Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:32][C@@H:33]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[O:35][C@H:34]1[C:64]1[CH:69]=[C:68](CO)[CH:67]=[CH:66][C:65]=1[CH3:72])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:25]([O:32][C@@H:33]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[O:35][C@H:34]1[C:64]1[CH:69]=[C:68]([CH2:1][Br:5])[CH:67]=[CH:66][C:65]=1[CH3:72])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc(CO)cc1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(CBr)cc1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Carbon tetrabromide (0.62 g) and triphenylphosphine (0.49 g) were added to a solution of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[5-(hydroxymethyl)-2-methylphenyl]-D-glucitol (1.0 g) in methylene chloride (10 ml) at room temperature and the mixture was stirred for one hour. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[5-(bromomethyl)-2-methylphenyl]-D-glucitol (0.8 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[N:13]([CH2:25][CH3:26])[C:14]3[C:19]([C:20]=2[C:21]#[N:22])=[CH:18][CH:17]=[C:16]([O:23][CH3:24])[CH:15]=3)[CH:9]=[CH:8][C:7]=1[OH:27])=[O:4].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:25]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([O:23][CH3:24])[CH:15]=2)[C:20]([C:21]#[N:22])=[C:12]1[C:10]1[CH:9]=[CH:8][C:7]2[O:27][CH2:2][C:3](=[O:4])[NH:5][C:6]=2[CH:11]=1)[CH3:26]
Reactant: CCn1c(-c2ccc(O)c(NC(=O)CCl)c2)c(C#N)c2ccc(OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2ccc3c(c2)NC(=O)CO3)c(C#N)c2ccc(OC)cc21
Temperature: 80 °C
Yield: 99.7 %

Procedure:
2-Chloro-N-[5-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-hydroxy-phenyl]acetamide (57 mg, 0.13 mmol), prepared in step A, is combined with K2CO3 (55 mg, 0.4 mmol), and DMF (400 μL). This is heated at 80° C. for 1 hour. The reaction mixture is then partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2Cl2/EtOAc) yields 1-ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (45 mg, 90%) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH:24]1[O:26][CH2:25]1>CO>[CH2:1]([N:8]([CH2:25][CH:24]([OH:26])[C:23]1[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=1[Cl:21])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CCNCc2ccccc2)cc1OC
Reactant: Clc1ccccc1C1CO1
Solvent: CO
Product: COc1ccc(CCN(Cc2ccccc2)CC(O)c2ccccc2Cl)cc1OC

Procedure:
Similarly 2.71 g. (0.01 mol) of N-benzyl-3,4-dimethoxyphenethylamine and 2.33 g. (0.015 mol) of o-chlorostyrene oxide are reacted in methanol to give N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-chlorophenyl)ethylamine. The latter is converted to its hydrochloride, dissoved in 90 ml. of methanol and hydrogenated over 1 g. of 10% palladium-on-carbon in 10 ml. of ethyl acetate at room temperature for 6 hours. The reaction mixture is filtered and evaporated in vacuo to leave N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-chlorophenyl)ethylamine hydrochloride, m.p. 128°-132° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9](O)=[O:10])([O-:3])=[O:2].S(Cl)([Cl:15])=O>>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([Cl:15])=[O:10])([O-:3])=[O:2]
Reactant: O=C(O)c1cncc([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cncc([N+](=O)[O-])c1

Procedure:
A mixture of 2 g of 5-nitronicotinic acid and 30 ml. of thionyl chloride was refluxed for 3 hours. Excess thionyl chloride was distilled off to give oily 5-nitronicotinoyl chloride. The acid chloride thus obtained was added to 10 ml of pyridine at -15° C. and 1.4 g of 2-thiophene carboxamide was added thereto. The resulting mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure at a temperature below 40° C. and the residue was purified over silica gel chromatography and recrystallized from ethyl acetate-n-hexane to give 200 mg of the desired product. mp 187° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:2]1[O:4][CH2:3]1.C(=O)(O)[O-:19].[Na+]>O>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:2]([CH2:3][OH:19])[OH:4]
Reactant: O=C([O-])O
Reactant: CCCCCCCCCCCCOCC1CO1
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCOCC(O)CO
Temperature: 200 °C
Reaction time: 8 h

Procedure:
In an autoclave, 249 of the resulting dodecyl glycidyl ether, 97.2 g of water and 34.8 g of sodium bicarbonate were charged and were stirred at 200° C. for 8 hours. After completion of the reaction, the reaction mixture was dehydrated at 120° C. under reduced pressure (6.67 kPa), followed by purification by distillation under reduced pressure (13 to 26 Pa, 160 to 170° C.), whereby 117 g of monododecyl glyceryl ether was obtained. As a result of gas chromatographic analysis (hereinafter abbreviated as “GLC”), it was found that the resulting product had a purity not less than 99% and the content of a chlorohydrin ether isomer different in alcohol added position and a 2-mole adduct of epichlorohydrin (hereinafter called “organochlorine compounds”, for simplicity) was not greater than 100 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]([C:13]([O:15]CC)=[O:14])[C:8]([O:10]CC)=[O:9])=[CH:4][CH:3]=1.[OH-].[K+]>OC(C)=O.O.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([C:8]([OH:10])=[O:9])[C:13]([OH:15])=[O:14])=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)C(Cc1ccc(Br)cc1)C(=O)O
Yield: 873.2 %

Procedure:
Diethyl 2-(4-bromobenzyl)malonate (40 g, 13 mmol) and KOH (42.8 g, 76 mmol) was dissolved in a mixture of HOAc-H2O-THF (1:2:3, 200 mL), the mixture was refluxed for 12 hours. The solvent was removed in vacuo, the residue was added HCl aqueous, then extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated to give 2-(4-bromobenzyl)malonic acid (31 g, 95%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][O:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)[CH2:16]1)=O)(C)(C)C>ClCCl>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[O:22][CH2:21][CH:17]1[CH2:18][CH2:19][CH2:20][NH:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCCC(COc2nc3ccccc3s2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2sc(OCC3CCCNC3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
Trifluoroacetic acid (2 mL) was added to 1-tert-butoxycarbonyl-3-[(benzothiazol-2-yl)oxymethyl]piperidine (460 mg, 1.32 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature for 3 hours. Subsequently, the solvent was evaporated and water was added to the residue, followed by a 1 mol/L aqueous sodium hydroxide solution to make the mixture basic. The mixture was then extracted with ethyl acetate and the extract washed with brine. The washed product was dried over magnesium sulfate and the solvent was evaporated to give 297 mg (91%) of the desired compound as a colorless oil.
Reaction SMILES: [Na].[CH3:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][C:9]#[N:10])[CH:4]=1.[N:11]([C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=O)=[N+:12]=[N-:13]>CCO>[CH3:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:13]=[N:12][N:11]3[C:14]4[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:16](=[O:18])[NH:10][C:9]=23)[CH:4]=1
Reactant: Cc1cc(CC#N)no1
Reactant: [N-]=[N+]=Nc1ccccc1C(=O)O
Agent: [Na]
Solvent: CCO
Product: Cc1cc(-c2nnn3c2[nH]c(=O)c2ccccc23)no1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
Sodium (0.2 g, 8.6 mmol) was dissolved in EtOH (9 mL) and (5-methylisoxazol-3-yl)acetonitrile (0.65 g, 5.3 mmol) was added. The solution was stirred for 15 min then a solution of 2-azidobenzoic acid (0.7 g, 4.3 mmol) in EtOH (7 mL) was added and the mixture stirred for 1 h. After this time the mixture was heated at reflux for 5 h. The suspension was then allowed to cool to room temperature and the solvent removed in vacuo. The residue was taken up in water and 1N citric acid was added to pH4. The resultant precipitate was collected by filtration, washed with water then dried in vacuo at 60° C. The title compound (0.92 g, 80%) was isolated as a colourless solid. 1HNMR (360 MHz, d6-DMSO) δ 2.51 (3H, s), 6.83 (1H, q, J=0.8 Hz), 7.72 (1H, d of t, J=8.1 and 1.0 Hz), 8.01 (1H, d of t, J=7.5 and 1.4 Hz), 8.24 (1H, dd, J=8.0 and 1.3 Hz), 8.36 (1H, d, J=8.0 Hz), 12.16 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1.[CH3:26][NH2:27]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:21]=[CH:22]/[C:23]([NH:27][CH3:26])=[O:25])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1
Reactant: CN
Reactant: COc1cc(/C=C/C(=O)O)cc(-c2ccc3cc(OC)ccc3c2)c1
Product: CNC(=O)/C=C/c1cc(OC)cc(-c2ccc3cc(OC)ccc3c2)c1
Yield: 53 %

Procedure:
The compound was prepared by reaction of (E)-3-[3-methoxy-5-(6-methoxynaphthalene-2-yl)phenyl]acrylic acid (300 mg, 0.89 mmol, 1 eq) with 33% methylamine (1 eq) according to method D. Purification by column chromatography with hexane/ethyl acetate 2/1 as the eluent yielded the desired product in a yield of 53%, 200 mg.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.O1CCOCC1.[OH-].[Na+].Cl[CH:24]([F:26])[F:25]>O>[F:25][CH:24]([F:26])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)C(C(=O)O)c1ccc(O)cc1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C(C(=O)O)c1ccc(OC(F)F)cc1
Temperature: 0 °C
Yield: 43 %

Procedure:
To a stirred mixture of 2-(4-hydroxyphenyl)-3-methylbutyric acid (10.0 g; 0.0515 mol), dioxane (65 ml), sodium hydroxide (19.08 g, 18.56 g real; 0.464 mol), and water (30 ml) is bubbled chlorodifluoromethane (46 g; 0.532 mol) at 80° C. over a four-hour period. The reaction mixture is then poured into 250 ml of ice water, washed with ether, acidified with concentrated hydrochloric acid to pH 3, and extracted with 200 ml of ether. The ether extract is washed with 100 ml of water, dried with sodium sulfate, filtered, and evaporated to a white paste. A mixture of hexane and methylene chloride is added. The resulting mixture is filtered to remove the solid which is the starting material. The filtrate is evaporated to give 5.41 g of product as a clear brown oil. The product is at least 85% pure as calculated by NMR. NMR (CDCl3 -d5 pyridine): δ6.57 (t, J=74.3 Hz, 1 H); δ3.63 (s, imp.); δ3.25 (d, J=10 Hz, 1H); δ2.37 (m, 1H); δ1.19 (d, J=6.5 Hz, 3H); δ0.78 (d, J=6.5 Hz, 3H); δ13.82 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:14]2[NH:13][C:12]3[N:11]=[C:10]([C:15]#[N:16])[CH:9]=[CH:8][C:7]=3[C:6]=2[C:5](=[O:17])[C:4]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:21][C:3]1=2.[C:29]1(=O)[CH2:32][CH2:31][CH2:30]1>>[CH:29]1([N:25]2[CH2:24][CH2:23][N:22]([C:20]3[CH:19]=[CH:18][C:4]4[C:5](=[O:17])[C:6]5[C:7]6[CH:8]=[CH:9][C:10]([C:15]#[N:16])=[N:11][C:12]=6[NH:13][C:14]=5[C:2]([CH3:28])([CH3:1])[C:3]=4[CH:21]=3)[CH2:27][CH2:26]2)[CH2:32][CH2:31][CH2:30]1
Reactant: O=C1CCC1
Reactant: CC1(C)c2cc(N3CCNCC3)ccc2C(=O)c2c1[nH]c1nc(C#N)ccc21
Product: CC1(C)c2cc(N3CCN(C4CCC4)CC3)ccc2C(=O)c2c1[nH]c1nc(C#N)ccc21

Procedure:
According to the method used for synthesizing Compound B3-32, 10,10-dimethyl-5-oxo-8-piperazin-1-yl-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrile was subjected to reductive amination with cyclobutanone to obtain the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C@H:14]([C@@H:18]([O:35]C=O)[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([F:34])[CH:28]=2)=[CH:23][CH:22]=1)[C:15]([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].S([O-])(O)(=O)=O.[Na+]>CO.C(OCC)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C@H:14]([C@@H:18]([OH:35])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([F:34])[CH:28]=2)=[CH:23][CH:22]=1)[C:15]([OH:17])=[O:16]
Reactant: Cc1ccc(-c2ccc(CC[C@H](OC=O)[C@@H](CCN3C(=O)c4ccccc4C3=O)C(=O)O)cc2)cc1F
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(CC[C@H](O)[C@@H](CCN3C(=O)c4ccccc4C3=O)C(=O)O)cc2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the compound obtained from step o above (0.31 g) in methanol (5 mL), potassium carbonate (0.094 g) was added at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (50 mL), acidified with sodium hydrogen sulphate, and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a residue which was purified by preparative thin layer chromatography using 10% methanol in dichloromethane as eluant to afford the title compound (0.020 g).
Reaction SMILES: [O:1]1[CH:6]2[CH2:7][NH:8][CH2:9][CH:5]2[O:4][CH2:3][CH2:2]1.[C:10]([C:12]1[CH:13]=[C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:29][CH2:30][CH2:31][CH2:32]Cl)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1)#[CH:11].C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:10]([C:12]1[CH:13]=[C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:29][CH2:30][CH2:31][CH2:32][N:8]4[CH2:7][CH:6]5[O:1][CH2:2][CH2:3][O:4][CH:5]5[CH2:9]4)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1)#[CH:11]
Reactant: C1COC2CNCC2O1
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCCl)cc23)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCN4CC5OCCOC5C4)cc23)c1
Temperature: 70 °C
Yield: 49.9 %

Procedure:
A mixture of hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (0.31 g, 2.40 mmol, 1.20 eq), N-(3-ethynylphenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (0.74 g, 2.00 mmol, 1.00 eq), anhydrous K2CO3 (1.00 g, 7.20 mmol, 3.60 eq) and tetrabutylammonium iodide (37 mg, 0.10 mmol, 0.05 eq) in DMF (8 mL) was heated at 70° C. for 11 h. The reaction mixture was cooled to room temperature and quenched with water (10 mL). The resulted mixture was diluted with EtOAc (20 mL) and the organic phase was separated from the mixture. The water phase was extracted with EtOAc (20 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/CH3OH) to give the crude product, which was recrystallized from CH2Cl2/PE to afford the title compound as a pale yellow solid (0.46 g, 50.00%), HPLC: 96.10%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 461.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.98 (3H, s), 2.09 (2H, m), 2.73 (2H, m), 2.78 (2H, m), 2.97 (2H, dd, J=4.4, 10.4 Hz), 3.09 (1H, s), 3.55 (2H, m), 3.79 (2H, m), 3.99 (3H, s), 4.11 (2H, m), 4.22 (2H, t, J=6.8 Hz), 7.24 (2H, m), 7.25-7.28 (1H, m), 7.35 (1H, t, J=8.0 Hz), 7.67 (1H, br s), 7.80 (1H, m), 786 (1H, m) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C@@H:18]([C:33](=[O:43])[NH:34][O:35]CC3C=CC=CC=3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)(=[O:23])=[O:24])[C@@H:18]([C:33](=[O:43])[NH:34][OH:35])[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(S(=O)(=O)N2CC[C@@H](C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)C[C@@H]2C(=O)NOCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2CC[C@@H](C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)C[C@@H]2C(=O)NO)cc1

Procedure:
A mixture of (2R,4R)-4-[2-benzyloxycarbamoyl-1-(4-methoxy-benzene-sulfonyl)-piperidine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 0.81 mmol) and 5% palladium on barium sulfate (250 mg) in 10 mL of methanol was shaken under a 40 psi atmosphere of hydrogen gas for 1.5 hours. Filtration through nylon and concentration of the filtrate provided (2R,4R)-4-[2-hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-piperidine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester as a colorless solid, which was used in the subsequent step without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8](Br)[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[CH3:22][N:23]1CCCC1=O>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[C-]#N.[Zn+2]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:22]#[N:23])[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: CN1CCCC1=O
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC(=O)c1cc(C#N)c(F)c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 52 %

Procedure:
A mixture of 5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (14) (3.01 g, 7.99 mmol), 1,1′-bis(diphenylphosphino)ferrocene (dppf) (93 mg, 0.162 mmol), Pd2dba3 (73 mg, 0.080 mmol) and Zn(CN)2 (573 mg, 4.78 mmol) in 1-methyl-2-pyrrolidinone (NMP: 4.5 mL) was heated in a sealed tube reactor. After 20 hours, the reaction mixture was cooled to room temperature, quenched by the addition of 8 mL 4:1:4 (volume) mixture of saturated NH4Cl, concentrated NH40H and water, and extracted with a mixture of EtOAc:THF. The combined organic extracts were washed with 4:1:4 (volume) mixture of saturated NH4Cl, concentrated NH4OH and water, and brine. The organic layer was dried (MgSO4) and concentrated. Purification by flash column chromatography using the Biotage system (twice: 100% hexanes to 35% CH2Cl2 in hexanes, then 30% CH2Cl2 in hexanes) provided 1.33 g (52%) of the desired product (15).
Reaction SMILES: Br[C:2]1[C:3]([N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:4][S:5][CH:6]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.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>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:6][S:5][CH:4]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cscc2Br)CCN(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cscc2-c2ccccc2)CCN(C)C1
Temperature: 95 °C

Procedure:
To a de-aerated solution of 5-(4-bromo-thiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (40 mg, 0.111 mmol), phenylboronic acid (20 mg, 0.166 mmol) and K3PO4 (58.8 mg, 0.217 mmol) in DMF-water (4.5:0.5 mL) was added PdCl2(PPh3)2 (3.8 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(4-phenyl-thiophen-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (4 mg). 1H NMR (TFA salt, CD3OD) d (ppm): 7.79-7.65 (m, 2H), 7.3 (s, 1H), 7.2-7.1 (m, 4H), 7.1-7.0 (m, 2H), 6.9 (d, 1H), 4.7 (d, 1H), 4.3 (d, 1H), 3.61-3.60 (m, 1H), 3.25-3.2 (m, 1H), 3.05-3.00 (m, 1H), 2.9 (s, 3H), 2.4 (s, 3H), 2.4-2.39 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[C:14]([F:31])=[C:15]([NH:18][S:19]([N:22]([CH2:24][CH:25]4[CH2:30][O:29][CH2:28][CH2:27][O:26]4)[CH3:23])(=[O:21])=[O:20])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[K+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:26]1[CH2:27][CH2:28][O:29][CH2:30][CH:25]1[CH2:24][N:22]([CH3:23])[S:19]([NH:18][C:15]1[CH:16]=[CH:17][C:10]2[CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]([C:36]4[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=4)[CH:3]=[C:4]3[C:12](=[O:13])[C:11]=2[C:14]=1[F:31])(=[O:21])=[O:20]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN(CC1COCCO1)S(=O)(=O)Nc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1F
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CN(CC1COCCO1)S(=O)(=O)Nc1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1F
Temperature: 25 °C

Procedure:
To a stirred solution of N′-(3-chloro-6-fluoro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-(1,4-dioxan-2-ylmethyl)-N-methylsulfamide (127 mg, 0.271 mmol) in DMF (7 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (113 mg, 0.543 mmol), tri-t-butylphosphonium tetraflroroborate (16 mg, 0.054 mmol), potassium fluoride (52 mg, 0.896 mmol), and Pd2(dba)3 (25 mg, 0.027 mmol). The reaction mixture was purged with N2 for 5 min, heated to 130 C for 9 h, cooled to room temperature, treated with water, and extracted with CH2Cl2 (×3). The combined organics were dried (Na2SO4), concentrated, and purified by prep-HPLC to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.99 (d, 1H); 8.31 (d, 1H); 7.91 (s, 1H); 7.90 (m, 2H); 7.81 (s, 1H); 7.36 (d, 1H); 7.26 (d, 1H); 7.17 (d, 1H); 4.00 (s, 3H); 3.64-4.00 (series of m, 7H); 3.36 (dd, 1H); 3.09 (dd, 1H); 2.99 (s, 3H). LRMS (ESI) calc'd for (C24H24F5O5S) [M+H]+, 514.1; found 514.1.