Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(=O)C.[Na+].C(O)C>O.Cl>[C:20]1([NH:26][N:27]=[C:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([C:13]([NH2:15])=[O:14])[C:5]3[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=3[CH2:3]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Reactant: NNc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)N1c2ccccc2CC(=NNc2ccccc2)c2ccccc21
Temperature: 60 °C

Procedure:
A mixture of 0.2 g (0.8 mmol) of 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide, 0.5 g (4.6 mmol) of phenylhydrazine and 0.5 g (6 mmol) of sodium acetate in a mixture of 5 mL of water, 5 mL of ethanol and 3 drops of concentrated hydrochloric acid was heated at 60° C. for thirty minutes and then allowed to cool to room temperature. The precipitate was then filtered and washed with cold water and dilute ethanol to give the desired product as yellow crystals of m.p. 220° to 220.8° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][C@:13]([CH3:49])([CH2:47]O)[C:14](=[O:46])[C@@H:15]([NH:23][C:24](=[O:45])[C@@H:25]([NH:29][C:30](=[O:44])[C@@H:31]([NH:35][C:36]([C:38]1[S:42][C:41]([CH3:43])=[N:40][CH:39]=1)=[O:37])[CH2:32][O:33][CH3:34])[CH2:26][O:27][CH3:28])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:9][CH2:49][C@:13]([OH:12])([CH3:47])[C:14](=[O:46])[C@@H:15]([NH:23][C:24](=[O:45])[C@@H:25]([NH:29][C:30](=[O:44])[C@@H:31]([NH:35][C:36]([C:38]2[S:42][C:41]([CH3:43])=[N:40][CH:39]=2)=[O:37])[CH2:32][O:33][CH3:34])[CH2:26][O:27][CH3:28])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(=O)c1ccc(C)cc1

Procedure:
Prepared according to procedures described above, by reacting p-toluenesulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C32H40N4O10S2 m/z: 705 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1B(O)O>>[C:18]([N:13]1[C:12]([C:31]2[S:30][CH:34]=[CH:33][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])([CH3:20])[CH3:21]
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C(C)(C)C)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: CC(C)(C)n1nc2c(c1-c1cccs1)CCNCC2
Yield: 65.5 %

Procedure:
The title compound (83 mg) was prepared according to Example 215 using 203 mg of 2-(tert-butyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 215, Step A) and 176 mg of 2-thiopheneboronic acid. MS (ESI): exact mass calculated for C15H21N3S, 275.15; found, m/z 276.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.57-7.56 (m, 1H), 7.08-7.06 (m, 1H), 7.01-7.00 (m, 1H), 3.29-3.27 (m, 2H), 3.17-3.14 (m, 2H), 2.51-2.48 (m, 2H), 1.37 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][NH2:3].O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:42])=[C:10]([C@:12]23[CH2:21][O:20][C@@H:19]([CH:22]([CH:28](OC)OC)[CH:23](OC)OC)[CH2:18][C@H:17]2[CH2:16][S:15][C:14]([NH:33]C(=O)C2C=CC=CC=2)=[N:13]3)[CH:11]=1.S(=O)(=O)(O)O>C(O)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:42])=[C:10]([C@:12]23[CH2:21][O:20][C@@H:19]([C:22]4[CH:23]=[N:3][N:2]([CH3:1])[CH:28]=4)[CH2:18][C@H:17]2[CH2:16][S:15][C:14]([NH2:33])=[N:13]3)[CH:11]=1
Reactant: COC(OC)C(C(OC)OC)[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(Br)ccc2F)CO1
Reactant: CNN
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: Cn1cc([C@H]2C[C@H]3CSC(N)=N[C@@]3(c3cc(Br)ccc3F)CO2)cn1
Temperature: 60 °C

Procedure:
Methylhydrazine (0.0834 mL, 1.60 mmol) followed by water (2.2 mL) was added to a solution of N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1,1,3,3-tetramethoxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C44) (0.65 g, 1.06 mmol) in ethanol (5 mL). Sulfuric acid (0.110 mL, 2.07 mmol) was then added in a drop-wise manner to the reaction mixture. The resulting solution was heated to 60° C. for 16 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and a saturated aqueous solution of sodium bicarbonate (100 mL). The layers were separated and the resulting aqueous layer was further extracted with ethyl acetate (3×100 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated to give a mixture of product and benzoylated product (0.79 g), which was taken directly to the following step. LCMS m/z 427.1 [M+H+] (product) and m/z 527.1 [M+H+] (benzoylated product).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([C:6]([Br:14])=[N:7][NH:8]2)=[CH:4][C:3]=1[Cl:15].[Cl:16][C:17]1[C:18]([N:23]2[C:27]([C:28](O)=O)=[CH:26][C:25]([O:31][CH3:32])=[N:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Br:14][C:6]1[C:5]2=[CH:4][C:3]([Cl:15])=[C:2]3[C:10]([C:11](=[O:13])[O:12][C:28]([C:27]4[N:23]([C:18]5[C:17]([Cl:16])=[CH:22][CH:21]=[CH:20][N:19]=5)[N:24]=[C:25]([O:31][CH3:32])[CH:26]=4)=[N:1]3)=[C:9]2[NH:8][N:7]=1
Reactant: COc1cc(C(=O)O)n(-c2ncccc2Cl)n1
Reactant: Nc1c(Cl)cc2c(Br)n[nH]c2c1C(=O)O
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(-c2nc3c(Cl)cc4c(Br)n[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Temperature: 0 °C
Yield: 34.1 %

Procedure:
To a suspension of 400 mg (1.38 mmol) of 6-amino-3-bromo-5-chloro-1H-indazole-7-carboxylic acid in 16 mL of anhydrous tetrahydrofuran at 10° C., is added 349 mg (1.38 mmol) of 2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carboxylic acid followed by 499 μL (6.20 mmol) of pyridine. Then the suspension is cooled to 0° C. and 376 μL (4.82 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at ambient temperature over the night. The reaction is not complete and therefore 166 μL (2.07 mmol) of pyridine are added followed by 349 mg (1.38 mmol) of 2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carboxylic acid. The reaction is stirred again at ambient temperature for 5 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated and washed with cold water. The pale yellowish product obtained is purified by flash chromatography (SiO2, heptane/ethyl acetate 1:1) affords 200 mg (0.47 mmol, 34%) of the product as a solid; LC/MS:509/511 (M+H)+.
Reaction SMILES: CS(Cl)(=O)=O.O[C@@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[CH2:22]([N:24](CC)CC)C>C(Cl)Cl>[CH3:22][NH:24][C@@H:9]1[C:14]2[C:15](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:16][CH2:7][C@H:8]1[N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O[C@@H]1CCc2ccccc2[C@H]1N1CCCC1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN[C@@H]1c2ccccc2CC[C@H]1N1CCCC1
Yield: 56.8 %

Procedure:
A solution of methanesulfonyl chloride (10.3 g) in methylene chloride (50 ml) was added rapidly in drops to a stirred and cooled (0.5° C.) solution of trans-1,2,3,4-tetrahydro-2-hydroxy-1-(pyrrolidin-1yl)naphthalene (10.3 g) and triethylamine (10 g) in methylene chloride (100 ml). After the addition was complete, the mixture was stirred at room temperature for 3 hours and then evaporated under reduced pressure. The residue was treated carefully with a 33% solution of methylamine in ethanol (125 ml) and the mixture was stirred at reflux for 2 hours followed by evaporation of the solvent under reduced pressure. The residue was treated with water and extracted twice with ether. The combined ether extracts were washed with 2N sodium hydroxide and then with water, dried over magnesium sulfate and evaporated under reduced pressure. The residual viscous liquid was distilled under vacuum to yield trans-1,2,3,4-tetrahydro-1-methylamino-2-(pyrrolidin-1-yl)naphthalene (6.2 g), b.p. 126°-134°/0.25 torr.
Reaction SMILES: [OH:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:12][C:13]1[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([CH:20]=1)[CH:18]=O.[C:25](#[N:29])[CH2:26][C:27]#[N:28].C1N2CCN(CC2)C1>C(O)C.O>[NH2:29][C:25]1[O:1][C:2]2[N:3]=[CH:4][C:5]3[C:10]([C:11]=2[CH:18]([C:17]2[CH:16]=[C:15]([O:21][CH3:22])[C:14]([O:23][CH3:24])=[C:13]([Br:12])[CH:20]=2)[C:26]=1[C:27]#[N:28])=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: N#CCC#N
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: Oc1cc2ccccc2cn1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CCO
Product: COc1cc(C2C(C#N)=C(N)Oc3ncc4ccccc4c32)cc(Br)c1OC
Temperature: 80 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
3-Hydroxyisoquinoline (638 mg, 4.4 mmol), 5-bromo-3,4-dimethoxy-benzaldehyde (1.077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 40 ml ethanol at room temperature, charged with DABCO (48.4 μl, 1.46 mmol) and then stirred at 80° C. under LC-MS control for 24 h. The reaction mixture was cooled down to room temperature, diluted with water to about 100 ml and the precipitates were collected by filtration, washed well with 50% aqueous ethanol and dried under vacuum to yield the title compound (1.35 g, 3.08 mmol, 70%).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]([C:20]1[CH:32]=[CH:31][C:30]2[C:29]3[C:24](=[CH:25][C:26]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:28]=3)[C:23](=[O:38])[C:22]=2[CH:21]=1)([O:17][CH2:18][CH3:19])=[O:16]>C(OCC)C>[C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:23]1([OH:38])[C:24]2[CH:25]=[C:26]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][C:29]=2[C:30]2[C:22]1=[CH:21][C:20]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:32][CH:31]=2
Reactant: CCOC(=O)c1ccc2c(c1)C(=O)c1cc(C(=O)OCC)ccc1-2
Reactant: Brc1ccccc1-c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(=O)c1ccc2c(c1)C(O)(c1ccccc1-c1ccccc1)c1cc(C(=O)OCC)ccc1-2
Reaction time: 3 h

Procedure:
The Grignard reagent prepared from 0.97 g (40 mmol) of magnesium turnings and 9.32 g (6.8 ml, 40 mmol) of 2-bromobiphenyl in 50 ml of dry diethyl ether is added dropwise over a period of 2 hours to a boiling solution of 13 g (40 mmol) of 2,7-dicarbethoxy-9-fluorenone in 100 ml of dry diethyl ether. After the addition is complete, the mixture is boiled for a further 3 hours. After cooling overnight, the precipitated solid is filtered off with suction and washed with cold ether. The magnesium complex filtered off with suction is hydrolyzed in a solution of 15 g of ammonium chloride in 250 ml of ice water. After 1 hour, the 9-(2-biphenylyl) -2,7-dicarbethoxy-9-fluorenol formed is filtered off with suction, washed with water and sucked dry. For the ring-closure reaction, the dried fluorenol is boiled in 100 ml of glacial acetic acid for 6 hours, after addition of 3 drops of concentrated HCl. The mixture is allowed to crystallize overnight, the product formed is filtered off with suction and washed with glacial acetic acid and water.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2C(=O)O[CH:17]([C:21]([F:24])([F:23])[F:22])[N:16]=2)=[CH:11][CH:10]=1.Cl[C:26](=[CH2:31])[C:27]([O:29][CH3:30])=[O:28]>C(#N)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:16][C:17]([C:21]([F:22])([F:23])[F:24])=[CH:31][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:13][CH:14]=1
Reactant: O=C1OC(C(F)(F)F)N=C1c1ccc(Cl)cc1
Reactant: C=C(Cl)C(=O)OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
Triethylamine (5.58 g, 0.055 mol) is added dropwise to a mixture of 4-(p-chlorophenyl)-2-(tri-fluoromethyl)-5(2H)-oxazolone (15.6 g, 0.054 mol), methyl α-chloroacrylate (6.52. g, 0.054 mol) and acetonitrile (50 mL). The reaction mixture heats up to 55° C. during the addition. After the addition is complete, the reaction mixture is heated at reflux temperature for one hour, cooled to room temperature and filtered. The filtrate is poured into an ether/water mixture and extracted with ether. The combined organic extracts are dried over anhydrous magnesium sulfate and concentrated in vacuo to give a black residue. Recrystallization of the residue from hexane gives the title compound as an orange solid (8.25 g, 50.2%). Indentified by NMR spectral analyses.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:32]=[CH:31][C:21]3[NH:22][C:23]([CH2:25][C:26]([O:28]CC)=O)=[N:24][C:20]=3[CH:19]=2)[CH2:14][CH2:13]1.[NH2:33][C:34]1[C:35]([C:40]#[N:41])=[N:36][CH:37]=[CH:38][CH:39]=1>C1COCC1>[NH2:41][C:40]1[C:35]2[C:34](=[CH:39][CH:38]=[CH:37][N:36]=2)[NH:33][C:26](=[O:28])[C:25]=1[C:23]1[NH:22][C:21]2[CH:31]=[CH:32][C:18]([N:15]3[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]3)=[CH:19][C:20]=2[N:24]=1
Reactant: N#Cc1ncccc1N
Reactant: CCOC(=O)Cc1nc2cc(N3CCN(C)CC3)ccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc3[nH]c(-c4c(N)c5ncccc5[nH]c4=O)nc3c2)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
LiHMDS (3.6 eq) was added to ethyl [5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]acetate (1.0 eq) and 3-aminopyridine-2-carbonitrile (1.0 eq) in THF at 0° C. The reaction was stirred overnight and then heated at 40° C. for 3 hours. The resulting mixture was quenched with an aqueous saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a green solid. The crude material was washed successively with CH2Cl2 and MeOH, and then was purified by reverse phase HPLC to provide the desired product. LC/MS m/z 376.1 (MH+), Rt 1.50 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7](=[O:21])[C:6](=[O:22])[NH:5]2.CO[CH:25]1[CH2:29][CH2:28][CH:27](OC)O1>C(O)(=O)C.O>[CH:15]1([N:8]2[C:9]3[C:4](=[CH:3][C:2]([N:1]4[CH:25]=[CH:29][CH:28]=[CH:27]4)=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=3)[NH:5][C:6](=[O:22])[C:7]2=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1cc2[nH]c(=O)c(=O)n(C3CCCCC3)c2cc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2cc(-n3cccc3)c([N+](=O)[O-])cc2n(C2CCCCC2)c1=O
Yield: 6.8 %

Procedure:
3.0 g (99 mmol) of 6-amino-1-cyclohexyl-7-nitro-2,3(1H,4H)-quinoxalinedione and 1.3 g (99 mmol) of 2,5-dimethoxytetrahydrofuran were refluxed in 70 ml of acetic acid for 30minutes. The mixture was then diluted with water, and the precipitate was filtered off with suction to yield 2.4 g (69%) of the product. Melting point 197° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2].[NH2:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]2[C:17]=1[CH2:18][O:19][C:20]2=[O:26]>C(#N)C>[CH:1](=[N:15]/[C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]2[C:17]=1[CH2:18][O:19][C:20]2=[O:26])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(F)cc2c1COC2=O
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: O=C1OCc2c(/N=C/c3ccccc3)cc(F)cc21
Temperature: 25 °C
Reaction time: 144 h
Yield: 65.5 %

Procedure:
To a stirred mixture of benzaldehyde (4.125 g, 29.9 mmol) and anhydrous magnesium sulfate (36 g, 299 mmol) in anhydrous acetonitrile (200 mL) was added 4-amino-6-fluoroisobenzofuran-1(3H)-one (5 g, 29.9 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 6 days. The mixture was filtered and the cake was washed with ethyl acetate (50 mL×3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether to give (E)-4-(benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one (5 g, yield: 66%). 1H-NMR (400 MHz, CDCl3) δ (ppm): 5.40 (s, 2); 7.11-7.14 (dd, 1H), 7.44-7.46 (dd, 2H), 7.53-7.59 (m, 3H), 7.93-7.95 (m, 2H), 8.54 (s, 1H); LC-MS (ESI) m/z: 256 (M+1)+.
Reaction SMILES: C(O[C:4](=O)[CH:5]([C:16]1[C:21]([NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[CH:20][CH:19]=[C:18]([O:33][CH3:34])[N:17]=1)S(C1C=CC(C)=CC=1)(=O)=O)C.[CH3:36][C:37](C)([O-:39])C.[K+].C1C[O:45][CH2:44]C1>>[CH2:37]([O:39][C:44](=[O:45])[CH:4]=[CH:5][C:16]1[C:21]([NH:22][C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])=[CH:20][CH:19]=[C:18]([O:33][CH3:34])[N:17]=1)[CH3:36]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(c1nc(OC)ccc1NC(=O)OCc1ccccc1)S(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)C=Cc1nc(OC)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (5° C.) solution of 15.7 g (0.031 mol) of (3-benzyloxycarbonylamino-6-methoxy-pyridin-2-yl)-(toluene-4-sulfonyl)-acetic acid ethyl ester dissolved in 160 mL of THF is added, dropwise, 31 mL of a 1N solution of potassium-t-butoxide dissolved in THF. The reaction mixture is warmed to room temperature and stirred for 2 hours. The reaction is quenched with 5 mL of water and evaporated. The residue is dissolved in 200 mL of ethyl acetate and 200 mL of water. The ethyl acetate layers are dried (Na2SO4) and evaporated. The residue is chromatographed on 375 grams of silica gel using 7/3 hexanes/ethyl acetate as the eluant. Appropriate fractions are combined and evaporated to yield 5.57 grams of 3-[3-benzyloxycarbonylamino-6-methoxy-pyridin-2-yl]-acrylic acid ethyl ester. 1H NMR (CDCl3) δ 7.8 (m, 2H), 7.4 (m, 2H), 7.0 (m, 1H), 6.8 (m, 1H), 6.7 (m, 1H), 5.2 (s, 2H), 4.2 (q, 2H), 3.9 (s, 3H), 1.3 (t, 3H). Mass spectrum: m/e=357 (p+1). Step 6:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:33]1(S(N2CCNCC2)(=O)=O)[CH:38]=[CH:37]C=[CH:35][CH:34]=1>>[C:32]1([S:29]([N:26]2[CH2:25][CH2:24][N:23]([C:21]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[CH:13][C:12]([C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)=[O:11])=[CH:20][CH:19]=4)=[O:22])[CH2:28][CH2:27]2)(=[O:30])=[O:31])[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=1
Reactant: O=S(=O)(c1ccccc1)N1CCNCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)c5ccccc5)CC4)cc3c2)CC1
Yield: 92 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate b) and 1-benzenesulfonyl-piperazine to afford the desired product as a light-brown foam (92%). MS (ISP): 524.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:21]([C:22](=[O:44])[NH:23][C@H:24]([C:40]([O:42][CH3:43])=[O:41])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:45]4[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]5[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=5)=[CH:47][CH:46]=4)[CH2:15][NH:16]3)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:61](Cl)(=[O:63])[CH3:62].C(N(CC)CC)C.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:21]([C:22](=[O:44])[NH:23][C@H:24]([C:40]([O:42][CH3:43])=[O:41])[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)=[CH:30][CH:31]=2)[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:45]4[CH:46]=[CH:47][C:48]([O:51][CH2:52][C:53]5[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=5)=[CH:49][CH:50]=4)[CH2:15][N:16]3[C:61](=[O:63])[CH3:62])=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CN3
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CN3C(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (S)-7-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tert-butyl ester (85 mg) in DCM (5 mL) at 0° C. was treated with acetyl chloride, and triethylamine. The mixture was allowed to slowly warm to room temperature. After 3 hours, ethyl acetate was added and the organic layer was washed with 1N HCl. The organic layer was washed saturated sodium bicarbonate solution and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to give the crude amide. The residue was purified by flash chromatography (using hexanes/ethyl acetate, from 70:30 to 55:45, as an eluent) to give the product (76 mg).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[CH3:10][NH:11][C:12]([NH2:14])=[O:13].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH3:10][N:11]1[CH2:7][CH:3]([C:2]([F:9])([F:8])[F:1])[C:4](=[O:5])[NH:14][C:12]1=[O:13].[CH3:10][N:11]1[C:4](=[O:5])[CH:3]([C:2]([F:9])([F:8])[F:1])[CH2:7][NH:14][C:12]1=[O:13]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: CNC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CN1C(=O)NCC(C(F)(F)F)C1=O
Product: CN1CC(C(F)(F)F)C(=O)NC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 15 %
Yield: 43 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (700 mg; 5.0 mmoles) and methylurea (378 mg; 5.1 mmoles) in DMF (5 ml) was cooled to 0° C., and a solution of DCC (1.07 g; 5.2 mmoles) in DMF (3 ml) was added dropwise. The mixture was stirred for 1 hour, and the precipitated solid was filtered off and washed with ethyl acetate. DMF was evaporated under reduced pressure from the combined filtrates. The residue was purified by a column chromatography on silica gel (ethyl acetate:chloroform=1:3) to give 420 mg (yield: 43%) of 1-methyl-5-trifluoromethyl-5,6-dihydrouracil (OF-3) and 30 mg (yield: 15%) of 3-methyl-5-trifluoromethyl-5,6-dihydrouracil (OF-2).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[Cl:15][C:16]1[CH:37]=[C:36]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:35]=[CH:34][C:17]=1OC1C=C(C(F)(F)F)C=CC=1CCC(O)=O.CN(C=[O:46])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([OH:12])=[O:46])=[C:10]([NH:9][C:17]2[CH:34]=[CH:35][C:36]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:37][C:16]=2[Cl:15])[CH:11]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(C(F)(F)F)ccc2CCC(=O)O)c(Cl)c1
Reactant: O=C1CCc2ccc(Cl)cc2N1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(Nc2cc(Cl)ccc2CCC(=O)O)c(Cl)c1
Temperature: 90 °C

Procedure:
A solution of the product from step (ii) (0.174 g) and sodium hydride (60% wt. disp. oil, 0.039 g) in DMF (10 ml) was stirred at 50° C. for 1 hour. The product from example 3 step (vi)-(vii) (0.200 g) was added and the mixture was refluxed at 90° C. for 3 hours. The mixture was partitioned between 2M sodium hydroxide and diethyl ether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate and the organic layer dried and concentrated under reduced pressure to give an oil. The residue was purified using RP prep HPLC. Yield 0.061 g