Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:38]([CH3:40])([CH3:39])[C@H:37]2[C@@:5]3([O:33][C:9]4[C:10]5[CH2:11][N:12](C(OC(C)(C)C)=O)[C:13](=[O:25])[C:14]=5[CH:15]=[C:16]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[C:8]=4[CH2:7][C@:6]3([CH3:42])[C@@H:34]([CH3:41])[CH2:35][CH2:36]2)[CH2:4][CH2:3]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:1][C@@H:2]1[C:38]([CH3:40])([CH3:39])[C@H:37]2[C@@:5]3([O:33][C:9]4[C:10]5[CH2:11][NH:12][C:13](=[O:25])[C:14]=5[CH:15]=[C:16]([O:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:8]=4[CH2:7][C@:6]3([CH3:42])[C@@H:34]([CH3:41])[CH2:35][CH2:36]2)[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](N)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](N)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CNC4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
To a solution of Compound (45a) (50 mg, 0.087 mmol) in 5 ml of dry dichloromethane were added 30 μl (0.28 mmol) of anisole and 35 μl (0.45 mmol) of trifluoroacetic acid, and the mixture stirred for 3 hours at room temperature. Under ice-cooling, to the reaction mixture was added an aqueous saturated sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The extract was washed with water and an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 30 mg (73%) of the crude Compound (46a) as a powdery material.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:10]=[C:11]([O:16][CH3:17])[CH:12]=[CH:13][C:14]=1[CH3:15].[N:18]([O-:20])=[O:19].[Na+]>O>[CH3:15][C:14]1[C:9]([CH3:8])=[CH:10][C:11]([O:16][CH3:17])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: O=N[O-]
Reactant: COc1ccc(C)c(C)c1
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 55 %

Procedure:
Trifluoroacetic acid(250 ml) was added into 3,4-dimethylanisole(17.1 g, 0.13 mol), successively sodium nitrite(16.6 g, 0.24 mol) was added slowly in water bath, and stirred at room temperature for 14 hrs. After trifluoroacetic acid was removed and water was added thereto, the resulting mixture was extracted with ether, and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[C:7]1([N:13]2[CH2:17][CH2:16][C:15]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1>[C:7]1([N:13]2[CH2:17][CH2:16][C:15]([N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:4](=[O:5])[O:3][CH2:1][CH3:2])=[N:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc(N2CCC(Nc3cccnc3)=N2)cc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N(C1=NN(c2ccccc2)CC1)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethylchloroformate (0.75 ml) was added dropwise to a solution of 4,5-dihydro-1-phenyl-N-(3-pyridinyl)-1H-pyrazol-3-amine (1.66 g) and triethylamine (2.85 ml) in tetrahydrofuran (150 ml) at -45° under N2. The solution was allowed to warm to room temperature and stirred for 24 hours. The solution was filtered, evaporated to dryness, and the residue chromatographed on silica gel eluting with ethyl acetate in dichloromethane to give an oil which crystallised on triturating with ether. The solid was recrystallised from ether and petrol to give the title compound (0.66 g) mp 110°-12° (dec).
Reaction SMILES: [CH:1]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:2]=1[C:3]1[C:11]([CH:12]=[CH:13]2)=[C:10]([CH:18]=O)[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[NH2:20][C:21]([CH3:26])([CH2:24][OH:25])[CH2:22][OH:23]>CCO.CCOCC>[CH3:26][C:21]([NH:20][CH2:18][C:10]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=[C:3]2[C:11]=1[CH:12]=[CH:13][C:14]1[C:2]2=[CH:1][CH:17]=[CH:16][CH:15]=1)([CH2:24][OH:25])[CH2:22][OH:23]
Reactant: CC(N)(CO)CO
Reactant: O=Cc1c2ccc3ccccc3c2cc2ccsc12
Solvent: CCOCC
Solvent: CCO
Product: CC(CO)(CO)NCc1c2ccc3ccccc3c2cc2ccsc12
Yield: 71.2 %

Procedure:
Using the procedure outlined in Example 1, phenanthro[2,3-b]thiophene-7-carbaldehyde (24A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 71.2% yield of 2-methyl-2-[[(phenanthro[2,3-b]thiophen-7-yl)methyl]amino]-1,3-propanediol methanesulsonate, mp 212°-215° (EtOH/Et2O), (C,H,N,S).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].[Cl:30][C:31]1[C:32]([CH:40]([CH3:42])[CH3:41])=[CH:33][C:34]2[N:35]([N:37]=[CH:38][N:39]=2)[N:36]=1>O1CCCC1>[ClH:30].[ClH:30].[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:31]3[C:32]([CH:40]([CH3:42])[CH3:41])=[CH:33][C:34]4[N:35]([N:37]=[CH:38][N:39]=4)[N:36]=3)[CH2:12][CH2:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)c1cc2ncnn2nc1Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc2ncnn2nc1OCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: Cl
Temperature: 0 °C
Yield: 142.7 %

Procedure:
4-(Diphenylmethyl)-1-piperazinepropanol (466 mg) was dissolved in dried tetrahydrofuran (10 ml), followed by addition of sodium t-butoxide (173 mg). The mixture was refluxed under heating for 30 minutes. After the mixture was cooled, 6-chloro-7-isopropyl[1,2,4]triazolo[1,5-b]pyridazine (295 mg) was added thereto. The resulting mixture was refluxed for 3 hours under heating. After cooling, ice-water was added to the mixture, followed by extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of ethyl acetate and methanol (10:1). Fractions containing the objective compound were collected and dissolved in ethanol (10 ml), followed by addition of 1N-HCl (3 ml). The mixture was concentrated under reduced pressure. The resulting crystals were recrystallized from ethyl acetate to yield the title compound (582 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16](I)[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1.[CH:21]1([N:24]2[C:33]3[C:28](=[CH:29][C:30]([F:37])=[C:31]([CH:35]=[CH2:36])[C:32]=3[F:34])[C:27](=[O:38])[C:26]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:25]2)[CH2:23][CH2:22]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[NH2:13][C:10]1[N:9]=[C:8]([NH2:14])[C:7]([CH2:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:17]([O:18][CH3:19])=[C:16](/[CH:36]=[CH:35]/[C:31]3[C:32]([F:34])=[C:33]4[C:28]([C:27](=[O:38])[C:26]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:25][N:24]4[CH:21]4[CH2:23][CH2:22]4)=[CH:29][C:30]=3[F:37])[CH:15]=2)=[CH:12][N:11]=1
Reactant: C=Cc1c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c2c1F
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(I)c1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(/C=C/c3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)c(F)cc2c1=O
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A mixture of 193 mg of 5-(3,4-dimethoxy-5-iodo-benzyl)-pyrimidine-2,4-diamine, 224 mg of ethyl 1-cyclopropyl-6,8-difluoro-7-vinyl-4-oxo-1,4-dihydro-quinoline-3-carboxylate (J. Heterocyclic Chem., 28, 1581 (1991)), 26 mg of triphenylphosphine, 0.084 ml of triethylamine and 11.2 mg of palladium acetate in 2 ml of dimethylformamide is heated at 100° for 5 hrs. The reaction mixture is cooled to room temperature, poured into 50 ml of water and extracted twice with 25 ml of ethyl acetate each time. The organic phases are washed twice with 25 ml of 2N aqueous hydrochloric acid each time. The hydrochloric acid phases are made basic with sodium bicarbonate and extracted three times with 25 ml of methylene chloride each time. The combined organic phases are washed with 25 ml of water, dried over magnesium sulphate and concentrated. The crude product is recrystallized from methylene chloride/diethyl ether. 140 mg (49%) of ethyl (E)-7-[2-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenyl]-vinyl]-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate are obtained as a yellowish solid. Mass spectrum (ISP): 578 (M++H, 100%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:22])[CH2:15][S:16]([CH2:19][CH2:20]Cl)(=[O:18])=[O:17])([CH3:3])[CH3:2].[C:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:22])[CH2:15][S:16]([CH2:19][CH2:20][N:32]1[CH2:33][CH2:34][N:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:30][CH2:31]1)(=[O:18])=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CS(=O)(=O)CCCl
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CS(=O)(=O)CCN1CCN(c2ccccc2)CC1
Yield: 70.7 %

Procedure:
A mixture of 3.46 g of N-(2,6-diisopropylphenyl)-2(2-chloroethylsulfonyl)acetamide synthesized in (1) above, 1.62 g of N-phenylpiperazine, and 50 ml of toluene was heated under reflux for 4 hours. To the reaction mixture was added 100 ml of ethyl acetate, and the mixture was washed successively with a sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography using a mixture of ethyl acetate and hexane at a ratio varying from 1:1 to 1:0 as a developing solvent. The solvent was evaporated, and the residue was dissolved in ethyl acetate and crystallized from a 4N hydrochloric acid solution in ethyl acetate to obtain 3.33 g of the title compound as white powder (m.p.=197.0°-200.0° C.).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:22])[C@H:10]2[NH:14][C:15]([N:17]=[CH:18]N(C)C)=[S:16])[C:7]=1[C:23]([O:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(=[O:3])[CH3:2].[C:39](Cl)(=[O:42])[CH2:40]C.[I-].[Na+].N1C=CC=C[CH:47]=1>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:22])[C@H:10]2[NH:14][C:15]2[S:16][C:47]([C:39](=[O:42])[CH3:40])=[CH:18][N:17]=2)[C:7]=1[C:23]([O:25][CH:26]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(=[O:3])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=S)N=CN(C)C)[C@H]2SC1
Reactant: c1ccncc1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3ncc(C(C)=O)s3)[C@H]2SC1
Reaction time: 1.5 h
Yield: 70.1 %

Procedure:
A mixture of 585 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[[[[(dimethylamino)methylene]amino]thioxomethyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 127 mg of propionyl chloride, 188 mg of sodium iodide and 15 ml of acetontrile was stirred for 90 minutes, then 99 mg of pyridine was added. This mixture was stirred for 90 minutes, then dichloromethane was added and the mixture was refluxed for 20 minutes. The solution was washed with 10% hydrochloric acid, brine and aqueous sodium bicarbonate, dried and evaporated, giving 418 mg of the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11]2[C:6](=[CH:7][C:8]([CH3:18])=[C:9]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=2)[C:5](OS(C(F)(F)F)(=O)=O)=[CH:4][CH2:3]1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)[CH:59]=[O:60].[CH2:62]([OH:64])[CH3:63]>CCCCCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:62]([O:64][C:59]([C:5]1[C:6]2[C:11](=[CH:10][C:9]([C:12]#[C:13][Si:14]([CH3:16])([CH3:17])[CH3:15])=[C:8]([CH3:18])[CH:7]=2)[C:2]([CH3:1])([CH3:27])[CH2:3][CH:4]=1)=[O:60])[CH3:63]
Reactant: CN(C)C=O
Reactant: Cc1cc2c(cc1C#C[Si](C)(C)C)C(C)(C)CC=C2OS(=O)(=O)C(F)(F)F
Reactant: CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=CCC(C)(C)c2cc(C#C[Si](C)(C)C)c(C)cc21

Procedure:
Following General Procedure E and using trifluoro-methanesulfonic acid 4,4,7-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalen-1-yl ester (Intermediate 183, 0.73 g, 1.75 mmol), palladium acetate (0.1 g, 0.45 mmol), 1,3-bis(diphenylphosphino)propane (0.1 g, 0.24 mmol), N,N-dimethylformamide (3.5 mL), ethanol (3.5 mL) and triethyl amine (3.5 mL) followed by flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent the title compound was obtained (0.435 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:13](O)(=[O:33])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C>ClCCl>[OH:12][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:13](=[O:33])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)ccc1O
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)Nc1ccc(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a solution of methyl 5-amino-2-hydroxybenzoate (0.27 g, 1.6 mmol) in dichloromethane (10 mL) was added arachidonic acid (0.5 g, 1.6 mmol), EDCI (0.32 g, 1.7 mmol) and dimethylaminopyridine (0.020 g, 0.2 mmol). The reaction was stirred (RT, 2 h), and then partitioned between CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were washed with 1 N HCl, water, saturated aqueous NaHCO3 and water, and then dried over MgSO4. The crude product was purified by silica chromatography (0-5% MeOH/CH2Cl2) to afford 0.6 g of methyl 2-hydroxy-5-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidobenzoate as a brown oil. Mass calculated for C28H39NO4=453.61. found: [M+H]+=454.3.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][NH:7][C:8](=[O:36])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Br[C:40]1[CH:41]=[CH:42][C:43]([F:46])=[N:44][CH:45]=1.[F-].[Cs+]>CN(C=O)C.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>[F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][NH:7][C:8](=[O:36])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:40]4[CH:45]=[N:44][C:43]([F:46])=[CH:42][CH:41]=4)=[CH:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccc(C(=O)NCc4ccc(F)cc4)cc3)c3ccccc23)OC1(C)C
Reactant: Fc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(-c3ccc(F)nc3)c3ccccc32)cc1
Yield: 69.5 %

Procedure:
Combine N-(4-Fluoro-benzyl)-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indole-1-sulfonyl]-benzamide (150 mg, 0.28 mmol), 5-Bromo-2-fluoro-pyridine (0.05 mL, 0.56 mmol), CsF (212 mg, 1.4 mmol) and Pd(Ph3P)4 (32 mg, 0.028 mmol) in 1.0 mL DMF and 0.100 mL of water. Evacuate the reaction vessel and place under an atmosphere of nitrogen. Heat the resulting reaction at 90 degrees 12 h. Load the reaction directly onto silica gel and purify by flash column chromatography (EtOAc/Hexanes) to yield 98 mg of white foam (70%) LRMS: MH+ 504.02.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6]C=C[C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:22]([O:24]C)=[O:23])(=[O:10])=[O:9].[C:26]([N:33]1[CH:37]=[CH:36]N=C1)([N:28]1[CH:32]=[CH:31]N=C1)=[O:27].NCC[CH:41]1[CH2:45][CH2:44][CH2:43][N:42]1[CH3:46].[Li+].[I-]>C1COCC1>[CH3:46][N:42]1[CH2:41][CH2:45][CH2:44][CH:43]1[CH2:36][CH2:37][NH:33][C:26]([NH:28][C:32]1[CH:31]=[CH:6][CH:7]=[CH:2][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:22]([OH:24])=[O:23])(=[O:9])=[O:10])=[O:27]
Reactant: CN1CCCC1CCN
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2N)ccc2c1CCCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCCC1CCNC(=O)Nc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of Example 418C (145.6 mg, 0.404 mmol) in THF (0.25 mL) was treated with carbonyldiimidazole (65.5 mg, 0.404 mmol), heated to 50° C. for 1.5 hours, cooled to room temperature, treated with 2-(2-aminoethyl)-1-methylpyrrolidine. (58 μL, 0.404 mmol), stirred for 24 hours, and concentrated. The residue was dissolved in pyridine (0.5 mL), treated with LiI (162.2 mg, 1.212 mmol), heated in a microwave reactor at 150° C. for 25 minutes, concentrated, and purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. (58.7 mg, 29%). MS (ESI(−)) m/e 499 (M−H)-; 1H NMR (300 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.21 (m, 1H), 7.66 (dd, 1H), 7.53 (ddd, 1H), 7.32 (t, 1H), 7.07 (td, 1H), 6.96 (d, 1H), 6.53 (d, 1H), 3.18 (m, 3H), 3.01 (m, 2H), 2.78 (s, 3H), 2.66 (m, 4H), 2.30 (m, 2H), 1.92 (m, 2H), 1.67 (m, 4H), 1.28 (m, 1H), 0.87 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH3:5].[O:6]=[CH:7][C:8]1[CH:16]=[CH:15][C:13]([OH:14])=[C:10]([O:11]C)[CH:9]=1.[C:17](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([O:11][C:10]1[CH:9]=[C:8]([CH:16]=[CH:15][C:13]=1[O:14][CH3:17])[CH:7]=[O:6])[C:3]#[C:4][CH3:5]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC#CCBr
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCOc1cc(C=O)ccc1OC
Yield: 95.3 %

Procedure:
1-Bromobut-2-yne (0.37 mL, 4.0 mmol) was added to a suspension of vanillin (0.56 g, 3.7 mmol) and potassium carbonate (1.82 g, 11.0 mmol) in acetone (10 mL) and treated according to Procedure 3. 3-(But-2-ynyloxy)-4-methoxybenzaldehyde (0.72 g, 96%) was obtained as a pale yellow crystalline solid; mp 81-83° C.; δH (400 MHz, CDCl3) 1.84 (t, J=2.0 Hz, 3H, CH3), 3.95 (s, 3H, OCH3), 4.77 (q, J=2.0 Hz, 2H, OCH2), 6.99 (d, J5,6=8.0 Hz, 1H, H5), 7.49 (dd, J5,6=8.4, J2,6=2.0 Hz, 1H, H6), 7.51 (d, J2,6=2.0 Hz, 1H, H2), 9.86 (s, 1H, CHO); δC (100 MHz, CDCl3) 3.7, 56.1, 57.1, 73.2, 84.7, 110.6, 111.4, 126.9, 129.9, 147.6, 154.8, 190.8; vmax 1003, 1259, 1506, 1583, 1681, 2226, 2297, 2841, 2916 cm−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:20])[NH2:19])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[C:22]([O-])([O-])=O.[Cs+].[Cs+].CI>CS(C)=O>[C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:22])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:20])[NH2:19])=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Cn1cc(C(N)=O)c2cc(O)ccc21
Agent: [Cs+]
Solvent: CI
Solvent: CS(C)=O
Product: COc1ccc2c(c1)c(C(N)=O)cn2CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (3-carbamoyl-5-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (50 mg, 0.172 mmol) in DMSO (1.7 mL) was added Cs2CO3 (336 mg, 1.03 mmol). The mixture was stirred at RT for 5 min, followed by addition of methyl iodide (0.048 mL, 0.774 mmol), and stirring was continued at RT for 3 days. The reaction mixture was partitioned between water and CH2Cl2, the layers were separated and the aqueous phase was extracted twice with CH2Cl2. The combined organics were washed twice with brine, dried (phase separator) and concentrated in vacuo to afford the title compound as a yellow solid: MS (LC/MS): 305 [M+H]+, 327 [M+Na]+, 609 [2M+H]+; tR (HPLC conditions c): 4.31 min. The material thus obtained was used in the next reaction step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1.Br[C:18]1[CH:26]=[C:25]2[C:21]([C:22]([OH:29])([CH3:28])[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1.C[Mg]Br.BrC1C=C2C(C(=O)C(=O)N2)=CC=1>>[OH:29][C:22]1([CH3:28])[C:21]2[C:25](=[CH:26][C:18]([NH:16][C:14]3[N:15]=[C:8]4[C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[N:12][CH:11]=[CH:10][N:9]4[N:13]=3)=[CH:19][CH:20]=2)[NH:24][C:23]1=[O:27]
Reactant: CC1(O)C(=O)Nc2cc(Br)ccc21
Reactant: Cn1cc(-c2nccn3nc(N)nc23)cn1
Agent: C[Mg]Br
Agent: O=C1Nc2cc(Br)ccc2C1=O
Product: Cn1cc(-c2nccn3nc(Nc4ccc5c(c4)NC(=O)C5(C)O)nc23)cn1

Procedure:
8-(1-Methylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine is reacted with 6-bromo-3-hydroxy-3-methyl-1,3-dihydro-indol-2-one, available via addition of methymagnesiumbromide to 6-bromo-Isatin, to give the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[CH2:18][C@@H:17]([NH:16][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH:4]=1)=[O:9])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1ccnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (200 mg, 0.90 mmol) [Prepared according to the procedure of Example 151], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (291 mg, 0.87 mmol) [Prepared according to the procedure of preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (512 mg, 1.09 mmol) in Chloroform (9 mL). DIEA (790 μL, 4.52 mmol) was added and the mixture stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (250 mg, 50%): LC-MS (ES) m/z=503 (M+H)+.