Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[C:8]([C:15]([F:18])([F:17])[F:16])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[CH3:19].C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:61][C:62]([F:71])([F:70])[C:63]1[CH:64]=[CH:65][C:66](=O)[NH:67][CH:68]=1>C(Cl)Cl>[CH3:19][C:5]1[N:4]([CH2:3][CH2:2][O:1][C:66]2[CH:65]=[CH:64][C:63]([C:62]([F:71])([F:70])[F:61])=[CH:68][N:67]=2)[C:12]2[C:7]([CH:6]=1)=[C:8]([C:15]([F:18])([F:16])[F:17])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CCO
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
A solution of 1-(2-hydroxyethyl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.130 g, 0.49 mmol) in CH2Cl2 (3 mL) at 0° C. was treated with DBAD (0.302 g, 1.31 mmol), PPh3 (0.343 g, 1.31 mmol) and 5-(trifluoromethyl)-2(1H)-pyridinone (0.87 g, 0.53 mmol). The mixture was allowed to slowly warm to rt and then stirred for 14 h. Concentration was followed by column chromatography (SiO2, hexanes/EtOAc) to afford the title compound (0.160 g): 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.75 (dd, J=8.8 and 2.5 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 6.57 (s, 1H), 4.67 (t, J=5.6 Hz, 2H), 4.54 (t, J=5.6 Hz, 2H), 2.54 (s, 3H); MS (ES) m/z 414 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].Br[CH2:12][CH:13]1[O:18][CH:17]([CH3:19])[CH:16]([CH3:20])[CH2:15][O:14]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][CH2:12][CH:13]1[O:18][CH:17]([CH3:19])[CH:16]([CH3:20])[CH2:15][O:14]1)[CH3:2]
Reactant: CCOC(CCN)OCC
Reactant: CC1COC(CBr)OC1C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(CCNCC1OCC(C)C(C)O1)OCC
Temperature: 25 °C

Procedure:
3,3-Diethoxypropylamine (0.11 mole), 2-bromomethyl-4,5-dimethyl-1,3-dioxane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(3,3-diethoxypropyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)amine.
Reaction SMILES: O[C:2]1[C:7]([I:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:12]>>[Cl:12][C:2]1[C:7]([I:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ncnc(O)c1I
Product: Cc1ncnc(Cl)c1I
Temperature: 90 °C

Procedure:
A suspension of 90 g (0.38 mol) 4-hydroxy-5-iodo-6-methylpyrimidine in 600 mL POCl3 is heated for 1 h at 90° C. The reaction mixture is concentrated under reduced pressure and the residue is poured into crushed ice. The precipitated solid is collected by filtration and washed with water. After drying, the desired product is obtained as a solid (90 g; 93%).
Reaction SMILES: [CH2:1]([N:3]([CH2:57][CH3:58])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:6]([C:37]2[CH:42]=[C:41]([C:43](=[O:56])[NH:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=3)[CH:40]=[CH:39][N:38]=2)[CH:5]=1)[CH3:2].[N:59]1(C(OC(C)(C)C)=O)[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:57]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34](=[O:35])[N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)[CH:14]=2)=[C:6]([C:37]2[CH:42]=[C:41]([CH:40]=[CH:39][N:38]=2)[C:43]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:53])([F:54])[F:55])[CH:47]=2)=[O:56])[CH:5]=1)[CH3:58]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)N3CCNCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 0.5 h
Yield: 177.4 %

Procedure:
To a mixture of 16-(3-(4-(diethylamino)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)phenyl)-4,7,10,13-tetraoxahexadecan-1-oic acid (292 mg, 0.36 mmol), tert-butyl piperazine-1-carboxylate (75 mg, 0.40 mmol) and DIPEA (142 mg, 1.1 mmol) in DMF (3 mL) was added HATU (160 mg, 0.42 mmol). After 30 minutes, the solvent was removed under vacuum and the residue was dissolved in DCM (50 mL). This was washed with water (4×25 mL), dried (Na2SO4) and concentrated. The resulting oil was dissolved in DCM (2 mL) and TFA (2 mL) was added dropwise. After 30 minutes, the solvents were removed under vacuum. The residue was dissolved in 50% ACN/water (30 mL) and freeze dried to give the title compound (560 mg) as a TFA salt.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CN(C)C=O.C(O)(=O)C>[CH3:1][S:2]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:25]3[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]3)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: OC1CCNCC1
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(Oc2ccc(CN3CCC(O)CC3)cc2)cc1
Yield: 58.8 %

Procedure:
To a solution of 4-(4-methylsulfonylaminophenoxy)benzaldehyde (2.50 g) in dimethyl formamide (25 mL) were added 4-hydroxypiperidine (1.74 g) and acetic acid (2.5 mL), and the solution was stirred. To the reaction solution was added sodium triacetoxyborohydride (2.18 g) and the solution was stirred for 2 days. After finishing the reaction, the reaction solution was neutralized with 2N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (methylene chloride:methanol=10:1) to give the title compound (1.90 g) having the following physical data.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[O:18][C@H:19]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]([O:33][CH3:34])=[O:32])[CH2:20]1.[CH:35]([Sn](CCCC)(CCCC)CCCC)=[CH2:36]>C1(C)C=CC=CC=1>[C:12]1([C:7]2[CH:6]=[C:5]([O:18][C@H:19]3[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C@H:21]([C:31]([O:33][CH3:34])=[O:32])[CH2:20]3)[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH:35]=[CH2:36])[CH:3]=3)[N:8]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3ccc(Br)cc23)CN1C(=O)OC(C)(C)C
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1ccc2nc(-c3ccccc3)cc(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)c2c1
Temperature: 110 °C
Yield: 56.7 %

Procedure:
To a solution of 1-tert-butyl 2-methyl (2S,4R)-4-[(6-bromo-2-phenylquinolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate 24 (1.45 g, 2.75 mmol) in toluene (20 mL) was added vinyltributyltin (0.96 mL, 3.3 mmol) and tetrakis-triphenylphosphine palladium (318 mg, 0.27 mmol). The mixture was then heated to 110° C. for 3 h, at which time, LC-MS revealed the disappearance of starting material. The reaction mixture was concentrated and purified on silica gel (gradient elution 15% to 50% EtOAc in hexanes) to give 1-tert-butyl 2-methyl (2S,4R)-4-[(2-phenyl-6-vinylquinolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate 25 (0.74 g, 56% yield) as a yellow solid. LRMS (M+H)+ Calcd.: 475. found 475.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]1[S:16][C:17]([S:23][C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[CH:26][C:25]=2[Cl:31])=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)=[O:14])(C(C)(C)C)(C)C.Cl>CCOCC.O>[Cl:30][C:29]1[CH:28]=[N:27][CH:26]=[C:25]([Cl:31])[C:24]=1[S:23][C:17]1[S:16][C:15]([C:13]([NH:12][CH2:11][CH2:10][CH2:9][OH:8])=[O:14])=[CH:19][C:18]=1[N+:20]([O-:22])=[O:21]
Reactant: CC(C)(C)[Si](C)(C)OCCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: O=C(NCCCO)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
N-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamide (1.0 g, 1.92 mmol) from the above was added to a solution of hydrogen chloride in ether (2.0 M, 15 mL) and dry ether (15 mL), and the resulting mixture was stirred at ambient temperature for 1 hour. After this time, the reaction mixture was diluted with water, extracted with ethyl acetate and washed with brine and water. The organic layer was separated, dried (Na2SO4) and concentrated. The crude residue was purified by silica gel chromatography using a 97:3 mixture of dichloromethane and methanol as eluent to afford the title product as a solid (550 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, s), 8.81 (1H, m), 8.43 (1H, s), 3.41 (2H, m), 3.24 (2H, m), 1.61 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.B(O)(O)[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)cc1
Yield: 81.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), p-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.056 g (82%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2>>[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])/[C:24]/2=[CH:16]\[C:13]1[NH:12][C:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])[C:6](=[O:18])[C:7]=2[C:14]=1[CH3:15]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Yield: 77 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and 5-bromo-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-dimethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 24 (71 mg, yield 77%) as a red solid.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([C:4]#[C:5][CH:6]([OH:13])[C:7]#[C:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:3]>C1C=CC=CC=1.[O-2].[O-2].[O-2].[Ni+3].[Ni+3]>[CH3:11][C:9]([CH3:12])([C:8]#[C:7][C:6](=[O:13])[C:5]#[C:4][C:2]([CH3:14])([CH3:3])[CH3:1])[CH3:10]
Reactant: CC(C)(C)C#CC(O)C#CC(C)(C)C
Agent: [Ni+3]
Agent: [O-2]
Solvent: c1ccccc1
Product: CC(C)(C)C#CC(=O)C#CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The 2,2,8,8-tetramethyl-nona-3,6-diyn-5-ol prepared in Part A (7.0 g, 36 mmole) was dissolved in 150 mL of benzene, cooled to 5°-10° C. and nickel peroxide (18.15 g, 465 mmole) was added over a period of 20 minutes. After the addition had been completed, the reaction mixture was stirred at room temperature for 30 minutes, then filtered, and the nickel peroxide left on the filter was washed well with benzene and then with dichloromethane. The filtrate was evaporated to give a yellow solid, which was recrystallized from benzene to give 2,2,8,8-tetramethyl-nona-3,6-diyn-5-one as pale yellow crystals (4.2 g). The structure of this product was confirmed by FAB mass spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[CH:7][N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:52][C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[NH:59][CH2:58][CH2:57][CH2:56]2>CN(C)C=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:59]2[C:60]3[C:55](=[CH:54][C:53]([F:52])=[CH:62][CH:61]=3)[CH2:56][CH2:57][CH2:58]2)=[O:13])=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: O=C(O)c1cncnc1Oc1cc(Cl)ccc1Cl
Reactant: Fc1ccc2c(c1)CCCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cncnc1Oc1cc(Cl)ccc1Cl)N1CCCc2cc(F)ccc21
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 3 %

Procedure:
To a solution of 57 mg (0.2 mmol) 4-(2,5-dichloro-phenoxy)-pyrimidine-5-carboxylic acid (Example 76, intermediate a) in 1.5 mL N,N-dimethylformamide were added 91 mg (0.24 mmol) 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.102 mL (0.6 mmol) N,N-diisopropyl-ethylamine. The solution was stirred 15 minutes at 45° C. followed by addition of 36 mg (0.22 mmol) 6-fluoro-1,2,3,4-tetrahydroquinoline (commercially available, CAS RN 59611-52-8). The reaction was stirred at 45° C. overnight and purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 2.5 mg (3%) of the desired compound. MS (ESI): m/z=418.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[OH:11].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[O:11][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCc2c(Br)cccc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution of the crude 4-bromo-1-indanol (1.02 g) in dimethylformamide (10 ml) were added at an ice temperature imidazole (0.645 g) and tert-butyldimethylsilyl chloride (0.857 g). The reaction mixture was stirred at the same temperature overnight, poured into a saturated aqueous saline solution and extracted with ether. The organic layer was washed with a saturated aqueous saline, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residual concentrate (1.6 g) was purified by chromatography on a silica gel column to give the title compound (1.51 g).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.Br[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2
Reactant: Brc1ccc2ncccc2c1
Reactant: Fc1cccc(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: Fc1cccc(F)c1-c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
A 1.55 M solution of n-butyllithium (40 ml) in hexanes was added dropwise to a stirred solution of 1,3-difluorobenzene (5.7 g) in 150 ml of dry tetrahydrofuran at -78° C. After one hour at -78° C. a solution of anhydrous zinc chloride (10.22 g) in 40 ml of tetrahydrofuran was added. After a further 10 minutes at -78° C., 9.36 g (45 mmoles) 6-bromoquinoline was added neat followed by tetrakistriphenylphosphine palladium (2.5 g, 2.16 mmoles). The solution was then allowed to warm slowly to room temperature and heated to 40° C. for 12 hours. The mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The pH was adjusted to 9 and the product was extracted with ethyl acetate, dried over MgSO4 ; filtered and concentrated in vacuo to give a white solid (9.5 g, 88%) of m.p. 112°-113° C.
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[C:3]([C:2]([NH:1][C:25](=[S:26])[C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=1)([CH3:18])[CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12]2)=[N:7]1)#[N:4]
Reactant: CC(N)(C#N)Cn1cc2cc([N+](=O)[O-])ccc2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1cc2cc([N+](=O)[O-])ccc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(5-nitro-2H-indazol-2-yl)propionitrile (62 mg, described in Example 96) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (96 mg, 84%). MS (ES): M/Z [M+H]=450. 1H NMR: (400 MHz, DMSO-d6): 1.72 (s, 3H), 5.22 (q, 2H), 7.81 (d, J=9.5 Hz, 1H), 7.86-7.90 (m, 2H), 7.92-7.97 (m, 2H), 8.00-8.05 (m, 1H), 8.83 (s, 1H), 8.95 (d, J=1.9 Hz, 1H) and 9.07 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.9 (s, 3F).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:29])[NH:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([C:21]([OH:23])=O)[CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:8][C:7]=1[F:28])[CH3:2].[C:30]([CH2:32][CH2:33][NH2:34])#[N:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(N(CC)CC)C>[C:30]([CH2:32][CH2:33][NH:34][C:21]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:24][CH3:25])[N:14]=[CH:13][CH:12]=[C:11]2[O:10][C:9]1[CH:26]=[CH:27][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:29])=[C:7]([F:28])[CH:8]=1)=[O:23])#[N:31]
Reactant: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)O)cc23)cc1F
Reactant: N#CCCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)NCCC#N)cc23)cc1F

Procedure:
4-(4-(3-Ethylureido)-3-fluoro-phenoxy)-7-methoxyquinoline-6-carboxylic acid (40 mg) was treated with cyanoethylamine, triethylamine and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in the same manner as Example 634, to obtain the title compound (29 mg) as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[N+:14]([O-])=O)([CH3:3])=[CH2:2].[H][H]>CO.[Pd]>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[NH2:14])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C=C(C)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)c(C(C)C)cc1OC
Yield: 94.5 %

Procedure:
1-Isopropenyl-4,5-dimethoxy-2-nitro-benzene (446 mg, 2.0 mmol) was dissolved in 50 ml of methanol at room temperature. 10% Palladium on Carbon (200 mg) was added and the mixture was stirred under a balloon of hydrogen overnight. The mixture was filtered through celite. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography (4:1 Hexanes/Ethyl Acetate) to give 2-isopropyl-4,5-dimethoxy-phenylamine (369 mg, 94.6%) as a tan oil.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.C(OCC)(=O)C>[O:4]1[CH:5]=[CH:6][C:2]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=2)=[CH:3]1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1ccoc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ccoc2)cc1
Temperature: 150 °C
Yield: 59.2 %

Procedure:
In a microwave vial, 3-bromo-furan (590 mg, 4.02 mmol), 4-formyl phenylboronic acid (600 mg, 4.02 mmol) and 7 ml of actonitrile were mixed. 8 ml of 1N aqueous sodium carbonate was then added to the mixture, followed by 5 mole percent of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 7 minutes with microwave irradiation. After cooling, 50 ml of ethyl acetate was added, the organic layer was separated, washed with water, dried over sodium sulfate. The organic solvent was evaporated to give crude product, which was purified by ISCO to give 410 mg of 4-furan-3-yl-benzaldehyde, yield: 60%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH3:20])=[N:18][N:19]=[C:15]3[C@H:14]([CH2:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[N:13]=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:11]=2[CH:34]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:43][O:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1.C1(C)C=CC=CC=1>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.C(O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:12]2[C:11]3[CH:34]=[C:7]([C:49]4[CH:48]=[CH:47][CH:46]=[C:45]([O:44][CH3:43])[CH:50]=4)[CH:8]=[CH:9][C:10]=3[N:16]3[C:17]([CH3:20])=[N:18][N:19]=[C:15]3[C@H:14]([CH2:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[N:13]=2)=[CH:32][CH:31]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3cccc(OC)c3)ccc2-n2c(C)nnc21
Temperature: 120 °C

Procedure:
(S)-6-(4-Chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (for a preparation see Intermediate 3) (100 mg), bis(triphenylphosphine)palladium(II) chloride (12.95 mg), potassium carbonate (128 mg) and 3-methoxyphenylboronic acid (33.6 mg) were added to a 2-5 ml microwave vial. Toluene (2 ml) and ethanol (2 ml) were added to the vial and the reaction mixture was heated at 120° C. for 20 min (microwave). The reaction mixture was filtered through Celite™ and the filter bed was washed with ethanol. The solvent was evaporated and the residue was chromatographed (0-5% methanol:DCM), triturated with diethyl ether and dried in a vacuum dessicator at 40° C. overnight to give (S)-2-(6-(4-chlorophenyl)-8-(3-methoxyphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide as a cream solid (59.6 mg). LCMS (formate): MH+ 500/502, RT 1.09 min