Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(I)cc2)n1-c1ccc(Cl)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(-c3cccc(F)c3)cc2)n1-c1ccc(Cl)cc1
Temperature: 170 °C
Yield: 53.5 %

Procedure:
A microwave reaction tube charged with 5-(4-chloro-phenyl)-6-(4-iodo-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (74.9 mg, 0.143 mmol), 3-fluorophenylboronic acid (39.9 mg, 0.285 mmol), and Pd(PPh3)4 (16.5 mg, 0.014 mmol) is purged with nitrogen. Toluene (3.5 mL) and Na2CO3 aqueous solution (2.0M, 0.75 mL) are added via syringe. The reaction mixture is heated in a microwave at 170° C. for 20 min, and is partitioned between water and ethyl acetate. The organic phase is washed with brine, dried over MgSC4, concentrated, and purified by silica gel chromatography to provide the title compound (37.7 mg, 54% yield) as a white solid product; 1H NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 8.16 (dd, 2H), 7.52 (t, 2H), 7.48 (d, 2H), 7.43-7.33 (m, 7H), 7.25 (dt, 1H), 7.13 (d, 2H), 7.07 (td, 1H); HPLC-MS calculated for C29H18ClFN4O (M+H+) 493.1. Found: 493.1.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[C:23]([Br:24])=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[CH:11][CH:12]=1.[I:25]I.S(=O)(O)[O-].[Na+]>CCCCCC.C1COCC1.O>[I:25][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][Br:24])[CH:10]=[CH:11][CH:12]=1
Reactant: Brc1cccc(CCCCOc2ccccc2Br)c1
Reactant: II
Agent: O=S([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: BrCCCCCCOCCCCc1cccc(I)c1
Temperature: 0 °C
Yield: 70.8 %

Procedure:
A solution of n-butyl lithium in hexane (1.6 M; 50 ml) was added to a stirred solution of 6-bromophenyl 4-(3-bromophenyl)butyl ether (21 g) in dry THF (150 ml) at −85° C. under nitrogen. After 15 min a solution of iodine (19.8 g) in THF (100 ml) was added dropwise over 20 min. The solution was then allowed to warm up to 0° C. and aqueous sodium bisulphite was added. The mixture was poured into water and extracted into ether. The combined extracts were dried (Na2SO4) and evaporated. The residue was purified by flash silica gel column chromatography (1 kg) eluting with cyclohexane-ether (9:1). The appropriate fractions were evaporated to give the title compound (17 g). LCMS RT=4.41 min.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[H-].[Na+].Cl.[CH:11]1([CH:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=2)[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12]1>COCCOC>[CH:11]1([CH:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[O:24])=[CH:21][CH:20]=2)[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)CC(C)=O
Reactant: CC(Nc1ccc(C(=O)Cl)cc1)C1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(C(C)=O)C(=O)c1ccc(NC(C)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 28.4 g. of 2,4-pentanedione and 20 ml. of 1,2-dimethoxyethane is added to a suspension of 13.6 g. of sodium hydride in 220 ml. of 1,2-dimethoxyethane under argon. A solution of 28.7 g. of 4-(1-cyclopentylethylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is stirred at room temperature for 12 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue is then chromatographed over silica gel to yield 3-[4'-(1-cyclopentylethylamino)benzoyl]-2,4-pentanedione.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[N:17]([CH2:19][CH2:20][NH:21][CH3:22])[CH3:18])=[O:5].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34](Cl)=[O:35])[CH:29]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[N:17]([CH2:19][CH2:20][N:21]([CH3:22])[C:34]([C:30]1[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=1)=[O:35])[CH3:18])=[O:5]
Reactant: CNCCN(C)c1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: O=C(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN(C)c1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A mixture of 8-(2,6-dichlorobenzoylamino)-4-[N-(2-methylaminoethyl)-N-methylamino]quinoline (130 mg), 3-pyridinecarbonyl chloride (60.3 mg) and triethylamine (97.9 mg) in dichloromethane (2 ml) was stirred at ambient temperature overnight. The mixture was diluted with dichloromethane, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethanol and collected by filtration. The residue was washed with ethanol to give 8-(2,6-dichlorobenzoylamino)-4-[N-[2-(N-methyl-3-pyridinecarboxamido)ethyl]-N-methylamino]quinoline (150 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24]([O:26]CC)=[O:25])[N:6]2[CH2:21][O:22][CH3:23].CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24]([OH:26])=[O:25])[N:6]2[CH2:21][O:22][CH3:23]
Reactant: CCOC(=O)c1cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCn1c(C(=O)O)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
To a mixed solution of ethyl 4-fluoro-1-(methoxymethyl)-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.45 g) in tetrahydrofuran (10 mL)-methanol (10 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (0.25 g), and the mixture was stirred at room temperature for 18 hr. The reaction solution was acidified with aqueous citric acid solution, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.41 g, yield 98%) as pale-yellow crystals.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[CH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])(=[O:3])N.S(=O)(=O)(O)[OH:25].N([O-])=O.[Na+]>O>[C:1]([C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[CH:18][CH2:19][CH2:20][N:21]([CH3:22])[CH3:23])([OH:3])=[O:25]
Reactant: CN(C)CCC=C1c2ccccc2C=Cn2cc(C(N)=O)cc21
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CN(C)CCC=C1c2ccccc2C=Cn2cc(C(=O)O)cc21

Procedure:
To 2-carbamoyl-11-(3-dimethylaminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine (0.112 moles) in 300 ml. of 50% sulfuric acid maintained at 50° C. is added slowly 25 g. of sodium nitrite in 75 ml. of water. At the end of the addition, the solid is filtered, washed with water and air-dried to yield 2-carboxy-11-(3-dimethylaminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][CH2:5][N:6]([CH3:9])[CH2:7][CH:8]=1.[I:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1O>>[I:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:1][CH2:2][C:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH:4]=1
Reactant: CN1CC=C(CO)CC1
Reactant: Oc1ccccc1I
Product: CN1CC=C(COc2ccccc2I)CC1
Yield: 74 %

Procedure:
The title compound was prepared from 4-(hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (D9) and 2-iodophenol, using a procedure similar to that of Description 1 in 74% yield.
Reaction SMILES: [NH2:1][C:2](=[O:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([S:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[CH:17][C:16]([CH2:26][N:27](C)[C:28](=O)OC(C)(C)C)=[CH:15]2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[N:14]([S:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[O:4][CH2:3][C:2]([NH2:1])=[O:36])(=[O:12])=[O:13])[CH:15]=[C:16]([CH2:26][NH:27][CH3:28])[CH:17]=1
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(N)=O)c2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(N)=O)c2)c1
Reaction time: 2 h

Procedure:
tert-Butyl ((1-((3-(2-amino-2-oxoethoxy)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 2a (100 mg, 0.19 mmol) was dissolved in 20 mL of dichloromethane. The reaction solution was cooled in an ice bath, 5 mL of trifluoroacetic acid were dropwise added, and then the reaction solution was stirred for 2 h. 50 mL of saturated sodium bicarbonate solution were added, and the reaction solution was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title product 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetamide 2 (60 mg, a yellow oil) in 75% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([N+:23]([O-])=O)[C:17]=1[OH:26])(=[O:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([NH2:23])[C:17]=1[OH:26])(=[O:15])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 94.9 %

Procedure:
N-[3-(tert-butoxycarbonylamino)propyl]-6-chloro-2-hydroxy-3-nitrobenzene-sulfonamide (250 mg, 0.61 mmol) was reduced with hydrogen and 10% Pd/C (100 mg) to form the desired product (220 mg, 95%). 1H NMR (MeOD-d4): δ 6.82 (m, 2H), 3.06 (t, 2H), 2.92 (t, 2H), 1.60 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: Br[CH2:2]/[C:3](/[F:15])=[C:4](/[CH3:14])\[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH:16]1([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:23]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:2]/[C:3](/[F:15])=[C:4](/[CH3:14])\[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:26][CH:25]=2)=[O:31])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(NC1CCCCC1)c1ccc(O)cc1
Reactant: C/C(CNC(=O)OC(C)(C)C)=C(\F)CBr
Product: C/C(CNC(=O)OC(C)(C)C)=C(\F)COc1ccc(C(=O)NC2CCCCC2)cc1

Procedure:
This compound was synthesized from tert-butyl [(2E)-4-bromo-3-fluoro-2-methylbut-2-en-1-yl]carbamate and N-cyclohexyl-4-hydroxybenzamide following procedure F and was obtained as a colorless solid; 1H-NMR (400 MHz, CDCl3): δppm: 1.15-1.27 (3H, m), 1.37-1.48 (2H, m), 1.43 (9H, s), 1.62-1.67 (1H, m), 1.72-1.77 (2H, m), 1.76 (3H, d, J 4.0 Hz), 2.00-2.04 (2H, m), 3.77 (2H, d, J 5.7 Hz), 3.95 (1H, m), 4.61 (1H, br s), 4.75 (2H, d, J 21.4 Hz), 5.85 (1H, br s), 6.95 (2H, d, J 9.0 Hz), 7.72 (2H, d, J 9.0 Hz).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH3:14][N:15]([CH3:24])[C:16]([CH2:18][C:19]([O:21]CC)=[O:20])=[O:17].N1CCCCC1.[OH-].[K+]>C(O)C.O1CCCC1.C(OCC)(=O)C>[CH3:14][N:15]([CH3:24])[C:16]([C:18](=[CH:1][C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1)[C:19]([OH:21])=[O:20])=[O:17]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: CCOC(=O)CC(=O)N(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C=C(C(=O)O)C(=O)N(C)C)cc(OC)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.1 %

Procedure:
A 8.1 g (44.5 mmol) of syringaldehyde, 7.2 g (44.4 mmol) of ethyl a-dimethylcarbamoylacetate and 6.6 ml (66.7 mmol) of piperidine in 150 ml of ethanol solution was stirred at 110° C. for about 12 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (methanol/chloroform=2-4%). An oily product thus obtained was dissolved in 50 ml of tetrahydrofuran. To the solution was added an aqueous potassium hydroxide solution (4.3 g/10 ml), and the solution was stirred at room temperature for 15 hours. A 50 ml of ethyl acetate was added to the solution. The mixture was extracted with 100 ml of water. The aqueous layer was acidified with conc. hydrochloric acid and extracted with 120 ml of methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 4.6 g (yield 35%) of objective α-dimethylcarbamoyl-3,5-dimethoxy-4-hydroxycinnamic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12]CC)=[O:11].[OH-].[Na+].Cl>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH3:16])([CH3:15])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C(C)(C)Cc1ccccc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(Cc1ccccc1Br)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
A solution of the crude ester (482 mg) in dioxane (2 mL) was combined with aqueous sodium hydroxide (20%, 4 mL) and stirred at room temperature for 2 hrs. The reaction mixture was diluted with ethyl acetate and the aqueous fraction was acidified to pH 2 with conc. hydrochloric acid. After extraction with ethyl acetate, the combined organic fractions were dried over sodium sulfate and concentrated under vacuum to give 121 mg (47% yield for two steps) of 3-(2-bromophenyl)-2,2-dimethylpropanoic acid as a white solid. The crude carboxylic acid was used in the next step without further purification: MS m/z: 255.0 (M−1).
Reaction SMILES: C([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C@H:21]([C:23]2[O:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:26][N:27]=2)[CH3:22])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O.O>>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[O:24][C:23]([C@@H:21]([NH:20][C:16]3[N:15]=[C:14]([N:9]4[C@@H:8]([C@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]4=[O:13])[CH:19]=[CH:18][N:17]=3)[CH3:22])=[N:27][CH:26]=2)=[CH:29][CH:30]=1
Reactant: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1ncc(-c2ccc(Cl)cc2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)O)n1)c1ncc(-c2ccc(Cl)cc2)o1
Yield: 37.7 %

Procedure:
(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (360 mg, 0.741 mg) was treated with 90% TFA/water for 2 hours. Concentrated in vacuo and neutralized by passing through a column of MP-carbonate resin (2.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded the desired product (120 mg, pale yellow foam). 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=6.0 Hz, 1H), 7.64-7.49 (m, 3H), 7.49-7.35 (m, 2H), 7.29 (s, 1H), 5.33 (dd, J=9.4, 5.1 Hz, 1H), 5.04-4.81 (m, 1H), 1.80-1.69 (m, 3H), 4.71-4.53 (m, 1H), 4.45 (dd, J=9.4, 8.1 Hz, 1H), 4.28-3.97 (m, 1H), 3.51 (s, 3H), 1.14 (d, J=6.4 Hz, 3H). HRMS(B) m/z 429.1204. RT=2.22 min.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:13][C:12]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=3[N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[NH:19]1[CH:24]=[CH:23][C:22](=[O:25])[CH:21]=[CH:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O.[Cu]>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([N:19]2[CH:24]=[CH:23][C:22](=[O:25])[CH:21]=[CH:20]2)=[N:3][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N)[nH]c2c1
Reactant: O=c1cc[nH]cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc2nc(-c3nc(-n4ccc(=O)cc4)cnc3N)[nH]c2c1
Yield: 29.5 %

Procedure:
A mixture of 5-bromo-3-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-amine (80 mg, 0.263 mmol), pyridin-4(1H)-one (287 mg, 2.63 mmol), cesium carbonate (257 mg, 0.8 mmol) and copper (5 mg, 0.08 mmol) were heated in NMP (2 mL) at 150° C. for 1 hour. The reaction mixture was diluted with EtOAc, washed with 1N NaOH, and the organic layer filtered through a pad of celite and concentrated in vacuo. The resulting solid was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (24.7 mg, 30% Yield).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][S:17][CH2:16][CH2:15]3)[S:11][C:10]=2[CH2:20][CH3:21])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:24])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:24][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([CH:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[S:11][C:10]=1[CH2:20][CH3:21]
Reactant: CCc1sc(C2CCSCC2)cc1C(O)C1CCCCC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1sc(C2CCSCC2)cc1C(Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a solution of cyclohexyl[2-ethyl-5-(tetrahydro-2H-thiopyran-4-yl)thiophen-3-yl]methanol (1.91 g) synthesized above in toluene (20 mL) was added thionyl chloride (516 μL), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (1.91 g, 95%) as a pale-yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].[OH:19][CH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl.CO>C1(C)C=CC=CC=1.C(O)C.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:1]([C:3]1[CH:17]=[C:16]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:20][OH:19])[CH:26]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: OCc1cccc(B(O)O)c1
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: CCO
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cc(-c2cccc(CO)c2)c2c(c1)ncn2-c1ccccc1

Procedure:
5-Cyano-7-iodo-1-phenylbenzimidazole (1.0 g, 2.90 mmol), 3-hydroxymethyl-phenylboronic acid (440 mg, 2.90 mmol) and tetrakis(triphenylphosphine)palladium(0) (330 mg, 2.90 mmol) were dissolved in toluene (8.0 ml) and ethanol (2.0 ml). Potassium carbonate (2M in water, 2.9 ml, 800 mg, 5.8 mmol) was added and the reaction mixture heated at reflux under a nitrogen atmosphere for 16 h. The reaction mixture was passed through a plug of silica gel using dichloromethane/methanol (19:1) to elute. The organic phase was concentrated under reduced pressure and the resultant gum triturated with ethyl acetate and dichloromethane. 5-Cyano-7-(3-hydroxymethylphenyl)-1-phenylbenzimidazole was obtained as an off-white solid (500 mg, 39%) m/z, 326.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2Cl.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:22][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25]2)=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccc(N)cn2)C1
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 21.4 %

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)propan-1-one (235 mg, 0.792 mmol) was reacted with tert-butyl 1-(5-aminopyridin-2-yl)piperidin-3-ylcarbamate (348 mg, 1.19 mmol) to afford the desired product (94 mg, 21%) as an orange solid: ESI MS m/z 554, [C27H32BrN5O3+H]+
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:7][O:8][CH3:9])=[CH:5][CH:6]=1.C([Li])CCC.CN(C)[CH:17]=[O:18].Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:9][O:8][CH2:7][C:4]1[S:3][C:2]([CH:17]=[O:18])=[CH:6][CH:5]=1
Reactant: COCc1ccc(Br)s1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COCc1ccc(C=O)s1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 31.1 %

Procedure:
To a solution of 2-bromo-5-(methoxymethyl)thiophene (439 mg, 2.12 mmol) in 6 mL of 9:1 tetrahydrofuran/hexamethylphosphoramide under argon at −78° C. was added n-butyllithium (0.93 mL, 2.5 M in hexanes) dropwise. After stirring for 2 minutes at −78° C., dimethylformamide (0.82 mL, 10.6 mmol) was added in a single portion and the reaction mixture was allowed to warm to room temperature before being poured into 30 mL of 1 N hydrochloric acid. Organics were extracted with 1:1 ether/hexanes (3×30 mL), washed with water (2×30 mL, brine (30 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (5-20% ethyl acetate in hexanes) to give 5-(methoxymethyl)thiophene-2-carbaldehyde (103 mg, 31%) as an oil. Used without further characterization.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[C:19]([Cl:24])[N:18]=1.Cl>O.CC(O)C>[Cl:24][C:19]1[N:18]=[C:17]([NH2:16])[N:22]=[C:21]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[CH:10][CH:11]=2)[CH:20]=1
Reactant: Cc1cc(Oc2ccc(N)cc2)ccn1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(Oc2ccc(Nc3cc(Cl)nc(N)n3)cc2)ccn1
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 64.4 %

Procedure:
{4-[(2-Methylpyridin-4-yl) oxy] phenyl} amine (47.5 g, 237 mmol) and 2-amino-4,6-dichloropyrimidine (40.8 g, 249 mmol) were suspended in water (900 mL) and 2-propanol (300 mL). 2M aqueous hydrochloric acid solution (23.7 mL) was then added and the mixture was then heated at 95° C. for 17 h. The mixture was then allowed to come to rt and solids were collected by suction filtration and washed with small amount of isopropanol. The solids were then resuspended in DMF and heated at 90° C. Triethylamine (20 mL) was then added and the mixture was stir for additional 10 min at 90° C. Water was then added in excess until cloudiness persisted at temperature. This was cooled to about 5° C. and precipitate formed were collected by suction filtration, washed with water and dried in vacuum oven at 40° C. to afford desired product (50 g, 64%) as light tan solid. 1H NMR (DMSO-d6) δ 9.40 (s, 1H), 8.27 (d, 1H), 7.76 (d, 2H), 7.06 (d, 2H), 6.75 (brs, 2H), 6.72 (d, 1H), 6.66 (s, 1H), 5.98 (s, 1H); MS ES 328 (M+H)+, calcd 328, RT=1.45 min.