Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:44])[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]3[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[O:33][C:32]=3[CH2:40][CH2:41][CH2:42][CH3:43])=[CH:26][CH:25]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6])C.[OH-].[Na+].Cl>C(O)C>[CH2:40]([C:32]1[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:31]=1[CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:8]([NH:7][C:5](=[O:6])[C:4]([OH:44])=[O:3])[CH:9]=2)=[CH:25][CH:26]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCc1oc2ccccc2c1Cc1ccc(-c2ccc(OCCCc3ccccc3)c(NC(=O)C(=O)OCC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1oc2ccccc2c1Cc1ccc(-c2ccc(OCCCc3ccccc3)c(NC(=O)C(=O)O)c2)cc1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
A solution of N-[4′-(2-butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-yl]-oxalamic acid ethyl ester (120 mg, 0.204 mmol) in ethanol (3 mL) was treated with aq 1 N NaOH (0.3 mL, 1.5 equiv., 0.306 mmol) and stirred at room temperature. After stirring 1 h, the solution was acidified to pH<4 with 10% HCl, concentrated and purified by prep thin layer chromatography (10% methanol in dichloromethane) afforded N-[4′-(2-Butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-yl]-oxalamic acid (32 mg, 28%). Rf 0.39 (10% methanol in dichloromethane), 1H NMR (DMSO-d6, 300 MHz) δ 10.26 (s, 1H), 8.58 (d, J=2.1 Hz, 1H), 7.43-7.05 (m, 16H), 4.07 (t, J=6.0 Hz, 2H), 3.95 (s, 2H), 2.82-2.77 (m, 4H), 2.13-1.97 (m, 2H), 1.67-1.59 (m, 2H), 1.37-1.24 (m, 2H), 0.86 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([O:16]CC2C=CC=CC=2)[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]>C(OCC)(=O)C.[Pd]>[OH:16][C:14]1[CH:13]=[C:8]([CH:7]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COCCOc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCOc1cc(O)cc(C(=O)OC)c1

Procedure:
The product from step (ii) (2.74 g) was reduced by catalytic hydrogenation at 1 at. for 16 hours in ethyl acetate solution with 10% palladium on charcoal. Yield 1.5 g.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]=2[N:4]=[C:3]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+].O>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([OH:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]=2[N:4]=[C:3]1[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CC(=O)c1cccc2c1nc(CCc1ccccc1)n2C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CC(O)c1cccc2c1nc(CCc1ccccc1)n2C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.5 %

Procedure:
To a suspension of ethyl 3-(1-methyl-2-(2-phenylethyl)benzimidazol-4-yl)-3-oxopropanoate (0.80 g) obtained in Inventive Example 10 in anhydrous methanol (16 mL), was added sodium borohydride in small portions which was cooled in an ice bath. After stirring for 20 minutes at room temperature, the reaction solution was poured into water and concentrated under a reduced pressure. The thus obtained residue was extracted with ethyl acetate, and the organic layer was washed with water and brine in that order. The organic layer was dried over anhydrous sodium sulfate and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound as white crystal (0.39 g).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[C:29]([OH:31])=O)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[NH2:32][NH:33][C:34]([NH2:36])=[S:35]>O1CCCC1.O1CCOCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[C:29]([NH:32][NH:33][C:34](=[S:35])[NH2:36])=[O:31])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: NNC(N)=S
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC(=S)NNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Yield: 49.4 %

Procedure:
1,1′-Carbonyidimidazole (195 mg) was added to a solution of (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid (287 mg) [see Preparation 38] in tetrahydrofuran (5 ml). The reaction mixture was stirred and heated under reflux for 1 hour and then evaporated under reduced pressure to afford a yellow gum. The gum was dissolved in 1,4-dioxane (5 ml) and thiosemicarbazide (182 mg) was added. The reaction mixture was heated under reflux for 1.25 hour. After this time the cooled mixture was purified by column chromatography on MCI (trade mark) reverse phase gel eluting with a solvent gradient of 30:70 changing to 70:30, by volume, methanol:water to afford 2-((2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidylcarbonyl)-1-hydrazinecarbothioamide (178 mg) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH2:17].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C(F)(F)F)cc1N
Product: COC(=O)c1cc([N+](=O)[O-])c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of 2.0 g (7.57 mmol) of 2-amino-5-nitro-4-trifluoromethyl-benzoic acid methyl ester in 20 ml of acetic anhydride is heated to reflux for 4 hours. The mixture is allowed to cool to room temperature and concentrated in vacuo. The residue is taken up in ethyl acetate and washed with water, aqueous saturated NaHCO3-solution and brine. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, hexane/ethyl acetate 3:1) provided 1.79 g (77%) of 2-acetylamino-5-nitro-4-trifluoromethyl-benzoic acid methyl ester as yellow crystals, m.p. 75-80° C.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH:12](OCC)(OCC)[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C>>[C:1]([C:6](=[CH:12][O:13][CH2:14][CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(OCC)OCC
Reactant: CCCC(=O)CC(=O)OCC
Solvent: CC(=O)OC(C)=O
Product: CCCC(=O)C(=COCC)C(=O)OCC

Procedure:
A mixture of ethyl butyrylacetate (100 g, 0.63 mol), triethyl orthoformate (210 ml, 1.26 mol) and acetic anhydride (60 ml, 0.63 mol) was heated under reflux for 6 hours, then excess triethyl orthoformate evaporated in vacuo. The residue consisted mainly of ethyl 2-butyryl-b 3-ethoxyacrylate as a mixture of E and Z isomers, and was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16](B4OC(C)(C)C(C)(C)O4)[CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[C:6]([F:28])[CH:5]=[CH:4][C:3]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31].Br[C:37]1[CH:38]=[C:39]2[CH:45]=[N:44][NH:43][C:40]2=[N:41][CH:42]=1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[F:1][C:2]1[C:7]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:37]4[CH:38]=[C:39]5[CH:45]=[N:44][NH:43][C:40]5=[N:41][CH:42]=4)[CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[C:6]([F:28])[CH:5]=[CH:4][C:3]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)c1F
Reactant: Brc1cnc2[nH]ncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnc5[nH]ncc5c4)cc23)c1F
Temperature: 145 °C

Procedure:
In a microwave vial, propane-1-sulfonic acid {2,4-difluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (30, 0.050 g, 0.099 mmol) is combined with 5-bromo-1H-pyrazolo[3,4-b]pyridine (31, 0.030 g, 0.15 mmol), 1 mL of tetrahydrofuran, 1 mL of acetonitrile, tetrakis(triphenylphosphine)palladium(0) (0.050 g, 0.043 mmol), and potassium carbonate (0.400 mL, 1.00 M in water). The reaction is heated at 145° C. for 45 minutes in a microwave, then extracted with ethyl acetate, and the organic layer is washed with water and brine. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of methanol:dichloromethane. Appropriate fractions are combined, concentrated under vacuum and the resulting solid is further washed with a mixture of ethyl acetate:hexane to provide the desired compound. MS (ESI) [M−H+]−=495.05.
Reaction SMILES: II.[I-].[K+].[SH:5][C:6](=[CH:10][C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[C:7]([OH:9])=[O:8]>O.C(#N)C>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[CH:10]=[C:6]([S:5][S:5][C:6](=[CH:10][C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[C:7]([OH:9])=[O:8])[C:7]([OH:9])=[O:8]
Reactant: O=C(O)C(S)=Cc1ccco1
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)C(=Cc1ccco1)SSC(=Cc1ccco1)C(=O)O

Procedure:
Iodine is added to a solution of 100 g of potassium iodide in 500 ml of water to saturation. This saturated solution is added dropwise to a solution of α-mercapto-β-(2-furyl)acrylic acid in 500 ml of acetonitrile and 30 ml of water until the color of iodine persists. The crude product which precipitates is recrystallized from methanol. M.P. 215° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:55]1[CH:59]=[C:58]([CH2:60][NH2:61])[O:57][CH:56]=1>C(Cl)Cl.CCOCC>[O:57]1[CH:56]=[CH:55][CH:59]=[C:58]1[CH2:60][NH:61][C:29]([C:28]1[CH:32]=[CH:33][C:25]([C:7]2[C:8]3[C:15](=[O:16])[N:14]4[C@H:10]([C:9]=3[N:17]=[C:18]([CH2:19][C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]4)=[CH:26][CH:27]=1)=[O:30]
Reactant: NCc1ccco1
Reactant: CCOC(=O)c1c(Cc2ccsc2)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1c(Cc2ccsc2)nc2c(c1-c1ccc(C(=O)NCc3ccco3)cc1)C(=O)N1CCC[C@@H]21
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
A stirred solution of 28 mg (0.060 mmol) of 4-[(9aS)-3-(ethoxycarbonyl)-5-oxo-2-(3-thienylmethyl)-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl]benzoic acid, 14 mg (1.2 equiv, 0.072 mmol) of EDCI and 10 mg (1.2 equiv., 0.072 mmol) of HOBT in 1 mL of DCM was treated with 13 mg (2.2 equiv., 0.133 mmol) of 2-furfurylamine. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was then poured into Et2O (10 mL) and extracted with H2O (1×10 mL) and NaHCO3 (1×10 mL). The organic layer was separated, dried (MgSO4), filtered to remove solids, and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography on an Elution Solutions medium pressure chromatography system using a gradient elution of hexanes/EtOAc 1:1 to 1:4 to afford a clear golden oil. The oil was then triturated with Et2O to afford 22 mg (68%) the title compound as a light yellow solid: 1H NMR (CDCl3, 400 MHz) δ 7.78 (d, 2H, J=7.9), 7.40 (d, 2H, J=7.9), 7.35 (s, 1H), 7.19 (m, 1H), 7.02 (s, 1H), 6.97 (d, 1H, J=4.8), 6.47 (m, 1H), 6.29 (d, 2H, J=15.4), 4.70 (dd, 1H, J=6.3, 10.2), 4.61 (d, 2H, J=5.4), 4.33 (AB quartet, 2H, J=14.5, 41.7), 3.86 (q, 2H, J=6.9), 3.65 (m, 1H), 2.47 (m, 1H), 2.30 (m, 2H), 1.41 (m, 1H), 1.22 (m, 2H), 1.18 (t, 3H, J=6.9); low resolution MS (ES+) m/e 543, (MH+1), 542 (MH+); TLC (hexanes/EtOAc (1:5)): Rf=0.25; HPLC (Dynamax RP-18, 4.6 mm×25 cm; 50–100% CH3CN/H2O with 0.1% TFA; 25 minutes; 1 mL/min): tR=7.73 min, 97% purity; Anal. (C30H27N3O5S) Calc. C, 66.53; H, 5.02; N, 7.76. Found C, 66.26; H, 4.87; N, 7.96.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=O.N1CCCC1>CO>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=Cc1ccccn1
Reactant: O=C1Cc2ccccc2N1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1Nc2ccccc2C1=Cc1ccccn1
Yield: 84.4 %

Procedure:
A mixture of oxindole (37.5 g, 0.28 mole), pyridine2-carboxaldehyde (31.8 g, 0.29 mole) and pyrrolidine (21 ml) in 90 ml of methanol is heated on a steam bath. Within a short time an exothermic reaction occurs, resulting in the deposition of a thick solid mass. The solids are collected, washed with methanol and recrystallized from methanol to give 52.5 g of product: m.p. 204°-205°.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)CO)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f2) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: O=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:16][C:3]1=2.Cl.O>C1(C)C=CC=CC=1>[CH:16]1[C:3]2[CH2:2][CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH:13]=[C:14]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:15]=1
Reactant: COC(=O)C(C)c1ccc2c(c1)Oc1ccccc1CC2=O
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(C)c1ccc2c(c1)Oc1ccccc1CC2
Reaction time: 1 h
Yield: 33.1 %

Procedure:
To 95 mg of methyl 2-(10,11-dihydro-11-oxo dibenzo[b,f]-oxepin-3-yl)-propionate in 1 ml of toluene were added a small amount of zinc-amalgam, 0.3 ml of conc. hydochloric acid and 0.2 ml of water, and the mixture was refluxed with stirring for 1 hour. After cooling, the mixture was filtered and the filtrate was extracted with benzene. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain pale yellow oil, which was subjected to thin-layer chromatography to give 30 mg of methyl 2-(10,11-dihydro dibenzo[b,f]oxepin-3-yl)-propionate as pale yellow oil.
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])(=O)=O.[F:22][C:23]1[CH:45]=[CH:44][C:26]([C:27]([C:29]2[C:38](O)=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:34]3)=[O:28])=[CH:25][CH:24]=1.S(=O)(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[C:38]([O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15])=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:34]3)=[O:28])=[CH:44][CH:45]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(O)ccc2c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reaction time: 0.5 h
Yield: 108.6 %

Procedure:
Pyridine (0.38 ml, 4.65 mmol) and trifluoromethanesulfonic anhydride (0.39 ml, 2.32 mmol) were added to a solution of 5-(4-fluorobenzoyl)-6-hydroxy-2-methylsulfonylnaphthalene (0.4 g, 1.16 mmol), [prepared as described in Example 2, step 3 above], in methylene chloride (10 ml) at 0° C. After 0.5 h, additional amounts of pyridine (0.38 ml, 4.65 mmol) and trifluoromethanesulfonic anhydride (0.39 ml, 2.32 mmol) were added and stirring was continued. After 0.5 h, 1N sodium bisulfate was added and the stirring was continued for an additional 30 minutes. The organic layer was separated, washed with brine, and dried over sodium sulfate. The solvent was removed in vacuo to give 0.6 g of 5-(4-fluorobenzoyl)-6-trifluoromethylsulfonyloxy-2-methylsulfonylnaphthalene as an oil (90% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[C:7]2[C:18]([C:19](=[O:23])[C:20]([NH2:22])=[O:21])=[C:17]([CH2:24][CH3:25])[N:16]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:8]=2[N:9]=[C:10](S(C)(=O)=O)[N:11]=1.[O:34]1CCC[CH2:35]1>CO.C[O-].[Na+]>[CH3:1][O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[C:7]2[C:18]([C:19](=[O:23])[C:20]([NH2:22])=[O:21])=[C:17]([CH2:24][CH3:25])[N:16]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:8]=2[N:9]=[C:10]([O:34][CH3:35])[N:11]=1
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(S(C)(=O)=O)nc2n1Cc1ccccc1
Reactant: C1CCOC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(OC)nc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 150 mg (0.316 mmol) of [[2-(methylsulfonyl)-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy] acetic acid methyl ester in 3 mL of tetrahydrofuran and 0.5 mL of methanol was added 4 drops of 28% sodium methoxide in methanol solution. The reaction was stirred at ambient temperature for 3 hours. The reaction was quenched by the addition of 3 mL of saturated sodium bicarbonate solution and the phases separated. The organic phase was dried with sodium sulfate and concentrated to a yellow solid. The solid was purified by flash chromatography (5.0 g silica, ethyl acetate) to provide 41 mg of [[2-methoxy-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as an off white solid. nmr (500 MHz, CDCl3) δ1.11 (t, J=7.5 Hz, 3H), 2.90 (q, J=7.5 Hz, 2H), 3.77 (s, 3H), 3.96 (s, 3H), 5.04 (s, 2H), 5.43 (s, 2H), 5.74 (s, 1H), 6.58 (s, 1H), 7.16 (d, J=7.0 Hz, 2H), 7.29 (m, 3H)
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[O:3][CH:2]1[CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH2:10][CH:2]1[O:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[O:1]1)(=[O:22])=[O:21]
Reactant: OCC1Oc2cccnc2O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1Oc2cccnc2O1
Reaction time: 1 h
Yield: 100.9 %

Procedure:
A solution of intermediate (5) (0.018 mol) and triethyl amine (0.036 mol) in DCM (80 ml) was stirred and cooled with an ice-water bath. Methanesulfonyl chloride (0.027 mol) was added dropwise and the resulting reaction mixture was stirred for one hour while cooling on an ice-bath. The crude reaction mixture was washed with water and brine, then extracted. The separated organic layer was dried, filtered and the solvent was evaporated, yielding 4.2 g of (±)-1,3-dioxolo[4,5-b]pyridine-2-methanol methanesulfonate (ester) (intermediate 6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:11]3[C:12](=[O:18])[C:13]([CH:16]=O)=[CH:14][CH:15]=[C:10]3[N:9]2[S:27]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])(=[O:29])=[O:28])=[CH:4][CH:3]=1.[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])[CH3:39]>>[C:38]([N:41]1[CH2:46][CH2:45][N:44]([CH2:16][C:13]2[C:12](=[O:18])[N:11]3[C@H:19]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)[C@H:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]([S:27]([C:30]4[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=4)[C:33]#[N:34])(=[O:29])=[O:28])[C:10]3=[CH:15][CH:14]=2)[CH2:43][CH2:42]1)(=[O:40])[CH3:39]
Reactant: N#Cc1cccc(S(=O)(=O)N2c3ccc(C=O)c(=O)n3[C@H](c3ccc(Cl)cc3)[C@@H]2c2ccc(Cl)cc2)c1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(Cc2ccc3n(c2=O)[C@H](c2ccc(Cl)cc2)[C@H](c2ccc(Cl)cc2)N3S(=O)(=O)c2cccc(C#N)c2)CC1

Procedure:
rac-3-[cis-6-(4-Acetyl-piperazin-1-ylmethyl)-2,3-bis-(4-chloro-phenyl)-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-sulfonyl]-benzonitrile was prepared according to general method E by reaction of rac-3-[cis-2,3-bis-(4-chloro-phenyl)-6-formyl-5-oxo-2,3-dihydro-5H-imidazo[1 2-a]pyridine-1-sulfonyl]-benzonitrile with N-acetyl-piperazine. The compound was isolated by preparative HPLC. The expected product was characterized by LC/MS (M+H) where the mass was observed as 662.12; the expected mass is 661. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: C(O[C:6](=O)[NH:7]C1(C2C=CC(C3C(=O)C4C(=CC=C(C#N)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[C:38]([O:42][C:43](=[O:75])[NH:44][C:45]1([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[C:64](=[O:65])[C:63]4[C:58](=[C:59](Br)[C:60]([O:66][CH3:67])=[CH:61][CH:62]=4)[O:57][C:56]=3[C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)=[CH:51][CH:50]=2)[CH2:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43](=[O:75])[NH:44][C:45]1([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[C:64](=[O:65])[C:63]4[C:58](=[C:59]([C:6]#[N:7])[C:60]([O:66][CH3:67])=[CH:61][CH:62]=4)[O:57][C:56]=3[C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)=[CH:51][CH:50]=2)[CH2:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]
Reactant: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1Br
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(C#N)cc4c3=O)cc2)CCC1
Product: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1C#N
Yield: 33 %

Procedure:
Following the procedure used to prepare {1-[4-(6-cyano-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, {1-[4-(8-bromo-7-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (150 mg, 0.0867 mmol) was reacted to give the title compound (15 mg, 33%). LCMS (Method B): RT=4.79 min, [M+H]+=523.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([NH2:19])=[O:18])[CH:11]=2)=[C:4]([CH3:20])[CH:3]=1.[H][H]>CO.C(Cl)Cl.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([NH2:19])=[O:18])[CH:11]=2)=[C:4]([CH3:20])[CH:3]=1
Reactant: Cc1cc(F)ccc1C#Cc1ccnc(NC(N)=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(F)ccc1CCc1ccnc(NC(N)=O)c1
Yield: 70.8 %

Procedure:
[4-(4-Fluoro-2-methyl-phenylethynyl)-pyridin-2-yl]-urea (25 mg, 0.093 mmol) is dissolved in methanol (1.0 mL) and DCM (1.0 mL). Then 5% palladium on carbon (20 mg, 0.0090 mmol) is added. The reaction is stirred for 16 hrs under the hydrogen atmosphere. The palladium on carbon is filtered and the filtrate is concentrated to give the crude product. Methanol (1 mL) is added into the crude and a white solid is formed. The solid is filtered, rinsed with more methanol and dried to give 18 mg of the titled product.