Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:10]([C:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH:28]=2)=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[N:13][CH:14]=1>C(Cl)Cl>[F:8][C:9]1[C:10]([C:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH:28]=2)=[C:11]([NH2:15])[CH:12]=[N:13][CH:14]=1
Reactant: CN1CC=C(c2c(F)cncc2NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC=C(c2c(N)cncc2F)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 19 %

Procedure:
TFA (2 mL, 25.96 mmol) was added to a stirred solution of tert-butyl N-[5-fluoro-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl]carbamate (483 mg, 1.571 mmol) in DCM (10 mL) and the reaction stirred at ambient temperature for 6 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The residue was passed through a 10 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 10% MeOH/DCM+1% NH4OH, loaded in DCM) to give 5-fluoro-1′-methyl-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridin]-3-amine as an off-white solid (61 mg, 19% Yield over 2 steps). MS (ES+) 208.1.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[N:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:26][CH2:27][C:28](N)([CH3:30])[CH3:29].[S]>C1(C)C=CC=CC=1>[CH3:29][C:28]1([CH3:30])[CH2:27][NH:26][C:22]([C:20]2[CH:19]=[N:18][C:14]3[O:15][CH2:16][CH2:17][N:12]([S:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:24])([F:1])[F:25])=[CH:4][CH:5]=4)(=[O:10])=[O:11])[C:13]=3[CH:21]=2)=[N:23]1
Reactant: N#Cc1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2
Reactant: CC(C)(N)CN
Agent: [S]
Solvent: Cc1ccccc1
Product: CC1(C)CNC(c2cnc3c(c2)N(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCO3)=N1
Temperature: 95 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
To a suspension of 1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonitrile (30 mg, 0.081 mmol) in toluene (2 mL) was added 1,2-diamino-2-methylpropane (200 μL, 1.908 mmol) and sulfur (20.84 mg, 0.081 mmol). The reaction was heated to 95° C. and stirred at that temperature for 2 h. The reaction mixture was load directly onto a silica gel column and was purified by flash column chromatography using a gradient elution of hexanes with 20-100% EtOAc to provide 7-(4,4-dimethyl-4,5-dihydro-1H-imidazol-2-yl)-1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (12 mg, 0.026 mmol, 31.9% yield) as an off white solid. LCMS (+ESI) m/z=441.1 [M+H]+; 1H-NMR (CDCl3) δ 8.54 (d, 1H), 8.50 (d, 1H), 7.81 (d, 2H), 7.76 (d, 2H), 3.94 (dd, 2H), 3.87 (dd, 2H), 3.57 (br s, 2H), 1.37 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([CH3:22])(=[O:21])=[O:20])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:12])[CH:10]=[CH2:11].[N+:23](=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N-:24]>C(OCC)(=O)C>[CH2:29]([O:28][C:26]([C:25]1[CH2:11][CH:10]([C:9](=[O:12])[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:3][C:2]=2[F:1])[NH:24][N:23]=1)=[O:27])[CH3:30]
Reactant: C=CC(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1F
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=NNC(C(=O)Nc2ccc(-c3ccccc3S(C)(=O)=O)cc2F)C1
Temperature: 60 °C

Procedure:
To N-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-yl)-acrylamide (4.47 g) in ethyl acetate (150 ml) was added ethyl diazoacetate (1.5 equiv.) and the mixture heated at 60° C. for 24 hours. Evaporated and then columned: eluant 10-100 EtOAc in hexane. Collected 5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester (1.67 g)
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.Br.C([O-])(O)=O.[Na+].[NH2:16][C:17]1[C:22]([Cl:23])=[N:21][CH:20]=[CH:19][N:18]=1>CC(O)C>[Cl:23][C:22]1[C:17]2[N:18]([CH:8]=[CH:9][N:16]=2)[CH:19]=[CH:20][N:21]=1
Reactant: Nc1nccnc1Cl
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Clc1nccn2ccnc12
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Bromoacetaldehyde diethyl acetal (200 mL, 1.3 mol) and a solution of 48% HBr (48 ml) are heated at reflux for 1.5 hours, then poured onto a suspension of NaHCO3 (100 g) in propan-2-ol (1.6 L). The resulting solid is filtered off and 2-amino-3-chloropyrazine (51.8 g, 0.4 mol) is added to the solution then heated to reflux, during which time a clear solution forms which precipitates over 2 hours. The reaction mixture is cooled and allowed to stand overnight, and the solid may be collected by filtration and washed with propan-2-ol and Et2O. The solid is added to a saturated solution of NaHCO3 (500 mL) and DCM (1 L). The aqueous layer is separated from the organic solvent and re-extracted with DCM (2×250 mL). The organic layers are combined and dried over MgSO4, filtered and evaporated to dryness, to afford a light brown solid. The propan-2-ol and Et2O liquors from washing the filter cake, are evaporated to give a pale brown solid which is washed with a saturated solution of NaHCO3 and extracted with DCM (X 3). The two solids were combined to afford compound 8-chloro-imidazo[1,2-a]pyrazine (59.1 g, 96%).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH2:14].[Br:20][C:21]1[CH:22]=[C:23]([C:27](F)=[CH:28][N:29]=1)[C:24]([OH:26])=[O:25]>C1COCC1.CCOC(C)=O>[Br:20][C:21]1[CH:22]=[C:23]([C:27]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([I:19])=[CH:18][C:12]=2[F:11])=[CH:28][N:29]=1)[C:24]([OH:26])=[O:25]
Reactant: O=C(O)c1cc(Br)ncc1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Temperature: -78 °C
Yield: 59.3 %

Procedure:
Lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (11.9 ml, 1.00 M, 11.82 mmol) was added to a solution of 2-fluoro-4-iodoaniline (1.40 g, 5.91 mmol) at −78° C. The pale green colored solution was stirred for 1½ h at −78° C. Then, lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (5.45 ml, 1.00 M, 5.45 mmol) was added followed by 2-bromo-5-fluoroisonicotinic acid (1.00 g, 4.55 mmol) in THF (5 ml). The dark colored homogeneous mixture was warmed to room temperature and stirred overnight. The crude was diluted with EtOAc (300 ml). Then, it washed with dilute HCl solution (20 ml), H2O (20 ml), dried and purified on Flashmaster II using a 100 g cartridge to obtain 1.18 g (59%) of 2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:24]([O:26]CC)=[O:25])[CH:4]=[N:3]1.O.[OH-].[Li+]>CO.O>[CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:24]([OH:26])=[O:25])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 105.9 %

Procedure:
A mixture of ethyl 1-methyl-5-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylate (322 mg, 840 μmol) and lithium hydroxide hydrate (141 mg, 3.36 mmol) in methanol (20 ml) and water (5 ml) was stirred for 2.5 days at 25° C. The solvent was evaporated, the residue was acidified with hydrochloric acid 37% to pH=0, the precipitated solid was filtered off, washed with water and dried affording 1-methyl-5-(2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (316 mg, 106%) as an off-white solid. mp: >250° C., MS: m/z=356.4 (M+H+)
Reaction SMILES: CO.[CH2:3]([NH:7][C:8]([C@@H:10]1[C@@H:12]([CH2:13][CH2:14][CH2:15][CH3:16])[O:11]1)=[O:9])[CH2:4][CH2:5][CH3:6].[N-:17]=[N+:18]=[N-:19].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>>[CH2:3]([NH:7][C:8](=[O:9])[C@@H:10]([OH:11])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:4][CH2:5][CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCNC(=O)[C@H]1O[C@@H]1CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CO
Product: CCCCNC(=O)[C@@H](O)[C@H](CCCC)N=[N+]=[N-]
Yield: 68 %

Procedure:
A suspension of 30 ml of methanol containing 366 mg (1.84 mmol) of (2S-trans)-N-butyl-3-butyloxiranecarboxamide, 239 mg (3.68 mmol) of sodium azide and 228 mg (1.89 mmol) of anhydrous magnesium sulfate was refluxed for 5 hours. After the temperature of the reaction mixture was returned to room temperature, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the concentrate, and the resulting mixture was washed successively with water, and then a saturated NaCl solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 304 mg (Yield: 68%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH:3]=1.[C:37]([N:41]1[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]1)([CH3:40])([CH3:39])[CH3:38]>>[C:37]([N:41]1[CH2:46][CH2:45][CH:44]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][N:7]([CH2:21][C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)[C:8](=[O:20])[N:9]3[C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[C:4]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[CH:3]=2)[CH2:43][CH2:42]1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)N1CCC(=O)CC1
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(N)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(NC4CCN(C(C)(C)C)CC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1

Procedure:
The 7-[(1-tert-butylpiperidin-4-yl)amino]-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one was prepared from 7-amino-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (COMPOUND CCC4, STEP A) and the 1-tert-butylpiperidin-4-one (COMPOUND PPA-1) by a procedure analogous to that described in EXAMPLE CCC18, STEP A. Mass spectrum (ESI) 677.2 (M+1).
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>CC(C)=O.O>[CH:1]1([S:4]([NH:7][C:15](=[O:16])[O:17][CH2:18][CH3:19])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cl
Reactant: NS(=O)(=O)C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a solution of cyclopropanesulfonamide (Li, J. et al; Synlett 2006, 5, 725-728) (800 mg, 6.60 mmol) in acetone (25 ml) was added potassium carbonate (2.738 g, 3 eq, 19.81 mmol) and ethyl chloroformate (1.075 g, 1.5 eq, 9.90 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was poured into water and made acidic (pH 1) with cone HCl then extracted with EtOAc. The extract was collected, dried over Na2SO4, filtered and concentrated. Purification of the residue by column chromatography (eluent 30% EtOAc in hexanes) afforded 374 as a colourless oil (800 mg, 63%). 1H NMR (DMSO, d6) 11.47 (s, 1H), 4.10 (q, J=10.27 Hz, 2H), 2.90 (m, 1H), 1.19 (t, J=7.24 Hz, 3H), 1.039 (m, 4H).
Reaction SMILES: [C:1]([O:5][O:6][C:7]([CH2:10][CH3:11])([NH2:9])[CH3:8])(=[O:4])[CH:2]=[CH2:3].[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[C:1]([O:5][O:6][C:7]([CH2:10][CH3:11])([NH:9][C:19]([NH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:20])[CH3:8])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OOC(C)(N)CC
Reactant: O=C=Nc1ccccc1
Solvent: CC#N
Product: C=CC(=O)OOC(C)(CC)NC(=O)Nc1ccccc1
Reaction time: 5 h
Yield: 43.2 %

Procedure:
Into a solution of 15.9 g of ethyl-β-amino-β-ethoxy acrylate in 30 ml of acetonitrile there was dropped 11.9 g of phenyl isocyanate while cooling, and the resulting mixture was allowed to stand at room temperature for 5 hours. The acetonitrile was then distilled away. To the residue was added 100 ml of ether, which was then dried over anhydrous sodium sulfate. The ether was distilled away and the residue obtained was distilled under reduced pressure. Thus, 12 g of ethyl-β-phenylureido-β-ethoxy acrylate of a boiling point of 83° to 84° C./0.5 mmHg was obtained.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH:9]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:8][C:7]2=[O:32].[Cl:33][C:34]1[CH:35]=[N:36][CH:37]=[C:38]([Cl:42])[C:39]=1[CH:40]=O.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:33][C:34]1[CH:35]=[N:36][CH:37]=[C:38]([Cl:42])[C:39]=1[CH:40]=[C:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[CH:12][CH:11]=2)[C:7](=[O:32])[O:8]1
Reactant: O=Cc1c(Cl)cncc1Cl
Reactant: COc1ccc2c(c1)C(=O)OC2[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(=O)OC2=Cc1c(Cl)cncc1Cl
Reaction time: 8 h

Procedure:
A suspension under N2 of (5-methoxy-3-oxo-1,3-dihydro-isobenzofuran-1-yl)triphenyl-phosphonium bromide (74 g, 0.134 mole), prepared as described in example 36, and 3,5-dichloro-pyridin-4-carbaldehyde (23.6 g, 0.134 mole) in CH2Cl2 (500 ml) was dropwise added with triethylamine (18.5 ml, 0.134 mole), adjusting the temperature with a water bath. The mixture was stirred overnight, then cooled and treated with 5% HCl. The phases were separated and the acidic one was extracted with CH2Cl2, washed with H2O/NaCl, discoloured with charcoal, anhydrified and concentrated at high vacuum. There were obtained 85.4 g of a crude which was used as such in the subsequent step. A sample of the crude was purified by flash chromatography (eluent: hexane/ethyl acetate 1:1).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:23]([NH2:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[C:20]([F:22])[CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH:23]([NH:30][C:9]([CH2:8][NH:7][C:6](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=2)=[O:11])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: NC(c1ccccc1)c1cc(F)cc(F)c1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1cc(F)cc(F)c1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(3,5-difluoro-phenyl)-C-phenyl-methylamine (example 4.3).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([NH2:23])=[N:20][C:19]=1[CH3:24])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([NH:23][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[N:20][C:19]=1[CH3:24])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Product: Cc1nc(NC(=O)C(C)(C)C)sc1C(=O)NCc1ccccc1
Yield: 23 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2,2-dimethylpropionyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 23% yield; 1H NMR (CDCl3, 300 MHz) δ 8.85 (s, br, 1H), 7.36-7.25 (m, 5H), 5.91 (s, br, 1H), 4.56 (d, J=5.8 Hz, 2H), 2.60 (s, 3H), 1.27 (s, 9H); MS (ES+) m/z 332.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[O:20])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of the product from Example 10A (3.0 g, 8.44 mmol), 4-aminothiophenol (1.06 g, 8.44 mmol) and cesium carbonate (5.5 g, 17.0 mmol) in N,N-dimethylformamide (15 mL) was heated to 90° C. for 4 hours. After cooling to room temperature the mixture was poured into ice water (100 mL) and the resultant solution acidified to pH 5 with 1N aqueous hydrochloric acid. The solution was then extracted with ethyl acetate (3×50 mL), the combined extracts dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound as an orange solid (3.6 g, 96%).
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:42])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:41]=[CH:40][C:23]([C:24]([NH:26][C@H:27]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:25])=[CH:22][CH:21]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>[Pd].FC(F)(F)C(O)=O.C(Cl)Cl>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:42])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[CH:41]=[CH:40][C:23]([C:24]([NH:26][C@H:27]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:25])=[CH:22][CH:21]=3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1)C(=O)OCC
Agent: [Pd]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)cc1)C(=O)OCC
Reaction time: 24.5 h
Yield: 100.3 %

Procedure:
A mixture of 0.59 g of diethyl N-[4-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylethynyl)benzoyl]-L-glutamate and 1.5 g of 5% palladium on charcoal in 30 ml of trifluoroacetic acid is hydrogenated at 53 psi at room temperature for 24.5 hours. The reaction mixture is diluted with methylene chloride and filtered through Celite. The solvent is removed under reduced pressure. The residue is redissolved in methylene chloride and extracted with a saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the residue chromatographed on silica gel using a 4% methanol:methylene chloride mixture as the eluent. Evaporation of the eluate yields 0.60 g (100%) of diethyl N-(4-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate as a white solid: m.p. >250° C.; NMR (CDCl3, 300 MHz) delta 1.22 (t, 3H, J=7.20 Hz), 1.29 (s, 9H), 1.30 (t, 3H, J=7.20 Hz), 1.61-3.35 (m, 13H), 4.11 (q, 2H, J=7.20 Hz), 4.23 (q, 2H, J=7.20 Hz), 4.77-4.84 (m, 1H), 5.15 (brs, 1H), 7.17 (d, 1H, J=7.50 Hz), 7.23 (d, 2H, J=8.10 Hz), 8.56 (brs, 1H); IR (KBr) 3400, 3280, 2980, 1735, 1630, 1570, 1460, 1390, 1350, 1310, 1200, 1155, 1025, 930, and 800 cm-1.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10](=[O:29])[O:11][C:12]2[CH:25]=[C:24]3[CH2:26][CH2:27][CH2:28][C:23]3=[CH:22][C:13]=2[C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[C:10](=[O:29])[O:11][C:12]2[CH:25]=[C:24]3[CH2:26][CH2:27][CH2:28][C:23]3=[CH:22][C:13]=2[C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: Cc1ccccc1-c1c(NC(=O)OC(C)(C)C)c(=O)oc2cc3c(cc12)CCC3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1-c1c(N)c(=O)oc2cc3c(cc12)CCC3
Yield: 98.3 %

Procedure:
To a solution of 3-tert-butyloxycarbonylamino-4-(2-methylphenyl)-7,8-dihydro-6H-cyclopenta[g][1]benzopyran-2-one (2.05 g) in dichloromethane (20 ml) was added trifluoroacetic acid (10 ml) dropwise with ice-cooling. The mixture was stirred under ice-cooling for 1 hour, after which the solvent was distilled off. The residue was diluted with water, neutralized with saturated aqueous solution of NaHCO3 and extracted with chloroform. The extract was washed with water and dried (MgSO4) and the solvent was distilled off to give crystals of 3-amino-4-(2-methylphenyl)-7,8-dihydro-6H-cyclopenta[g][1]-benzopyran-2-one (1.5 g, 98.4%). Recrystallization from ethanol-dichloromethane gave colorless prisms, m.p. 275°-276° C.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:4]=1.[CH3:14][OH:15]>>[CH3:14][O:15][C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:4]=1
Reactant: Clc1cc(-n2cccn2)ncn1
Reactant: CO
Agent: [Na]
Product: COc1cc(-n2cccn2)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 3 ml of anhydrous methanol, 23 mg of sodium metal was dissolved, and to the resulting solution, 180 mg of 6-chloro-4-(1-pyrazolyl)pyrimidine in 2 ml of anhydrous methanol was added dropwise with stirring at room temperature in a stream of nitrogen overnight. The solvent was distilled off under reduced pressure, and the residue was extracted with 20 ml of methylene chloride. The organic layer was washed with 5 ml of saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled away, and a residue was purified by a silica gel column chromatography using chloroform to give an amorphous product. The product was recrystallized from n-hexane to provide 132 mg of the plate crystal 6-methoxy-4-(1-pyrazolyl)pyrimidine having a melting point of 108.5°-109° C.
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2[N:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH:17]=O)[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[S:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH2:29][NH2:30].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[S:23][C:5]2[N:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][NH:30][CH2:29][C:25]4[S:24][CH:28]=[CH:27][N:26]=4)[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(=O)[nH]c(Cn3cc(C=O)c(C(F)(F)F)n3)nc2s1
Reactant: NCc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc2c(=O)[nH]c(Cn3cc(CNCc4nccs4)c(C(F)(F)F)n3)nc2s1
Yield: 24.1 %

Procedure:
A mixture of 1-((6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (0.55 g, 1.62 mmol) and thiazol-2-ylmethanamine (925 mg, 8.10 mmol) in DCM (11 mL) was acidified to pH 5 with acetic acid (1 mL) before the addition of sodium triacetoxyborohydride (1.72 g, 8.10 mmol). The resultant mixture was stirred at RT overnight. The reaction mixture was quenched with MeOH, passed through an SCX column and eluted with 2M NH3 in MeOH. The sample was concentrated in vacuo. Purification by flash column chromatography-silica gel and elution with 3-5% MeOH:DCM (3 drops of DIPEA per litre), followed by a second flash column and elution with 3-4% MeOH:DCM (3 drops of DIPEA per litre) gave the title product as a white solid (172 mg, 0.391 mmol, 24%).