Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]([OH:15])=O)[S:10][C:6]=2[C:5]([F:16])=[CH:4][C:3]=1[F:17].S(Cl)(Cl)=O.Cl.[CH3:23][O:24][C:25](=[O:34])[CH2:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C=O.O>[CH3:23][O:24][C:25](=[O:34])[CH2:26][N:27]([C:13](=[O:15])[CH2:12][CH2:11][C:9]1[S:10][C:6]2[C:5]([F:16])=[CH:4][C:3]([F:17])=[C:2]([F:1])[C:7]=2[N:8]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)CCc1nc2c(F)c(F)cc(F)c2s1
Reactant: COC(=O)CNc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CN(C(=O)CCc1nc2c(F)c(F)cc(F)c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a solution of 3-(4,5,7-trifluorobenzothiazol-2-yl)propionic acid (522 mg, 2 mmol) obtained in Example 3-i) in a mixture of toluene (5 ml) and N,N-dimethylformamide (DMF; 1 ml) was added thionyl chloride (357 mg, 3 mmol) and the mixture was stirred for 1 hour at room temperature. To the ice cold reaction mixture was N-phenylglycine methyl ester hydrochloride (403 mg, 2 mmol) and triethylamine (400 mg, 4 mmol) and the mixture was stirred for 2 hours. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water, then dried and evaporated to yield a residue, which was purified on a silica gel column to give N-[3-(4,5,7-trifluorobenzothiazol-2-yl)propionyl]-N-phenylglycine methyl ester (240 mg, 29%) as an oil.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][CH:21]([CH2:24][CH3:25])[CH2:22][OH:23]>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([NH:20][C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reactant: CCC(N)CO
Solvent: CS(C)=O
Product: CC[C@@H](CO)Nc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 120 °C

Procedure:
200 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 350 μl (5 equivalents) of (+/−)-2-amino-1-butanol, and the mixture is then heated at 120° C. for approximately 2 days. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 95-5-0.3 mixture for eluent. 40 mg of expected product are obtained.
Reaction SMILES: [CH:1]([CH2:3][SiH:4](OC)OC)=C.[CH3:9][O:10][CH:11]([SiH3:14])[O:12][CH3:13]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)CCC>[CH3:9][O:10][CH:11]([SiH2:14][CH2:1][CH2:3][SiH2:4][CH:11]([O:12][CH3:13])[O:10][CH3:9])[O:12][CH3:13]
Reactant: C=CC[SiH](OC)OC
Reactant: COC([SiH3])OC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CCCCO
Product: COC(OC)[SiH2]CC[SiH2]C(OC)OC

Procedure:
Butanol solution of chloroplatinic acid was added to 198 g of vinylmethyldimethoxysilane, and to this mixture, 159 g of dimethoxymethylsilane was gradually added dropwise. Due to the exothermic nature of the reaction, the speed of the dropwise addition was adjusted so that temperature of the reaction mixture was up to 80° C. After the completion of the dropwise addition, the mixture was distilled at reduced pressure under clean conditions as in the case of Synthetic Example 1 to obtain 1,2-bis(dimethoxymethylsilyl)ethane.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH2:36][CH2:37][OH:38])(=[O:35])=[O:34])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH2:36][CH2:37][OH:38])(=[O:35])=[O:34])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(=O)(=O)CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2S(=O)(=O)CCO)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The reaction was carried out under argon. Allyl(rac)-4-[4-cyano-2-((2-hydroxyethyl)sulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (150 mg, 0.273 mmol) and morpholine (1.5 eq., 35.6 mg, 0.409 mmol) were initially charged in dry THF (4 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 15.8 mg, 0.014 mmol) was added, and the reaction mixture was stirred at RT for 1 h (HPLC control). The mixture was then concentrated, and the residue was taken up in ethyl acetate (60 ml). The organic phase was washed repeatedly with saturated ammonium chloride solution (3×20 ml), water (20 ml) and saturated sodium chloride solution (20 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). The title compound was obtained as a solid (60 mg, 43% of theory).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[S:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1.[F:16][C:17]([F:28])([F:27])[S:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>C1COCC1>[F:15][C:4]([F:14])([F:3])[S:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][O:11][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([S:18][C:17]([F:28])([F:16])[F:27])=[CH:20][CH:21]=2)=[CH:8][CH:7]=1
Reactant: FC(F)(F)Sc1ccc(CBr)cc1
Reactant: OCc1ccc(SC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)Sc1ccc(COCc2ccc(SC(F)(F)F)cc2)cc1
Reaction time: 0.17 h
Yield: 87.2 %

Procedure:
Sodium hydride (65 mg 60% dispersion oil, 1.58 mmol) was added to a solution of 4-(trifluoromethylthio)benzyl alcohol (300 mg, 1.44 mmol) in THF (10 mL) at rt. After stirring for 10 min, to the mixture was added 4-(trifluoromethylthio)benzyl bromide (410 mg, 1.51 mmol), stirring was continued overnight. The reaction was quenched with saturated ammonium chloride solution, extracted with EtOAc, washed with water and dried to give 0.5 g (85%) of bis(4-trifluoromethylthiobenzyl) ether as a yellow oil. 1HNMR (360 MHz, DMSO-d6) δ 7.70 (d, J=8.1 Hz, 4H), 7.53 (d, J=8.1 Hz, 4H), 4.65 (s, 4H, CH2OCH2). MS-EI m/z 398 [M+].
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10])([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH:9]([C:8]1[CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([O:14][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:6]([O:12][CH3:13])[CH:7]=1)=[O:10]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(OC)cc(C=O)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 0.05 h
Yield: 73.6 %

Procedure:
To a solution of 5-nitrovanilline (591 mg, 3.0 mmol) in DMF (9.0 mL) was added cesium carbonate (2.00 g, 6.16 mmol), followed by ethyl bromoacetate (3.33 mL, 30 mmol). The red mixture was left under stirring at 110° C. until it became yellow, and then for further 3 minutes. After evaporation of DMF under reduced pressure, 22 mL of water were added and the mixture was extracted with dichloromethane (60 mL). The organic phase was washed with brine (15 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: dichloromethane) to give 625 mg of a solid (74% yield). 1H NMR (250 MHz, CDCl3): δ 1.30 (t, J=7.2 Hz, 3H), 4.01 (s, 3H), 4.27 (q, J=7.2 Hz, 2H), 4.91 (s, 2H), 7.65 (s, 1H), 7.90 (s, 1H), 9.95 (s, 1H). 13C NMR (63 MHz, CDCl3): δ 14.6, 57.2, 62.0, 70.0, 113.9, 120.4, 132.0, 145.2, 145.9, 154.2, 168.5, 189.3.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][C:11]([NH:13][C:14](=[NH:17])[NH:15][CH3:16])=[O:12].[CH3:18]OC(OC)N(C)C>CC#N>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[N:10]1[CH:16]=[N:15][C:14]([NH:17][CH3:18])=[N:13][C:11]1=[O:12]
Reactant: CNC(=N)NC(=O)Nc1c(Cl)cccc1Cl
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CC#N
Product: CNc1ncn(-c2c(Cl)cccc2Cl)c(=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a magnetically stirred suspension of 11.88 g (40 mmol) of 1-(2,6-dichlorophenyl)-3-methylamidinourea hydrochloride in 30 ml of CH3CN was added 9.52 g (80 mmol) of N,N-dimethylformamide dimethylacetal in 20 ml of CH3CN. The solid material began to dissolve immediately but in a few minutes, before the starting material had dissolved, another fine white solid began to precipitate out. The reaction mixture was stirred at ambient temperature for one hour then heated to reflux for two hours. After two hours, the reaction mixture was allowed to come to ambient temperature and the white solid precipitate filtered out to yield the desired product, melting point 270° C.; TLC (EtoAc 9:1); one major spot, one minor spot at origin. A small sample recrystallized from CH3OH/EtOAc gave one spot on TLC. (9.6 g, 89%) was crystallized from MeOH to yield 1-(2,6-dichlorophenyl)-4-methylaminodihydro-s-triazin-2-one.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[Cl:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][N:29]=[C:30]([CH2:31][CH3:32])[C:23]=12.C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[N:28]([CH:1]([O:3][CH2:4][CH3:5])[CH3:2])[N:29]=[C:30]([CH2:31][CH3:32])[C:23]=12
Reactant: C=COCC
Reactant: CCc1n[nH]c2nccc(Cl)c12
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(C)n1nc(CC)c2c(Cl)ccnc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Ethyl vinyl ether (3.7 mL) and (+)-10-camphorsulfonic acid (0.162 g) were sequentially added to a solution of compound (3c) (2.36 g) in THF (13.0 mL), followed by stirring at 50° C. for 30 min. After cooling, the reaction solution was distributed between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain compound (3d) (3.01 g, 91%) as an oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O-:9])=[O:8])=[CH:5][S:4][N:3]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][S:4][N:3]=1
Reactant: Cc1nscc1C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nscc1C(=O)O
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of 3-methylisothiazole-4-carboxylate (E-3) (4.73 g, 30.1 mmol) in THF-MeOH—H2O (2:1:1, 50 mL), NaOH (3.61 g, 90.3 mmol) is added and the resulting mixture is stirred at 40° C. for 16 h. The mixture is allowed to cool to RT and then acidified with concentrated HCl to adjust the pH to 2-3. The precipitate is collected by filtration, rinsed with water and dried in vacuo to afford the product, 3-methylisothiazole-4-carboxylic acid (E-4).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19])=[C:11]2[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][N:31]([CH3:33])[CH3:32])[CH2:26][CH2:25]1.[Cl:34][C:35]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[C:37]([Cl:50])[C:36]=1[OH:51]>>[CH:20]1([C:18]([C:12]2[CH:13]=[N:14][C:15]3[C:10]([C:11]=2[NH:23][C@H:24]2[CH2:25][CH2:26][C@H:27]([CH2:30][N:31]([CH3:33])[CH3:32])[CH2:28][CH2:29]2)=[CH:9][C:8]([C:39]2[CH:40]=[C:35]([Cl:34])[C:36]([OH:51])=[C:37]([Cl:50])[CH:38]=2)=[CH:17][CH:16]=3)=[O:19])[CH2:21][CH2:22]1
Reactant: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure F except 2M Na2CO3 was used instead of 1M Cs2CO3, (6-bromo-4-(trans-4-((dimethylamino)methyl)cyclohexylamino)quinolin-3-yl)(cyclopropyl)methanone (4.29 g, 9.96 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (4.32 g, 14.95 mmol) to afford the desired product (3.0 g, 59%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 9.77 (br s, 1H), 9.05 (s, 1H), 8.36 (d, J=2.1 Hz, 1H), 8.03 (dd, J=8.7, 1.8 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.73 (s, 2H), 3.96-3.86 (m, 1H), 2.97-2.82 (m, 1H), 2.19 (s, 6H), 2.17-2.06 (m, 4H), 1.86 (d, J=12.7 Hz, 2H), 1.60-1.36 (m, 3H), 1.15-0.91 (m, 6H); APCI MS m/z 512 [C28H31Cl2N3O2+H]+; HPLC>99% (AUC), tR=5.15 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]1[CH:11]=[CH:10][C:9]([C:18](O)=[O:19])=[CH:8][C:7]=1[O:6]2.[CH:21]([N:24](CC)[CH:25](C)[CH3:26])(C)[CH3:22].C(NCC)C>CN(C)C=O>[CH2:21]([N:24]([CH2:25][CH3:26])[C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:17])[C:14]3[C:5]([O:6][C:7]=2[CH:8]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=3)=[O:19])[CH3:22]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc2c(=O)c3ccc(C(=O)O)cc3oc2c1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc2c(=O)c3ccc(OC)cc3oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.2 %

Procedure:
A mixture of compound 6i (0.707 g, 2.62 mmol) and O-benzotriazol-yl-N,N,N′,N-tetramethyluronium hexafluorophosphate (HBTU, 1.05 g, 2.74 mmol) in N,N-dimethylformamide (10 mL) was treated with N,N-diisopropylethylamine (DIEA, 0.685 mL, 3.92 mmol) and allowed to stir at rt for 15 min. Diethylamine (0.541 mL, 5.23 mL) was added and the resultant mixture was stirred for 2 h. The mixture was poured into ice water. A solid was collected by filtration, washed with water and air dried to give the title compound (0.445 g). MS: m/z 326.0 (MH+). 1H NMR (DMSO-d6): δ 1.07 (br t, 3 H), 1.19 (br t, 3 H), 3.20 (br q, 2 H), 3.48 (br t, 2 H), 3.95 (s, 3 H), 7.08 (m, 1 H), 7.17 (d, 1 H, J=2.1 Hz), 7.40 (d of d, 1H, J=1.3 & 8.1 Hz), 7.59 (d, 1 H, J=1.2 Hz), 8.12 (d of d, 1 H, J=1.3 & 8.9 Hz) and 8.21 (d, 1 H, J=8.1 Hz).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([CH2:16][S:17]C(=O)C)([CH3:15])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([NH2:14])=[C:11]([CH3:13])[CH:12]=1)C>Cl>[NH2:14][C:10]1[N:9]=[CH:8][C:7]([CH2:6][C:5]([CH2:16][SH:17])([CH3:15])[C:4]([OH:21])=[O:3])=[CH:12][C:11]=1[CH3:13]
Reactant: CCOC(=O)C(C)(CSC(C)=O)Cc1cnc(N)c(C)c1
Agent: Cl
Product: Cc1cc(CC(C)(CS)C(=O)O)cnc1N

Procedure:
2-Acetylsulfanylmethyl-3-(6-amino-5-methyl-pyridin-3-yl)-2-methyl-propionic acid ethyl ester (17 mg, 40 μmol) was dissolved in conc. HCl (2 mL) under argon. The solution was heated to reflux for 150 min. Concentration under reduced pressure gave the title compound as the hydrochloride salt (10.7 mg, 96%).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]2=[N:7][CH:8]=1)[NH2:2].[O:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[OH-].[Na+]>CO.C(Cl)Cl>[O:22]1[CH2:27][CH2:26][CH:25]([C:28]2[N:4]3[C:5]4[CH:11]=[CH:10][NH:9][C:6]=4[N:7]=[CH:8][C:3]3=[N:1][N:2]=2)[CH2:24][CH2:23]1
Reactant: O=CC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: c1cc2c(ncc3nnc(C4CCOCC4)n32)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.9 %

Procedure:
To a solution of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.100 g, 0.330 mmol, Preparation #9) in MeOH (2 mL) was added tetrahydro-2H-pyran-4-carbaldehyde (0.038 g, 0.330 mmol, J&W PharmLab) in DCM (1 mL). The reaction mixture was stirred at ambient temperature for about 2 h before iodobenzene diacetate (0.106 g, 0.330 mmol) was added. The reaction mixture was stirred at ambient temperature for about 15 min before it was concentrated to constant weight. To the residue was added MeOH (2 mL) followed by aqueous NaOH (2 N, 0.330 mL, 0.659 mmol). The reaction mixture was heated at about 60° C. for about 1 h. The crude reaction mixture was purified by RP-HPLC (Table 2, Method f). The combined product-containing fractions were concentrated under reduced pressure to remove MeCN and then lyophilized to afford 1-(tetrahydro-2H-pyran-4-yl)-6H-pyrrolo[2,3-e][1, 2, 4]triazolo[4,3-a]pyrazine as a white solid (0.028 g, 35%): LC/MS (Table 2, Method a) Rt=1.25 min; MS m/z: 244 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21](C)[CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>[Cu]I.CCCCCC.C(OCC)(=O)C.O1CCOCC1>[CH3:24][C:19]1[CH:20]=[CH:21][C:22]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[C:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:17][CH:18]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(-n2c(-c3ccccc3)cc3ccccc32)cc1
Yield: 77.6 %

Procedure:
Using the general procedure outlined in Example 63, 2-phenylindole (0.232 g, 1.20 mmol) was coupled with 5-iodo-m-xylene (144 μL, 1.00 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-1,2-cyclohexanediamine (24 μL, 0.20 mmol, 20 mol %) and dioxane (0.5 mL) to give the crude product. Column chromatography (2×15 cm, hexane:ethyl acetate 10:1) provided 0.220 g (74% yield) of the product as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.92 (m, 1H), 7.55 (m, 3H), 7.47 (m, 3H), 7.41 (m, 2H), 7.20 (bs, 2H), 7.05 (d, 1H, J=0.6 Hz), 2.52 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 140.63, 139.10, 138.82, 138.29, 132.60, 128.90, 128.70, 128.14, 128.03, 127.12, 125.66, 122.09, 120.48, 120.39, 21.19.
Reaction SMILES: [CH2:1]([CH:3]([NH2:6])[CH2:4][CH3:5])[CH3:2].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:1]([CH:3]([NH:6][CH:1]([CH3:2])[C:3]#[N:6])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(N)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(CC)NC(C)C#N
Temperature: 55 °C
Yield: 65.6 %

Procedure:
Part A: A solution of 1-ethylpropylamine (1.97 g, 22.6 mmol) in acetonitrile (50 mL) was treated with K2CO3 (9.3 g, 67.7 mmol) 2-bromopropionitrile (3.0 g, 22.6 mmol) and KI (4.13 g, 24.9 mmol). The mixture was heated at 55° C. for 20 h. The mixture was cooled to room temperature and was filtered through a pad of Celite. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (2% MeOH in CH2Cl2) to afford 2-(1-ethylpropylamino)-propionitrile (1.04 g, 36% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]2[C:37]1=[O:46])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>C(#N)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[C:37](=[O:46])[C:38]2=[CH:45][CH:44]=[CH:43][CH:42]=[C:39]2[C:40]1=[O:41])=[O:25])[CH3:28]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Reactant: CCOC(=O)C(Br)CCCCCCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Yield: 21.8 %

Procedure:
In 100 ml of acetonitrile are dissolved 2.0 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 3.0 g of ethyl 2-bromo-9-phthalimidononanoate, and 0.85 g of triethylamine is added to the solution. The mixture is heated at 80° C. for 3 days, concentrated under reduced pressure, diluted with 100 ml of water and extracted with 150 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is separated and purified by silicagel column chromatography (hexane:ethyl acetate=3:1 - 2:1) to give from the first fraction 0.9 g of tert-butyl 3(R)-[1(R)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(=O)(O)[O-].[Na+].Cl.[CH3:17][NH:18][O:19][CH3:20].Cl>C1COCC1.O>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:18]([O:19][CH3:20])[CH3:17])=[O:5]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)c1cccnc1Cl
Yield: 87.2 %

Procedure:
To a solution of 2-chloro-nicotinoyl chloride (7.00 g, 39.8 mmol) and sodium bicarbonate (10.0 g, 119 mmol) in 1:1 THF/H2O (110 mL) at 0° C. was added N,O-dimethyl hydroxylamine hydrochloride (4.68 g, 47.7 mmol). The resultant solution was stirred 2 h at 0° C., neutralized with 10% HCl to pH ˜7, and the aqueous layer was extracted two times with EtOAc. The combined organics were dried with sodium sulfate and concentrated in vacuo to produce 6.96 g (87%) of the crude nicotinamide, which was used without further purification.