Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCOCC1.[CH2:25]([O:27][CH:28]([N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1)[CH3:29])[CH3:26].O.C(=O)([O-])[O-].[K+].[K+]>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>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:33]3[CH:32]=[N:31][N:30]([CH:28]([O:27][CH2:25][CH3:26])[CH3:29])[CH:34]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(Cl)ncnc21
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(C)n1cc(-c2ncnc3c2ccn3COC(=O)C(C)(C)C)cn1
Temperature: 85 °C
Reaction time: 3.5 h

Procedure:
To a 250 mL round bottom flask equipped with a stir bar, condenser and 3-way valve was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (3f, 30 g, 0.112 mol), 1,4-dioxane (300 mL, 4.0 mol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14, 35.8 g, 0.134 mol, 1.2 equiv), water (150 mL, 8.3 mol) and potassium carbonate (K2CO3, 61.9 g, 0.448 mol, 4.0 equiv) at room temperature. The resulting mixture was degassed four times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (5.0 g, 0.00433 mol, 0.039 equiv). The reaction mixture was then degassed four times back filling with nitrogen each time before being warmed to 85° C. The reaction mixture was stirred at 85° C. for 2-5 h. When the reaction was deemed complete, the reaction mixture was allowed to cool to room temperature before being diluted with 20% aqueous brine (250 mL) and ethyl acetate (250 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (250 mL). The combined organic fractions was washed with water and brine, dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 25% to 40% ethyl acetate/hexane gradient elution) to afford {4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (18) as a orange oil, which was directly used in the subsequent reaction assuming the theoretical yield. For 18: C19H25N5O3 (MW, 371.43), LCMS (EI) m/e 372 (M++H).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([CH:16]=[N:17][OH:18])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19]NC(=O)CCC(N)=O>CN(C)C=O>[OH:18][N:17]=[C:16]([Cl:19])[C:10]1[O:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]=1[C:12]([F:13])([F:14])[F:15]
Reactant: NC(=O)CCC(=O)NCl
Reactant: ON=Cc1onc(-c2ccccc2)c1C(F)(F)F
Solvent: CN(C)C=O
Product: ON=C(Cl)c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbaldehyde oxime (Intermediate I-12C, 0.34 g, 1.327 mmol) in N,N-dimethylformamide (1 mL) was added N-chlorosuccinamide (0.177 g, 1.327 mmol) in batches over a period of 2 min. at room temperature. The reaction mixture was stirred at room temperature for 30 min. An additional 0.09 g of N-chlorosuccinamide was added in one lot at room temperature and the contents were stirred for 20 min. The reaction mixture was partitioned between ethyl acetate (20 mL) and brine (2×20 mL). The ethyl acetate layer was dried over sodium sulfate and purified by silica gel column chromatography using hexane/ethyl acetate to yield N-hydroxy-3-phenyl-4-(trifluoromethyl)isoxazole-5-carbimidoyl chloride (0.250 g, 0.860 mmol, 64.8% yield) as a white solid. LC/MS M+1=291.2.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])=[C:8]([F:20])[C:7]([CH:21]=[O:22])=[CH:6][CH:5]=1>C1COCC1.CO>[Br:3][C:4]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])=[C:8]([F:20])[C:7]([CH2:21][OH:22])=[CH:6][CH:5]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(C=O)c2F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CO)c2F)c1
Reaction time: 12 h
Yield: 47.2 %

Procedure:
NaBH4 (0.64 g, 1.5 equiv) was added portionwise to a stirred solution of 105 (4.0 g, 11.3 mmol) in a mixture of THF (20 mL) and MeOH (10 mL) at RT. The reaction mixture was stirred for 12 h, and quenched by the addition of saturated aqueous NH4Cl. The aqueous mixture was extracted with EtOAc, and the organic solution was washed with water and evaporated. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (20% to 50% EtOAc) to afford 1.9 g (47%) of 3-(6-bromo-2-fluoro-3-hydroxymethyl-phenoxy)-5-chloro-benzonitrile (107) as a yellow oil.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[OH:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].[NH2:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[N:23]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:22]([CH3:38])([CH3:37])[CH2:21]1>>[OH:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:1]([C:2]([NH:19][CH:20]1[CH2:25][C:24]([CH3:26])([CH3:27])[N:23]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:22]([CH3:37])([CH3:38])[CH2:21]1)=[O:4])=[O:8]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1ccccc1O
Reactant: CCCCCCCCON1C(C)(C)CC(N)CC1(C)C
Product: CCCCCCCCON1C(C)(C)CC(NC(=O)C(=O)Nc2ccccc2O)CC1(C)C

Procedure:
The title compound is prepared by the reaction of diethyl oxalate with one equivalent each of 2-hydroxyaniline and of 4-amino-1-octyloxy-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: [F:1][C:2](I)([F:31])[C:3]([F:30])([F:29])[C:4]([F:28])([F:27])[C:5]([F:26])([F:25])[C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12].[CH2:33]([Sn](CCCC)(CCCC)CCCC)[CH:34]=[CH2:35].CC(N=NC(C#N)(C)C)(C#N)C>CCCCCC>[F:1][C:2]([F:31])([CH2:35][CH:34]=[CH2:33])[C:3]([F:30])([F:29])[C:4]([F:28])([F:27])[C:5]([F:26])([F:25])[C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Product: C=CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 97 %

Procedure:
In a typical procedure for reverse fluorous solid phase extraction in the studies of FIG. 4, a perfluoroalkyl iodide such as perfluorodecyl iodide (RfI, 323 mg, 0.5 mmol), allyltributyltin (330 mg, 1 mmol), AIBN (9 mg, 0.05 mmol) and hexane (5 ml) were placed in a flask under an argon atmosphere and the mixture was refluxed for 5 h. After removal of the volatile components by evaporation, the mixture was submitted to separation by reverse fluorous solid phase extraction. A short column was packed with regular silica gel (6.0 g) using FC-72/Et2O (2/1) as the solvent. The crude reaction mixture was then loaded onto this column and eluted with 20 ml of FC-72/Et2O (2/1) to give 3-(perfluorodecyl)prop-1-ene in 97% yield (271 mg). After similar reactions and separations, the allylated products 2a-d, 3a-d and 4a-d were isolated in yields ranging from 69-93%. The nuclear magnetic resonance (NMR) spectra of these products were clean, and gas chromatography (GC) or high pressure liquid chromatography (HPLC) purities exceeded 90% in all cases. The purity of the products was determined by GC in the case of R═H or R═Me and HPLC (Nova Pak® Silica, UV detection at 254 nm) in the case of R═Ph.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](NCC3CCCO3)=O)[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])C.Cl.[NH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].[CH2:37]([N:39](CC)CC)C>CN(C=O)C>[C:37]([CH2:16][C:13]1[S:14][CH:15]=[C:11]([C:7]2[S:6][C:5]([NH:4][C:1]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:3])=[N:9][C:8]=2[CH3:10])[N:12]=1)#[N:39]
Reactant: CCN(CC)CC
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)NCC3CCCO3)n2)s1
Reactant: CC(C)(C)OC(=O)CCCN
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)NCCCC(=O)OC(C)(C)C)sc1-c1csc(CC#N)n1
Reaction time: 0.5 h

Procedure:
N-[2-(cyanomethyl)-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl]-1H-imidazole-1-carboxamide (Intermediate 6) (160 mg; 0.48 mmol; 1 eq) is dissolved in DMF (8 ml). Tert-butyl 4-aminobutanoate hydrochloride (94.8 mg; 0.48 mmol; 1 eq) and triethylamine (148 μl; 1.07 mmol; 2.20 eq) are added. After less than 1 min, the mixture becomes homogeneous. After 30 min the reaction is complete. DMF is removed under reduced pressure. The resulting crude oil is dissolved in DCM and washed twice with NH4Cl sat. solution and twice with NaHCO3 sat. solution. The organic layer is dried over Na2SO4, filtered and concentrated. The resulting crude product is purified by preparative HPLC. The purified fractions are neutralized with NaHCO3 sat. solution and the desired compound is extracted with DCM.
Reaction SMILES: Cl.Cl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][NH:22][CH2:21][CH2:20]2)=[O:14].[Cl:25][C:26]1[C:27]([C:36]([OH:38])=[O:37])=[N:28][C:29](S(C)(=O)=O)=[N:30][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][N:22]([C:29]1[N:28]=[C:27]([C:36]([OH:38])=[O:37])[C:26]([Cl:25])=[CH:31][N:30]=1)[CH2:21][CH2:20]2)=[O:14]
Reactant: CS(=O)(=O)c1ncc(Cl)c(C(=O)O)n1
Reactant: O=C(Nc1nc2ccccc2s1)c1cccc2c1CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1ncc(Cl)c(C(=O)O)n1)CC2
Temperature: 60 °C

Procedure:
A mixture of compound 1B (309 mg, 1 mmol), 5-chloro-2-methanesulfonyl-pyrimidine-4-carboxylic acid (236 mg, 1 mmol) and cesium carbonate (975 mg, 3 mmol) in 2 ml of DMSO was heated to 60° C. for 6 h. The product was precipitated out of solution by addition to water and collected by filtration. The crude material was chromatographed (SiO2, 20% methanol in dichloromethane) to afford title compound 123 as a white powder: LCMS (96% purity): m/z 465.9 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:16][CH2:17][N:18]([C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:19][CH:20]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[OH-:30].[Na+].BrBr>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@:15]23[O:30][C@@H:16]2[CH2:17][N:18]([C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])[CH2:19][CH2:20]3)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](c1ccccc1)N1CC=C(c2ccc(OCc3ccccc3)cc2)CC1
Reactant: [OH-]
Agent: Br
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](c1ccccc1)N1CC[C@]2(c3ccc(OCc4ccccc4)cc3)O[C@@H]2C1
Temperature: 2.5 °C
Reaction time: 1.5 h

Procedure:
44.3 g of (R)-4-(4-Benzyloxy-phenyl)-1-(1-phenyl-ethyl)-1,2,3,6 tetrahydropyridine (120 mmol) was suspended in 440 mL of dioxane at room temperature. Under stirring 40.4 g of 48% aqueous hydrogen bromide (240 mmol) was added at 15-20° C. within 5 minutes, followed by 24 mL of water. At the same temperature, the pH of the mixture was adjusted to pH 2 using 65 mL of 2 N NaOH. The slightly turbid solution was cooled to 2-3° C, and 21.2 g of bromine (133 mmol) was continuously added over 1.5 hours from a syringe pump via a teflon cannula. After the bromine addition, stirring at 2-3° C. was continued for another 1.5 hours. At this point, all starting material had reacted. At 0° C., 160 mL of 4 N NaOH (640 mmol) was added over 30 minutes and stirring was continued. After 2 hours the intermediate had completely reacted to the final product. The reaction mixture was extracted using a mixture of 500 mL of ethyl acetate and 200 mL of 20% aq. sodium chloride. The aqueous phase was separated and extracted with 1 portion of 300 mL of ethyl acetate. The organic phases were washed with 300 ml of 20% aq. sodium chloride, combined, dried (MgSO4) and evaporated under reduced pressure to give 51.3 g crude product as a brown oil. The crude product was taken up in 50 mL of ethyl acetate. Immediately after dissolution crystals started to separate. 50 mL of diethyl ether was added and the suspension was cooled to 0° C. A second portion of 25 mL of diethyl ether was added and the suspension was stirred for another 1 hour at 0° C. The crystals were collected on a filter funnel and washed with a portion of cold diethyl ether. The product was then dried for 2 hours at 26 mbar/45° C. There was obtained 23.5 g of (1R, 6R)-6-(4-benzyloxy-phenyl)-3-[(R)-1-phenyl-ethyl]-7-oxa-3-aza-bicyclo [4.1.0] heptane.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4](=[O:5])[CH3:15]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(F)ccc1Br
Solvent: C1CCOC1
Product: CC(=O)c1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
2-Bromo-5-fluoro-N-methoxy-N-methylbenzamide (4.0 g, 0.015 mol) was dissolved in THF (30 mL) and the solution was cooled to 0° C. under N2blanket. Methyl magnesium bromide (15.26 mL, 0.046 mol) was added dropwise over 30 min. The solution was warmed to room temperature and stirred for 1 hour. The solution was cooled to 0° C. and quenched with HCl/EtOH (9 mL, 4 M solution). The reaction mixture was transferred to a separatory funnel, diluted with H2O (30 mL), and extracted with Ethyl Acetate (2×40 mL). The combined organic extracts were washed with H2O, brine, and dried over Na2SO4. The solution was concentrated to afford 1-(2-bromo-5-fluorophenyl)ethanone as a yellow oil in 93% yield . This material was used in the subsequent step without further purification. 1H NMR (CDCl3, 500 MHz) δ2.61 (s, 3H), 7.00-7.04 (m, 1H) 7.15-7.18 (m, 1H), 7.53-7.59 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[CH:17][C:18]([C:20]([OH:22])=[O:21])=[CH:19][C:12]=2[N:11]=1.CN(C(O[N:31]1[N:39]=[N:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.C(OCC)(=O)C>[N:38]1([O:21][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:11][C:12]=3[CH:19]=2)=[O:22])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[N:39]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)O)ccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)On3nnc4ccccc43)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-(2,6-dichloro-phenylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (0.50 g, 1.5 mmol), HBTU (0.56 g, 1.5 mmol) and TEA (0.42 mL, 3.0 mmol) in 8 mL DMF was stirred for 3 days at ambient temperature. The mixture was diluted with water and ethyl acetate. The organic phase was washed with water and brine, dried and concentrated i.vac.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:23])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([C@H:13]3[CH2:18][CH2:17][C@@H:16]([O:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[Br:24]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:23])[C:5]2[CH:11]=[C:10]([Br:24])[C:9](=[O:12])[N:8]([C@H:13]3[CH2:14][CH2:15][C@@H:16]([O:19][CH2:20][CH2:21][OH:22])[CH2:17][CH2:18]3)[C:6]=2[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(N)nc2c1ccc(=O)n2[C@H]1CC[C@@H](OCCO)CC1
Solvent: CN(C)C=O
Product: Cc1nc(N)nc2c1cc(Br)c(=O)n2[C@H]1CC[C@@H](OCCO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-8-(cis-4-(2-hydroxyethoxy)cyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (411 mg, 1.29 mmol) in dimethylformamide (10 mL) was added N-bromosuccinimide (253 mg, 1.42 mmol). After stirring for 1 hour at room temperature the solution was concentrated. The residue was dissolved in chloroform (250 mL) and washed with 1 N sodium carbonate (2×25 mL) and brine (25 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with 1:1 ethyl acetate:chloroform/7N ammonia in methanol (0-4%) to afford the title compound (382 mg, 75%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[C:14]([NH:15][C:16]3[C:17]4[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[S:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[NH3:29]>CO.CN(C=O)C>[OH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([O:8][C:9]2[C:14]([NH:15][C:16]3[C:17]4[C:24]([CH3:25])=[C:23]([C:26]([NH2:29])=[O:27])[S:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:7]1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCC(O)CC3)c12
Reactant: N
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3O[C@H]3CC[C@@H](O)CC3)c12

Procedure:
Prepared analogously to 1.4 from 0.1 g 4-[2-(4-hydroxy-cyclohexyloxy)-pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia in methanol (7M) in DMF. Separated from trans isomer by chromatography.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.C(N(CC)CC)C.Cl[CH2:25][CH2:26][N:27]=[C:28]=[O:29].CC(C)([O-])C.[K+]>C1COCC1.O>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:15]=[CH:14][C:12]([N:13]3[CH2:25][CH2:26][NH:27][C:28]3=[O:29])=[CH:11][CH:10]=2)[O:5]1
Reactant: O=C=NCCCl
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(c2ccc(N3CCNC3=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.05 g) and triethylamine (1.34 mL) in THF (20 mL) was added 1-chloro-2-isocyanatoethane (0.409 mL) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a powder. A mixture of the obtained powder and potassium tert-butoxide (1.08 g) in THF (20 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate and diisopropyl ether to give the title compound (0.98 g).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH2:12])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:13][NH2:14]>C(O)(C)C>[NH:13]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH2:12])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[NH2:14]
Reactant: Nc1ncnc2cc(F)ccc12
Reactant: NN
Solvent: CC(C)O
Product: NNc1ccc2c(N)ncnc2c1
Reaction time: 0.5 h

Procedure:
7-Fluoro-quinazolin-4-ylamine (0.306 mmol, 50 mg) is dissolved in Hydrazine (2 mL) and heated in an open flask until all the liquid is gone. The resulting solid is taken up in isopropanol and stirred for 30 minutes and the solid is collected by filtration. This gives desired product 7-Hydrazino-quinazolin-4-ylamine (32 mg, LC/MS m/z=176 [M+H]+) as a tan powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C:10](O)=O)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.CN(C)[CH:27]=[O:28]>>[Cl:22][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]=1[CH:27]=[O:28]
Reactant: O=C(O)CC(Sc1ccccc1)c1ccc(F)cc1
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Product: O=CC1=C(Cl)c2ccccc2SC1c1ccc(F)cc1

Procedure:
As in example 18, but using 4.6 g 3-(4-fluorophenyl)-3-phenylmercapto-propionic acid, 40 ml dimethylformamide and 15 ml phosphorous oxychloride. After hydrolysis and work-up a residual oil is obtained which is purified by preparative HPLC. The oily fractions are crystallized in hexane and pure 4-chloro-4'-fluoro-3-formyl-thio-flav-3-ene is obtained as yellow crystals; m.p. 67°-69° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([CH:10]([S:12][CH:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[CH3:11])([OH:9])=O>CN(C=O)C.O1CCCC1>[CH2:26]1[O:27][C:21]2[C:22](=[CH:23][C:24]3[C:7](=[O:9])[C@H:10]([CH3:11])[S:12][C@@H:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:18][C:19]=3[CH:20]=2)[O:25]1
Reactant: COC(=O)C(Cc1ccc2c(c1)OCO2)SC(C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1Cc2cc3c(cc2C(=O)[C@H](C)S1)OCO3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.5 %

Procedure:
Oxalyl chloride (13.6 g) and DMF (3 drops) were successively added dropwise to a solution of methyl 2-(1-carboxyethyl)thio-3-(3,4-methylenedioxyphenyl)propionate (27.8 g) in tetrahydrofuran (THF) (200 ml), followed by stirring for 1.5 hours at room temperature and concentrated under reduced pressure. The residual oil was dissolved in dichloromethane (250 ml). To the solution was added dropwise tin(IV) tetrachloride (SnCl4)(51.0 g) under ice-cooling. The mixture was stirred for an hour under ice-cooing, to which 2NHCl (100 ml) was added dropwise. The dichloromethane layer was separated, washed with water, dried (MgSO4) and distilled off the solvent. The residual oil was dissolved in methanol (250 ml), to which a solution of sodium methoxide in methanol (28%, 10 ml) was added. The resultant solution was stirred for 1.5 hours at room temperature to which 2N--HCl (250 ml) was added. The precipitated crystals were collected by filtration to give methyl trans-7,8-methylenedioxy-4-methyl-5-oxo-1,2,4,5-tetrahydro-3-benzothiepine-2-carboxylate (19.0 g, 73%). Recrystallization from ethyl acetate gave colorless prisms.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH2:13].[O-]S([O-])(=O)=O.[Mg+2].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.CC#N>[C:17]([O:16][C:14]([NH:12][N:13]=[C:8]1[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN=C1CCC(C(C)(C)C)CC1
Reaction time: 18 h
Yield: 98.7 %

Procedure:
To a solution of 4-tert-butylcyclohexanone (3.95 g, 25.6 mmol) in CH2Cl2 (50 mL) was added tert-butyl hydrazinecarboxylate (3.83 g, 25.6 mmol). A 1:1 mixture of MgSO4/Na2SO4 was added to the reaction to make a slurry and the reaction was stirred vigorously. After 18 h, the reaction was diluted with CH3CN and filtered. The solvent was removed from the filtrate under reduced pressure to give 6.78 g of N′-(4-tert-butyl-cyclohexylidene)-hydrazinecarboxylic acid tert-butyl ester as a white foam. This material was used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 2.93 (d, J=15 Hz, 1H), 2.30 (d, J=13 Hz, 1H), 2.08 (m, 1H), 1.89 (m, 2H), 1.66 (m, 1H), 1.43 (s, 9H), 1.25 (m, 1H), 1.13 (m, 1H), 1.03 (m, 1H), 0.85 (s, 9H).