Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.C(O)C>CCCCCC>[CH2:23]([O:22][C:20]([C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])=[O:21])[CH3:24]
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)OCC
Yield: 79.4 %

Procedure:
Into an appropriate reactor fitted with warming, cooling and stirring means, were poured 152.5 ml (1.5 mol) of 2,4-difluoroaniline and 425 ml (2.1 mol) of diethyl ethoxymethylenemalonate. The mixture was warmed at 90° to 100° C. for about three hours with evacuation of ethanol appearing in the condensation. This lead to a solid product which was treated with hexane, washed, crystallized from hexane and dried to give 356.5 g (yield 76.5%) of 1-(2,2-diethoxycarbonyl-vinylamino)-2,4-difluoro-benzene. Elemental analysis of the product showed a good correspondence with the formula C14H15NO4F2. 350 g (1.17 mol) of this product were poured into a reactor with 1 liter of diphenyloxide. The mixture was refluxed at 265°-270° C. for 11/2 hours with a subsequent evacuation of the ethanol produced during the cyclisation. After cooling to ambient temperature, there was obtained a residue which was treated with benzene and then with hexane, dried and recrystallized from methanol. This gave 239 g (yiel 80.7%) of 1,4-dihydro-3-ethoxycarbonyl-6,8-difluoro-4-oxo-quinoline, elemental analysis of which showed a good correspondence with the formula C12H9NO3F2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]=[C:11]=[S:12])=[O:9].[Cl:13][C:14]1[CH:20]=[C:19]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:15]=1[NH2:16].C1(C)C=CC=CC=1>C(O)C>[Cl:13][C:14]1[CH:20]=[C:19]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:15]=1[NH:16][C:11]([NH:10][C:8](=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[S:12]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: Cc1ccccc1C(=O)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (40 mg, yield 52%).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:7][C:8]=1[CH:9]([CH3:12])[CH2:10][OH:11])([CH3:3])[CH3:2].C(P(CCCC)CCCC)CCC.[CH3:36][O:37][C:38](=[O:49])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44](O)=[CH:43][C:42]=1[CH3:48]>C1(C)C=CC=CC=1>[CH3:36][O:37][C:38](=[O:49])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:11][CH2:10][CH:9]([C:8]2[S:7][C:6]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:18]=3)=[N:5][C:4]=2[CH:1]([CH3:2])[CH3:3])[CH3:12])=[CH:43][C:42]=1[CH3:48]
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)CO
Reactant: COC(=O)CCc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCC(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1C
Temperature: 0 °C
Yield: 47.3 %

Procedure:
2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol (329 mg, 1.0 mmol) is dissolved into anhydrous toluene (5 mL) and cooled in an ice bath to 0° C. with stirring under nitrogen. Tributyl phosphine (400 uL, 1.50 mmol) is added by syringe followed by 1-1′-azodicarbonyl-dipiperidine (405 mg, 1.50 mmol). Finally, 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (200 mg, 1.20 mmol) is then added. The reaction is allowed to stir under nitrogen at 0° C. for 1 hour, then room temperature and monitored by TLC and HPLC. Upon completion, the reaction is diluted with hexanes and allowed to stir vigorously for 10 min. The resulting white precipitate is then filtered away and the solution is concentrated under vacuum. The residue is further purified using either EtOAc/Hexanes (1:9) or Acetone/Hexanes (1:9) gradients on silica gel chromatography to yield 3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionic acid methyl ester (239 mg, 0.4725 mmol) or 45%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH:17]=O)[CH:14]=[CH:13][C:12]=1[NH2:19])[CH3:2].[C:21]([C:23]1[C:24](=[C:31]([C:34]#[N:35])[C:32]#[N:33])[O:25][C:26]([CH3:30])([CH3:29])[C:27]=1[CH3:28])#[N:22].C(Cl)(Cl)Cl.CC(C)=O>C(O)(=O)C.N1C=CC=CC=1.O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH:17]=[CH:28][C:27]2[C:26]([CH3:30])([CH3:29])[O:25][C:24](=[C:31]([C:32]#[N:33])[C:34]#[N:35])[C:23]=2[C:21]#[N:22])[CH:14]=[CH:13][C:12]=1[NH2:19])[CH3:2]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCOC(=O)CCCCCOc1cc(C=O)ccc1N
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCOc1cc(C=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C)ccc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Acetic acid (5 drops) was added to a solution of 6-(2-amino-5-formyl-phenoxy)-hexanoic acid ethyl ester (0.310 g, 1.10 mmol) and 2-(3-cyano-4,5,5-trimethyl-5H-furan-2-ylidene)-malononitrile (0.26 g, 1.33 mmol) in pyridine (10 ml). After stirring for 24 hours at room temperature, the mixture was diluted with 100 mls of water causing the formation of a dark purple precipitate which was removed by suction filtration and washed with water. The material, was found to be pure 6-{2-amino-5-[2-(4-cyano-5-dicyanomethylene-2,2-dimethyl-2,5-dihydro-furan-3-yl)-vinyl]-phenoxy}-hexanoic acid ethyl ester by NMR (0.38 g, 75%). Small crystals of this product were obtained by pouring the NMR sample (chloroform) into a small amount of acetone and allowing this solution to slowly evaporate. Mp: 164.5° C. 1H NMR (400 MHz, CDCl3) δ: 7.58 (d, 1H, J=16 Hz), 7.17 (dd, 1H, J=8 Hz, J=1.6 Hz), 7.01 (d, 1H, J=1.6 Hz), 6.77 (d, 1H, J=16 Hz), 6.72 (d, 1H, J=8 Hz), 4.70 (s, 2H), 4.16 (q, 2H, J=7.2 Hz), 4.11 (t, 2H, J=6.2 Hz), 2.38 (t, 2H, J=7.2 Hz), 1.91 (m, 2H), 1.78 (s, 6H), 1.76 (m, 2H), 1.61 (m, 2H), 1.28 (t, 3H, J=7.2 Hz). 13C NMR (400 MHz, CDCl3) δ: 176.06, 174.30, 173.59, 148.75, 146.35, 143.18, 126.97, 124.02, 113.85, 112.40, 111.65, 111.16, 110.20, 109.73, 96.99, 68.41, 60.35, 34.14, 28.78, 26.75, 25.65, 24.63, 14.26. IR (neat): 3461, 3341, 3251, 3215, 2987, 2946, 2873, 2360, 2219, 2208, 1728, 1630, 1587, 1549, 1521, 1482, 1448, 1415, 1357, 1335, 1273, 1235, 1211, 1187, 1166, 1145, 1108, 1028, 1013, 961, 946, 906, 871, 861, 828, 816, 805, 748.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][CH2:20][O:21][Si](C(C)C)(C(C)C)C(C)C)[C:11]=1[C:32]([NH2:34])=[O:33].Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][CH2:20][OH:21])[C:11]=1[C:32]([NH2:34])=[O:33]
Reactant: CC(C)[Si](OCCn1c(C(N)=O)c(Nc2ccc(I)cc2F)c2cnccc21)(C(C)C)C(C)C
Agent: Cl
Solvent: CO
Product: NC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
To a suspension of 3-(2-fluoro-4-iodo-phenylamino)-1-(2-triisopropylsilanyloxy-ethyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid amide (100 mg, 0.17 mmol) in methanol was added a 1M solution of HCl (0.34 mL, 0.34 mmol). The reaction mixture was heated at reflux and stirred for 1 hour. After cooling to room temperature the reaction mixture was passed through a 5 g SCX-2 cartridge eluting with MeOH then 2M solution of ammonia in MeOH. The appropriate fractions were combined and concentrated to give a residue that was purified by flash chromatography (Si-PPC, MeOH:DCM, gradient 0:100 to 20:80) to provide the title compound as an off-white solid (40 mg, 53%). LCMS (method A): RT=5.78 min, M+H+=441. 1H NMR (DMSO-D6) 3.70 (2H, q, J=5.3 Hz), 4.53 (2H, t, J=5.3 Hz), 4.94 (1H, t, J=5.3 Hz), 6.19 (1H, t, J=8.9 Hz), 7.20 (1H, m), 7.53 (1H, dd, J=11.0, 2.0 Hz), 7.60 (1H, dd, J=6.0, 1.0 Hz), 7.72 (1H, d, J=2.0 Hz), 7.81 (2H, s, br), 8.28 (1H, d, J=6.0 Hz), 8.52 (1H, d, J=1.0 Hz).
Reaction SMILES: P(C(C)(C)C)(C(C)(C)C)[C:2](C)(C)[CH3:3].N(C(C)C)C(C)C.[CH:21]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][C:34]2[C:39]([CH3:40])=[C:38]([O:41][C:42]3[CH:47]=[CH:46][C:45](Br)=[CH:44][C:43]=3[F:49])[N:37]=[CH:36][N:35]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])[CH3:22].[Si](C#C)(C)(C)C.[OH-].[Na+].CC(O)=O>O1CCOCC1.C1COCC1.CO.[Cu]I>[CH:21]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][C:34]2[C:39]([CH3:40])=[C:38]([O:41][C:42]3[CH:47]=[CH:46][C:45]([C:2]#[CH:3])=[CH:44][C:43]=3[F:49])[N:37]=[CH:36][N:35]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])[CH3:22]
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Reactant: Cc1c(Oc2ccc(Br)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Product: C#Cc1ccc(Oc2ncnc(OC3CCN(C(=O)OC(C)C)CC3)c2C)c(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Pd (II)(PhCN)2Cl2 (15 mg, 0.039 mmol) and CuI (9 mg, 0.047 mmol) were dissolved in anhydrous dioxane (3 mL), 10 wt % P(t-Bu)3 in hexanes (0.200 mL, 13.6 mg, 0.067 mmol), NH(i-Pr)2, (0.085 mL, 0.60 mmol), 4-[6-(4-bromo-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (243 mg, 0.50 mmol), and TMS-acetylene (0.083 mL, 0.60 mmol), were added and the reaction mixture was sealed, purged with nitrogen, and stirred at room temperature for 12 h. The reaction mixture was diluted with EtOAc (15 mL), the mixture was filtered through a silica pad, the solvent was evaporated in vacuo at 23 C to give a dark oil which was dissolved in THF (3.5 mL) and MeOH (1.5 mL). 1.0 N NaOH (0.75 mL, 0.75 mmol) was added and after 5 min glacial AcOH (0.086 mL, 1.5 mmol) was added. After addition of silica (2.4 g) the solvent was evaporated in vacuo at 25 C to give a solid which was pulverized with mortar and pestle. This crude product was adsorbed onto silica and purified by flash chromatography using hexanes-EtOAc, 82:18, then hexanes-EtOAc, 75:25, v/v, to give the title Compound C240 as a resin (67 mg, 32% over 2 steps). 1H NMR (400 MHz, CDCl3) δ 1.25 (d, J=6 Hz, 6H), 1.78 (m, 2H), 1.98 (m, 2H), 2.17 (s, 3H), 3.07 (s, 1H), 3.40 (m, 2H), 3.74 (m, 2H), 4.92 (m, 1H), 5.32 (m, 1H), 7.14 (m, 1H), 7.29 (m, 2H), 8.18 (s, 1H). LRMS calculated for C22H24FN3O4: 413.18. Found: 414.5 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](/[C:8](=[CH:13]\[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=1)/[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>CCOC(C)=O>[C:1]([O:5][C:6]([C@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C(=C/c1ccc(Cl)c(F)c1)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H](Cc1ccc(Cl)c(F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 755.2 %

Procedure:
(Z)-methyl 2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)acrylate (200 mg) and ca. Rh—(R,R)-[Et-DuPhos(COD)]OTf (4 mg) in 1:1 MeOH:EtOAc (3 mL; degassed 1 h with N2 prior to use) was dissolved in 8 Argonaut Endeavor™ reaction tubes. The reaction mixtures were put on the Endeavor™ under 40 psi H2 and stirred for 12 hours at room temperature. All of the reaction mixtures were then combined and concentrated to give (R)-methyl 2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)propanoate (1.52 g, 94.4% yield) as a pale yellow solid, which was used without further purification in next step.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:19]=[CH:18][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2].C(O)(=O)C.[BH4-].[Na+]>CS(C)=O>[N+:1]([CH2:4][CH2:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])/C=C/c1ccc(COc2ccccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(COc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-((E)-2-nitro-vinyl)-benzyloxy)-pyridine described in Preparation Example 1-3-3 (21.0 g, 81.9 mmol), acetic acid (21 mL) and dimethylsulfoxide (200 mL) was added sodium borohydride (4.96 g, 131 mmol), while being suitably cooled at room temperature. After sodium borohydride was added, the cold bath was removed, the solution was stirred at room temperature for 15 minutes. The reaction solution was partitioned into water and ethyl acetate. The ethyl acetate layer was washed twice with water and once with sodium chloride water, this was dried over anhydrous magnesium sulfate, and the solvent thereof was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (16.3 g).
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1.[OH-].[Li+]>C(O)C>[F:1][C:2]1([F:17])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OCC2CC2(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCC2CC2(F)F)cc1
Reaction time: 18 h
Yield: 94.6 %

Procedure:
Methyl 4-[(2,2-difluorocyclopropyl)methoxy]benzoate (1.94 g, 8.01 mmol) prepared in Example 40 (40a) was dissolved in ethanol (24 mL), and a 2 M lithium hydroxide aqueous solution (8 mL, 16 mmol) was added thereto at room temperature. The resulting mixture was stirred at the same temperature for 18 hours. The solvents (mainly ethanol) were evaporated, and water was added to the obtained residue. Then, the resulting mixture was changed to weak acidic by adding 2 N hydrochloric acid under ice-cooling with stirring. The precipitated insoluble substance was collected by filtration, washed with water and n-hexane, and dried under reduced pressure to give 1.73 g of the title compound (white powder, yield: 95%).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[N:16](C(OC(C)(C)C)=O)[CH:10]([CH2:11][C:12]([C:39]3[S:43][C:42]([O:44][CH2:45][CH2:46][O:47][C:48]4[C:53]([Cl:54])=[CH:52][C:51]([CH3:55])=[CH:50][C:49]=4[Cl:56])=[N:41][CH:40]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=O)(C)(C)C.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH:35]1([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[C:24]([C:13]2[CH:14]3[NH:16][CH:10]([CH2:11][C:12]=2[C:39]2[S:43][C:42]([O:44][CH2:45][CH2:46][O:47][C:48]4[C:53]([Cl:54])=[CH:52][C:51]([CH3:55])=[CH:50][C:49]=4[Cl:56])=[N:41][CH:40]=2)[CH2:9][NH:8][CH2:15]3)=[O:38])[CH2:37][CH2:36]1
Reactant: Cc1cc(Cl)c(OCCOc2ncc(C3=C(C(=O)N(Cc4cccc(Cl)c4Cl)C4CC4)C4CN(C(=O)OC(C)(C)C)CC(C3)N4C(=O)OC(C)(C)C)s2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)c(OCCOc2ncc(C3=C(C(=O)N(Cc4cccc(Cl)c4Cl)C4CC4)C4CNCC(C3)N4)s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
A sol. of compound F6 (3.29 mmol; 2.86 g) in CH2Cl2 (16.5 mL) at 0° C. was treated with HCl (4.0 M in dioxane; 16.5 mL, 66 mmol) and stirred for 1 h at rt. Sat. aq. Na2CO3 (100 mL) was added and the aq. layer was extracted with EtOAc (3×100 mL), dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC(CH2Cl2/MeOH 75:25) yielded the title compound (1.51 g, 68%). LC-MS: tR=0.89 min; ES+: 669.09.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)#N.Cl.CC[O:13]CC>>[C:1]1(=[O:13])[C:9]2[N:5]([CH:6]=[CH:7][CH:8]=2)[CH2:4][CH2:3]1
Reactant: N#CCCn1cccc1
Reactant: CCOCC
Agent: Cl
Product: O=C1CCn2cccc21
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of 10 g N-cyanoethylpyrrole in 100 ml ether was added 2.5 g ZnCI2. Dried HCl was passed into the mixture at 5°-10° C. After 2 hours, the reaction mixture was allowed to stand at room temperature for 4 hours. Removed the solvent by suction, 20%. Aqueous NaOH was added until pH 3. The mixture was stirred at 80°-90° C. for 2 hours. Extracted with methylene chloride, dried over Na2SO4, evaporated the solvent, 8 g yellow solid was obtained. The crude product was crystallized from petroleum ether, 6.5 g compound (1) was obtained, as white crystals, mp 53°-54.5° C., yield 65%.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[CH3:11].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]2[C:5]=1[CH2:11][O:2][C:3]2=[O:12]
Reactant: COC(=O)c1cccc(Br)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OCc2c(Br)cccc21
Temperature: 25 °C

Procedure:
To a stirring solution of 3-Bromo-2-methyl-benzoic acid methyl ester (500 mg, 2.22 mmol) in carbon tetrachloride (6 mL) at 0° C., was added chromylchloride (0.36 mL, 4.45 mmol) and the reaction mixture was heated to reflux for 20 h. The reaction mixture was cooled to RT, added ice water and sat sodium bicarbonate solution at 0° C. Extracted with ethyl acetate (3×) the combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-10% ethyl acetate in pet. ether) afforded 4-bromo-3H-isobenzofuran-1-one as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:28]([OH:30])=[O:29])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)=[O:10])=[C:4]([CH3:31])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:44](O)[CH2:45][OH:46].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:28]([O:30][CH2:44][CH2:45][OH:46])=[O:29])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)=[O:10])=[C:4]([CH3:31])[CH:3]=1
Reactant: OCCO
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)O)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)OCCO)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.36 g (3 mmol) of 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-2-carboxylic acid (Example 20A) are dissolved in 6 ml of absolute DMF, and 0.58 g (3.6 mmol) of N,N-carbonyldiimidazole is added. The reaction mixture is stirred at RT for 3 h. Then 18.4 g (16.5 ml, 297 mmol) of 1,2-ethanediol and 303 mg (418 μl, 3 mmol) of triethylamine are added. The reaction mixture is stirred at 50° C. for 1.5 h and at RT overnight. Dilution with water is followed by extraction twice with ethyl acetate. The combined extracts are washed twice with saturated sodium bicarbonate solution, once with water and twice with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue from evaporation is purified by chromatography on silica gel with cyclohexane/ethyl acetate as eluent.
Reaction SMILES: C([O:5][C:6](=[O:21])/[CH:7]=[CH:8]/[C:9]1[CH:20]=[N:19][C:12]2[NH:13][C:14](=[O:18])[NH:15][C:16](=[O:17])[C:11]=2[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:18]=[C:14]1[NH:13][C:12]2[N:19]=[CH:20][C:9](/[CH:8]=[CH:7]/[C:6]([OH:21])=[O:5])=[CH:10][C:11]=2[C:16](=[O:17])[NH:15]1
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2[nH]c(=O)[nH]c(=O)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1cnc2[nH]c(=O)[nH]c(=O)c2c1
Reaction time: 6 h
Yield: 116.4 %

Procedure:
To a suspension of (E)-3-(2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl)acrylic acid tert-butyl ester (379 mg, 1.19 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (2 mL). After 6 h, the solvent was concentrated, the resulting solid was treated with anhydrous HCl (10 mL of a 4 M solution in dioxane, 40 mmol) and the mixture was sonicated for 10 min. The mixture was diluted with Et2O and the solution was filtered. The olive solid was dried under high vacuum at 45° C. overnight to give the title compound (323 mg, 91%) as the TFA salt: 1H NMR (300 MHz, DMSO-d6) δ 11.89 (s, 1H), 11.56 (s, 1H), 8.94 (d, J=1.8 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H), 7.69 (d, J=16.1 Hz, 1H), 6.72 (d, J=16.1 Hz, 1H), 4.40 (bs, 1H); ESI MS m/e 234 (C10H7N3O4+H)+.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[B-](F)(F)(F)/[CH:10]=[CH:11]/[CH3:12].[K+].FC(F)(F)S(O[C:23]1[C:24]([CH3:33])=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[O:27][CH2:26]2)(=O)=O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:33][C:24]1[C:23](/[CH:10]=[CH:11]/[CH3:12])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][O:27][C:28]2=[O:32]
Reactant: C/C=C/[B-](F)(F)F
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)ccc2c1COC2=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: C/C=C/c1ccc2c(c1C)COC2=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To Pd(dppf)Cl2 (0.220 g, 0.338 mmol), K3PO4 (6.75 mL, 1 M in water, 6.75 mmol) in THF (22 mL) was added potassium (E)-trifluoro(prop-1-en-1-yl)borate (0.749 g, 5.06 mmol) and 4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl trifluoromethanesulfonate (I-4B, Method 2, step D, 1.0 g, 3.38 mmol). The reaction mixture was de-gassed for 10 min and the resulting mixture was stirred overnight at 70° C. The reaction mixture was cooled to room temperature and diluted with EtOAc and water. After separation of layers, the aqueous layer was extracted with EtOAc, and combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, concentrated and purified by silica gel column chromatography using (0-50%) acetone-hexanes as mobile phase to give the title compound. LC/MS: [(M+1)]+=189
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([O:12]CC)=O.[NH2:15][NH2:16]>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([NH:15][NH2:16])=[O:12]
Reactant: NN
Reactant: CCOC(=O)c1nc2ccccc2s1
Solvent: CCO
Product: NNC(=O)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of ethyl benzo[d]thiazole-2-carboxylate (10 g, 48.25 mmol) in ethanol (200 mL) was added hydrazine (15.5 g, 482.5 mmol). The reaction mixture was stirred at RT for 30 min and concentrated under high vacuum to remove hydrazine. The resulting residue was triturated with ethanol (40 mL) to give benzo[d]thiazole-2-carbohydrazide (9.3 g, quant.) LRMS (M+H+) m/z 194.0.