Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1.Br[CH2:15][CH2:16][O:17][CH3:18]>CN(C)C=O>[CH3:18][O:17][CH2:16][CH2:15][N:6]1[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][C:4]([CH3:3])=[N:5]1
Reactant: COCCBr
Reactant: CCOC(=O)c1cc(C)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)nn1CCOC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30.8 %

Procedure:
To a suspension of sodium hydride (310 mg, 7.8 mmol) in N,N-dimethylformamide (10 mL) was slowly added a solution of ethyl 3-methyl-1H-pyrazole-5-carboxylate (1000 mg, 6.5 mmol) in N,N-dimethylformamide (5 mL) under ice-cooling, and the mixture was stirred at 0° C. for 10 min, then at room temperature for 20 min. To the reaction mixture was added a solution of 1-bromo-2-methoxyethane (1090 mg, 7.8 mmol) in N,N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 7 hr. The solvent was evaporated under reduced pressure, and ethyl acetate/tetrahydrofuran and water were added to the residue. The aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→70/30) to give ethyl 1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxylate (430 mg, 2.0 mmol) as a colorless liquid. To a solution of the obtained ethyl 1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxylate (430 mg, 2.0 mmol) in tetrahydrofuran (6 mL) was added 8N aqueous sodium hydroxide solution (1.3 mL), and the mixture was stirred at room temperature for 3 hr. 1N Hydrochloric acid (13 mL) and ethyl acetate were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (310 mg, 83%) as a white solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:15])[C:10]([O:12]CC)=[O:11])[N:8]=1)=[O:2].[OH-].[Na+]>O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:15])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: CCOC(=O)C(=O)c1csc(NC=O)n1
Agent: CCOC(=O)C(=O)c1csc(=NC=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=CNc1nc(C(=O)C(=O)O)cs1

Procedure:
To a suspension of ethyl 2-(2-formylaminothiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-formylimino-2,3-dihydrothiazol-4-yl)glyoxylate, (281 g.) in water (1100 ml.) was added an 1 N sodium hydroxide aqueous solution (2.23 l.) under stirring and ice-cooling, and then the mixture was stirred for 5 minutes at 10° to 15° C. After the reaction mixture was filtered, the filtrate was adjusted to pH 1 with concentrated hydrochloric acid with stirring. The precipitates were collected by filtration, washed with water and then dried to give 2-(2-formylaminothiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-formylimino-2,3-dihydrothiazol-4-yl)glyoxylic acid, (234 g.), mp 133° to 136° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([NH:16][C:17]2[N:22]=[C:21](SC#N)[C:20]([N+:26]([O-:28])=[O:27])=[CH:19][N:18]=2)[CH:3]=1.Cl.[F:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[O:39][CH2:38][CH2:37][C@H:36]2[NH2:41].C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[C:4]([NH:16][C:17]2[N:22]=[C:21]([NH:41][C@H:36]3[C:35]4[C:40](=[C:31]([F:30])[CH:32]=[CH:33][CH:34]=4)[O:39][CH2:38][CH2:37]3)[C:20]([N+:26]([O-:28])=[O:27])=[CH:19][N:18]=2)[CH:3]=1
Reactant: N[C@@H]1CCOc2c(F)cccc21
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@@H]2CCOc3c(F)cccc32)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
tert-Butyl 4-fluoro-2-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)phenylcarbamate (2.0 g) was added to a solution of (R)-8-fluorochroman-4-amine hydrochloride (1.1 gram) and N,N-diisopropylethylamine (2.2 mL) in THF (anhydrous, 50 mL). The mixture was stirred for 6 hr at room temperature then partitioned between water and EtOAc and separated. The aq. layer was washed with additional EtOAc and the combined organics were dried over Na2SO4 and concentrated in vacuo to give the title product in 94% yield. MH+=515, 459 (-tBu).
Reaction SMILES: [Br-].[Na+].[C:3]([O-:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na+].Cl[CH2:14][CH:15]1[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]1>CN(C)C=O>[C:3]([O:11][CH2:14][CH:15]1[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C([O-])c1ccccc1
Reactant: CC1(C)OCC(CCl)O1
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(COC(=O)c2ccccc2)O1
Temperature: 150 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
Then, sodium bromide (43.01 g, 0.42 mol) and sodium benzoate (60.24 g, 0.42 mol) were added to a mixture of the above 4-chloromethyl-2,2-dimethyl-1,3-dioxolane (60.02 g, 0.39 mol) and N,N-dimethylformamide (600 ml) and the resulting mixture was stirred for 15 hours at 150° C. After cooling the salt was filtered off and N,N-dimethylformamide was removed in vacuo and water was added to the residue and extracted with toluene. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and condensed in vacuo to give crude 4-benzoyloxymethyl-2,2-dimethyl-1,3-dioxolane (yield 90%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]Cl.C(O)(=O)C.C(N(CC)CC)C.C(#N)C.O.O>[C:15]1([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1ccccc1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 52.5 °C
Reaction time: 1 h

Procedure:
Carbazole was mixed in an amount of 16.47 g (98.52 mmol) with 31.0 g (197.04 mmol) of bromobenzene, 10.44 g (98.52 mmol) of sodium carbonate, 0.4 g (8.0 mmol) of copper-(I) chloride, and 3.0 g (8.0 mmol) of tetraphenylphosphonium chloride. This mixture was reacted at 115-125° C. for 2 hours in a nitrogen stream. After the reaction, 50 mL of toluene and 100 mL of water were added and the resultant mixture was subjected to liquid separation. Thereafter, the organic layer was washed with water and dried with anhydrous sodium sulfate. After the drying agent was removed by filtration, 15.6 g of activated clay was added. The resultant mixture was stirred at 50-55° C. for 1 hour and the clay was removed by filtration. The toluene was concentrated under reduced pressure and 352 mL of methanol was added to the residue. The resultant solution was subjected to crystallization. Thus, the target compound (I-27) was obtained as white crude crystals in an amount of 22.7 g (yield, 94.8%). The target compound obtained had a melting point of 96-97° C. and a content as determined by HPLC of 99.8% (HPLC conditions: column, ODS-80TM; eluent, acetonitrile/water (V/V=65/35); buffer, triethylamine and acetic acid each in an amount of 0.1%; detection UV, 254 nm; flow rate, 1.0 mL/min)
Reaction SMILES: [C:1]([C:5]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:6]=1[O:7][CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[K+].[Cl-].[Ca+2:32].[Cl-]>CO>[C:1]([C:5]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:6]=1[O:7][CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([O-:19])=[O:18])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3].[C:1]([C:5]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:6]=1[O:7][CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([O-:19])=[O:18])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3].[Ca+2:32]
Reactant: CC(C)(C)c1cc(F)ccc1OCC1CCN(C(=O)CCC(=O)O)C1
Agent: O=C([O-])O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CO
Product: CC(C)(C)c1cc(F)ccc1OCC1CCN(C(=O)CCC(=O)[O-])C1
Yield: 90.5 %

Procedure:
To a solution of 4-{3-[(2-tert-butyl-4-fluorophenoxy)methyl]pyrrolidin-1-yl}-4-oxobutanoic acid (260 mg, 0.74 mmol) obtained in Example 217 in methanol (10 mL) was added aqueous solution (10 mL) of potassium hydrogen carbonate (78 mg, 0.78 mmol). The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (10 mL), and aqueous solution (10 mL) of calcium chloride (43 g, 0.39 mmol) was added. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with THF. The resulting precipitate was filtered, and the filtrate was concentrated to give the title compound (248 mg, 90%) as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][CH:6]=[C:7]([CH:9]=O)[N:8]=1)[CH2:2][CH3:3].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[NH:12][NH2:13]>>[CH2:16]([O:15][C:11](=[O:14])[NH:12][N:13]=[CH:9][C:7]1[N:8]=[C:4]([CH2:1][CH2:2][CH3:3])[NH:5][CH:6]=1)[CH3:17]
Reactant: CCOC(=O)NN
Reactant: CCCc1nc(C=O)c[nH]1
Product: CCCc1nc(C=NNC(=O)OCC)c[nH]1

Procedure:
A 7.8 gm. portion of 2-n-propyl-4-imidazolecarboxaldehyde and 6.24 gm. of ethyl carbazate is reacted as described in Example 32 giving the desired product, m.p. 180°-182° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:15])[CH2:7]2>C(O)C.[Ni]>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:15])[CH2:7]2
Reactant: CN1CCc2c(Br)ccc([N+](=O)[O-])c2C1
Agent: [Ni]
Solvent: CCO
Product: CN1CCc2c(Br)ccc(N)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-methyl-5-bromo-8-nitro-1,2,3,4-tetrahydroisoquinoline (III, 4.7 gm, 17.3 mmol) in ethanol (50 ml), Raney Nickel (solution in water, 1.5 g) was added. The reaction mixture was stirred at room temperature overnight under H2. The mixture was filtered through celite and solvent was removed under vacuum to give IV.
Reaction SMILES: C([N:4]1[CH2:16][CH2:15][C:14]2[N:13]([CH2:17][CH:18]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[OH:19])[C:12]3[N:11]=[CH:10][C:9]([CH3:26])=[CH:8][C:7]=3[C:6]=2[CH2:5]1)C=C.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].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>[CH3:26][C:9]1[CH:10]=[N:11][C:12]2[N:13]([CH2:17][CH:18]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)[OH:19])[C:14]3[CH2:15][CH2:16][NH:4][CH2:5][C:6]=3[C:7]=2[CH:8]=1
Reactant: C=CCN1CCc2c(c3cc(C)cnc3n2CC(O)c2ccncc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1cnc2c(c1)c1c(n2CC(O)c2ccncc2)CCNC1

Procedure:
To a degassed solution of 2-(6-allyl-3-methyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-1-pyridin-4-yl-ethanol (300 mg, 0.862 mmol) and 1,3 dimethyl barbituric acid (403 mg, 2.586 mmol) in DCM (7 mL) was added and Pd(PPh3)4 (20 mg, 0.0172 mmol) and the reaction mixture stirred at RT for 1 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with 20% aq potassium carbonate solution and extracted with DCM (3×25 mL). The combined organic layer was washed with 20% aq potassium carbonate solution, dried over anhydrous sodium sulfate and concentrated to yield 2-(3-methyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-1-pyridin-4-yl-ethanol. 1H NMR (CDCl3, freebase) δ (ppm):8.5 (d, 2H), 8.03 (s, 1H), 7.51(s, 1H), 7.22 (d, 2H) 5.14 (d, 1H), 4.4 (dd, 1H), 4.27 (dd, 1H), 3.93 (q, 2H), 3.13 (m, 2H), 2.54 (dd, 1H), 2.42 (s, 3H), 2.3 (dd, 1H). Separation by chiral HPLC provided enantiomers 58a and 58b.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[OH-].[Na+]>C(Cl)Cl>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: NCCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: OCCCNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
16.5 g of 3-aminopropanol and 41.7 g of 1-benzyl-4-piperidone are dissolved in 350 ml of methylene chloride and 56 g of sodium triacetoxy-borohydride are slowly added at about 10° C. The mixture is stirred overnight at ambient temperature, then acidified with dilute hydrochloric acid while cooling and then made alkaline with conc. sodium hydroxide solution. The organic phase is separated off, the aqueous phase is washed once more with 150 ml of methylene chloride. The combined organic phases are dried over sodium sulphate and the solvent is eliminated in vacuo. 32 g of 1-benzyl-4-(3-hydroxy-propylamino)-piperidine are obtained as a yellow oil, which is used without further purification in the next reaction step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:10]3[CH:19]=[C:20]([S:23][CH3:24])[CH:21]=[CH:22][C:9]=3[S:8][C:7]=2[CH:25]=1.Cl[CH2:27][CH2:28][N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[NH:31][C:30]1=[O:38]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11]([N:13]3[CH2:14][CH2:15][N:16]([CH2:27][CH2:28][N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[NH:31][C:30]4=[O:38])[CH2:17][CH2:18]3)[C:10]3[CH:19]=[C:20]([S:23][CH3:24])[CH:21]=[CH:22][C:9]=3[S:8][C:7]=2[CH:25]=1
Reactant: O=c1[nH]c2ccccc2n1CCCl
Reactant: COc1ccc2c(c1)Sc1ccc(SC)cc1C(N1CCNCC1)C2
Product: COc1ccc2c(c1)Sc1ccc(SC)cc1C(N1CCN(CCn3c(=O)[nH]c4ccccc43)CC1)C2

Procedure:
In an analogous manner to that described in Example 7, 1-{2-[4-(10,11-dihydro-3-methoxy-8-methylthio-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-benzimidazolidnone (whose dihydrochloride melts at 250°C.) is prepared from 1-(10,11-dihydro-3-methoxy-8-methylthio-dibenzo[b,f]thiepin-10-yl)- piperazine and N-(2-chloroethyl)-2-benzimidazolidinone.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)CCC.Cl[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][N:40]=1>C1(C)C=CC=CC=1>[F:45][C:42]1[CH:43]=[CH:44][C:39]([C:6]2[N:7]=[CH:8][N:9]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:10]=2)=[N:40][CH:41]=1
Reactant: Fc1ccc(Cl)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)nc1
Temperature: 25 °C
Yield: 34 %

Procedure:
To the solution of 4-Tributylstannyl-1-trityl-1H-imidazole (1.00 g, 1.67 mmol) in toluene (10 ml) added 2-Chloro-5-fluoropyridine (0.31 g, 2.38 mmol) and tetrakis(triphenylphoshine)palladium (0) (0.19 g, 0.17 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at reflux under argon overnight. The reaction mixture was cooled to room temperature and concentrated in-vacuo. The residue was purified on silica gel using 30% diethyl ether in hexanes to isolate 4-(5-Fluoro-2-pyridyl)-1-trityl-1H-imidazole (0.23 g) as a clear oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:8][C:4]1[N:3]=[C:2]([NH:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=[N:6][CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNc2cncc(Cl)n2)cc1
Reaction time: 12 h
Yield: 74.7 %

Procedure:
To a solution of 2,6-dichloropyrazine (4.00 g, 26.8 mmol) and 4-methoxybenzylamine (7.02 mL, 53.7 mmol) in DMF (30 mL) was added K2CO3 (7.42 g, 53.7 mmol) at RT and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with cold water (100 mL) and extracted into ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give a residue that was purified by CombiFlash (REDISEP®, silica gel, 24 g, 25% EtOAc/petroleum ether) to give 6-chloro-N-(4-methoxybenzyl)pyrazin-2-amine (5.00 g, 74.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.31 (s, 3H), 4.37 (d, J=6.0 Hz, 2H), 6.87-6.93 (m, 2H), 7.24-7.31 (m, 2H), 7.70 (s, 1H), 7.90 (s, 1H), 7.95 (t, J=5.5 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]#[N:14])[NH:10]2)=[CH:6][CH:5]=1)([O-])=O>[Ni].CCO>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]#[N:14])[NH:10]2)=[CH:6][CH:5]=1
Reactant: N#Cc1cc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Ni]
Solvent: CCO
Product: N#Cc1cc2ccc(N)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
A mixture of 6-nitro-1H-indole-2-carbonitrile (2.5 g, 13 mmol) and Raney Nickel (500 mg) in EtOH (50 mL) was stirred at room temperature under H2 (1 atm) for 1 h. Raney Nickel was removed via filtration and the filtrate was evaporated under reduced pressure to give a residue, which was purified by column chromatograpy on silica get to give 6-amino-1H-indole-2-carbonitrile (1.0 g, 49%). 1H NMR (DMSO-d6) δ 12.75 (br s, 1H), 7.82 (d, J=8 Hz, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 7.15 (d, J=8 Hz, 1H); MS (ESI) m/e (M+H+) 158.2.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:30])[CH2:28][SH:29]>>[CH3:25][O:26][C:27](=[O:30])[CH2:28][S:29][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1
Reactant: COC(=O)CS
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: COC(=O)CSc1cnc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)s1
Yield: 30 %

Procedure:
{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid methyl ester (130 mg, 30%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol), and mercapto-acetic acid methyl ester (212 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:22])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][N:12]2[CH2:15][CH3:16])=[CH:7][C:6]=1[F:23])=O.[C:24]([NH:27][CH2:28][C:29]([NH2:31])=[S:30])(=[O:26])[CH3:25].C(N(CC)CC)C>CN(C)C=O>[C:24]([NH:27][CH2:28][C:29]1[S:30][CH:2]=[C:3]([C:5]2[CH:14]=[C:13]3[C:8]([C:9](=[O:22])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][N:12]3[CH2:15][CH3:16])=[CH:7][C:6]=2[F:23])[N:31]=1)(=[O:26])[CH3:25]
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)CBr)c(F)cc2c1=O
Reactant: CC(=O)NCC(N)=S
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(-c3csc(CNC(C)=O)n3)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
A suspension of 0.59 g (1.54 mmol) ethyl 7-bromoacetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3quinolinecarboxylate in 4 ml N,N-dimethylformamide was treated with 0.22 g (1.67 mmol) acetamidothioacetamide [prepared according to J. Am. Chem. Soc. 51, 1817 (1929)]. After stirring three hours the mixture was treated with 0.22 ml (1.58 mmol) triethylamine, stirred one hour more and poured into 40 ml ice water. The precipitate was filtered, washed with water and dried to afford 0.45 g crude solid. Chromatography on a column of 20 g silica gel with chloroform-methanol (9:1) and crystallization from ethanol gave 0.37 g ethyl 7-[2(acetamidomethyl)-4thiazolyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, mp 230°-233° C. (dec).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[F:29][C:30]([F:42])([F:41])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>N.CO>[F:42][C:30]([F:29])([F:41])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:38])=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(c1ccccc1C(F)(F)F)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 16.7 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 2-(Trifluoromethyl)benzenesulfonyl chloride (24 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (3.3 mg). MS m/z 397 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][C:5]([NH:7][C@@H:8]([CH3:19])[C:9]([O:11]CC1C=CC=CC=1)=[O:10])=[O:6]>CO.[Pd]>[F:1][C:2]([F:20])([F:21])[CH2:3][CH2:4][C:5]([NH:7][C@@H:8]([CH3:19])[C:9]([OH:11])=[O:10])=[O:6]
Reactant: C[C@H](NC(=O)CCC(F)(F)F)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)CCC(F)(F)F)C(=O)O
Reaction time: 5 h
Yield: 99 %

Procedure:
Add palladium/carbon (5%, 1.76 g, 0.8 mmol) in one portion to a solution of benzyl (2S)-2-(4,4,4-trifluorobutanoylamino)propanoate (8.80 g, 29 mmol) in methanol (88 mL) at ambient temperature. Degas the mixture (vacuum/nitrogen), fill with hydrogen (one atmosphere) and stir under hydrogen (29 mmol) for 5 hours. Filter through Celite®, rinse filter cake with methanol and concentrate the filtrate to obtain the title compound as a white solid (6.11 g, 28.7 mmol, 99%). MS (m/z): 214 (M+1); [α]Na25=−24.7° (c=5.0, methanol).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.Br[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: BrCc1cccc2ccccc12
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc2ccccc12

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 1-(bromomethyl)naphthalene were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: C(#N)C=C.CCCCC=C.[CH:11]1[C:24]2[NH:23][C:22]3C(=CC=[CH:20][CH:21]=3)S[C:15]=2[CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)[OH:26]>>[CH3:15][CH:24]([NH:23][C:22](=[O:26])[CH:21]=[CH2:20])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=S(=O)(O)O
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Solvent: C=CCCCC
Solvent: C=CC#N
Product: C=CC(=O)NC(C)CCCC

Procedure:
Following a procedure analogous to that of Examples 1 and 2 from 530 pbw of acrylonitrile, 841.6 pbw hexene-1, 1.0 pbw phenothiazine and 1300 pbw 83% sulfuric acid, there is obtained 1010 pbw of the title product.