Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[N:11]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:10][C:9](=[O:20])[NH:8][C:5]2=[N:6][CH:7]=1.C[Sn](C)(C)[C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[N:27][CH:28]=1>CN(C)C=O>[OH:32][C:29]([C:26]1[N:27]=[CH:28][C:23]([C:2]2[N:3]=[C:4]3[N:11]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:10][C:9](=[O:20])[NH:8][C:5]3=[N:6][CH:7]=2)=[CH:24][CH:25]=1)([CH3:31])[CH3:30]
Reactant: CC(C)(O)c1ccc([Sn](C)(C)C)cn1
Reactant: O=C1CN(CCN2CCOCC2)c2nc(Br)cnc2N1
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(-c2cnc3c(n2)N(CCN2CCOCC2)CC(=O)N3)cn1
Temperature: 100 °C
Yield: 27 %

Procedure:
6-Bromo-4-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.228 g, 0.666 mmol) and 2-(5-(trimethylstannyl)pyridin-2-yl)propan-2-ol (0.220 g, 0.733 mmol) were combined in dimethylformamide (3 mL). Solution was purged with nitrogen gas followed by the addition of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane (0.109 g, 0.133 mmol). Solution was heated to 100° C. for 2 h. Solution was condensed under reduced pressure and the resulting oil purified via reverse-phase-preparative HPLC (5-60% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) and desired fractions were loaded onto a Strata-XC ion exchange column. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol and was concentrated under reduced pressure and dried to afford the title compound (0.070 g, 0.18 mmol, 26% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.33 (br. s., 1H), 9.05 (d, J=1.56 Hz, 1H), 8.27 (dd, J=8.59, 2.34 Hz, 1H), 8.06 (s, 1H), 7.72 (d, J=8.59 Hz, 1H), 5.27 (s, 1H), 4.29 (s, 2H), 3.71 (t, J=6.44 Hz, 2H), 3.54 (t, J=4.49 Hz, 4H), 2.62 (t, J=6.44 Hz, 2H), 2.40-2.48 (m, 4H), 1.46 (s, 6H); MS (ESI) m/z 399.2 [M+1]+; mp 239-241° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.[CH2:25]([O:27][CH2:28][C:29](O)=[O:30])[CH3:26].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C1COCC1.C(N(CC)CC)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:29](=[O:30])[CH2:28][O:27][CH2:25][CH3:26])=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: CCOCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOCC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(F)c1
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (150 mg), ethoxyacetic acid (35 mg), 1H-benzotriazol-1-ol (67.8 mg) and triethylamine (0.146 ml) in THF (2.1 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (96 mg), and the mixture was stirred overnight. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (125 mg).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])=[N:6][C:5]=1[CH3:21])(=[O:3])[CH3:2].Br[CH2:23][CH2:24][CH2:25][CH3:26].CC(C)([O-])C.[K+]>CN(C)C=O>[C:1]([C:4]1[S:8]/[C:7](=[N:9]\[C:10](=[O:20])[C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])/[N:6]([CH2:23][CH2:24][CH2:25][CH3:26])[C:5]=1[CH3:21])(=[O:3])[CH3:2]
Reactant: CCCCBr
Reactant: COc1ccc(Cl)cc1C(=O)Nc1nc(C)c(C(C)=O)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(C)c(C(C)=O)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of Example 238A (0.40 g, 1.2 mmol), 1-bromobutane (0.16 mL, 1.5 mmol), and potassium t-butoxide (0.22 g, 1.9 mmol) in 5 mL N,N-dimethylformamide was warmed to 65° C. and stirred for 20 hours. The mixture was cooled to ambient temperature quenched with 5 mL of saturated aqueous NH4Cl and diluted with 5 mL of ethyl acetate. The layers were separated and the aqueous phase was extracted twice with 5 mL of ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 40% hexanes in ethyl acetate) afforded the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 1.04 (t, J=7.3 Hz, 3H), 1.42-1.55 (m, 2H), 1.77-1.90 (m, 2H), 2.51 (s, 3H), 2.76 (s, 3H), 3.889 (s, 3H), 4.32-4.41 (m, 2H), 7.10 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.7 Hz, 1H), 7.99 (d, J=3.1 Hz, 1H); MS (DCI/NH3) m/z 381 (M+H)+. Anal. Calculated for C18H21ClN2O3S: C, 56.76; H, 5.56, N, 7.35. Found: C, 56.68; H, 5.49; N, 7.26.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.C[O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:35])[C:14]2[O:20][C:19]3[C:21]([Cl:31])=[CH:22][C:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:33])(=[O:32])[C:15]=2[CH:34]=1)=[O:10]>ClCCl.N1C=CC=CC=1>[Cl:31][C:21]1[C:19]2[O:20][C:14]3[C:13]([CH3:35])=[CH:12][C:11]([C:9]([OH:10])=[O:8])=[CH:34][C:15]=3[S:16](=[O:32])(=[O:33])[CH2:17][C:18]=2[CH:24]=[C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:29][CH2:30]2)[CH:22]=1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N3CCN(C(=O)C4CC4)CC3)cc1CS2(=O)=O
Reaction time: 0.75 h

Procedure:
A solution of cyclopropyl carbonyl chloride (0.22 mL, 2.4 mmol) in dichloromethane (2 mL) was added to a suspension of Example 104k (0.35 g, 0.8 mmol) in pyridine (3 mL)/dichloromethane (1 mL) at 10° C. The reaction mixture was stirred for 45 min, concentrated, treated with chilled water and dilute HCl to pH 6. The precipitated solid was filtered and dried to obtain the title compound. Yield: 0.372 g, (91.5%); 1H NMR (DMSO-d6): δ 0.76 (m, 4H, 2CH2); 2.06 (m, 1H, CH); 2.68 (s, 3H, CH3); 3.24 (s, 2H, CH2); 3.32 (s, 2H, CH2); 3.64 (s, 2H, CH2); 3.84 (s, 2H, CH2); 5.15 (s, 2H, CH2); 7.12 (d, 1H, Ar); 7.2 (d, 1H, Ar); 8.1 (s, 1H, Ar); 8.2 (s, 1H, Ar); 8.38 (s, 1H, OH). MS: m/e (ES+) 532 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[CH:19]4)=[C:11]([F:25])[CH:10]=2)[CH:5]=[C:4](Cl)[N:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(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>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[CH:19]4)=[C:11]([F:25])[CH:10]=2)[CH:5]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1nc(Cl)cc(Nc2ccc(Oc3ccc4[nH]ncc4c3)c(F)c2)n1
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: Cc1ccccc1
Solvent: CCO
Product: Nc1nc(Nc2ccc(Oc3ccc4[nH]ncc4c3)c(F)c2)cc(-c2ccccc2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
50 mg (130 μmol) of N-[2-amino-6-chloro-4-pyrimidinyl]-N-[3-fluoro-4-(1H-indazol-5-yloxy)phenyl]amine (from example 8) are suspended in 3 ml of toluene/ethanol (2:1), and 4.68 mg of tetrakis(triphenylphosphine)palladium(0) are added. After addition of 19.7 mg (160 μmol) of phenylboronic acid and 0.50 ml of 2M aqueous sodium carbonate solution, the mixture is stirred at 100° C. overnight. The mixture is evaporated to dryness using a rotary evaporator and purified by preparative HPLC.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[N:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[N:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:26]=[N+:27]=[N-:28])=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(CCl)cc3)nc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CN=[N+]=[N-])cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a solution of 1-acetyl-4-(6-{2-[4-(chloromethyl)phenyl]ethyl}pyridin-3-yl)piperazine (234.8 mg, 0.656 mmol) in anhydrous N,N-dimethylformamide (5 ml) was added sodium azide (426.5 mg, 6.561 mmol), and the mixture was stirred at room temperature for 16 hrs. Aqueous sodium carbonate solution and ethyl acetate were added to the reaction mixture. The mixture was stirred, stood still and partitioned. The organic layer was dried over anhydrous magnesium sulfate, and concentrated to dryness to give 1-acetyl-4-(6-{2-[4-(azidomethyl)phenyl]ethyl}pyridin-3-yl)piperazine (226.8 mg, yield 94.9%) as a slightly yellow solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH:17]O>C[Re](=O)(=O)=O.C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][N+:12]([O-:17])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: OO
Reactant: FC(F)(F)c1ccc(-c2ccncc2)cc1
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: [O-][n+]1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 4-(4-trifluoromethyl-phenyl)-pyridine (5.0 g, 22 mmol) and methyltrioxorhenium (VII) (Aldrich) (110 mg, 0.45 mmol) in a 100-mL, round-bottomed flask was added CH2Cl2 (10 mL). Hydrogen peroxide (5 mL, Aldrich) was added drop-wise, and the reaction was stirred at room temperature under N2 for 48 h. The mixture was partitioned between CH2Cl2 and brine, and the aqueous layer was extracted with CH2Cl2 (40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 240 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][C:31]1([CH2:36][OH:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][C:31]2([CH2:36][OH:37])[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: NC1(CO)CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNC3(CO)CCCC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL), and the solution was treated with 1-amino-1-cyclopentanemethanol (23 mg, 0.20 mmol) and sodium triacetoxyborohydride (48 mg, 0.23 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[(1-hydroxymethylcyclopentyl)aminomethyl]indol-2-yl}isoindolinone was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[C:5](F)=[CH:4][N:3]=1.[CH3:12][NH:13][NH2:14]>C(O)CO.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:13]([CH3:12])[N:14]=[C:8]([CH3:9])[C:6]=2[N:7]=1
Reactant: CC(=O)c1nc(Cl)ncc1F
Reactant: CNN
Solvent: O
Solvent: OCCO
Product: Cc1nn(C)c2cnc(Cl)nc12
Temperature: 25 °C

Procedure:
A solution of 1-(2-chloro-5-fluoropyrimidin-4-yl)ethanone (4.00 g, 22.91 mmol) and methylhydrazine (0.724 mL, 13.75 mmol) in ethylene glycol was heated at 120° C. for 2 h. Reaction mixture was cooled to rt, diluted with H2O and extracted with ethyl acetate (3×). The combined organic layer was washed with H2O (2×), brine, dried (MgSO4), filtered and concentrated. The residue was purified by CombiFlash (0 to 30% EtOAc/Hex) to give the title compound. LCMS-ESI+: calc'd for C7H8ClN4: 183.0 (M+H+); Found: 183.0 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 4.12 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: CS[C:3](=[N:18][CH2:19][Si](C)(C)C)[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:16])[NH:11][CH:12]2[CH2:15][S:14][CH2:13]2)=[C:6]([CH3:17])[CH:5]=1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([C:33]([F:36])([F:35])[F:34])=[CH2:32])[CH:28]=[C:27]([Cl:37])[CH:26]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]2([C:33]([F:36])([F:34])[F:35])[CH2:19][N:18]=[C:3]([C:4]3[CH:9]=[CH:8][C:7]([C:10]([NH:11][CH:12]4[CH2:15][S:14][CH2:13]4)=[O:16])=[C:6]([CH3:17])[CH:5]=3)[CH2:32]2)[CH:28]=[C:27]([Cl:37])[CH:26]=1
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(C(=O)NC2CSC2)c(C)c1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CSC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a solution of 3-methyl-4-(thietan-3-ylcarbamoyl)-N-trimethylsilanylmethyl-thiobenzimidic acid methyl ester (Example I19) (16 mg) and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (see WO 2007/125984) (12 mg) in THF (2 ml) was added at −5° C. tetrabutylammonium fluoride trihydrate (TBAF) (0.41 g) dissolved in THF (1.5 ml). The reaction mixture was stirred at ambient temperature for 16 hours. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: ethyl acetate/heptanes 1:2) to give 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-N-thietan-3-yl-benzamide (20 mg). 1H-NMR (400 MHz, CDCl3): 7.75-7.25 (m, 6H), 6.30 (s, 1H), 5.45 (m, 1H), 4.90 (d, 1H), 4.45 (d, 1H), 3.82 (d, 1H), 3.55-3.38 (m, 5H), 2.48 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([OH:8])=O)[CH:2]=[CH2:3].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]([N:16]=[C:17]=[S:18])[CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:4]1[CH2:5][C:6](=[O:8])[N:16]([C:14]2[CH:15]=[C:10]([Cl:9])[CH:11]=[CH:12][C:13]=2[CH3:19])[C:17]1=[S:18])[CH:2]=[CH2:3]
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: C=CCNCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN1CC(=O)N(c2cc(Cl)ccc2C)C1=S
Yield: 15.6 %

Procedure:
A mixture of N-allyl glycine (17.4 g), 5-chloro-2-methylphenyl-isothiocyanate (20.1 g), triethylamine (20.2 g), and methylene chloride (150 mL) was heated at reflux for 2 hours. The reaction mixture was evaporated to dryness. Purification was achieved by flash chromatography on silica gel (methylene chloride). Recrystallization from Hexane-EtOAc afford the title compound (4.8 g) as yellow solid, m.p. 106°-109° C. Anal. Calcd. for. C13H13N2O Cl S: C, 55.61; H, 4.67; N, 9.98. Found: C, 55.45; H, 4.56; N, 9.72. Mass spectrum (EI, M.+) m/z 280.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[CH:8][CH:7]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:16][N:14]([CH:13]=[C:7]([C:6](=[O:10])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:8]#[N:9])[CH3:15]
Reactant: COC(OC)N(C)C
Reactant: c1csc(-c2ccno2)c1
Product: CN(C)C=C(C#N)C(=O)c1cccs1

Procedure:
A mixture of Compound 4 (13.0 g, 86 mmol) and dimethylformamide dimethyl acetal (22.4 g, 188 mmol) was refluxed under nitrogen for 3 hrs. Solid precipitated from the reaction mixture. The reaction mixture was cooled, diluted with dichloromethane and ether (1:10, 200 mL). The solid was collected by filtration, triturated with a solution of dichloromethane and ether (1:20, 100 mL). Compound 5 was obtained as an orange solid (13.5 g, 65.4 mmol, 76%). GC/MS, m/z=206 at tR=13.39 min (100%). LC/MS, [M+H]′=207.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][NH:15][C@H:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:15]2[CH2:16][C@H:12]([NH:11][S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])[CH2:13][C@H:14]2[C:17]([O:19][CH3:20])=[O:18])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: COC(=O)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 74.3 %

Procedure:
To a solution of (2S,4R)-4-(4-chlorophenyl-sulfonylamino)-2-methoxycarbonylpyrrolidine (10.0 g) in dichloromethane (200 ml) were added triethylamine (4.8 ml) and 4-chlorobenzenesulfonyl chloride (6.62 g) in an ice bath and the mixture was stirred in an ice bath for 3 hours. The resulting solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2S,4R)-1-(4-chlorophenylsulfonyl)-4-(4-chlorophenylsulfonylamino)-2-methoxycarbonylpyrrolidine (11.5 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([CH2:7][C:8]1[CH:9]=[N:10][C:11]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:12][CH:13]=1)=[CH2:6])[CH3:2].CCOC(C)=O.[C:36]([OH:39])(=[S:38])[CH3:37]>>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([CH2:6][S:38][C:36](=[O:39])[CH3:37])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([N:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:12][CH:13]=1)[CH3:2]
Reactant: CC(O)=S
Reactant: C=C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1)C(=O)OCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CSC(C)=O)Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 89 %

Procedure:
TEA (0.189 mL, 1.35 mmol) was added to a solution of 2-(2-[N,N-bis(tert-butoxycarbonyl)amino]-pyrimidin-5-ylmethyl)-acrylic acid ethyl ester (0.53 g, 1.30 mmol) in thioacetic acid (13 mL) at 0° C. under argon. The mixture was stirred at room temperature for 40 h. EtOAc was added and the solution was washed with Na2CO3 and brine, dried and concentrated under reduced pressure. Flash chromatography (heptane/EtOAc, 5:1→1:1) gave 2-acetylsulfanylmethyl-3-(2-[N,N-bis(tert-butoxycarbonyl)amino]-pyrimidin-5-yl)-propionic acid ethyl ester(0.56 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([S:19][CH3:18])=[CH:21][CH:22]=2)[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: CSc1ccc(CC(=O)O)cc1
Product: CSc1ccc(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1
Yield: 32.3 %

Procedure:
Example 5 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and 4-(methylthio)phenylacetic acid (0.036 g) to give the title compound (0.028 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:22])[C:17]=2[O:18][CH2:19][O:20][CH3:21])=[CH:14][CH:13]=[C:12]([O:23][CH2:24][O:25][CH3:26])[CH:11]=3)=[CH:4][C:3]=1[O:27][CH2:28][O:29][CH3:30].Br[CH2:32][CH2:33][F:34].C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CCOCC>[F:34][CH2:33][CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:22])[C:17]=2[O:18][CH2:19][O:20][CH3:21])=[CH:14][CH:13]=[C:12]([O:23][CH2:24][O:25][CH3:26])[CH:11]=3)=[CH:4][C:3]=1[O:27][CH2:28][O:29][CH3:30]
Reactant: COCOc1ccc2c(=O)c(OCOC)c(-c3ccc(O)c(OCOC)c3)oc2c1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: COCOc1ccc2c(=O)c(OCOC)c(-c3ccc(OCCF)c(OCOC)c3)oc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.2 %

Procedure:
To 2-(4-hydroxy-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)-4H-chromen-4-one (20 mg, 0.048 mmol) and 1-bromo-2-fluoroethane (18 mg, 0.14 mmol) in 0.3 mL NMP was added Cs2CO3 (39 mg, 0.12 mmol). The mixture was stirred at rt for 15 h under Ar atmosphere and diluted with ether (30 mL). It was washed with NaH2PO4 (sat. 30 mL) and water (2×30 mL) and dried over MgSO4 and concentrated. The crude product was purified with chromatography (hexane/EtOAc) to afford 2-(4-(2-fluoroethoxy)-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)-4H-chromen-4-one as a white solid (19 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=8.8 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.76 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 7.05 (dd, J=8.8, 2.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 5.29 (s, 4H), 5.22 (s, 2H), 4.89 (m, 1H), 4.78 (m, 1H), 4.40 (m. 1H), 4.32 (m, 1H), 3.56 (s, 3H), 3.51 (s, 3 H) 3.20 (s, 3H); MS (ESI) m/z 465 (M+H+).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([I:11])[C:3]=1[OH:12].[C:13]([CH:15]1[CH2:17][CH2:16]1)#[CH:14].O>N1C=CC=CC=1>[CH:15]1([C:13]2[O:12][C:3]3[C:4]([I:11])=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[CH:14]=2)[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1cc(I)c(O)c(I)c1
Reactant: C#CC1CC1
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(I)c2oc(C3CC3)cc2c1
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
A solution of 2,6-diiodo-4-nitrophenol (10 g, 25.6 mmol), ethynylcyclopropane (1.9 g, 28.8 mmol) and Cu2O (1.9 mg, 13.2 mmol) in 100 mL of dry pyridine was refluxed for 2 h. The reaction mixture was poured into 1 L of water and stirred for 10 min. The resulting mixture was filtered. The cake was purified by column chromatography on silica gel eluting with EtOAc/PE (0-20%) to give the title compound (6.6 g, 78% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.47 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 6.58 (s, 1H), 2.13-2.07 (m, 1H), 1.14-1.04 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Cl[CH:18]=[CH:19][CH:20]([Cl:22])[Cl:21]>CN(C)C=O>[C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C:8]([CH:18]=[CH:19][CH:20]([Cl:22])[Cl:21])([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: ClC=CC(Cl)Cl
Reactant: N#Cc1ccc(CC(C#N)C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CC(C#N)(C#N)C=CC(Cl)Cl)cc1
Yield: 34.1 %

Procedure:
Using 0.37 g of (4-cyanobenzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.25 g of 1,3,3-trichloropropene, and according to the process described in the Production Example 1, there was obtained 0.17 g of 2-(4-cyanobenzyl)-2-(3,3-dichloropropenyl)malononitrile (the present compound (56)).