Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]=1[C:8]([OH:10])=O.[F:11][C:12]1[CH:20]=[CH:19][C:15](C(O)=O)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:8]([C:3]2[NH:4][C:5](=[O:7])[NH:6][C:2]=2[CH3:1])=[O:10])=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)O
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(F)cc1
Temperature: 60 °C

Procedure:
2,3-Dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylic acid (71.0 g, 0.5 mol) and 4-fluorobenzoic acid (105 g, 0.75 mol) are mixed together then covered with polyphosphoric acid (1.6 Kg). The mixture is rapidly heated to 60° C. with stirring, then gradually heated to 110° C. over 2.5 hr with continued stirring. After stirring at ca. 110° C. for an additional 2 hr the mixture is cooled to 60° C. and mixed with crushed ice (3.5 Kg). After all the ice has melted, the mixture is filtered and the solid washed with water. The filter cake is suspended in water (800 mL) and the pH raised to approximately 8 by the gradual addition of 10% aqueous sodium hydroxide solution, and the mixture stirred overnight. The pH is adjusted to 8-9, the solid collected by filtration, washed throughly with water and dried. Recrystallization from isopropanol-water affords the title compound.
Reaction SMILES: [CH2:1]([NH:9][C:10]([NH2:12])=[S:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>C(O)C>[BrH:13].[CH2:1]([NH:9][C:10]1[S:11][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(=S)NCCc1ccccc1
Solvent: CCO
Product: Br
Product: c1ccc(CCNc2nc(-c3ccccc3)cs2)cc1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
N-phenethylthiourea (225 grams, 1.25 moles) and α-bromoacetophenone (250 grams, 1.25 moles, Aldrich Chem. Co.) in 1500 ml absolute ethanol were heated to reflux temperature for 21/2 hours under nitrogen. After reducing the solvent volume by 10%, the reaction mixture was cooled to room temperature and then to 0° C. in an ice bath. The solids were filtered off, redissolved in 2,500 ml of absolute ethanol and heated to reflux. The solvent volume was reduced to 2000 ml and the reaction mixture cooled to 0° C. This procedure was repeated and after the second recrystallization the solids were collected and dried under vacuum over phosphorous pentoxide, yielding 365 grams (81%) of 2-phenethylamino-4-phenyl-thiazole hydrobromide, m.p. 169°-172° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.[CH3:18][O:19][CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:18][O:19][CH2:20][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1
Reactant: COCCl
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 31.6 %

Procedure:
A mixture of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (4.5 g, 19.9 mmol), chloromethyl methyl ether (2.3 mL, 30.3 mmol), potassium carbonate (5.5 g, 39.8 mmol) and potassium iodide (0.66 g, 3.98 mmol) in N,N-dimethylformamide (50 mL) was stirred at 70° C. for 20 hrs. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:97-1:9) to give the title compound (1.7 g, yield 32%) as a colorless oil.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:10][CH2:11][CH3:12].[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(O)(=O)C>C1COCC1.O>[CH2:11]([CH:10]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:9]([O:14][CH2:15][CH3:16])=[O:13])[CH3:12]
Reactant: CCCC(=O)OCC
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)C(CC)C(=O)OCC
Temperature: -75 °C
Reaction time: 1 h

Procedure:
27.8 mL of lithium diisopropylamide (50.0 mmol, 1.00 eq, 1.8 M in THF/heptane/ethylbenzene) were dissolved in 50 mL of dry THF and an argon atmosphere and cooled to −75° C. 6.64 mL of ethyl butanoate (50.0 mmol, 1.00 eq) were dissolved in 25 mL of dry THF and added to the previous solution at a bath temperature of −60 to −75° C. and stirred for an additional 1 h at a bath temperature of −75° C. 6.92 mL of diethyl ethanedioate (51.0 mmol, 1.02 eq) were dissolved in 25 mL of dry THF and added to the previous solution at a bath temperature of −60 to −75° C. and stirred for an additional 30 min at a bath temperature of −75° C. The mixture was allowed to come to. −20° C., at which temperature 6.47 mL of acetic acid (113.0 mmol, 2.26 eq), followed by 100 mL of water. The mixture was then allowed to come to rt. The separated organic layer was washed, once with water, once with sodium bicarbonate solution and once with brine, before being dried over sodium sulfate and concentrated in vacuo. The crude reaction product was used for the next transformation without any further purification.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]1([O:23][CH3:24])[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16]1.[CH:25](=[O:27])[CH3:26]>C1COCC1.O>[OH:27][CH:25]([C:17]1([C:19]([O:21][CH3:22])=[O:20])[CH2:16][C:15]([O:14][CH3:13])([O:23][CH3:24])[CH2:18]1)[CH3:26]
Reactant: COC(=O)C1CC(OC)(OC)C1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(C(C)O)CC(OC)(OC)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.6 %

Procedure:
To a solution of diisopropylamine (3.2 mL, 22.67 mmol) in THF (45 mL) was added n-BuLi (2.69 M in hexane, 7.7 mL, 20.71 mmol) at −78° C. under argon. The mixture was stirred for 10 minutes at 0° C., then cooled to −78° C. and added a solution of methyl 3,3-dimethoxycyclobutanecarboxylate (3.0 g, 17.22 mmol) in THF (10 mL). The mixture was stirred for 30 minutes at −78° C., then added a solution of acetaldehyde (1.9 mL, 33.86 mmol) in THF (10 mL). The mixture was stirred for 30 minutes at −78° C., and water was added. The aqueous layer was extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure to give methyl 1-(1-hydroxyethyl)-3,3-dimethoxycyclobutanecarboxylate (3.33 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[NH2:11].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[NH:11][S:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=1)(=[O:23])=[O:22]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cccc(O)c1N
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(O)c1NS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.9 %

Procedure:
To a solution of 0.748 g (4.48 mmol) of the product of Example 30 in 10.0 mL of pyridine was added 0.928 g (4.48 mmol) of p-methoxybenzenesulfonyl chloride. The reaction mixture was stirred for 24 h at room temperature and then diluted with chloroform and washed with 5% HCl solution and water. The organic layer was then dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether-hexanes and the resulting solid was filtered and dried to provide 0.86 g (57%) of the desired product as a tan solid. Electrospray Mass Spec: 338.2 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[C:11]([O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH:26]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)(=[O:16])[CH2:12][C:13]([CH3:15])=O.[NH2:41]/[C:42](/[CH3:49])=[CH:43]\[C:44]([O:46][CH2:47][CH3:48])=[O:45]>C(O)(C)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[C:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[C:42]([CH3:49])[NH:41][C:13]([CH3:15])=[C:12]2[C:11]([O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH:26]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=3)[CH2:22][CH2:21]2)=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccc(C)cc2)c2ccc(C)cc2)CC1
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccc(C)cc3)c3ccc(C)cc3)CC2)C1c1ccc(C#N)cc1

Procedure:
A mixture of p-cyanobenzaldehyde, 2-[4-(4,4'-dimethylbenzhydryl)-1-piperazinyl]ethyl acetoacetate and ethyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-[4-(4,4'-dimethylbenzhydryl)-1-piperazinyl]ethyl ethyl 4-(4-cyanophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 93°-96° C. (sintering). Yield 61.9. IR(Nujol)cm-1 : 3330, 2220, 1685. NMR(CDCl3) δ: 1.15(3H,t,J=7,--CH2CH3), 2.24(6H,s, ##STR51## 2.29(6H,s, ##STR52## 4.03(2H,q,J=7,--CH2CH3), 4.11(1H,s,>N--CH<), 4.13(2H,t,J=7,--COOCH2 --), 5.01(1H, s,C(4) --H), 5.77(1H,broad s, NH).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH2:22][OH:23])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:24]([C:28]1[CH:29]=[C:30]([CH2:39][CH2:40][C:41](O)=[O:42])[CH:31]=[C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]=1[OH:34])([CH3:27])([CH3:26])[CH3:25].C1(C)C(C)=CC=CC=1>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4].O>[C:35]([C:32]1[CH:31]=[C:30]([CH2:39][CH2:40][C:41]([O:23][CH2:22][CH2:21][NH:20][C:18](=[O:19])[CH2:17][CH2:16][C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[CH:8]=2)=[O:42])[CH:29]=[C:28]([C:24]([CH3:26])([CH3:25])[CH3:27])[C:33]=1[OH:34])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(CCC(=O)NCCO)cc(C(C)(C)C)c1O
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1cc(CCC(=O)NCCOC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O

Procedure:
A mixture of 32 g (0.1 mole) of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-(2-hydroxyethyl)propionamide, 27 g (0.1 mole) of 3(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid, 1 g Tyzor TBT catalyst and 100 ml xylene was refluxed at 150° until evolution of water ceased. In the course of four hours, two ml water was collected in the Stark & Dean trap. The xylene was removed by vacuum stripping. The title compound (54 g) was recrystallized from a toluene/hexane mixture. It melted at 151°-154° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:15]=[C:14]([N:16]2[C@H:20]([CH3:21])[CH2:19][CH2:18][S:17]2(=[O:23])=[O:22])[CH:13]=[CH:12][C:6]=1[C:7](OCC)=[O:8])(=[O:4])=[O:3].[CH:24]1([C:27]2[C:28]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:29][CH:30]=[C:31]([CH3:33])[CH:32]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[C:28]([N:34]3[CH2:39][CH2:38][N:37]([C:7]([C:6]4[CH:12]=[CH:13][C:14]([N:16]5[C@H:20]([CH3:21])[CH2:19][CH2:18][S:17]5(=[O:22])=[O:23])=[CH:15][C:5]=4[S:2]([CH3:1])(=[O:3])=[O:4])=[O:8])[CH2:36][CH2:35]3)=[N:29][CH:30]=[C:31]([CH3:33])[CH:32]=2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1ccc(N2[C@H](C)CCS2(=O)=O)cc1S(C)(=O)=O
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C2CC2)c1
Yield: 75.7 %

Procedure:
Using ethyl (R)-2-methanesulfonyl-4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate (181 mg) described in Preparation Example 28 and 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine (109 mg) described in Preparation Example 86 and by the reaction and treatment in the same manner as in Example 109, the title compound (202 mg) was obtained.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C(=O)C)=[C:20]([F:28])[CH:19]=2)=[N:16][N:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O.S(=O)(=O)(O)O>C(O)C.CCCCCC>[CH2:3]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([F:28])[CH:19]=2)=[N:16][N:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCc1nnc(-c2ccc(OC(C)=O)c(F)c2)s1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCc1nnc(-c2ccc(O)c(F)c2)s1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
1.59 g (24.1 mM) of 85%-potassium hydroxide was dissolved in 50 ml of ethanol on an oil bath (bath temperature: about 70° C.). To the solution, 3.37 g (wet, 8.90 mM) of 2-decyl-5-(4-acetoxy-3-fluorophenyl)-1,3,4-thiadiazole was added, followed by stirring for 10 minutes at about 70° C. After the reaction, the reaction mixture was poured into iced water, followed by filtration under reduced pressure. The filtrate was condensed, followed by successive addition of about 100 ml of water, 2.3 ml of concentrated sulfuric acid and common salt and stirring at room temperature to precipitate a crystal. The crystal was dissolved in ethyl acetate and dried with anhydrous sodium sulfuric acid. The sodium sulfuric acid was recovered by filtration and the filtrate was condensed into a solid; n-hexane was added to the solid and stirred at room temperature, followed by filtration to obtain 2.78 g of 2-decyl-5-(3-fluoro-4-hydroxyphenyl)-1,3,4-thiadiazole (Yield: 92.8%, Yield through the steps iii) and iv): 82.7%).
Reaction SMILES: C([N:3]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C@H:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1)[C:4](=[NH:7])SC)#N.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[N:30]1C=CC=C[CH:31]=1>>[CH2:22]([NH:29][C:4](=[N:7][C:31]#[N:30])[NH:3][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C@H:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:12][CH:13]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: CSC(=N)N(C#N)c1ccc(C2=NNC(=O)C[C@H]2C)cc1
Reactant: c1ccncc1
Product: C[C@@H]1CC(=O)NN=C1c1ccc(NC(=NC#N)NCc2ccccc2)cc1

Procedure:
A stirred mixture of (R)-6-(4-(N-cyano-S-methylisothioureido)phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone and benzylamine in pyridine is heated to afford (R)-6-[4-(N3 -benzyl-N2 -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]([NH:23][CH3:24])=[O:22])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C3CCCCO3)=[CH:10][CH:9]=2)=[CH:6][N:7]=1.Cl.[OH2:26]>CO>[NH2:1][C:2]1[C:3]([C:21]([NH:23][CH3:24])=[O:22])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][OH:26])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: O
Reactant: CNC(=O)c1nc(-c2ccc(OC3CCCCO3)cc2)cnc1N
Agent: Cl
Solvent: CO
Product: CNC(=O)c1nc(-c2ccc(OO)cc2)cnc1N
Reaction time: 0.25 h
Yield: 64 %

Procedure:
3-amino-N-methyl-6-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrazine-2-carboxamide (63 mg) was suspended in methanol followed by addition of aqueous hydrochloric acid (2 mL). The mixture was stirred for 15 min., poured into water (10 mL), and extracted with ethyl acetate (10 mL). The organic layer was washed with saturate aqueous sodium chloride then dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography on silica followed by drying in vacuo afforded 3-amino-N-methyl-6-(4-hydroxyoxyphenyl)pyrazine-2-carboxamide (30 mg, 64% yield): 1H NMR (400 MHz; DMSO-D6): 9.62 (s, 1H); 8.78 (m, 1H); 8.82 (m, 1H); 8.7 (s, 1H); 7.98 (d, 2H); 7.5 (br s, 1H); 6.8 (d, 2H); 2.85 (d, 3H); MS (EI) for C12H12N4O2:245 (MH+).
Reaction SMILES: F[C:2]1[C:3]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[CH3:19][NH2:20].Cl>>[CH3:19][NH:20][C:2]1[C:3]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6]
Reactant: CN
Reactant: CS(=O)(=O)c1c(C(=O)O)ccc(C(F)(F)F)c1F
Agent: Cl
Product: CNc1c(C(F)(F)F)ccc(C(=O)O)c1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.40 g (8.4 mmol) of 3-fluoro-2-methylsulfonyl-4-trifluoromethylbenzoic acid were treated with 12.1 ml (168 mmol; 40 percent strength) of aqueous methylamine solution and the mixture was stirred for 4 h at RT. For work-up, the contents were poured into 6 N HCl, the mixture was subsequently cooled in an ice-bath. The precipitate was filtered off with suction. This gave 2.50 g of product in 95% purity.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.O.[C:19](#[N:22])[CH:20]=[CH2:21]>>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][CH2:21][CH2:20][C:19]#[N:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: C=CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCOCCC#N
Temperature: 50 °C

Procedure:
[2-(2-Cyano-ethoxy)-ethyl]-carbamic acid tert-butyl ester (430 mg) was prepared starting from (2-hydroxy-ethyl)-carbamic acid tert-butyl ester (320 mg) in acrylonitrile (1.5 mL). The reaction was heated to 50° C. for 1 h. The reaction was added to ethyl acetate (20 mL) and water (20 mL). The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organics were dried over sodium sulfate and then filtered. The solvent was evaporated and crude compound was purified by flash chromatography using hexane:ethyl actetate gradient.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:13]=3[CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.Cl.O1CCOCC1>[Fe].O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:13]=3[CH:14]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc3cc([N+](=O)[O-])ccc3o2)cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-c2cc3cc(N)ccc3o2)cc1
Temperature: 110 °C
Yield: 72.5 %

Procedure:
Then, 12.42 g (1.0 equivalent) of the obtained 2-(p-nitrophenyl)-5-nitrobenzofurane was added to 48.85 g (20.0 equivalents) of a 100 mesh iron powder previously activated by 0.5 ml of concentrated hydrochloric acid in 150 ml of a mixed solvent of 1,4-dioxane and water in proportions of 1:1, and the resulting mixture was refluxed by heating at about 110° C. for 2 hours and heavily stirred. The hot supernatant was filtered with Celite immediately after confirming a completion of the reaction by TLC (Thin-Layer Chromatography). The residual material was adequately washed with hot 1,4-dioxane and filtered. This operation was repeated three or four times, and then filtrates were combined and concentrated by an evaporator. After concentration, recrystallization was carried out with ethanol to obtain 7.1 g of orange-colored 2-(p-aminophenyl)-5-aminobenzofurane (amino compound A) at an yield of 90%.
Reaction SMILES: C(O)C.C([Cl:7])(=O)C.[CH2:8]([O:10][C:11]([C@@:13]1([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([O:26][C:27](=[O:37])[C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)[CH2:23][N:22]2C(OC(C)(C)C)=O)=[O:20])[CH2:15][C@H:14]1[CH:16]=[CH2:17])=[O:12])[CH3:9]>CCOC(C)=O>[Cl-:7].[CH2:8]([O:10][C:11]([C@@:13]1([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([O:26][C:27](=[O:37])[C:28]3[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=3)[CH2:23][NH2+:22]2)=[O:20])[CH2:15][C@H:14]1[CH:16]=[CH2:17])=[O:12])[CH3:9]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C)C(=O)OCC
Reactant: CC(=O)Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C[NH2+]1)C(=O)OCC
Product: [Cl-]
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 104.9 %

Procedure:
To a stirring solution of ethanol at 0° C., was added acetyl chloride (5.7 g). The resulting solution was aged for 30 min. (2S,4R)-tert-Butyl 2-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-(4-nitrobenzoyloxy)pyrrolidine-1-carboxylate (7.5 g) was then added as a solution in EtOAc (30 mL) to the acidic ethanol slurry solution at 10° C. The reaction was allowed to proceed for 1 h at 10° C., warmed to 15° C. for 1 h and then warmed to 20° C. After 16 h, EtOAc (30 mL) was added to the slurry and the resulting slurry was filtered. The cake was rinsed with EtOAc (30 mL) that had been cooled to 0° C. The title compound was placed in a vacuum oven, at 43° C., to remove residual solvent (6.9 g, 100% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]#[N:20]>C(#N)C>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[O:1][CH2:18][C:19]#[N:20])[CH:7]=[CH:8]1
Reactant: Oc1cccc2cc[nH]c12
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCOc1cccc2cc[nH]c12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In a 100 mL roundbottom flask equipped with a magnetic stirrer and rubber septum, 7-hydroxy-1H-indole (1.66 g., 12.48 mmol) was dissolved 50 mL anhydrous acetonitrile. The flask was charged with potassium carbonate (6.88 g., 49.9 mmol) and cooled to 0° C. While stirring, bromoacetonitrile (1.64 g., 13.73 mmol) was added dropwise over two minutes. The reaction mixture was allowed to warm to ambient temperature and stirring was continued for three hours. The solution was washed with water (2×30 mL) and brine (1×30 mL), dried over MgSO4 and concentrated in vacuo. The resulting oily brown residue was purified by flash chromatography (95:5 ethyl acetate:hexanes to 85:15 ethyl acetate:hexanes over minutes) to give (1H-Indol-7-yloxy)-acetonitrile as a crystalline solid (0.244-g.) ms: (M−H)−=171.2.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][CH:7]([F:21])[C:8]1[N:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH3:20])[N:9]=1>C(Cl)Cl>[F:21][CH:7]([F:6])[C:8]1[N:12]=[CH:11][N:10]([C:13]2[C:14]([CH3:20])=[CH:15][C:16]([CH3:19])=[C:17]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:18]=2)[N:9]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(-n2cnc(C(F)F)n2)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)Cl)cc1-n1cnc(C(F)F)n1
Temperature: 45 °C
Reaction time: 5 h

Procedure:
Under a nitrogen atmosphere, 14.2 g of chlorosulphonic acid are introduced and are admixed at room temperature, in portions, with 4 g of 3-(difluoromethyl)-1-(2,4-dimethylphenyl)-1H-1,2,4-triazole. The exothermic reaction raises the temperature of the mixture to around 45° C. The mixture is subsequently stirred at 70° C. for 5 hours and then cooled, and diluted with 20 ml of methylene chloride. The mixture is added with stirring to 40 g of ice and then the phases are separated and extracted with twice 20 ml of methylene chloride. The combined organic phases are concentrated on a rotary evaporator. This gives 4.5 g of brown oil. This oil is chromatographed using CH2Cl2. A white solid (2.9 g; 52% of theory) is isolated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12][C:11]=2[O:17][CH2:18][CH:19]([F:21])[F:20])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])=[O:36])=[CH:29][C:25]=1[C:26](O)=[O:27]>C1COCC1>[F:21][CH:19]([F:20])[CH2:18][O:17][C:11]1[C:10]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[O:22])=[CH:15][C:14]([NH:16][C:26](=[O:27])[C:25]2[CH:29]=[C:30]([CH2:33][NH:34][C:35]([C:37]([CH3:38])([CH3:40])[CH3:39])=[O:36])[CH:31]=[CH:32][C:24]=2[Cl:23])=[CH:13][N:12]=1
Reactant: Nc1cnc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)c1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cnc(OCC(F)F)c(C(=O)Nc3ccc(Br)cc3)c2)c1

Procedure:
Prepared analogously to Example 2f from N-(4-bromophenyl)-2-(2,2-difluoroethyl)oxy-5-amino-nicotinic acid amide and 2-chloro-5-(tert-butylcarbonylamino)methyl-benzoic acid with PPA and TEA in THF. Purification via HPLC (Method A)