Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[C:21]([P:26](=[O:29])([OH:28])[OH:27])[P:22](=[O:25])([OH:24])[OH:23])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[O-]CC.[Na+:33].C(O)C>O1CCCC1>[C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[C:21]([P:26](=[O:27])([O-:28])[O-:29])[P:22](=[O:23])([OH:24])[OH:25])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Na+:33].[Na+:33]
Reactant: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)(O)O)P(=O)(O)O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)([O-])[O-])P(=O)(O)O
Reaction time: 0.33 h
Yield: 94 %

Procedure:
[2-[2-(1-Tridecynyl)phenyl]ethenylidene]bisphosphonic acid (0.101 g, 0.228 mmol) prepared according to Example 10 was dissolved in dry tetrahydrofuran (10 ml) and stirred while sodium ethoxide in ethanol (0.177M, 2.58 ml, 0.457 mmol) was added. After 20 minutes, the solvent was removed under reduced pressure to give a yellowish solid. This solid was pulverized and washed successively with dry ether, tetrahydrofuran, acetone, acetonitrile, and ethanol, then dried on the vacuum line, 0.104 g, 0.214 mmol, 94% yield. 1H NMR (D2O) ∂ 0.74 (m, 3H), 1.17 (m, 14H), 1.35 (m, 2H), 1.52 (m, 2H), 2.39 (t, J=7.1H, 2H), 7.24 (m, 2H), 7.37 (m, 1H), 7.92 (dd+m, J=43.8, 27.0 Hz, 2H); FAB mass spectrum m/z 443 (M-2Na+3H)+, 465 (M-Na+2H)+, 487 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:14][CH:13]=2)[CH:9]=1)=[O:4]>O1CCCC1>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[O:6][C:7]=2[CH3:26])=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc(COc2ccc(-c3ccccc3OC)cc2)c(C)o1
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc(OCc2cc(C(=O)O)oc2C)cc1
Reaction time: 16 h
Yield: 77.9 %

Procedure:
A solution of 4-(2′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (125) (40 mg, 0.11 mmoles) in dry tetrahydrofuran (25 ml) was treated with potassium trimethylsilanoate (73 mg, 0.56 mmoles) and the mixture stirred under an argon atmosphere for 16 h. After evaporation of the solvent the residue was acidified to pH=2 with 0.1M aqueous hydrochloric acid and the mixture extracted with ethyl acetate. The dried extracts were evaporated and the residue pumped under high vacuum at 40° C. to afford compound 126 (29 mg) as an off-white solid. LC/MS System D; Rt=8.30 mins, m/z (ES+)=339 (M+H for C20H18O5).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.[C@@H:24]1([NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[NH2:30]>CN1C(=O)CCC1>[NH2:30][C@@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@H:24]1[NH:31][C:16]1[S:17][C:13]2[CH:12]=[C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:23])[CH:9]=3)[CH:22]=[CH:21][C:14]=2[N:15]=1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4N)sc3c2)ccn1
Temperature: 105 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
To the solution of N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (15 mg, 43 μmole) in 400 μL of NMP was added (1R,2R)-cyclohexane-1,2-diamine (17 mg, 150 μmole). The reaction solution was stirred at 105° C. for 24 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give 4-(2-((1R,2R)-2-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (12 mg, 30 μmole) as white powder. ES/MS m/z 398.1 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)C.Cl.[NH2:13][OH:14].[OH-].[Na+].Cl>O.C(O)C>[OH:14][N:13]=[CH:9][C:3]1[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[OH:1]
Reactant: NO
Reactant: CC(=O)c1ccc(O)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 2.0 grams (0.013 mole) of 1-(2,4-dihydroxyphenyl)ethan-1-one (commercially available) and 1.4 grams (0.019 mole) of hydroxylamine hydrochloride in 20 mL of water and 100 mL of ethanol was cooled to about 0° C. to 4° C. and 2.7 grams (0.068 mole) of sodium hydroxide was added. Upon completion of addition the reaction mixture was warmed to reflux where it stirred during a 30 minute period. After this time the reaction mixture was cooled to ambient temperature and 400 mL of aqueous 5% hydrochloric acid was added. The mixture was extracted with diethyl ether, and the extract was washed with water. The organic layer was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, yielding 1.5 grains of the subject compound.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[N:5]1>O>[Br:1][C:7]1[C:6]([C:9]([F:17])([F:18])[C:10]([F:15])([F:16])[C:11]([F:12])([F:13])[F:14])=[N:5][N:4]([CH3:3])[CH:8]=1
Reactant: Cn1ccc(C(F)(F)C(F)(F)C(F)(F)F)n1
Reactant: BrBr
Solvent: O
Product: Cn1cc(Br)c(C(F)(F)C(F)(F)C(F)(F)F)n1
Reaction time: 1 h

Procedure:
At 40° C., 3.27 g (20.45 mmol) of bromine are added dropwise to a solution of 4.65 g (18.59 mmol) of 1-methyl-3-heptafluoropropyl-1H-pyrazole in 18 ml of water and the reaction mixture is afterstirred firstly at 60° C. for 1 hour and then at room temperature for 18 hours. The aqueous phase is extracted three times with dichloromethane and the organic phase is dried over sodium sulphate. The dichloromethane is distilled off at reduced pressure on a rotary evaporator. This gives 5.75 g (77.85% of theory) of 1-methyl-3-heptafluoropropyl-4-bromo-1H-pyrazole as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[N:32]=[C:33]=[O:34].Cl>C(#N)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[NH:32][C:33]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2)=[O:34]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1Cl
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4cc(C(F)(F)F)ccc4Cl)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 1-chloro-2-isocyanato-4-trifluoromethyl-benzene (0.15 ml, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding the 1-(2-chloro-5-trifluoromethyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (240 mg, 49%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4 in H2O: tR=7.88 min (99%); mp. 240-242° C.; 1H NMR (DMSO-d6) δ 1.93-2.06 (m, 1H, CHH), 2.39 (qd, J=4.3, 13.2 Hz, 1H, CH), 2.63 (br. s., 1H, CHH), 2.82-3.02 (m, 1H, CHH), 4.24-4.55 (m, 4H, C+C2), 5.12 (dd, J=5.0, 13.1 Hz, 1H, NCH), 7.30 (dd, J=1.6, 8.4 Hz, 1H, Ar), 7.47 (d, J=7.9 Hz, 1H, Ar), 7.55 (s, 1H, Ar), 7.69 (dd, J=8.0, 15.4 Hz, 2H, Ar), 7.78 (t, J=5.7 Hz, 1H, Ar), 8.49 (s, 1H, NH), 8.66 (s, 1H, NH), 10.99 (s, 1H, NH). 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.80, 47.13, 51.58, 116.19, 116.25, 118.54, 122.07, 123.06, 124.60, 125.64, 127.02, 127.90, 128.32, 130.23, 130.49, 137.51, 142.49, 143.95, 154.67, 167.89, 170.98, 172.85. LCMS MH=495; Anal Calcd for: C22H18ClF3N4O4+0.05 HCl: C, 53.20; H, 3.66; N, 7.49; Cl, 11.28. found: C, 53.08; H, 3.39; N, 7.64; Cl, 11.29.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[N:13]=[C:14]([CH2:17]OS(C)(=O)=O)[S:15][CH:16]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].OCC1S[CH:27]=[C:28]([C:30]([N:32]2[CH2:37][CH2:36]N(C(C)C)CC2)=O)N=1.CS(Cl)(=O)=O>C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[N:13]=[C:14]([CH2:17][N:32]3[CH2:30][CH2:28][CH2:27][CH2:36][CH2:37]3)[S:15][CH:16]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2csc(COS(C)(=O)=O)n2)CC1
Reactant: CC(C)N1CCN(C(=O)c2csc(CO)n2)CC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2csc(CN3CCCCC3)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Methanesulfonic acid 4-(4-isopropyl-piperazine-1-carbonyl)-thiazol-2-ylmethyl ester. (2-Hydroxymethyl-thiazol-4-yl)-(4-isopropyl-piperazin-1-yl)-methanone (0.95 g. 3.5 mmol) and TEA (0.542 mL, 3.89 mmol) were suspended in DCM (50 mL). The suspension was cooled to 0° C. and methanesulfonyl chloride (0.3 mL) was added dropwise. The mixture was stirred at 0° C. for 30 min, then warmed to rt and stirred for 2 h. The mixture was concentrated at rt to yield the title compound (0.50 g, 41%). The crude mesylate was carried forward to the next step. MS (ESI): exact mass calcd. for C14H22N2O4S2, 347.10; m/z found, 348.5 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH:9]=[C:8](C(O)=O)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1.Cl>[Cu].C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2c(Br)cccc2s1
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: Brc1cccc2sccc12
Temperature: 185 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
A mixture of 4-bromobenzo[b]thiophene-2-carboxylic acid (21.05 g), copper powder (7.0 g) and quinoline (170 ml) was stirred at 180-190° C. for 1 hour, allowed to cool to ambient temperature and poured into 2M hydrochloric acid (900 ml). Ethyl acetate (500 ml) was added, the mixture was stirred for 15 minutes, then it was filtered through Celite. The aqueous phase was separated and shaken with ethyl acetate (200 ml), then the combined ethyl acetate solutions were washed with water (500 ml) and saturated aqueous sodium chloride solution (500 ml), dried (Na2SO4), and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using petroleum ether (b.p. 60-80° C.) as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 4-bromobenzo[b]thiophene (9.55 g) as a colourless oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:17])([C:13]#[C:14][CH2:15][CH3:16])[C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([Cl:18])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[CH2:26][C:27](Br)=[O:28]>CCOCC>[C:13]([C:8]1([C:9]([F:10])([F:11])[F:12])[C:7]2[CH:6]=[C:5]([Cl:18])[CH:4]=[CH:3][C:2]=2[NH:1][C:27](=[O:28])[CH2:26][O:17]1)#[C:14][CH2:15][CH3:16]
Reactant: O=C(Br)CBr
Reactant: CCC#CC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCC#CC1(C(F)(F)F)OCC(=O)Nc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred ice-cooled solition of 167 mg of 6-amino-3-chloro-α-(1-butynyl)-α-(trifluoromethyl)benzyl alcohol in 15 mL of dry ether was added 0.100 mL of dry pyridine and 0.066 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 15 mL of dry DMF and was treated at room temperature with 25 mg of 100% sodium hydride for 1.5 h. The reaction was partitioned between ethyl acetate and water and the ethyl acetate layer was washed with brine, dried and evaporated. The crude product wes purified by preparative silica gel TLC. (elution with ethel acetate/hexanes 1:2) affording after crystallization from ethyl acetate/hexanes 106 mg of the title compound as colorless crystals: mp 167 -168°; Anal. Calcd. for C14H11NO2ClF3 : C, 52.93; H, 3.49; N, 4.42. Found: C, 52.73; H, 3.64; N, 4.13.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].C([O-])([O-])=O.[K+].[K+]>Cl[Cu].O>[NH:6]1[C:10]2[C:3](=[CH:2][CH:13]=[CH:12][CH:11]=2)[CH2:4][C@H:5]1[C:7]([OH:9])=[O:8]
Reactant: N[C@@H](Cc1ccccc1Br)C(=O)O
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)[C@@H]1Cc2ccccc2N1
Temperature: 95 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
A flask was charged successively with 4.89 g (20.0 mmol) (S)-2-bromophenylalanine, 2.93 g (21.2 mmol) K2CO3, 0.2 mg CuCl (2.9 mmol) and 39.7 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95° C. and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 4 h hour full conversion of (S)-2-bromophenylalanine was found. The reaction mixture was cooled to 25° C. Then the reaction mixture was acidified with 4.47 g 5M aqueous HCl until pH=4.4. The precipitated (S)-2,3-dihydro-1H-indole-2-carboxylic acid was isolated by filtration and washed with 2×10 mL H2O. Found after drying 2.24 g (13.7 mmol) (S)-2,3-dihydro-1H-indole-2-carboxylic acid. Yield 69%, ee>99%.
Reaction SMILES: [CH3:1]O.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[N:4]1.Cl>O1CCOCC1>[CH3:1][O:13][C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:3][N:4]=1)=[O:14]
Reactant: CO
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the methanol solution of 1H-indazole-3-carboxylic acid (162 mg, 1 mmol) was added 4N HCl in dioxane (2 mL) and the mixture was stirred at the room temperature for 24 h. After evaporation of the volatiles, the mixture was partitioned between aqueous NaHCO3 solution and ethyl acetate. The aqueous phase was extracted with ethyl acetate (2×15 mL), and the combined organic layer was dried over sodium sulfate. The volatiles were removed, and the residue was filtered over silica gel to provide 1H-Indazole-3-carboxylic acid methyl ester (123 mg). LCMS m/z: 177 (M+1)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([O:16][CH3:17])[CH:4]=1.[C-:18]#[N:19].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[C:18]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([O:16][CH3:17])[CH:4]=1)#[N:19]
Reactant: [C-]#N
Reactant: COc1cc(CCl)ccc1Sc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CC#N)ccc1Sc1ccccc1
Temperature: 30 °C
Reaction time: 14 h

Procedure:
Thus obtained 1-chloromethyl-3-methoxy-4-phenylthiobenzene was dissolved in 200 ml of N,N-dimethylformamide, and 7.34 g of finely ground sodium cyanide was added and stirred for 14 hours at 30° C. To the reaction mixture, 300 ml of saturated brine and 300 ml of ice water were added, and the mixture was extracted with ethyl acetate (300 ml×3). The extract was washed with saturated brine (200 ml×3), and dried with anhydrous sodium sulfate, and 1-cyanomethyl-3-methoxy-4-phenylthiobenzene was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C@@H:5]([NH:9]C(=O)OC(C)(C)C)[CH:6]([CH3:8])[CH3:7])=[O:4].[ClH:18]>O1CCOCC1>[ClH:18].[NH2:9][C@@H:5]([CH:6]([CH3:8])[CH3:7])[C:3]([N:2]([CH3:17])[CH3:1])=[O:4]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@H](N)C(=O)N(C)C

Procedure:
tert-Butyl (1S)-1-[(dimethylamino)carbonyl]-2-methylpropylcarbamate (131 mg) was treated with 4M of hydrogen chloride in 1,4-dioxane (1.0 mL) at RT for 2 h. The solvent was evaporated under reduced pressure. The residue was dried to give the desired product (96 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[N-:10]([C:13]#[N:14])[C:11]#[N:12].[Na+]>>[C:11]([N:10]=[C:13]([NH2:14])[NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[O:2][CH3:1])#[N:12]
Reactant: N#C[N-]C#N
Reactant: COc1ccccc1N
Agent: [Na+]
Product: COc1ccccc1NC(N)=NC#N

Procedure:
A solution of 2-methoxyaniline and sodium dicyanamide was processed as described in Example 71A to provide the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:5]=1)(=O)[CH3:2].Cl.[NH2:25][NH:26][C:27]([NH2:29])=[O:28].N1C=CC=CC=1>C(O)C>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[O:15][C:6]1[CH:5]=[C:4]([C:1](=[N:25][NH:26][C:27]([NH2:29])=[O:28])[CH3:2])[CH:14]=[CH:13][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Reactant: NNC(N)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NNC(N)=O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Yield: 62.8 %

Procedure:
A mixture of 4'-acetyl-2'-(2,4-difluorophenoxy)methanesulfonanilide (1.5 g), semicarbazide hydrochloride (0.5 g), and pyridine (0.35 g) in ethanol (20 ml) was stirred and refluxed for 2 hours. The mixture was concentrated under reduced pressure. The residue was triturated with water, filtered, and recrystallized from methanol to give a powder of 3'-(2,4-difluorophenoxy)-4'-methanesulfonamidoacetophenone semicarbazone (1.1 g).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:13][CH:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:15](=[O:16])[CH:14]([CH3:13])[CH2:18][CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: CCC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of t-butyl alcohol (40.7 g, 549 mmol), Et3N (70 mL, 505 mmol), and DMAP (0.366 mL, 3 mmol) in anhydrous CH2Cl2 (100 mL) at 0° C. was added 2-methyl-butyryl chloride (38 g from step 1). The reaction was stirred at 0° C. for 2 h and then room temperature overnight. The cloudy reaction mixture was filtered through celite and concentrated. The residue was diluted with Et2O and washed with 0.1 N HCl. The organic layer was dried (MgSO4), filtered, and concentrated. The residue was distillated at ˜100° C. bath temperature under weak in-house vacuum twice to give the desired 2-methyl-butyric acid tert-butyl ester 2-2 as a clear oil (42 g, ˜85% purity by 1HNMR analysis). 1HNMR (CDCl3, 500 Hz): 2.28-2.20 (m 1H), 1.68-1.56 (m, 1H), 1.44 (s, 9H), 1.46-1.37 (m, 1H), 1.44 (s, 9H), 1.09 (d, J=7.0 hz, 3H), 0.9 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][CH2:11][CH2:12][CH2:13][CH2:14]C>>[C:1]([O:5][C:6]([NH:7][N:8]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCCCCC
Product: CCCCC=NNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of valeraldehydede (2.0 g; 23 mmoles) and t-butylcarbazate (3.1 g; 23 mmoles) in hexane (25 mL) is heated under reflux conditions for 30 minutes. At the end the solution is cooled at room temperature. The solvent is removed under vacuum and the obtained residue purified by chromatography on silica gel eluting with chloroform. 4.1 g of t-butyl-2-pentylidenhydrazinecarboxylate (white solid; yield 89%) are obtained. Rf=0.32 chloroform; 1H NMR (CDCl3) δ (ppm): 8.02 (s broad, 1H, NH), 7.19 (t, 1H, CH), 2.29 (m, 2H, CH2), 1.46 (m, 11H, CH2 and CH3), 1.36 (m, 2H, CH2), 0.91 (t, 3H, CH3); 13C NMR (CDCl3) δ (ppm): 147.6, 146.7, 80.8, 31.9, 28.8, 28.3, 22.3, 13.8.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1.[C:20]1([C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[N:30][CH:31]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[N:30][CH:31]=[C:26]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:27]=3)[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=1
Reactant: Fc1ccc(Cl)cc1-c1cc(Cl)c2cccnc2n1
Reactant: OB(O)c1cncc(-c2ccccc2)c1
Product: Fc1ccc(Cl)cc1-c1cc(-c2cncc(-c3ccccc3)c2)c2cccnc2n1

Procedure:
150 mg 4-chloronaphthyridine from example 1, 184 mg 5-phenyl-3-pyridyl boronic acid,
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([O-:13])=O)=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[Na+].[CH3:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:32])[C:28]=2[F:31])[NH:23]1>>[F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([N:23]2[C:24]3[C:29](=[C:28]([F:31])[C:27]([F:32])=[CH:26][CH:25]=3)[CH2:30][CH:22]2[CH3:21])=[O:13])=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CC1Cc2c(ccc(F)c2F)N1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)c(F)c1=O
Agent: [Na+]
Product: CC1Cc2c(ccc(F)c2F)N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)n1C
Yield: 46.9 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 80 mg of sodium (5-fluoro-1-methyl-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate obtained in step 2a of example 8a and 51 mg of (+)-2-methyl-4,5-difluoro-2,3-dihydro-1H-indole (reference example 2a). After silica column purification: eluent 98/02 dichloromethane/methanol, 54 mg of 5-fluoro-2-[2-((−)-4,5-difluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-3-methyl-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: Br[CH2:2][C@@H:3]([NH:5][C:6]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])[CH3:4].[C-:28]#[N:29].[Na+]>CS(C)=O.C(OCC)(=O)C>[C:26]([C:23]1[CH:24]=[CH:25][C:6]([NH:5][C@@H:3]([CH3:4])[CH2:2][C:28]#[N:29])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])#[N:27]
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CBr)cc1OC
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CC#N)cc1OC
Temperature: 90 °C
Yield: 71.3 %

Procedure:
To a solution of (S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (117 mg) in dimethylsulfoxide (2 mL) was added sodium cyanide (26.5 mg), and the mixture was stirred for an hour at 90° C. The resulting mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate (9:1) to give (S)-5-cyano-2-(2-cyano-1-methylethylamino)-N-(3,4-dimethoxybenzyl)benzamide (73 mg) as a solid substance.