Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[C:12]([O:26][S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[CH:11]=2)=[CH:4][N:3]=1.[CH3:33][C:34]([O-:37])(C)C.[K+].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>CN(C)C=O>[C:34]([O:25][C:22]1[CH:21]=[CH:20][C:19]([C:13]2[C:14]([O:16][CH2:17][CH3:18])=[CH:15][C:10]([CH2:9][C:5]3[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[CH:11][C:12]=2[O:26][S:27]([CH:30]([CH3:31])[CH3:32])(=[O:29])=[O:28])=[CH:24][CH:23]=1)(=[O:37])[CH3:33]
Reactant: CC(C)(C)[O-]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C(C)C)c1-c1ccc(O)cc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C(C)C)c1-c1ccc(OC(C)=O)cc1
Yield: 26 %

Procedure:
Starting from propane-2-sulphonic acid 4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-4′-hydroxy-biphenyl-2-yl ester (example 15c) (137 mg; 0.30 mmol), potassium tert-butylate (42 mg; 0.37 mmol) and acetic anhydiide (0.028 ml; 0.30 mmol) in dimethylformamide (3.5 ml) at 0-5° C. (15 minutes) and then room temperature (3 hours), 39 mg (27%) 4′-(2,4-diamino-pyrimidin-5-ylmethyl)-6′-ethoxy-2′-(propane-2-sulphonyloxy)-biphenyl-4-yl acetate are obtained as a colourless powder.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].[C:12](/[CH:14]=[C:15](/[O-])\[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:13].[Na+].FC(F)(F)C(O)=O>O1CCOCC1>[NH2:13][C:12]1[N:5]([CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:2]=2[F:1])[N:6]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=1
Reactant: NNCc1cccc(F)c1F
Reactant: CCOC(=O)/C([O-])=C\C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(N)n(Cc2cccc(F)c2F)n1

Procedure:
Preparation takes place in analogy to that described in Example 7 A from 1.50 g (9.48 mmol) of 1-(2,3-difluorobenzyl)hydrazine from Example 2 A, 1.55 g (9.48 mmol) of sodium (1E)-1-cyano-3-ethoxy-3-oxo-1-propen-2-olate from Example 6 A, 1.73 g (1.17 ml; 15.18 mmol) of trifluoroacetic acid and 40 ml of dioxane.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[C:10]#[CH:11]>C(N(CC)CC)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:4]=1
Reactant: Ic1ccc(I)cc1
Reactant: C#CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C#Cc1ccc(I)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
To a mixture of 1,4-diiodobenzene (1.0 g, 3.03 mmol), Pd(PPh3)2Cl2 (580 mg, 0.606 mmol) and CuI (115 mg, 0.606 mmol) in triethylamine (20 mL), ethyl propiolate (590 mg, 6.06 mmol) was added under N2. The resulting mixture was stirred at 80° C. for 16 h under N2. The reaction mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was washed with water (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified on a silica gel column using 0-10% EtOAc in petroleum ether to afford the title compound (360 mg, 30%). 1H NMR (DMSO-d6, 400 MHz): δ 7.86 (d, 2H), 7.45 (d, 2H), 4.24 (q, 2H), 1.25 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH:24]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH2:25].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2](/[CH:25]=[CH:24]/[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(/C=C/S(C)(=O)=O)cc1-2
Yield: 73.1 %

Procedure:
A mixture of 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 (0.36 g, 0.92 mmol), methyl vinyl sulfone (0.24 mL, 2.8 mmol), bis(triphenylphosphine)palladium(II) chloride (64 mg, 0.092 mmol) and triethylamine (0.64 mL, 4.6 mmol) in DMF (10 mL) was heated under an argon atmosphere for 16 h. The reaction mixture was concentrated and purified by column chromatography (40 g column, 0-100% EtOAc/heptane) to provide 280 mg (73% yield) of 143. LC/MS (ESI+): m/z 417 (M+H). 1H NMR (400 MHz, DMSO) δ 8.59 (d, J=2.0, 1H), 8.11 (s, 1H), 7.71 (dd, J=8.4, 2.1, 1H), 7.59-7.26 (m, 2H), 7.17 (d, J=8.4, 1H), 5.88-5.67 (m, 1H), 4.43 (t, J=4.8, 2H), 3.48 (dd, J=12.3, 7.5, 2H), 3.12 (s, 1H), 1.58 (d, J=6.6, 6H)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([OH:18])[CH:17]=1.C(N(CC)CC)C>O1CCOCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:18][C:16]2[CH:17]=[C:12]([Cl:11])[CH:13]=[N:14][CH:15]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1cncc(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Oc2cncc(Cl)c2)cc1
Yield: 44.5 %

Procedure:
To a stirred solution of 4-fluoro-nitrobenzene (913 μL, 8.61 mmol, from Aldrich) in dioxane (1 mL) was added 3-chloro-5-hydroxypyridine (558 mg, 4.31 mmol, from Aldrich) followed by triethylamine (661 μL, 4.74 mmol). The solution was refluxed for 4.5 hours, evaporated and the crude solid was dissolved in ethyl acetate. The solution was washed three times with saturated K2CO3 solution, once with brine and then back-extracted with ethyl acetate. The two organic solutions were combined, concentrated and the residue was purified by chromatography (diethyl ether as eluant) to provide 481 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[F:12])#[N:2].O=S(Cl)[Cl:15]>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[CH:5][C:4]=1[F:12])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(C(=O)O)cc1F
Product: N#Cc1ccc(C(=O)Cl)cc1F
Yield: 99 %

Procedure:
A mixture of 4-cyano-3-fluoro-benzoic acid (2.0 g, 12.12 mmol) in SOCl2 (20 mL) was refluxed for 2 h, and SOCl2 was removed in vacuo to give 4-cyano-3-fluoro-benzoyl chloride (2.2 g, 99%). The crude was carried to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[C:7](=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=1)[C:6]2=[O:25].[H][H]>[Pd].C(OCC)(=O)C.O1CCCC1>[NH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][CH:7]1[C:6](=[O:25])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:9][C:8]1([CH3:13])[CH3:14]
Reactant: COc1ccc2c(c1)C(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)(C)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(=O)C(Cc1cccc(N)c1)C(C)(C)O2
Yield: 99 %

Procedure:
A mixture of 7.3 g (0.0125) of the product of Example 110 and 700 mg 5% palladium on carbon in 200 mL ethyl acetate and 50 mL tetrahydrofuran was shaken in a Parr hydrogenator under 30 psi hydrogen for 3 hours. The mixture was filtered through Celite and concentrated to give an oil. Flash chromatography on silica gel eluting with 50% ethyl acetate in hexanes yielded 6.8 g (99%) of the title product as an oil. NMR (CDCl3): δ1.38 (s, 3H); 1.47 (s, 3H); 2.20 (dd, 1H); 2.90 (m, 1H); 3.00 (dd, 1H); 3.60 (s, br, 2H); 3.78 (s, 3H). MS (Cl, NH3) m/e: 329 (M+ +18), 312 (M+ +1,2 100).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]C(C)(C)C)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:28][CH:29]1[CH2:31][CH2:30]1>CCO.CCO.CCO.CCO.[Ti]>[Br:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:28][CH:29]3[CH2:31][CH2:30]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CC1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Agent: [Ti]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Reaction time: 8 h

Procedure:
A mixture of 10 g (24 mmol) of tert.butyl (S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 31 g (430 mmol) of hydroxymethyl-cyclopropane and 1.80 g (8 mmol) of tetraethyl orthotitanate is stirred at 125° overnight, the solution obtained is evaporated to dryness, the residue is taken up in chloroform and stirred for 0.5 hour with 40 ml of a saturated potassium fluoride solution. The resulting emulsion is filtered through siliceous earth, the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated. By recrystallization from ethyl acetate and hexane there is obtained cyclopropylmethyl (S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 135°-136°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:21](Cl)(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].Cl>N1C=CC=CC=1>[C:17]([C:14]1[S:13][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:21](=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:16][N:15]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Reactant: CCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(C(C)(C)C)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
Compound 113 (250 mg, 0.80 mmol) was suspended in pyridine (1.5 mL). Decanoyl chloride (122 mg, 0.64 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred for 1 h. The reaction mixture was then added to aqueous 3 N HCl solution (4 mL) and the mixture extracted with ethyl acetate (3×10 mL). The organic extracts were washed with water (3×20 mL), brine (3×20 mL), dried over anhydrous Na2SO4, and filtered. Evaporation of the solvent left a residue which was crystallized from hexanes and ethyl acetate (1:2) to give the product (294 mg, 0.63 mmol, 98%) as a solid, mp 156-157° C.; 1H NMR (500 MHz, DMSO) δ 0.80 (3, t, J=7.0 Hz), 1.15-1.33 (21, m), 1.56 (2, t, J=7.0 Hz), 2.32 (3, t, J=7.0 Hz), 7.74 (2, d, J=8.0 Hz), 7.77 (2, d, J=8.0 Hz), 10.21 (1, s), 13.90 (1, s); 13C NMR (125 MHz, DMSO): δ 13.9, 22.1, 25.0, 28.6, 28.7, 28.8, 28.9, 29.3, 31.1, 36.0, 36.5, 118.6, 126.9, 135.7, 142.9, 167.0, 167.2, 171.9; MS (LCQ, ESI+) Calculated for C22H35N4O3S2 467.2. found 467.2 (M+H)+; HRMS (FAB+, m/z) Calculated for C22H35N4O3S2 467.2151. found 467.2131 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=[C:4]1[C:18](Cl)=[O:19])[CH3:2].Cl.[CH3:22][N:23](C)O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:22][NH:23][C:18]([C:4]1[N:3]([CH2:1][CH3:2])[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=1)=[O:19]
Reactant: CCn1cc(C#Cc2cccc(OC)c2)cc1C(=O)Cl
Reactant: CN(C)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(C#Cc2cccc(OC)c2)cc1C(=O)NC
Reaction time: 4 h
Yield: 93.6 %

Procedure:
This intermediate (2.5 g, 9.28 mmol) was treated with oxalyl chloride (4.1 mL, 46.4 mmol), DMF (2 drops) in methylene chloride (70 mL) and stirred at room temperature for 2 hours to give 1-ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid chloride (2.7 g, 9.38 mmol) after a usual workup. 1-Ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid chloride (2.7 g, 9.38 mmol) was diluted with methylene chloride (35 mL) and added to a prepared solution of N,O, dimethyl-hydroxylamine hydrochloride (4.6 g, 46.4 mmol) and diisopropyl-ethyl amine (13 mL, 74.3 mmol) in methylene chloride (35 mL) over 5 minutes. The reaction was complete after 4 hours. Solvent was removed in vacuo and the residue was taken back in a mixture of saturated aqueous NH4Cl:H2O (1:1, 150 mL) solution and extracted with ether. Combined ether extracts were washed with brine dried (MgSO4) and filtered. Evaporation and purification by flash chromatography (hexane/ethyl acetate 9/1) gave the title compound as a light yellow oil (2.48 g g, 82% yield), 1H NMR (400 MHZ, CDCl3) □ 1.35-1.37 (t, 3H), 3.31 (s, 3H), 3.67 (s, 3H), 3.78 (s, 3H), 4.29-4.30 (q, 2H), 6.83 (m, 1H), 6.99 (m, 2H), 7.01 (m, 2H), 7.19 (m, 1H), MS m/e (M+H)+ 313.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1.[CH3:28][OH:29].C[O-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([O:29][CH3:28])[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(F)c(N)c2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1Cl
Temperature: 45 °C
Reaction time: 72 h
Yield: 79 %

Procedure:
5-Amino-1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg) and a methanol solution (about 28%; 200 mg) of sodium methoxide were added to methanol (2 ml), and the mixture was stirred at 45° C. for 3 days. Acetic acid (80 mg) was added to the reaction mixture, and the mixture was heated under reflux for 1 hour. After the reaction mixture was allowed to cool, deposits were collected by filtration and washed with methanol and diisopropyl ether in that order to obtain the title compound (122 mg) as a yellow powder.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:8]=2)([O:3][CH3:4])=[O:2].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[SH:26].C1C=CC(I(OC(C(F)(F)F)=O)OC(C(F)(F)F)=O)=CC=1>FC(F)(F)C(O)C(F)(F)F>[CH3:4][O:3][C:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[S:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[F:18])=[CH:11][CH:10]=[C:9]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:8]=2)=[O:2]
Reactant: COC(=O)c1cc2ccc(S(C)(=O)=O)cc2[nH]1
Reactant: Fc1ccc(S)c(F)c1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: COC(=O)c1[nH]c2cc(S(C)(=O)=O)ccc2c1Sc1ccc(F)cc1F
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of 2-carbomethoxy-6-methylsulfonylindole (750 mg, 2.8 mmol), in 10 mL hexafluoroisopropanol was treated with 2,4-difluorothiophenol (7.5 mmol) followed by addition of PIFA (5.6 mmol). The dark colored solution was stirred overnight then partitioned between methylene chloride and water. After concentration of the methylene chloride layer to 20 mL the product was precipitated by addition of 30 mL hexane. An 88% yield of 3-(2,4-difluoro-phenylsulfanyl)-6-methanesulfonyl-1H-indole-2-carboxylic acid methyl ester was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[Cl:18][C:19]1[N:24]=[CH:23][C:22]([S:25]([N:28]2[CH2:33][CH2:32][NH:31][CH:30]([C:34]#[C:35][CH3:36])[CH2:29]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([S:25]([N:28]2[CH2:33][CH2:32][N:31]([C:2]3[N:3]=[CH:4][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:10])([F:11])[F:12])=[CH:6][N:7]=3)[CH:30]([C:34]#[C:35][CH3:36])[CH2:29]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 120 °C
Reaction time: 24 h
Yield: 113 %

Procedure:
A mixture of 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (490 mg, 1.747 mmol, Intermediate D), 1-((6-chloropyridin-3-yl)sulfonyl)-3-(prop-1-yn-1-yl)piperazine (325 mg, 1.08 mmol), Hünig's base (1.0 mL, 5.73 mmol) and dioxane (5.0 mL) was heated at 120° C. for 15 h. The temperature was increased to 130° C. and stirring was continued for 24 h. The dark mixture was allowed to cool to room temperature and was then purified by silica gel chromatography (80 g silica gel, 10-50% EtOAc in hexane) to give 2-(2-(4-((6-chloro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol as a white foam (0.664 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:3]=1.[Br:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[Br:26][C:27]1[CH:28]=[C:29]([C:6]2[CH:5]=[C:4]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=3)[CH:3]=[C:2]([CH3:1])[N:7]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(OS(=O)(=O)C(F)(F)F)n1
Reactant: OB(O)c1cccc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl ester (example A.32) (1.0 g, 2.6 mmol) and commercially available 3-bromo-benzene-boronic acid (0.573 g, 2.85 mmol) according to the general procedure IVb. Obtained as an off-white solid (1.00 g, 98%). MS (ISP) 392.0 [(M+H)+] and 394.0 [(M+2+H)+].
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[Na].[CH3:13][CH:14]1[CH2:19][C:18](=O)[CH2:17][C:16](=[O:21])[CH:15]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C.O>[OH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]1[C:17]2[C:16](=[O:21])[CH:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:14]([CH3:13])[CH2:19][C:18]=2[O:1][N:2]=1
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1C
Reactant: ON=C(Cl)c1ccccc1O
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1C(=O)c2c(-c3ccccc3O)noc2CC1C
Temperature: 25 °C

Procedure:
N,2-Dihydroxybenzenecarboximidoyl chloride in 100 mL of ethanol was added to sodium salt of ethyl 2-methyl4,6-dioxocyclohexanecarboxylate in a solvent mixture of 125 mL of water and 75 mL of ethanol at a temperature of 55° C. over an hour. The reaction mixture was maintained at this temperature for 4 hours and then cooled down to room temperature. After diluting with water (100 mL), the mixture was extracted with ethyl acetate (2×100 mL). The resulting extract was washed with saturated sodium chloride aqueous solution (150 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was treated with diethyl ether to give the product (2.48 g) as white powders. The residue was further purified by silica gel preparative thin layer chromatography to give additional 2.15 g of the product as white powders (total amount yielded at the 2 steps: 4.63 g, yield: 60%). The physicochemical properties of the compound obtained are shown below.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:31]5[CH:30]=[CH:29][N:28]=[CH:27][C:26]=5[N:25]=[C:24]4[CH3:32])=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>O1CCCC1.CO.[Pd]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:31]5[CH:30]=[CH:29][N:28]=[CH:27][C:26]=5[N:25]=[C:24]4[CH3:32])=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=Cc2ccc(-n3c(C)nc4cnccc43)cc2)cc1OC1CCCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CCc2ccc(-n3c(C)nc4cnccc43)cc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.3 %

Procedure:
A cis and trans mixture of 1-[4-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]-ethenyl]phenyl]-2-methyl-1H-imidazo[4,5-c]pyridine (300 mg, 0.705 mmol 1.0 eq) and 300 mg of 10% Pd/C in 10 ml of tetrahydrofuran and 10 ml of methanol was placed on a Parr hydrogenation apparatus and shaken under 50 psi H2 at room temperature for 6 hours. The reaction mixture was filtered through celite, concentrated, and chromatographed on a silica gel column eluting with 5% CH3OH-CH2Cl2 to give 230 mg of clear oil. Recrystallization from ether-hexane gave 239 mg, 79%, of white crystals. M.P.: 123°-125° C. Elemental Analysis Calc'd for C27 H28N3O2 : Calc'd: C, 75.85; H, 6.84; N, 9.83. Found: C, 75.83; H, 6.74; N, 9.65.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>C(#N)C>[CH3:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:15](=[O:16])[CH2:14][C:13](=[O:17])[CH3:12])[CH:3]=2)[NH:7][N:6]=1
Reactant: Cc1n[nH]c2ccc(N)cc12
Reactant: C=C1CC(=O)O1
Solvent: CC#N
Product: CC(=O)CC(=O)Nc1ccc2[nH]nc(C)c2c1
Reaction time: 8 h

Procedure:
5-Amino-3-methylindazole (300 mg, 2.04 mmol, 1.00 equiv) was dissolved in acetonitrile (4 mL) and diketene (151 uL, 2.04 mmol, 1.00 equiv) was added. The reaction mixture was stirred overnight, and the reaction mixture was purified directly by silica gel chromatography (50→100% EtOAc/hexanes)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[Cl:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14]>C1(C)C=CC=CC=1>[Cl:9][CH2:10][CH2:11][NH:12][C:13]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1)=[O:14]
Reactant: Nc1ccnc(Cl)c1
Reactant: O=C=NCCCl
Solvent: Cc1ccccc1
Product: O=C(NCCCl)Nc1ccnc(Cl)c1
Yield: 60.4 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 4-amino-2-chloro pyridine (3.0 g, 23.33 mmol) in toluene (30 mL) was reacted with 1-chloro-2-isocyanatoethane (3.69 g, 35.0 mmol) and purified by column chromatography on silica gel (1.5% methanol in DCM) to afford 3.3 g of the product (61% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH:13]=1)[C:9]([NH:11][NH2:12])=[O:10])([O-:3])=[O:2].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O>>[F:21][C:22]([F:31])([F:32])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[N:12][NH:11][C:9](=[O:10])[C:8]1[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NNC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1cc([N+](=O)[O-])ccc1Oc1ccccc1

Procedure:
A mixture of 5-nitro-2-phenoxy-benzoic acid methyl ester (4.0 g, 14.7 mmol) and hydrazine (5 mL, 80%) was refluxed for 4 h to yield 5-nitro-2-phenoxy-benzoic acid hydrazide (2.97 g, 74%). The title compound was prepared from 5-nitro-2-phenoxy-benzoic acid hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (DMSO-d6): 12.20 (s, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.35 (d, J=7.2 Hz, 1H), 8.17 (s, 1H), 8.10 (d, J=6.6 Hz, 1H), 7.81 (m, 1H), 7.75 (t, J=6.6 Hz, 1H), 7.54 (t, J=7.2 Hz, 1H), 7.35 (m, 2H), 7.27 (d, =J=7.2 Hz, 1H), 7.03 (m, 2H).