Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([O:16]CC)=[O:15])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([CH2:20][CH3:21])[C:3]=1[C:22]([NH2:24])=[O:23].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](OC)=O)=[CH:29][CH:28]=1.[Na].CC(O)=O>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=[C:8]([Cl:19])[C:7]=1[N:6]1[C:2]2=[N:1][C:34]([CH2:33][C:30]3[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[N:24][C:22](=[O:23])[C:3]2=[C:4]([CH2:20][CH3:21])[NH:5]1
Reactant: COC(=O)Cc1ccc(OC)cc1
Reactant: CCOC(=O)c1cc(Cl)c(-n2nc(CC)c(C(N)=O)c2N)c(Cl)c1
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1[nH]n(-c2c(Cl)cc(C(=O)O)cc2Cl)c2nc(Cc3ccc(OC)cc3)nc(=O)c1-2
Yield: 75.1 %

Procedure:
Part D: To a stirred solution of 500 mg (1.35 mmol) of 5-amino-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl) pyrazole-4-carboxamide in 10 mL ethanol was added 1.45 g (8.1 mmol) of methyl 4-methoxyphenylacetate followed by 2.6 mL (8.1 mmol) of 2.66 M sodium ehtoxide in ethanol. The reaction was heated at relux for 18 h and then 10% aq. HOAc was added. After stirring an additional hour at relux, the heat was removed and the reaction solution was poured into ice water, stirred 10 min. and filtered. The solid was washed with water and diethyl ether and dried to give 480 mg (75%) of 1-(2,6-dichloro-4-carboxyphenyl)-3-ethyl-6-(4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 277° C. Mass Spec.: (ES−) 471 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](Cl)(=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>O.C(O)(C)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 67.5 °C
Reaction time: 1 h

Procedure:
69.1 g (0.5 mol) of para-hydroxybenzoic acid were first dissolved in 200 ml of water and 300 ml of isopropanol and this solution was adjusted to a pH of 10.5 at 20 to 25° C. using 87.4 g of NaOH solution (32% strength by weight aqueous solution, 0.7 mol). Metered in to this solution at a pH of 10.5 subsequently, over the course of three hours, were 95.4 g (0.5 mol) of decanoyl chloride. The pH was held at 10.5 using 40.5 g of NaOH solution (32% strength by weight aqueous solution, 0.324 mol) and the temperature was held at 20 to 25° C. The batch was stirred for one hour thereafter. Subsequently the reaction mixture was adjusted to a pH of 7 at 20 to 25° C. using 5.3 g of HCl solution (32% strength by weight aqueous solution), and the complete solution was heated to 65 to 70° C. and then adjusted to a pH of 1.5 to 3 using 60 g of HCl solution (32% strength by weight aqueous solution). The reaction mixture was cooled to room temperature (25° C.), and the solid was filtered off on a suction filter and washed ten times with 150 ml of water. The yield after drying under reduced pressure at 100° C. was 134.1 g (91.7% of theory). According to HPLC and NMR measurement, the product was free from decanoic acid and from unreacted para-hydroxybenzoic acid. The purity of the product is >99.9% by weight.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]#[N:16])=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21](=[O:55])[N:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]3[N:32]=[CH:33][N:34](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:35]=3)=[CH:26][N:25]=2)[CH:23]=1>CC#N>[Cl:17][C:18]1[CH:19]=[CH:20][C:21](=[O:55])[N:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]3[N:32]([CH2:2][C:3]4[CH:8]=[C:7]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)[C:6]([C:15]#[N:16])=[CH:5][CH:4]=4)[CH:33]=[N:34][CH:35]=3)=[CH:26][N:25]=2)[CH:23]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: N#Cc1ccc(CBr)cc1-c1ccccc1
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1-c1ccccc1
Temperature: 60 °C

Procedure:
5-Bromomethyl-biphenyl-2-carbonitrile from step 4 (51 mg, 0.19 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (100 mg, 0.19 mmol) were dissolved in CH3CN (950 μl) and heated to 60° C. for 14 hours. The solvent was removed in vacuo and th ressidue dissolved in MeOH (950 μl). The reaction mixture was heated to 60° C. for 4 hours. Solvent was removed in vacuo and the residue was purified by flash chromatography [15% MeOH(5% NH4OH)/CH2Cl2 ] to yield the final product.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:26][CH3:27])[CH2:4][O:5][C:6]1[C:7]([CH3:25])=[C:8]([CH:18]=[CH:19][C:20]=1[S:21]([CH3:24])(=[O:23])=[O:22])[C:9]([O:11]CC(OC)OC)=[O:10].[OH-].[Na+].Cl>CO>[CH3:27][O:26][CH:3]([O:2][CH3:1])[CH2:4][O:5][C:6]1[C:7]([CH3:25])=[C:8]([CH:18]=[CH:19][C:20]=1[S:21]([CH3:24])(=[O:23])=[O:22])[C:9]([OH:11])=[O:10]
Reactant: COC(COC(=O)c1ccc(S(C)(=O)=O)c(OCC(OC)OC)c1C)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(COc1c(S(C)(=O)=O)ccc(C(=O)O)c1C)OC
Reaction time: 0.5 h

Procedure:
The 2,2-dimethoxyethyl 3-(2,2-dimethoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoate obtained in the above step (1) was dissolved in methanol (20 mL), and an aqueous sodium hydroxide solution (2 mL) at a concentration of 20% was added thereto at room temperature. After stirring for 30 minutes, 100 mL of 1N hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. (200 mL). The organic layer was washed twice with a saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3-(2,2-dimethoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (390 mg) as a white solid.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:7]1[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=1[O:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12](Cl)[N:11]=1)([CH3:6])([CH3:5])[CH3:4].[Cl-]>O1CCOCC1.O>[C:3]([C:7]1[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=1[O:9][C:10]1[N:11]=[C:12]([NH:2][CH3:1])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])([CH3:6])([CH3:5])[CH3:4]
Reactant: CN
Reactant: CC(C)(C)c1ccccc1Oc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: CNc1ccc([N+](=O)[O-])c(Oc2ccccc2C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.2 %

Procedure:
Methylamine (280 μL, 0.56 mmol) was added into a solution of 136b (157 mg, 0.51 mmol) in 1,4-dioxane at 0° C. (1 mL) over 1 h and the resulting reaction mixture was stirred at rt. After 72 h, 40% of the starting chloride remained by HPLC. Another 1.1 eq of methylamine was added at −10° C. over 30 min. The reaction was allowed to warm to rt, stir for 30 min and was then diluted with water (1 mL) and extracted with ethyl acetate (3×1 mL). The combined organic layer was washed with brine (1 mL), dried over sodium sulfate, and concentrated to give a yellow oil. The oil was purified by SiO2 chromatography (12 g) using a gradient of ethyl acetate in hexanes to afford 136c (94 mg, 61% yield) as a yellow oil; HPLC purity 100%, 3.76 min (Method A); [M+H]+=302.24.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[OH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1F
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccccc2C(C)=O)c(OC)c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 41.7 %

Procedure:
2′-Fluoroacetophenone (1.38 g) and methyl 4-hydroxy-3-methoxybenzoate (1.82 g) were dissolved in dimethylformamide (10 ml), and potassium carbonate (1.45 g) was added. The mixture was stirred at 100° C. for 15 hrs. The reaction mixture was cooled to room temperature, and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine and dried over sodium sulfate. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the title compound (1.25 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[O:14]=[C:4]1[CH:3]([CH2:2][O:1][C:30](=[O:31])[NH:29][C:26]2[CH:27]=[CH:28][C:23]([Br:22])=[CH:24][CH:25]=2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]1=2
Reactant: O=C1c2ccccc2SCCC1CO
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Br)cc1)OCC1CCSc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxymethyl-3,4-dihydro-2H-benzo[b]thiepin-5-one (224 mg, 1.08 mmol) in 14 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.16 ml, 1.18 mmol) and 4-bromophenyl isocyanate (0.423 g, 2.15 mmol). The mixture was stirred at room temperature for 2 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 250 mg (57%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10](=[O:16])[C:11]([O:13]CC)=[O:12])[CH:7]=[CH:8][CH:9]=1>C1COCC1.CO>[Cl:3][C:4]1[CH:5]=[C:6]([C:10](=[O:16])[C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(=O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.2 %

Procedure:
An aqueous 2 mol/L NaOH solution (24 mL) was added to a solution of ethyl (3-chlorophenyl)(oxo)acetate (2.00 g) in THF/MeOH (1:1) (48 mL) in an ice bath, followed by stirring at room temperature overnight. The solvent was distilled off under reduced pressure, and an aqueous 3 mol/L HCl solution was added thereto in an ice bath. The precipitated solid was collected by filtration to yield the title compound (2.00 g, colorless solid).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([OH:22])[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].[C:24]([Si:28](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:27])([CH3:26])[CH3:25].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([O:22][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)C(O)CN(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)C(CN(Cc1ccccc1)Cc1ccccc1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
(5.8 g, 18.6 mmol) (RS)-3-Dibenzylamino-2-hydroxy-propionic acid ethyl ester (CAS 93715-75-4) was dissolved in DMF (40 ml) and tert-butylchlorodiphenylsilane (6.76 ml, 26 mmol, 1.4 equiv.), Imidazole (1.9 g, 27.9 mmol, 1.5 equiv.) and DMAP (227 mg, 1.9 mmol, 0.1 equiv.) were added at room temperature. The mixture was stirred for 3 hours at 80° C. The reaction mixture was evaporated and extracted with saturated NaHCO3 solution and two times with EtOAc. The organic layers were extracted with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 40:60. The desired (RS)-2-(tert-butyl-diphenyl-silanyloxy)-3-dibenzylamino-propionic acid ethyl ester (8.1 g, 79% yield) was obtained as a colorless oil, MS: m/e=552.5 (M+H+).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[NH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([OH:21])=[C:16]([Cl:22])[CH:15]=1>>[Cl:20][C:18]1[CH:19]=[C:14]([NH2:13])[CH:15]=[C:16]([Cl:22])[C:17]=1[O:21][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1
Reactant: COc1cccc2sc(Cl)nc12
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Product: COc1cccc2sc(Oc3c(Cl)cc(N)cc3Cl)nc12

Procedure:
3,5-Dichloro-4-(4-methoxy-benzothiazol-2-yloxy)-phenylamine was synthesized (21%) from 2-chloro-4-methoxybenzotiazole (257) and 4-amino-2,6-dichlorophenol (Aldrich) in a similar manner as described in Example 417.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH2:4][CH2:3]1.[C:18](O)(=[O:22])[C@@H:19]([CH3:21])[OH:20].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:20][C@H:19]([CH3:21])[C:18]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH2:4][CH2:3]1)=[O:22]
Reactant: C[C@@H](O)C(=O)O
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@H]1CC[C@H](N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)C(=O)N[C@H]1CC[C@H]([C@@H](C)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trans-tert-butyl (R)-1-(4-aminocyclohexyl)ethylcarbamate (125 mg, 0.52 mmol) was dissolved in DMF (3 mL). D-Lactic Acid (49.52 mg, 0.52 mmol), diisopropylethylamine (166.6 mg, 224.5 μL, 1.29 mmol) and TBTU (165.6 mg, 0.5158 mmol) were successively added. The reaction mixture was allowed to stir at ambient temperature for 3 hours. The crude mixture was partitioned between ethyl acetate and brine. The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by column chromatography (ISCO Companion□, 12 g column, 0-10% MeOH/DCM) to afford the title compound (66.1 mg, 41% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:6]1[CH2:23][CH:24]3[NH:29][CH:28]([C:5]2=1)[CH2:27][CH2:26][CH2:25]3>[Pd].C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:14]=1)[C:6]1[CH2:23][C@H:24]3[NH:29][C@@H:28]([C:5]2=1)[CH2:27][CH2:26][CH2:25]3
Reactant: Cc1ccc2c(c1)c1c(n2/C=C/c2cccc(C(F)(F)F)c2)CC2CCCC1N2
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CCc2cccc(C(F)(F)F)c2)C[C@@H]2CCC[C@H]1N2
Temperature: 40 °C

Procedure:
In a 100 mL round-bottomed flask were combined 2-methyl-5-{(E)-2-[3-(trifluoromethyl)phenyl]vinyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (300 mg, 0.757 mmol; Example 134), 10% palladium on carbon (35 mg; Aldrich) in ethanol (30 mL). The reaction mixture was heated to 40° C. under a hydrogen balloon atmosphere for 16 hours, then cooled to room temperature. The catalyst and solvent were removed, and the residue was purified by reverse-phase HPLC [Waters XBridge C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1% trifluoroacetic acid) over 15 minutes] to afford the title compound as a racemic mixture. This material was purified further by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine, 20 minutes) to afford the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 0.97-1.17 (m, 1H), 1.22-1.42 (m, 2H), 1.61 (dd, J=13, 2 Hz, 1H), 1.74-1.95 (m, 2H), 2.06 (d, J=17 Hz, 1H), 2.40 (s, 3H), 2.87 (dd, J=17, 7 Hz, 1H), 3.10-3.23 (m, 2H), 3.44 (t, J=6 Hz, 1H), 4.25-4.44 (m, 3H), 6.93 (d, J=8 Hz, 1H), 7.13 (s, 1H), 7.17-7.23 (m, 2H), 7.29 (s, 1H), 7.35 (t, J=8 Hz, 1H), 7.42-7.48 (m, 1H); MS (DCI/NH3) m/z 399 (M+H)+.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12][C:11]=2[CH2:10]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[ClH:1].[N:15]1[C:16]2[CH2:17][CH2:18][NH:9][CH2:10][C:11]=2[CH:12]=[CH:13][C:14]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc2c(n1)CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc2c(n1)CCNC2
Temperature: 25 °C
Reaction time: 13 h
Yield: 112.8 %

Procedure:
The crude methyl 6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate hydrochloride (1.20 g, 3.76 mmol) was dissolved in MeOH (100 mL) and thoroughly degassed. Palladium hydroxide (0.185 g, 1.32 mmol) was added to the solution before being purged with H2 gas three times. The reaction was allowed to stir at rt for 13 h under 1 atm of H2 gas. The mixture was then filtered through a pad of Celite and rinsed with EtOH. The filtrate was then concentrated down to yield methyl 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate hydrochloride (0.97 g, 100%). LC-MS: (FA) ES+ 220; 1H NMR (Methanol-d4, 400 MHz) δ 8.05 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 4.52 (s, 2H), 3.98 (s, 3H), 3.66 (t, J=6.5 Hz, 2H), 3.33 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33]>>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[CH2:25][N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)(=[O:10])=[O:11]
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Product: COc1ccc(CN(Cc2cc(F)ccc2F)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)-benzoate (Example 5-10b) and 2-(bromomethyl)-1,4-difluorobenzene. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.66 (s, 3H), 4.31 (s, 2H), 4.33 (s, 2H), 6.74-7.06 (m, 7H), 7.95 (d, 2H, J=8 Hz), 8.09 (d, 2H, J=8 Hz).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1.[CH3:18][C:19]1([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)[CH2:21][O:20]1>CCCCCC.CN(C=O)C>[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[N:8]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][N:23]=3)([OH:20])[CH3:21])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC1(c2ccncn2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccncn2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
Sodium hydride (200 mg, 8.33 mmol) was washed with hexane and dried under vacuum. DMF (4 mL) was added, resulting in a suspension. 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (400 mg, 2 mmol) in 2 mL DMF was added dropwise and stirred for 30 min at RT. 4-(2-Methyl-oxiranyl)-pyrimidine (490 mg, 3.60 mmol) in 2 mL DMF was added dropwise and the reaction mixture was stirred overnight at RT. After the completion of reaction, the reaction mixture was quenched with ice-cold water and extracted three times with EtOAc. The combined organic layers were washed with water several times followed by brine, and then dried over sodium sulfate. The solvent was evaporated and the residue washed with hexane and crystallized from ether-DCM and hexane to obtain 350 mg of desired product. 1HNMR (CD3OD, Oxalate salt) d (ppm): 9.10 (s, 1H), 8.50 (d, 1H), 7.50 (d, 1H), 7.10 (s, 1H), 6.95 (d, 1H), 6.80 (d, 1H), 4.40 (m, 4H), 3.60 (m, 2H), 3.40 (m, 1H), 3.20 (m, 1H), 3.0 (s, 3H), 2.50 (s, 3H), 1.60 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:6]2=[N:7][CH:8]=[C:9]([NH2:11])[CH:10]=[C:5]2[CH:4]=1)[CH3:2].[F:13][C:14]1[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])=[CH:21][CH:20]=[C:19]([F:30])[C:15]=1[C:16](O)=[O:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([C:3]1[NH:12][C:6]2=[N:7][CH:8]=[C:9]([NH:11][C:16](=[O:17])[C:15]3[C:19]([F:30])=[CH:20][CH:21]=[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[C:14]=3[F:13])[CH:10]=[C:5]2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2cc(N)cnc2[nH]1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(CC)cc3c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
2-Ethyl-1H-pyrrolo[2,3-b]pyridin-5-amine (0.100 g, 0.62 mmol), 2,6-difluoro-3-(propylsulfonamido)benzoic acid (0.182 g, 0.65 mmol), EDCI (0.125 g, 0.65 mmol) and HOBt (0.084 g, 0.65 mmol) were dissolved in DMF (1.5 mL) and stirred at room temperature overnight. The solution was then directly purified by reverse phase HPLC to afford N-(2-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.061 g, 23% yield). 1H NMR (400 MHz, d6-DMSO) δ 11.46 (s, 1H), 10.75 (s, 1H), 9.79 (br s, 1H), 8.26-8.25 (m, 1H), 8.19-8.18 (m, 1H), 7.56-7.50 (m, 1H), 7.24 (t, 1H), 6.18-6.17 (m, 1H), 3.13-3.09 (m, 2H), 2.74 (q, 2H), 1.77 (sx, 2H), 1.28 (t, 3H), 0.99 (t, 3H); m/z (ES-MS) 423.2 (100.0%) [M+1].
Reaction SMILES: [CH:1]([O:8]CC)([O:5][CH2:6][CH3:7])OCC.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=O)#[N:12]>C(OC(=O)C)(=O)C>[C:11]([C:13](=[CH:14][O:16][CH2:17][CH3:18])[C:1]([O:5][CH2:6][CH3:7])=[O:8])#[N:12]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC#N
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C#N)C(=O)OCC
Temperature: 155 °C
Yield: 84.2 %

Procedure:
The mixture of triethyl orthoformate (33.3 mL, 0.2 mol) and ethyl cyanoacetate (21.3 mL, 0.2 mol) in acetic anhydride (80 mL) was heated at 150-160° C. for 5 h. After cooling to room temperature, the solvent was removed under reduced pressure to give ethyl 2-cyano-3-ethoxyacrylate as a yellow solid (28.5 g, 84%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39]>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:33](=[O:35])[C:32]3[CH:36]=[CH:37][C:29]([F:28])=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:31]=3)[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(F)c(C(F)(F)F)c3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 78 and 4-fluoro-3-trifluoromethylbenzoic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][C:16]#[C:17][CH3:18])[C:3]1=2.N12CCCN=C1CCCCC2.[CH3:30][N:31]=[C:32]=[O:33]>C(Cl)Cl>[CH3:30][NH:31][C:32](=[O:33])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:2]([CH3:1])[C:3]3[C:14](=[N:15][C:16]#[C:17][CH3:18])[CH2:13][CH2:12][C:4]=3[C:5]=2[CH:6]=1
Reactant: CN=C=O
Reactant: CC#CN=C1CCc2c1n(C)c1ccc(O)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC#CN=C1CCc2c1n(C)c1ccc(OC(=O)NC)cc21
Reaction time: 1 h
Yield: 29 %

Procedure:
To a stirred solution of 4-methyl-3-propynylimino-1,2,3,4-tetrahydrocyclopent[b]indol7-ol (3.4 g) in CH2Cl2 (15.0 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (326 mg) followed by the dropwise addition of methyl isocyanate (0.8 g) in CH2Cl2 (5.0 ml). The reaction was monitored via TLC and after 1.0 hour, the solution was concentrated and the crude product was purified via flash chromatography eluting with hexane/acetone (2:1). The product which precipitated out of the pure fractions was collected to give 4-methyl-3-propynylimino-1,2,3,4-tetrahydrocyclopent[b]indol7-yl methylcarbamate (1.2 grams) and the fractions were concentrated to give an additional 0.9 gram.