Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:12]=[C:13]([CH:16]=O)[S:14][CH:15]=2)=[CH:8][CH:7]=1.[S:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[S:22].C([O-])(=O)C.[Na+]>O>[Cl:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:26]3[S:20][C:21](=[S:22])[NH:23][C:24]3=[O:25])[S:14][CH:15]=2)=[CH:8][CH:7]=1
Reactant: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=S)SC1=Cc1cc(Cc2ccc(Cl)cc2)cs1
Temperature: 80 °C
Yield: 81 %

Procedure:
To a 20-mL scintillation vial fitted with a magnetic stir bar was added 3 mL of glacial acetic acid (AcOH). The vial was capped tightly and heated to 80° C. To the hot AcOH was added 4-(4-chlorobenzyl)thiophene-2-carbaldehyde (example 1.1.a); 0.37 g, 1.56 mmol, 1 equiv) and rhodanine (0.23 g, 1.7 mmol, 1.1 equiv) with stirring until a solution was formed. To the mixture was then added anhydrous sodium acetate (0.45 g, 5.5 mmol, 3.5 equiv), and the vial was capped tightly and heated to 110° C. for approx. 1 h. The reaction vial was cooled to rt and the contents were poured into water. The resulting precipitate was filtered, washed with water and a cold mixture of 1:1 water/ethanol. The solid was dried thoroughly in vacuo at 40° C. to give 5-((4-(4-chlorobenzyl)thiophen-2-yl)methylene)-2-thioxothiazolidin-4-one (451 mg, 81%). 1H NMR (400 MHz, (CD3)2SO) δ (ppm): 7.70 (s, 1H), 7.67 (s, 1H), 7.46 (s, 1H), 7.34-7.38 (m, 2H), 7.25-7.29 (m, 2H), 3.96 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:18])([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH2:3][NH:4][C@H:5]1[CH2:9][CH2:8][C@H:7]([NH2:10])[CH2:6]1.Cl[C:20]1[C:21]2[C:22](=[N:26][N:27]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:28]=2)[N:23]=[CH:24][N:25]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[F:1][C:2]([F:18])([C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH2:3][NH:4][C@H:5]1[CH2:9][CH2:8][C@H:7]([NH:10][C:20]2[C:21]3[C:22](=[N:26][N:27]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][O:30]4)[CH:28]=3)[N:23]=[CH:24][N:25]=2)[CH2:6]1
Reactant: Clc1ncnc2nn(C3CCCCO3)cc12
Reactant: Cc1ccc(C(F)(F)CN[C@H]2CC[C@H](N)C2)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(F)(F)CN[C@H]2CC[C@H](Nc3ncnc4nn(C5CCCCO5)cc34)C2)cc1
Temperature: 150 °C
Yield: 87.4 %

Procedure:
A mixture of (1S,3S)-N-[2,2-difluoro-2-(4-methylphenyl)ethyl]cyclopentane-1,3-diamine (627 mg, 2.46 mmol), 4-chloro-2-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[3,4-d]pyrimidine (588 mg, 2.46 mmol), n-butanol (1.6 mL) and diisopropylethylamine (1.6 mL) was heated in microwave for 15 min at 150° C. The reaction mixture was concentrated in vacuo to a viscous brown oil, which was purified by silica gel chromatography (CH2Cl2/MeOH gradient) to give the title compound (0.982 g) as a cream colored foam: MS=457.4 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20][C:21]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:22]=2[C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)=[O:24])[CH2:16][CH2:15]1>C(Cl)(Cl)Cl>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][NH:25][C:23](=[O:24])[C:22]1[CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=[CH:40][C:21]=1[NH:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([NH:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:19][CH2:18]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](N)CC2)cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](NS(C)(=O)=O)CC2)cc1OC
Temperature: 25 °C

Procedure:
Methanesulfonyl chloride (54 mg) and triethylamine (48 mg) were added to a solution of 2-(trans-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (134 mg) in chloroform (2 mL). The mixture was stirred for an hour at ambient temperature. Methanesulfonyl chloride (54 mg) and triethylamine (48 mg) were added to the reaction mixture. After stirring for an hour at ambient temperature, the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and 3.6% hydrochloric acid. The separated organic layer was washed with an saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residual crystals were suspended in hot ethanol and cooled with stirring. The resultant was collected by filtration and washed with ethanol to give N-(3,4-dimethoxybenzyl)-2-[trans-4-(methanesulfonylamino)cyclohexylamino]-5-nitrobenzamide (142 mg) as yellow crystals.
Reaction SMILES: [F:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[S:13]1[C:17]2=[CH:18][CH:19]=[CH:20][C:21]([S:22]([NH:25][C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)(=[O:24])=[O:23])=[C:16]2[N:15]=[CH:14]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1([OH:10])[CH2:5][CH2:6][N:7]([C:30]([C:29]2[CH:28]=[CH:27][C:26]([NH:25][S:22]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]4[S:13][CH:14]=[N:15][C:16]=34)(=[O:24])=[O:23])=[CH:34][CH:33]=2)=[O:31])[CH2:8][CH2:9]1
Reactant: CC(C)(F)CC1(O)CCNCC1
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2cccc3scnc23)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(F)CC1(O)CCN(C(=O)c2ccc(NS(=O)(=O)c3cccc4scnc34)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottom flask was added with 4-(2-fluoro-2-methylpropyl)piperidin-4-ol (25 mg 0.143 mmol), 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (47 mg, 0.143 mmol), DIPEA (110 mg, 0.85 mmol), HATU (54 mg, 0.143 mmol), and DCM (5 mL). The mixture was stirred at r.t. for 16 hours. After washing with satd. NaHCO3, brine, the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Purification by a standard method gave the desired compound. 1H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (dd, J=8.1, 0.8 Hz, 1H), 8.10 (dd, J=7.5, 1.1 Hz, 1H), 7.93 (s, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.16-7.23 (m, J=8.3 Hz, 2H), 7.05-7.15 (m, J=8.3 Hz, 2H), 4.19-4.47 (m, 1H), 3.46 (d, J=15.6 Hz, 1H), 3.35 (d, J=15.3 Hz, 2H), 1.89 (s, 3H), 1.84 (s, 3H), 1.49-1.55 (m, 3H), 1.46 (s, 3H). LC-MS: m/z 492.65 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:32]=[O:33])=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[BH4-].[Na+].O.Cl>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:32][OH:33])=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=C(CO)NC(C)=C(C(=O)OCc2ccccc2)C1c1ccccc1[N+](=O)[O-]

Procedure:
To a suspended solution of benzyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (1.2 g) in ethanol (20 ml) was added sodium borohydride (60.6 mg) under ice-cooling and stirred, and further stirred for an hour at 0° C. and another an hour at 3° C. The reaction mixture was added with water and the resultant mixture was adjusted to pH 6 to 7 with 2 N hydrochloric acid, and the solvent was distilled off. The residue was extracted with ethyl acetate and washed with water and dried. After removal of the solvent, the resultant oil (1.3 g) was purified by column chromatography on silica gel with an eluent (a mixture of ten parts of benzene and one part of ethyl acetate by volume) to give an oil which was immediately crystallized. The resultant crystals were recrystallized from a mixture of diethyl ether and n-hexane and dissolved in benzene. The benzene solution was subjected to azeotropic process five times to give pure crystals of benzyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 51° to 57° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:22]=4)[CH:19]=3)[N:14]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:13]=2)[CH:9]=[N:8]1.Cl[CH2:48][C:49]([NH2:51])=[O:50].C(=O)(O)[O-].[Na+]>CC(C)=O.C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=4)[CH2:27][CH:28]4[CH2:29][CH2:30][N:31]([CH2:48][C:49]([NH2:51])=[O:50])[CH2:32][CH2:33]4)[CH:19]=3)[N:14]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:35])=[O:36])[CH:13]=2)[CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(CC5CCNCC5)c4)cnc32)cc1
Reactant: NC(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(CC5CCN(CC(N)=O)CC5)c4)cnc32)cc1
Yield: 38.9 %

Procedure:
Using the same reaction conditions as described in step-i of example-82A 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(3-(piperidin-4-ylmethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (75 mg, 0.114 mmol) was alkylated using 2-chloroacetamide (16 mg, 0.171 mmol) and sodium bicarbonate (29 mg, 0.342 mmol) in acetone/ethanol (5/5 mL) to get 30 mg (38.96% yield) of the titled compound. MS: m/z=676.8 (M+1).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:75][N:76]([CH3:81])[CH2:77][CH2:78][CH2:79][NH2:80]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:80][CH2:79][CH2:78][CH2:77][N:76]([CH3:81])[CH3:75])=[O:28])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CCCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
To a mixture of 0.060 g (0.139 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-184) and 8 mL of dimethylformamide was added 0.0282 g (0.209 mmole) of 1-hydroxybenzotriazole, 0.079 g (0.208 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.072 g (0.555 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0212 g (0.207 mmole) of 3-(dimethylamino)propylamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0651 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-methyl-benzamide (I-189) as a white solid
Reaction SMILES: C[O:2][CH:3](Cl)Cl.[Sn](Cl)(Cl)(Cl)Cl.[F:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>ClCCl>[F:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:3]=[O:2])=[CH:14][CH:13]=1
Reactant: Fc1cccc2ccccc12
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ccc(F)c2ccccc12
Reaction time: 0.25 h
Yield: 100.7 %

Procedure:
19.9 g Dichloromethyl methyl ether and 45.7 g tin chloride were dissolved in 70 mL dichloromethane. The solution was cooled to +5° C. and 20.0 g fluoronaphthalene in dichloromethane (49 mL) was added over a 60 min period, while keeping the temperature at 5° C. The reaction was brought to room temperature after the addition. After 4 h the reaction was quenched by slowly pouring it into an ice/water mixture. This mixture was stirred for 15 min and left standing overnight. The dichloromethane layer was washed with water, dried (sodium sulfate), filtered through celite and concentrated in vacuo to obtain 24.0 g of 4-fluoro-naphthalene-1-carbaldehyde as an off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:13])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12]
Reactant: Cc1c(Br)ccc(O)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(Br)c(C)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-3-methyl-2-nitrophenol (2.200 g, 9.48 mmol) in acetone (35 mL) was added potassium carbonate (3.276 g, 23.70 mmol) and methyl iodide (1.47 mL, 23.70 mmol) and the mixture was heated to reflux for 4 h. The reaction was cooled to rt, filtered and the filtrate was evaporated under reduced pressure to afford the crude product. Purification of the crude product by column chromatography over silica gel eluting with EtOAc/hexane afforded pure 1-bromo-4-methoxy-2-methyl-3-nitrobenzene as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ=2.33 (s, 2H), 3.87 (s, 3H), 6.78 (d, J=8.84 Hz, 1H) and 7.58 (d, J=8.84 Hz, 1H); MS (ES+): m/z 247.26 [MH+].
Reaction SMILES: [CH:1]([CH:3]=O)=O.[N+:5]([C:8]1[C:9]([NH2:15])=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6]>CCO>[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:9]=1[N:15]=[CH:1][CH:3]=[N:14]2)([O-:7])=[O:6]
Reactant: O=CC=O
Reactant: Nc1cccc([N+](=O)[O-])c1N
Solvent: CCO
Product: O=[N+]([O-])c1cccc2nccnc12
Temperature: 85 °C
Yield: 97.5 %

Procedure:
Oxaldehyde (40% in water; 1.43 ml, 31.3 mmol) was added to a solution of 3-nitro-o-phenylene-diamine (600 mg, 3.9 mmol) in EtOH (15 ml) and the mixture was heated at 85° C. for 2 h. The solvent was removed in vacuo, the residue was diluted in water and the aqueous phase was extracted with DCM. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (99:1) as the eluent to give the title compound (666 mg, 97%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](C2C=CC(C(OC(C)(C)C)=O)=CC=2)=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[C:40]([OH:46])(C(F)(F)F)=[O:41]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:39])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[C:22]([C:40]([OH:46])=[O:41])[CH:23]=[CH:24][C:25]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][CH:10]=1)=[O:6])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)C(=O)N(Cc1ccc(-c2ccc(C(=O)OC(C)(C)C)cc2)cc1)Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: CCOC(=O)C(=O)N(Cc1ccc(C(F)(F)F)cc1)Cc1cc(C(=O)O)ccc1-c1ccccc1
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of tert-butyl 4′-({[ethoxy(oxo)acetyl][4-(trifluoromethyl)benzyl]amino}methyl)-1,1′-biphenyl-4-carboxylate (1.37 g) in DCM (15 mL) was added TFA (15 mL). The resulting mixture was stirred for 30 min. Evaporation of the solvents gave the title compound as a colorless oil (1.10 g, 67%). M+(LC/MS(ESI)): 486.1; M−(LC/MS(ESI)): 484.6. HPLC (Condition A), Rt: 4.13 min (HPLC purity: 91.7%) 1H NMR (DMSO, 300 MHz) δ 7.94 (d, 2H, J=7.9 Hz), 7.72-7.61 (m, 6H), 7.42 (d, 1H, J=7.9 Hz), 7.33 (t, 2H, J=7.5 Hz), 7.25 (d, 1H, J=8.3 Hz), 4.49 (m, 4H), 4.20 (m, 2H), 1.10 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)([O-:3])=[O:2].[CH2:14]([C:18]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH2:23][NH:24][CH2:25][CH2:26][C:21]=2[C:20](=[O:27])[O:19]1)[CH:15]([CH3:17])[CH3:16].CCN(C(C)C)C(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH2:14]([C:18]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH2:23][N:24]([C:11](=[O:13])[CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:25][CH2:26][C:21]=2[C:20](=[O:27])[O:19]1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)Cc1ccccc1[N+](=O)[O-])CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
To a solution of 2-(2-nitrophenyl)acetic acid (79 mg, 0.435 mmol), 3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.184 mmol), and N,N′-diisopropylethylamine (112 mg, 0.870 mmol) in THF (5 mL) was added BOP reagent (144 mg, 0.326 mmol) and the mixture was stirred at room temperature for 16 hours. The crude reaction mixture was concentrated to dryness and purified by column chromatography (12 g, SiO2, 0 to 100% ethyl acetate in hexanes) to provide 3-isobutyl-5-(2-(2-nitrophenyl)acetyl)-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (57 mg, 60%) as a white solid: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.80-1.01 (m, 6H), 1.54-1.73 (m, 1H), 1.74-1.87 (m, 1H), 2.20-2.36 (m, 1H), 2.37-2.63 (m, 2H), 3.42-3.58 (m, 1H), 3.76-3.92 (m, 1H), 3.93-4.14 (m, 2H), 4.40 (m, 1H), 4.75 (d, J=19.59 Hz, 1H), 7.19-7.42 (m, 6H), 7.42-7.53 (m, 1H), 7.53-7.64 (m, 1H), 8.04-8.16 (m, 1H); MS m/z 435 (M+H)+, 457 (M+23)+, 433 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>CCO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Palladium (10 wt. %) on carbon (50 mg) was added in one portion to a solution of ethyl cis-4-(4-nitrophenoxy)cyclohexanecarboxylate (0.23 g, 0.78 mmol) in a mixture of EtOH (15 mL) and THF (10 mL) and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 h. The reaction mixture was filtered and then concentrated in vacuo to leave the title compound (0.20 g, 100%) as an oil; 1H NMR (CDCl3) δ 1.23-1.28 (3H, t), 1.55-1.63 (2H, m), 1.68-1.74 (2H, m), 1.93-2.03 (4H, m), 2.34-2.40 (1H, m), 4.10-4.17 (2H, q), 4.26-4.30 (1H, m), 6.60-6.63 (2H, d), 6.73-6.78 (2H, d) MS m/e MH+ 264.
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18]CC)=[O:17])=[CH:8][N:9]2[CH:13]2[CH2:15][CH2:14]2)=[C:4]([F:22])[C:3]=1[F:23].[CH3:24][C:25]1[CH:30]=[C:29]([Sn](C)(C)C)[CH:28]=[C:27]([CH3:35])[N:26]=1.CN(C)P(N(C)C)(N(C)C)=O>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.O1CCOCC1>[CH:13]1([N:9]2[C:10]3[C:5](=[C:4]([F:22])[C:3]([F:23])=[C:2]([C:30]4[C:25]([CH3:24])=[N:26][C:27]([CH3:35])=[CH:28][CH:29]=4)[C:11]=3[F:12])[C:6](=[O:21])[C:7]([C:16]([OH:18])=[O:17])=[CH:8]2)[CH2:15][CH2:14]1
Reactant: Cc1cc([Sn](C)(C)C)cc(C)n1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(Br)c(F)c(F)c2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)c(C)n1
Yield: 57.4 %

Procedure:
A mixture of 2.8 g ethyl 7-bromo-1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 2.2 g 2,6-dimethyl-4-(trimethylstannyl)pyridine (Example 1, part g), 2 ml hexamethylphosphoramide, 320 mg dichlorobis(triphenylphosphine)palladium and 50 ml dioxane was stirred and heated under reflux in an argon atmosphere for 24 hours. The reaction mixture was concentrated to dryness and the residue was treated with 100 ml of 1N hydrochloric acid and heated at reflux for 2 hours. The latter mixture was filtered and the filtrate concentrated to dryness. The residue was dissolved in 50 ml 5% aqueous potassium carbonate, decolorized with charcoal and filtered. The filtrate was acidified with concentrated hydrochloric acid, sodium acetate added, and the resulting precipitate was collected, dried and recrystallized from ethanol to give 1.6 g 1-cyclopropyl-7-(2,6-dimethylpyridinyl)-5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as a cream-colored solid, m.p. 264°-266° C.
Reaction SMILES: Cl[CH2:2]CCC(Cl)=O.[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]=[C:15]=[S:16])=[O:13].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24]N=[C:22]2[O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=1[F:39].C1(C)C=CC=CC=1>C(O)C>[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]=[C:15]=[S:16])=[O:13].[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]([NH:36][C:35]1[CH:37]=[CH:38][C:32]([O:31][C:22]2[C:21]3[C:26](=[CH:27][C:28]([O:29][CH3:30])=[C:19]([O:18][CH3:17])[CH:20]=3)[N:25]=[CH:24][CH:2]=2)=[C:33]([F:39])[CH:34]=1)=[S:16])=[O:13]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: O=C(Cl)CCCCl
Agent: O=C(CCCCl)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCCCl)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
4-Chlorobutanoyl isothiocyanate was prepared using commercially available 4-chlorobutanoyl chloride (80 mg) as a starting compound according to the description of the literature. 4-Chlorobutanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (41 mg, yield 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2([CH3:22])[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:21])[N:4]=1.CN1C=CN=C1.[F:29][CH:30]([F:35])[S:31](Cl)(=[O:33])=[O:32]>ClCCl>[F:29][CH:30]([F:35])[S:31]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:11]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)([CH3:22])[C:12]1=[O:21])(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)C(F)F
Reactant: COc1nc(OC)nc(C2(C)C(=O)Nc3c(F)cccc32)n1
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1nc(OC)nc(C2(C)C(=O)N(S(=O)(=O)C(F)F)c3c(F)cccc32)n1
Temperature: -20 °C
Yield: 25 %

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-7-fluoro-3-methyl-1,3-dihydro-2H-indol-2-one (0.50 g) and 1-methyl-1H-imidazole (0.37 g) are introduced as initial charge in 5 ml of dichloromethane and cooled to −20° C. With stirring, difluoromethanesulfonyl chloride (0.58 g) is added dropwise and the mixture is slowly warmed to room temperature. The mixture is stirred for 3 hours at room temperature. HPLC analysis detects starting material (67%), the desired product (25%) and further components. The mixture is added to 10 ml of water, the phases are separated and the organic phase is concentrated by evaporation in vacuo. The residue is purified by chromatography and the product is separated off from the unreacted starting material. This gives the title compound in an HPLC purity of 86% (0.16 g, 22% of theory). By means of 2D-NMR, it is possible to confirm the structure as N-sulfonylated compound.