Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[N:8]/[CH:9]([CH3:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][NH:8][CH:9]([CH3:12])[CH2:10][OH:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=N/C(C)CO)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNC(C)CO)cc1
Temperature: -5 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed a solution of (E)-2-(4-methoxybenzylideneamino)propan-1-ol (15 g, 77.72 mmol, 1.00 equiv) in methanol (150 mL). This was followed by the addition of NaBH4 (5.88 g, 155.56 mmol, 2.00 equiv) in several batches at −10-0° C. The resulting solution was stirred for 2 hs at −10-0° C. in an ice/salt bath. The resulting mixture was concentrated under vacuum and diluted with 200 mL of water. The resulting aqueous solution was extracted with 3×100 mL of ethyl acetate and the organic layers was combined and dried over anhydrous magnesium sulfate, concentrated under vacuum. This resulted in 11.1 g (73%) of 2-(4-methoxybenzylamino)propan-1-ol as a white solid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>S(Cl)(Cl)=O>[CH3:6][C:7]1[NH:8][CH:9]=[C:10]([S:2]([Cl:1])(=[O:5])=[O:3])[N:11]=1
Reactant: Cc1ncc[nH]1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: Cc1nc(S(=O)(=O)Cl)c[nH]1
Temperature: 150 °C
Yield: 40 %

Procedure:
Carefully add chlorosulfonic acid (30 mL) to neat 2-methylimidazole (5 g, 60.9 mmol). Heat the mixture at 150° C. for 3 h and cool to room temperature. Add thionyl chloride (10 mL), heat at 100° C. for 3 h and cool to room temperature. Carefully pour the mixture into ice. Slowly add solid sodium carbonate to neutralize the solution. Filter the precipitate formed and wash with water. Dry the solid under high vacuum overnight at 45° C. to give the desired intermediate (4.38 g, 40%). MS (ES+) m/z: 181 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:13][CH2:12][O:11][C:9](=[O:10])[CH2:8][CH2:7]1.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C)C=O>[Si:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:13][CH2:12][O:11][C:9](=[O:10])[CH2:8][CH2:7]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC(CCCCO)CCO1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCC1CCOC(=O)CC1
Reaction time: 16 h

Procedure:
To a solution of 8.77 g (47 mmol) of 4-(4-hydroxybutyl)-epsilon-caprolactone (example 28) in 52 ml dry dimethylformamide is added 6.16 g (90 mmol) of imidazole followed by 11.1 g (71 mmol) of t-butyldimethylsilyl chloride (97% pure) and then the mixture is stirred for 16 h. The reaction mixture is poured into water and extracted twice with ether. The combined organic extracts are washed twice with water, brine, dried, filtered and concentrated to give an oil which is purified by flash chromatography using 3:2 hexane/ether to yield 4-(4-t-butyldimethylsilyloxybutyl)-epsilon-caprolactone as an oil; NMR (CDCl3): delta 4-4.3 (m,2H), 3.6 (t,2H), 0.88 (s,9H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]>>[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([N:4]5[CH2:5][CH2:6][CH2:7][CH:3]5[CH2:2][OH:1])[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: OCC1CCCN1
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(N5CCCC5CO)n4)cc3)cc12

Procedure:
Using 2-(hydroxymethyl)-pyrrolidine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 467 (M+H)+.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:17][C:16]([C@@H:11]2[CH2:12][S:13][CH2:14][CH2:15][N:10]2[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])=[O:18])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 110.7 %

Procedure:
0.200 g (0.6 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.190 g (1.0 mmol) of 4-nitrobenzyl alcohol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:9) to obtain the product as a oil (0.29 g).
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:16]=[CH:15][C:10]2[S:11][CH:12]=[C:13]([CH3:14])[C:9]=2[CH:8]=1.[Cl:17][CH2:18][CH2:19][CH2:20]I>C1COCC1.[Cu]I>[Cl:17][CH2:18][CH2:19][CH2:20][C:12]1[S:11][C:10]2[CH:15]=[CH:16][C:7]([F:6])=[CH:8][C:9]=2[C:13]=1[CH3:14]
Reactant: Cc1csc2ccc(F)cc12
Reactant: ClCCCI
Agent: [Cu]I
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(CCCCl)sc2ccc(F)cc12
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
n-BuLi in heptanes (1.5 ml, 2.4 mmol, 1.6M) was added drop wise to 5-fluoro-3-methyl-benzo[b]thiophene (332 mg, 2.0 mmol) in THF (5 ml) at −20° C. under argon. The reaction mixture was stirred at −15° C. for 30 min, then 1-chloro-3-iodopropane (322 μl, 3.0 mmol) and copper (I) iodide (38 mg, 0.2 mmol) were added. The reaction was stirred at −15° C. for 1 h, then NH4H4Cl (sat'd aq., 5 ml) was added. The product was extracted with diethyl ether (2×30 ml) and the organic layer was washed with brine (10 ml), dried (K2CO3), filtered and concentrated in vacuo. The product was purified by column chromatography (0-1% diethyl ether in heptanes) to give 2-(3-chloro-propyl)-5-fluoro-3-methyl-benzo[b]thiophene (180 mg, 37%). 1H NMR (CDCl3): δ2.19 (tt, 2H), 2.22 (s, 3H), 2.94 (t, 2H), 3.57 (t, 2H), 7.04 (dt, 1H), 7.28 (dd, 1H), 7.66 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].CC(C)([O-])C.[K+].[CH2:29]([O:31][P:32]([CH3:37])([CH2:34][CH:35]=O)=[O:33])[CH3:30]>C(Cl)Cl>[CH2:10]([O:9][C:7]([NH:6]/[C:5](=[CH:35]\[CH2:34][P:32]([O:31][CH2:29][CH3:30])([CH3:37])=[O:33])/[C:3]([O:2][CH3:1])=[O:4])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOP(C)(=O)CC=O
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOP(C)(=O)C/C=C(\NC(=O)OCc1ccccc1)C(=O)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
After 214 mg of N-(benzyloxycarbonyl)-alpha-phosphonoglycine trimethyl ester was dissolved in 5 ml of methylene chloride, 74 mg of potassium t-butoxide was added, followed by stirring at −78° C. for 30 minutes. 76.5 mg of 2-(ethoxy(methyl)phosphinyl)-acetaldehyde in methylene chloride solution (1 ml) was gradually added dropwise into this reaction solution, which was stirred for 1 hour. After the reaction temperature was gradually raised up to room temperature, further the reaction solution was stirred for 3 hours. Consuming of ingredients was confirmed by using TLC, and the solvent was removed off under reduced pressure. The residual was purified by silica gel column chromatography (chloroform-methanol (100:1-50:1)), 168 mg of an objective compound was obtained (93% yield).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C([O-])C.[Na+].[Cl:13][C:14]1[C:15]([C:24]2[CH:29]=[C:28]([CH:30]=O)[C:27]([Cl:32])=[CH:26][C:25]=2[Cl:33])=[N:16][N:17]([CH3:23])[C:18]=1[O:19][CH:20]([F:22])[F:21]>C(O)C>[Cl:32][C:27]1[CH:26]=[C:25]([Cl:33])[C:24]([C:15]2[C:14]([Cl:13])=[C:18]([O:19][CH:20]([F:21])[F:22])[N:17]([CH3:23])[N:16]=2)=[CH:29][C:28]=1[CH:30]=[C:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C#N)=Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2.4 g (21 mmol) of ethyl cyanoacetate and 0.3 g (4.2 mmol) of sodium ethanolate were added to a solution of 7.5 g (21 mmol) of 4-chloro-3-(2,4-dichloro-5-formylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 70 ml of ethanol. The mixture was stirred for 4 hours then poured into ice-water, after which the solid product was filtered off, washed with n-hexane and then dried. Yield: 4.9 g.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([CH3:15])[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:5].[CH:21](OCC)(OCC)OCC>C(O)C>[Br:20][C:17]1[CH:16]=[C:3]2[C:2](=[CH:19][CH:18]=1)[N:1]=[CH:21][N:6]([CH2:7][CH:8]([CH3:15])[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[C:4]2=[O:5]
Reactant: CC(CNC(=O)c1cc(Br)ccc1N)Cn1ccnc1
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: CC(Cn1ccnc1)Cn1cnc2ccc(Br)cc2c1=O

Procedure:
A mixture of 3.37 g of 2-amino-5-bromo-N-[3-(1H-imidazol-1-yl)-2-methylpropyl]benzamide, 5 ml of triethyl orthoformate and 10 ml of ethanol was heated at reflux temperature for 20 hours. The reaction mixture was concentrated, triturated with ether and then boiled with ethyl acetate. The insoluble product was filtered off, mp 159°-162° C.
Reaction SMILES: [NH2:1][C:2]1([C:10]#[N:11])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH2:3]1.N.[OH:13]S(O)(=O)=O>O>[NH2:1][C:2]1([C:10]([NH2:11])=[O:13])[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[CH2:3]1
Reactant: CC1(C)CCCC(N)(C#N)C1
Reactant: O=S(=O)(O)O
Agent: N
Solvent: O
Product: CC1(C)CCCC(N)(C(N)=O)C1
Temperature: 0 °C

Procedure:
A solution of EXAMPLE 145A (4.6 g) in concentrated H2SO4 (9 mL) was heated to 70° C. for 20 minutes. The reaction mixture was cooled to about 0° C. in an ice bath and diluted with water. The pH of the solution was adjusted to pH 7-8 by addition of concentrated aqueous ammonia solution. The aqueous layer was extracted with methylene chloride (2×50 mL). The combined organic layers were washed with water (1×20 mL), dried over MgSO4, filtered, and concentrated to give the title compound, which was used in the next step without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:30]=1[CH2:31]Br>C1COCC1>[C:13]([NH:21][CH:22]([CH2:31][C:30]1[C:29]([Cl:28])=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:37])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CNC(=O)c1ccccc1
Reactant: Clc1cccc(Cl)c1CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(Cc1c(Cl)cccc1Cl)NC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution comprised of N,N-diisopropylamine (3.97 mL, 22.8 mmol) in dry THF (57 mL) was cooled to −78° C. under nitrogen and then solutions of n-butyl lithium in hexanes (14.25 mL, 22.8 mmol) and ethyl benzoylaminoacetate (2.37 g, 11.4 mmol) in dry THF (23 mL) were added dropwise sequentially. The mixture was stirred for 1 hour and then a solution comprised of 2,6-dichlorobenzyl bromide (1.87 g, 11.4 mmol) in dry TMF (2 mL) was added dropwise. The mixture was stirred for 1 hour at −78° C. and then for 30 minutes while allowing to warm. The mixture then was quenched with water (8 mL) and extracted with ethyl acetate (2×54 mL). The combined extracts were washed with 1M hydrochloric acid (1×27 mL) and saturated sodium chloride solution (1×27 mL), dried (Na2SO4) and concentrated on a rotary evaporator. Product was purified from the residue by flash column (silica gel, 10:90 to 50:50 v/v EtOAc-hexane) to provide crude ethyl 2-benzoylamino-3-(2,6-dichlorophenyl)propionate. The propionate ester was treated with lithium hydroxide (118.8 mg, 4.96 mmol) in ethanol (12 mL) and water (50 mL) for 15 hours. The mixture was then diluted with 1M hydrochloric acid (12 mL) and ethyl acetate (24 mL). The aqueous layer was separated and extracted with ethyl acetate (2×4 mL). The combined organic layers were washed with saturated sodium chloride solution (25 mL), dried (Na2SO4), filtered and concentrated on a rotary evaporator to provide 2-benzoylamino-3-(2,6-dichlorophenyl)propionic acid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH:6]([CH2:8][CH2:9][OH:10])[NH2:7].C(N(CC)CC)C>C(Cl)Cl>[NH2:7][N:6]([CH2:8][CH2:9][OH:10])[C:2](=[O:3])[O:4][CH3:5]
Reactant: COC(=O)Cl
Reactant: NNCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N(N)CCO
Reaction time: 3 h
Yield: 98.9 %

Procedure:
At 0-5° C., 248.4 g (2.628 mol) of methyl chloroformate were added with stirring, over a period of 30 min, to a mixture of 200 g (2.628 mol) of 2-hydrazinoethanol and 266 g (2.628 mol) of triethylamine in 1600 ml of methylene chloride. After 3 h of stirring at from 3 to 22 C, the resulting hydrochloride was removed by filtration and washed with THF. The filtrates were combined. The filter cake was suspended in 800 ml of THF and filtered again. This filtrate, too, was combined with the previous filtrate. The combined filtrates were concentrated under reduced pressure. This gave 366 g of the title compound as colorless oil having an HPLC purity of 95.3%, corresponding to a yield of 98.9% of theory. According to GC, the purity was 85.2%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][NH:31][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: NC1CCCC1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2CCCC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and cyclopentylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([Cl:13])=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[C:14]([O:19]CC)(=[O:18])/[CH:15]=[CH:16]/[CH3:17].CC(C)([O-])C.[K+].Cl>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:17][CH:16]=[CH:15][C:14]([OH:19])=[O:18])[C:8]([Cl:13])=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: C/C=C/C(=O)OCC
Reactant: COc1cc(Cl)c(C=O)cc1OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(Cl)c(C=CC=CC(=O)O)cc1OC

Procedure:
To a solution containing 10.0 g 3,4 dimethoxy-6-chlorobenzaldehyde and 8 ml of ethyl crotonate in 60 ml of N-methylpyrrolidone 6.0 g of potassium tert.-butoxide was added while stirring. The solution was stirred for 0.5 h more at 20° C. and poured then to a mixture of ice and hydrochloric acid. The solution was extracted with ether. The ether solution was washed with water and extracted with 2.5 N NaOH-solution. The aqueous phase was acidified with hydrochloric acid and the semisolid product was separated. Yield 10.8 g (81%).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:18](=O)[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:9]=3[NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>O.CO>[C:1]1([C:7]2[C:8]3[C:18](=[N:21][OH:22])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:9]=3[NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2-c2[nH]nc(-c3ccccc3)c21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=C1c2ccccc2-c2[nH]nc(-c3ccccc3)c21

Procedure:
A mixture of 3-phenylindeno[1,2-c]pyrazol-4(1H)-one (1.28 g, prepared as described in JP60-130521), hydroxylamine hydrochloride (0.5 g), sodium acetate (0.8 g), water (10 ml) and methanol (100 ml) was boiled under reflux for 66 hours. More hydroxylamine hydrochloride (0.5 g), sodium acetate (0.8 g) and water (10 ml) were added and the mixture was boiled under reflux for a further 16 hours. Further hydroxylamine hydrochloride (0.5 g) and sodium acetate (0.8 g) were added and the mixture was boiled under reflux for a further 20 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure until crystallization began. The mixture was cooled and filtered to give a solid which was washed with water and dried to give 3-phenylindeno[1,2-c]pyrazol-4(1H)-one oxime, m.p. 280° C. (with decomposition).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:15])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:20]=[C:21]([NH2:32])[CH:22]=[CH:23][C:24]=1[S:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:18][C:19]1[CH:20]=[C:21]([NH:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:15])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:22]=[CH:23][C:24]=1[S:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1
Reactant: CCOc1cc2c(Cl)c(C#N)cnc2cc1F
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: CCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F

Procedure:
Following the procedure of Example 1, a mixture of 2.4 g (9.72 mmol) 4-chloro-6-ethoxy-7-fluoro-3-quinolinecarbonitrile, 2.56 g (10.7 mmol) of 3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamine and 1.2 g (10.38 mmol) of pyridine hydrochloride are refluxed in 2-ethoxyethanol (30 mL) at 110°0 C. for 1 hour to yield 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]phenyl}amino)-6-ethoxy-7-fluoro-3-quinolinecarbonitrile as a pink solid, mp 251-254° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].[H-].[Na+]>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:17][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])(=[O:13])=[O:12])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sccc1N
Reactant: COc1cc(C(C)(C)C)ccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1OC
Yield: 29 %

Procedure:
To a solution of 31 (8.45 g; 32.16 mmol) and methyl 3-aminothiophene-2-carboxylate (5.60 g; 35.38 mmol) in tetrahydrofuran (160 mL) at room temperature was added sodium hydride (1.5 g; 38.59 mmol; 60% mineral oil). The reaction mixture was stirred at room temperature under nitrogen for 16 hours (an additional equivalent of sodium hydride was found to be necessary to drive reaction to an acceptable level of completion) and then quenched with water and aqueous hydrochloric acid (2N) and extracted with ethyl acetate. The combined organic phases were successively washed with water and aqueous saturated sodium chloride, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting crude residue was taken up in ethyl acetate. The resulting precipitate was filtered and triturated from diethyl ether to yield the title compound as a light brown solid (3.58 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2(O)[CH2:11][S:10](=[O:13])(=[O:12])[CH2:9]2)=[N:6][CH:7]=1.C(N(S(F)(F)[F:21])CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([F:21])[CH2:11][S:10](=[O:13])(=[O:12])[CH2:9]2)=[N:6][CH:7]=1
Reactant: O=S1(=O)CC(O)(c2ccc(Br)cn2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=S1(=O)CC(F)(c2ccc(Br)cn2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To a stirred solution of the product of step 2, Example 18 (0.3 g, 1.097 mmol, 1 eq) in methylene chloride (30 mL) is added diethylaminosulfur trifluoride (0.175 mL, 1.295 mmol, 1.1 eq) at −78° C. Resulting reaction mixture is stirred at −78° C. for 1 hour. The reaction mixture is quenched with aqueous bicarbonate solution (15 mL) and extracted with methylene chloride (3×20 mL). Combined organic layer dried over sodium sulphate and concentrated in vacuo. The crude compound is purified by column chromatography using (100-200 mesh silica). Desired compound is eluted in 10% ethyl acetate/hexane to afford title compound (0.15 g): 1H NMR (400 MHz, DMSO) δ: 4.77-4.86 (m, 2H), 4.94-5.05 (m, 2H), 7.62 (d, 1H, J=8.4 Hz), 8.21-8.24 (dd, 1H, J1=8.44 Hz, J2=2.12 Hz), 8.85 (s, 1H). LC-MS (m/z): [M+H] 281.9.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=O)(=[O:4])=[O:3]>P(Cl)(Cl)(Cl)=O>[CH3:1][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]#[N:9])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccccc1C(N)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccccc1C#N
Yield: 87.3 %

Procedure:
2-Methanesulphonylbenzamide (34 g.) was added to phosphorus oxychloride (100 ml.) and the mixture was refluxed for 90 minutes. The excess of phosphorus oxychloride was evaporated in vacuo, and the oily residue was treated with water (200 ml.), with ice cooling. The solid which separated was filtered off, washed with water and recrystallised from ethanol to give 2-methanesulphonylbenzonitrile (27 g.), m.p. 105°-106° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.C[N:21](C=O)C>C1COCC1>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([NH2:21])=[O:8]
Reactant: CN(C)C=O
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1ccc(N)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 5-methyl-2-nitrobenzoic acid (25.4 g) in THF (150 ml) was added oxalyl chloride (13.5 ml) and DMF (0.1 ml) dropwise and the mixture was stirred at room temperature for 14 hours and concentrated to dryness. To an ice-cooled, stirred 25% aqueous solution of ammonia (150 ml) was added the resulting acid chloride dropwise and the mixture was stirred at the same temperature for 1 hour. The white precipitates were collected by filtration, washed with water, and dried in vacuo. A suspension of the white precipitates and 10% Pd/C (2.4 g) in a mixture of THF (200 ml) and methanol (150 ml) was stirred under hydrogen atmosphere at room temperature for 4 hours. After removal of insoluble materials by filtration, the filtrate was concentrated to dryness. Recrystallization of the resultant crystalline residue from ethyl acetate-hexane afforded colorless crystals (18.7 g, 89%), m.p. 178°-180° C.