Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([O:5][C:6]1[CH:23]=[CH:22][C:21]2[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15]([C:24](=[O:33])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH2:13]4)[CH2:10][CH2:9][C:8]=2[CH:7]=1)(=[O:4])(=[O:3])[NH2:2]>CCOC(C)=O.C(O)C.[Pt](=O)=O>[S:1]([O:5][C:6]1[CH:23]=[CH:22][C:21]2[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([C:24](=[O:33])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]=2[CH:7]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: CCCCCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCNC(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Yield: 95.3 %

Procedure:
A solution comprising about 210 mg of compound 5a (m=6) in about 6 ml of EtOAc and about 2 ml of ethanol (EtOH, 2 ml) was stirred over about 40 mg of platinum (IV) oxide (PtO2) under an atmosphere of hydrogen for 2.5 h. The catalyst was removed by filtration and the filtrate concentrated. The residue was purified by silica gel chromatography (Petroleum ether: EtOAc, 1:1), yielding pure compound 6a (201 mg, 95.3%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=1[CH2:15][O:16][CH3:17])([CH3:3])[CH3:2].[OH-].[Na+]>CCO.O>[CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[CH2:15][O:16][CH3:17])([CH3:3])[CH3:2]
Reactant: COCc1cc(C(=O)OC)ccc1OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCc1cc(C(=O)O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
A solution of methyl 4-isopropoxy-3-(methoxymethyl)benzoate (11.30 g; 47.42 mmol; 1 eq.) in EtOH (339 mL) at RT was treated with NaOH (47.42 mL; 5 M; 237.11 mmol; 5 eq.). The reaction mixture was stirred at RT for 12 hours. The reaction mixture was concentrated to give a yellow solid. It was taken up in water and the aqueous phase was washed with EtOAc and then acidified with HCl cc to pH 2. The aqueous layer was extracted with EtOAc (twice). The combined organics were washed with brine, dried over MgSO4 and concentrated affording the title compound as a beige solid (9.71 g, 91%). 1H NMR (DMSO-d6, 300 MHz) δ 12.39 (br s, 1H), 7.89-7.82 (m, 2H), 7.11-7.07 (d, J=8.75 Hz, 1H), 4.79-4.67 (sept, J=5.92 Hz, 1H), 4.39 (s, 2H), 3.35 (s, 3H), 1.31-1.28 (d, J=6.06 Hz, 6H). LC/MS (Method B): 223.2 (M−H)−. HPLC (Method A) Rt 3.71 min (Purity: 92.8%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].[C:22](=[O:31])([O:27][CH:28]([CH3:30])[CH3:29])[O:23][CH:24](Cl)[CH3:25]>>[F:17][C@@H:16]1[C@@:11]2([C:10](=[O:21])[O:9][CH2:8][N:7]2[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:12]2[C@H:14]([C@@H:13]2[C:18]([O:20][C@@H:24]([O:23][C:22]([O:27][CH:28]([CH3:30])[CH3:29])=[O:31])[CH3:25])=[O:19])[CH2:15]1
Reactant: CC(C)OC(=O)OC(C)Cl
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Product: C=CCOC(=O)N1COC(=O)[C@]12C1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O[C@H](C)OC(=O)OC(C)C
Yield: 18.1 %

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 400 mg) and 1-chloroethyl isopropyl carbonate (204 mg) were treated in the same manner as in Example A-1 (3) to give (1S,2S,3S,5R,6S)-3′-allyl 6-(1-((isopropyloxycarbonyl)oxy)ethyl) 3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-3′,6-dicarboxylate (A-15-1, 95 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]([C:13]#[N:14])[C:11]#[N:12])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]([CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])([C:11]#[N:12])[C:13]#[N:14])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(c1ccc(Cl)cc1)C(C#N)C#N
Reactant: FC(F)(F)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1ccc(Cl)cc1)C(C#N)(C#N)CCC(F)(F)F
Yield: 16.3 %

Procedure:
Using 2.05 g of 2-(1-(4-chlorophenyl)ethyl)malononitrile, 10 ml of N,N-dimethylformamide, 1.38 g of potassium carbonate, and 1.77 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.49 g of 2-(1-(4-chlorophenyl)ethyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (42)).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:21][CH3:22])[NH:9][C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].[H-].[Ca+2].[H-]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:21][CH3:22])[N:9]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CCOC(=O)c1nc(SC)[nH]c(=O)c1OCc1ccccc1
Agent: [Ca+2]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(SC)n(CC(=O)OC)c(=O)c1OCc1ccccc1
Yield: 44.9 %

Procedure:
A solution of intermediate 1, 5-benzyloxy-2-methylsulfanyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester, (2.00 g, 6.24 mmol) in dry tetrahydrofuran (100 ml) was treated with methyl bromoacetate (1.05 g, 6.86 mmol) followed by powdered calcium hydride (0.59 g, 14.0 mmol) and the resulting mixture was heated under reflux for 18 h. The reaction mixture was then cooled, quenched by the addition of a few drops of acetic acid and concentrated in vacuo. The residue was then diluted with ethyl acetate, washed successively with saturated sodium bicarbonate and brine then dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by chromatography on silica gel (elution toluene/ethyl acetate 95:5) gave 1.10 g (45% yield) of the title ester as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.31 (3H, t, J=7.2 Hz, CH3), 2.60 (3H, s, SCH3), 3.80 (3H, s, OCH3), 4.33 (2H, q, J=7.2 Hz, OCH2), 4.84 (2H, s, NCH2), 5.21 (2H, s, OCH2), 7.3–7.5 (5H, m, aromatics). HRMS (FAB POS) calculated for C18H21N2O6S [M+H+]: 393.112033. found: 393.112070.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([CH:9]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:10][C:11]([OH:13])=[O:12])#[N:8].COS(OC)(=O)=O>C(#N)C>[C:7]([CH:9]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:10][C:11]([O:13][CH3:1])=[O:12])#[N:8]
Reactant: O=C([O-])[O-]
Reactant: N#CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: COC(=O)CC(C#N)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
320 g of potassium carbonate are added to a solution of 260 g of 3-cyano-3-(3,4-dichlorophenyl) propionic acid in 2.7 litres of acetonitrile. The suspension is heated under reflux in adding progressively 110 ml of dimethylsulphate. The mixture is left to return to room temperature after 15 minutes. The reaction mixture is concentrated and then taken up into 2 litres of dichloromethane. The organic phase is washed with water and then concentrated. The residue is taken up into 500 ml of methanol in order to provide the expected ester with a yield of 80%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>CO.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:11][CH3:10])=[CH:4][N:3]=1
Reactant: BrCc1ccc(Br)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Bromo-5-bromomethyl-pyridine, 4 (3.58 g, 14.3 mmoles) was dissolved in methanol (20 mL) under nitrogen. Sodium methoxide (0.89 g, 15.7 mmoles, 95%) was added and the mixture stirred at room temperature. After 3 hours, the methanol was rotovapped off and the residue dissolved in dichloromethane and washed with water. The organic extract was adsorbed onto silica gel and chromatographed. The column was eluted with a gradient of hexane to 20% ethyl acetate/hekane. Pure fractions were combined and concentrated to provide the title compound as a colorless oil, 2.62 g (90%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[C:15]([F:32])=[CH:16][C:17]3[O:22][CH2:21][C:20](=S)[N:19]([CH:24]([C:26](OCC)=[O:27])[CH3:25])[C:18]=3[CH:31]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:34][NH2:35]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([O:13][C:14]2[CH:31]=[C:18]3[C:17](=[CH:16][C:15]=2[F:32])[O:22][CH2:21][C:20]2[N:19]3[CH:24]([CH3:25])[C:26](=[O:27])[NH:34][N:35]=2)([CH3:12])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NN
Reactant: CCOC(=O)C(C)N1C(=S)COc2cc(F)c(OC3(C)CN(C(=O)OC(C)(C)C)C3)cc21
Solvent: CCO
Solvent: O
Product: CC1C(=O)NN=C2COc3cc(F)c(OC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 45.9 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-7-fluoro-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.080 g, 0.171 mmol) in EtOH (5 mL) was added hydrazine hydrate (0.085 g, 1.707 mmol) and the mixture was heated to reflux for 2 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by preparative TLC (eluting with 30% EtOAc in petroleum ether) to give 3-(7-fluoro-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.033 g, 46%) as a white solid. LC/MS (Table 1, Method 2) Rt=1.144 min.; MS m/z: 421 [M+H]+.
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[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[O:18]1[CH2:22][CH2:21][NH:20]C1=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu](I)I>[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[S:10][C:9]([NH:20][CH2:21][CH2:22][OH:18])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1NCCO1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: OCCNc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (150 mg), 2-oxazolidinone (103 mg), potassium phosphate tribasic (250 mg), copper iodide (7 mg), 4 μL, of N,N-dimeyhylethylenediamine in 2 mL of 1,4-dioxane was heated to 100° C. for 15 hr. The reaction mixture was evaporated and the residue was diluted with ethyl acetate (50 mL), washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified on reverse phase HPLC to give 2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-ylamino)ethanol as a by-product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:24])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=[C:12]([C:14](OC)=[O:15])[CH:13]=1.BrC1C(=O)N(C2C=CC=CC=2)C=C(C(OC)=O)C=1.[H-].C([Al+]C(C)C)(C)C.Cl.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:24])[N:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=[C:12]([CH2:14][OH:15])[CH:13]=1
Reactant: COC(=O)c1cc(-c2ccccc2Cl)c(=O)n(-c2ccccc2)c1
Agent: CC(C)[Al+]C(C)C
Agent: COC(=O)c1cc(Br)c(=O)n(-c2ccccc2)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=c1c(-c2ccccc2Cl)cc(CO)cn1-c1ccccc1
Temperature: -78 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
36 mg of 3-(2-chlorophenyl)-5-methoxycarbonyl-1-phenyl-1,2-dihydropyridin-2-one synthesized by the method of Referential Example 3 from 3-bromo-5-methoxycarbonyl-1-phenyl-1,2-dihydropyridin-2-one and 2-chloroboronic acid, was dissolved in 20 ml of toluene. After cooling to −78° C., 0.1 ml diisopropyl aluminum hydride (1.5M tetrahydrofuran solution) was added dropwise thereinto. While heating from −78° C. to room temperature, the mixture was stirred overnight. Then, 1N hydrochloric acid was added thereto, followed by stirring. The mixture was neutralized with an aqueous solution of sodium hydrogen carbonate, and then extracted with ethyl acetate. Then, the extract was successively washed with water and brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 12 mg of the title compound.
Reaction SMILES: C(=S)(OC1C=CC=CC=1)O[C@@H:3]1[C@@H:7]2[O:8][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[O:10][CH2:11][C@@H:6]2[CH2:5][C@H:4]1[N:20]1[C:24]2[N:25]=[CH:26][N:27]=[C:28]([S:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:23]=2[CH:22]=[CH:21]1.N(C(C)(C)C#N)=NC(C)(C)C#N.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:30]([S:29][C:28]1[C:23]2[CH:22]=[CH:21][N:20]([C@H:4]3[CH2:3][C@@H:7]4[O:8][CH:9]([C:12]5[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=5)[O:10][CH2:11][C@@H:6]4[CH2:5]3)[C:24]=2[N:25]=[CH:26][N:27]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(SCc6ccccc6)ncnc54)[C@H](OC(=S)Oc4ccccc4)[C@@H]3O2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(SCc6ccccc6)ncnc54)C[C@@H]3O2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of O-[(4aS,6R,7S,7aR)-6-[4-(benzylsulfanyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl]-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-yl] O-phenyl thiocarbonate (1.77 g, 1.98 mmol) in toluene (91.0 mL) was added 2,2′-azo-bis-isobutyronitrile (67.7 mg, 0.404 mmol) and tri-n-butyltin hydride (1.11 mL, 4.00 mmol) under an atmosphere of nitrogen. The yellow solution was heated to reflux at 140° C. After 2 h, the reaction mixture was cooled, silica gel was added, and the solvent was removed in vacuo. Silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexanes afforded the title compound as a semi-solid (800 mg, 85%). LC/MS: Rt=2.38 min, ES+ 475 (FA standard).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH2:15])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4].[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:15][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1ccc2c(c1)SCC[C@H]2N
Product: COC(=O)c1ccc2c(c1)SCC[C@H]2NC(=O)OCc1ccccc1

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 4 using (R)-4-aminothiochromane-7-carboxylic acid methyl ester (5.70 g) and benzyloxycarbonyl chloride (5.50 ml), the objective (R)-4-(benzyloxycarbonylamino)thiochromane-7-carboxylic acid methyl ester (7.35 g) was obtained as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:3]=1.[OH-].[Na+].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>CN(C=O)C>[N:24]1([C:2]2[N:7]=[C:6]([N:8]([CH3:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:5]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:3]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: c1c[nH]cn1
Reactant: CN(c1ccccc1)c1nc(Cl)nc(N2CCOCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1nc(N2CCOCC2)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.2 %

Procedure:
The obtained 2-chloro-4-(N-methyl-N-phenylamino)-6-morpholino-1,3,5-triazine (135 mg, 0.457 mmol) was dissolved in DMF (5 ml), added with sodium hydroxide (19.2 mg, 0.480 mmol) and imidazole (32.7 mg, 0.480 mmol) and stirred at 110° C.-120° C. for 5 hours. After allowing to cool to room temperature, the solvent was removed under reduced pressure. The residue was added with ethyl acetate and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, using dichloromethane and methanol (20:1) as eluant, to obtain 71.3 mg (yield: 52.8%) of the titled compound as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[N:8]=[C:7]2[S:22][CH3:23].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[CH:66]([NH2:68])=[O:67].C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[C:9]1[N:8]=[C:7]([S:22][CH3:23])[C:6]2[C:11](=[C:2]([NH:68][CH:66]=[O:67])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: NC=O
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(Br)cccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(NC=O)cccc12
Temperature: 90 °C
Yield: 73.2 %

Procedure:
To a mixture of 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Example 35 step B (250 mg, 0.63 mmol), tris(dibenzylideneacetone)dipalladium (58 mg, 0.063 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (109 mg, 0.19 mmol), formamide (0.075 mL, 1.875 mmol) and Cs2CO3 (284 mg, 0.875 mmol) was added dioxane (4 mL). The reaction vessel was evacuated and flushed with argon (3×) and the mixture was heated at 90° C. overnight. The mixture was diluted with DCM and concentrated under reduced pressure onto Celite. The residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexanes to afford N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)formamide (168 mg, 74%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[C:23]2[CH2:22][CH2:21][NH:20][CH:19]([CH3:24])[C:18]=2[S:17][CH:16]=1>>[Br:14][C:15]1[C:23]2[CH2:22][CH2:21][N:20]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:19]([CH3:24])[C:18]=2[S:17][CH:16]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c(Br)csc21
Product: CC1c2scc(Br)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-bromo-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][C:17]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=1)=[O:4].C([O-])([O-])=O.[K+].[K+]>>[F:1][C:2]([F:25])([F:26])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][C:17]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=1)=[O:4]
Reactant: O=C(NCCCc1cccc(C#CC2(O)CCCCCC2)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NCCCc1cccc(CCC2(O)CCCCCC2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Deprotection of 2,2,2-trifluoro-N-(3-(3-((1-hydroxycycloheptyl)ethynyl)-phenyl)propyl)acetamide was conducted following the method used to prepare Example 2 except that 5 equivalents of K2CO3 were used and the reaction was stirred at room temperature overnight. Purification by flash chromatography (10% 7M NH3 in MeOH/CH2Cl2) gave 2,2,2-trifluoro-N-(3-(3-(2-(1-hydroxycycloheptyl)ethyl)phenyl)propyl)acetamide as a clear oil. Yield (0.635 g, 86%): 1H NMR (400 MHz, DMSO-d6) δ 7.16-7.32 (m, 4H), 5.13 (s, 1H), 4.65 (t, J=6.0 Hz, 1H), 2.56-2.64 (m, 2H), 1.44-1.63 (m, 12H), 0.90 (t, J=7.6 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-])=O)[C:5]([N:12]2[C:16](=[O:17])[CH:15]3[CH2:18][CH2:19][CH:20]=[CH:21][CH:14]3[C:13]2=[O:22])=[C:4]([F:23])[CH:3]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:9][C:6]1[C:5]([N:12]2[C:16](=[O:17])[CH:15]3[CH2:18][CH2:19][CH:20]=[CH:21][CH:14]3[C:13]2=[O:22])=[C:4]([F:23])[CH:3]=[C:2]([Cl:1])[C:7]=1[OH:8]
Reactant: O=C1C2C=CCCC2C(=O)N1c1c(F)cc(Cl)c(O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1c(O)c(Cl)cc(F)c1N1C(=O)C2C=CCCC2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.6 %

Procedure:
Iron powder (2.48 g) was added into a solution of 6-chloro-4-fluoro-2-nitro-3-(tetrahydrophthalimido)phenol (3.67 g) in acetic acid (60 ml) and stirred at room temperature for two hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, evaporated to give 3.6 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[C:9]2[CH:10]=[C:11]([B-](F)(F)F)[S:12][C:13]=2[C:14]2[N:18]=[CH:17][N:16](C3CCCCO3)[N:15]=2)=[CH:4][CH:3]=1.[K+].Br[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.O1CCOCC1.C(O)(C)(C)C.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:29])[C:9]2[CH:10]=[C:11]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=3)[S:12][C:13]=2[C:14]2[NH:18][CH:17]=[N:16][N:15]=2)=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Cl)cc1)c1cc([B-](F)(F)F)sc1-c1ncn(C2CCCCO2)n1
Reactant: N#Cc1cc(Br)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC(C)(C)O
Solvent: CCO
Solvent: C1COCCO1
Product: N#Cc1cc(-c2cc(C(O)c3ccc(Cl)cc3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 85 °C
Yield: 11.4 %

Procedure:
A mixture of potassium (4-((4-chlorophenyl)(hydroxy)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)trifluoroborate (0.133 g, 0.276 mmol), 4-bromo-pyridine-2-carbonitrile (60.6 mg, 0.331 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (24.8 mg, 0.0533 mmol), palladium acetate (4.6 mg, 0.020 mmol) and sodium carbonate (77 mg, 0.73 mmol) in ethanol (6.2 mL, 110 mmol) was degassed with argon and then heated at 85° C. for 13 h. The mixture was absorbed on silica gel and purified by chromatography to afford an intermediate. LCMS: (AA) ES+ 478.1, 480.0. This intermediate in 1,4-dioxane (2.0 mL, 26 mmol), tert-butyl alcohol (2.0 mL, 21 mmol) and 4.00 M HCl in dioxane (3.0 mL, 14 mmol) was heated at 60° C. for 1 h. The mixture was evaporated to dryness and then purified by HPLC to afford 4-(4-((4-chlorophenyl)(hydroxy)methyl)-5-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)picolinonitrile (12.4 mg, 11.4%). LCMS: (FA) ES+ 394.3, 396.1. 1H NMR (400 MHz, d6-DMSO) δ: 14.69-13.48 (br, 1H), 8.69 (d, J=6.79 Hz, 2H), 8.45 (s, 1H), 8.08-7.88 (m, 2H), 7.56 (d, J=8.39 Hz, 2H), 7.35 (d, J=8.40 Hz, 2H), 6.79 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[C:17]1([N:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(O)C>[C:17]1([N:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](=[O:25])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: Nc1cccc(C(=O)Nc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Nc1ccccc1)c1cccc(NC(=O)N(c2ccccc2)c2ccccc2)c1
Yield: 42.6 %

Procedure:
A mixture of 3-amino-N-phenylbenzamide (2.0 g, 9.4 mmol), diphenylcarbamoyl chloride (2.2 g, 9.4 mmol) and triethylamine (2.6 mL, 19 mmol) in ethanol (10 mL) was heated to reflux for 4.5 hours. The mixture was cooled and concentrated, water was added, the slurry was acidified with 1 N HCl and the solid was collected, washed with water, dried and recrystallized from acetone/hexanes, to give a colorless solid (1.63 g, 42%).