Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]#[CH:4]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCCCCC>[CH3:1][C:2]([OH:11])([CH2:5][CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])[CH:3]=[CH2:4]
Reactant: C#CC(C)(O)CCCC(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Product: C=CC(C)(O)CCCC(C)C

Procedure:
An autoclave having an internal volume of 3 liters was charged with 1,140 g of the hexane solution containing 3,7-dimethyl-1-octyn-3-ol thus obtained and 0.27 g of a Lindlar catalyst (supported on calcium carbonate) to carry out the hydrogenation for 4 hours under hydrogen pressure of 5 to 8 kg/cm2 (gauge pressure) at a temperature of 25 to 43° C. Thereafter, the catalyst was filtered off, and the resultant filtrate was concentrated with a rotary evaporator to give crude 3,7-dimethyl-1-octen-3-ol. Above the procedures for the hydrogenation of 3,7-dimethyl-1-octyn-3-ol were repeated once more to obtain, in total, 1,590 g of crude 3,7-dimethyl-1-octen-3-ol. Analysis by gas chromatography (column: DC-550, available from Gasukuro Kogyo Inc.; column length: 3 m; column temperature: 100° C.; and column: PEG-HT, available from Gasukuro Kogyo Inc.; column length: 3 m; column temperature: 130° C.) revealed that the conversions of 3,7-dimethyl-1-octyn-3-ol were 99.7% and 97.3% for the respective runs of the hydrogenation, and the selectivities to 3,7-dimethyl-1-octen-3-ol were 95.0% and 95.8%, respectively.
Reaction SMILES: [OH-].[Li+].[CH2:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:32]([C:33]([O:35]C)=[O:34])=[C:31]2[C:26]([C@H:27]3[CH2:37][C@H:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1)(=[O:21])=[O:20])[CH3:4]>O1CCOCC1.O>[CH2:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:32]([C:33]([OH:35])=[O:34])=[C:31]2[C:26]([C@H:27]3[CH2:37][C@H:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1)(=[O:20])=[O:21])[CH3:4]
Reactant: CCN1CCC[C@H]1CCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OC[C@@H]1C[C@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN1CCC[C@H]1CCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OC[C@@H]1C[C@H]21
Yield: 43.5 %

Procedure:
Lithium hydroxide (0.22 g) was added to a solution of methyl (1aR,7bS)-5-{2-[2-((R)-1-ethyl-pyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 229, 0.26 g) in a mixture of dioxane (12 mL) and water (4 mL) and the mixture was irradiated in a microwave at 150° C. for 20 minutes. After cooling, the mixture was evaporated to dryness and the residue was acidified by addition of 10% aqueous citric acid (3 mL) and then extracted with DCM. The organic layer was dried (MgSO4) and filtered and the filtrate was evaporated to dryness. The residue was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 25-35% to give (1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.11 g) as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH:9]([CH2:10]OCC2C=CC=CC=2)[CH2:8][N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:6](=[O:27])[CH2:5]1)(=[O:3])[CH3:2].[S:28]1(=[O:35])(=[O:34])[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1.C(C=P(CCCC)(CCCC)CCCC)#N>C(O)C.C1C=CC=CC=1.[Pd]>[C:1]([N:4]1[CH:9]([CH2:10][N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][S:28]2(=[O:35])=[O:34])[CH2:8][N:7]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:6](=[O:27])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)CC1COCc1ccccc1
Reactant: O=S1(=O)CCCCN1
Agent: [Pd]
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Solvent: CCO
Product: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)CC1CN1CCCCS1(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-acetyl-5-[(benzyloxy)methyl]-1-(4-fluorobenzyl)piperazin-2-one (6.5 g) and 20% Pd/C (1.4 g) in ethanol (175 mL) was shaken under an atmosphere of hydrogen (60 psi) at room temperature overnight. The product mixture was filtered through a pad of Celite, and concentrated under vacuum. Residual ethanol was removed by co-evaporation with toluene under vacuum (3×). The resultant alcohol was used without further purification. A mixture of the alcohol (1.0 g, 3.57 mmol), 1,2-thiazinane 1,1-dioxide (0.73, 5.4 mmol), and cyanomethylenetri-n-butylphosphorane (1.3 g, 5.4 mmol; [157141-27-0]) in benzene (20 mL) was purged with nitrogen and heated in a sealed tube at 100° C. overnight. The reaction mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluting with a mixture of 5% methanol in ethyl acetate. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCN(CC)CC>C(Cl)Cl>[CH3:16][C:10]1([CH3:17])[C@@H:11]([C:13]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:15])[CH2:12][C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)N2CCOCC2)C1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.1 %

Procedure:
To a stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (Intermediate 1-Step 3, 0.3 g, 1.23 mmol) in DCM (5 ml) EDCI (0.237 g, 1.23 mmol) and HOBt (0.167 g, 1.23 mmol) were added at about 0° C., after 10 minutes morpholine (0.2 ml, 2.469 mmol) and Et3N (0.9 ml, 6.2 mmol) were added drop wise and the reaction mixture was stirred at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, 1N HCl, water and saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude purified by a silica gel column (100-200 mesh, elution 90% EtOAC in hexane) to afford the title compound as a syrup. Wt: 0.205 g; Yield: 53.1%; 1H NMR (300 MHz, CDCl3): δ 4.75 (d, 1H, J=8.4 Hz), 3.90-3.40 (m, 8H), 2.83-2.74 (m, 1H), 2.40-2.21 (m, 2H), 1.43 (s, 9H), 1.32 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[F:17])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[F:17])[CH3:2]
Reactant: CCOCCCNc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Product: CCOCCCNc1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of N-(3-ethoxypropyl)-2-fluoro-4-nitroaniline (8.68 g, 36 mmol) in MeOH (50 mL) was added catalyst Pd/C (0.87 g). The reaction mixture was stirred at rt under H2 overnight. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as blackish oil (5.52 g, 72%).
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([CH2:12][CH3:13])[N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([C:5]1[N:10]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:9](=[O:11])[CH:8]=[C:7]([CH2:12][CH3:13])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CC)cc(=O)[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCc1nc(CC)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 25.4 %

Procedure:
To a solution of 2-butyl-6-ethylpyrimidin-4(3H)-one (4 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (6.64 g) in acetonitrile (120 mL) was added potassium carbonate (6.1 g), and the mixture was stirred at 50° C. for 12 hr. The insoluble material was filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (2.09 g, 25%) as a colorless solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([C:18]([F:21])([F:20])[F:19])[CH:10]=2)=[O:8])[CH2:3][CH2:2]1>C(O)C.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[O:8])=[CH:10][C:11]=1[C:18]([F:21])([F:20])[F:19]
Reactant: O=C(c1ccc([N+](=O)[O-])c(C(F)(F)F)c1)N1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCOCC2)cc1C(F)(F)F

Procedure:
A mixture of EXAMPLE 144A (13 g) and Pd/C (1.3 g, 10%) in ethanol (300 mL) was stirred under hydrogen at room temperature for two days. The catalyst was filtered off and the solvent was evaporated to provide the final compound.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[Cl:17][C:18]1[CH:46]=[CH:45][C:21]([CH:22]([N:30]2[C:38]3[C:33](=[CH:34][C:35](/[C:39](/[CH3:44])=[CH:40]/[C:41](O)=[O:42])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH:22]([N:30]2[C:38]3[C:33](=[CH:34][C:35](/[C:39](/[CH3:44])=[CH:40]/[C:41]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:42])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:21]2[CH:45]=[CH:46][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)c1
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)c1

Procedure:
217 mg of compound 61 was obtained in a similar manner to those described in the Examples 1 and 2 using 438 mg of ethyl 4-(2-aminophenoxy)butyrate and 429 mg of 3-[1-(4,4'-dichlorobenzhydryl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:23][CH:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1
Reactant: CN1CCC(N)CC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCN(C)CC1
Yield: 68.9 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (220 mg, 0.91 mmol) was reacted with 1-methylpiperidin-4-amine (160 mg, 1.4 mmol) to afford the desired product (200 mg, 69%) as a light brown solid: 1H NMR (500 MHz, CDCl3) δ 10.98 (s, 1H), 8.96 (s, 1H), 8.10 (d, J=8.7 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 5.11 (br s, 1H), 2.98-2.870 (m, 2H), 2.69 (s, 3H), 2.41-2.28 (m, 5H), 2.28-2.20 (m, 2H), 1.85-1.73 (m, 2H); ESI MS m/z 319 [M+H]+; ESI MS m/z 319 [M+H]+
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[CH3:9][C:10]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15].[H-].[Na+].Cl>C1C=CC=CC=1>[CH3:9][C:10]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:11][CH2:12][CH2:13][C:14](=[O:16])[CH2:15][C:1]([O:5][CH2:6][CH3:7])=[O:8]
Reactant: CC(=O)CCC=C(C)CCC=C(C)C
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)CC(=O)CCC=C(C)CCC=C(C)C
Yield: 37 %

Procedure:
9.45 g of diethyl carbonate and 7.8 g of 6,10-dimethyl- 2-oxo-5,9-undecadiene were added to a suspension of 3.84g of sodium hydride in a 50% oil suspension in 40 ml of benzene and the mixture was refluxed for 21/2 hours and then cooled. The mixture was poured into dilute hydrochloric acid and was then extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed over silica and was eluted with benzene to obtain 3.96 g of ethyl 7,11-dimethyl- 3-oxo-6,10-dodecadienoate in the form of a yellow oil which was used as is for the next step.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([Cl:17])[CH:15]=2)[N:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:20][C:21]1[N:26]=[C:25]([NH2:27])[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[C:16]([C:24]1[C:25]([NH2:27])=[N:26][C:21]([CH3:20])=[CH:22][C:23]=1[C:7]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([Cl:17])[CH:15]=2)[N:10]=[CH:9][CH:8]=1)([CH3:11])([CH3:7])[CH3:15]
Reactant: O=S(=O)(Oc1ccnc2cnc(Cl)cc12)C(F)(F)F
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(N)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1cc(-c2ccnc3cnc(Cl)cc23)c(C(C)(C)C)c(N)n1
Yield: 17 %

Procedure:
A solution of 6-chloro-1,7-naphthyridin-4-yl trifluoromethanesulfonate (1.0 equiv.), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.0 equiv.) and Pd(dppf)Cl2—CH2Cl2 (0.1 equiv.) in 3:1 DME/2M Na2CO3 was heated in a microwave at 100° C. for 15 minutes. Upon cooling, the solution was partitioned between EtOAc and Na2CO3(sat.) washed further with NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography (2-4% MeOH/CH2Cl2 w/0.1% DIEA eluant) to yield tert-butyl 4-(6-chloro-1,7-naphthyridin-4-yl)-6-methylpyridin-2-amine (17%). LC/MS=271.0 (M+H), LC=1.81 min.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:14]1(=O)[O:19][C:17](=[O:18])[CH:16]=[CH:15]1>C1(C)C=CC=CC=1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[CH:16]=[CH:15][C:14]1=[O:19])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCN1C(=O)C=CC1=O

Procedure:
To a solution of N-BOC-1,4-diaminobutane (8.324 g, 0.044 mol) in dry toluene (50 ml) was added maleic anhydride (4.336 g, 0.044 mol) and the solution heated at reflux under Dean-Stark conditions for two days. The solvent was removed and the residue purified by silica column chromatography eluting with 25-40% ethyl acetate in hexane to give the title compound, 1.461 g, 12%, as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][NH:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)[N:13]=1.[Cl:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH:38]=O>>[Cl:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38][N:17]1[CH2:18][C@@H:14]([N:12]2[N:11]=[N:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:13]2)[CH2:15][C@H:16]1[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[C:29]#[N:30])[CH2:25][CH2:26]1)=[O:20]
Reactant: O=Cc1ccccc1Cl
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2Cc2ccccc2Cl)CC1
Yield: 14.4 %

Procedure:
As described for Example 1e, 2-(4-{4-[5-(2,4-difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (60 mg, 0.13 mmol) was converted, using 2-chloro-benzaldehyde (20 mg, 0.14 mmol) instead of benzaldehyde, to the title compound (11 mg, 14.4%) as light yellow oil. MS m/e=589.1 (75%); 591.1 (25%) [M+H]+.
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(C)(C)C.[K+].[C:15]1([CH3:23])[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1>C(O)CCC.O>[C:15]1([CH3:23])[CH:20]=[CH:19][C:18]([CH:21]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=2[O-:8])=[CH:17][CH:16]=1
Reactant: Cc1cccc[n+]1[O-]
Reactant: Cc1ccc(C=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: Cc1ccc(C=Cc2cccc[n+]2[O-])cc1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
To a refluxing solution of 2-picoline-1-oxide (10.9 g, 100 mmol), potassium tert.-butanolate (11.2 g, 100 mmol) in butanol (100 ml) was added portion-wise p-tolualdehyde (12.0 g, 100 mmol). Reflux was maintained for 90 min. Then the mixture was cooled to rt, diluted with H2O (100 ml) and extracted with CH2Cl2. The combined organic phases were dried with MgSO4, concentrated and chromatographed (SiO2 with CH2Cl2/MeOH=95:5) to provide the title compound (11.6 g, 55%) as a yellow solid material. MS: m/e=211 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH:9]1([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:19]2[CH:20]=[CH:21][C:16]([S:13]([NH:12][CH:9]3[CH2:11][CH2:10]3)(=[O:15])=[O:14])=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)NC3CC3)cc2)OC1(C)C
Reactant: Nc1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1ccc(-c2ccc(S(=O)(=O)NC3CC3)cc2)cn1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 34.7 %

Procedure:
A mixture of 2-amino-5-bromopyridine (3.58 g, 20.7 mmol), N-cyclopropyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (5.00 g, 20.7 mmol), sodium carbonate (3.29 g, 31.05 mmol), and PdCl2(PPh3)2 (0.436 g, 0.62 mmol) in 3:1 acetonitrile:water was microwave heated at 80° C. for 20 min, and then at 100° C. for 15 min. The reaction was then heated in an oil bath at 80° C. for 16 h. The reaction was cooled to room temperature and filtered. The solid was washed with methanol (10 mL), and the combined filtrates were concentrated. The crude material was purified by flash chromatography over silica gel (0-5% MeOH/DCM) to give 4-(6-aminopyridin-3-yl)-N-cyclopropylbenzenesulfonamide (2.08 g, 35% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.27 (d, J=2.01 Hz, 1H), 7.88-7.95 (m, 2H), 7.85 (d, J=2.51 Hz, 1H), 7.81-7.84 (m, 1H), 7.71-7.79 (m, 2H), 6.45-6.88 (m, 1H), 1.89-2.41 (m, 1H), 0.13-0.82 (m, 4H); MS (EI) m/z: 290 [M+H]+. HPLC (Sunfire C18 4.6 mm×50 mm, 10-90% MeCN:10 mM aq. NH4OAc, 2 min gradient) tR=1.34 min, 88% integrated area.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12](OC)=[O:13])=[CH:7][C:6]=2[CH:16]=1.CC(C[AlH]CC(C)C)C>C(OCC)C.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][OH:13])=[CH:7][C:6]=2[CH:16]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2CCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC1=Cc2cc(Br)ccc2CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of methyl 2-bromo-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate from step A4 (170 mg, 0.605 mmol) in diethyl ether (2 mL) and THF (1 mL) was added 1.0 M DIBAL-H/hexanes (0.726 mL, 0.726 mmol) at −78° C. The mixture was stirred at rt for 16 h. Another 0.726 mL portion of DIBAL-H was added at 0° C., and the mixture was stirred at rt for an additional 2 h. The reaction mixture was diluted with 50 mL of diethyl ether, quenched with water, and extracted with EtOAc (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give (2-bromo-6,7-dihydro-5H-benzo[7]annulen-8-yl)methanol (150 mg, 0.593 mmol, 98% yield). 1H NMR (500 MHz, chloroform-d) δ 7.30 (s, 1H), 7.22 (dd, J=7.9, 1.8 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 6.45 (s, 1H), 4.21 (br. s., 2H), 2.81-2.71 (m, 2H), 2.34 (t, J=6.4 Hz, 2H), 2.08-1.98 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[CH3:28])=[C:10]([C:29]([NH2:31])=[O:30])[CH:9]=2)[C:5](I)=[CH:4][N:3]=1.[C:33]([C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)=[O:42])=[CH:37][CH:36]=1)#[CH:34]>C(#N)C.[Cu](I)I.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>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[CH3:28])=[C:10]([C:29]([NH2:31])=[O:30])[CH:9]=2)[C:5]([C:34]#[C:33][C:35]2[CH:36]=[CH:37][C:38]([C:41]([N:43]3[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]3)=[O:42])=[CH:39][CH:40]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(Cl)cc1-c1c(C(N)=O)cc(-c2nc(N)ncc2I)n1COCC[Si](C)(C)C
Reactant: C#Cc1ccc(C(=O)N2CCN(C)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Product: Cc1ccc(Cl)cc1-c1c(C(N)=O)cc(-c2nc(N)ncc2C#Cc2ccc(C(=O)N3CCN(C)CC3)cc2)n1COCC[Si](C)(C)C
Temperature: 80 °C
Yield: 79.8 %

Procedure:
To a degassed solution of 5-(2-amino-5-iodopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxamide (140 mg, 0.24 mmol), (4-ethynylphenyl)(4-methylpiperazin-1-yl)methanone (98 mg, 0.43 mmol) and TEA (0.335 mL, 2.4 mmol) in dry ACN (2.5 mL) were added copper iodide (2.5 mg, 0.012 mmol) and Pd(PPh3)2Cl2 (8.4 mg, 0.012 mmol). The mixture was heated at 80° C. for 2 h, then the solvent was evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH/7N NH3 in MeOH 95/4/1) to afford the title compound (131 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[C:12]([N:14]([CH3:28])[C:15](=[O:27])[C:16]=1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=2)[NH:19][CH:18]=1)=[O:13]>CN(C=O)C.[C].[Pd]>[F:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH:16]1[CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)[C:12](=[O:13])[N:14]([CH3:28])[C:15]1=[O:27]
Reactant: CN1C(=O)C(c2c[nH]c3ccc(F)cc23)=C(c2c[nH]c3ccc(F)cc23)C1=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: CN1C(=O)C(c2c[nH]c3ccc(F)cc23)C(c2c[nH]c3ccc(F)cc23)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.9 %

Procedure:
To a solution of 2,3-bis(5-fluoro-1H-indol-3-yl)-N-methylmaleimide (60 mg, 0.16 mmol) in DMF (3 mL) was added a small amount of 10% palladium-carbon, and the whole was stirred at room temperature for 1 day under hydrogen atmosphere. The palladium-carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=2:1) to obtain 3,4-bis(5-fluoro-1H-indol-3-yl)-1-methyl-2,5-dioxopyrrolidine (58.8 mg, 97.5%) as pale red solids. 1H-NMR(CDCl3): δ 3.11(s, 3H), 4.90(s, 2H), 6.74(dt, J=2.5, 9.0 Hz, 2H), 6.99(d, J=2.5 Hz, 2H), 7.01(dd, J=9.0, 2.5 Hz, 2H), 7.09(dd, J=9.0,4.6 Hz, 2H), 10.77(br s, 2H). IR(KBr): 3420, 1700, 1490, 1440, 1295, 940, 800 cm−1. MS m/z: 379(M+).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C1CCCCC1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8]/[C:9](=[CH:22]\[N:23]([CH3:25])[CH3:24])/[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CCCOc2ccc(Br)cc21
Solvent: C1CCCCC1
Product: CN(C)/C=C1\CCOc2ccc(Br)cc2C1=O
Temperature: 25 °C
Yield: 67 %

Procedure:
7-Bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (10.0 g, 41.5 mmol) in dimethylformamide dimethylacetal (100 mL) was heated at 110° C. for 18 h. The reaction was allowed to cool to room temperature and cyclohexane (100 mL) was added. The resulting solid precipitate was collected by filtration, washed with cyclohexane and then dried under vacuum at 40° C. to yield 7-Bromo-4-[1-dimethylamino-meth-(E)-ylidene]-3,4-dihydro-2H-benzo[b]-oxepin-5-one as yellow crystals (8.19 g, 67%). 1H NMR δ (ppm)(CDCl3): 7.83 (1 H, d, J=2.59 Hz), 7.74 (1 H, s), 7.46 (1 H, dd, J=8.51, 2.58 Hz), 6.88 (1 H, d, J=8.52 Hz), 4.27-4.19 (2 H, m), 3.14 (6 H, s), 2.76-2.69 (2 H, m).