Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]1([N:13]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([NH:22][C@@H:23]([CH3:36])[CH2:24][N:25]4[C:28]([O:30][CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:29])=[CH:20][CH:19]=3)[CH:15]=[N:14]2)[CH2:12][CH2:11]1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1>ClCCCl>[CH:37]1([C:40]([N:22]2[C:21]3[C:26](=[CH:27][C:18]([C:16]4[CH:15]=[N:14][N:13]([CH:10]5[CH2:12][CH2:11]5)[CH:17]=4)=[CH:19][CH:20]=3)[N:25]([C:28]([O:30][CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)=[O:29])[CH2:24][C@@H:23]2[CH3:36])=[O:41])[CH2:39][CH2:38]1
Reactant: O=C(Cl)C1CC1
Reactant: C[C@H]1CN(C(=O)OC2CCCC2)c2cc(-c3cnn(C4CC4)c3)ccc2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[C@H]1CN(C(=O)OC2CCCC2)c2cc(-c3cnn(C4CC4)c3)ccc2N1C(=O)C1CC1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 76.3 %

Procedure:
N,N-Diisopropylethylamine (0.148 mL 0.846 mmol) was added to a solution of (S)-cyclopentyl 7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.062 g, 0.169 mmol) and cyclopropanecarbonyl chloride (0.077 mL, 0.846 mmol) in 1,2-dichloroethane (2.0 mL), and the mixture stirred at 50° C. for 2.5 h. The reaction mixture was concentrated to afford a brown oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford (S)-cyclopentyl 4-(cyclopropanecarbonyl)-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.056 g, 76%) as a an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.71-0.91 (m, 3 H), 0.93-1.12 (m, 8 H), 1.48-1.99 (m, 9 H), 3.42-3.55 (m, 1 H), 3.75 (tt, J=7.33, 3.81 Hz, 1 H), 3.93 (br dd, J=12.75, 6.30 Hz, 1 H), 4.86-4.98 (m, 1 H), 5.14 (td, J=5.50, 2.79 Hz, 1 H), 7.29-7.44 (m, 2 H), 7.76 (s, 1 H), 7.91 (s, 1 H), 8.17 (s, 1 H). MS (ESI, pos. ion) m/z 435 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[O:35])[CH:28]=1>>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:35])[C:36]2[CH:37]=[CH:38][C:39]([C:40]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]5[CH:20]=[CH:19][C:18]([N:21]6[CH2:25][CH2:24][CH2:23][CH2:22]6)=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:42][CH:43]=2)[CH:28]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Reactant: O=Cc1ccc(C(=O)Nc2cccnc2)cc1
Product: O=C(Nc1cccnc1)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 241 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-(3-pyridinylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C30H26N6O2: 503.22; found: 502.97.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:28]1([NH2:32])[CH2:31][CH2:30][CH2:29]1>>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([NH:32][CH:28]2[CH2:31][CH2:30][CH2:29]2)=[C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:16]#[N:17])[CH:4]=[C:3]([C:2]([F:26])([F:1])[F:27])[CH:8]=1
Reactant: NC1CCC1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)C(C)C
Product: CC(C)S(=O)(=O)C(C#N)=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CCC1
Yield: 89 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-methylsulfanyl-2-propenenitrile (0.500 g, 1.16 mmol) was stirred in cyclobutylamine (2 ml) for 24 h at 80° C. under nitrogen in a sealed flask. Work up as described in Example 40, 2) gave 470 mg (89%) of the title compound as white crystals. Mp 148-150° C. 1H NMR (200 MHz, CDCl3): δ=1.38 (d, 6H), 1.49-1.85 (m, 2H), 2.02 (q, 4H), 3.26 (heptet, 1H), 3.53-3.77 (m, 1H), 7.46 (s, 2H), 7.64 (s, 1H), 7.96-8.14 (m, 1H), 9.17 (brs, 1H)
Reaction SMILES: N1(C(Cl)=O)CCCC1.[N:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C1(C)C=CC=CC=1>C(O)C>[N:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:35]=[CH:36][C:37]([NH:38][C:17]([NH:16][C:14]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:15])=[S:18])=[CH:39][CH:40]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)N1CCCC1
Agent: O=C(N=C=S)N1CCCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N4CCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
1-Pyrrolidinecarbonyl isothiocyanate was prepared using commercially available 1-pyrrolidinecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 1-Pyrrolidinecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (48 mg, yield 63%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:33])[C:13]([CH2:23][NH:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1>[C:35]([N:24]([CH2:23][C:13]1[C:12](=[O:33])[C:11]2[C:16](=[CH:17][C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:9]([F:34])[CH:10]=2)[N:15]([CH:18]([CH2:19][CH3:20])[CH2:21][CH3:22])[CH:14]=1)[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:37])[CH3:36]
Reactant: CCOC(=O)CCCNCc1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CCCN(Cc1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
170 mg of ethyl 4-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]methyl}amino)butanoate was dissolved in 2.0 ml of pyridine, and 0.040 ml of acetic anhydride was added, followed by overnight stirring at room temperature. After concentrating the reaction mixture under a reduced pressure, water was added to the resulting residue, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered and concentrated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography, 165 mg of ethyl 4-(acetyl{[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]methyl}amino)butanoate was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1([CH3:20])[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1>>[CH3:12][C:13]1([CH3:20])[CH2:18][CH2:17][CH:16]([O:19][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC1(C)CCC(O)CC1
Product: CC1(C)CCC(Oc2cc(F)ccc2[N+](=O)[O-])CC1

Procedure:
Prepared analogously to III.1 from 2 ml 2,4-difluoro-nitrobenzene and 2.339 g 4,4-dimethyl-cyclohexanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](Br)[CH2:37][CH2:38][CH3:39]>>[CH2:36]([O:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:37][CH2:38][CH3:39]
Reactant: CCCCBr
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Product: CCCCOc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1OC

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with butyl bromide
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C@H:3]([OH:7])[CH2:4][CH2:5]I.[N-:10]=[N+:11]=[N-:12].[Na+]>CS(C)=O.O>[N:10]([CH2:5][CH2:4][C@@H:3]([OH:7])[C:2]([F:9])([F:8])[F:1])=[N+:11]=[N-:12]
Reactant: O[C@H](CCI)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC[C@@H](O)C(F)(F)F
Temperature: 50 °C
Yield: 100.1 %

Procedure:
A solution of (R)-1,1,1-trifluoro-4-iodo-2-butanol (3.30 g, 13.0 mmol) in DMSO (22 mL) was treated with sodium azide (0.930 g, 14.3 mmol) at ambient temperature, followed by heating at 50° C. for 20 h. The mixture was diluted with cold water (250 mL) and extracted with diethyl ether. The combined organic extracts were washed (brine), dried, and evaporated without heat to give the product as a pale yellow oil (2.20 g, 100%).
Reaction SMILES: I[C:2]1[C:7]([C@H:8]([CH3:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:6]([I:15])[N:5]=[CH:4][N:3]=1.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(CC)C(C)C)(C)C>CO>[I:15][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:26]2[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]2)[C:7]=1[C@@H:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH3:14]
Reactant: COC(=O)C[C@@H](C)c1c(I)ncnc1I
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)C[C@@H](C)c1c(I)ncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C

Procedure:
Into a solution of (R)-methyl 3-(4,6-diiodopyrimidin-5-yl)butanoate (212 g, 491 mmol) and Boc-piperazine (101 g, 540 mmol) in methanol (424 mL) was added N,N-diisopropylethylamine (94.3 mL, 540 mmol). The mixture was heated at 60° C. for 24 h. Methanol was distilled off under reduced pressure below 40° C. To the mixture was added 318 mL of tetrahydrofuran. The above solvent swap process was repeated twice. To the mixture were added 424 mL of tetrahydrofuran, 212 mL of saturated aqueous ammonium chloride, and 21.2 mL of water. The organic layer was washed with 212 mL (1.00 vol.) of saturated aqueous ammonium chloride. This tetrahydrofuran solution was used for next step without further purification (91% weight assay yield). 1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), 3.80-3.67 (m, 1H), 3.65 (s, 3H), 3.60-3.56 (m, 4H), 3.21-3.18 (m, 4H), 3.14 (dd, J=16.2, 9.0 Hz, 1H), 2.81 (dd, J=16.2, 5.7 Hz, 1H), 1.48 (s, 9H), 1.47 (d, J=7.2 Hz, 3H). HRMS calcd. For C18H28IN4O4 [M+H]+: 491.1150. found 491.1154.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.COC(OC)C.[CH2:17]1[CH2:27]CN2C(=NCCC2)[CH2:19][CH2:18]1>CN(C=O)C>[CH3:19][C:18]1[CH:17]=[CH:27][N:10]=[C:2]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:9]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: N=C(N)c1ccncc1
Agent: COC(C)OC
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccnc(-c2ccncc2)n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Isonicotinamidine hydrochloride (5.00 g, 31.7 mmol) and acetaldehyde dimethylacetal (8.44 mL, 63.5 mmol) were combined and heated to 110° C. in anhydrous DMF (35 mL) in the presence of DBU (14.20 mL, 95.2 mmol) for 3 h. The reaction mixture was cooled to 20° C., then stirred for 16 h, before being concentrated in vacuo. The residue was partitioned between H2O (100 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (2×50 mL), then the combined organics were washed with brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure. Flash column chromatography (EtOAc) of the residue gave 4-methyl-2-pyridin-4-yl-pyrimidine: δH ((CD3)2SO): 2.57 (3H, s), 7.45 (1H, d), 8.21-8.26 (2H, m), 8.72-8.77 (2H, m), 8.82 (1H, d). To a solution of this compound (1.06 g, 6.17 mmol) in anhydrous dioxane (20 mL) was added SeO2 (2.05 g, 18.51 mol), then the mixture was heated to reflux for 90 h. The reaction mixture was cooled to 20° C. then filtered, washing with EtOAc. The filtrate was evaporated to dryness, then the residue was suspended in CH2Cl2. The suspension was filtered, washing with CH2Cl2, then the filtrate was evaporated to dryness to furnish the title compound: δH (CDCl3): 7.80 (1H, d), 8.38 (2H, d), 8.83 (2H, d), 9.13 (1H, d), 10.15 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:21]([OH:23])=O)=[CH:19][NH:20][C:15]3=[N:14][CH:13]=2)=[N:3]1.Cl.[CH:25]1([C:28]([NH2:31])([CH3:30])[CH3:29])[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:25]1([C:28]([NH:31][C:21]([C:18]2[C:16]3=[N:17][C:12]([C:4]4[C:5]5[C:10](=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=5)[N:2]([CH3:1])[N:3]=4)=[CH:13][N:14]=[C:15]3[NH:20][CH:19]=2)=[O:23])([CH3:30])[CH3:29])[CH2:27][CH2:26]1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)nn(C)c2c1
Reactant: CC(C)(N)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)C5CC5)c4n3)nn(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.8 %

Procedure:
To a stirred mixture of 2-(1,6-dimethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (80 mg, 0.26 mmol) and 2-cyclopropylpropan-2-amine hydrochloride (53 mg, 0.39 mmol) in DMF (3 mL), was added EDCI (100 mg, 0.52 mmol) followed by DMAP (63 mg, 0.52 mmol). The mixture was stirred at room temperature for 16 hours, and then poured into water (5 mL) and filtered. The crude solid was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 58% acetonitrile/42% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 88% acetonitrile/12% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(2-cyclopropylpropan-2-yl)-2-(1,6-dimethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (25 mg, 25%) as a white solid. MS: (M+H)+=389; 1H NMR (300 MHz, DMSO): δ 9.10 (s, 1H), 8.39-8.36 (m, 2H), 7.97 (s, 1H), 7.55 (s, 1H), 7.08 (d, 1H, J=8.1 Hz), Hz), 4.16 (s, 3H), 2.52 (s, 3H), 1.59-1.53 (m, 1H), 1.25 (s, 6H), 0.47-0.43 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:17]([C:6]1([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2cc(Cl)ccc2C1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1ccccc1)C1CCCC1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-cyclopentyl-1,3-dihydro-indol-2-one (0.24 g, 1 mmol) (from Example 3b, supra), benzyl bromide (0.21 g, 1.2 mmol), potassium iodide (0.20 g, 1.2 mmol) and potassium carbonate (0.3 g, 2.2 mmol) in acetone (6 mL) was heated at 60° C. for 13 days in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloromethane, then 3% ethyl acetate in dichloromethane as solvent) to give two products. Lower Rf sample was recrystallized from dichloromethane-hexanes to give rac-3-benzyl-6-chloro-3-cyclopentyl-1,3-dihydro-indol-2-one as white prisms. (Yield 0.13 g, 39.2%).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.Cl.[NH:22]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:23]([C:27](O)=[O:28])[CH:24]([CH3:26])[CH3:25]>CO>[NH:22]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:23]([C:27]([NH:1][C@H:2]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:8][CH:9]=1)=[O:28])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)OC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Product: CC(C)OC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C

Procedure:
7.9 g (25 mmoles) of H-Tyr(But)-O-CH(CH3)2 hydrochloride and 6.27 g (25 mmoles) of Z-Val-OH are subjected to a condensation reaction analogously to Example 30 C. Yield 11.8 g (92%), melting point 133°-134°, [α]D26 =-25.2° (c=1, methanol).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Cl:19])=[CH:12][C:13]([C:17]#[N:18])=[N:14]2)=[CH:9][CH:8]=1.O>CCO>[N:1]([CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Cl:19])=[CH:12][C:13]([C:17]#[N:18])=[N:14]2)=[CH:9][CH:8]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(Cl)c2ccc(CBr)cc2n1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1cc(Cl)c2ccc(CN=[N+]=[N-])cc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
Sodium azide (1.690 g, 26.0 mmol, 1.3 equiv.) was added to a stirred solution of 7-(bromomethyl)-4-chloroquinoline-2-carbonitrile (2-4, 5.63 g, 20.00 mmol) in 100 ml of EtOH, and the resulting slurry mixture was refluxed for 1 h. The mixture was cooled to rt, water (100 ml) was added, and the slurry was stirred at rt for 30 min. The resulting solid was collected by filtration and air dried to afford 7-(azidomethyl)-4-chloroquinoline-2-carbonitrile (3-12, 4.75 g, 97%) as a white solid. LRMS m/z (M+H)+ 244.1 found, 244.65 required.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:15]1[C:24]([CH:25]=[O:26])=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([C:15]3[C:24]([CH:25]=[O:26])=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:12][CH2:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1cc2ccccc2nc1Cl
Reactant: C1CCC(CN2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc2ccccc2nc1N1CCN(CC2CCCCC2)CC1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
1-(Cyclohexylmethyl)piperazine (0.42 mL, 2.2 mmol) was added to a mixture of 2-chloro-3-quinolinecarboxaldehyde (0.383 g, 2.0 mmol) and potassium carbonate (0.7 g, 5.0 mmol) in anhydrous DMF (4 mL) at ambient temperature under a nitrogen atmosphere. After being stirred for 20 minutes, the reaction mixture was heated at 110° C. for 4.5 h. After cooling to room temperature this mixture was diluted with water (40 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and then concentrated under vacuum to give a pale brown crude product. Purification by silica gel column chromatography and eluting with 2.5% methanol in dichloromethane afforded the title compound (0.56 g), yield: 86%.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:22])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][CH:16]=[N:15][C:14]=2[N:13]([CH3:21])[C:11]1=[O:12])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:28]Br>C(O)(=O)C>[C:1]([O:4][C@H:5]([CH3:22])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([Br:28])=[N:15][C:14]=2[N:13]([CH3:21])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(Br)nc2n(C)c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a stirring suspension of (R)-1-(5-acetoxyhexyl)-3-methylxanthine (9.3 g, 30.2 mmol) and sodium acetate (4.92 g, 60.0 mmol) in acetic acid (200 ml) at 60° C. was added bromine (5.76 g, 36.0 mmol) dropwise. After stirring at 60° C. for an additional 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was treated with water (100 ml) and stirred at room temperature for 1 hour. After filtration, the solids were washed with water (3×15 ml) and dried under vacuum to provide (R)-1-(5-acetoxyhexyl)-8-bromo-3-methylxanthine (8.8 g, 75% yield) as a beige powder.
Reaction SMILES: [SH:1][CH:2]([CH3:6])[C:3](=O)[CH3:4].[C:7](#[N:11])[CH2:8][C:9]#[N:10].C(N(CC)CC)C>C(O)C>[NH2:10][C:9]1[S:1][C:2]([CH3:6])=[C:3]([CH3:4])[C:8]=1[C:7]#[N:11]
Reactant: N#CCC#N
Reactant: CC(=O)C(C)S
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1sc(N)c(C#N)c1C
Temperature: -2 °C
Yield: 64.2 %

Procedure:
A solution of 3-mercapto-2-butanone (1.00 kg, 9.0 mole, 93.6% assay) in 2.0 L SDA 3C 200 Proof, absolute Ethanol (Ethanol) is prepared in a 5 L 1N RBF fitted with torian and transfer tubing. Malononitrile (588.8 g, 8.9 mole) is dissolved in 5.0 L Ethanol and cooled to 4° C. at which point triethylamine (250 mL, 1.8 mole, 0.2 eq) is added with a 560 mL ethanol rinse. The anionic malononitrile solution is cooled to −2° C. and the 3-mercaptobutanone solution is added over 1.3 hrs at −1 to −5° C. After an hour, the reaction shows less than 0.1% malononitrile. The reaction is concentrated on the rotovap (40° C. bath) to a slurry of approximately 2.5 L and 3.0 L of heptanes are added. The slurry is cooled to 5° C. for 30 minutes and the solids collected by filtration. The solids are rinsed with 2.5 L of 20% Ethanol in heptanes in 7 portions. The excess solvent is removed on the filter, and the wet cake dried in a vacuum oven overnight at 40° C. and full vacuum to give an off white solid as 2-amino-4,5-dimethylthiophene-3-carbonitrile (870 g, 64.1% yield, 99.7% purity shown by HPLC). The filtrates are reconcentrated to an oily slurry which is filtered and rinsed with 0.5 L of 20% Ethanol in heptanes. The second crop of solids is dried separately (47 g, 3.5% yield, 98.6% purity shown by HPLC). NMR (400 MHz, DMSO-d6) δ 1.93 (d, J=1.2 Hz, 3H), 2.07 (d, J=1.2 Hz, 3H), 3.33 (s, 2H). MS 153 (MH+). HPLC Retention Time: approximately 10.9 minute (Phenomenex Luna C18 (2) column, acetonitrile/water with 0.1% AcOH).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([CH2:10]Cl)[N:9]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[N+:42]([C:45]1[CH:52]=[CH:51][C:48]([CH:49]=O)=[CH:47][CH:46]=1)([O-:44])=[O:43]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8](/[CH:10]=[CH:49]/[C:48]2[CH:51]=[CH:52][C:45]([N+:42]([O-:44])=[O:43])=[CH:46][CH:47]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1sc(NC(C)=O)nc1CCl
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(NC(C)=O)nc1/C=C/c1ccc([N+](=O)[O-])cc1

Procedure:
To a stirring solution of ethyl 2-(acetylamino)-4-(chloromethyl)-1,3-thiazole-5-carboxylate (1.0 g, 3.81 mmol) in N,N-dimethylformamide (20 mL) was added triphenylphosphine (1.2 g, 4.57 mmol) at room temperature. The resultant mixture was stirred at 65° C. for 5 hours. To the mixture was added potassium tert-butoxide (555 mg, 4.95 mmol) at 5° C., and the resultant mixture was stirred at 5° C. for 30 minutes. p-Nitrobenzaldehyde (805 mg, 5.33 mmol) was added at 5° C.