Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]#[N:12].[F:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>N1C=CC=CC=1>[C:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=3)(=[O:22])=[O:21])[CH:3]=2)[NH:7][N:6]=1)#[N:12]
Reactant: N#Cc1n[nH]c2ccc(N)cc12
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Product: N#Cc1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Yield: 84.3 %

Procedure:
N-(3-Cyano-1H-indazol-5-yl)-3-fluorobenzenesulfonamide can be obtained as described in Example 2 from 0.6 g of 5-amino-3-cyano-1H-indazole, 12 ml of pyridine and 0.73 g of 3-fluorobenzenesulfonyl chloride. 1 g of N-(3-cyano-1H-indazol-5-yl)-3-fluorobenzenesulfonamide is thus obtained in the form of a yellow solid melting at 227° C. (analysis C14H9FN4O2S % calculated C, 53.16; H, 2.87; F, 6.01; N, 17.71; O, 10.12; S, 10.14% found C, 52.86; H, 2.63; F, 5.67; N, 16.04).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:40]=[CH:39][NH:38][N:37]=2)=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:38]4[CH:39]=[CH:40][C:36]([C:33]5[CH:32]=[CH:31][C:30]([Br:29])=[CH:35][CH:34]=5)=[N:37]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: Brc1ccc(-c2cc[nH]n2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4ccc(-c5ccc(Br)cc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-(4-bromo-phenyl)-1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[N:27][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[N:27][CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cncc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (147 mg, 0.5 mmol) and 5-bromo-pyridine-3-sulfonic acid amide (119 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (177 mg, 79%). MS (ISP) 449.9 [(M+H)+]; mp 252-254° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=3)([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1c1cccnc1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)c1cccnc1
Temperature: 67 °C

Procedure:
A mixture of rac-6-chloro-3-pyridin-3-yl-1,3-dihydro-indol-2-one (0.081 g, 0.33 mmol) (from Example 39b supra), 3-chlorobenzyl bromide (0.080 g, 0.39 mmol) (Aldrich), potassium iodide (0.065 g, 0.39 mmol) and potassium carbonate (0.098 g, 0.72 mmol) in acetone (3 mL) was heated at 67° C. for 2 hours in a capped pressure tube. After cooling, the mixture was diluted with ethyl acetate and extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography to give rac-6-chloro-3-(3-chloro-benzyl)-3-pyridin-3-yl-1,3-dihydro-indol-2-one as an off-white solid. (Yield, 0.05 g, 42%).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].O1CCCC1.C([Li])CCC.[CH3:18][C:19]([CH3:30])([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20](Cl)=[O:21]>CCCCCC.C(O)(=O)C>[CH3:18][C:19]([CH3:30])([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20](=[O:21])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CC(C)(Cc1ccccc1)C(=O)Cl
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)C(C)(C)Cc1ccccc1)OC

Procedure:
To a solution of 63 g. of dimethyl methylphosphonate in 600 ml. of tetrahydrofuran under nitrogen atmosphere at -75° C. is added with stirring 312 ml. of 1.6 M n-butyllithium in hexane. The condition is regulated so as to maintain a reaction temperature below -55° C. Ten minutes after the addition, 48.2 g. of the reaction product of step B above (2,2-dimethyl-3-phenylpropionyl chloride) in 15 ml. of tetrahydrofuran is added dropswise. The dropwise addition is regulated so as to maintain a reaction temperature below -60° C. The mixture is stirred at -75° C. for 2 hr. and at ambient temperature overnight. Acetic acid (20 ml.) is added and the tetrahydrofuran is removed by distillation. The residue is shaken with diethyl ether-methylene chloride (3:1, by volume) and dilute sodium bicarbonate solution. The organic layer is washed with saturated saline and then dried and concentrated. The residue is recrystallized in diethyl ether to give 54 g. of the title compound of this preparation. Melting point 49°-51° C.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C:3]1[CH:8]=[CH:7][N:6]=C(C#N)[CH:4]=1.[OH-:17].[Na+].Cl.[CH2:20]([OH:22])[CH3:21]>CO.C(Cl)Cl>[CH3:1][N:2]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C:3]1[CH:8]=[CH:7][N:6]=[C:21]([C:20]([OH:17])=[O:22])[CH:4]=1
Reactant: CCO
Reactant: CN(c1cccnc1)c1ccnc(C#N)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN(c1cccnc1)c1ccnc(C(=O)O)c1
Yield: 89 %

Procedure:
Compound 11 (0.473 g, 2.25 mmol, 1.00 eq) was dissolved in ethanol (10 mL) and 1N NaOH (5 mL) was added. The mixture was refluxed for 18 h and after cooling the reaction was neutralized with 1N HCl (5 mL) and the reaction was concentrated in vacuo. The crude reaction was dissolved in 10% MeOH/CH2Cl2 and the undissolved salt was filtered off and the solvents were removed in vacuo to afford 0.461 g (89%) of the title compound as a tan solid: 1H NMR (400 MHz, CDCl3) δ8.65-8.61 (m, 2H), 8.12 (d, J=6.7 Hz, 1H), 7.88 (ddd, J=8.1, 2.5, 1.6 Hz, 1H), 7.60 (dd, J=8.2, 4.8 Hz 1H), 7.4 (d, J=2.9 Hz, 1H), 6.88 (dd, J=6.7, 2.9 Hz, 1H), 3.46 (s, 3H); [M+1]+: 230.2.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:10]([OH:23])[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[Cl:24][CH2:25][C:26](O)=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:10]([O:23][C:26](=[O:27])[CH2:25][Cl:24])[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CCl
Reactant: CCCCOC(=O)N1CC[C@@H](CCCc2ccccc2)[C@H](O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCOC(=O)N1CC[C@H](CCCc2ccccc2)[C@H](OC(=O)CCl)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.242 g (0.75 mmol) of 1-butyloxycarbonyl (trans)-3-hydroxy4-(3-phenylpropyl)piperidine, 0.189 g (1.5 mmol) of chloroacetic acid, and 0.524 g (1.5 mmol) of triphenylphosphine in 5 mL of THF at 0° C. was slowly added 0.348 g (1.5 mmol) of diethylazodicarboxylate (DEAD). The reaction mixture was allowed to warm to rt and was stirred for 16 h. To the reaction mixture was added 20 mL of ether and it was filtered through a thin pad of celite. The filtrate was washed with sat'd NaHCO3 solution and sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate, 1:1) to give the title compound.
Reaction SMILES: [OH-].[Ba+2:2].[OH-].[C:4]([OH:23])(=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(C1C=CC=CC=1[OH:39])CCCCCCCC.[C:40](=[O:42])=[O:41]>COCCO>[C:4]([O-:23])(=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Ba+2:2].[C:4]([O-:23])(=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[C:40](=[O:39])([O-:42])[O-:41]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CCCCCCCCCc1ccccc1O
Reactant: O=C=O
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Product: O=C([O-])[O-]
Reaction time: 0.5 h
Yield: 32 %

Procedure:
41 g of anhydrous barium hydroxide was slowly added to 300 g of methyl cellosolve and dissolved therein. Next, 11 g of oleic acid and a mixture of 10 g of nonyl phenol with 36 g of an alkylbenzene solvent were added thereto followed by stirring for approximately 30 minutes. Then the mixture was allowed to react while blowing carbon dioxide into the reaction system and the temperature was slowly elevated to 150° C. while removing the water thus formed. After dehydrating and removing the methyl cellosolve under reduced pressure, overbased barium oleate/carbonate (Ba=32%, metal ratio=12) was obtained as a brown viscous product.
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])/[CH:3]=[CH:4]/[CH:5]1[CH2:7][C:6]1([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].O.[C:22]1(C)C=[CH:26][C:25](S(O)(=O)=O)=[CH:24][CH:23]=1.C([O-])([O-])=[O:34].[Na+].[Na+]>O1C=CCCC1>[O:34]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:1][CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])/[CH:3]=[CH:4]/[CH:5]1[CH2:7][C:6]1([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCC(O)/C=C/C1CC1(C(=O)OC)C(=O)OC
Agent: C1=COCCC1
Agent: [Na+]
Solvent: O
Product: CCCCCC(/C=C/C1CC1(C(=O)OC)C(=O)OC)OC1CCCCO1
Reaction time: 0.5 h

Procedure:
A solution of dimethyl trans-2-(3-hydroxy-1-octenyl)cyclopropane-1,1-dicarboxylate (22.4 g), described in Example 42, dihydropyran (80 ml, distilled over sodium) and p-toluenesulfonic acid monohydrate (300 mg) is allowed to stand at room temperature for 30 min. After adding a few ml of 10% Na2CO3 solution the mixture is extracted with ether. The ether extract is washed with water, dried (Na2SO4) and evaporated. Purification of the residue by chromatography on silica gel gives the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[CH:14])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[N:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH2:18]1>>[C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:21]3[CH:22]=[N:17][CH:18]=[N:19][CH:20]=3)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrN1C=CC=NC1
Reactant: C#Cc1cnc2cc(C(C)(C)C)nn2c1
Product: CC(C)(C)c1cc2ncc(C#Cc3cncnc3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=278.2 (M+H+), can be prepared in accordance with the general method of example 1 from 2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 3-bromopyrimidine.
Reaction SMILES: [F:1][CH:2]([F:15])[C:3]([C:12](Cl)=[O:13])([CH2:9][CH:10]=[CH2:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])(=O)C.[NH4+:20]>CC(C)=O>[C:12]([C:3]([CH:2]([F:15])[F:1])([CH2:9][CH:10]=[CH2:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:13])[NH2:20]
Reactant: [NH4+]
Reactant: C=CCC(C(=O)Cl)(C(=O)OCC)C(F)F
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Product: C=CCC(C(N)=O)(C(=O)OCC)C(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-difluoromethyl-2-chlorocarbonyl-4-pentenoate prepared as in Step A above (3.16 g) in acetone (25 mL) is added ammonium acetate (3.16 g). The mixture is stirred at room temperature for 3 hours. The insoluble material is filtered and the filtrate concentrated at reduced pressure. The residue is dissolved in ether (50 mL). The organic phase is washed with water, brine and dried over magnesium sulfate to give ethyl 2-carbamoyl-2-difluoromethyl-4-pentenoate (2.65 g) as an oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([S:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=1)[CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>CO>[ClH:3].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([S:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=1)[CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cl
Product: O=C(O)c1ccc(SC(Cn2ccnc2)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 167.9 %

Procedure:
43 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 4.01 g of methyl 4-[1-(2-chlorophenyl)-2-(imidazol-1-yl)ethylthio]benzoate (prepared as described in Example 21) in 43 ml of methanol, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then treated and purified by the same method as described in Example 10, to give 3.57 g of the title compound as colorless crystals, melting at 210°-215° C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.C(=O)=O.CC(C)=O.O[C:18]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[F:7][C:18]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
A solution of diethylaminosulfur trifluoride (4 mL, 32.7 mmol) in dichloromethane (10 mL) was added to a cold (−78° C.; dry ice/acetone bath) solution of tert-butyl 4-hydroxy-4-phenylpiperidine-1-carboxylate (8.05 g, 29.0 mmol) in dichloromethane (100 mL) under nitrogen. The reaction was stirred at −78° C. for ˜1 hour. The reaction was removed from the bath and warmed to ambient temperature then stirred another 30 minutes. The reaction was quenched with saturated aqueous NaHCO3 (100 mL). The organic fraction was washed with brine (˜50 mL). Then 3-chloroperoxybenzoic acid (1.0995 g, 6.37 mmol) was added to the reaction and stirred at ambient temperature for 30 minutes. This step was quenched with saturated aqueous NaHCO3 (100 mL). The organic fraction was washed with saturated aqueous NaHCO3 (1×100 mL), water (1×100 mL), and brine (1×100 mL), dried (MgSO4), tested for peroxide (3-10 ppm) and concentrated to light yellow oil. The oil was dried under vacuum to afford 8.27 g (100%) of the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (d, J=5.7, 9H), 1.96-1.85 (m, 3.5H), 2.03 (ddd, J=5.2, 13.3, 17.8, 1.5H), 3.06 (s, 2H), 3.98 (d, J=12.0, 2H), 7.33 (d, J=7.1, 1H), 7.46-7.36 (m, 4H); MS (DCI) m/z 280 (M+H+, 60%), 297 (M+NH4+, 100%).
Reaction SMILES: [CH2:1]([N:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]([C:10]1[C:11](=[O:20])[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Cl)[CH:30]=1.O>CN(C)C=O>[CH2:21]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]([C:10]1[C:11](=[O:20])[N:12]([CH2:35][C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: ClCc1cccnc1
Reactant: CCCCCCN(CCCCCC)C(=O)c1cc2ccccc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCN(CCCCCC)C(=O)c1cc2ccccc2n(Cc2cccnc2)c1=O
Temperature: 25 °C
Yield: 37.1 %

Procedure:
To a solution of 1.01 g of N,N-dihexyl-1,2-dihydro-2-oxoquinoline-3-carboxamide in 13 ml of N,N-dimethylformamide was added 136 mg of 60% sodium hydride/oil, followed by stirring at room temperature for an hour. To the reaction solution was added 434 mg of 3-picolyl chloride, followed by stirring at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel; Wakogel C200 (manufactured by Wako Pure Chemicals), developing solvent; hexane−ethyl acetate=7:13−1:19) and recrystallized from ethyl acetate to give 0.47 g of N,N-dihexyl-1-(3-picolyl)-1,2-dihydro-2-oxoquinoline-3-carboxamide.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>N1C=CC=CC=1>[C:22]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Oc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O)c1ccccc1
Temperature: 25 °C

Procedure:
After 6-hydroxy-2-piperonylidene-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, benzoyl chloride 0.282 ml was added, and the mixture was refluxed for two hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml twice. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The crude extract was dissolved in ethyl acetate 10 ml and hexane 20 ml, and the precipitated crystals were dried over phosphorous pentoxide at a temperature of 60° C. for six hours under reduced pressure to obtain the desired compound 182.3 mg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.N1C=CC=CC=1C([OH:28])C.[CH2:29]1[CH2:39][CH2:38][N:37]2C(=N[CH2:34][CH2:35][CH2:36]2)C[CH2:30]1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:5]([C:15]#[N:16])=[C:4]([O:28][CH2:34][CH2:35][C:36]2[CH:30]=[CH:29][CH:39]=[CH:38][N:37]=2)[N:3]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(O)c1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2cccc(F)c2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(OCCc2ccccn2)nc(N)nc1-c1cccc(F)c1

Procedure:
From 2-amino-4-(3-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, (2-pyridyl)ethanol and DBU in DME. ES-MS m/e (%): 336 (M+H+, 100).
Reaction SMILES: CN1CCOCC1.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2([C:21]([OH:23])=O)[CH2:20][CH2:19]2)=[CH:10][CH:9]=1.Cl.Cl.[F:26][C:27]1[C:32]2[C:33](=[O:40])[O:34][C:35]3([CH2:39][CH2:38][NH:37][CH2:36]3)[C:31]=2[CH:30]=[CH:29][N:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CN(C)C=O>>[F:26][C:27]1[C:32]2[C:33](=[O:40])[O:34][C:35]3([CH2:39][CH2:38][N:37]([C:21]([C:18]4([C:11]5[C:12]6[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=6)[N:8]=[CH:9][CH:10]=5)[CH2:19][CH2:20]4)=[O:23])[CH2:36]3)[C:31]=2[CH:30]=[CH:29][N:28]=1
Reactant: O=C1OC2(CCNC2)c2ccnc(F)c21
Reactant: O=C(O)C1(c2ccnc3ccccc23)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1OC2(CCN(C(=O)C3(c4ccnc5ccccc45)CC3)C2)c2ccnc(F)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HCl in dioxane (4.0 M, 1 mL) was added to tert-butyl 4-fluoro-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidine]-1′-carboxylate (25.8 mg, 0.0000837 mol). The reaction mixture was stirred at room temperature for 30 minutes before the volatiles was removed to afford the free amine (hydrochloric acid salt), which was subsequently used in the coupling reaction. 4-Methylmorpholine (50 μL, 0.0004 mol) was added to a mixture of 1-quinolin-4-ylcyclopropanecarboxylic acid (17.8 mg, 0.0000837 mol), 4-fluoro-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one dihydrochloride (23.5 mg, 0.0000837 mol), and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (45.7 mg, 0.0000879 mol) in N,N-dimethylformamide (0.5 mL, 0.006 mol). The reaction mixture was stirred at room temperature for 2 hours. The crude product was purified by prep-LCMS. LC/MS: 402.1 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([C:27]([F:30])([F:29])[F:28])[O:18][N:17]=[C:16]([C:19]3[S:23][C:22]([CH3:24])=[C:21]([CH2:25][NH2:26])[CH:20]=3)[CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([C:27]([F:29])([F:28])[F:30])[O:18][N:17]=[C:16]([C:19]3[S:23][C:22]([CH3:24])=[C:21]([CH2:25][NH:26][C:1](=[O:4])[CH2:2][CH3:3])[CH:20]=3)[CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1
Reactant: Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1CN
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)NCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C
Reaction time: 3 h

Procedure:
Propionyl chloride (0.17 ml) is added to a solution of C-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-thiophen-3-yl}-methylamine (816 mg) and DIPEA (1 ml) in dichloromethane (10 ml) at room temperature. After 3 hours at RT, the reaction is quenched with water. The aqueous phase is separated and further extracted two times with dichloromethane. The organic phases are combined, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC and by crystallization in a diethylether/petroleum ether mixture to yield N-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-thiophen-3-ylmethyl}-propionamide (compound 1.6, 122 mg) as white crystals. MS (HPLC/MS): 465 (MH+). Retention time: 1.96 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[SH:11].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](O)=O>C(Cl)(Cl)Cl>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[S:11][C:17]([C:13]3[S:12][CH:16]=[CH:15][CH:14]=3)=[N:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: O=C(O)c1cccs1
Reactant: Nc1cc([N+](=O)[O-])ccc1S
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc2sc(-c3cccs3)nc2c1

Procedure:
2-Amino-4-nitrobenzenethiol, 9.6 g (0.054 mole) and thiophene-2-carboxylic acid, 10.0 g (0.075 mole) are added to a solution of 54 g of PPE in 130 cc CHCl3. The mixture is heated at reflux for 2 hours. It is then concentrated in vacuo and the residue poured over ice. The pH is adjusted to 10 with 50% NaOH solution, and the precipitate filtered and washed with H2O. Drying in vacuo yields 15 g of the title compound.