Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](N(CC)CC)C.CI>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][CH3:31])=[CH:27][CH:28]=2)[N:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CI
Product: CNc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1

Procedure:
2-[4-(4-amino-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (Compound 5050, 38 mg, 0.092 mmol) was dissolved in 3.5 mL of methylene chloride. To this solution was added triethylamine (12.8 μL, 0.092 mmol) followed by 6 μL (0.092 mmol) of methyl iodide. This solution was heated under reflux for 1 hour. It was evaporated and redissolved in 5 mL of DMF. The crude was purified using reverse phase HPLC to furnish the desired product. MS: 437.1 (M+H+).
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:9][N:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:11]2[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][C@H:12]2[O:22][CH3:23])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CC(O)C>[CH3:23][O:22][C@H:12]1[C@@H:11]([N:10]([CH2:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:15][NH:14][CH2:13]1
Reactant: CCOC(=O)N1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)[C@H](OC)C1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CO[C@@H]1CNCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Yield: 55 %

Procedure:
To a stirred mixture of 230 parts of potassium hydroxide and 1600 parts of 2-propanol was added 155 parts of ethyl cis-4-[bis(phenylmethyl)amino]-3-methoxy-1-piperidinecarboxylate. The whole was stirred and refluxed for 7 hours. The reaction mixture was evaporated. Water was added and the mixture was evaporated till all traces of 2-propanol were removed. The product was extracted with dichloromethane. The extract was washed twice with a sodium chloride solution in water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was taken up in dichloromethane. The solution was washed with a sodium hydroxide solution 5%, dried, filtered and evaporated, yielding 70 parts (55%) of cis-3-methoxy-N,N-bis(phenylmethyl)-4-piperidinamine as a residue (int. 47).
Reaction SMILES: [OH:1][C@@H:2]([C:7]1[C:36]([CH3:37])=[N:35][C:34]2=[CH:38][C:31]3=[N:32][N:33]2[C:8]=1[N:9]1[CH2:43][CH2:42][C:12]([CH3:44])([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([CH3:41])[O:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:40])=[CH:24][C:25]=2[C:26]2[CH:39]=[C:30]3[CH:29]=[CH:28][CH:27]=2)[CH2:11][CH2:10]1)[C:3]([O:5]C)=[O:4].C(O[C:49]1([CH3:53])[CH2:52][CH2:51][CH2:50]1)(=O)C.Cl(O)(=O)(=O)=O.[OH-].[Na+]>C(Cl)Cl.CO>[CH3:53][C:49]1([O:1][C@@H:2]([C:7]2[C:36]([CH3:37])=[N:35][C:34]3=[CH:38][C:31]4=[N:32][N:33]3[C:8]=2[N:9]2[CH2:43][CH2:42][C:12]([CH3:44])([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([CH3:41])[O:19][C:20]3[CH:21]=[CH:22][C:23]([CH3:40])=[CH:24][C:25]=3[C:26]3[CH:39]=[C:30]4[CH:29]=[CH:28][CH:27]=3)[CH2:11][CH2:10]2)[C:3]([OH:5])=[O:4])[CH2:52][CH2:51][CH2:50]1
Reactant: CC(=O)OC1(C)CCC1
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C)cc1-c1cccc-3c1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc2c(c1)-c1cccc(c1)-c1cc3nc(C)c([C@H](OC4(C)CCC4)C(=O)O)c(n3n1)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Reaction time: 3 h
Yield: 35.8 %

Procedure:
To a stirred solution of methyl (2S)-2-hydroxy-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (40 mg, 0.067 mmol) in DCM (2 mL) and 1-methylcyclobutyl acetate (599 mg, 4.68 mmol) at rt was added 70 wt % perchloric acid (0.017 mL, 0.200 mmol). After 3 h, the reaction mixture was diluted with DCM (25 mL), carefully quenched with sat. NaHCO3 (5 mL), organic layer separated and washed with brine (10 mL), dried (Na2SO4), filtered and concentrated to give yellow paste. The crude was then tretated with 1N NaOH (0.334 mL, 0.334 mmol) in MeOH (1 mL) at 75° C. for 3 h. Mixture was then cooled and purified by prep HPLC to afford (2S)-2-(1-methylcyclobutoxy)-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid (15.8 mg, 0.024 mmol, 36.2% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.17-7.11 (m, 2H), 7.08 (s, 1H), 7.05 (d, J=8.2 Hz, 1H), 5.49 (s, 1H), 4.62 (d, J=5.5 Hz, 1H), 4.45 (t, J=12.2 Hz, 1H), 3.61-3.53 (m, 1H), 3.40-3.20 (m, 7H), 2.83 (d, J=10.4 Hz, 1H), 2.29 (s, 3H), 2.22 (q, J=10.0 Hz, 1H), 2.01-1.86 (m, 4H), 1.82 (br. s., 1H), 1.70-1.62 (m, 5H), 1.58-1.41 (m, 4H), 1.28 (s, 3H), 1.17 (s, 3H), 1.07 (d, J=5.8 Hz, 3H). LCMS (M+H)=653.6.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([C:8]#[N:9])[CH:7]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.O>CN1C(=O)CCC1>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([C:8]#[N:9])[CH:7]=2)[CH2:16][CH2:15]1
Reactant: N#Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(C#N)c2)CC1
Temperature: 100 °C

Procedure:
5-Fluoro-2-nitrobenzenecarbonitrile (1.02 eq) and N-methylpiperazine, (1.0 eq) were dissolved in NMP. Triethylamine (2.1 eq) was added, and the resulting solution heated at 100° C. for 1 hour. The solution was cooled to room temperature and poured into H2O. A precipitate formed which was filtered to yield the desired product as a green solid. LC/MS m/z 247.3 (MH+), Rf 1.46 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8](C(OC)=O)[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)n1ccc2ccc(Cl)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Clc1ccc2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
The synthesis was performed with reference to the known literature (International Patent Publication WO2008/080015). A solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.37 g, 1.8 mmol) in methanol (10 mL) was added with 5 N aqueous sodium hydroxide (2.0 mL), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, the residue was added with water, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 6-chloro-1H-pyrrolo[2,3-b]pyridine (0.26 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:18])=[CH:4][C:5]([Cl:17])=[C:6]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)[CH:7]=1.[N:19]([O-])=O.[Na+]>Cl.O>[ClH:17].[Cl:18][C:3]1[CH:4]=[C:5]([Cl:17])[C:6]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[CH:7][C:2]=1[NH:1][NH2:19]
Reactant: O=N[O-]
Reactant: CC1(C)CON(Cc2cc(N)c(Cl)cc2Cl)C1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)CON(Cc2cc(NN)c(Cl)cc2Cl)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.4 %

Procedure:
A solution of 2-[(5-amino-2,4-dichlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone (16.3 g, 0.564 mole) in concentrated hydrochloric acid (75 ml) was cooled to 0° C., and a solution of sodium nitrite (3.9 g, 0.564 mole) in water (50 ml) was added dropwise with the tip of the addition funnel below the surface of the solution. The reaction mixture temperature was kept below 2° C. during the addition. Upon completion of addition, the reaction mixture was stirred at 0° C. for 30 minutes, and then stannous chloride (28 g, 0.124 mole) in concentrated hydrochloric acid (50 ml) was added dropwise maintaining the temperature below 2° C. The reaction mixture was stirred for one hour at 0° C., and then a tan solid was removed by filtration to yield 10.0 g of [2,4-dichloro-5-[(4,4-dimethyl-3-oxoisoxazolidin-2-yl)methyl]phenyl]hydrazine hydrochloride; m.p. 202°-205° C.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26])([O-:21])=[O:20]>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:26][C:25]([C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(OC)cc1
Product: CCOC(=O)c1nc(-c2cccc([N+](=O)[O-])c2)[nH]c1-c1ccc(OC)cc1
Yield: 45.5 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methoxyphenyl)-3-oxopropionate (20.0 g) and 3-nitrobenzylamine (15.0 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 10 to give ethyl 5-(4-methoxyphenyl)-2-(3-nitrophenyl)imidazole-4-carboxylate (13.3 g), melting point 208-210° C.
Reaction SMILES: CC([O-])(C)C.[Na+].C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C.Cl[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][N:32]=1.[F:39][C:40]1[CH:45]=[C:44]([S:46]([CH3:49])(=[O:48])=[O:47])[CH:43]=[CH:42][C:41]=1[NH:50][C@H:51]1[CH2:55][CH2:54][N:53]([CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[C:52]1=[O:62]>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:37]([C:34]1[CH:35]=[CH:36][C:31]([N:59]2[CH2:58][CH2:57][CH:56]([N:53]3[CH2:54][CH2:55][CH:51]([NH:50][C:41]4[CH:42]=[CH:43][C:44]([S:46]([CH3:49])(=[O:47])=[O:48])=[CH:45][C:40]=4[F:39])[C:52]3=[O:62])[CH2:61][CH2:60]2)=[N:32][CH:33]=1)[CH3:38]
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCNCC3)C2=O)c(F)c1
Reactant: CCc1ccc(Cl)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)CN1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCc1ccc(N2CCC(N3CCC(Nc4ccc(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Temperature: 100 °C
Yield: 54.7 %

Procedure:
To a nitrogen purged vessel was added Pd2 dba3 (0.0386 g, 0.0422 mmol), NaOtBu (0.169 g, 1.76 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (0.0600 mL, 0.169 mmol), 2-chloro-5-ethylpyridine (0.100 g, 0.703 mmol) and (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (Preparation E; 0.300 g, 0.844 mmol). Toluene (4 mL, purged with nitrogen) was added and the reaction was heated at 100° C. overnight. The mixture was cooled to ambient temperature, diluted with EtOAc, and washed with water. The organics were dried over Na2SO4, concentrated and purified on silica eluting with 100% EtOAc to give 1-(1-(5-ethylpyridin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.177 g, 54% yield) as white solids. Mass spectrum (apci) m/z=461.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]([CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:26])[NH:1][C:2]2[CH:16]=[CH:15][C:5]([C:6]([N:8]([CH2:10][CH2:11][N:12]([CH3:13])[CH3:14])[CH3:9])=[O:7])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: CN(C)CCN(C)C(=O)c1ccc(N)cc1
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: ClCCl
Product: CN(C)CCN(C)C(=O)c1ccc(NC(=O)Nc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.9 %

Procedure:
To a solution of 4-amino-N-(2-dimethylamino-ethyl)-N-methyl-benzamide (4.0 g, 0.01809 mol) and TEA (2.01 g, 0.01809 mol) in DCM (50 mL) was added 4-bromophenyl isocyanate (4.3 g, 0.0217 mol). The reaction mixture was stirred at room temperature for 12 h. The white solid was obtained and was filtered and dried to afford the title compound [5.0 g, 67%]; LC-MS (ESI): Calculated mass: 418.1; Observed mass: 421.1 [M+H]+ (RT: 1.23 min).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[CH:14]([CH2:23][C:24]([OH:26])=[O:25])[CH:13]3[CH3:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([OH:26])=[O:25])=[C:13]3[CH3:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(CC(=O)O)C(C)N2c1ccnc2cc(Cl)ccc12
Solvent: Cc1ccccc1C
Product: COc1ccc2c(c1)c(CC(=O)O)c(C)n2-c1ccnc2cc(Cl)ccc12

Procedure:
A mixture of 1-(7-chloroquinol-4-yl)-5-methoxy-2-methylindolin-3-ylacetic acid (1g.) and 2,3,5,6-tetrachloro-1,4-benzoquinone (1g.) in dry xylene (50ml.) was refluxed for 2 hours. The solvent was removed in vacuo and the residue adsorbed on a column of chromatographic silica gel (50g.). The column was eluted with chloroform containing increasing amounts of methanol (starting with pure chloroform, and then using increments of 1% v/v of methanol in chloroform; product mainly eluted with 5% methanol in chloroform) to give 1-(7-chloroquinol-4-yl)-5-methoxy-2-methylindol-3-ylacetic acid, m.p. 248°-250° C.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:22]2[C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:24])[C:13]=2[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(OC(O)C)C>[C:1]1([S:7][C:16]2[C:15]3[C:14](=[O:24])[C:13]4[C:22](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:21](=[O:23])[C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1c2ccccc2C(=O)c2c(Sc3ccccc3)cccc21
Temperature: 120 °C
Yield: 96 %

Procedure:
45 g Thiophenol are added dropwise to a suspension of 100 g 1-chloro-anthraquinone and 63 g potassium carbonate in 150 ml ethoxyethanol at 23° C. under stirring. The reaction is strongly exotherm and addition must be performed very slowly, and subsequent addition of solvent improves fluidity and stirring of the reaction mixture. After heating at 120° C. for 3½ hours and subsequent cooling to 23° C., the mixture is filtered on glass (porosity 3) to afford a presscake which is washed with 1 l of methanol. The presscake is in turn suspended in 1 l water at 50° C. and again filtered on a glass filter (porosity 3). Further washing of the presscake with warm water (4 l) affords a filtrate of neutral pH. The presscake is finally dried at 60° C./5·103 Pa for 12 hours to provide 124.1 g of powdery orange 1-phenylsulfanyl-anthraquinone of formula
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:19][C:20]1[CH:27]=[C:26]([CH2:28][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:25]=[C:22]([CH3:23])[CH:21]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: Cc1cc(C)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cc(C)cc(C)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 66.5 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (850 mg, 3.5 mM), 3,5-dimethylbenzyl bromide (765 mg, 3.8 mM), and potassium carbonate (500 mg, 3.61 mM) in 25 mL DMF was stirred at room temperature for 19 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 0.84 g (67%) of the 9-[(3,5-dimethylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a foam. 1H NMR (DMSO-d6) δ7.7 (dd, 1H, J=1 and 8 Hz), 7.3-7.2 (m, 2H), 6.9 (s, 1H), 6.75 (s, 2H), 5.45 (s, 2H), 3.8 (s, 3H), 3.0 (m, 2H), 2.45 (m, 2H), 2.2 (s, 6H), and 2.1 (m, 2H). IR (KBr, cm−1) 1726, 1653, 1602, 1465, 1442, 1282, 1172, and 1116. MS (ES) m/e 362.
Reaction SMILES: NC(C(N)=S)=S.CO.C(N)C1C=CC=CC=1.C([NH:24][C:25]([C:27]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[S:28])=[S:26])C1C=CC=CC=1>O>[CH2:30]([NH:29][C:27]([C:25]([NH2:24])=[S:26])=[S:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: S=C(NCc1ccccc1)C(=S)NCc1ccccc1
Agent: NC(=S)C(N)=S
Solvent: NCc1ccccc1
Solvent: O
Solvent: CO
Product: NC(=S)C(=S)NCc1ccccc1
Reaction time: 0.33 h

Procedure:
Into a 5 liter, 3-necked flask equipped with a mechanical stirrer, thermometer, and reflux condenser were placed 212 g (1.77 mol) of dithiooxamide (DTO), 2,200 g of methanol, and 224 g of deionized water. The reaction mixture was stirred and heated to reflux. At that point, 126 g (1.18 mol) of benzylamine, i.e., the reactive amine, was added. The progress of the reaction was monitored by thin layer chromatography (TLC) to detect the initial formation of N,N'-dibenzyldithiooxamide. After about 20 minutes, formation of the disubstituted product was detected and the reaction was quenched by the addition of 100 g of concentrated HCl.
Reaction SMILES: [OH:1][CH2:2][CH:3]([OH:6])[CH:4]=[CH2:5].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>N1C=CC=CC=1>[S:13]([O:1][CH2:2][CH:3]([OH:6])[CH:4]=[CH2:5])([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CC(O)CO
Solvent: c1ccncc1
Product: C=CC(O)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 18 h

Procedure:
1,2-Dihydroxy-3-butene (20.00 g; 0.227 mole; 1.05 equivalent) was dissolved in pyridine (200 ml). The reaction mixture was cooled in an ice bath and p-toluenesulfonyl chloride (p-TsCl) (41.11 g; 0.216 mole) was added in four portions over 30 min. After thorough mixing, the reaction mixture was placed at 4° C. for 18 h, at which time thin layer chromatography (TLC) analysis indicated no p-TsCl. The mixture was concentrated to about half the original volume at reduced pressure from a 40° C. water bath and then diluted with ether (220 ml). The mixture was washed with water (100 ml), ice-cold 3N HCl until the washes remained acidic (2×100 ml), and saturated sodium bicarbonate (100 ml). After drying the organic solution (MgSO4), the solvent was removed to afford 41.73 g of a 91:9 mixture (1H NMR analysis) of the desired compound and the corresponding di-tosylate. The crude product solidified over several days at -20° C. to afford two crops (total 33.33 g: 61%) of the desired compound, 1-tosyloxy-2-hydroxy-3-butene, which was pure by TLC analysis, mp 38°-44° C. 1H NMR (300 MHz, CDCl3): 7.800 (2H, d, J=8.25 Hz); 7.356 (2H, d, J=8.19 Hz); 5.751 (1H, ddd, J=5.38, 10.46, 16.55 Hz); 5.378 (1H, br d, J=17.05 Hz); 5.247 (1H, br d, J=10.48 HZ); 4.396 (1H, m); 4.066 (1H, dd, J=3.39, 10.20 Hz); 3.906 (1H, dd, J=7.41, 10.22 Hz); 2.451 (3H, s); 2.276 (1H, d, J=4.50 Hz). IR (KBr, cm-1): 3520 (s,b); 1650 (w); 1600 (s); 1350 (s); 1170 (s). Combustion Analysis Calculated--C, 54.53; H, 5.82: N, O. Found --C, 54.84; H, 5.86; N, <0.3.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:40]=[CH:39][C:10]([CH2:11][C:12]2[S:16][C:15]([C:17]3[C:22]([Br:23])=[CH:21][N:20]=[C:19]([NH:24][CH2:25][CH2:26][N:27]4[C:31]([CH3:33])([CH3:32])[C:30](=[O:34])[NH:29][C:28]4=[O:35])[N:18]=3)=[CH:14][C:13]=2[CH2:36][CH2:37]O)=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+].[NH:52]1[CH2:56][CH2:55][CH2:54][C@H:53]1[CH2:57][OH:58]>ClCCl.O>[F:6][C:7]1[CH:40]=[CH:39][C:10]([CH2:11][C:12]2[S:16][C:15]([C:17]3[C:22]([Br:23])=[CH:21][N:20]=[C:19]([NH:24][CH2:25][CH2:26][N:27]4[C:31]([CH3:32])([CH3:33])[C:30](=[O:34])[NH:29][C:28]4=[O:35])[N:18]=3)=[CH:14][C:13]=2[CH2:36][CH2:37][N:52]2[CH2:56][CH2:55][CH2:54][C@H:53]2[CH2:57][OH:58])=[CH:9][CH:8]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc(CCO)c(Cc3ccc(F)cc3)s2)n1
Reactant: OC[C@@H]1CCCN1
Agent: CS(=O)(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc(CCN3CCC[C@H]3CO)c(Cc3ccc(F)cc3)s2)n1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Methanesulfonyl chloride (82 mg, 0.72 mmol) was added to a mixture of 1-(2-(4-(5-(4-fluorobenzyl)-4-(2-hydroxyethyl)thiophen-2-yl)-5-bromopyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidine-2,4-dione (200 mg, 0.36 mmol) and diisopropylethylamine (93 mg, 0.72 mmol) in dichloromethane (10 mL) at 0° C. After stirring at 0° C. for 5 h, the solvent was removed in vacuo and 5 mL of N-methylpyrrolidine, a catalytic amount of sodium iodide and (S)-pyrrolidin-2-ylmethanol (0.3 g, 2.97 mmol) were added. The mixture was heated at 100° C. for 15 h and then cooled to rt. 50 mL of water was added and the mixture extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the product purified by flash chromatography eluting with methanol (1M, ammonia)/dichloromethane (1:20) to give the title compound as a slightly yellow solid (105 mg, 46%). MS (M+H)+ 645/647.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:43])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:25](=[O:42])[C@@H:26]([NH:34]C(OC(C)(C)C)=O)[CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:43])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:25](=[O:42])[C@@H:26]([NH2:34])[CH2:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)[C@@H](N)CC1CCCCC1

Procedure:
A solution of 1-[2-(S)-[[2-(S)-[[(1,1-dimethylethoxy)-carbonyl]amino]-1-oxo-3-cyclohexylpropyl]amino]-4-methylpentyl]-L-proline 4-phenylbutylamide (62.8 mg, 104 mmol) in dichloromethane (5 mL) was treated with trifluoroacetic acid (3.0 mL). After TLC indicated the reaction was complete, the mixture was concentrated to a residue, taken up in fresh dichloromethane (10 mL) and washed with satd. aq. NaHCO3 and dried (MgSO4). The solution was concentrated to an oil and chromatographed with acidic silica to provide 48.8 mg of the the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](C)=[N:13][N:14]=[C:7]1[CH:6]=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].I([O-])(=O)(=O)=[O:24].[Na+]>[Ru](=O)=O>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:5](=[O:24])[C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=1[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[CH3:6]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1nnc2cc(-c3ccccc3F)c3cc(Cl)ccc3n12
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1F

Procedure:
In the manner given in Example 3, 7-chloro-1-methyl-5-(o-fluorophenyl)-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 2'-fluoro-5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone.