Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Br[C:15]1[CH:16]=[C:17]([C:20]([OH:22])=[O:21])[S:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(#N)C>[CH:1]([S:4][C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:16]=[C:17]([C:20]([OH:22])=[O:21])[S:18][CH:19]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Sc1ccc(B(O)O)cc1
Reactant: O=C(O)c1cc(Br)cs1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)Sc1ccc(-c2csc(C(=O)O)c2)cc1
Temperature: 150 °C
Yield: 94.8 %

Procedure:
A mixture of commercially available 4-(isopropylthio)phenylboronic acid (735 mg, 3.75 mmol), 4-bromothiophene-2-carboxylic acid (776 mg, 3.75 mmol), Bis(triphenylphosphine)palladium (II) chloride (131 mg, 0.188 mmol), acetonitrile (7.5 mL) and aqueous sodium carbonate (1M, 7.5 mL) was heated to 150° C. by microwave irradiation (Biotage Intiator™ Sixty, 0-300 W, pre-stirring 2 minutes) for 5 minutes under an argon atmosphere. The reaction mixture was cooled to ambient temperature, diluted with water (75 mL), and extracted with EtOAc (2×50 mL). The aqueous layer obtained was then acidified with aqueous HCl (3.0M) to pH 2 and extracted with EtOAc (2×50 mL). The combined organic layers were dried over sodium sulfate, filtrated and concentrated to afford compound 73 (990 mg) which was used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]C#N)[CH:5]=[C:4]([Cl:11])[C:3]=1[O:12][C:13](=[O:15])[CH3:14].C[S-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([SH:8])[CH:5]=[C:4]([Cl:11])[C:3]=1[O:12][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)Oc1c(Cl)cc(SC#N)cc1Cl
Agent: C[S-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Oc1c(Cl)cc(S)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a suspension of compound from step (ii) (472 mg, 1.69 mmol) in MeOH (17 mL), a solution of sodium thiomethoxide (130 mg, 1.86 mmol) in MeOH (4 mL) was added at room temperature. The reaction mixture was allowed to stir at rt, under nitrogen atmosphere overnight. Then it was concentrated in vacuo and a 0.1 M solution of HCl (30 mL) and CH2Cl2 were added. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic phase was dried over MgSO4, filtered and CIV to afford 315 mg (79%) of the final compound as a white solid.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:5]1)([OH:3])=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.OC1C2N=NNC=2C=CC=1.CN1CCOCC1>CCOCC>[C:25]1([NH:24][C:1]([CH:4]2[CH2:9][CH2:8][CH2:7][N:6]([C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)=[O:11])[CH2:5]2)=[O:3])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)C1CCCN(C(=O)C2CCN(c3ccncc3)CC2)C1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: O=C(Nc1ccccc1)C1CCCN(C(=O)C2CCN(c3ccncc3)CC2)C1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
Dicyclocarbodiimide (620 mg) was added to a stirred mixture of the crude 3-carboxy-1-[4-pyridylpiperidin-4-ylcarbonyl]piperidine product from step (b) (1 g), aniline (0.17 ml), hydroxybenztriazole, (236 mg), N-methylmorpholine (0.29 ml) under an atmosphere of argon with cooling to 0 to 5° C. The mixture was stirred at 0° C. for 30 minutes and then allowed to warm to ambient temperature and stirred overnight. The mixture was quenched with water and the solvent removed by evaporation. The residue was partitioned between dichloromethane and water. The aqueous phase was seperated and washed with dichloromethane. The aqueous phase was evaporated and the residue purified by flash chromatography on silica gel using 15% MeOH/CHCl2 as eluent to give a crude product which was further purified by flash chromatography on silica gel using a gradient of 4 to 10% MeOH/CH2Cl2 as eluent to give an oil. Ether was added and then evaporated to yield 3-(phenylaminocarbonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperidine as a foam (200 mg; 80% pure);
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([NH2:21])=O)=[CH:15]2)(=[O:8])=[O:7].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])#[N:21]
Reactant: NC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (4.65 g) and pyridine (20 mL) was slowly added trifluoroacetic anhydride (4.50 mL) at 0° C., and the mixture was stirred for 1 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography, and eluted with tetrahydrofuran-hexane (2:3, volume ratio). The eluate was treated with activated carbon and concentrated to give the title compound (4.04 g, yield 92%) as pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point 283-284° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[BrH:19].BrBr>C(O)(=O)C>[Br:19][CH:10]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:9]([C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1)=[O:18]
Reactant: CSc1ccc(C(=O)Cc2ccc(F)cc2)cc1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: CSc1ccc(C(=O)C(Br)c2ccc(F)cc2)cc1
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a stirred slurry of 2-(4-fluorophenyl)-1-(4-methylthiophenyl)ethanone from Step 1 (5.04 g, 19.36 mmol) in acetic acid (100 mL) was added HBr in acetic acid (45 mL, 48% by wt.) and bromine (1.0 mL, 3.09 g, 19.36 mmol). The resulting green slurry became homogeneous within 30 minutes. After 4 hours, the reaction was concentrated in vacuo, the residue diluted with toluene, and reconcentrated in vacuo. The crude haloketone was purified by flash chromatography (2:1 hexane:methylene chloride) and recrystallized from ethyl acetate and isooctane yielding 2-bromo-2-(4-fluorophenyl)-1-(4-methylthiophenyl)ethanone as an off-white solid (4.51 g, 69%): mp 108°-111° C. 1H NMR (CDCl3) 300 mHz δ7.94 (d, J=8.79 Hz, 2H), 7.60-7.50 (m, 2H), 7.25 (d, J=8.79 Hz, 2H), 7.10 (t, J=8.67 Hz, 2H), 6.34 (s, 1H), 2.56 (s, 3 H).
Reaction SMILES: BrC1C=CC(C2C=CC=C3C=2CC(=O)N3)=CC=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2C=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][CH:29]=2)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Agent: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCn2ccnn2)c[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 160.6 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[44-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)amide as a yellow solid (88 mg, 68%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Cl.Cl[CH2:16][CH:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:18]>>[N:19]1([CH:17]([CH3:18])[CH2:16][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(CCl)N1CCCC1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Agent: Cl
Product: CC(Cn1cnc(-c2cc(C#N)ccn2)c1)N1CCCC1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 1-(2-chloro-1-methylethyl)pyrrolidine hydrogen chloride according to the procedure for the preparation of Example 43, part A (heating to 120°). [M+H] Calc'd for C16H19N5, 282. Found, 282.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.N1C=CC=CC=1.N1([CH:30]=[CH:31][C:32]([O:34][CH3:35])=[O:33])CCCC1>C(Cl)(Cl)Cl.Cl.O.C(N(CC)CC)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(F)cc1
Reactant: COC(=O)C=CN1CCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC(=O)c1conc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
To a solution of 1.05 g of 4-fluorobenzaldoxime (Beil. 7, I 132d, II 177d, III 863c) in 15 mL of chloroform were added 1.35 g of N-bromosuccinimide (NBS) and 0.04 mL of pyridine; the resulting mixture was stirred at r.t for 4 h under nitrogen atmosphere. After cooling at 0° C., 1.75 g of methyl β-pyrrolidinoacrylate (prepared as described in U.S. Pat. No. 4,144,047) and 1.26 mL of triethylamine were added and the suspension was stirred at r.t. for 18 h. The reaction mixture was diluted with 20 mL of 2 N hydrochloric acid, 20 mL of water; the organic layer was separated, washed again with 2 N hydrochloric acid and water, dried (sodium sulphate), and evaporated to dryness in vacuo. The crude was purified by flash chromatography (toluene-dichloromethane 1:9) to afford the title compound (47%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:43]=[CH:42][C:38]([CH:39]=[N:40][OH:41])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:41]/[N:40]=[CH:39]/[C:38]2[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:45])[F:44])=[CH:43][CH:42]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: ON=Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(F)(F)F)cc2)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 78.6 %

Procedure:
This compound was produced using similar methods as those used in Step 5, example 27, starting with 2-(3,5-bis-trifluoromethyl-benzoylamino)-4-(3-bromo-propoxy)-benzoic acid methyl ester (0.35 g, 0.66 mmol), 4-trifluoromethyl-benzaldehyde oxime (0.13 g, 0.70 mmol) and cesium carbonate (0.86 g, 2.65 mmol) in acetone (25 mL). The crude material was purified by flash chromatography through silica gel using diethyl ether/hexanes (0/100 gradient to 10/90) to give 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-4-{3-[({(1E)-[4-(trifluoromethyl)phenyl]methylidene}amino)oxy]propoxy}benzoic acid methyl ester (0.33 g, 78%) as a white solid. 1H NMR (500 MHz, DMSO-d6); δ 11.78 (s, 1H), 8.51 (s, 2H), 8.45 (s, 1H), 8.37 (s, 1H), 8.10 (d, 1H), 7.97 (d, 1H), 7.79-7.71 (AA′BB′, 4H), 6.88 (dd, 1H), 4.34 (t, 2H), 4.22 (t, 2H), 3.85 (s, 3H), 2.18 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[CH:9][C:7]=2[CH:8]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[CH:9][C:7]=2[CH:8]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(-c2ccc3oc(CCO)cc3c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
To a solution of Example 1B (0.57 g, 2.2 mmol) and triethylamine (0.9 mL, 6.5 mmol) in dichloromethane (10 mL) at 20° C. was added methane sulfonyl chloride (0.79 g, 4.5 mmol). The mixture was stirred for 30 min., diluted with dichloromethane, washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was chromatographed on silica with dichloromethane to give the titled compound (0.66 g, 89%). MS (DCI) m/z 359 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][C:6]([OH:23])=[C:5]([CH3:24])[CH:4]=1.Cl.[CH3:26][N:27]([CH3:34])[CH2:28]/[CH:29]=[CH:30]/[C:31](O)=[O:32]>>[CH3:26][N:27]([CH3:34])[CH2:28]/[CH:29]=[CH:30]/[C:31]([N:21]1[CH2:20][CH2:19][C:18]2[C:11]3[C:10]([NH:9][C:8]4[C:3]([F:2])=[CH:4][C:5]([CH3:24])=[C:6]([OH:23])[CH:7]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:16][C:17]=2[CH2:22]1)=[O:32]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Cc1cc(F)c(Nc2ncnc3sc4c(c23)CCNC4)cc1O
Agent: Cl
Product: Cc1cc(F)c(Nc2ncnc3sc4c(c23)CCN(C(=O)/C=C/CN(C)C)C4)cc1O

Procedure:
The compound was synthesized in analogy to Example 122 from 4-fluoro-2-methyl-5-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 72A (100 mg, 0.27 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (63 mg, 0.38 mmol) to yield 29 mg (24%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9](O)[CH3:10]>C(O)C1C=CC=CC=1>[CH:6]1[C:1]2[NH:8][C:9]3[C:10](=[CH:6][C:1]4[C:2]([CH:3]=3)=[N:8][C:1]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:7]=4)[NH:7][C:2]=2[CH:3]=[CH:4][CH:5]=1
Reactant: CCO
Reactant: Nc1ccccc1N
Solvent: OCc1ccccc1
Product: c1ccc2c(c1)Nc1cc3nc4ccccc4nc3cc1N2
Temperature: 137.5 °C
Reaction time: 20 h
Yield: 92 %

Procedure:
2,5-Dihydroxy-1,4-dibenzoquinone (4, 30.0 g, 0.2 mol) was added to a solution of o-phenylendiamine (5, 115.79 g, 1.1 mol) in benzyl alcohol (11.6 vol). The reaction mixture was heated to 135-140° C. and stirred for 20 hours. The reaction mixture was cooled to room temperature, and ethanol (120 mL) was added. The resulting suspension was filtered through a Buchner funnel and the solid was washed with ethanol (120 mL) and dried under vacuum in an oven at 60-70° C. to furnish 5,14-Dihydro-5,7,12,14-tetraazapentacene 3. Yield: 92%; HPLC purity: 99.56%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]([NH:18]C(OCC1C=CC=CC=1)=O)=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH2:15][CH3:16])[CH:14]=1)[NH:11][N:10]=[C:9]2[CH3:17]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:29])[CH:4]([NH2:18])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH2:15][CH3:16])[CH:14]=1)[NH:11][N:10]=[C:9]2[CH3:17]
Reactant: CCc1cc(C=C(NC(=O)OCc2ccccc2)C(=O)OC)cc2c(C)n[nH]c12
Agent: [Pd]
Solvent: CO
Product: CCc1cc(CC(N)C(=O)OC)cc2c(C)n[nH]c12
Reaction time: 8 h
Yield: 90.4 %

Procedure:
2-Benzyloxycarbonylamino-3-(7-ethyl-3-methyl-1H-indazol-5-yl)-acrylic acid methyl ester (1.0 g, 2.54 mmol) in methanol (15 mL) was flushed with nitrogen, and treated with palladium on charcoal (10%, 100 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 0.6 g (91%) of the desired material. 1H-NMR (CD3OD) δ 1.32 (m, 3H), 2.50 (s, 3H), 2.88 (dd, J=7.3, 7.6, 1H), 2.89 (dd, J=7.6, 7.6, 1H), 3.02 (dd, J=6.4, 7.0, 1H), 3.11 (dd, J=7.6, 5.8, 1H), 3.35 (s, 1H), 3.65 (m, 3H), 7.00 (s, 1H), 7.33 (s, 1H). Mass spec.: 262.24 (MH)+.
Reaction SMILES: C[NH2:2].[C:3]([O:13]C)(=O)[C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]>>[C:3]([NH2:2])(=[O:13])[C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: CN
Reactant: COC(=O)[C@@H](O)c1ccccc1
Product: NC(=O)[C@@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of methylamine (40% in water, 3.8 equivalents) is added, at ambient temperature, methyl (S)-mandelate (1.0 equivalent; commercially available), while keeping the temperature below 30° C. and stirred at ambient temperature until full conversion is achieved. Excess methylamine is removed by azeotropic distillation. Alternatively, after neutralisation with aqueous hydrochloric acid the aqueous solution is saturated with sodium chloride and extracted several times with dichloromethane. The organic layers are combined and the water is removed by azeotropic distillation.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9](=[O:22])[N:8]([CH:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:24]([O:26]C(C)(C)C)=[O:25])[C:7]=2[CH:37]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]([S:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)(=[O:13])=[O:12])[C:9](=[O:22])[N:8]([CH:23]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:24]([OH:26])=[O:25])[C:7]=2[CH:37]=1)#[N:2]
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)OC(C)(C)C)c3ccccc3)c3cc(C#N)ccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)O)c3ccccc3)c3cc(C#N)ccc32)cc1
Temperature: 25 °C

Procedure:
1.75 g (3.37 mmol) of tert-butyl [6-cyano-3-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydrobenzimidazol-1-yl]phenylacetate (XIIc) were dissolved in dichloromethane (20 ml) and, while stirring at room temperature, trifluoroacetic acid (10 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 1.49 g (96%) of white solid
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[S:29][C:30]2[C:35]([N:36]=1)=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:20]>C1COCC1.CC(O)=O.O>[O:1]=[CH:2][CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[S:29][C:30]2[C:35]([N:36]=1)=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:20]
Reactant: O=C(Nc1ccccc1-c1nc2cccnc2s1)c1nc(-c2ccccc2)sc1CCC1OCCO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=CCCc1sc(-c2ccccc2)nc1C(=O)Nc1ccccc1-c1nc2cccnc2s1
Yield: 85 %

Procedure:
5-(2-(1,3-dioxolan-2-yl)ethyl)-2-phenyl-N-(2-(thiazolo[5,4-b]pyridin-2-yl)phenyl)thiazole-4-carboxamide (250 mg, 0.5 mmol) was dissolved in a mixture of THF (4 mL), AcOH (8 mL) and H2O (0.5 mL), heated at reflux for 16 h, then concentrated to dryness. The residue was dissolved in EtOAc, washed with sat aq NaHCO3, dried (MgSO4), and concentrated under reduced pressure. The crude product was purified by MPLC eluting with CH2Cl2/MeOH (0-5% gradient) to give 5-(3-oxopropyl)-2-phenyl-N-(2-(thiazolo[5,4-b]pyridin-2-yl)phenyl)thiazole-4-carboxamide (200 mg, 87% yield).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][CH2:16][CH:15]3[OH:21])[C:7](=[O:22])[C:6]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:40][C:39](=[O:41])[O:38][N:37]=2)=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][CH2:16][C:15]3=[O:21])[C:7](=[O:22])[C:6]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:40][C:39](=[O:41])[O:38][N:37]=2)=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2ccc3c(c2)C(O)CC3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2ccc3c(c2)C(=O)CC3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a solution of 6-butyl-3-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (0.30 g) in acetonitrile (3 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.35 g), and the mixture was stirred at room temperature for 3 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 82%).
Reaction SMILES: CN(C=O)C.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH:11]([CH3:18])[CH2:10]2.Br[Zn][CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:23]1[CH2:24][CH2:25][O:26][CH:22]1[CH2:21][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH:11]([CH3:18])[CH2:10]2
Reactant: Br[Zn]CC1OCCO1
Reactant: CC1Cc2cc(Br)ccc2C(=O)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1Cc2cc(CC3OCCO3)ccc2C(=O)O1
Temperature: 110 °C

Procedure:
A sealed tube was charged with aryl bromide, palladium(II) acetate (0.028 g, 0.124 mmol) and tri-t-butylphosphine-BF4 complex (0.072 g, 0.249 mmol) and sealed. The tube was evacuated and refilled with nitrogen before DMF (12.44 ml) and 6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (0.75 g, 3.11 mmol) were added followed by bromo(1,3-dioxolan-2-ylmethyl)zinc (6.22 ml, 3.11 mmol). The tube was heated to 110° C. in the microwave for 75 minutes, after which it was cooled, diluted with EtOAc, filtered, concentrated and purified via MPLC (20-50% E/H) to afford 6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one. 1H NMR (500 MHz; CDCl3): δ 8.04 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.17 (s, 1H), 5.11 (t, J=4.7 Hz, 1H), 4.68 (m, 1H), 3.96 (m, 2H), 3.88 (m, 2H), 3.03 (d, J=4.9 Hz, 2H), 2.93 (m, 2H), 1.54 (d, J=6.4 Hz, 3H); LC-MS (IE, m/z): 249 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][O:5][C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:3]1.[C:14]1([Li])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH3:1][C:2]1([CH3:13])[CH2:6][O:5][C:4]([C:7]2[CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][NH:9][CH:8]=2)=[N:3]1
Reactant: CC1(C)COC(c2cccnc2)=N1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: CC1(C)COC(C2=CNC=CC2c2ccccc2)=N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
To a cooled (-78° C.) solution of 3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)pyridine [Hauck A. E., et al., J. Chem. Soc. Perkin I 1980:2070-2076] (140.0 g, 0.79 mol) in 500 mL dry tetrahydrofuran (THF), phenyllithium (1.42 mol, 1.8 eq) is added under a nitrogen atmosphere until gas chromatography (GC) analysis indicates no more starting material is present. The reaction mixture is stirred for 10 minutes and then quenched with 500 mL water at -78° C. After warming the reaction mixture to room temperature with a water bath, 700 mLof diethyl ether is added to the mixture. The resulting solid is filtered, rinsed once with chilled methanol, and then dried at 40° C. in a vacuum oven overnight to yield 166.6 g (0.65 mol) of 1,4-dihydro-3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-4-phenylpyridine.