Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH:13]1([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2I)[CH2:15][CH2:14]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:16]=3[CH:13]3[CH2:15][CH2:14]3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Ic1cnccc1C1CC1
Reactant: O=C1NCCc2ccc(Cl)cc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2cc(Cl)ccc2CCN1c1cnccc1C1CC1
Yield: 25.5 %

Procedure:
7-Chloro-3,4-dihydroisoquinolin-1(2H)-one (I-1d: 100 mg, 0.552 mmol) was reacted with 4-cyclopropyl-3-iodopyridine (I-73c: 162 mg, 0.662 mmol), 1,4-dioxane (5 mL), copper iodide (31 mg, 0.165 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (8 mg, 0.055 mmol) and potassium phosphate (351 mg, 1.657 mmol for 48 hours at 120° C. to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 42 mg of the product (25.45% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:37]1[CH2:41][CH2:40][N:39]=[C:38]1[C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][CH2:51][NH:50][CH2:49]2)=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>ClCCCl>[NH:39]1[CH2:40][CH2:41][N:37]=[C:38]1[C:42]1[CH:43]=[CH:44][C:45]([CH:48]2[CH2:53][CH2:52][CH2:51][N:50]([C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([CH3:14])[S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:11])=[O:12])[O:20][CH:19]=3)=[O:23])[CH2:49]2)=[CH:46][CH:47]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: c1cc(C2CCCNC2)ccc1C1=NCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N3CCCC(c4ccc(C5=NCCN5)cc4)C3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.15 mmol), CDI (51 mg, 0.31 mmol), 3-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]piperidine (49 mg, 0.15 mmol) and DIPEA (0.134 mL, 0.76 mmol) in DCE (1.2 mL).
Reaction SMILES: C(O)(=O)C([O:4][CH:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:6][NH:7][CH:8]([CH3:20])[CH2:9][NH:10][C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:20][CH:8]([NH:7][CH2:6][CH:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:4])[CH2:9][NH:10][C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(CNC(=O)Cc1ccccc1)NCC(OC(=O)C(=O)O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(CNC(=O)Cc1ccccc1)NCC(O)c1ccccc1

Procedure:
A mixture of 3.8 g. of 2-(1-methyl-2-phenylacetamidoethyl)amino-1-phenylethanol hydrogen oxalate (m.p. 160°-161° C.; Example 4) is stirred with 50 ml. of 10% aqueous potassium carbonate solution and 50 ml. of ethyl acetate. The ethyl acetate phase is separated, dried over anhydrous magnesium sulphate, and evaporated to dryness under reduced pressure. The residue is crystallised four times from 20 ml. of toluene each time. There is thus obtained one specific diastereoisomer (Isomer A) of 2-(1-methyl-2-phenylacetamidoethyl)amino-1-phenylethanol, m.p. 100°-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:20][C:19]([CH2:21][N:22]4[CH2:25][CH:24]([C:26]([O:28]C)=[O:27])[CH2:23]4)=[CH:18][C:17]=3[CH2:30][CH3:31])[N:12]=2)=[CH:7][CH:6]=1.O.[OH-].[Li+].C(O)(=O)C.C(O)(=O)C(O)=O>>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:20][C:19]([CH2:21][N:22]4[CH2:23][CH:24]([C:26]([OH:28])=[O:27])[CH2:25]4)=[CH:18][C:17]=3[CH2:30][CH3:31])[N:12]=2)=[CH:9][CH:10]=1
Reactant: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3ccccc3Cl)cc2)n1
Agent: O=C(O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(CN2CC(C(=O)O)C2)sc1-c1noc(-c2ccc(Oc3ccccc3Cl)cc2)n1
Yield: 68.8 %

Procedure:
The title compound (140 mg) was synthesized in a yield of 67% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 1 (1g) using methyl 1-[(5-{5-[4-(2-chlorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-4-ethyl-2-thienyl)methyl]azetidine-3-carboxylate (0.21 g, 0.41 mmol) that was obtained in Example 19 (19c), lithium hydroxide monohydrate (38 mg, 0.90 mmol), acetic acid (49 μL, 0.90 mmol), and oxalic acid (18 mg, 0.20 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[C:12]([Cl:29])=[N:13][C:14]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@H:19]2[CH3:28])=[N:15][C:16]=1[CH3:17]>CN(C)C=O>[ClH:29].[CH3:10][C:11]1[C:12]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])=[N:13][C:14]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@H:19]2[CH3:28])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1cc(F)ccc1N
Reactant: Cc1nc(N2CCc3ccccc3[C@H]2C)nc(Cl)c1C
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc(N2CCc3ccccc3[C@H]2C)nc(C)c1C
Product: Cl
Yield: 83 %

Procedure:
After 2-methyl-4-fluoroaniline(0.82 ml, 7.35 mmol) was added to a mixture solution of (R)-5,6-dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloropyrimidine(1.0 g, 3.5 mmol) prepared in the above Step 2 and dimethylformamide (10 ml), 1.2 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27][CH2:28][C:29]([C:31]1[CH:35]=[CH:34][S:33][CH:32]=1)=[O:30]>C(OCC)(=O)C.C(#N)C>[Br-:27].[CH2:1]([NH:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:17][CH2:16][N+:15]([CH2:28][C:29](=[O:30])[C:31]3[CH:35]=[CH:34][S:33][CH:32]=3)([CH2:20][CH2:19]2)[CH2:14]1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccsc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(NCc1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(NCc1ccccc1)c1ccccc1)C2)c1ccsc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.6 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-(benzylamino)-2-phenylacetate (C80) (116 mg, 0.33 mmol) in ethyl acetate (3.31 mL) and acetonitrile (3.31 mL), is added 2-bromo-1-(thiophen-3-yl)ethanone (66.5 mg, 0.32 mmol). The mixture is stirred at RT overnight. The insoluble precipitate is filtered on a buckner funnel and washed with acetonitrile. The clear solution is evaporated and purified by flash chromatography (DCM/EtOH=9/1) to obtain the title compound as a white solid (26 mg, 14% yield, bromide salt, mixture of diastereoisomers).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Si:10]([O:17][CH:18]1[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24]2[N:23]=[C:22]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:21]([CH:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)O)=[C:20]([C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)[C:19]1=2)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[Si:10]([O:17][CH:18]1[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24]2[N:23]=[C:22]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:21]([CH:35]([F:7])[C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:39][CH:38]=3)=[C:20]([C:47]3[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=3)[C:19]1=2)([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C(O)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)cc3)c2C(O[Si](C)(C)C(C)(C)C)C1
Solvent: Cc1ccccc1
Product: CC1(C)Cc2nc(C3CCCC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)cc3)c2C(O[Si](C)(C)C(C)(C)C)C1

Procedure:
1.46 g of diethylaminosulphur trifluoride dissolved in 10 ml of toluene were added dropwise at −5° C. to 3.8 g of [5-(tert-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-5,6,7, 8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanol dissolved in 37.8 ml of toluene. The reaction was quenched after 30 minutes using saturated aqueous sodium hydrogencarbonate solution and the organic phase was washed again using saturated aqueous sodium hydrogencarbonate solution and dried. After distilling off the solvent in vacuo, the residue was recrystallized from ethanol. A total of 3.33 g of colorless crystals having a purity of 99.4% according to HPLC resulted. By chromatography on silica gel, it was possible from the mother liquor of the crystallization, using petroleum ether/ethyl acetate 10:1, to obtain a further 0.26 g of the same quality.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][P:14](=[O:21])([O:18]CC)[O:15]CC.[Si](Br)(C)(C)C>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][P:14](=[O:15])([OH:21])[OH:18]
Reactant: CCOP(=O)(CCCCCCCCCCCCBr)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)CCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound BDPA was synthesized in two steps. In the first step, diethyl 12-bromododecylphosphonate is prepared as specified in Example 1. In the second step, diethyl 12-bromododecylphosphonate (2.43 g; 6.32 mmol) is reacted with Me3SiBr (2.89 g; 18.93 mmol) in 50 ml of dry CH2Cl2 with stirring at room temperature for 12 hours.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[C:5]([N:14]=[C:15]=[O:16])=[C:4]([F:17])[CH:3]=1.[H-].[Na+].[NH2:20]/[C:21](/[C:28]([F:31])([F:30])[F:29])=[CH:22]\[C:23](OCC)=[O:24].CI.[C:34](=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[C:5]([N:14]2[C:23](=[O:24])[CH:22]=[C:21]([C:28]([F:31])([F:30])[F:29])[N:20]([CH3:34])[C:15]2=[O:16])=[C:4]([F:17])[CH:3]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CC1(C)C=Cc2c(Cl)cc(F)c(N=C=O)c2O1
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2OC(C)(C)C=C3)c1=O
Yield: 74.1 %

Procedure:
By the method of Example 1, Step G, 1.4 grams (0.005 mole) of 5-chloro-2,2-dimethyl-7-fluoro-2H-1-benzopyran-8-yl isocyanate was reacted with 0.3 gram (0.008 mole) of sodium hydride and 1.1 grams (0.006 mole) of ethyl 3-amino-4,4,4-trifluorocrotonate in 100 mL of tetrahydrofuran. Subsequently, 1.6 grams (0.011 mole) of methyl iodide and 1.5 grams (0.011 mole) of potassium carbonate were reacted with the product of the first reaction. The crude reaction product was purified by column chromatography on silica gel, with 1:9 methylene chloride:hexane and pure methylene chloride as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.5 grams of 3-(5-chloro-2,2-dimethyl-7-fluoro-2H-1-benzopyran-8-yl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[C:21](=[O:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][C:13]([F:24])=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[CH:21]([OH:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][C:13]([F:24])=[CH:12][CH:11]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2nc3cc(F)ccc3c(NCc3ccccc3)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2nc3cc(F)ccc3c(NCc3ccccc3)c21
Reaction time: 1 h

Procedure:
To a cooled suspension of 4.85 g of 9-benzylamino-3,4-dihydro-6-fluoroacridin-1(2H)-one in 80 ml of tetrahydrofuran was added 7.5 ml of 1 molar solution of lithium aluminum hydride in THF. This was stirred for 1 hour.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1.C([O-])(O)=O.[Na+]>C(O)C.O>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([O:9][CH2:13][CH3:14])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)C(O)c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(O)c1ccc(O)cc1
Temperature: 50 °C
Yield: 288 %

Procedure:
A mixture of 5 g of 4-hydroxymandelic acid and 1.28 g of p-toluenesulfonic acid in 200 ml of ethanol is heated at 50° C. for 4 hours. The mixture is poured into saturated aqueous NaHCO3 solution, and a white precipitate is formed. The mixture is diluted with water until the precipitate disintegrates, and then is extracted with diethyl ether. The organic phases are dried over sodium sulfate. Filtration and evaporation of the solvent give ethyl 4-hydroxymandelate (4.2 g, 82%) as a pale yellowish solid.
Reaction SMILES: [CH3:1][NH:2]N.Cl.[CH2:5]([O:7][C:8](=[O:21])[C:9](=[CH:17][N:18](C)C)[C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:6]>C(O)C>[CH2:14]([O:13][C:11]([C:10]1[N:2]([CH3:1])[N:18]=[CH:17][C:9]=1[C:8]([O:7][CH2:5][CH3:6])=[O:21])=[O:12])[CH3:15]
Reactant: CNN
Reactant: CCOC(=O)C(=O)C(=CN(C)C)C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(C)c1C(=O)OCC
Temperature: 60 °C
Yield: 36 %

Procedure:
Under an atmosphere of argon, methylhydrazine (1.15 g, 25 mmol) and HCl (36.5% in water, 2.5 ml) were added to a solution of 2-dimethylaminomethylene-3-oxo-succinic acid diethyl ester (6.07 g, 25 mmol, obtained by the method of Hanzlowsky et al., J. Heterocyclic Chem. 2003, 40(3), 487-498) in ethanol (200 ml). The mixture was heated to 60° C. until HPLC analysis indicated the disappearance of the starting material (2 h). The solvent was evaporated, and the residue was taken up in dichloromethane and washed (water). The organic layer was dried (Na2SO4), the solvent was evaporated and the title compound (2.06 mg, 36%) was isolated from the mixture by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40). (The regioisomeric 1-methyl-1H-pyrazole-3,4-dicarboxylic acid diethyl ester can also be isolated, and can be distinguished from the desired product by NOE-1H-NMR.) MS (m/e)=227.2 [M+H+].
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:17][CH2:18][CH3:19])[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([OH:16])=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:25]([O:24][C:22](=[O:23])[C:21]([CH3:28])([O:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:17][CH2:18][CH3:19])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:15]2)[CH3:27])[CH3:26]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(-c2ccccc2)cc2cc(O)ccc21
Product: CCCn1c(-c2ccccc2)cc2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 2-phenyl-1-propyl-1H-indole-5-ol and ethyl 2-bromo-2-methyl-propanoate using a procedure analogous to that of Example 10.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=O.[CH3:11][O:12][C:13](=[O:16])[CH2:14][SH:15].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[F:10][C:6]1[CH:5]=[N:4][CH:3]=[C:2]2[S:15][C:14]([C:13]([O:12][CH3:11])=[O:16])=[CH:8][C:7]=12
Reactant: O=Cc1c(F)cncc1F
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(F)cncc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a cooled (0° C.) solution of 3,5-difluoro-4-formylpyridine (1.00 g, 6.99 mmol) in THF (12.3 mL) was added mercaptoacetic acid methyl ester (625 μL, 6.99 mmol). The reaction stirred 1 h at 0° C. and 1 h at room temperature, and then cesium carbonate (2.28 g, 6.99 mmol) was added. The reaction then stirred a further 18 h at room temperature. The reaction mixture was then partitioned between ethyl acetate (50 mL) and brine (50 mL). The layers were separated and the organic fraction was washed with water (1×50 mL) and brine (1×25 mL), then dried over sodium sulfate, filtered, and concentrated. Purification by ISCO chromatography (20 to 40% ethyl acetate:hexanes) afforded 942 mg (64%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.23-9.29 (m, 1 H), 8.56 (dd, J=2.0, 0.5 Hz, 1 H), 8.25 (d, J=0.8 Hz, 1 H), 3.94 (s, 3 H); MS (ESI): 212.09 [M+H]+; HPLC tR=3.17 min (ZQ3, polar—4 min).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28](=[S:30])[NH2:29])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].Br[CH2:32][C:33](=O)[C:34]([CH3:37])([CH3:36])[CH3:35]>>[C:34]([C:33]1[N:29]=[C:28]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[S:30][CH:32]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)C(=O)CBr
Reactant: N#CC1CCN(C(=O)N2CC(C(N)=S)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Product: CC(C)(C)c1csc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
200 mg (about 0.204 mmol) of the compound from Example 117A and 55 mg (0.300 mmol) of 1-bromo-3,3-dimethylbutan-2-one were reacted according to the General Method 3. Yield: 43 mg (40% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=2[CH3:33])(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:34]1([CH2:39][C@@H:40]2[CH2:44][CH2:43][CH2:42][NH:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:41]3[CH2:42][CH2:43][CH2:44][C@H:40]3[CH2:39][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:32])[C:25]=2[CH3:33])(=[O:11])=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)O
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)N1CCC[C@H]1CN1CCCC1

Procedure:
5-[5-(3,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.24 mmol) was coupled with (S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (40 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) at rt for 2 days to give the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:5]=[CH:6][C:7]([NH:9][C:10]1[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:12]([O-:14])=[O:13])=[O:8].[NH2+]1CCOCC1.Cl>O.CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:5]=[CH:6][C:7]([NH:9][C:10]1[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:12]([OH:14])=[O:13])=[O:8]
Reactant: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)[O-])cc1O
Agent: C1COCC[NH2+]1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)O)cc1O
Yield: 74 %

Procedure:
A 10 g quantity of morpholinium N-(3-hydroxy-4-methoxycinnamoyl)anthranilate is dissolved in a mixture of 80 ml of water and 60 ml of methyl alcohol with heating, and the resultant solution is added dropwise to 85 ml of diluted hydrochloric acid (5 ml of conc. hydrochloric acid and 80 ml of water) with stirring. The precipitated crystals which form are collected by filtration, washed with water and then dried at 90°-100° C. under reduced pressure for 3 hours to yield N-(3-hydroxy-4-methoxycinnamoyl)anthranilic acid (74.0% yield). The compound is confirmed as identical to that obtained in Example IV.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[CH3:11][C:12]([S:15]([NH2:17])=[O:16])([CH3:14])[CH3:13].O>C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5](/[C:8](=[N:17]/[S:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])/[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(N)=O
Reactant: CC(=O)c1ccc(Cl)nn1
Solvent: C1CCOC1
Solvent: O
Product: C/C(=N\S(=O)C(C)(C)C)c1ccc(Cl)nn1
Temperature: 60 °C

Procedure:
To a solution of 1-(6-chloro-pyridazin-3-yl)-ethanone (34 mg, 0.22 mmol) in dry THF (1.0 mL) was added 2-methyl-propane-2-sulfinic acid amide (29 mg, 0.24 mmol). Ti(OEt)4 (0.090 mL, 0.43 mmol) was added in one portion and the reaction was heated to 60° C. for 1 h. Water was added to the reaction mixture and the resulting slurry was filtered through a pad of diatomaceous earth. The filtrate was dried over Na2SO4 and was concentrated to provide 2-methyl-propane-2-sulfinic acid[1-(6-chloro-pyridazin-3-yl)-eth-(E)-ylidene]-amide as a crude residue that was used without purification, m/z 260.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][N:7]=1.[CH2:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)[CH2:21][CH3:22].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:28][CH2:27][C:26]3[CH:29]=[CH:30][C:23]([CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(C=O)c2)cnc1N
Reactant: CCCc1ccc(CN)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCc1ccc(CNCc2cccc(-c3cnc(N)c(C(=O)NC)n3)c2)cc1
Yield: 32.4 %

Procedure:
To a stirred solution of 3-amino-6-(3-formylphenyl)-N-methylpyrazine-2-carboxamide (50 mg, 0.19 mmol) and 4-propylbenzylamine (35.7 mg, 0.24 mmol) in TBF (5 mL) was added sodium cyanoborohydride (ca. 5 eq.) and the solution was stirred until refluxed for 1 h. The solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and saturated aqueous solution of Na2CO3 (10 mL). The phases were separated. The organic layer was washed with saturated aqueous sodium chloride then dried (Na2SO4). Filtration and concentration followed by HPLC purification gave (24 mg, 32% yield) of 3-amino-N-methyl-6-[3-({[(4-propylphenyl)methyl]amino}methyl)phenyl]pyrazine-2-carboxamide: 1H NMR (400 MHz; DMSO-d6): 9.7 (br s, 1H); 9.0 (m, 1H); 8.87 (s, 1H); 8.5 (s, 1H); 8.4 (d, 1H); 7.5 (m, 6H); 7.43 (m, 2H); 4.2 (d, 2H); 2.82 (d, 3H); 2.56 (m, 2H); 1.6 (m, 2H); 0.9 (m, 3H); MS (EI) for C23H27N5O: 390 (MH+).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH:3]=[CH:4][N+:5]([O-:7])=[O:6].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH2:10]([NH:17][CH:3]([CH2:4][N+:5]([O-:7])=[O:6])[C:2]([F:9])([F:8])[F:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])C=CC(F)(F)F
Solvent: Cc1ccccc1
Product: O=[N+]([O-])CC(NCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of 3,3,3-trifluoro-1-nitroprop-1-ene (4 g, 28.4 mmol) and benzylamine (3.2 g, 30.0 mmol) in toluene (50 mL) was stirred for RT or 1 h. The mixture was concentrated and the residue was purified by column chromatography (EtOAc/PE=1/10) to give the title compound (5.5 g, 78%). 1H NMR (400 MHz, CDCl3) δ ppm 3.91-3.95 (m, 1H), 4.06-4.14 (m, 1H), 4.45-4.51 (m, 1H), 4.63-4.67 (m, 1H), 7.30-7.39 (m, 5H).