Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:18]([O-])=O)=[CH:5][C:6]([CH3:17])=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:8]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:18][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([C:9]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[O:10])=[C:6]([CH3:17])[CH:5]=1
Reactant: COc1cc(C(=O)N2CCOCC2)c(C)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)N2CCOCC2)c(C)cc1N
Temperature: 90 °C
Yield: 83.1 %

Procedure:
To (5-methoxy-2-methyl-4-nitrophenyl)(morpholino)methanone (1.76 g, 6.3 mmol) in ethanol (25 mL) and water (25 mL) was added ammonium chloride (1.72 g, 31.5 mmol) and iron powder (1.41 g, 25.2 mmol). The mixture was heated to 90° C. for 2 hours and then filtered through celite, washed through with ethanol. The solvent was removed in vacuo and the residue was partitioned between water (50 mL) and DCM (50 mL). The layers were separated and the aqueous phase was washed with DCM (3×50 mL). The combined organic phases were dried over MgSO4, filtered and the solvent removed in vacuo. The residue was triturated with diethyl ether/40-60 petroleum ether and dried to give (4-amino-5-methoxy-2-methylphenyl)(morpholino)methanone (1.31 g, 82%) as an off-white solid.
Reaction SMILES: [CH3:1][CH:2](OC(=O)C)[C:3]#[CH:4].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>O1CCCC1.C(OCC)C.[Cu]Cl>[N:9]1([CH:2]([C:3]#[CH:4])[CH3:1])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C#CC(C)OC(C)=O
Reactant: C1CCNC1
Agent: Cl[Cu]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC(C)N1CCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution acetic acid 1-methyl-prop-2-ynyl ester (prepared by the method of Clarke and Pinder, J. Chem. Soc. 1958, 1967).(7 g) and pyrrolidine (10.4 ml) in anhydrous tetrahydrofuran (125 ml) was treated with copper (I) chloride (0.3 g) and the mixture was heated to reflux temperatures for 1.5 hours. After then allowing the mixture to stir at room temperature for approximately 15 hours, the mixture was diluted with diethyl ether, and extracted thrice with 2N aqueous hydrochloric acid. These pooled acidic extracts were basified by addition of solid sodium hydroxide, and the solution was then extracted three times with ethyl acetate. These pooled organic extracts were then washed with water, brine, and dried over anhydrous magnesium sulfate. After removing the solvent in vacuo the resulting residue was distilled to obtain the desired product as a colorless oil. b.p. 35° C. (1.1 mm Hg). MS(+ES), m/z: 124 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C(Cl)Cl>[CH2:33]([O:32][C:30]([NH:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][CH2:8]1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1(CN)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1(CNC(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-(aminomethyl)piperidine-1,4-dicarboxylate (0.300 g, 1.1 mmol) and N,N-diisopropylethylamine (0.229 mL, 1.32 mmol) in CH2Cl2 (5 mL) at 0° C. was added benzyl chloroformate. The reaction was stirred overnight, and then diluted with CH2Cl2 and washed with H2O and brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (EtOAc:hexanes gradient) to give the title compound in 82% yield. MS (ES+) [M+H]+=407.
Reaction SMILES: [N:1]#CBr.C([O-])([O-])=O.[K+].[K+].[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19][N:18]=2)[CH2:13][CH2:12]1>C(Cl)(Cl)Cl>[C:10]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19][N:18]=2)[CH2:13][CH2:12]1)#[N:1]
Reactant: N#CBr
Reactant: CN1CCC(c2nsc3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC(c2nsc3ccccc23)CC1
Yield: 108.8 %

Procedure:
To a stirred mixture of CNBr (5.9 g, 0.056 mole), K2CO3 (8.6 g) and CHCl3 (80 ml) was added dropwise 3-(1-methyl-4-piperidinyl)-1,2-benzisothiazole (11.0 g, 0.051 mole) in CHCl3 (30 ml). The mixture was stirred and refluxed for 4 hours and thereafter cooled and filtered. The filtrate was concentrated in vacuo to a solid. The solid was triturated with hexane and collected to yield 13.5 g of the desired compound. Recrystallization from MeOH--H2O (twice) yielded 4.5 g (36%) of the benzisothiazole, m.p. 118°-120°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]([OH:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][OH:15])=[CH:5][CH:4]=1.C(O)(=O)C.[Se](=O)=O>CC(O)C>[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[O:15])(=[O:16])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(O)c2ccccc2CO)cc1
Agent: O=[Se]=O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COc1ccc(C(=O)c2ccccc2C=O)cc1

Procedure:
A solution of 26 g. of 4'-methoxy-2-hydroxymethylbenzhydrol in 140 ml. of acetic acid and 14.5 g. selenium dioxide was refluxed for 2 hours. The mixture was filtered and the filtrate was made basic. An oil separated which crystallized on standing and was collected. Recrystallization from a mixture of methylene chloride and petroleum ether gave off-white platelets melting at 90°-91°. Ultraviolet maxima (2-propanol) at 221 mμ (ε = 21,600), 258 mμ (ε = 12,400) and 292 mμ (ε = 17,000); infrared absorption (CHCl3) at 1660 cm-1 and at 1700 cm-1.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].[H-].[Na+].I[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].[Cl-].[Na+]>CN(C)C=O>[F:28][C:3]1[CH:4]=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCI
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Reaction time: 2 h
Yield: 73 %

Procedure:
505 mg (1.29 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one obtained in Example 66 was dissolved in 15 ml of dimethylformamide under argon atmosphere, 156 mg of sodium hydride (60% oil dispersion) and 0.42 ml of 1-iodoheptane were added under ice-cooling and the mixture was stirred for 2 hours. An aqueous saturated solution of sodium chloride was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to give 460 mg (73%) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-heptylamino-4H-1-benzopyran-4-one.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C@H:25]([CH3:29])[C:26](O)=[O:27])[CH:19]=[CH:18]2.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C@H:25]([CH3:29])[C:26]([O:1][N:2]1[C:3](=[O:12])[C:4]3[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=3[C:6]1=[O:7])=[O:27])[CH:19]=[CH:18]2
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)ON3C(=O)c4ccccc4C3=O)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.7 %

Procedure:
A mixture of N-hydroxyphthalimide (7.1 g, 43.4 mmol), (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 10 g, 43.4 mmol) and N,N-dimethylaminopyridine (DMAP, 5.3 g, 43.4 mmol) in CH2Cl2 (70 mL) and DMF (30 mL) at 0° C. was treated with 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (8.3 g, 43.4 mmol) in CH2Cl2 (50 mL). The reaction mixture was stirred at room temperature for 16 hours and the solvent was evaporated under vacuum. The residue was then dissolved in EtOAc, washed with brine, dried over Na2SO4 and filtered. The residue after evaporation of the solvent was chromatographed on silica gel eluting with EtOAc:hexane (1:1) to give the title compound (7.6 g, 47% yield) as a white solid. Mp 110-112° C. 1H NMR (300 MHz, d6-DMSO) δ 7.80-8.06 (m, 7H), 7.50 (dd, J=1.7 and 8.5 Hz, 1H), 7.32-7.37 (m, 1H), 7.20 (dd, J=2.5 and 9.0 Hz, 1H), 4.50 (q, J=7.1 Hz, 1H), 3.89 (s, 3H), 1.64 (d, J=7.1 Hz, 3H). 13C NMR (75 MHz, d6-DMSO) δ 171.2, 161.8, 157.5, 153.0, 135.5, 133.6, 133.5, 129.3, 128.4, 128.2, 127.3, 126.1, 126.0, 124.0, 119.0, 105.8, 55.2, 41.8, 18.6. Mass spectrum (API-TIS) m/z 376 (MH+), 393 (MNH4+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[N:16]=[C:15]([C:26]([NH:28][CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)=[O:27])[C:14]=2[CH3:42])=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[N:16]=[C:15]([C:26]([NH:28][CH:29]3[CH2:34][CH2:33][N:32]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:31][CH2:30]3)=[O:27])[C:14]=2[CH3:42])=[CH:9][CH:8]=1
Reactant: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(C(=O)NC2CCN(S(C)(=O)=O)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 87.4 %

Procedure:
Methanesulfonyl chloride (2 eq., 0.01 mL, 0.15 mmol) was added to tert-Butyl 4-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido]piperidine-1-carboxylate (1 eq., 35 mg, 0.076 mmol) and triethyamine (3 eq., 0.03 mL, 0.227 mmol) in tetrahydrofuran (2 mL). The reaction was stirred for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(1-methanesulfonyl-piperidin-4-yl)-4-methyl-1H-pyrazole-3-carboxamide (36 mg, 87%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.53-1.78 (m, 2H) 2.06-2.22 (m, 2H) 2.37 (s, 3H) 2.67-3.00 (m, 5H) 3.82 (d, J=12.24 Hz, 2H) 4.01-4.17 (m, 1H) 6.88 (d, J=8.01 Hz, 1H) 7.07 (s, 2H) 7.19-7.36 (m, 4H) 7.43 (d, J=1.70 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:15]=[CH:14][C:7]([NH:8][C:9](=[O:13])[CH2:10][O:11][CH3:12])=[CH:6][C:5]=1[N+:16]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:30]([N:37]1[C:41](=[O:42])[C:40](=[C:43]2[N:47]([CH3:48])[C:46]3[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=3[S:44]2)[S:39][CH2+:38]1SC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([N:37]1[C:41](=[O:42])[C:40](=[C:43]2[N:47]([CH3:48])[C:46]3[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=3[S:44]2)[S:39][C:38]1=[N:16][C:5]1[CH:6]=[C:7]([NH:8][C:9](=[O:13])[CH2:10][O:11][CH3:12])[CH:14]=[CH:15][C:4]=1[NH:3][CH2:1][CH3:2])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(NC(=O)COC)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)COC)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4′-ethylamino-2-methoxy-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.99 (1H, s), 7.39–7.44 (3H, m), 7.17–7.28 (5H, m), 7.05–7.11 (2H, m), 6.94 (1H, d), 6.50 (1H, d), 5.08 (2H, s), 3.92 (2H, s), 3.66 (3H, s), 3.41 (3H, s), 2.91 (2H, q), 0.96 (3H, t); MS(ESI): 560(MH+).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[N:9]([CH:16]3[CH2:18][CH2:17]3)[C:8]2=[O:19])[CH2:4]1.Cl[C:21]1[N:25]([CH3:26])[C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[N:22]=1.C(NC(C)C)(C)C>CS(C)=O>[CH:16]1([N:9]2[C:10]3=[N:15][CH:14]=[CH:13][N:12]=[C:11]3[N:7]([C@H:5]3[CH2:6][C@H:3]([NH:2][C:21]4[N:25]([CH3:26])[C:24]5[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=5[N:22]=4)[CH2:4]3)[C:8]2=[O:19])[CH2:17][CH2:18]1
Reactant: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nccnc32)C1
Reactant: Cn1c(Cl)nc2ccccc21
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CS(C)=O
Product: Cn1c(N[C@H]2C[C@H](n3c(=O)n(C4CC4)c4nccnc43)C2)nc2ccccc21
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A glass microwave reaction vessel was charged with 1-(trans-3-aminocyclobutyl)-3-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride (Intermediate 79, 0.1138 g, 0.404 mmol), 2-chloro-1-methyl-1H-benzo[d]imidazole (0.081 g, 0.485 mmol), and diisopropylamine (0.211 ml, 1.212 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO (0.577 ml) and heated to 120° C. to stir for 2 days. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CNiH2O, gradient 10% to 100% over min. Fractions containing product were collected and concentrated. Residue taken up in DCM and loaded onto a Silicycle Si-carbonate cartridge to remove any salts to give the title compound (103 mg, 0.027 mmol, 6.79 yield). LCMS showed product peak at 1.57 min (m+1=376.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97-1.03 (m, 2 H) 1.04-1.11 (m, 2 H) 2.47 (d, J=3.33 Hz, 1 H) 2.98 (tt, f=7.04, 3.72 Hz, 1 H) 3.27 (dt, J=13.30, 8.12 Hz, 2 H) 3.56 (s, 3 H) 4.53-4.66 (m, 1 H) 5.24 (quin, J=8.31 Hz, 1 H) 6.89-6.99 (m, 2 H) 7.02 (d, J=6.46 Hz, 1 H) 7.13-7.19 (m, 1 H) 7.19-7.25 (m, 1 H) 7.96-8.00 (m, 1 H) 8.00-8.04 (m, 1 H)
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6](=[N:8][OH:9])[Cl:7].[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>CCOCC>[CH3:10][S:11]([O:9][N:8]=[C:6]([Cl:7])[CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1)(=[O:13])=[O:12]
Reactant: ON=C(Cl)C1CCCO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)ON=C(Cl)C1CCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
A 500 mL round-bottomed flask was charged with tetrahydrofuran-2-carbonyl chloride oxime (2.6 g, 17.4 mmol), methanesulfonyl chloride (1.4 mL, 17.4 mmol), and Et2O (200 mL). Triethylamine (2.4 mL, 17.4 mmol) was added dropwise over 1 minute and stirred at ambient temperature for 10 minutes. The solids were filtered and the filtrate was concentrated. The residue was purified on silica gel (100% CH2Cl2) to afford the title compound (2.1 g, 53.07% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:19](=O)[CH3:20])=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(O)C.[OH-].[Na+].Cl.[NH2:28][NH:29][C:30]([NH2:32])=[O:31]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:19](=[N:28][NH:29][C:30]([NH2:32])=[O:31])[CH3:20])=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2nc(C)c(C(C)=O)s2)cc(OC)c1OC
Reactant: NNC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(-c2nc(C)c(C(C)=NNC(N)=O)s2)cc(OC)c1OC
Temperature: 25 °C
Yield: 69 %

Procedure:
2-(3,4,5-trimethoxyphenyl)-4-methyl-5-acetylthiazole (3.7 g corresponding to its 0.012 mol) was dissolved into 50 ml of ethanol, and 32 ml of an aqueous 2% solution of sodium hydroxide (0.013 mol) and 1.8 g (0.016 mol) of semicarbazide hydrochloride were added to the solution. The whole mixture was then heated for 5 hours under a reflux condenser. After cooling the reaction mixture to room temperature, the mixture was introduced into one liter of iced water. The precipitate which separated was collected by filtration, washed with water and was recrystallized from ethanol to obtain the object consisting of yellow needle-like crystals amounting to 3.0 g and melting at 240° to 242° C. The yield was 69%.
Reaction SMILES: C(O)C.[CH:4]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C@@H:26]([CH3:30])[NH:25][CH2:24]5)[C:15]=3[O:17][CH:18]([F:20])[F:19])[C:10](=[O:31])[C:9]([C:32]([OH:34])=[O:33])=[CH:8]2)[CH2:6][CH2:5]1.[OH-].[Na+:36]>O>[CH:4]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C@@H:26]([CH3:30])[NH:25][CH2:24]5)[C:15]=3[O:17][CH:18]([F:20])[F:19])[C:10](=[O:31])[C:9]([C:32]([O-:34])=[O:33])=[CH:8]2)[CH2:6][CH2:5]1.[Na+:36]
Reactant: C[C@H]1NCc2cc(-c3ccc4c(=O)c(C(=O)O)cn(C5CC5)c4c3OC(F)F)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@H]1NCc2cc(-c3ccc4c(=O)c(C(=O)[O-])cn(C5CC5)c4c3OC(F)F)ccc21
Reaction time: 1 h

Procedure:
In 9.4 ml of 25% water-containing ethanol is suspended 1.2 g of (R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, and 2.57 ml of 1 mole/liter aqueous sodium hydroxide solution is added thereto, after which the resulting mixture is exposed to ultrasonic wave for 1 hour to form a uniform solution. Subsequently, the reaction mixture is washed twice with chloroform, and concentrated, and the crystals deposited are collected by filtration to obtain 0.49 g of sodium (R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19]C#N)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].SC[C@@H]([C@@H](CS)O)O.[CH2:37]([N:39]([CH2:43][CH3:44])[CH2:40][CH2:41]S)[CH3:38]>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([C@H:22]2[CH2:23][CH2:24][C@H:25]([CH3:28])[CH2:26][CH2:27]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:38][CH2:37][N:39]([CH2:43][CH3:44])[CH2:40][CH3:41])=[CH:17][N:18]=2)=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)[C@H]2CC[C@H](C)CC2)CC1
Reactant: CCN(CC)CCS
Agent: O[C@H](CS)[C@@H](O)CS
Product: CCN(CC)CCSc1cnc(NC(=O)N(C2CCN(C(C)=O)CC2)[C@H]2CC[C@H](C)CC2)s1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-diethylamino-ethanethiol
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].CN1CCOCC1.[C:16]1(=[O:35])[N:20]([C@@H:21]([CH2:25][CH2:26][CH2:27][CH2:28]O)[C:22](O)=[O:23])[C:19](=[O:30])[C:18]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:17]12.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[C:19]1(=[O:30])[N:20]([C@@H:21]([CH2:25][CH2:26][CH2:27][CH3:28])[C:22]([NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:23])[C:16](=[O:35])[C:17]2=[CH:34][CH:33]=[CH:32][CH:31]=[C:18]12
Reactant: CCOC(=O)CN
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCC[C@@H](C(=O)NCC(=O)OCC)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A slurry of glycine, ethyl ester, hydrochloride salt (2.718 g, 19.5 mmol.) in dimethylformamide (36 ml.) was treated with 4-methyl morpholine (2.60 ml., 2.39 g., 23.6 mmol.) and stirred at room temperature for 5 minutes. The mixture was then treated with (S)-2-phthalimido-6-hydroxyhexanoic acid (4.50 g., 16.2 mmol.) and hydroxybenzotriazole (2.225 g., 16.5 mmol.), cooled to 0° C., and then treated with ethyl-3-(3-dimethylamino)-propyl carbodiimide, hydrochloride salt (3.438 g., 17.9 mmol.). After stirring at 0° C. for 1 hour and at room temperature for 2 hours, the mixture was partitioned between ethyl acetate and 0.5N hydrochloric acid and subsequently extracted three times with ethyl acetate. The pooled ethyl acetate extracts were washed in succession with water, saturated sodium bicarbonate, and brine, then dried (sodium sulfate), filtered and stripped to give 5.77 g. of title product as a colorless oil. TLC (ethyl acetate) Rf =0.34.
Reaction SMILES: [Cl:1][C:2]([Cl:20])([Cl:19])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1)=[O:4].[Cl:21][S:22](O)(=[O:24])=[O:23]>ClCCl>[Cl:20][C:2]([Cl:1])([Cl:19])[C:3]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[C:15]([S:22]([Cl:21])(=[O:24])=[O:23])[CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:9][CH2:10]1)=[O:4]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1N1CCN(C(=O)C(Cl)(Cl)Cl)CC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(Cl)(Cl)Cl)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A solution of 2-(4-trichloroacetylpiperazin-1-yl) anisole (D3) (10 g) in dichloromethane (115 ml) was added over 0.3 h to ice-cooled chlorosulfonic acid (52 ml). After 0.5 h at 0° C. then 1 h at ambient temperature, the solution was poured onto a mixture of ice-water (500 g) and dichloromethane (500 ml) with rapid stirring. The layers were separated and the organic phase was washed with water (2×800 ml), dried (MgSO4) and concentrated to give the title compound (D4) as a foam (6.0 g, 46%). MH+ 435/437.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:11]=2[CH2:10][CH2:9]1.O1CCOCC1CN1CCC2C=C(OC)C(N)=CC=2CC1.Cl[C:42]1[N:47]=[C:46]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[S:55]([N:58]([CH3:60])[CH3:59])(=[O:57])=[O:56])[C:45]([Cl:61])=[CH:44][N:43]=1>>[Cl:61][C:45]1[C:46]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[S:55]([N:58]([CH3:60])[CH3:59])(=[O:57])=[O:56])=[N:47][C:42]([NH:19][C:17]2[CH:16]=[CH:15][C:12]3[CH2:13][CH2:14][N:8]([CH2:7][CH:2]4[CH2:3][O:4][CH2:5][CH2:6][O:1]4)[CH2:9][CH2:10][C:11]=3[CH:18]=2)=[N:43][CH:44]=1
Reactant: Nc1ccc2c(c1)CCN(CC1COCCO1)CC2
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: COc1cc2c(cc1N)CCN(CC1COCCO1)CC2
Product: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CC2COCCO2)CC3)ncc1Cl

Procedure:
3-1,4-Dioxinan-2-ylmethyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine, prepared in a similar manner as 3-1,4-Dioxinan-2-ylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine of Example 636b, was reacted with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide, in a similar manner as Example 601b, to yield desired product 2-[5-Chloro-2-(3-[1,4]dioxan-2-ylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N,N-dimethyl-benzenesulfonamide as a lyophylate (38%); 1H NMR (400 MHz, DMSO-d6) δ 9.82 (bs, 1H), 9.56 (s, 1H), 9.29 (s, 1H), 8.51 (bs, 1H), 8.29 (s, 1H), 7.84 (d, J=8.08 Hz, 1H), 7.71 (m, 1H), 7.46-7.37 (m, 3H), 7.08 (d, J=6.57 Hz, 1H), 4.07 (m, 1H), 3.82-3.60 (m, 6H), 3.48 (bs, H2O), 3.3-2.9 (m, 9H), 2.75 (m, 1H), 2.65 (s, 6H); MS (m/e) 573.16 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#N.[C:9](#N)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:9]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1ccccc1
Reactant: N#Cc1cccnc1
Product: C(#Cc1cccnc1)c1ccccc1
Reaction time: 20 h
Yield: 45 %

Procedure:
The procedure was identical to Example 2, with the exception that 3-cyanopyridine (0.208 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 20 h at 65° C. showed the presence of 0.89 mmol (45% yield) of 3-(phenylethynyl)pyridine and no remaining 3-cyanopyridine in the reaction mixture.