Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[NH:7][N:6]=[C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]=1.[F:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([NH:24][NH2:25])=O>C(Cl)(Cl)Cl.C1(C)C(C)=CC=CC=1.[O-2].[O-2].[Mn+4]>[F:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]1[N:7]2[N:6]=[C:5]([O:8][S:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)(=[O:11])=[O:10])[CH:4]=[C:3]2[CH:2]=[N:25][N:24]=1
Reactant: NNC(=O)c1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(CO)[nH]n2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Product: Cc1ccc(S(=O)(=O)Oc2cc3cnnc(-c4ccccc4F)n3n2)cc1
Temperature: 70 °C
Yield: 92.4 %

Procedure:
To a solution of toluene-4-sulfonic acid 5-hydroxymethyl-1H-pyrazol-3-yl ester (25 g, 93 mmol) in chloroform (800 ml) was added manganese dioxide (40.3 g, 465 mmol) and the suspension was heated at 70° C. for 14 h. The reaction mixture was filtered through sand/silica and the plug of silica was then washed several times with 10% methanol/dichloromethane. The combined filtrates were concentrated under vacuum to give crude aldehyde (25 g). Some of the crude aldehyde (2 g, 7.6 mmol) and 2-fluorobenzoic hydrazide (1.16 g, 7.6 mmol) were suspended in xylene (60 ml) and heated together at reflux for 3 h. After cooling, the solid formed was collected by filtration and dried under vacuum at 80° C. to afford 2.7 g (94%) of the condensation product as a light brown solid. Some of this condensation product, which existed in nmr solution as a mixture of isomers (1 g, 2.5 mmol), was dissolved in Dowtherm A (100 ml) and heated at 180° C. for 72 h. The whole reaction solution was cooled and eluted through a silica gel column using 0 to 15% ethyl acetate/dichloromethane to give the title compound as a light tan solid (0.614 g, 64%); 1H NMR (360 MHz, CDCl3) δ 2.46 (3H, s), 6.73 (1H, s), 7.18-7.35 (4H, m), 7.61 (1H, m), 7.71 (1H, m), 7.82 (2H, d, J 8.3 Hz), 9.33 (1H, s).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].C([O-])=O.[NH4+:23]>>[NH2:23][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11]
Reactant: [NH4+]
Reactant: O=C1CCC(N2Cc3c(Cl)cccc3C2=O)C(=O)N1
Agent: O=C[O-]
Product: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Yield: 85 %

Procedure:
A mixture of 3-(4-chloro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine (5 g) in ammonium formate (30 ml) was stirred by heating up slowly to reflux and then reacted under ammonia for 6˜8 hours. The reaction mixture concentrated to dryness under reduced pressure. Recrystallization from heated isopropanol gave 3.96 g of target yield. yield: 85%. Purity: 99.17%. mp: 251.6˜253.9° C.
Reaction SMILES: Cl.[F:2][C@@H:3]1[CH2:7][NH:6][C@@H:5]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=2[O:15][CH:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[CH2:4]1.C([O-])([O-])=O.[K+].[K+].F[C:28]1[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[N:32][CH:33]=1.O>CN(C=O)C>[F:2][C@@H:3]1[CH2:7][N:6]([C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[N:32][CH:33]=2)[C@@H:5]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=2[O:15][C@H:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[CH2:4]1
Reactant: Fc1ccc(OC2CCOC2)c([C@H]2C[C@H](F)CN2)c1
Reactant: O=[N+]([O-])c1ccc(F)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2C[C@@H](F)C[C@@H]2c2cc(F)ccc2O[C@H]2CCOC2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
To a solution of (2R,4S)-4-fluoro-2-(5-fluoro-2-((tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidine hydrochloride (4.74 g, 15.49 mmol) in dry DMF (20 ml), was added K2CO3 (4.85 g, 35.2 mmol) and stirred for 5 min at room temperature, then added 5-fluoro-2-nitropyridine (2.0 g, 14.08 mmol) under N2 atmosphere and stirred for 16 h at 80° C. After completion of reaction, poured the reaction mixture in ice cooled water and stirred for 10 min, solid precipitated was collected by filtration. Solid was dried under high vacuum to afford 5-((2R,4S)-4-fluoro-2-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidin-1-yl)-2-nitropyridine as yellow solid (5.1 g, yield: 93%) MS (ESI): 392.1 (M+H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]2=[N:8][CH:7]=1)CCC.Br[C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH:38]=[CH:37][CH:36]=[CH:35]2)=[N:32][CH:33]=1>>[N:34]1([C:31]2[CH:30]=[CH:29][C:28]([C:6]3[N:10]4[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[N:14][C:9]4=[N:8][CH:7]=3)=[CH:33][N:32]=2)[CH:38]=[CH:37][CH:36]=[CH:35]1
Reactant: Brc1ccc(-n2cccc2)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1ccn2c(-c3ccc(-n4cccc4)nc3)cnc2n1

Procedure:
3-Tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine was reacted with 5-bromo-2-(pyrrol-1-yl)pyridine by the method of Example 1 to afford 3-[2-(1H-pyrrol-1-yl)pyridin-5-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 6.42 (2H, m), 7.28 (1H, d, J 8), 7.52 (1H, dd, J 8 and 1), 7.58 (2H, m), 7.92 (1H, dd, J 8 and 2), 8.14 (1H, s), 8.64 (1H, dd, J 2 and 1), 8.74 (1H, d, J 8), m/z (ES+) 329, 330 (M++H).
Reaction SMILES: [CH3:1][NH2:2].[O:3]=[C:4]1[CH:9]=[C:8]([CH3:10])O[CH:6]=[C:5]1[O:11][CH2:12][C:13]([OH:15])=[O:14]>O>[CH3:1][N:2]1[C:8]([CH3:10])=[CH:9][C:4](=[O:3])[C:5]([O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6]1
Reactant: CN
Reactant: Cc1cc(=O)c(OCC(=O)O)co1
Solvent: O
Product: Cc1cc(=O)c(OCC(=O)O)cn1C
Reaction time: 3 h

Procedure:
To a stirred solution of 40% aqueous methylamine (9.0 ml) and water (9.0 ml) was added 2-(4-oxo-6-methyl-4H-pyran-3-yloxy)acetic acid (6.0 g) in small portions at room temperature. The mixture was stirred at the same temperature for 3 hours and concentrated. To the residue was added water (5 ml) and the mixture was adjusted to pH 3. The resulting precipitates were collected and washed with water to give crystals of 2-(1,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yloxy)acetic acid (1.53 g), mp 240° to 242° C. The filtrate and the washings were combined together and adsorbed on Amberlite IRA-400 (Tradename, prepared by Rohm and Haas Co.) and eluted with water and then 0.3 N hydrochloric acid. The hydrochloric acid fraction was concentrated and dried to give crystals (3.7 g) of 2-(1,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yloxy)acetic acid hyrochloride. The hydrochloride was dissolved in a small amount of water and the solution was adjusted to pH 3. The resulting crystals were collected by filtration and washed with water to give an additional amount of the same product (2.2 g) as obtained above.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[C:24]3[S:20][C:21](=[O:26])[NH:22][C:23]3=[O:25])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCC(O)c2cccc(Cl)c2)cc1
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccc(OCC(O)c3cccc(Cl)c3)cc2)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8937.6 %

Procedure:
To a stirring solution of 4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzaldehyde (1.08 g, 3.90 mmol) in absolute EtOH (50 mL) was added 2,4-thiazolidinedione (0.50 g, 4.29 mmol) and piperidine (0.42 mL, 4.3 mmol), and the resulting solution was heated to reflux and then stirred overnight at room temperature. The reaction mixture was evaporated in vacuo and the residue was dissolved in EtOAc. This solution was washed with aqueous HOAc (pH 5-6), brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was adsorbed onto silica gel and chromatographed eluting with 10-20% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 131 g (89%) of the product as a light yellow solid. MS (ESI+) for C18H14ClNO4S m/z 375.0 (M+H)+. MS (ESI−) for C18H14ClNO4S m/z 374.1 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:16][NH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:17]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH3:16])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CNCCN1CCCCC1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CN(CCN1CCCCC1)C(=O)Cc1ccc(Br)cc1
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a solution of 4-bromophenylacetic acid (10 g, 46.5 mmol) in CHCl3 (100 ml) was added thionyl chloride (8 ml) in CHCl3 (10 ml) and three drops of DMF. The mixture was reflux for one to two hours. The volatiles were removed in vacuo to give a light yellow oil. This acid chloride was dissolved in CHCl3 30 ml and added dropwise to another flask containing N-methyl-2-(1-piperidinyl)ethyl amine (6.1 g, 48 mmol) and triethylamine (25 ml) and CHCl3 (100 ml) at 0° C. The reaction mixture was stirred overnight at room. The volatiles were removed, the residue dissolved in CHCl3 (150 ml) and washed with (2×100 ml) water and 2% NaHCO3 (50 ml). The organic layer was dried and the volatiles were removed to give a light yellow oil (15.0 g). The oil was passed through a silica gel column and eluted with CHCl3 /MeOH to give 13 g, (87%) of the desired pure compound. 1H NMR 1.30-1.54 (m, 6 H, piperidinyl CH2); 2.33-2.43 (m, 6 H, NCH2); 2.92 (44%), 2.96 (56%) (s, 3 H, N-Me); 3.32-3.37 (46%), 3.45-3.49 (54%), (t, 2 H, J=7.1 Hz, NCH2); 3.61 (56%), 3.67 (44%), (s, 2 H, benzylic); 7.09-7.11 (d, 2 H, arom); 7.38-7.41 (d, 2 H, arom).
Reaction SMILES: [CH2:1]([S:5][C:6]1[NH:11][C:10](=O)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:15])=O>>[CH2:1]([S:5][C:6]1[N:11]=[C:10]([Cl:15])[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1nccc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCSc1nccc(Cl)n1
Temperature: 25 °C

Procedure:
A mixture of 2-butylsulfanyl-3H-pyrimidin-4-one (3.0 g) and phosphorus oxychloride (15 mL) was heated at reflux for 3 h; it was then cooled to RT and evaporated under reduced pressure. The residue was poured into an ice-water mixture, and the resulting mixture was extracted with DCM. The combined organic extracts were washed with a diluted aqueous solution of NaHCO3, dried over Na2SO4, filtered and evaporated under reduced pressure to give 1.2 g of 2-butylsulfanyl-4-chloro-pyrimidine.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].O.Cl>CCCCCC>[CH:6]([C:8]1([C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1=[O:14])=[CH:8][CH2:9][CH3:10]
Reactant: CCOC(=O)C1CCCCC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: CCC=CC1(C(=O)OCC)CCCCC1=O
Temperature: 25 °C
Yield: 186.4 %

Procedure:
Sodium hydride, 60% in mineral oil (8,3 g, 200 mmol) was washed with 2 portions of hexane and then dried under an N2 flow. This was suspended in dimethylformamide and ethyl 2-cyclohexanonecarboxylate (34.1 g, 200 mmol) was added slowly under N2 (note the foaming and exotherm), with cooling with a 25° C. water bath. After complete addition, the mixture was stirred at 25° C. for ~1 hour and the treagents added. The stirring mixture was heated to 50° C. for 18 hours (overnight). The reaction was then cooled to room temperature. The entire mixture was poured into water, neutralized with dilute HCl and extracted with two portions of 1:1 ether-hexane The combined organics were then washed with two portions of water followed by saturated brine, then dried over MgSO4, filtered and stripped giving 41.8 g of an impure mixture of products. Purification of the product by chromatography (silica gel, 5% methyl t-butyl ether/90% hexane) gave 28.4 g of the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([F:19])[C:12]=3[C:14]#[C:15][C:16]([CH3:18])=[CH2:17])[C:7](=[O:21])[C:6]([C:22]([O:24]CC)=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([F:19])[C:12]=3[C:14]#[C:15][C:16]([CH3:18])=[CH2:17])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C=C(C)C#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: C=C(C)C#Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 80.4 %

Procedure:
0.715 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-4-oxo-3-quinolinecarboxylate is refluxed for 1.5 hours in a mixture of 10 ml of glacial acetic acid, 0.5 ml of water and 0.2 ml of concentrated sulphuric acid. The reaction mixture is poured into 100 ml of water. The solid which has precipitated is filtered off with suction, washed with water and dried. 0.53 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-4-oxo-3-quinolinecarboxylic acid is obtained (80% of theory).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]([N:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])/[C:8]([O:10]CC)=[O:9])[N:6]=1.O.[OH-].[Na+]>CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]([N:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OCC(=O)N1CCCCCC1)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1nc(/C(=N/OCC(=O)N2CCCCCC2)C(=O)O)cs1
Yield: 81.4 %

Procedure:
68 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-[[(hexahydro-1H-azepin-1-yl)carbonyl]methoxy]imino]-acetate are dissolved in 2.5 l of methanol and 250 ml of water and the solution is treated with 220 ml of 1N aqueous sodium hydroxide solution. The methanol is removed under reduced pressure after 48 hours. The aqueous solution is washed with ethyl acetate and treated with 220 ml of 1N aqueous hydrochloric acid. The acid which crystallizes out is filtered off and dried. There are obtained 51 g of 2-(2-amino-4-thiazolyl)-2-[(Z)-[[(hexahydro-1H-azepin-1-yl)carbonyl]methoxy]imino]-acetic acid of melting point 178°-179° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH2:20][S:21][CH:22]=NN)[CH:14]=1)[C:10]([OH:12])=[O:11])[CH3:7])[CH3:2].C(OC(=O)C=C(NC(C1C=CC(O)=C(CSC2NCCN=2)C=1)C(O)=O)C)C>>[CH2:1]([O:3][C:4](=[O:25])[CH:5]=[C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH2:20][S:21][CH3:22])[CH:14]=1)[C:10]([OH:12])=[O:11])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C=C(C)NC(C(=O)O)c1ccc(O)c(CSC=NN)c1
Agent: CCOC(=O)C=C(C)NC(C(=O)O)c1ccc(O)c(CSC2=NCCN2)c1
Product: CCOC(=O)C=C(C)NC(C(=O)O)c1ccc(O)c(CSC)c1

Procedure:
In like manner and using the appropriate quantities of reagents, substitution of α-(3-ethoxy-1-methyl-3-oxo-1-propen-1-yl)amino-3-[[(aminoiminomethyl)thio]methyl]-4-hydroxybenzeneacetic acid; α-(3-ethoxy-1-methyl-3-oxo-1-propen-1-yl)amino-3-[[(4,5-dihydro-1H-imidazol-2-yl)-thio]methyl]-4-hydroxybenzeneacetic acid; or α-(3-ethoxy-1-methyl-3-oxo-1-propen-1-yl)amino-4-hydroxy-3-[(methylthio)methyl]benzeneacetic acid in place of α-(3-ethoxy-1-methyl-3-oxo-1-propen-1-yl)amino-3-(azidomethyl)-4-hydroxybenzeneacetic acid gives the following respective compounds: 6-[[Amino[3-[[(aminoiminomethyl)thio]methyl]-4-hydroxyphenyl]acetyl]amino]3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; 6-[[amino-3-[[[(4,5-dihydro-1H-imidazol-2-yl)thio]methyl]-4-hydroxyphenyl]acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; and 6-[[amino[4-hydroxy-3-[(methylthio)methyl]phenyl]acetyl]-amino]-3,3-dimethyl-7-oxo-5-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.ClC1C2C(=CC(O)=C(C#N)C=2)[N:27]=[CH:26]C=1.OCCCN1CCN(C)CC1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][N:27]([CH3:26])[CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1O
Agent: CN1CCN(CCCO)CC1
Product: CN1CCN(CCCOc2cc3nccc(Cl)c3cc2C#N)CC1
Yield: 90 %

Procedure:
Using an analogous procedure to that described for the preparation of 4-chloro-6-cyano-7-(3-(pyrrolidin-1-yl)propoxy)quinoline, (starting material in Example 11), 4-chloro-6-cyano-7-hydroxyquinoline (8.2 g, 40 mmol), (prepared as described for the starting material in Example 1), was reacted with 1-(3-hydroxypropyl)-4-methylpiperazine (7.6 g, 48 mmol) to give 4-chloro-6-cyano-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline (12.4 g, 90%).
Reaction SMILES: CO[C:3]1([CH2:10][CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][C:17]([O:22]C)([O:20]C)OC)[CH:7]=[CH:6][CH:5]([O:8]C)O1.O.P([O-])(O)(O)=[O:26].[Na+].O1CCOCC1.S(=O)(=O)(O)O>P([O-])([O-])(O)=O.[Na+].[Na+].O>[OH:26][CH:7]1[CH2:6][C:5](=[O:8])[C:10]([CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][C:17]([OH:20])=[O:22])=[CH:3]1
Reactant: O=P([O-])(O)O
Reactant: COC1C=CC(CCC#CCCCC(OC)(OC)OC)(OC)O1
Agent: O=P([O-])([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCC#CCC1=CC(O)CC1=O
Temperature: 50 °C
Yield: 112.5 %

Procedure:
A stirred mixture of 7.1 g of 2,5-dihydro-2,5-di- methoxy-2-(8,8,8-trimethoxy-3-octynyl)furan, 2.76 g of sodium dihydrogen phosphate monohydrate, 140 mg of disodium hydrogen phosphate, 60 ml of dioxane and 40 ml of water was boiled under reflux for 19 hours, then cooled to 50° C. and treated dropwise with 4.1 ml of concentrated sulfuric acid. The resulting solution was boiled under reflux for 12 hours, cooled and partitioned with ether and brine. The ether layer was separated, washed with brine, dried and concentrated, giving 5.0 g of crude 7-(4-hydroxycyclopent-2-en-1-on-2-yl)-5-heptynoic acid. This crude product was dissolved in 40 ml of pyridine and the stirred solution treated at 0° to 10° C. with 10.5 ml of hexamethyldisilizane followed by 6.3 ml of chlorotrimethylsilane. The resulting mixture was stirred at 25° C. for 3 hours and then concentrated to dryness at 30° C. The residue was extracted with hexane, the extract filtered through diatomaceous earth and concentrated. The residue was distilled at 0.11 mm on a Kugelrohr at 155°-170° C., giving 1.66 g of the desired compound as an oil.
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.NC1C=CC=CC=1>C1C=CC=CC=1>[C:14]1([N:13]2[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C:10]2=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCC(c2ccccc2)O1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: c1ccccc1
Product: O=C1CCC(c2ccccc2)N1c1ccccc1
Temperature: 180 °C
Reaction time: 5 h
Yield: 85.1 %

Procedure:
To 20 g of 4-phenyl-γ-butyrolactone were added 28 g of aniline and 7.6 g of aniline hydrochloride, and the mixture was heated with stirring at 180° C. for 5 hours while evaporating the water formed. After cooling, 200 ml of benzene was added, and the mixture was washed with 10% hydrochloric acid and a saturated aqueous sodium chloride solution and dried. After removal of the solvent, the residue was recrystallized from ethyl acetate to give 24.9 g of 1,5-diphenyl-2-pyrrolidone.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([C:11]#[N:12])=[C:9]([NH:13][CH:14]2[CH2:16][CH2:15]2)[N:8]=[C:7]([NH:17][C:18]([C:21]#[N:22])([CH3:20])[CH3:19])[N:6]=1>CO>[C:21]([C:18]([NH:17][C:7]1[N:6]=[C:5]([O:2][CH3:1])[C:10]([C:11]#[N:12])=[C:9]([NH:13][CH:14]2[CH2:16][CH2:15]2)[N:8]=1)([CH3:20])[CH3:19])#[N:22]
Reactant: C[O-]
Reactant: CC(C)(C#N)Nc1nc(Cl)c(C#N)c(NC2CC2)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(NC(C)(C)C#N)nc(NC2CC2)c1C#N
Reaction time: 16 h
Yield: 59.5 %

Procedure:
To a stirred solution of 0.8 gram of sodium methoxide in 100 ml of methanol was added portionwise 4.2 grams of 4-chloro-2-(1-cyano-1-methylethylamino)-6-cyclopropylamino-5-pyrimidinecarbonitrile. Upon complete addition, the reaction mixture was heated under reflux for 3.5 hours, then allowed to stand at room temperature for 16 hours. The methanol was removed by evaporation under reduced pressure. The residue was extracted with a mixture of water and methylene chloride. The methylene chloride layer was separated and dried over magnesium sulfate. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was recrystallized twice from carbon tetrachloride to give 2.4 grams of 2-(1-cyano-1-methylethylamino)-6-cyclopropylamino-4-methoxy-5-pyrimidinecarbonitrile; mp, 138°-140°.
Reaction SMILES: C(O)C.[BH4-].[Na+].[Cl-].[Ca+2].[Cl-].[CH3:9][C:10]([OH:37])([CH2:12][CH2:13][CH2:14][C@H:15]([C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24]([CH2:25][C:26](=[O:36])[CH:27]=[CH:28]2)=[CH:23][CH:22]=3)[CH2:19][CH2:18]1)[CH3:16])[CH3:11]>C(O)(=O)C.CCOCC.CO>[CH3:9][C:10]([OH:37])([CH2:12][CH2:13][CH2:14][C@H:15]([C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24]([CH2:25][C@@H:26]([OH:36])[CH:27]=[CH:28]2)=[CH:23][CH:22]=3)[CH2:19][CH2:18]1)[CH3:16])[CH3:11]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CO
Solvent: CCOCC
Solvent: CC(=O)O
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 10 °C
Reaction time: 0.33 h

Procedure:
100 ml of an ethanol solution containing 2.5 g of sodium borohydride was added dropwise under agitation to 110 ml of methanol containing 4.9 g of calcium chloride, which was cooled below - 10° C. The mixture was agitated for 20 minutes while maintaining the temperature at about -10° C. Then, 100 ml of the ether solution containing crude cholesta-1,5,7-trien-3-on-25-ol, which was prepared in (1.) above, was added dropwise to the above mixture. The reaction mixture was further agitated at -10° C. for 1 hour and at 0° C. for 1 hour, and was then neutralized with 10% acetic acid after which the solvent was distilled off under reduced pressure. The residue was extracted with methylene chloride and the extract was washed with water and dried with magnesium sulfate. Methylene chloride was distilled off to obtain crude cholesta-1,5,7-triene-3β,25-diol (about 1 g).
Reaction SMILES: NC1C=CC(N2CCCN(C(OC(C)(C)C)=O)CC2)=CC=1N.[F:23][C:24]1[CH:25]=[C:26]([S:30]([Cl:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.[NH2:34][C:35]1[CH:40]=[C:39]([N:41]2[CH2:47][CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]2)[CH:38]=[CH:37][C:36]=1[NH:55][S:56]([C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([F:65])[CH:60]=1)(=[O:58])=[O:57].FC1C=C(S(N)(=O)=O)C=CC=1.Cl.CCOCC>CO>[ClH:33].[N:41]1([C:39]2[CH:38]=[CH:37][C:36]([NH:55][S:56]([C:59]3[CH:64]=[CH:63][CH:62]=[C:61]([F:65])[CH:60]=3)(=[O:57])=[O:58])=[C:35]([NH:34][S:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=3)(=[O:32])=[O:31])[CH:40]=2)[CH2:47][CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(NS(=O)(=O)c3cccc(F)c3)c(N)c2)CC1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(N)c2)CC1
Agent: Cl
Agent: NS(=O)(=O)c1cccc(F)c1
Solvent: CO
Solvent: CCOCC
Product: O=S(=O)(Nc1ccc(N2CCCNCC2)cc1NS(=O)(=O)c1cccc(F)c1)c1cccc(F)c1
Reaction time: 0.5 h

Procedure:
The compound was prepared from 2-amino-5-(4-t-butyloxycarbonyl-1-homopiperazinyl)aniline and 3-flourobenzenesulfonyl chloride. Purification by column chromatography (CH2Cl2/MeOH/heptane, 4:1:15) gave a mixture of N-{2-amino-4-[4-t-butyloxycarbonyl-homopiperazin-1-yl-]phenyl}3-fluorobenzenesulfonamide and N-{4-[4-t-butyloxycarbonyl]homopiperazinyl)-2-[(3-flourophenylsulfonyl)amino]phenyl}-3-fluorobenzenesulfonamide (0.180 g, 73%). Boc-deprotection was achieved by dissolving the mixture in small amount of MeOH and adding HCl/ether. The mixture was let at r.t. for 0.5 h. Purification by preparative HPLC gave N-(4-(1,4-diazepan-1-yl)-2-{[(3-fluorophenyl)sulfonyl]amino}phenyl)-3-fluorobenzenesulfonamide hydrochloride Anal. (C23H27ClN4O4S2) C, H, N, S.; M+524.4 Calcd 522.12.