Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[Cl:30])[NH2:26].O1CCOCC1>CC(O)C.Cl.O1CCOCC1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][NH:13][CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Clc1ccc(Nc2ncnc3sc4c(c23)CCNC4)cc1Cl
Temperature: 80 °C
Yield: 94 %

Procedure:
tert-Butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (407.5 g, 1.251 mol) was dissolved in 2-propanol (5.7 L). 3,4-Dichloroaniline (213.8 g, 1.313 mol) and a 4 M solution of gaseous hydrogen chloride in dioxane (17.4 mL, 63 mmol) were added. The mixture was heated to 80° C. for 3 days. The thick suspension was then diluted with additional 2-propanol (1 L), and further 4 M hydrogen chloride in dioxane (695 mL, 2.5 mol) was added. The mixture was again heated to 80° C. for 3 h. The solvent was then removed in vacuo, and the residue was treated with 1 M aqueous sodium hydroxide solution (12 L). The precipitate was collected by suction filtration and washed with water. The product was dried for 2 days at 50° C., then triturated with tert-butyl methyl ether and collected by suction filtration to yield 413 g (92%) of the title compound.
Reaction SMILES: [Bi](Cl)(Cl)Cl.[I-].[Na+].[C:7](Cl)(=[O:9])[CH3:8].[CH2:11]([O:13][C:14]([C:16]1[C:17]2[C:32]([O:33][Si](C)(C)C)=[CH:31][CH2:30][CH2:29][CH2:28][C:18]=2[N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:20]=1)=[O:15])[CH3:12]>C(Cl)Cl.CCOCC>[CH2:11]([O:13][C:14]([C:16]1[C:17]2[C:32](=[O:33])[CH:31]([C:7](=[O:9])[CH3:8])[CH2:30][CH2:29][CH2:28][C:18]=2[N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:20]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(O[Si](C)(C)C)=CCCC2
Reactant: CC(=O)Cl
Agent: Cl[Bi](Cl)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(C(C)=O)CCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
Bismuth (III) chloride (0.1 mmol) and sodium iodide (0.3 mmol) are transferred to a dried flask under nitrogen and 5 mL of a mixture of CH2Cl2/ether (9/1) is added by a syringe. This is followed by the addition of acetyl chloride (2.2 mmol) and the suspension is stirred for 5 min at RT. 4-trimethylsilanyloxy-7,8-dihydro-6H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2 mmol) in 5 mL of the same solvent mixture is added. After 2 hours at RT, the mixture is quenched with 20 mL saturated NaHCO3 solution and extracted several times with CH2Cl2. The organic layers are combined, dried over Na2SO4 and evaporated in vacuo yielding 5-acetyl-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester as an oil (86%). LRMS 363.4 found (M+1) 364.2 Step 3: In a sealed tube are 5-acetyl-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.1 mmol) and formamidine acetate (5.5 mmol) and 10 mL EtOH. The mixture is heated at 120° C. for 48 hours. The solvent is evaporated in vacuo and the residue is taken up in CH2Cl2 and washed two times with NaHCO3 (aq). The organic layer is dried over Na2SO4 and evaporated in vacuo and the residue chromatographed using 10% MeOH in CH2Cl2 as mobile phase to yield 7-Methyl-3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylic acid ethyl ester (36%). LRMS 271.1 found (M+1) 272
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>C(O)C.O1CCOCC1>[ClH:32].[ClH:32].[F:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(-c3ccccc3F)c3ccccc3n2)CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Fc1ccccc1-c1nc(NC2CCNCC2)nc2ccccc12

Procedure:
A solution of 4-[4-(2-fluoro-phenyl)-quinazolin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.86 g, 2.04 mmol) in ethanol (5 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 322.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=O)=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([CH3:33])[CH:3]=1.[CH3:34][C:35]1[N:39]=[C:38]([NH2:40])[S:37][N:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:40][C:38]4[S:37][N:36]=[C:35]([CH3:34])[N:39]=4)(=[O:21])=[O:20])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([CH3:33])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Cc1nsc(N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nsc(NS(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4C)nccc3c2)n1
Reaction time: 2 h
Yield: 75 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-(4-chloro-2-methylphenyl)isoquinoline-6-sulfonate (Intermediate DDDDD; 59.9 mg, 0.120 mmol), 3-methyl-1,2,4-thiadiazol-5-amine (27.6 mg, 0.240 mmol), cesium carbonate (117 mg, 0.360 mmol), and DMF (0.6 mL). The vial was sonicated for 20 s, and the mixture was stirred further for 2 h. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g Interchim 15-micron column, 0-5% MeOH/DCM) to give 1-(4-chloro-2-methylphenyl)-N-(3-methyl-1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (38.94 mg, 0.090 mmol, 75% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.72 (d, J=5.7 Hz, 1H), 8.60 (d, J=1.8 Hz, 1H), 8.16 (d, J=5.8 Hz, 1H), 7.89 (dd, J=1.9, 8.9 Hz, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.44-7.39 (m, 1H), 7.33 (d, J=8.1 Hz, 1H), 2.27 (s, 3H), 1.97 (s, 3H). m/z (ESI) 431.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH2:33][CH2:34][CH:35]([OH:40])[CH2:36][C:37]([OH:39])=[O:38]>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([NH:33][CH2:34][CH:35]([OH:40])[CH2:36][C:37]([OH:39])=[O:38])=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:30])([F:32])[F:31])[CH:3]=1
Reactant: NCC(O)CC(=O)O
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C(O)CC(O)CNC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-butyric acid was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-amino-3-hydroxy-butyric acid following General Procedure B.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[NH2:11])[CH3:2].Cl[CH2:14][CH:15]=O.C([O-])(O)=O.[Na+]>CCO>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[N:7]([CH:14]=[CH:15][N:11]=2)[CH:8]=[CH:9][CH:10]=1)=[O:12])[CH3:2]
Reactant: O=CCCl
Reactant: CCOC(=O)c1cccnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cccn2ccnc12

Procedure:
A mixture of 2-amino-nicotinic acid ethyl ester (13.845 g), ClCH2CHO (58 mL), and NaHCO3 (11.85 g) was stirred in EtOH (500 mL) at reflux overnight. The reaction mixture was concentrated, diluted with H2O, and extracted with DCM. The product was purified by ISCO using 100% EtOAc first (to remove unreacted starting material), then using 100% DCM to 5% MeOH/DCM. The product eluted at 3% MeOH/DCM, providing imidazo[1,2-a]pyridine-8-carboxylic acid ethyl ester (10.5 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[CH3:33][C:34]1([C:40]2[CH:41]=[CH:42][C:43](=[C:45]([CH3:47])[CH3:46])[CH:44]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C1COCC1.CCOCC.O>[CH3:33][C:34]1([C:40]2[CH:41]=[CH:42][CH:43]([C:45]([C:11]3[C:10]4[CH2:9][C:8]5[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=5)[C:15]=4[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)([CH3:47])[CH3:46])[CH:44]=2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: CC(C)=C1C=CC(C2(C)CCCCC2)=C1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C2=CC(C(C)(C)c3cc(C(C)(C)C)cc4c3Cc3ccc(C(C)(C)C)cc3-4)C=C2)CCCCC1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
To a solution of 2.64 g (9.5 mmol) of 3,6-di-tert-butylfluorene in 45 ml of THF, 6.4 ml (10.4 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. To the resulting red solution, a solution of 2.00 g (9.9 mmol) of 3-(1-methyl-1-cyclohexyl)-6,6-dimethylfulvene in 30 ml of THF was further dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for 3 days. After the reaction solution was diluted with 100 ml of ether, 50 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was isolated and purified by column chromatography (silica gel, developing solvent: hexane) to obtain 1.96 g (4.08 mmol) of a white solid (yield: 43%). The analyzed values are given below.
Reaction SMILES: N1C2C(=CC=C3C=CC=CC3=2)C[CH2:2]1.[C:14]1([N:20]2[C:28]3[C:23](=[C:24]([OH:33])[CH:25]=[C:26]4[CH:32]=[CH:31][CH:30]=[CH:29][C:27]4=3)C(C)(C)C2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O-]S(C(F)(F)F)(=O)=O.NC1C=CC=CC=1>[Pd]>[NH:20]([C:28]1[C:27]2[C:26](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[C:24]([O:33][CH3:2])[CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1(C)CN(c2ccccc2)c2c1c(O)cc1ccccc21
Reactant: c1ccc2c3c(ccc2c1)CCN3
Agent: [Pd]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Nc1ccccc1
Product: COc1cc(Nc2ccccc2)c2ccccc2c1

Procedure:
A second preferred synthesis method suitable for the synthesis of benzoindoline compounds, e.g., N-phenyl-3,3-dimethyl-4-hydroxy-benzoindoline 9, is also shown in FIG. 1. In this method, the 3-methoxynapthalene-1-triflate 2 is derivatized with a primary amine, e.g., aniline, using a palladium catalyzed triflate coupling reaction to give a secondary amine, e.g., 1-anilino-3-methoxynapthalene 5. The secondary amine 5 is acetylated using an acid chloride, e.g., an haloacetylchloride, to give a disubstituted amide, e.g., 1-amido-3-methoxynapthalene 6. The tertiary amide 6 is cyclized using a Lewis-acid-catalyzed Friedel-Crafts cyclization procedure to give compound 7, e.g., using AlCl3. Coumpound 7 is than reduced, e.g., using LAH, to give coumpound 8. Subsequent methoxy group deprotection by a boron tribromide deprotection procedure gives the benzoindoline, e.g., N-phenyl-3,3-dimethyl-4-hydroxy-benzoindoline 9. An example of this synthesis is provided in Example 2 below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:9])[CH:8]=[CH:12][N:13]([CH3:15])[CH3:14])[S:5][CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cc(Br)cs1
Product: CN(C)C=CC(=O)c1cc(Br)cs1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A mixture of 1-(4-bromo-2-thienyl)ethanone (48.8 mmol) and N,N-dimethylformamide dimethyl acetal (73.1 mmol) was refluxed overnight and then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure and dried in vacuo to afford 12.6 g (99% yield) of 1-(4-bromo-2-thienyl)-3-(dimethylamino)prop-2-en-1-one which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:19]1[N:20]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)=[O:4].[OH-].[Li+]>>[C:13]1([S:10]([C@H:8]2[CH2:7][N:6]([C:19]3[N:20]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=4)[N:21]=[C:22]([CH3:24])[CH:23]=3)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]2)(=[O:11])=[O:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1c1cc(C)nn1-c1ccnc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3)C[C@H]2C(=O)O)n(-c2ccnc(Cl)c2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-benzenesulfonyl-1-[2-(2-chloro-pyridin-4-yl)-5-methyl-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow solid. MS (ESI): m/z=447.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH2:28])[CH2:26][CH3:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH:28][CH2:16][CH2:15][C:2]2([OH:1])[CH2:14][CH2:13][C:5]3([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10]3)[CH2:4][CH2:3]2)[CH2:26][CH3:27])=[CH:23][CH:24]=1
Reactant: CC[C@H](N)c1ccc(Cl)cc1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: CC[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(Cl)cc1
Yield: 60 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-chloro-phenyl)-propylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 60% of theory; LC (method 5): tR=1.15 min; Mass spectrum (ESI+): m/z=396/398 (Cl) [M+H]+.
Reaction SMILES: FC1C=C(C=CC=1)N.Cl.N([O-])=O.[Na+].O=C1C2C(=CC=CC=2)C(=O)N1CC(=O)CC#N.CC([O-])=O.[Na+].[NH2:36][C:37]1[C:38](=[N:54][NH:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([F:62])[CH:57]=2)[C:39]([CH2:42][N:43]2C(=O)C3C(=CC=CC=3)C2=O)=[N:40][N:41]=1.NN>O.CN(C=O)C.O.C(O)C>[NH2:43][CH2:42][C:39]1[C:38](=[N:54][NH:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([F:62])[CH:57]=2)[C:37]([NH2:36])=[N:41][N:40]=1
Reactant: NC1=NN=C(CN2C(=O)c3ccccc3C2=O)C1=NNc1cccc(F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: N#CCC(=O)CN1C(=O)c2ccccc2C1=O
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: NCC1=NN=C(N)C1=NNc1cccc(F)c1
Yield: 68.6 %

Procedure:
A solution of 3-fluoroaniline (1.67 g, 15 mmole) in 17 mL of water, acidified with 3.75 mL of conc. HCl (45 mmole) in an ice bath, was treated with NaNO2 (1.35 g, 19.5 mmole). The diazonium solution was then added to the solution of 4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-oxobutyronitrile (2.28 g, 10 mmole) with NaOAc (6.12 g, 45 mmole) in DMF/water mixture (30:35 mL). From this reaction, 3.4 g of 2-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}isoindole-1,3-dione, as a yellow powder, was obtained, which was then treated with hydrazine (22 mmole) portionwise in hot ethanol. After the reaction was completed, a few grams of silica gel was mixed and the solvent was evaporated. The powdery residue was purified by column chromatography (CH2Cl2:MeOH:NH3.H2O=600:150:6) to yield 1.5 g (61%) of the title compound as an orange powder. 1H NMR (ppm, 200 MHz, DMSO-d6) δ 7.40-7.70 (m, 3H), 7.12 (m, 1H), 7.00 (br s, 2H), 4.01 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([NH2:11])[CH:10]=[C:4]2[CH2:3]1.Br[C:13]1[C:14](=[O:20])[NH:15][N:16]=[C:17]([Cl:19])[CH:18]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O.C1COCC1.O1CCOCC1>[Cl:19][C:17]1[CH:18]=[C:13]([NH:11][C:9]2[CH:10]=[C:4]3[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][N:5]3[N:8]=2)[C:14](=[O:20])[NH:15][N:16]=1
Reactant: O=c1[nH]nc(Cl)cc1Br
Reactant: CN1CCn2nc(N)cc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN1CCn2nc(Nc3cc(Cl)n[nH]c3=O)cc2C1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (5.0 mL), 101e (152 mg, 1.00 mmol), 4-bromo-6-chloropyridazin-3(2H)-one (209 mg, 1.00 mmol) and a 1 M THF solution of LiHMDS (5.0 mL, 5.00 mmol). After bubbling nitrogen through the resulting solution for 30 min, Xantphos (49 mg, 0.05 mmol) and tris(dibenzylideneacetone) dipalladium(0) (59 mg, 0.085 mmol) were added, and the reaction mixture was heated at reflux for 3 h. After this time, the reaction was cooled to room temperature, and water (10 mL) was added. The pH was adjusted to 6.5 with 2 N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water (2×25 mL), absorbed on silica gel and purified by flash chromatography to afford a 74% yield (210 mg) of 101f as a light brown solid: 1H NMR (300 MHz, DMSO-d6) δ 12.94 (s, 1H), 9.55 (s, 1H), 7.68 (s, 1H), 5.96 (s, 1H), 4.04 (t, 1H, J=5.7 Hz), 3.53 (s, 2H), 2.82 (t, 2H, J=5.7 Hz), 2.36 (s, 3H); MS (ESI+) m/z 281.1 (M+H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.O1CCCC1.CS(Cl)(=O)=O.Cl.[NH2:25][C:26]([CH3:31])([CH2:29][CH3:30])[C:27]#[CH:28]>C(Cl)Cl.C(OCC)(=O)C.O.C(N(CC)CC)C>[CH3:31][C:26]([NH:25][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([CH3:1])[CH:3]=1)([CH2:29][CH3:30])[C:27]#[CH:28]
Reactant: C#CC(C)(N)CC
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CC(C)(CC)NC(=O)c1ccc([N+](=O)[O-])c(C)c1
Temperature: -30 °C
Yield: 28.6 %

Procedure:
In a 500 mL, three-necked, round-bottomed flask fitted with a mechanical stirrer, nitrogen inlet and thermometer were placed 10 g of 3-methyl-4-nitrobenzoic acid, 200 mL of tetrahydrofuran and 38 mL triethylamine were added to The resulting well-stirred mixture was cooled to -30° C. and 4.7 mL of methane sulfonyl chloride were added dropwise keeping the reaction temperature at -30° C. The resulting suspension was stirred at -30° C. during 30 minutes, after which 8.1 g of 3-amino-3-methyl-1-pentyne hydrochloride were added slowly over a 20 minute period. After the addition was complete the reaction mixture was stirred at -30° C. for an additional 30 minutes. The reaction mixture was then poured into a mixture of 400 mL water and 200 mL of ethyl acetate. The phases were separated and the aqueous layer was extracted with ethyl acetate (2×150 mL). The combined organic phases were washed sequentially with water (1×200 mL), 5% aqueous hydrochloric acid (2×200 mL), water (1×200 mL), 5% aqueous sodium hydroxide (2×200 mL) and finally with water (1×200 mL) and then dried over anhydrous magnesium sulfate. The solvent was removed using a rotary evaporator, yielding the crude product. The crude product was dissolved in 100 mL of methylene chloride and filtered through a small silica gel column yielding 4.11 g of N-(3-methylpent-1-yn-3-yl)-3-methyl-4-nitrobenzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:14]([O-])=O.[Na+].[Sn](Cl)Cl.[OH-].[Na+]>Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][NH2:14])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: O=N[O-]
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(NN)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Following the procedure described in Journal of Organic Chemistry (1972), 37(18), 2849-53, 0.5 g (2.62 mmol) of 3-methoxy-5-trifluoromethyl-phenylamine was suspended in 4.6 ml of 25% aqueous HCl, cooled (0° C.) and carefully treated (without exceeding 10° C.) with 0.189 g (2.75 mmol) of sodium nitrite dissolved in 2.7 ml of water. The solution was stirred for 1 h at this temperature and 30 min at RT. Then, 2.48 g (13.08 mmol) of tin(II) chloride in 2.5 ml of 25% aqueous HCl were dropped carefully to the cooled (0° C.) solution and stirred for 1 h. The reaction was neutralized and basified with 32% aqueous NaOH (pH14), partitioned three times between CH2Cl2 and water. The organic phase was dried over Na2SO4 and evaporated to give 0.50 g (93%) of the title compound as a yellow solid. MS: 206.8 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl.O.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: O=C1CCNCC1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: O
Product: Brc1ccc2[nH]cc(C3=CCNCC3)c2c1
Yield: 93.5 %

Procedure:
Beginning with 6.2 gm (31.6 mMol) 5-bromo-1H-indole and 4.7 gm (30.6 mMol) 4-piperidone monohydrate hydrochloride, 7.93 gm (93%) of the title compound were recovered as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16](Br)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1(B(O)O)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1=CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Br)c2)CC1
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: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCCCC3)c2)CC1
Temperature: 80 °C
Yield: 77.9 %

Procedure:
A flask was charged with 4-(4-amino-3-bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.13 g, 0.36 mmol) (as prepared in the previous step), cyclohex-1-enyl boronic acid (0.060 g, 0.48 mmol), Pd(PPh3)4 (0.04 g, 10 mol %), aqueous 2M Na2CO3 (1.5 mL), ethanol (1.5 mL), and toluene (3 mL), and heated at 80° C. for 3 h. The reaction was diluted EtOAc (10 mL), washed with NaHCO3 (2×10 mL) and brine (10 mL), and the organic layer was dried over Na2SO4 and then concentrated. The title compound was eluted from a 20-g SPE cartridge (silica) with 30% EtOAc/hexane to give 0.10 g (85%) of the title compound as a yellow oil. Mass spectrum (ESI, m/z): Calcd. for C22H32N2O2, 357.2 (M+H), found 357.1.