Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].[OH2:25]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([O:1][C:2]2[C:11]3[C:6](=[C:7]([O:12][C:20](=[O:21])[C:19]4[CH:23]=[CH:24][C:16]([N+:13]([O-:14])=[O:25])=[CH:17][CH:18]=4)[CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=2)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O
Reactant: Oc1cccc2c(O)cccc12
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(Oc1cccc2c(OC(=O)c3ccc([N+](=O)[O-])cc3)cccc12)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
8.0 g of 1,5-dihydroxynaphtalene (50.0 mM) were dissolved in 150 ml of pyridine and the solution was cooled to 0° C. At this temperature were added portionwise 27.8 g of 4-nitrobenzoylchloride (150.0 mM), whereupon the temperature rose to Ca. 30° C. Then, 0.6 g of DMAP (5.0 mM) were added and the mixture was stirred overnight at 140° C. bath-temperature. The next day, the reaction mixture was allowed to cool to room temperature and 500 ml of water were added and the resulting mixture was stirred for 1 h at 140° C. bath-temperature. It was then cooled to room temperature and filtered. The cake was washed with water and dried to give 22.2 9 (48.4 mM, 97%) of 5-[(4-nitrobenzoyl)oxy]-1-naphthyl 4-nitrobenzoate as beige crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CS(C)=O>[ClH:1].[Cl:8][C:4]1[N:3]=[C:2]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CN1CCNCC1
Reactant: Clc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(c2cccc(Cl)n2)CC1
Product: Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 7.5 g (0.05 mol) of 2,6-dichloropyridine in 70 ml of DMSO, 6.9 g (0.05 tool) of anhydrous K2CO3 and 5.5 ml (0.05 tool) of N-methyl piperazine are added. The mixture is stirred at 80° C. for 4 hours, then poured into ice/water and extracted with ethyl acetate, dried over Na2SO4 , filtered and the solvent is evaporated off. The residue is dissolved in 30 ml of hydrogen chloride saturated isopropanol. The precipitate is collected by filtration and recrystallized from isopropanol to provide 4.8 g of a white powder. M.p. 225°-227° C. For a better purification, the above product is dissolved in a diluited solution of NaOH, extracted with ethyl acetate, the organic phase is washed with water, stirred for 10 min. with some silica gel, dried over Na2SO4, filtered and the solvent is evaporated off.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)#[N:2].[OH-:23].[Na+].OO>CCO.O.[Na+].[Cl-]>[NH2:2][C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=[O:23]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C#N)CC1
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(N)=O)CC1
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[(2-cyanophenyl)amino]-1-piperidinecarboxylate (D17) (355 mg, 1.18 mmol) in EtOH (6 ml) at 40° C. was added 2M NaOH solution (2.6 ml) followed by a mixture of hydrogen peroxide solution (27% w/w, 3.7 ml) in water (2.9 ml) and the reaction stirred for 2 h. Further hydrogen peroxide solution (27% w/w, 3.7 ml) in water (2.9 ml) was added and the reaction stirred at 40° C. for 1.5 h. Another portion of hydrogen peroxide solution (27% w/w, 7.4 ml) in water (5.8 ml) was added and stirring and heating were continued overnight. The reaction mixture was diluted with saturated aqueous NaCl solution (4 ml) and extracted with tBuOH (5 ml). The organic extract was diluted with EtOAc (15 ml), dried (MgSO4) and concentrated. Column chromatography eluting with 0-100% EtOAc/petroleum ether gave the title compound (150 mg). δH (CDCl3, 250 MHz) 7.96 (1H, br d), 7.40 (1H, m), 7.31 (1H, m), 6.71 (1H, d), 6.57 (1H, t), 5.80 (2H, br s), 3.93 (2H, m), 3.53 (1H, m), 3.06 (2H, m), 1.99 (2H, m), 1.50 (2H, m), 1.47 (9H, s). MS (ES): MH+ 320.
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][CH:4]=1.N([O-])=O.[Na+].[BrH:18]>C(O)(=O)C.O>[Br:18][C:6]1[CH:8]=[CH:9][C:3]([S:2]([F:13])([F:12])([F:11])([F:10])[F:1])=[CH:4][CH:5]=1
Reactant: Br
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FS(F)(F)(F)(F)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5.0 g of 4-pentafluorosulfanylaniline were dissolved in 20 ml of acetic acid and, at 0° C., a saturated aqueous HBr solution was added. Then at 0° C., a solution of 1.9 of NaNO2 in 5 ml of water was slowly added dropwise over the course of 5 minutes. The reaction mixture was stirred at 0° C. for 10 minutes and then added in portions to a suspension of 6.5 g of CuBr in 20 ml of a half-saturated aqueous HBr solution at 0° C. Nitrogen is liberated during this. The mixture was stirred at 0° C. for 30 minutes and then at RT for 1 h. It was subsequently extracted 3 times with 100 ml of HEP each time, and then the HEP was washed twice with 50 ml of a saturated aqueous Na2CO3 solution each time. The residue after drying over MgSO4 and removal of the solvent in vacuo was chromatographed on silica gel with HEP. 1.8 g of a colorless oil were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=O)[C:10]([OH:12])=[O:11].C1CCN2C(=NCCC2)CC1.[NH2:25][C:26]1[C:31]([CH:32]=O)=[CH:30][N:29]=[C:28]([S:34][CH3:35])[N:27]=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:10]([OH:12])=[O:11])=[N:25][C:26]2[N:27]=[C:28]([S:34][CH3:35])[N:29]=[CH:30][C:31]=2[CH:32]=1
Reactant: CSc1ncc(C=O)c(N)n1
Reactant: O=C(O)C(=O)Cc1ccccc1Br
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1ncc2cc(-c3ccccc3Br)c(C(=O)O)nc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.4 %

Procedure:
3.372 g 3-(2-bromophenyl)2-oxopropionic acid in 20 ml DMF were treated with 4.434 g DBU under cooling and stirred for 10 min at RT. 2.728 g 4-amino-2-methylsulfanylpyrimidine-5-carbaldehyde were added and the mixture was stirred at 85° C. for 4.5 hrs. Stirring was continued over night at RT, then the solvent was evaporated and the residue dispensed in aqueous sodium carbonate solution. The mixture is extracted with ethyl acetate, then acidified to pH 2 and again extracted with chloroform. The chloroform extracts were dried and evaporated and the residue triturated with hot ethyl acetate. 2.786 g of the title product were thus obtained after filtration.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]=3[N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)=[N:32][CH:33]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C(OCC)(=O)C.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>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:28]2[CH:33]=[N:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:3][C:4]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COc1ccc2[nH]c(-c3cc(I)cnc3N)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc3N)[nH]c2c1
Temperature: 25 °C

Procedure:
128.87 mg (0.273 mmol) of 5-iodo-3-(5-methoxy-1H-benzimidazol-2-yl)pyridin-2-ylamine and 191.38 mg (0.492 mmol) of tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate are suspended in 2.5 ml of N,N-dimethylformamide in a nitrogen-filled microwave vessel, and 0.6 ml (1.2 mmol) of 2M sodium carbonate solution and 31.5 mg (0.027 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. The reaction solution is irradiated with microwaves for 30 min at 120° C. in the Biotage SmithSynthesizer. The reaction mixture is cooled to room temperature and diluted with water/ethyl acetate and filtered. The aqueous phase is extracted a further 2× with ethyl acetate, and the combined organic phases are dried using sodium sulfate, filtered and evaporated to dryness. The residue is purified by means of RP-HPLC, giving tert-butyl 4-[6′-amino-5′-(6-methoxy-1H-benzimidazol-2-yl)-[3,3′]bipyridinyl-6-yl]-piperazine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=O>>[CH2:19]([O:18][C:12]([C:13]1[C:14]([CH3:16])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)=[O:17])[CH3:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(N)c(C#N)c1
Product: CCOC(=O)c1c(C)nc2ccc(OC)cc2c1N

Procedure:
Prepared as in Example 2a from 2-amino-5-methoxybenzonitrile (Campbell, J. B. et al. Synth. Commun. 1989, 19, 2255-2263) and ethyl acetoacetate as an off-white solid (92%). 1H NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=6.8 Hz, 3H), 2.57 (s, 3H), 3.86 (s, 3H), 4.33 (q, J=6.8 Hz, 2H), 7.28 (dd, J=2.8, 9.2 Hz, 1H), 7.59 (d, J=9.2 Hz, 1H), 7.60 (bs, 2H), 7.63 (d, J=2.8 Hz, 1H). MS 261 (MH+).
Reaction SMILES: [C:1]([CH:4]([CH2:9][C:10]([O:12]C)=[O:11])[C:5]([O:7]C)=O)(=O)[CH3:2].C[O-].[Na+].CO.Cl.[C:20]([NH2:23])(=[NH:22])[CH3:21]>>[CH3:21][C:20]1[N:23]=[C:5]([OH:7])[C:4]([CH2:9][C:10]([OH:12])=[O:11])=[C:1]([CH3:2])[N:22]=1
Reactant: CC(=N)N
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C)c(CC(=O)O)c(O)n1
Yield: 93.3 %

Procedure:
Dimethyl acetylsuccinate (188 g, 1 mol) is dissolved in sodiummethylate/methanol (1.1 mol in 500 ml) and added within 30 minutes to a solution of acetamidine hydrochloride (104 g, 1.1 mol) at 60° C. with stirring. After refluxing the mixture for 14 hours, the precipitated salt is removed by filtration and the filtrate is evaporated to dryness under reduced pressure. The resulting solid is suspended in acetone, filtered and dried to give (2,6-dimethyl-4-hydroxy-5-pyrimidinyl) acetic acid crystalline product (170 g, 93%).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:11]1[N:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=2C)=[O:18])[CH:12]=1>O1CCCC1>[CH:1]1([O:7][C:11]2[N:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[O:18])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)cc1)c1cc(OC2CCCCC2)ncn1
Reaction time: 0.17 h

Procedure:
Cyclohexanol (Fluka, 4.00 mL; 37.8 mmol) was treated with sodium hydride (35.0 mg; 0.80 mmol) and stirred during 10 minutes. Tetrahydrofuran (3 mL) was added, followed by 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide, Intermediate 7 (50.0 mg; 0.20 mmol). After 2 hours the solvents were removed in vacuo, the crude was redissolved in EtOAc. The organic phase was washed with sat. ammonium chloride and brine, dried over magnesium sulfate, filtered and evaporated in vacuo to give a residue, which was purified by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc. The title compound was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)#[CH:13]>>[CH3:11][C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:13]#[C:12][C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:7][N:6]2[N:8]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: Cc1cc2ncc(Br)cn2n1
Product: Cc1ccc(C#Cc2cnc3cc(C)nn3c2)cc1

Procedure:
The title compound, brown solid, MS: m/e=248.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 4-ethynyltoluene.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]2[CH:15]=[C:16]([O:21][CH2:22]C3C=CC=CC=3)[C:17]([O:19]C)=[CH:18][C:10]=2[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:33]CC1>CO.[Pd]>[CH2:1]([N:8]1[C:14](=[O:33])[CH2:13][CH2:12][CH2:11][C:10]2[CH:18]=[C:17]([OH:19])[C:16]([O:21][CH3:22])=[CH:15][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)CCCN(Cc1ccccc1)C2=O
Reactant: C1CCOC1
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1O)CCCC(=O)N2Cc1ccccc1

Procedure:
A solution of 2-benzyl-7-(benzyloxy)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (1 mmol) in THF (20 mL) and methanol (20 mL) was treated with 10% Pd/C (40 mg) and stirred under an atmosphere of hydrogen. The reaction was monitored by TLC. Upon completion, the resultant suspension was filtered through celite, washed with ethyl acetate and then evaporated under reduced pressure. The resulting solid was stirred in diethyl ether, filtered and dried under vacuum or purified by flash chromatography (hexane/ethyl acetate) then stirred in diethyl ether, filtered and dried under vacuum.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.Cl.[Cl:11]C[C:13]1[NH:14][CH2:15][CH2:16][N:17]=1.[CH2:18](O)C>>[ClH:11].[CH3:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:13]1[N:14]([CH3:18])[CH2:15][CH2:16][N:17]=1
Reactant: CCO
Reactant: Cc1cc(O)ccc1N
Reactant: ClCC1=NCCN1
Agent: Cl
Product: Cc1cc(O)ccc1NC1=NCCN1C

Procedure:
Two moles 4-amino-m-cresol and 1 mole 2-chloromethyl-2-imidazoline hydrochloride are refluxed for 3 hours, within absolute ethanol. After cooling, the insoluble fraction is suction filtered and the ethanol solution is evaporated in vacuo. The evaporation residue is recrystallized from methanol:diethyl ether; M.p.=205°-207° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:15]2[CH:21]([C:22]([O-:24])=[O:23])[NH:20][CH2:19][CH2:18][CH2:17][S:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:15]2[CH:21]([C:22]([OH:24])=[O:23])[NH:20][CH2:19][CH2:18][CH2:17][S:16]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2SCCCNC2C(=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)C2SCCCNC2C(=O)O)cc1

Procedure:
Following the procedure of Step 3 of Example 173, tert-butyl (3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-thiazepane-3-carboxylate (800 mg, 1.88 mmol), trifluoroacetic acid (6 mL) in methylene chloride (15 mL) provide 650 mg (94%) of (3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-thiazepane-3-carboxylic acid; 1H NMR (300 MHz, acetone-d6): δ1.74 (m, 3H), 1.90 (m, 2H), 2.59 (m, 2H), 2.90 (m, 1H), 3.18 (m, 1H), 3.26 (m, 1H), 3.70 (m, 1H), 4.70 (m, 3H), 7.03 (d, 2H, J=8.7 Hz), 7.77 (d, 2H, J=8.7 Hz); HRMS (C16H19NO5S2)(M+H); calcd. 370.0777, found 370.0765.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][OH:12])=[CH:8][C:6]=2[N:7]=1.[CH2:19](N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:19][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][O:12][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(N2CCOCC2)c2sc(COS(C)(=O)=O)cc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol (500 mg) and triethylamine (0.5 mL) in dichloromethane (20 mL) at 0° C. was added methanesulfonyl chloride (0.27 mL). The reaction mixture was stirred at room temperature for 16 h and then quenched with water (20 mL) and extracted into dichloromethane (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4) and concentrated to give methanesulfonic acid 2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl ester as a yellow solid (523 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([C:15]([O:17]CC)=[O:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].C([OH:24])C>O>[C:15]([C:11]1[CH:10]=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12]=1[C:13]([NH2:14])=[O:24])([OH:17])=[O:16]
Reactant: CCO
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1c(C(=O)O)cnn1-c1ccc(Cl)cc1

Procedure:
The process of Example 2 was followed, starting with 3.7 g. of ethyl 1-(4-chlorophenyl)-5-cyano-4-pyrazolecarboxylate and 2 g. of sodium hydroxide in 60 ml. of denatured ethanol and 60 ml. of water to obtain 2.3g. of the desired product, m.p. 249°-250°. The elemental analysis was as follows.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([C:16]([Cl:37])=[CH:17][C:18]1[CH:19]=[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]2=[O:36])[CH:21]=[CH:22][CH:23]=1)([OH:15])=O.[ClH:38].[CH3:39][O:40][NH2:41].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:38][C:23]1[CH:22]=[CH:21][C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:18]=1[CH:17]=[C:16]([Cl:37])[C:13]([NH:41][O:40][CH3:39])=[O:15]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cccc(C=C(Cl)C(=O)O)c2)c1=O
Reactant: Cl
Reactant: CON
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: C1CCOC1
Product: CONC(=O)C(Cl)=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Carbonyldiimidazole (0.9 g) was added to a solution of 3-[3-(2-carboxy-2-chloroethenyl)phenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine (2.1 g) in 80 ml of tetrahydrofuran, after which the mixture was stirred at 25° C. for one hour. Methoxyamine hydrochloride (1.67 g as a 30% strength by weight aqueous solution) and potassium carbonate (0.83 g), dissolved in 20 ml of tetrahydrofuran, were then added dropwise. After stirring for 5 hours, the solvent was distilled off, after which the residue was taken up in 150 ml of dichloromethane. The organic phase was washed twice with 30 ml each of water, twice with 30 ml each of 10% strength by weight sodium hydrogencarbonate solution and again with 30 ml of water, then dried over sodium sulfate and concentrated. After crystallization using petroleum ether, 1.5 g of the product were obtained; m.p.: 136-141° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1Cl)=[O:11]>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH2:9][CH:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:13][CH:14]=1
Reactant: CC(=O)c1ccc(F)cc1Cl
Reactant: CCOC(=O)CC#N
Product: CCOC(=O)C(C#N)CC(=O)c1ccc(F)cc1

Procedure:
The compound of formula III, when n and p are equal to 1 and q is equal to 1, is prepared from ethyl cyanoacetate and 2-chloro-4-fluoroacetophenone. The ethyl 2-(4-fluorophenacyl)cyanoacetate thereby obtained is then reacted with anhydrous ethylene glycol to obtain 2-[2-(2-cyanoethoxycarbonyl) ethyl]-2-(4-fluorophenyl)-l,3-dioxolane. Hydrogenation of the latter compound leads to 2-[2-(2-aminomethylethoxycarbonyl)ethyl]-2-(4-fluorophenyl)- 1,3-dioxolane, which is reacted with methylmagnesium iodide to obtain 2 (4-fluorophenyl)-2-[(2-oxo-azetidin-3-yl) methyl]dioxolane. This compound is subjected to the action of lithium aluminum hydride to obtain the expected compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>COCCOC.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:10][OH:11])[CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1cc(F)cc(F)c1
Temperature: -20 °C
Yield: 79.9 %

Procedure:
Dissolve commercially available 2-(S)-tert-butoxycarbonylamino-3-(3,5-difluorophenyl)propionic acid (5.995 g, 19.9 mmol) in ethylene glycol dimethyl ether (20 mL) and cool −20° C. Add 4-methylmorpholine (2.4 mL, 21.89 mmol) and stir 5 min, then add isobutyl chloroformate (2.9 mL, 21.89 mmol) dropwise and stir 5 min. Filter into −15° C. cooled flask with course frit, rinse with cold ethylene glycol dimethyl ether. Add sodium borohydride (1.129 g, 29.85 mmol) in water (9 mL) followed by water (500 mL), then warm to room temperature. Filter and dissolve solid in dichloromethane. Wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as a solid (4.57 g, 80%).
Reaction SMILES: [CH3:1][C:2]([N:7]1[C:12](=[O:13])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([CH3:20])[O:9][CH2:8]1)([CH3:6])[C:3]([OH:5])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:41]1([NH:40][C:3](=[O:5])[C:2]([CH3:1])([N:7]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([CH3:20])[O:9][CH2:8]2)[CH3:6])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Nc1ccccc1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a suspension of 2-methyl-2-(6-methyl-5-phenyl-2,3-dihydro-4-oxo-4H-1,3-oxazin-3-yl)-propionic acid (0.83 g) in 10.4 ml of CCl4 --CH2Cl2 (1:1) was added triphenylphosphin (1.04 g), then the mixture was refluxed for 40 min. The reaction mixture was ice-cooled and aniline (0.28 g) and triethylamine (0.3 g) were slowly added, then it was stirred at room temperature for 1 h. After evaporation of the solvent, the residue was dissolved in ethyl acetate. The insolubles were filtered off and the filtrate was evaporated. The residue was purified by chromatography on a silica gel column to get the captioned compound (0.58 g).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: CC1(C)OB(c2ccc(F)cc2OCC2CC2)OC1(C)C
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-cyclopropylmethoxy-4-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c3) the title compound is obtained as off-white solid.