Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([CH2:19][C:20]#[N:21])=[CH:18][C:13]=2[O:12][CH2:11]1.CC(C)([O-])C.[K+].Cl[CH2:29][C:30]([O:32][CH3:33])=[O:31].Cl>CN(C)C=O.C1(C)C=CC=CC=1.CCCCCCC>[CH3:33][O:32][C:30]([C:29]1[C:19]([C:17]2[CH:16]=[CH:15][C:14]3[O:10][CH2:11][O:12][C:13]=3[CH:18]=2)([C:20]#[N:21])[C:2]2[C:3]([C:4]=1[NH2:5])=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:31]
Reactant: N#CCc1ccc2c(c1)OCO2
Reactant: N#Cc1ccccc1Cl
Reactant: COC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: COC(=O)C1=C(N)c2ccccc2C1(C#N)c1ccc2c(c1)OCO2
Yield: 79 %

Procedure:
A mixture of 2-chlorobenzonitrile (12.3 g) and benzo[1,3]dioxol-5-yl-acetonitrile (10 g) in dimethylformamide (25 mL) was added with stirring and cooling in an ice bath to potassium tert-butoxide (20.1 g) dissolved in dimethylformamide (50 mL) at such a rate that the temperature did not exceed 25° C. After stirring for 0.5 h, methyl chloroacetate (11.1 g) was added in 10 min. After being stirred for 24 h at rt, the mixture was poured into a mixture of 0.1 M HCl (200 mL), heptane (30 mL) and toluene (15 mL). Stirring for 1 h, filtration and washing with water (2×50 mL), toluene (2×10 mL) and heptane (2×25 mL) afforded 79% of 3-Amino-1-benzo[1,3]dioxol-5-yl-1-cyano-1H-indene-2-carboxylic acid methyl ester.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]=[C:35]([C:41](=[O:45])[CH2:42][CH2:43][CH3:44])[C:36]([O:38]CC)=O)=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:28]=[C:29]2[C:30](=[CH:31][CH:32]=1)[N:33]=[CH:34][C:35]([C:41](=[O:45])[CH2:42][CH2:43][CH3:44])=[C:36]2[OH:38]
Reactant: CCCC(=O)C(=CNc1ccc(Br)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCCC(=O)c1cnc2ccc(Br)cc2c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 187.9 %

Procedure:
To Dowtherm (82 mL) at 250° C. was added ethyl 2-(((4-bromophenyl)amino)methylene)-3-oxohexanoate (700 mg, 6.75 mmol) portionwise and the reaction mixture was stirred for 1.5 h. The reaction mixture was cooled to room temperature, and the precipitate was filtered and rinsed with hexanes to afford the desired product (3.73 g, 53%) as a light brown solid. ESI MS m/z 294 [C13H12BrNO2+H]+
Reaction SMILES: Cl[C:2]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH:6](C(OCC)=O)[CH:5]=[CH:4][S:3]1.Cl.[NH2:17][CH2:18][CH:19]([SH:21])[CH3:20].[O-:22][CH2:23]C.[Na+]>>[CH3:20][CH:19]1[CH2:18][NH:17][C:23](=[O:22])[C:5]2[CH:6]=[C:2]([S:12](=[O:13])(=[O:14])[NH2:15])[S:3][C:4]=2[S:21]1
Reactant: CCOC(=O)C1C=CSC1(Cl)S(N)(=O)=O
Reactant: CC(S)CN
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CC1CNC(=O)c2cc(S(N)(=O)=O)sc2S1
Yield: 51 %

Procedure:
Following the procedure described in Example 1, Step E, 2-chloro-3-carboethoxythiophene-2-sulfonamide was reacted with 1-amino-2-propanethiol hydrochloride in the presence of four equivalents of sodium ethoxide to give, after recrystallization from ethyl acetate, a 51% yield of title compound, mp 199°-201° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[NH2:17][OH:18]>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([NH:17][OH:18])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: NO
Agent: Cl
Product: CCCNc1nc(NO)nc(NCCC)n1

Procedure:
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLV) was prepared from 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and hydroxylamine hydrochloride as described in Example 13 (99% yield). 400 MHz 1H NMR (DMSO-d6, ppm) 9.0-8.6 (1H, br s), 8.39-8.14 (1H, s), 6.89-6.55 (2H, m), 3.23-3.06 (4H, m), 1.54-1.40 (4H, m), 0.84 (6H, t, J=7.4 Hz). ESI-MS (m/z): 227 [M+H]+. MP: 138-141° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[N:11]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(N)ccc1Br
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(NN)ccc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-Bromo-3-methoxyaniline (3.0 g, 14.85 mmol) was suspended in concentrated HCl (50 mL) and the mixture was cooled to 0° C. in the ice-water bath. A solution of sodium nitrite (1.23 g, 17.82 mmol) in 10 mL water was added very slowly to the reaction mixture. The mixture turned yellow, then brown with a yellow haze indicating diazotization. The diazonium salt was held at 0° C. for an hour and then a solution of tin(II) chloride dihydrate (10.05 g, 44.5 mmol) in concentrated HCl (20 mL) was added very slowly (caution, extremely exothermic). The reaction was stirred for 2 h at 0° C. then at RT overnight. The reaction was filtered and the filter cake was washed with cold H2O to afford (4-bromo-3-methoxyphenyl)hydrazine as a tan solid (3.1 g, MS: 218 [M+H+]).
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[C:9]([C:11](=[O:32])[NH:12][C:13]2[CH:14]=[N:15][C:16]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH:18]=2)[CH:8]=[N:7][CH:6]=1)C.C1COCC1.CO>O>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[CH:18]=[C:13]([NH:12][C:11]([C:9]3[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=3)[C:4]([OH:33])=[O:3])=[O:32])[CH:14]=[N:15][C:16]=2[O:26][CH2:27][C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cncc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)c1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cncc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)c1
Reaction time: 4 h

Procedure:
5-[5-(4-Chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylcarbamoyl]-nicotinic acid ethyl ester (510 mg, 1.06 mmol) was combined with THF (25 mL), methanol (5 mL) and water (5 mL) to give a light yellow suspension. The reaction mixture was stirred for 4 h, and concentrated in vacuo. The reaction mixture was poured into 100 mL ethyl acetate and extracted with 1 M HCl (1×25 mL) and brine (1×25 mL). The aqueous layer phases were extracted with ethyl acetate (1×50 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 100% ethyl acetate in heptane) to deliver 0.17 g (48.7%) of the title compound as white solid; MS (ESI) 450.0(M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[N:12]([C:13](=[O:17])[CH2:14][CH2:15][SH:16])[C@H:11]([C:18]([OH:20])=[O:19])[CH2:10][S:9]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C.[CH2:32]([N:35]([CH2:48][CH2:49][CH3:50])[S:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1)(=[O:38])=[O:37])[CH2:33][CH3:34]>O>[CH2:48]([N:35]([CH2:32][CH2:33][CH3:34])[S:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43]([S:16][CH2:15][CH2:14][C:13]([N:12]2[C@H:11]([C:18]([OH:20])=[O:19])[CH2:10][S:9][C@@H:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])=[O:17])=[O:44])=[CH:41][CH:40]=1)(=[O:38])=[O:37])[CH2:49][CH3:50]
Reactant: O=C(O)[C@@H]1CS[C@H](c2ccccc2O)N1C(=O)CCS
Reactant: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)SCCC(=O)N2[C@@H](c3ccccc3O)SC[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
9.7 g of (2R,4R)--2--(2--hydroxyphenyl) --3--(3--mercaptopropionyl)--4--thiazolidinecarboxylic acid and 12.9 g of potassium carbonate are dissolved in 80 ml of water, and 40 ml of ethyl ether solution of 9.4 g of 4--(dipropylsulfamoyl)benzoyl chloride is added dropwise under ice-cooling. After the addition the reaction mixture is stirred for 1 hour under ice-cooling and for another 1 hour at room temperature. Ether is removed in vacuo and residual solution is adjusted to pH 1 with 6N hydrochloric acid. Produced oily residue is extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give 10.5 g of the titled compound as amorphous powder.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:4][CH:3]=1.[Li]CCCC.C([C:22]([O:24][CH2:25][CH3:26])=[O:23])#N>C1COCC1.CCOC(C)=O>[CH2:25]([O:24][C:22]([C:5]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[C:2]([CH3:1])=[CH:3][N:4]=1)=[O:23])[CH3:26]
Reactant: Cc1cncn1COCC[Si](C)(C)C
Reactant: CCOC(=O)C#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc(C)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of 5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (as prepared in the previous step, 0.320 g, 1.50 mmol) in 5 mL of THF at −78° C. was added n-BuLi (0.80 mL, 2 M in cyclohexane) and the mixture was allowed to attain RT and stirred for 30 min. The mixture was cooled to −78° C. and ethyl cyanoformate (0.160 g, 1.65 mmol) was added and the mixture allowed to stir for 10 h at RT. The reaction was diluted with 15 mL of EtOAc and washed with NaHCO3 (2×15 mL) and brine (15 mL). The title compound was eluted from a 20-g SPE with 50% EtOAc/hexanes to give 0.160 g (38%) of a light brown oil: Mass spectrum (ESI, m/z): Calcd. for C13H24N2O3Si, 285.2 (M+H), found 284.9.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[C:13]([C:15]1[C:16]([NH:33][C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([Cl:42])=[CH:36][C:35]=2[Cl:43])=[C:17]2[S:23][C:22]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=3)=[CH:21][C:18]2=[N:19][CH:20]=1)#[N:14]>CN(C)C=O>[C:13]([C:15]1[C:16]([NH:33][C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([Cl:42])=[CH:36][C:35]=2[Cl:43])=[C:17]2[S:23][C:22]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH2:3])=[O:30])=[CH:26][CH:25]=3)=[CH:21][C:18]2=[N:19][CH:20]=1)#[N:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C(=O)O)cc4)sc23)c(Cl)cc1Cl
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C(N)=O)cc4)sc23)c(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 9.4 %

Procedure:
1,1′-Carbonyldiimidazole (100 mg, 0.61 mmol) is added to a suspension of 4-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-yl]benzoic acid (130 mg, 0.28 mmol) in 10 mL of N,N-dimethylformamide. After stirring at 60° C. for 2 hours the reaction mixture is allowed to cool to room temperature and ammonia gas is bubbled through the mixture for 15 minutes. The mixture is stirred at room temperature for an additional 60 minutes and poured into 50 g of ice and stirred for 30 minutes. The mixture is adjusted to pH 4 with concentrated hydrochloric acid and stirred for 60 minutes. The resulting precipitate is collected by filtration washing with water and dried under reduced pressure. The resulting solid is purified by flash column chromatography eluting with a gradient of ethyl acetate to 20% methanol in ethyl acetate to provide 12.3 mg of 4-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-yl}benzamide as a gray solid, mp>300° C.; 1H NMR (DMSO-d6) δ3.86 (s, 3H), 7.40 (s, 1H), 7.48 (s, 1H), 7.78 (s, 1H), 7.82 (d, J=8 Hz, 2H), 7.97 (d, J=8 Hz, 2H), 8.06 (s, 2H), 8.08 (s, 1H), 8.63 (s, 1H), 9.78 (s, 1H); MS 468.9, 471.1 (M+H)+.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)=[C:6]([O:20][CH3:21])[CH:5]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CN(C=[O:34])C>O.C(OCC)(=O)C>[CH3:21][O:20][C:6]1[CH:5]=[C:4]([CH2:3][C:2]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[O:34])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(-c2ccc(C=C(Br)Br)cc2OC)cc1
Reactant: CN1CCNCC1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(CC(=O)N3CCN(C)CC3)cc2OC)cc1

Procedure:
A mixture of Example 328A (213 mg, 0.5 mmol), 1-methylpiperazine (2.5 mmol), and bis(tricyclohexylphosphine)palladium chloride (0.0025 mmol) in DMF (1.5 mL) and water (0.25 mL) was heated to 80° C. for 8 hours, diluted with ethyl acetate (100 mL), washed with water (45 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silical gel with 2-10% methanol/dichloromethane to provide the desired product.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:19]1([CH:27]=O)[C:20]([CH:25]=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.C(O)(=O)C>ClCCl>[O:26]=[C:25]1[C:20]2[C:19](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][N:1]1[CH:2]([C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=Cc1ccccc1C=O
Reactant: COc1cc(C(N)CC(=O)O)cc(OC)c1OC
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
3-Amino-3-(3,4,5-trimethoxy-phenyl)-propionic acid (3.66 mmol, 1 eq), benzene-1,2-dicarbaldehyde (1 eq) and acetic acid (16 eq) are suspended in dichloromethane and refluxed for 2 h. The filtrate is concentrated in vacuo, dissolved in DCM and extracted with water. The organic phase is reduced under vacuum. The resulting oil is suspended in 1 M NaOH and stirred for 30 min at room temperature. The solution is washed with EtOAc and the aqueous phase is acidified with 1 M HCl (pH 2) and extracted with EtOAc. The organic phase is reduced under vacuum, dissolved in DCM and 3-(4-(hydrazinosulfonyl)phenyl)propionyl AM resin is added. The suspension is shaken at rt for 16 h. The filtrate is concentrated in vacuo, dissolved in DMSO and purified by prep. LC/MS (reversed phase). 3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionic acid is obtained as a clear colourless film (20% yield); ES-MS (MH+)=372.0; mp. 162-164° C.; 1H-NMR (DMSO-d6, 300 MHz): δ [ppm] 12.37 (br s, 1H), 7.69 (d, 1H, 7.6 Hz), 7.62-7.45 (m, 3H), 6.70 (s, 2H), 5.68 (t, 1H, 7.9 Hz); 4.53 (d, 1H, 17.9 Hz), 4.20 (d, 1H, 17.9 Hz), 3.76 (s, 6H), 3.63 (s, 3H), 3.14 (d, 2H, 7.9 Hz).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)#[CH:15].C(#N)C>COCCOC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]#[C:15][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:17][CH:18]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COCCOC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2nccs2)cc1
Yield: 3.9 %

Procedure:
2-Bromo-1,3-thiazole (1.0 g, 6.2 mmol) and CuI (152.4 mg, 0.8 mmol) were combined in DME (17 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (3 mL, 21 mmol) and PdCl2(PPh3)2 (280 mg, 0.40 mmol) were added and 1-ethynyl-4-fluorobenzene (500 mg, 4.2 mmol) was added dropwise. The reaction was heated under reflux for 4 h at which time GC/MS showed the reaction was complete. The mixture was filtered through Celite™, and the filter pad was washed thoroughly with Ethyl acetate. The combined filtrates were then concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane then 98:2 hexane:ethyl acetate to 2-[(4-fluorophenyl)ethynyl]-1,3-thiazole as a white solid which was impure by 1H NMR analysis. The compound (280 mg) was dissolved in DMSO and purified by preparative HPLC with a 30 min gradient from 60:40 water:acetonitrile to 100% acetonitrile to afford 2-[(4-fluorophenyl)ethynyl]-1,3-thiazole (33 mg, 3% yield) as a white solid. M.p. 78–79° C. 1H NMR (CDCl3, 300 MHz) δ 7.83 (d, J=3.0 Hz, 1H), 7.60–7.55(m, 2H), 7.39 (d, J=3.0 Hz, 1H), 7.14–7.00 (m, 2H). MS (ESI) 204 (M++H).
Reaction SMILES: [OH:1][C@H:2]([CH2:18][OH:19])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[N:8][C:7]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[N:15][C:6]1=2.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>ClCCl.O>[CH3:46][C:36]1[CH:41]=[CH:40][C:39]([S:42]([O:19][CH2:18][C@@H:2]([OH:1])[CH2:3][CH2:4][N:5]2[C:10](=[O:11])[CH:9]=[N:8][C:7]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[N:15][C:6]2=3)(=[O:44])=[O:43])=[CH:38][CH:37]=1
Reactant: COc1ccc2ncc(=O)n(CC[C@H](O)CO)c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CC[C@H](O)COS(=O)(=O)c3ccc(C)cc3)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.8 %

Procedure:
In dichloromethane (4 ml) was dissolved 4-[(3S)-3,4-dihydroxybutyl]-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (200 mg, 0.754 mmol), and triethylamine (0.126 ml, 0.905 mmol), dimethylamino pyridine (18.4 mg, 0.151 mmol) and p-toluene sulfonyl chloride (158 mg, 0.829 mmol) were added thereto under cooling on ice and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, water was added to the reaction solution which was extracted with dichloromethane. After drying the extract with anhydrous sodium sulfate, the solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 227 mg (72%) of the title compound in the form of a yellow oily product.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12](OCC)=[O:13])=[CH:4][C:3]=1[Cl:17].O.[NH2:19][NH2:20]>C(O)C>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([NH:19][NH2:20])=[O:13])=[CH:4][C:3]=1[Cl:17]
Reactant: NN
Reactant: CCOC(=O)c1cc(Cl)c(N)c2c1OCCO2
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc(Cl)c(N)c2c1OCCO2

Procedure:
38.4 g (0.149 mol) of ethyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylate suspended in 150 ml of ethanol are introduced into a 1 l reactor, 149 g (2.98 mol) of hydrazine hydrate are added, over 15 min, and the mixture is refluxed for 1 h.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH:18]=1)([O-])=O.[H][H]>C(O)C.Cl.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]1
Reactant: [H][H]
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Yield: 147.1 %

Procedure:
To a solution of 38.2 gm (145 mMol) 5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 1.9 L ethanol and 30 mL 5N HCl were added 10.0 gm 5% palladium on carbon. The reaction mixture was hydrogenated at ambient for 18 hours with an initial hydrogen pressure of 60 p.s.i. The reaction mixture was filtered and then concentrated under reduced pressure. The residue was dissolved in methanol and the solution filtered. This filtrate was concentrated under reduced pressure and the residue redissolved in ethanol. The solution was concentrated to about 500 mL and product allowed to crystallize. The crystals were filtered to give 48.9 gm (95%) of the title compound as its dihydrochloride salt, ethanol solvate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=3)[C:16]([S:26][CH3:27])=[CH:15]2)=[N:12][CH:13]=1.CN(C([O:35]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:50]1[CH2:54][CH2:53][C@@H:52]([CH2:55][OH:56])[CH2:51]1.ClC1C=C(C=CC=1)C(OO)=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([N:50]4[CH2:54][CH2:53][C@@H:52]([CH2:55][OH:56])[CH2:51]4)=[O:24])[CH:21]=3)[C:16]([S:26]([CH3:27])=[O:35])=[CH:15]2)=[N:12][CH:13]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CSc1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Reactant: OC[C@@H]1CCNC1
Agent: F[B-](F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CC[C@@H](CO)C3)ccc12

Procedure:
Prepared from 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylthio)-1H-indole-6-carboxylic acid in two reaction steps comprising a TBTU mediated amide coupling with (R)-pyrrolidin-3-ylmethanol (see also procedure 244c) and an oxidation utilizing m-chloroperoxybenzoic acid as oxidizing agent. Yellow solid. Yield: 0.12 g
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29].O>C1(C)C=CC=CC=1.C1COCC1>[F:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[CH:11]/[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 130.1 mg (3.25 mmol) of sodium hydride were initially charged in 2 ml of toluene and 2 ml of THF. The mixture was cooled to 0° C., and 857.7 mg (3.40 mmol) of tert-butyl (diethoxyphosphoryl)acetate were added slowly. The mixture was stirred for another 30 min, and 500 mg (2.96 mmol) of 4-fluoro-3-nitrobenzaldehyde were then added. The reaction mixture was slowly warmed to RT and stirred for 3 h. The reaction mixture was then added to water and extracted three times with ethyl acetate. The organic phase was concentrated under reduced pressure and the residue purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 30:1→10:1). This gave 543 mg (69% of theory) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:3].[H-].[Na+].[CH2:15]([N:17]=[C:18]=[O:19])[CH3:16]>O1CCCC1>[CH2:15]([NH:17][C:18]([O:12][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[N:5]=[CH:4][N:2]([CH3:1])[CH3:3])=[O:19])[CH3:16]
Reactant: CCN=C=O
Reactant: CN(C)C=Nc1ccncc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)Oc1cnccc1N=CN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a warm solution of 4-[[(dimethylamino)methylene]amino]-3-pyridinol (7.12 g) in dry tetrahydrofuran (150 mL) were added sodium hydride (173 mg) and ethyl isocyanate (3.59 mL). The reaction mixture was stirred at room temperature overnight, cooled in an ice bath and filtered, and the solid was washed with diethyl ether. The solid was distributed between methylene chloride (250 mL) and saturated ammonium chloride (30 mL) and extracted twice more with methylene chloride (100 mL). The solution was dried (MgSO4) and concentrated, and the solid was recrystallized from ethyl acetate to yield 5.7 g of needles, m.p. 138° C. (dec.).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][S:8][CH2:9][CH2:10][C:11]2[O:12][C:13]([CH2:16][N:17]([CH3:19])[CH3:18])=[CH:14][CH:15]=2)C(=O)C2=CC=CC=C12.NN.[C:28]([N:30]=[C:31]([S:34][CH3:35])SC)#[N:29]>>[C:28]([NH:30][C:31](=[N:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][C:11]1[O:12][C:13]([CH2:16][N:17]([CH3:18])[CH3:19])=[CH:14][CH:15]=1)[S:34][CH3:35])#[N:29]
Reactant: CSC(=NC#N)SC
Reactant: CN(C)Cc1ccc(CCSCCN2C(=O)c3ccccc3C2=O)o1
Agent: NN
Product: CSC(=NCCSCCc1ccc(CN(C)C)o1)NC#N

Procedure:
When 1-phthalimido-2-[2-(5-dimethylaminomethyl-2-furyl)ethylthio]ethane is treated with hydrazine and the resultant substituted ethylamine is reacted with dimethyl cyanodithioimidocarbonate there is produced N-cyano-N'-{2-[2-(5-dimethylaminomethyl-2-furyl)ethylthio]ethyl}-S-methylisothiourea, and when this is reacted with propargylamine according to the general procedure of Example 3 the title compound is produced.