, 1H), 10.12 (s, 1H), 8.68 (s, 1H), 7.44 (m, 1H), 7.35 (m, 1H), 7.24-7.18 (m, 5H), 6.72 (m, 1H), 3.77-3.74 (m, partially obscured by residual water signal), 3.44 (m, 3H), 3.17-3.03 (m, 8H), 2.78 (s, 3H). LCMS Method C: rt 4.92 min; m/z 500.3 (M+1), 498.2 (M−1), 454.3 (M-COOH).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([CH3:25])=[N:7][C:8]2[N:9]([CH:19]=[C:20]([C:22]([OH:24])=O)[N:21]=2)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[N+:2]=[N-:3].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C1COCC1>[N:1]([CH2:4][C:5]1[C:6]([CH3:25])=[N:7][C:8]2[N:9]([CH:19]=[C:20]([C:22]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:24])[N:21]=2)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[N+:2]=[N-:3]
Reactant: Cc1nc2nc(C(=O)O)cn2c(-c2ccc(Cl)cc2Cl)c1CN=[N+]=[N-]
Reactant: C1COCCN1
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2nc(C(=O)N3CCOCC3)cn2c(-c2ccc(Cl)cc2Cl)c1CN=[N+]=[N-]
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a stirred solution of (+)-6-(azidomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylic acid (150 mg, 0.40 mmol) in THF (10 mL) was added morpholine (52 mg, 0.60 mmol), HOAt (81 mg, 0.60 mmol), EDC (114 mg, 0.60 mmol) and iPr2NEt (103 mg, 0.80 mmol). The reaction was kept at room temperature for 2 h and was concentrated under reduced pressure. The residue was diluted with EtOAc and the organic layer was washed with 1N HCl, 1N NaOH and brine prior to drying over anhydrous MgSO4. Filtration and concentration under reduced pressure afforded (+)-(6-(azidomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl)(morpholino)methanone (177 mg, 100% crude yield) as a clear glass.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][NH:21][CH2:22]4)=[CH:17][CH:16]=3)[N:12]=[C:11]([NH2:25])[N:10]=2)[CH2:5][CH2:4]1.F[C:27]1[N:32]=[CH:31][C:30]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([NH:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>>[NH2:25][C:11]1[N:12]=[C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]([C:27]4[N:32]=[CH:31][C:30]([C:33]5[CH:42]=[CH:41][C:36]([C:37]([NH:39][CH3:40])=[O:38])=[CH:35][CH:34]=5)=[CH:29][CH:28]=4)[CH2:22]3)=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)[N:10]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: CNC(=O)c1ccc(-c2ccc(F)nc2)cc1
Agent: Cl
Product: CNC(=O)c1ccc(-c2ccc(N3CCc4ccc(-c5cc(N6CCN(C)CC6)nc(N)n5)cc4C3)nc2)cc1

Procedure:
This compound was prepared from 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt and 4-(6-fluoropyridin-3-yl)-N-methylbenzamide using procedures analogous to those for Example 14. Analytic LCMS (M+H)+: m/z=535.5.
Reaction SMILES: C1COCC1.C[O:7][C:8](=[O:49])[C:9]([CH3:48])([CH3:47])[CH:10]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)=[CH:31][CH:30]=1)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:13][CH:12]=1.O[Li].O.[Li+].[OH-]>CO>[CH3:47][C:9]([CH3:48])([CH:10]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)=[CH:31][CH:30]=1)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:13][CH:12]=1)[C:8]([OH:49])=[O:7]
Reactant: COC(=O)C(C)(C)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Li+]
Agent: [Li]O
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C(=O)O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 24 h
Yield: 40.8 %

Procedure:
To a solution in methanol (8 mL) and THF (4 mL) of 2,2-dimethyl-3,3-bis(4-(2-quinolylmethoxy)phenyl)propionic acid methyl ester (0.4 g, 0.69 mmol), prepared as in step 2, was added LiOH.H2O (4 ml, 4 mmole, 1M solution) dropwise, and the mixture was stirred overnight after which an additional 2 mL of the LiOH solution was added and the mixture was stirred an additional 24 hours. The mixture was concentrated to dryness, acidified with excess 0.5M citric acid, diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. 1 o Purification by chromatography on silica gel (7% MeOH/CH2Cl2) provided 0.16 g (40%) of 2,2-dimethyl-3,3-bis(4-(2-quinolylmethoxy)phenyl)propionic acid as a white solid: mp 124°-127° C. Anal. Calc'd. for C37H32 N2O4 : C, 78.14; H, 5.67; N 4.92. Found C, 77.45; H, 5.74; N, 4.67.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:35])[C@@H:13]([N:18]2[CH2:22][C:21]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]4[CH2:32][CH2:31]4)[C:25]=3[F:33])=[CH:20][C:19]2=[O:34])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:7]1)C.[OH-].[Li+]>O1CCCC1>[CH:30]1([C:26]2[C:25]([F:33])=[C:24]([CH:29]=[CH:28][CH:27]=2)[O:23][C:21]2[CH2:22][N:18]([C@@H:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:12]([NH:11][C:8]3[CH:9]=[CH:10][N:6]([CH2:5][C:4]([OH:36])=[O:3])[N:7]=3)=[O:35])[C:19](=[O:34])[CH:20]=2)[CH2:32][CH2:31]1
Reactant: CCOC(=O)Cn1ccc(NC(=O)[C@H](CC(C)C)N2CC(Oc3cccc(C4CC4)c3F)=CC2=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)Nc1ccn(CC(=O)O)n1)N1CC(Oc2cccc(C3CC3)c2F)=CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
To a solution of (3-{(S)-2-[4-(3-cyclopropyl-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoylamino}-pyrazol-1-yl)-acetic acid ethyl ester (prepared as in Example 148, 0.130 g, 0.26 mmol) in tetrahydrofuran (5 mL) was added an aqueous lithium hydroxide solution (0.5N, 2 mL). The resulting mixture was stirred at room temperature for 3 h. The solvents were evaporated and the residue neutralized with 1N aqueous hydrochloric acid, extracted with ethyl acetate. The combined organic layers were washed with water, saturated sodium chloride solution and dried over sodium sulfate. The mixture was filtered and evaporated which afforded (3-{(S)-2-[4-(3-cyclopropyl-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoylamino}-pyrazol-1-yl)-acetic acid (0.118 g, 96%) as a white solid: HR-ES-MS m/z calculated for C24H27FN4O5 [M+H]+ 471.2038 observed 471.2036; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.72-0.81 (m, 2H), 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 0.97-1.06 (m, 2H), 1.37-1.51 (m, 1H), 1.52-1.65 (m, 1H), 1.65-1.82 (m, 1H), 2.00-2.15 (m, 1H), 4.21 (d, J=18.4 Hz, 1H), 4.59 (d, J=18.4 Hz, 1H), 4.62 (s, 2H), 4.86 (s, 1H), 4.85-4.93 (m, 1H), 6.42 (d, J=2.0 Hz, 1H), 6.94 (t, J=6.9 Hz, 1H), 7.15 (t, J=7.8 Hz, 1H), 7.21-7.31 (m, 1H), 7.54 (d, J=2.0 Hz, 1H), 10.75 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:17]2[C:16](=[O:28])[CH2:15][CH2:14][CH2:13][C:12]=2[NH:11][C:10]=1[CH3:29])=[O:8].Cl.[C:31]1([C:37]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[C:31]1([C:37]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:38][CH2:39][N:40]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]3[CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=4)[C:17]4[C:16](=[O:28])[CH2:15][CH2:14][CH2:13][C:12]=4[NH:11][C:10]=3[CH3:29])=[O:8])[CH2:41][CH2:42]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC1=C(C(=O)CCCCCCl)C(c2cccc([N+](=O)[O-])c2)C2=C(CCCC2=O)N1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CC1=C(C(=O)CCCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)C(c2cccc([N+](=O)[O-])c2)C2=C(CCCC2=O)N1

Procedure:
6.6 g (16 mmol) 3-(6-chlorohexanoyl)-1,4,5,6,7,8,-hexahydro-2-methyl-4-(3-nitrophenyl) 5-oxo-quinoline and 9 g( 32 mmol) 4,4-diphenylpiperidine hydrochloride are boiled under reflux with 2.5 g (16 mmol) sodium iodide and 7 g (66 mmol) sodium carbonate in 150 ml acetone for 6 days. The mixture is filtered and concentrated, and the residue is taken up in 150 ml ethyl acetate. The mixture is extracted by shaking with 40 ml sodium thiosulphate solution (5%). The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is chromatographed over silica gel with toluene/acetone=8/2. The title compound is obtained as a yellow oil. Yield: 8 g (82%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:27]=3)[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CS(=O)(=O)c1cccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)c1

Procedure:
5-Chloro-2-iodo-7-morpholinothiazolo[5,4-d]pyrimidine was reacted with 3-(methylsulfonyl)phenylboronic acid via General Procedure A to give crude 5-chloro-2-(3-(methylsulfonyl)phenyl)-7-morpholinothiazolo[5,4-d]pyrimidine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A again to give 132 after purification by reverse HPLC. MS (Q1) 470 (M+)
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([CH3:19])=[C:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:9]2)=[CH:4][CH:3]=1.[F:21][C:22]([F:28])([F:27])[CH2:23][C:24](O)=[O:25].Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([CH3:19])=[C:8]([CH:13]3[CH2:18][CH2:17][N:16]([C:24](=[O:25])[CH2:23][C:22]([F:28])([F:27])[F:21])[CH2:15][CH2:14]3)[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CC(F)(F)F
Reactant: Cc1c(C2CCNCC2)oc2c(C)c(O)ccc2c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C2CCN(C(=O)CC(F)(F)F)CC2)oc2c(C)c(O)ccc2c1=O
Yield: 13.6 %

Procedure:
A solution of 7-hydroxy-3,8-dimethyl-2-(piperidin-4-yl)-4H-chromen-4-one (68 mg, 0.25 mmol) obtained in Example 7-2, 3,3,3-trifluoropropionic acid (33 μL, 0.30 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 1.00 mmol), and diisopropylethylamine (86 μL, 0.50 mmol) in dimethylformamide (1.5 mL) was stirred at room temperature for 4 hours. The reaction solution was concentrated, and water was added to the obtained residue, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0→95/5) to obtain 13 mg of the title compound (yield: 13%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Product: CCOC(=O)CCCOc1ccc(O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
To a solution of 4-hydroxyphenol (3.3 g, 30 mmol) in ethanol (60 mL) was added K2CO3 (6.21 g, 45 mmol), Bu4NI (1.11 g, 3 mmol), and ethyl 4-bromobutanoate (4.68 g, 24 mmol). The resulting mixture was stirred at 60° C. overnight and filtered. To the filtrate was added water, and extracted with ethyl acetate, washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatograph on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford title product 0112-54 (1.6 g, 30%) as a brown solid. LCMS: 247 [M+23]+. 1H NMR (400 MHz, DMSO-d6): δ 1.26 (t, J=7.2 Hz, 3H), 2.08 (m, 2H), 2.51 (t, J=7.2 Hz, 2H), 3.93 (t, J=6.0 Hz, 2H), 4.15 (q, J=7.2 Hz, 2H), 6.75 (s, 4H).
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([O:9]C)[C:6]([C:11]2[N:12]=[C:13]([CH3:16])[S:14][CH:15]=2)=[CH:5][N:4]=1.[ClH:17]>O1CCOCC1>[ClH:17].[CH3:16][C:13]1[S:14][CH:15]=[C:11]([C:6]2[C:7](=[O:9])[NH:8][C:3](=[O:2])[NH:4][CH:5]=2)[N:12]=1
Reactant: COc1ncc(-c2csc(C)n2)c(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(-c2c[nH]c(=O)[nH]c2=O)cs1
Reaction time: 8 h

Procedure:
2,4-bis(methyloxy)-5-(2-methyl-1,3-thiazol-4-yl)pyrimidine (Prep19, 290 mg, 1.222 mmol) was suspended in HCl 4M in 1,4-dioxane (10 ml). The reaction mixture was heated at 90° for 1 h and left at room temperature overnight. The solvent was then removed in vacuo to give the title compound as a solid (287 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33]>C(O)C.O.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Yield: 64.3 %

Procedure:
A mixture of 1.0 g (3.2 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20) and 0.63 g (3.8 mmole) of 4-amino-3-methoxy-benzoic acid in 76 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then cooled and partially concentrated under reduced pressure. The resulting solid was collected by filtration, washed with water and dried to give 0.92 g of crude 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22).