Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([CH:15]([CH3:19])[C:16](O)=[O:17])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.[N+](=C)=[N-].[C:23](=O)([O-])[O-:24].[K+].[K+].CI.[CH3:31][OH:32]>CC(C)=O>[CH3:31][O:32][C:16](=[O:17])[CH:15]([CH3:19])[C:9]1[CH:8]=[CH:7][C:12]2[C:13]3[C:5](=[CH:4][C:3]([O:24][CH3:23])=[CH:2][CH:14]=3)[CH2:6][C:11]=2[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C(=O)O)c1ccc2c(c1)Cc1cc(O)ccc1-2
Reactant: CO
Agent: C=[N+]=[N-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C(C)c1ccc2c(c1)Cc1cc(OC)ccc1-2

Procedure:
A solution of 7-hydroxy-α-methylfluorene-2-acetic acid (10.8 g) in methanol is treated with an excess of ethereal diazomethane to prepare the methyl ester. The ester is dissolved in acetone (550 ml) containing potassium carbonate (110 g) treated with methyl iodide (83 ml) and refluxed overnight. The mixture is filtered and the filtrate evaporated to dryness. The residue is treated with ethyl acetate and filtered to give the crude product. A portion of this material is plate chromatographed on silica gel employing chloroform-hexane (1:1) as the developing solvent. Elution of the least polar band with ethyl acetate, evaporation and crystallization of the residue from acetone-isopropyl ether gave the titled product (mp 98.5°-100.5°). The analytical sample is prepared by recrystallization from acetone-isopropyl ether, mp 101°-103°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[CH3:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=1.C[Si](C)(C)N[Si](C)(C)C.[Li]>O1CCCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:14]([C:13]2[CH:18]=[CH:19][C:10]([CH3:9])=[CH:11][CH:12]=2)=[O:15])[CH:3]=1
Reactant: COC(=O)c1ccc(C)cc1
Reactant: Cc1cc(Br)ccn1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Cc2cc(Br)ccn2)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
Under a stream of nitrogen, 1 g (5.81 mmol) of 4-bromo-2-methylpyridine and 1.75 g (11.60 mmol) of methyl 4-methylbenzoate are placed in a round-bottomed flask and dissolved in 30 mL of anhydrous tetrahydrofuran. The solution is cooled to 5° C. and 14 mL (14 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at room temperature for 2 hours 30 minutes and then cooled to 5° C., followed by gradual addition of 20 mL of water. The medium is then diluted with 200 mL of ethyl acetate and 200 mL of water. The organic phase is separated out, dried over sodium sulfate and filtered. 5 g of silica are then added to the filtrate, which is then concentrated under reduced pressure. The powder obtained is used as a solid deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (95/5) to give 1.03 g (61%) of compound in the form of a yellow powder.
Reaction SMILES: C([C@H]1CC[C@H](OC2C(C(F)(F)F)=C3C(=CC=2)C=C(C([N+]([O-])=O)CCC(O)=O)C=C3)CC1)(C)(C)C.[C:35]([C@H:39]1[CH2:44][CH2:43][C@H:42]([O:45][C:46]2[CH:47]=[C:48]3[C:53](=[CH:54][CH:55]=2)[CH:52]=[C:51]([C:56]([N+:64]([O-:66])=[O:65])([CH3:63])[CH2:57][CH2:58][C:59]([O:61]C)=[O:60])[CH:50]=[CH:49]3)[CH2:41][CH2:40]1)([CH3:38])([CH3:37])[CH3:36]>>[C:35]([C@H:39]1[CH2:40][CH2:41][C@H:42]([O:45][C:46]2[CH:47]=[C:48]3[C:53](=[CH:54][CH:55]=2)[CH:52]=[C:51]([C:56]([N+:64]([O-:66])=[O:65])([CH3:63])[CH2:57][CH2:58][C:59]([OH:61])=[O:60])[CH:50]=[CH:49]3)[CH2:43][CH2:44]1)([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)CCC(C)(c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C(CCC(=O)O)[N+](=O)[O-])ccc3c2C(F)(F)F)CC1
Product: CC(CCC(=O)O)(c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]

Procedure:
4-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)-4-nitropentanoic acid was synthesized as per 4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-4-nitrobutanoic acid (Example 202) in 96% yield using methyl 4-(6-(trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl)-4-nitropentanoate as starting material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH2:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17](O)=[O:18])[CH3:11].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:17]([C@@H:13]2[CH2:14][CH2:15][CH2:16][N:12]2[CH2:10][CH3:11])=[O:18])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CCN1CCC[C@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCC[C@H]1C(=O)NNc1ccc(F)cn1
Reaction time: 4 h
Yield: 54.2 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (178 mg, 1.39 mmol) in DMF (10.0 mL) was added (S)-1-ethyl-pyrrolidine-2-carboxylic acid (200 mg, 1.39 mmol), EDC (293 mg, 1.53 mmol) and HOBt.H2O (18.0 mg, 0.14 mmol). The reaction was stirred for 4 h then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (190 mg, 54%). LCMS (Method 4): Rt 0.29 min, m/z 253.1 [MH+].
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([O:28]C)=[O:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[CH:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:14]2[C:23]([CH3:24])([CH3:25])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1)(=[O:6])=[O:7])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)NC(C)C)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)NS(=O)(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Yield: 28.5 %

Procedure:
To a stirred solution of methyl 2-(3-(N-isopropylsulfamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (120 mg, 0.288 mmol) in methanol/tetrahydrofuran (4 mL/4 mL) was added 1N sodium hydroxide (4.32 mL). The resultant mixture was heated to reflux for 1.5 h. Organic solvent was removed and the residue was dissolved in water. The aqueous layer was acidified to pH=4. The precipitates were filtered, and redissolved in tetrahydrofuran, dried over anhydrous magnesium sulfate. anhydrous magnesium sulfate was removed, and after evaporation, the residue was treated with dichloromethane to afford 33 mg of 2-(3-(N-isopropylsulfamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (Yield: 28%). MS (ESI+APCI) M+1=403.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8](Cl)Cl)[N:3]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-:18].[K+]>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([O:18][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: [OH-]
Reactant: Oc1ccccc1
Reactant: Clc1cccc(C(Cl)Cl)n1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A mixture of 25 grams (g) (0.13 mole (m)) of 2-chloro-6-(dichloromethyl)pyridine, 29.91 g (0.32 m) of phenol and 17.84 g (0.32 m) of potassium hydroxide in 100 milliliters (ml) of dimethylsulfoxide was heated, with stirring, for 6 hours at 70° C. The reaction mixture was cooled, diluted with water and extracted with 1,1,1-trichloroethane. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to Kugelrohr distillation and 27.3 g of a yellow viscous liquid was recovered. This liquid was determined to be the desired 2-chloro-6-(diphenoxymethyl)pyridine by its nuclear magnetic resonance spectra and its elemental analysis. The product boiled at 150° C. at 0.1 millimeter of mercury (mm) and had a refractive index of nD25 =1.5991. The elemental analysis showed the product to have carbon, hydrogen and nitrogen contents of 68.63, 4.40 and 4.49 percent, respectively, as compared with the theoretical contents of 69.34, 4.49 and 4.49 percent, respectively, as calculated for the above named compound.
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH2:6][NH2:7].[O:12]1[CH2:17][CH2:16][O:15]CC1.[C:18]([O-:21])(O)=O.[Na+]>O>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH2:6][NH:7][C:18](=[O:21])/[CH:9]=[CH:8]/[C:5]1[CH:4]=[CH:3][C:17]([OH:12])=[C:16]([OH:15])[CH:6]=1
Reactant: NCc1ccc(O)c(O)c1
Reactant: C1COCCO1
Reactant: O=C([O-])O
Agent: Br
Agent: [Na+]
Solvent: O
Product: O=C(/C=C/c1ccc(O)c(O)c1)NCc1ccc(O)c(O)c1
Temperature: 70 °C
Reaction time: 2.75 h

Procedure:
N-Succinimidyl 3,4-bis(acetyloxy)-E-cinnamate (502 mg, 1.39 mmol) and 3,4-dihy-droxybenzylamine hydrobromide (311 mg, 1.41 mmol) were dissolved in water (10 ml) and 1.4-dioxane (10 ml) under nitrogen. After NaHCO3 (350 mg, 4.16 mmol) had been added, the solution was stirred for 2.5-3 h at about 70° C. and left to cool. The mixture was extracted with ethyl acetate the combined organic phases were washed with hydrochloric acid (10%), water and saturated aqueous NaCl solution, dried over Na2SO4 and filtered, and the filtrate was evaporated under reduced pressure and the residue was purified by chromatography on silica gel. Yield: 254 mg (61%); 1H-NMR (400 MHz, CD3OD): δ=7.41 (1H, d, 15.6 Hz), 7.00 (1H, d, 2.1 Hz), 6.90 (1H, ddd, 8.13 Hz, 2.13 Hz, 0.5 Hz), 6.78-6.70 (3H, m), 6.63 (1H, dd, 8.1 Hz, 2.1 Hz), 6.39 (1H, d, 15.6 Hz), 4.32 (2H, s) ppm; 13C-NMR (100 MHz, CD3OD): δ=169.1 (s), 148.8 (s), 146.8 (s), 146.5 (s), 145.7 (s), 142.4 (d), 131.5 (s), 128.4 (s), 122.1 (d), 120.3 (d), 118.4 (d), 116.5 (d), 116.3 (d), 116.0 (d), 115.1 (d), 44.1 (t) ppm; MS (EI): m/z=301.2 (52%), 179.1 (45%), 178.2 (26%), 163.1 (64%), 138.1 (100%), 135.1 (22%), 134.1 (23%), 123.1 (25%), 89.1 (34%), 77.1 (23%).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[O:10][CH:11]([CH3:15])[C:12]([NH2:14])=O)([O-:3])=[O:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1.O1CCOCC1>[N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[O:10][CH:11]([CH3:15])[C:12]#[N:14])([O-:3])=[O:2]
Reactant: CC(Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1)C(N)=O
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CC(C#N)Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Temperature: 0 °C
Yield: 100.5 %

Procedure:
In a mixture of 12 ml of pyridine and 35 ml of dioxane was suspended 4.55 g of 2-[3-(2-nitrophenoxy)phenoxy]propionamide and, then, 3.6 g of trifluoroacetic anhydride was added dropwise with ice-cooling and stirring. The mixture was then stirred at that temperature for 30 minutes and, following addition of ice-water, extracted with ether. The ether extract was washed with diluted hydrochloric acid and sodium hydrogen carbonate solution in that order, dried and concentrated to give 4.3 g of the title compound as a light yellow oil.
Reaction SMILES: [C:1]([O-:4])([O-:3])=O.[K+].[K+].C(N[C:15](=[O:29])[C@H:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]=[CH2:28])=[CH:21][CH:20]=1)[NH2:17])(OC(C)(C)C)=O.[CH3:30][OH:31]>>[CH3:30][O:31][C:15](=[O:29])[C@H:16]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]=[CH2:28])=[CH:23][CH:24]=1)[NH:17][C:1]([O:4][C:19]([CH3:24])([CH3:20])[CH3:18])=[O:3]
Reactant: C=CCOc1ccc(C[C@H](N)C(=O)NC(=O)OC(C)(C)C)cc1
Reactant: CO
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
K2CO3 (20 mg, 0.145 mmol) was added to a stirred solution of 3 (100 mg, 0.131 mmol) in CH3OH (2 mL). After 30 min, the reaction mixture was filtered, diluted with ether (10 mL), and washed with aq NH4Cl and brine. Concentration followed by flash chromatography (20% diethyl ether/pentane) afforded N-Boc-O-allyltyrosine methyl ester (40.0 mg, 92%).
Reaction SMILES: [C:1](O)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CN1CCOCC1.ClC(OCC)=O.[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=1.Cl[Si](C)(C)C>C(#N)C.C(C1C=CC(CNC(=O)CCCC2C=CC=CC=2)=CC=1)(O)=O.C(N(CC)CC)C>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][NH:22][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:29][CH:28]=1)([OH:32])=[O:31]
Reactant: CCCCCC(=O)O
Reactant: NCc1ccc(C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: O=C(CCCc1ccccc1)NCc1ccc(C(=O)O)cc1
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: CCCCCC(=O)NCc1ccc(C(=O)O)cc1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
Hexanoic acid (3.06 g) in 20 mL acetonitrile is treated with N-methylmorpholine (2.9 mL) and the mixture cooled to -20° C. with stirring. Ethyl chloroformate (2.8 mL) is then added dropwise, keeping the temperature below or at -20° C. After stirring for an additional 40 min at that temperature, the solution is transferred to a cooled (-15° C.) solution of alpha-amino-p-toluic acid (2.0 g), triethylamine (15 mL), a chlorotrimethylsilane (5.0 mL) in methylene chloride (60 mL; prepared as described in Example 7). After the addition is complete, the mixture is stirred at 5° C. for hrs, followed by overnight stirring at room temperature. After removal of the solvents by evaporation, the residue is redissolved in methylene chloride (100 mL) and extracted with 1 N HCl (2×50 mL) and brine (2×50 mL). The organic layer is dried over magnesium sulfate and evaporated, leaving N-(4-carboxybenzyl)hexanamide as an off-white solid. The N-(4-carboxybenzyl)hexanamide product is crystallized from methanol/2N HCl, m.p. 178°-179° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.O(CC)P(OP(OCC)OCC)OCC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)=[O:9]
Reactant: Cc1cccc(N)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: CCOP(OCC)OP(OCC)OCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(=O)c2cc(Cl)ccc2O)c1
Yield: 26.9 %

Procedure:
A mixture of 5-Chlorosalicylic acid (0.338 g, 1.9 mmol), m-Toluidine (0.2 g, 1.9 mmol) and Tetraethyl pyrophosphite (0.53 g, 2.0 mmol) in dry toluene was refluxed 7 hrs under nitrogen atmosphere. It was diluted with ethyl acetate, washed with HCl (10%) and then with water (3×30 mL). The organic layer was dried (Na2SO4), filtered and evaporated under vacuum. The resulting crude material was purified by column chromatography over SiO2 using mixture of ethyl acetate and hexanes (2:8) to give title compound (0.134 g,) 1H NMR (CDCl3/DMSO-d6) δ 2.38 (s, 3H), 6.89-7.03 (m, 2H), 7.19-7.59 (m, 4H), 8.08 (d, 1H), 9.92 (bs, 1H), 12.05 (s, 1H).
Reaction SMILES: P(=O)(O)(O)O.C([N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])CCC.Cl[C:20]1C=CC(C(OC[C@H]2O[C@H](Cl)CC2)=O)=C[CH:21]=1.[C:36](#N)[CH3:37]>>[CH:15]1([NH:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:37][CH2:36]2)[CH2:16][CH2:17][CH2:18][CH2:21][CH2:20]1
Reactant: CCCCN(CCCC)CCCC
Reactant: CC#N
Reactant: O=C(OC[C@@H]1CC[C@@H](Cl)O1)c1ccc(Cl)cc1
Agent: O=P(O)(O)O
Product: C1CCC(NC2CCCCC2)CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a mixture of 3.5 g of orthophosphoric acid in 33 mL of acetonitrile were added 2.2 g of tri-n-butylamine and 3.3 g of molecular sieves 4A, and the mixture was cooled to 5° C. with stirring. To the mixture was added 3.28 g of 5-O-(4-chlorobenzoyl)-2,3-dideoxy-α-D-ribosyl chloride. After 1 hour, precipitation of crystals initiated and then a thick suspension was provided. After 20 hours, the ratio of α-form/β-form for compound (23) in the reaction suspension was 10:1. To the suspension was added 6.5 g of tri-n-butylamine to dissolve the precipitated crystals and molecular sieves were removed by filtration. The filtrate was diluted with 70 mL of toluene and then washed with 55 mL of water. The organic layer was ice-cooled. To the mixture was added 2.5 g of cyclohexylamine for crystallization with stirring. After 1 hour, the precipitated crystals were collected by filtration and dried in vacuo at room temperature to provide 4.56 g of a dicyclohexylamine salt of compound (23) as a colorless powder (Yield: 71.5%; α-form:β-form=97:3).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[C:21]([CH:27]=O)[NH:22]2.N1CCCCC1>C(O)C>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:21]1[NH:22][C:23]2[C:19]([CH:20]=1)=[C:18]([O:17][CH3:16])[CH:26]=[CH:25][CH:24]=2)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: COc1cccc2[nH]c(C=O)cc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1cc3c(OC)cccc3[nH]1)C(=O)N2
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (194 mg, 0.86 mmol), 4-methoxy-1H-indole-2-carbaldehyde (150 mg, 0.86 mmol) and piperidine (36 mg, 0.43 mmol) in ethanol (0.2M) was stirred at room temperature for a total of 5 days. The reaction was concentrated to ¼ of its volume and the precipitate was collected by vacuum filtration to give the title compound as a pale orangish-red solid.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[N:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:11]=1.C(OCC)(=O)C.O>O1CCOCC1>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[CH:11]=[C:6]([NH:4][CH2:3][CH2:1][OH:2])[N:7]=[N:8][CH:9]=2)=[CH:17][CH:16]=1
Reactant: Fc1ccc(-c2cnnc(Cl)c2)cc1
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: OCCNc1cc(-c2ccc(F)cc2)cnn1
Temperature: 120 °C

Procedure:
Ethanolamine (4.82 mL, 80 mmol) was added to a stirred mixture of 3-chloro-5-(4-fluorophenyl)pyridazine (2.08 g, 9.97 mmol) in Dioxane (40 mL) in a sealed tube. The mixture was heated to 120° C. overnight, treated with additional ethanolamine (1.2 mL, 20 mmol), and heated to 150° C. for 2 h. The mixture was cooled and poured into ethyl acetate (100 mL) and water (100 mL). The precipitate was filtered and dried to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 8.76 (d, 1H); 7.78 (dd, 2H); 7.36 (t, 2H); 7.02 (d, 1H); 6.85 (t, 1H); 4.78 (t, 1H); 3.58 (q, 2H); 3.45 (q, 2H). LRMS (APCI) calc'd for (C12H13FN3O) [M+H]+, 234.1. found 234.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=2)=[N:7]1)=[O:5])[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=2)[NH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CCC(c2cc(F)c(F)c(F)c2)=N1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reaction time: 16 h
Yield: 95.9 %

Procedure:
10% palladium on carbon (1.2 g, 50% water content) was added to an ethanol (170 mL) solution of (R)-5-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylic acid ethyl ester (12.4 g). Under a hydrogen atmosphere, stirring was continued for 16 hours at room temperature. The catalyst was filtered on celite, and the filtrate was concentrated, and the title compound (11.98 g) was obtained. The physical property values are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN([CH2:24][CH3:25])CC.[S:26](Cl)(Cl)(=[O:28])=[O:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:12][CH:13]3[CH:17]([CH2:16][N:15]([S:26]([CH:24]=[CH2:25])(=[O:28])=[O:27])[CH2:14]3)[CH2:18]2)=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(c1ccc(Cl)c(Cl)c1)N1CC2CNCC2C1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CC2CN(C(=O)c3ccc(Cl)c(Cl)c3)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
To a solution of (3,4-dichlorophenyl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (100 mg, 0.35 mmol) in DCM (10 mL) at 0° C., Et3N (106 mg, 1 mmol) was added followed by sulfonyl chloride (60 mg, 0.37 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was partitioned between DCM and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Isolera One (silica gel cartridge, 10-100% ethyl acetate/hexanes) to afford the desired product (14 mg, 11%). 1H NMR (300 MHz, CDCl3) δ: 7.60 (d, J=2.0 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.35 (dd, J=2.0, 8.2 Hz, 1H), 6.50 (dd, J=9.9, 16.5 Hz, 1H), 6.30 (d, J=16.6 Hz, 1H), 6.09 (d, J=9.9 Hz, 1H), 2.90-4.10 (m, 10H). ESI-MS m/z: 375.0[M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([NH:15][CH:16]([CH3:21])[CH2:17][C:18](O)=[O:19])=[O:14])=[CH:11][N:10]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(Cl)CCl.Cl.[CH2:35]([NH2:37])[CH3:36]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH2:35]([NH:37][C:18]([CH2:17][CH:16]([NH:15][C:13]([C:12]1[C:6]2[C:7](=[N:8][CH:9]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:5]=2)[N:10]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[CH:11]=1)=[O:14])[CH3:21])=[O:19])[CH3:36]
Reactant: CCN
Reactant: CC(CC(=O)O)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of 3-{[2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-butyric acid (0.14 g, 0.33 mmol) in CH2Cl2 (5 mL) was added EDC (0.083 g, 0.43 mmol), 4-(dimethylamino)pyridine (0.053 g, 0.43 mmol), and ethylamine hydrochloride (0.035 g, 0.43 mmol). The reaction mixture was stirred at room temperature overnight then diluted with H2O and extracted with CH2Cl2. The combined organics were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by SiO2 chromatography (2% MeOH/CH2Cl2) to obtain 0.114 g (78%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-ethylcarbamoyl-1-methyl-ethyl)-amide as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.C([Li])CCC.[C:20](=[O:22])=[O:21]>C1COCC1.O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([C:20]([OH:22])=[O:21])[C:4]=2[CH:3]=1
Reactant: O=C=O
Reactant: Cc1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
A solution of 2-methylfluorene (6 g, 33.2 mmol) in 100 ml of THF at -78° C. was charged with butyl lithium (2.18 g, 34.0 mmol). The reaction mixture was stirred for 15 min then CO2 gaseous (5 g, 113.6 mmol) was introduced via a cannula over a period of 15 min at -78° C. The reaction mixture was warmed up to room temperature and stirred for additional 2 hr until colorless. The reaction mixture was diluted with 250 mL of water and 100 mL of ethyl acetate, the layers were separated, the aqueous phase was washed with ethyl acetate (3×50 mL) and acidified to pH 2 with conc. HCl. The precipitate was filtered off, washed with water and dried to afford 6.1 g (81.9%) of 2-methyl-9-fluorenecarboxylic acid.