Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](N)C.Cl[C:5]1[C:14]([C:15]([C:17](=[CH:23][N:24](C)[CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([F:28])=[C:10]([F:27])[CH:11]=2)[N:6]=1>C(O)C>[CH2:21]([O:20][C:18]([C:17]1[C:15](=[O:16])[C:14]2[CH:13]=[C:12]3[CH:11]=[C:10]([F:27])[C:9]([F:28])=[CH:8][C:7]3=[N:6][C:5]=2[N:24]([CH2:25][CH3:1])[CH:23]=1)=[O:19])[CH3:22]
Reactant: CCN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)cc2nc1Cl
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2nc3cc(F)c(F)cc3cc2c1=O
Reaction time: 0.67 h
Yield: 90.7 %

Procedure:
A solution at approximately 2° C. of ethylamine (14.6 g) in ethanol (200 cc) is added in the course of 10 minutes at between 2° and 5° C. and with stirring to a suspension of ethyl 2-(2-chloro-6,7-difluoro-3-quinolinecarbonyl)-3-(dimethylamino)acrylate (20 g) in ethanol (200 cc) at approximately 2° C., the mixture is stirred for a further 40 minutes at between 2° and 5° C. and the temperature is then allowed to rise to approximately 20° C. in the course of 2 hours. After 24 hours at approximately 20° C., the insoluble matter is drained and washed with ethanol (2×30 cc) and isopropyl ether (2×50 cc). 3-Ethoxycarbonyl-1-ethyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo [b][1,8]naphthyridine (16.35 g) is obtained in the form of a beige solid, m.p. 290° C.
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]2[C:8]([CH:16]3[CH2:19][CH2:18][CH2:17]3)=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][N:3]=1.[OH-].[K+].Cl.[CH3:23]O>>[CH:16]1([C:8]2[C:7]([C:5]3[NH:1][C:2]([O:6][CH3:23])=[N:3][N:4]=3)=[CH:14][C:11]([C:12]#[N:13])=[C:10]([CH3:15])[CH:9]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: CO
Reactant: Cc1cc(C2CCC2)c(-c2nnc(N)o2)cc1C#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COc1nnc(-c2cc(C#N)c(C)cc2C2CCC2)[nH]1
Temperature: 85 °C
Yield: 34 %

Procedure:
To a solution of 5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-methylbenzonitrile (compound 89.6, 0.5 g, 2.0 mmol) in MeOH (40 mL) was added KOH (1.11 g, 20.0 mmol). The mixture was heated at 85° C. overnight, then cooled to 0° C. and neutralized to pH 7 with aqueous 1 M HCl. The mixture was extracted with EtOAc (×2), and the combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc 1:1 to EtOAc) to yield 0.2 g (34%) of the title compound as a white solid. m/z (ES+) 269 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 10.96 (br, 1H), 7.82 (s, 1H), 7.35 (s, 1H), 4.11 (s, 3H), 4.15-4.05 (m, 1H), 2.59 (s, 3H), 2.31-2.16 (m, 2H), 2.14-1.89 (m, 3H), 1.87-1.71 (m, 1H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12].F[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N+:37]([O-:39])=[O:38].C(N(CC)CC)C>C(O)C>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N+:37]([O-:39])=[O:38])[CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1cc2ccccc2o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3[N+](=O)[O-])CC2O)CCCCC1)c1cc2ccccc2o1

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride (6.0 g) obtained in Step 2 of Example 1 in 50 ml of ethanol, were added 3.7 ml of 2-fluoronitrobenzene and 4.8 ml of triethylamine. The reaction mixture was refluxed overnight and concentrated. The resulting residue was filtered and dried to give 7.2 g of the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=4)[CH2:12]3)=[C:8]([C:25]([NH2:27])=[O:26])[CH:7]=[N:6][N:5]2[CH:28]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][N:40]([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:41]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[C:25]([C:8]1[CH:7]=[N:6][N:5]2[CH:28]=[C:2]([C:37]3[CH:38]=[N:39][N:40]([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:41]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][C@H:11]1[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=2)[CH2:12]1)(=[O:26])[NH2:27]
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H]1CN(c2ccc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(-c2cc3c(N[C@@H]4CN(c5ccc(C#N)cn5)C[C@@H]4C)c(C(N)=O)cnn3c2)cn1
Temperature: 100 °C
Yield: 119.6 %

Procedure:
A stirred solution of 6-bromo-4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (55 mg, 0.125 mmol, from Step 1 of Example 158), ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate (70.0 mg, 0.250 mmol), potassium phosphate tribasic (80 mg, 0.375 mmol), palladium(II) acetate (5.61 mg, 0.025 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene (12.00 mg, 0.025 mmol) in N,N-dimethylformamide (1 mL) was degassed by vacuum-N2 refill cycle twice. The sealed tube was then heated at 100° C. for 40 min. The reaction mixture was diluted with water and filtered. The filter cake was washed with water and dried under vacuum to give crude ethyl 2-(4-(3-carbamoyl-4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-1H-pyrazol-1-yl)acetate (76.8 mg), which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.Cl.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[N:17][CH:18]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][C:13]2[CH:18]=[N:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(O)nc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)nc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6-chloro-nicotinoyl chloride (0.40 g, 2.27 mmol) and 5-amino-2-hydroxypyridine hydrochloride (0.33 g, 2.25 mmol) in dry tetrahydrofuran (15 mL) was stirred at room temperature for 1 hour. Saturated sodium bicarbonate (aq) was added and the solution was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in a mixture of methanol (10 mL) and aqueous sodium hydroxide (1N, 2 mL). After stirring for 2 hours at room temperature water was added and the solution was extracted with dichloromethane. The organic layer was dried over sodium sulphate, filtered and evaporated in vacuo, yielding the title compound which was used without further purification.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2-].[Na+].C[N:17](C)C1C=CC=CC=1>>[NH2:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1
Reactant: c1ccc(Cc2ccccn2)cc1
Reactant: CN(C)c1ccccc1
Agent: [NH2-]
Agent: [Na+]
Product: Nc1cccc(Cc2ccccc2)n1

Procedure:
2-benzylpyridine (Aldrich, 2.5 g, 0.015 mole), sodium amide (780 mg, 0.02 mole) and N, N-dimethylaniline (25 mL) were refluxed overnight. The contents were allowed to cool and were partitioned between ether and water. The ether layer was dried (MgSO4) and concentrated in vacuo leaving an oil. The oil was purified by chromatography. The purified material was dissolved in 1N HCl, lyophilized, and triturated with EtOAc to give 2-amino-6-benzylpyridine as a white solid.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[OH:13][C:14]1[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1.[OH-].[Na+]>O=S(Cl)Cl>[F:8][C:7]1[C:2]([O:13][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:23])[C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: CC(Oc1ccc(O)cc1)C(=O)O
Reactant: Fc1cc(C(F)(F)F)cnc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1)C(=O)O
Temperature: 115 °C

Procedure:
A fresh sample of 2-(4-((3-fluoro-5-(trifluoromethyl)-2-pyridinyl)oxy)phenoxy propanoic acid was prepared by the reaction of 2,3-difluoro-5-(trifluoromethyl)pyridine with 2-(4-hydroxyphenoxy)propanoic acid in the presence of 2 moles of sodium hydroxide as above described and 9.0 g (0.026 mole) was refluxed in excess SOCl2 for about 1/2 hour to prepare the corresponding acid chloride. The excess SOCl2 was removed by heating to 115° C. under an aspirator vacuum. The resulting acid chloride was added to a mixture of concentrated ammonium hydroxide (30 ml) and methanol (60 ml). The flask was rinsed with an additional 15 ml ammonium hydroxide mixed with about 25 ml of methanol and the two fractions were combined. The acid amide formed as a solid which was filtered out, rinsed with water, slurried in water, filtered, dried and analyzed. M.P. 140°-141° C.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9]N)N=1>C(O)C>[C:5](#[N:9])[CH:6]=[CH:7][C:8]1[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NNc1cccc(Cl)n1
Agent: [Na]
Solvent: CCO
Product: N#CC=Cc1ccccc1

Procedure:
As for Example 2, a mixture of 0.23 g. of sodium metal, 50 ml. of absolute ethanol, 7.11 g. of 2-chloro-6-hydrazinopyridine and 6.5 g. of cinnamonitrile yields 7.35 g. of crude product. The crude material is dissolved in dichloromethane, filtered through hydrous magnesium silicate and concentrated while adding hexane to give 5.90 g. of the desired product as off-white crystals, m.p. 187.5°-188.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]([OH:16])=[O:15])[C:11]3[CH:23]=[C:24](F)[C:25](F)=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C(OC(=O)C(N1C2C=CC=CC=2N=C1C1C=CC(Cl)=CC=1)C1CCCCC1)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]([OH:16])=[O:15])[C:11]3[CH:23]=[CH:24][CH:25]=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CCOC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2ccccc21
Product: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2ccccc21
Yield: 99 %

Procedure:
This compound was synthesized in analogy to example 22, intermediate c, from [2-(4-chloro-phenyl)-benzoimidazol-1-yl]-cyclohexyl-acetic acid ethyl ester to give the desired compound as a colorless solid (99%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C-:28]#[N:29].[Na+]>CN(C)C=O>[C:28]([C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1)#[N:29]
Reactant: [C-]#N
Reactant: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(Br)n3)c2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(C#N)n3)c2)cc1

Procedure:
6-Cyano-4′-(4-methoxyphenyl)-2,2′:6′,2″-terpyridine is prepared by the method of example 27 from 6-bromo-4′-(4-methoxyphenyl)-2,2′:6′,2″-terpyridine (0.0745 mol), cuprous cyanide (0.296 mol), sodium cyanide (0.297 mol), and dimethylformamide (300 ml).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:14]([C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=1[S:29](Cl)(=[O:31])=[O:30])([CH3:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH:14]([C:17]1[CH:22]=[C:21]([CH:23]([CH3:24])[CH3:25])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=1[S:29]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1)(=[O:31])=[O:30])([CH3:15])[CH3:16]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)c2ccc3c(c2)Cc2ccccc2-3)c(C(C)C)c1

Procedure:
For example, fluorene can be reacted with 2,4,6-triisopropylbenzenesulfonyl chloride in the presence of aluminum chloride to yield 2-(2,4,6-triisopropylphenylsulfonyl)fluorene, which can be refluxed with sodium dichromate dihydrate in glacial acetic acid to yield 2-(2,4,6-triisopropylphenylsulfonyl)fluorenone, which in turn can be refluxed with malononitrile in methanol in the presence of piperidine to yield 2-(2,4,6-triisopropylphenylsulfonyl)-9-(dicyanomethylene)fluorene.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@:5]([C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[CH2:6][CH2:7][CH3:8].CCN(CC)CC.Cl[C:37]([O:39][CH3:40])=[O:38].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:15][C:11]1[CH:10]=[C:9]([C@@:5]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:17]2)([O:4][CH2:3][CH2:2][NH:1][C:37]([O:39][CH3:40])=[O:38])[CH2:6][CH2:7][CH3:8])[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)Cl
Reactant: CCC[C@](OCCN)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC[C@](OCCNC(=O)OC)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-1-(2-aminoethoxy)-1-(3-chlorophenyl)butyl)piperidine-1-carboxylate (410 mg, 1 mmol) and DMAP (61 mg, 0.5 mmol) in dry CH2Cl2 (3 mL), Et3N (303 mg, 3 mmol) was added. The resulting mixture was cooled to 0-5° C. using a ice-water bath, a solution of methyl chloroformate (472 mg, 5 mmol) in dry CH2Cl2 (2 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 h at 0-5° C. Upon completion of the reaction water (5 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with 10% citric acid (2×10 mL) and brine, then dried over Na2SO4, filtered and concentrated to afford (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-(methoxycarbonylamino)ethoxy)butyl)piperidine-1-carboxylate (460 mg, 98%), which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:9]([Mg]Br)=[CH2:10].[Cl-].[NH4+]>O1CCCC1.O>[CH:1]1([CH:7]([OH:8])[CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[Mg]Br
Reactant: O=CC1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(O)C1CCCCC1
Temperature: -20 °C
Yield: 37.8 %

Procedure:
A solution of cyclohexanecarbaldehyde (4.79 mL, 39.8 mmol) in tetrahydrofuran (30 mL) was added dropwise to a solution of vinylmagnesium bromide (47.8 mL, 1 M in tetrahydrofuran, 47.8 mmol) stirring at −20° C. The solution was stirred for 30 minutes at −20° C. at which time saturated ammonium chloride solution (75 mL) was added and the reaction was allowed to warm to 25° C. The solution was diluted with water and extracted three times with ethyl acetate. The ethyl acetate layers were combined and washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, followed by 5% and 10% ethyl acetate in hexane to give the title compound (2.11 g, 38%). 1H NMR (300 MHz, CDCl3): δ ppm 1.40 (m, 11 H) 3.85 (m, 1H) 5.17 (m, 2 H) 5.86 (m, 1 H).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1.[C:18]12([CH2:28][C:29](O)=[O:30])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2>>[C:18]12([CH2:28][C:29]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[S:9][CH:10]=[CH:11][C:5]=4[C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:3]3)=[O:30])[CH2:25][CH:24]3[CH2:23][CH:22]([CH2:21][CH:20]([CH2:26]3)[CH2:19]1)[CH2:27]2
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1nc(-c2ccccc2)c2ccsc2c1=O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(-c2ccccc2)c2ccsc2c1=O

Procedure:
The product from Example 29B and 2-(adamant-1-yl)acetic acid was processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.52-1.81 (m, 12H) 1.95 (s, 3H) 2.07 (s, 2H) 7.46-7.64 (m, 4H) 7.71 (dd, J=7.48, 1.98 Hz, 2H) 8.35 (d, J=5.49 Hz, 1H) 11.36 (s, 1H); MS (ESI) m/z 420 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([C:14]1[C:15]([F:35])=[C:16]([N:22](S(CCC)(=O)=O)[S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH:17]=[C:18]([F:21])[C:19]=1[F:20])=[O:13])=[CH:7][CH:6]=2.[C-:36]#[N:37].[Na+]>CN(C=O)C.O>[C:36]([C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([C:14]1[C:15]([F:35])=[C:16]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:24])=[O:25])[CH:17]=[C:18]([F:21])[C:19]=1[F:20])=[O:13])=[CH:7][CH:6]=2)#[N:37]
Reactant: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F)S(=O)(=O)CCC
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCS(=O)(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(C#N)nc3c2)c1F
Temperature: 100 °C

Procedure:
A mixture of N-(3-(3-chloroquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)-N-(propylsulfonyl)propane-1-sulfonamide (50 mg, 0.1 mmol, 1.0 eq.) and NaCN (9.8 mg, 0.002 mol, 2.0 eq.) in DMF (10 mL) was heated at 100° C. for 10 h under N2 protection. The mixture was cooled, diluted with water and extracted with EA (20 mL×3). The combined organic layers were washed with water, saline and dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=4/1, v/v) to afford N-(3-(3-cyanoquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)propane-1-sulfonamide. LRMS (MAT) m/z calculated 435.1, found 435.0. 1H NMR (DMSO-d6, 400 MHz) δ 10.11 (brs, 1 H), 9.52 (s, 1 H), 8.75 (s, 1 H), 8.52 (d, 1 H), 8.41 (d, 1 H), 7.79 (m, 1 H), 3.22 (t, 2 H), 1.72 (m, 2 H), 0.95 (t, 3 H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.Cl.[O:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([NH2:21])[CH2:16]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:21][C@H:17]2[CH2:18][CH2:19][CH2:20][O:15][CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: N[C@H]1CCCOC1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CCCOC1
Temperature: 60 °C
Yield: 38.4 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.060 g, 0.28 mmol), (3S)-tetrahydro-2H-pyran-3-amine hydrochloride (from J&W Pharmatech, 0.059 g, 0.43 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.84 mmol) in isopropyl alcohol (0.95 mL) was heated at 60° C. overnight. The resulting mixture was concentrated and purified on silica gel (eluting with 0 to 50% ethyl acetate (EtOAc) in hexanes) to give the desired product (30 mg, 38%). LCMS calculated for C12H14N3O3S (M+H)+: m/z=280.1. Found: 280.0.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C:17]3[CH:29]=[CH:28][O:27][C:18]=3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].C([Sn](CCCC)(CCCC)/[CH:35]=[CH:36]\[CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)CCC>CS(C)=O.O1CCOCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH:12][C:13]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]3[C:16]([C:17]4[CH:29]=[CH:28][O:27][C:18]=4[CH2:19][O:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[C:2](/[CH:35]=[CH:36]\[CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:7]=1
Reactant: CCCC[Sn](/C=C\CN1CCCC1)(CCCC)CCCC
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occc1-2
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CCCC2)ccc2c1OCc1occc1-2
Temperature: 90 °C
Yield: 38.9 %

Procedure:
A mixture of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 7, 0.300 g) and 1-((Z)-3-tributylstannanyl-allyl)-pyrrolidine (Intermediate 54, 0.390 g) in DMSO (2 mL) and dioxane (8 mL) was de-gassed and purged with nitrogen before tris-(dibenzylideneacetone)dipalladium (0) (0.076 g) and tri-tert-butylphosphonium tetrafluoroborate (0.048 g) were added and the mixture was heated at 90° C. for 3 hours. After cooling, the mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water, dried (MgSO4), and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10%. The resultant product was triturated with ether to give methyl 7-{4-fluoro-2-[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]benzenesulfonyl-amino}-4H-furo[2,3-c]chromene-6-carboxylate (0.124 g), as a pale orange solid.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][P:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:9])[O:7][CH3:8].[C:15]([O:23][CH3:24])(=[O:22])/[CH:16]=[CH:17]\[C:18]([O:20][CH3:21])=[O:19].Cl>CO>[CH3:4][O:5][P:6]([CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH:16]([C:15]([O:23][CH3:24])=[O:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19])(=[O:9])[O:7][CH3:8]
Reactant: COC(=O)/C=C\C(=O)OC
Reactant: COC(=O)CP(=O)(OC)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(C(=O)OC)C(C(=O)OC)P(=O)(OC)OC

Procedure:
0.09 mol of sodium methylate in 25 cc of methanol was added within 45 minutes to a mixture of 136.5 g (0.75 mol) of carbomethoxy-methane-phosphonic acid dimethyl ester and 108 g (0.75 mol) of dimethyl maleate. The temperature was found to increase from 22° C to 41° C. The whole was allowed to further react for 30 minutes at 100° C. After neutralization by the addition of 5 cc of concentrated hydrochloric acid and filtration, all volatile matter was distilled off under vacuum at a base temperature up to 120° C. 1,2,3-tricarbomethoxy-propane-1-phosphonic acid dimethyl ester was obtained in a crude yield of 237 g (97 % of the theoretical). The ester had a boiling point of 169°-172° C under 0.7 mm of mercury. n25D = 1.4520.
Reaction SMILES: FC(F)(F)C1C=CC=CC=1N=S(C)C.CS[CH2:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:19]=1[NH2:20]>>[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[C:19]=1[NH2:20]
Reactant: CSCc1cccc(C(F)(F)F)c1N
Agent: CS(C)=Nc1ccccc1C(F)(F)F
Product: Cc1cccc(C(F)(F)F)c1N

Procedure:
The process of claim 18 in which 2-methyl-6-trifluoromethyl aniline is prepared by reacting 1-nitro-2-trifluromethylbenzene with carbon monoxide at elevated pressure over a noble metal catalyst to obtain 2-trifluoromethylphenyl isocyanate, such isocyanate is reacted with dimethyl sulfoxide in the presence of strong acid to produce 2-trifluoromethylphenyl-S,S-dimethylsulfilimine; the sulfilimine is rearranged in the presence of a rearrangement catalyst to 2-methylthiomethyl-6-trifluoromethylaniline and desulfurized under reductive conditions to obtain 2-methyl-6-trifluoromethylaniline.