Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:15][C:10]2[CH2:11][O:12][CH:13]([CH3:14])[C:9]=2[C:8]=1[C:16]([O:18]CC)=[O:17])=[O:5].[OH-].[K+].Cl>C(O)C.O>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:15][C:10]2[CH2:11][O:12][CH:13]([CH3:14])[C:9]=2[C:8]=1[C:16]([OH:18])=[O:17])=[O:5]
Reactant: CCOC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1C(C)OC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1OCc2sc(NC(=O)c3c(F)cccc3C(F)(F)F)c(C(=O)O)c21
Temperature: 25 °C

Procedure:
A mixture of Example 1B (334 mg, 0.800 mmol) and solid potassium hydroxide (337 mg, 6.00 mmol) in ethanol (4 mL) and water (1 mL) were heated to reflux for 1 hour. After cooling to room temperature, 1 N aqueous HCl was added dropwise to adjust the mixture to pH 1. The mixture was extracted with ethyl acetate (3×10 mL). The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the title compound. LC-MS (ESI+) m/z 390 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1.C([Li])CCC.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>O1CCCC1.C(OCC)C>[CH2:26]([Sn:21]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:22][CH2:23][CH2:24][CH3:25])[C:5]1[S:4][C:3]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)=[C:2]([CH3:1])[CH:6]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ccsc1C1OCCO1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)c(C2OCCO2)s1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(3-methylthien-2-yl)-1,3-dioxolane (intermediate 75, 1.5 g) in tetrahydrofuran (50 ml), stirred at −60° C. under a nitrogen atmosphere, was treated drop-wise with 1.6M n-butyl lithium in hexanes (6.1 ml). The reaction mixture was stirred at this temperature for 1 hour and tributyltin chloride (2.6 ml) was added; stirring was continued at −60° C. for 1 hour and then the reaction allowed to warm to ambient temperature. After 18 hours the reaction mixture was diluted with diethylether and this mixture was extracted with water and the ether layer dried with brine and over magnesium sulfate. The product isolated after evaporation of the solvent was further purified by flash column chromatography using cyclohexane:ethyl acetate (50:1) as eluent to give the title compound as a yellow oil.
Reaction SMILES: [CH:1]1([C:7](=[O:11])/[CH:8]=[CH:9]/Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-:12].[Na+]>CC(C)=O>[CH:1]1([C:7](=[O:11])/[CH:8]=[CH:9]/[I:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [I-]
Reactant: O=C(/C=C/Cl)C1CCCCC1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(/C=C/I)C1CCCCC1
Yield: 101.7 %

Procedure:
A solution of 153 g of (25C) and 500 g of sodium iodide in 700 ml of dry acetone (distilled from anhydrous potassium carbonate) was refluxed under argon for 18 hours. The solvent was then removed by evaporation in vacuo. The residue was mixed with water and extracted three times with ether. The combined extract was dried over anhydrous magnesium sulfate and then evaporated in vacuo to yield 238 g of the desired product which had the following spectral properties: nmr (CDCl3) δ 0.9-2.8 (11H, m), 7.30 (1H, d, J=15 Hz) and 7.92 ppm (1H, d, J=15 Hz).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[F:23][C:24]([F:36])([F:35])[C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>ClCCl>[F:36][C:24]([F:23])([F:35])[C:25]1[CH:26]=[C:27]([S:31]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:32])=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reaction time: 8 h

Procedure:
To tert-butyl piperazine-1-carboxylate (1.39 g, 7.46 mmol) and diisopropylethylamine (1.955 mL, 11.19 mmol) in dichloromethane (10 mL) was added 3-(trifluoromethyl)benzene-1-sulfonyl chloride (1.196 mL, 7.46 mmol) dropwise. The reaction was stirred overnight. Thin layer chromatography indicated formation of a new product (hexanes/ethyl acetate 1:1). The reaction was diluted with dichloromethane (50 mL), washed with 1 N HCl (50 mL) and brine (50 mL), dried over magnesium sulfate, and concentrated to give the title compound.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][NH:13][NH2:14]>C(O)(=O)C.O>[OH:6][C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[N:13]([CH3:12])[N:14]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CNN
Solvent: CC(=O)O
Solvent: O
Product: Cn1nc(O)c2ccccc2c1=O

Procedure:
Phthalic anhydride (7.4 g) was dissolved in hot acetic acid (50 ml) and a solution of methylhydrazine (2.7 ml) in water (50 ml) was added. The mixture was heated under reflux for 15 minutes and left to cool overnight. The precipitate that formed was filtered off, washed with water and dried under reduced pressure at 65° C. to yield 1,2-dihydro-4-hydroxy-2-methyl-1-oxophthalazin (7.6 g) as a white solid. m.p. 243-244° C.
Reaction SMILES: [H-].[Na+].[C:3]1([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH3:16].O>CN(C)C=O>[CH3:16][N:12]1[CH2:13][CH2:14][N:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][CH2:11]1
Reactant: CI
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 68.2 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 2.70 g, 67.8 mmol) was added to a solution of 1-phenylpiperazine (10.0 g, 61.6 mmol) in N,N-dimethylformamide (80 mL) at 0° C., and the mixture was stirred for 10 minutes at the same temperature. To the reaction mixture was added Iodomethane (8.74 g, 67.8 mmol), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into water (80 mL), and extracted twice with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from hexane-isopropyl ether to obtain 1-methyl-4-phenylpiperazine (7.40 g). Bromine (7.00 g, 43.8 mmol) was added to a solution of this compound in ethanol (80 mL) at 0° C., and the mixture was stirred for 1 hour at room temperature. Water (80 mL) was poured into the reaction mixture, which was then extracted twice with ethyl acetate. The organic layer was combined, washed with an aqueous saturated sodium hydrogencarbonate and water, then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the title compound (8.1 g, yield 52%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]2[C:16]([NH:17][C@@H:18]3[CH2:32][C@@H:21]4[CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][C@@H:20]4[C@H:19]3[CH3:33])=[C:15]([C:34](=[O:36])[NH2:35])[CH:14]=[N:13][N:12]2[CH:37]=1>ClCCl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]2[C:16]([NH:17][C@@H:18]3[CH2:32][C@@H:21]4[CH2:22][NH:23][CH2:24][C@@H:20]4[C@H:19]3[CH3:33])=[C:15]([C:34]([NH2:35])=[O:36])[CH:14]=[N:13][N:12]2[CH:37]=1
Reactant: C[C@@H]1[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1[C@H]2CNC[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Trifluoroacetic acid (1 mL, 12.98 mmol) was added to a solution of (3 aS,4R,5R,6aS)-tert-butyl 5-(6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-4-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (250 mg, 0.523 mmol) in dichloromethane (2 mL). After stirring for 1 h at room temperature, the mixture was concentrated and dried under high vacuum to give 6-bromo-4-(((3aS,4R,5R,6aS)-4-methyloctahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide TFA salt (255 mg). 1H NMR (400 MHz, methanol-d4) δ ppm 8.15 (1 H, s), 7.66 (1 H, d, J=1.54 Hz), 7.06 (1 H, d, J=1.54 Hz), 4.03-4.34 (1 H, m), 3.31-3.59 (3 H, m), 3.01-3.25 (2 H, m), 2.53-2.83 (2 H, m), 1.60-1.84 (1 H, m), 1.36-1.60 (1 H, m), 1.17 (3 H, d); MS (ES+) m/z: 378.1, 380.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.[CH3:34][N:35]([CH2:37][CH2:38][CH2:39]Cl)[CH3:36]>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:39][CH2:38][CH2:37][N:35]([CH3:36])[CH3:34])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: CN(C)CCCCl
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC
Product: COc1cc(-c2nc3ccc(OCCCN(C)C)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 104 with 3-(N,N-dimethylamino)propyl chloride essentially as previously described. mp 142° C., NMR, IR, MS 543.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[NH4+].[Cl-].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]1[NH:13][N:12]=[N:11][N:7]=1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CC#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nnn[nH]1
Temperature: 100 °C

Procedure:
To a solution of ethylcyanoacetate (20.0 g, 0.177 mol) in dimethylformamide (DMF) (180 mL) was added NH4Cl (10.4 g, 0.19 mol) and sodium azide (12.6 g, 0.19 mol) sequentially. The mixture was heated for 5 hours at 100° C., allowed to cool, and the DMF removed in vacuo. The residue was taken up in water (150 mL), acidified to pH 2 with concentrated HCl, and filtered. The filtrate was cooled to 5° C. and allowed to crystallize. The solid was filtered, dried in vacuo over self-indicating silica gel to give 10.61 g, 42%, mp 124°14 129° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]2[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=2)=[C:4]([O:22][CH3:23])[CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:31](O)=[O:32])(=[O:27])=[O:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][C:16]2[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=2)[C:31](=[O:32])[C:30]2[CH:34]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:36]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:29]=2)=[C:4]([O:22][CH3:23])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1NCc1nccn1C
Product: COc1cc(F)ccc1-c1ccncc1N(Cc1nccn1C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(1-methyl-1H-imidazol-2-ylmethyl)-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 18 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of CH2Cl2:MeOH (100:0 to 80:15). Further purification by preparative HPLC (Gemini NX) with a gradient of MeOH:water (containing 0.05% formic acid) (80:20 to 98:2). Light yellow foam (54%). MS (ESI): m/z=563.135 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.O.CN(C)[CH:31]=[O:32]>>[C:22]1([CH2:21][N:18]2[CH2:19][CH2:20][CH:15]([N:14]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[NH:1][C:31]3=[O:32])[CH2:16][CH2:17]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccccc1-c1ccccc1NC1CCN(Cc2ccccc2)CC1
Reactant: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2-c2ccccc2N1C1CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 36.0 g (0.101 mol) of 2-amino-2′-[[1-(phenylmethyl)-4-piperidinyl]amino]-biphenyl in 200 mL of dimethylformamide were added 40.5 g (0.250 mol) of N,N′-carbonyldiimidazole, then the mixture was stirred for 2 hours at 100° C., after which the solvent was eliminated in vacuo. The residue was stirred with water, then extracted exhaustively with dichloromethane. The combined organic extracts were dried over sodium sulfate, clarified with active charcoal and evaporated down. The residue (60 g) was purified by chromatography on aluminium oxide of activity stage 3 using PE/EE 2/1 (v/v). The desired compound was obtained from the corresponding fractions in a yield of 6.2 g (16% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Temperature: 17.5 °C
Reaction time: 0.5 h

Procedure:
To 2-(4-hydroxyphenyl)acetic acid in DMF cooled to 0° C. was added K2CO3 and the solution was stirred for 30 min. Then, benzyl bromide was added and the solution stirred at 0° C. and was allowed to slowly warm to 15-20° C. After all the ice was melted the solution was poured into NH4Cl(sat) and extracted with EtOAc. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 0-35% EtOAc/Hex) gave pure benzyl 2-(4-hydroxyphenyl)acetate (E301).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:6]([CH:12](O)[CH3:13])=[N:7]2.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]1(=[O:56])[NH:50][C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:6]([CH:12]([N:50]1[C:46](=[O:56])[C:47]3[C:48](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:49]1=[O:51])[CH3:13])=[N:7]2
Reactant: CC(O)c1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1nc2cccc(Cl)c2nc1-c1cccc(F)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(5-chloro-3-(3-fluorophenyl)quinoxalin-2-yl)ethanol (0.2875 g, 0.9497 mmol) in tetrahydrofuran (9.497 mL, 0.9497 mmol) were added triphenyl-phosphine (0.7473 g, 2.849 mmol), phthalimide (0.4192 g, 2.849 mmol), and diisopropyl azodicarboxylate (0.5518 mL, 2.849 mmol). The reaction mixture was stirred at room temperature. After 1 h, the mixture was concentrated under reduced pressure and partitioned between EtOAc (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 20 min and 50% isocratic of EtOAc for 5 min as eluent to give 2-(1-(5-chloro-3-(3-fluorophenyl)quinoxalin-2-yl)ethyl)isoindoline-1,3-dione as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.19 (1 H, dd, J=8.4, 1.4 Hz), 8.09 (1 H, dd, J=7.6, 1.4 Hz), 7.91 (1 H, dd, J=8.4, 7.6 Hz), 7.73-7.80 (2 H, m), 7.60-7.68 (2 H, m), 7.31-7.38 (1 H, m), 7.14-7.24 (2 H, m), 7.00-7.09 (1 H, m), 6.04-6.13 (1 H, m), 1.77 (3 H, d, J=6.7 Hz); LC-MS (ESI) m/z 432.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>>[C:26]([O:25][C@@H:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:40]#[C:39][C:37]([OH:41])([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=3)[CH3:38])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:20]([OH:22])=[O:21])([CH3:29])([CH3:28])[CH3:27]
Reactant: C#CC(C)(O)c1ccccn1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Product: Cc1cc2ccc(C#CC(C)(O)c3ccccn3)cc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-(pyridin-2-yl)but-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid was prepared by the method in Example 8 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate and 2-(pyridin-2-yl)but-3-yn-2-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 8.61 (d, J=6 Hz, 1H), 8.22 (t, J=8 Hz, 1H), 8.05 (d, J=8 Hz, 1H), 7.78 (d, J=8 Hz, 1H), 7.66 (m, 2H), 7.57 (m, 3H), 7.47 (d, J=8 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J=8 Hz, 1H), 5.16 (s, 1H), 2.61 (s, 3H), 1.87 (s, 3H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H30ClNO4: 528.2. found: 528.1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][CH2:20][CH:19]([C:24](O)=[O:25])[C:18]=2[C:17]2[C:12]1=[C:13]([Cl:29])[CH:14]=[CH:15][C:16]=2[O:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:33])=O>ClCCl.CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][CH2:20][CH:19]([C:24]([Cl:33])=[O:25])[C:18]=2[C:17]2[C:12]1=[C:13]([Cl:29])[CH:14]=[CH:15][C:16]=2[O:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cl)c2c1c1c(n2CCOCc2ccccc2)CCCC1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Cl)c2c1c1c(n2CCOCc2ccccc2)CCCC1C(=O)Cl
Temperature: 20 °C
Reaction time: 2 h

Procedure:
9-(2-Benzyloxy-ethyl)-8-chloro-5-methoxy-2,3,4,9,-tetrahydro-1H-carbazole-4-carboxylic acid (7) (1.5 g, 3.7 mmol) was dissolved in dichloromethane (50 mL) and oxalyl chloride (700 mg, 5.5 mmol, 470 μL) and DMF (1 drop) were added and the reaction stirred at 20° C. for 2 h. There was a moderate evolution of gas for about 30 min as the reaction proceeded. The reaction was then concentrated in vacuo to give 9-(2-Benzyloxy-ethyl)-8-chloro-5-methoxy-2,3,4,9,-tetrahydro-1H-carbazole-4-carbonyl chloride (8) as a gum which was used into the next step without purification. The structure was confirmed by 13C NMR (75 MHz; CDCl3): δC 20.8, 22.1, 26.4, 44.2, 51.8, 55.1, 70.7, 73.3, 100.7, 106.0, 108.6, 119.5, 123.4, 127.3, 127.7, 128.3, 131.9, 138.0, 138.2, 152.0. and 176.3.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH2:7](O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:7]([O:4][C:3](=[O:5])[CH:2]([Br:1])[CH3:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(Br)C(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(Br)C(=O)OCc1ccccc1

Procedure:
20.0 g (0.13 moles) of 2-bromopropionic acid were stirred with 14.1 g (0.13 moles) of benzyl alcohol in dry methylene chloride at 5°-10° C., before 0.16 g (1.3e-3 moles) of 4-dimethylaminopyridine (DMAP) were added. The temperature was raised to ~15° C. before a solution of dicyclohexylcarbodiimide (DCC) (26.7 g, 0.13 moles) in dry methylene chloride was added dropwise. The solution was added at a rate as to not increase the reaction temperature above 35° C. After the imide addition was complete, the reaction proceeded at 25° C. for several hours or until infrared spectroscopy analysis indicated the absence of a carboxylic acid stretch at 1730 cm-1. Upon completion, the reaction mixture was filtered under vacuum to remove the dicyclohexyl urea (DCU) byproduct and the filtrate was extracted once with water, once with 5% acetic acid solution (to remove DMAP) and again with water. The organic layer was dried over anhydrous magnesium sulfate before being filtered and concentrated under reduced pressure. Yield was 25 g (72%) of a mixture of Benzyl-2-bromopropionate and Benzyl-2-chloropropionate.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>O1CCCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[NH:4][C:3]2=[O:20])=[O:30])=[CH:24][CH:23]=1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reaction time: 8 h

Procedure:
To a solution of 85 mg (0.315 mmole) of 1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one in 8 ml of dry tetrahydrofuran was added 4-chlorophenylisocyanate (40 μl, 0.315 mmole) at room temperature. Within 15 minutes a flocculant, white precipitate formed. Stirring was continued for 8 hours more and the reaction mixture was filtered. The collected solids were washed with hot methanol and dried in vacuo to give the analytical product: m.p. 278° C. NMR (DMSO-d6): Confirms structure assignment of product.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([NH:9][C:10](=O)OCC2C=CC=CC=2)[CH2:4]1)#[N:2].CCN(C(C)C)C(C)C.[Cl:29][C:30]1[CH:31]=[C:32]2[C:38]([C:39]3[N:44]=C(S(C)=O)[C:42]([F:48])=[CH:41][N:40]=3)=[CH:37][N:36]([S:49]([C:52]3[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=3)(=[O:51])=[O:50])[C:33]2=[N:34][CH:35]=1>C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:29][C:30]1[CH:31]=[C:32]2[C:38]([C:39]3[N:44]=[C:10]([NH:9][C@H:5]4[CH2:6][CH2:7][CH2:8][C@@H:3]([C:1]#[N:2])[CH2:4]4)[C:42]([F:48])=[CH:41][N:40]=3)=[CH:37][N:36]([S:49]([C:52]3[CH:53]=[CH:54][C:55]([CH3:56])=[CH:57][CH:58]=3)(=[O:51])=[O:50])[C:33]2=[N:34][CH:35]=1
Reactant: N#C[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](C#N)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 45 °C
Reaction time: 2.25 h

Procedure:
Benzyl N-[(1S,3R)-3-cyanocyclohexyl]carbamate (0.26 g, 1.02 mmol) was dissolved in THF (15 mL) and treated with 0.13 g of 20% Pearlman's catalyst (50% wet by weight). The suspension was degassed with hydrogen for 2 min then placed under static hydrogen atmosphere. After 135 min, TLC showed no remaining starting material. The suspension was filtered through celite, washed with THF and degassed with nitrogen followed by the addition of iPr2NEt (0.21 mL, 1.23 mmol) and 5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 1a, (0.48 g, 1.02 mmol). The mixture was allowed to stir overnight at 45° C. then concentrated to dryness, absorbed on silica-gel and purified by silica gel chromatography using 0-60% EtOAc/hexanes gradient to afford 293 mg of a white solid.