Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:41]=[CH:40][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[N:20][C:21]([O:37]C)=[C:22]([NH:24][C:25]4[N:26]=[N:27][C:28]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:29][CH:30]=4)[CH:23]=3)[C:13]=2[CH3:39])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.Cl.[OH-].[Na+]>O>[C:1]([C:5]1[CH:41]=[CH:40][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:26]=[N:27][C:28]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:29][CH:30]=4)[C:21](=[O:37])[NH:20][CH:19]=3)[C:13]=2[CH3:39])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncc(-c2cccc(NC(=O)c3ccc(C(C)(C)C)cc3)c2C)cc1Nc1ccc(N2CCOCC2)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1c[nH]c(=O)c(Nc2ccc(N3CCOCC3)nn2)c1
Yield: 41.3 %

Procedure:
A 25-mL round-bottomed flask equipped with a magnetic stirrer was charged with 4-tert-butyl-N-(3-(6-methoxy-5-(6-morpholinopyridazin-3-ylamino)pyridin-3-yl)-2-methylphenyl)benzamide (7) (0.10 g, 0.18 mmol), dioxane (3 mL), H2O (1 mL), and conc. HCl (0.3 mL). After the reaction mixture was refluxed for 2 h, it was basified with 10 N NaOH (1 mL). The mixture was then diluted with water (5 mL), extracted with dichloromethane (3×5 mL), washed with H2O (5 mL) and brine (5 mL), dried over sodium sulfate, and concentrated in vacuo. The crude mixture was purified by column chromatography, gradient 0-33% MeOH in dichloromethane, to afford 0.040 g (41%) of 4-tert-butyl-N-(2-methyl-3-(5-(6-morpholinopyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)benzamide (8) as a solid: LCMS m/z 552.2342 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:25][C:26]1[CH:30]=[C:29]([Br:31])[S:28][C:27]=1[C:32]([NH2:34])=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[Br:31][C:29]1[S:28][C:27]([C:32](=[O:33])[NH2:34])=[C:26]([NH:25][C:14]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)Nc1cc(Br)sc1C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (518 mg) and triethylamine (0.392 mL) in tetrahydrofuran (5 mL) was added 2-methylpropyl chlorocarbonate (0.309 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added a solution of 3-amino-5-bromothiophene-2-carboxamide (250 mg) produced in Example 1, step D, in tetrahydrofuran (5 mL), and the mixture was stirred at 60° C. for 15 hr. Ethyl acetate (20 mL) and aqueous sodium hydrogen carbonate (10 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl 2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate as a pale-yellow oil. To a solution of tert-butyl 2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate produced above in ethanol (5 mL) was added 2M aqueous sodium hydroxide solution (1.70 mL), and the mixture was stirred at 70° C. for 4 hr. The reaction mixture was neutralized with 6M hydrochloric acid (0.6 mL) under ice-cooling, and water (5 mL) was added dropwise at room temperature. The precipitated solid was collected by filtration to give the title compound (240 mg) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:3]=1/[CH:4]=[N:5]/[S@@:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7].O.[CH3:18][Mg+].[Br-]>C(Cl)Cl.C(OCC)C>[F:1][C:2]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C@@H:4]([NH:5][S@@:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[CH3:18]
Reactant: C[Mg+]
Reactant: CC(C)(C)[S@@](=O)/N=C/c1cccc(F)c1F
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](N[S@](=O)C(C)(C)C)c1cccc(F)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of (R,E)-N-(2,3-difluorobenzylidene)-2-methylpropane-2-sulfinamide (0.800 g, 3.26 mmol) in DCM (32.6 mL), cooled to 0° C. (water/icebath) under N2, was added 3M MeMgBr (4.35 mL, 13.05 mmol) in diethyl ether. Reaction mixture allowed to stir for 30 min at 0° C. Then gradually allowed to warm to room temperature and stirred for 30 min at room temperature. Reaction mixture was cooled to 0° C. then quenched with the slow addition of a saturated solution of NH4Cl and diluted with EtOAc. Phases partitioned aqueous phase extracted with EtOAc and the organic layers combined washed with water, brine, dried with MgSO4, filtered and concentrated to afford (R)—N—((S)-1-(2,3-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (0.7868 g, 3.01 mmol, 92% yield) as yellow solid. MS m/z 262.0 (M+H)+; Rt-0.70 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:20]=[C:21]2[NH:25][CH2:24][CH2:23][S:22]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:25]2[CH2:24][CH2:23][S:22][C:21]2=[N:20][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[CH:6][N:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: Cc1ccc(S(=O)(=O)N=C2NCCS2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N=C2SCCN2Cc2ccc(Cl)nc2)cc1
Yield: 92 %

Procedure:
A mixture of 1.62 g of 6-chloro-3-chloromethyl pyridine (CCMP), 2.56 g of 2-[(4-methylphenyl) sulfonylimino]thiazolidine, 3.0 g of potassium carbonate, and 50 ml acetonitrile was heated under reflux for 3 hours. After the reaction, the product in the reaction mixture was purified by known crystallization techniques to yield pale yellowish crystals of 3.51 g 3-(2-chloro-5-pyridylmethyl)-2-[(4-methylphenyl)sulfonylimino]thiazolidine. The thus formed crystals have a melting point in a range of from 162.1 to 162.8° C.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[NH:17](C(OC(C)(C)C)=O)[C@@H:18]([C:27](O)=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][C@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:27]([N:13]1[CH2:14][CH2:15][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][N:2]([CH3:16])[CH3:1])[CH2:11][CH2:12]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CN(C)Cc1ccccc1N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Yield: 94.4 %

Procedure:
(2R)-2-amino-1-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-3-(4-chlorophenyl)propan-1-one was prepared according to the procedure described in Preparation V using dimethyl[(2-piperazinylphenyl)methyl]amine (Step 3) (0.35 g, 1.4 mmol), Boc-p-Cl-D-Phe-OH (Peptech Corp.) (0.53 g, 1.8 mmol) in CH2Cl2 (7 mL), EDC (Aldrich Chemical Company) (0.37 g, 1.9 mmol) and HOBT (used in place of HOAT) (Bachem) (0.27 g, 1.8 mmol). After workup as described in Preparation V, the crude compound was dissolved in CH2Cl2 (10 mL) and treated with TFA (5 mL). After stirring the reaction at RT for 1 h, the solvent was concentrated in vacuo and the residue was partitioned between CH2Cl2 and satd NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give (2R)-2-amino-1-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-3-(4-chlorophenyl)propan-1-one as a yellow oil (0.53 g). MS m/z: 401 (M+H). Calc'd for C22H29ClN4O: 400.94.
Reaction SMILES: [CH3:1][N:2]([CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]>CCO.[Pd]>[CH3:1][N:2]([CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:12]([F:15])([F:13])[F:14]
Reactant: CN1CCC(N(C)c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(N(C)c2ccc(N)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A suspension of methyl-(1-methyl-piperidin-4-yl)-(4-nitro-2-trifluoromethyl-phenyl)amine (0.812 g, 2.56 mmol) and Pd/C (10%) (0.200 g) in EtOH (20 mL) is stirred for 1 h 25 min at rt, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of Celite and concentrated to afford the title compound as a yellow oil: ES-MS: 288.1 [M+H]+; single peak at tR=1.50 min (System 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C1C(=O)N([I:17])C(=O)C1>CC(O)=O>[Cl:1][C:2]1[C:8]([F:9])=[CH:7][C:6]([I:17])=[C:4]([CH:3]=1)[NH2:5]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(F)cc1I
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-chloro-4-fluoroaniline (12.9 g, 88.9 mmol) and NIS (22.0 g, 97.8 mmol) in AcOH (90 mL) is stirred at RT for 1.5 h. After completion, the reaction mixture is quenched by H2O, DCM is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords 5-chloro-4-fluoro-2-iodoaniline as a colorless powder; HPLC: AtRet=4.75 min; 1HNMR (CDCl3) 7.40 (d, 1H), 6.75 (d, 1H), 4.00 (bs, 2H).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[CH:16]1.[Li]CCCC>>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[CH:10]([OH:11])[C@@H:9]1[CH2:12][CH2:13][CH2:14][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: c1ccc2scnc2c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)c1nc2ccccc2s1

Procedure:
31 (1.0 g, 5.02 mmol), benzothiazole (0.6 ml, 5.52 mmol), n-BuLi (1.6M) (3.45 ml 5.52 mmol).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][C@@H:8]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C@H:7]12)C.[NH3:18].C(OCC)C>CO>[O:11]=[C:10]1[N:6]([CH2:5][C:4]([NH2:18])=[O:3])[C@H:7]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@H:8]2[CH2:9]1
Reactant: CCOC(=O)CN1C(=O)C[C@@H]2CCCCC[C@@H]21
Reactant: N
Solvent: CO
Solvent: CCOCC
Product: NC(=O)CN1C(=O)C[C@@H]2CCCCC[C@@H]21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of cis-octahydro-2-oxo-cyclohepta[b]pyrrole-1(2H)-acetic acid ethyl ester (3.0 g, 0.0125 mole) in methanol (50 ml) is saturated with anhydrous ammonia. The solution is stirred at ambient temperature for 72 hours. the solution is concentrated at reduced pressure to yield a solid. Trituration with anhydrous diethyl ether yields pure cis-octahydro-2-oxo-cyclohepta[b]pyrrole-1(2H)acetamide with mp 140°-142° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.C(OCC)C.[CH3:20][Si:21]([CH2:24][Mg]Cl)([CH3:23])[CH3:22].Cl>O1CCCC1>[C:9]1([C:7]([OH:8])([CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cn1cncn1)c1ccccc1
Reactant: C[Si](C)(C)C[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)CC(O)(Cn1cncn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
0.505 g (2.7 mmole) of 2-(1H-1,2,4-triazol-1-yl)-acetophenone was added to 50 ml of diethyl ether. The solution was then stirred at room temperature under a stream of nitrogen, and 13.5 ml (13.5 mmole) of a 1 M tetrahydrofuran solution of trimethylsilylmethylmagnesium chloride were added dropwise at such a rate that the temperature of the reaction mixture did not rise higher than 25° C. After the addition was complete, the reaction mixture was stirred for 30 minutes at room temperature; it was then heated under reflux for 6 hours. At the end of this time, the reaction mixture was cooled, and it was then poured into 100 ml of ice-water. Its pH was adjusted to a value of 6 by the addition of 5% w/v aqueous hydrochloric acid, after which it was extracted three times, each time with 50 ml of ethyl acetate. The organic layers were collected, washed three times, each time with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure, to afford a crude oily product. 0.112 g (yield 15%) of the title compound, melting at 86°-87° C., was obtained from this crude oily product by purification through a silica gel chromatography column, eluted with mixtures of ethyl acetate and hexane ranging from 1:1 to 2:1 by volume.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([CH3:42])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[C:37]([CH3:42])[N:38]=[C:39]([CH3:41])[CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (187 mg, 0.68 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (220 mg, 0.68 mmol) according to the general procedure M. Obtained as an off-white foam (270 mg, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([Cl:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4].Cl.Cl.Cl.C1(NC(C2C3C=C(C4C(Cl)=CN=C([NH:47][CH2:48][CH2:49][CH2:50][N:51]5[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]5)N=4)SC=3C=CC=2)=O)CC1>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:47][CH2:48][CH2:49][CH2:50][N:51]4[CH2:52][CH2:53][N:54]([CH3:57])[CH2:55][CH2:56]4)[N:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc(-c3nc(Cl)ncc3Cl)sc2c1
Reactant: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Agent: Cl
Product: COC(=O)c1ccc2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)sc2c1

Procedure:
Using the method of Preparation E in 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide tri-hydrochloride, the title compound is synthesized from 2-(2,5-dichloro-pyrimidin-4-yl)-benzo[b]thiophene-6-carboxylic acid methyl ester and isolated as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[N:12]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[F:23])[CH2:11]3)[C:9](=[O:24])[N:8]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:5]2=[CH:6][CH:7]=1.[Cl:33]C1C=CC(F)=C(C=1)CBr>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[N:12]([CH2:16][C:17]4[CH:22]=[C:21]([Cl:33])[CH:20]=[CH:19][C:18]=4[F:23])[CH2:11]3)[C:9](=[O:24])[N:8]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C2(CC(=O)N(Cc3ccccc3F)C2)c2cc(Cl)ccc21
Reactant: Fc1ccc(Cl)cc1CBr
Product: CC(C)(C)OC(=O)CN1C(=O)C2(CC(=O)N(Cc3cc(Cl)ccc3F)C2)c2cc(Cl)ccc21
Yield: 72.7 %

Procedure:
Following the general method as outlined for Intermediate 33, starting from tert-butyl [5-chloro-1′-(2-fluorobenzyl)-2,5′-dioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetate (intermediate 32) and 5-chloro-2-fluorobenzyl bromide, the title compound was isolated, after purification by chromatography (silica) eluting with cyclohexane containing increasing amounts of ethyl acetate (5 to 40%), as a white solid in 72.7% yield (HPLC purity 94%). MS (ESI+): 493.4; MS (ESI−): 491.0
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH2:21][CH3:22])[C:19]#[N:20]>C(O)C>[C:19]([CH2:18][CH2:21][CH2:22][S:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])#[N:20]
Reactant: CCC(Br)C#N
Reactant: O=C(O)c1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#CCCCSc1cccc(C(=O)O)c1
Yield: 54.7 %

Procedure:
To solution of 3-mercaptobenzoic acid (250 mg, 1.62 mmole) in ethanol (10 ml), anhydrous potassium carbonate (896 mg, 6.48 mmole) was added followed by bromobutyronitrile (239.97 mg, 1.62 mmole). The reaction mixture was refluxed overnight. The ethanol was evaporated and water added. The basic solution was extracted with ethyl acetate. The aqueous layer was acidified and the resulting precipitate filtered and dried to yield 196 mg product. M.S. m/s 220 (M−1)+. 1H NMR (DMSO) δ 1.79 (2H, m, —CH2-), 2.37 (2H, t, —CH2-), 3.02 (2H, t, CH2), 7.56 (1H, d, 1×ArH), 7.74 (1H, d, 1×ArH), 7.83 (1H, bs, 1H, 1×ArH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.ClCCl.Cl.[CH2:20](O)[CH3:21]>C(OCC)C>[CH2:20]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)[CH3:21]
Reactant: CCO
Reactant: Nc1cccc(CC(=O)O)c1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)Cc1cccc(N)c1
Reaction time: 24 h
Yield: 100 %

Procedure:
To a cooled solution (−15° C.) of 3-aminophenylacetic acid (10.2, 67 mmol) in ethanol (200 mL) was added dropwise thionyl chloride (10 mL, 0.14 mol). The reaction mixture was stirred for 24 h allowing the temperature to slowly rise to rt. Evaporation of the volatiles gave a beige solid that was stripped several times with dichloromethane. The solid was then treated with hot diethyl ether and filtered to remove diethyl sulphite. Recrystallization from dietyl ether gave 14.4 g, 67 mmol, 100% of the desired compound as an off-white crystalline hydrochloride, mp 135° C. IR (KBr) cm−1 2857,2614, 1740
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1.[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH2:17].CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH:17][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1
Reactant: Cc1cccc(C)c1N
Reactant: CC1(c2ccccc2Br)OCCO1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1Nc1ccccc1C1(C)OCCO1
Temperature: 105 °C

Procedure:
A mixture of 2-(2′-bromophenyl)-2-methyl-1,3-dioxolane (362 mg, 1.49 mmol), 2,6-dimethylaniline(189 mg, 1.56 mmol), NaOtBu (172 mg, 1.79 mmol), Pd(dba)2 (17 mg, 0.03 mmol), ligand A (21 mg, 0.06 mmol) in toluene (4 mL) was heated to 105° C. for 4.5 hours. The reaction was cooled to room temperature, taken up in diethyl ether (125 mL), washed with water (2×30 mL) and brine (30 mL), dried over MgSO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel using hexane (or hexanes: ethyl acetate) as the eluent to afford compound 2b-1, after drying under vacuum, as an off-white solid (yield: 391 mg, 93%) 1H NMR (CDCl3): δ7.41 (dd, 1H, J=7.8, 1.8 Hz, ArH), 7.13-6.99 (m, 4H, ArH), 6.70 (dt, 1H, J=7.5, 1.2 Hz, ArH), 6.15 (dd, 1H, J=7.8, 0.9, ArH), 4.12 (m, 2H, O—CH—CH—O), 3.93 (m, 2H, O—CH—CH—O), 2.18 (s, 6H, Ar—CH3), 1.84 (s, 3H, CH3). 13C NMR (CDCl3): δ143.5, 138.6, 135.2, 129.1, 128.5, 126.3, 125.6, 125.2, 117.3, 112.6, 109.8, 64.1, 24.1, 18.3. Anal. for C18H21NO2; Calcd: C, 76.29, H, 7.47; N, 4.94; Found: C, 75.86; H, 7.46; N, 4.89.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10](=O)[C:11](=[O:13])[NH:12][C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][N:2]=1.[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>CCOC(C)=O>[O:13]=[C:11]1[NH:12][C:7]2[CH:6]=[CH:5][C:4]3[NH:3][N:2]=[CH:1][C:9]=3[C:8]=2[C:10]1=[N:22][NH:21][C:20]1[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccc3[nH]ncc3c2C1=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc4[nH]ncc4c32)cc1
Yield: 8 %

Procedure:
The title compound was prepared from 3,6-dihydro-pyrrolo[3,2-e]indazole-7,8-dione (Cuny, et al., Chemie Berichte 1981, 114,1624–35) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 8% yield: 1H NMR (DMSO-d6): δ 7.02 (d, J=8.7 Hz, 1H), 7.28 Z (s, 2H), 7.51 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.7 Hz, 2H), 8.34 (s, 1H), 10.98 (s, 1H), 12.90 (s, 1H), 13.20 (s, 1H); APCI-MS m/z 356 (M)−. Anal. Calcd for C15H12N6O3S.1.46H2O.0.2 EtOAc: C, 47.41, H, 4.16; N, 20.99; S, 8.01. Found C, 47.40, H, 3.70; N, 21.00; S, 7.85.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:32]=[CH:31][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][CH:22]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]4=[CH:14][C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:33]([F:36])([F:35])[F:34])([CH3:3])[CH3:2].C1C(=O)N([I:44])C(=O)C1>C(Cl)Cl>[I:44][C:14]1[C:13]2[CH:12]=[C:11]([O:10][CH2:9][C:8]3[CH:31]=[CH:32][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([C:33]([F:36])([F:34])[F:35])[CH:7]=3)[CH:19]=[CH:18][C:17]=2[N:16]2[CH2:20][CH2:21][CH:22]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]=12
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: CC(C)Oc1ccc(COc2ccc3c(c2)c(I)c2n3CCC2CC(=O)OC(C)(C)C)cc1C(F)(F)F
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl 2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.722 g, 1.434 mmol) in DCM (24 mL) at 0° C. was added NIS (1.434 mmol). After 5 minutes, the reaction was diluted with DCM and washed with water (twice) and saturated sodium thiolsulfate (aq). The organics were dried over Na2SO4, filtered, and concentrated to give the title compound as a light-brown solid. LCMS m/z=630.5 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (d, J=6.06 Hz, 6H), 1.38 (s, 9H), 2.27-2.38 (m, 1H), 2.51-2.56 (m, 1H), 2.77-2.89 (m, 1H), 2.94 (dd, J=15.92, 3.41 Hz, 1H), 3.51-3.61 (m, 1H), 3.99-4.09 (m, 1H), 4.12-4.21 (m, 1H), 4.74-4.83 (m, 1H), 5.10 (s, 2H), 6.78 (d, J=2.27 Hz, 1H), 6.85 (dd, J=8.72, 2.40 Hz, 1H), 7.25 (d, J=8.84 Hz, 1H), 7.30 (d, J=8.34 Hz, 1H), 7.66-7.73 (m, 2H).