Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]=[C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[C:12]([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)[N:13]3[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:6]([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[N:5]1)[CH3:3].[CH2:44]([NH:46][CH2:47][CH2:48][OH:49])[CH3:45]>>[CH2:44]([N:46]([CH2:31][C:30]1[CH:29]=[CH:28][C:27]([C:12]2[N:13]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:19])=[O:20])[C:14]3[C:10]([CH:11]=2)=[C:9]([C:7]2[C:6]([C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[N:5][N:4]([CH:2]([CH3:3])[CH3:1])[CH:8]=2)[CH:17]=[CH:16][CH:15]=3)=[CH:34][CH:33]=1)[CH2:47][CH2:48][OH:49])[CH3:45]
Reactant: CC(C)n1cc(-c2cccc3c2cc(-c2ccc(C=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CCNCCO
Product: CCN(CCO)Cc1ccc(-c2cc3c(-c4cn(C(C)C)nc4-c4ccc([N+](=O)[O-])cc4)cccc3n2S(=O)(=O)c2ccccc2)cc1

Procedure:
Following the procedure described for Intermediate 101 using 4-[4-[1-(1-methylethyl)-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-indol-2-yl]benzaldehyde and 2-(ethylamino)ethanol (18.8 mmol) provided the title compound. ESMS [M+H]+: 665.4.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)#[N:15].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[CH:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][C:19]2[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)=[CH:3][CH:4]=1)=[O:13]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Oc2ccc(C=O)c3ccccc23)cc1

Procedure:
To a solution of 4-hydroxy-1-napthaldehyde (172 mg, 1.0 mmol) in DCM (10 mL) was added copper (II) diacetate (181 mg, 1.0 mmol), 4-cyanophenyl boronic acid (441 mg, 3.0 mmol), triethylamine (0.7 mL, 5.0 mmol) and 4 Å molecular sieves. After 48 h at rt the mixture was filtered. Solvent was removed in vacuo and the residue purified by column chromatography (EtOAc:isohexane 3:7). The resulting solid was washed with ether (10 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound: δH (CDCl3) 7.06 (1H, d), 7.21 (2H, d), 7.49 (1H, t), 7.62-7.82 (3H, m), 7.96 (1H, d), 8.28 (1H, d), 9.36 (1H, d), 10.33 (1H, s).
Reaction SMILES: COS(O)(=O)=O.[CH2:7]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[NH:14])[CH2:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].C([O:28][CH:29]=[C:30]([C:36](OCC)=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32])C.C(O)(=O)C>C(O)C>[O:28]=[C:29]1[NH:15][C:13]([C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[O:10][CH2:7][CH2:8][CH3:9])=[N:14][CH:36]=[C:30]1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCCOc1ccccc1C(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: COS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 17 h
Yield: 85 %

Procedure:
A mixture of 2;l -n-propoxybenzamidine methyl sulfate (7.4 g., 0.0255 mole), potassium carbonate (3.53 g., 0.025 mole), and diethyl ethoxymethylenemalonate (5.99 g., 0.0277 mole) in ethanol (80 ml.) was heated under reflux with stirring for 17 hours. The cooled mixture was added to ice-water (160 ml.) which was then acidified with glacial acetic acid. The precipitate was collected by filtration, washed with water, and dried to give the title compound (6.55 g., 89%), m.p. 106°-107°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]>CO.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)c(F)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(O)CCc1ccc(C(F)(F)F)c(F)c1
Reaction time: 4 h
Yield: 81.4 %

Procedure:
10% NIX was added to a stirred solution of 3-(3-fluoro-4-(trifluoromethyl)phenyl)-acrylic acid (I-77a: 5.5 g, 0.0234 mol) in methanol. The resulting mixture was stirred under hydrogen atmosphere for 4 hours. The reaction was monitored by TLC (5% methanol in CHCl3). The catalyst was filtered through celite bed and the solvent distilled under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 4.5 g of the product (81.8% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([CH2:28][O:29][CH3:30])[N:20]=2)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:24])=[C:21]([CH2:28][O:29][CH3:30])[N:20]=2)=[CH:15][CH:14]=1
Reactant: COCc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Reactant: Nc1ccc2cccnc2c1
Product: COCc1nc(-c2ccc(F)cc2)ccc1C(=O)Nc1ccc2cccnc2c1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (11 mg, 0.076 mmol) and 6-(4-fluorophenyl)-2-(methoxymethyl)-nicotinic acid (D86) (19 mg, 0.073 mmol) as an orange solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 10.40 (br.s, 1H), 8.92 (dd, 1H), 8.41 (d, 1H), 8.29 (d, 1H), 8.05-8.20 (m, 4H), 7.85 (m, 2H), 7.36 (dd, 1H), 7.20 (t, 2H), 4.91 (s, 2H), 3.68 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:17][CH:16]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH:19]=4)[CH2:14][CH2:13]3)[C:6]=2[CH:27]=1.[CH3:28]CCCCC.CI>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]([CH3:28])[CH:19]=4)[CH2:16][CH2:17]3)[C:6]=2[CH:27]=1
Reactant: CCCCCC
Reactant: Clc1ccc2scc(CCN3CC=C(c4c[nH]c5ccccc45)CC3)c2c1
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cc(C2=CCN(CCc3csc4ccc(Cl)cc34)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (392 mg, 1 mmol) (obtained from example 32, step 2) in dry THF (50 ml) was slowly added to a stirred suspension of hexane washed 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 30 min and methyl iodide (213 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Brown semi-solid. Yield: 150 mg (36%); 407 (M+H); 1H NMR: δ 7.91(1H, m), 7.78(3H,m), 7.26(6H, m), 6.21(1H, s), 3.77(3H,s), 3.40(2H, s), 3.15(2H, m), 2.92(4H, m), 2.68(2H, s).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([SH:12])=[N:6][C:5]=2[NH:4][CH:3]=1.[OH-].[Na+].[F:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1>CO.COCCOC>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26][S:12][C:7]3[NH:8][C:9](=[O:11])[C:10]4[C:2]([CH3:1])=[CH:3][NH:4][C:5]=4[N:6]=3)=[CH:24][CH:23]=2)=[O:21])=[CH:30][CH:31]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: Cc1c[nH]c2nc(S)[nH]c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Product: Cc1c[nH]c2nc(SCc3ccc(C(=O)c4ccc(F)cc4)cc3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
In methanol (25 ml) was suspended 5-methyl-2-mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.82 g) followed by addition of 1N-sodium hydroxide (10.5 ml) for dissolution. Then, under ice-cooling, a solution of 4-(4-fluorobenzoyl)benzyl bromide (3.51 g) in DME (10 ml) was added dropwise. The mixture was stirred at room temperature for 4 hours and the resulting crystalline precipitate was collected by filtration and rinsed with water. The crystals were further rinsed with 50% ethanol/water, methanol and ether serially, dried, and recrystallized from DME (1,2-dimethoxyethane) to provide the title compound (2.71 g). 1H-NMR (DMSO-d6) δ: 2.24(3H,s), 4.51(2H,s), 6.65(1H,s), 7.37(2H,t,J=8.8Hz), 7.64(2H,d,J=8.8Hz), 7.70(2H,d,J=8.8Hz), 7.81(2H,dd,J=5.6,8.8Hz), 11.43(1H,s), 11.97(1H,s).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:36])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:21]=[C:20]([CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)[O:19][N:18]=3)[CH:15]=2)[N:10]([C:32](=[O:34])[CH3:33])[C@@H:9]([CH3:35])[CH2:8]1)[CH3:3].[ClH:37].CCOCC>O1CCOCC1>[ClH:37].[C:32]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[N:21]=[C:20]([CH2:22][CH2:23][NH2:24])[O:19][N:18]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:36])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:35])(=[O:34])[CH3:33]
Reactant: CC(=O)N1c2ccc(-c3noc(CCNC(=O)OC(C)(C)C)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3noc(CCN)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
A solution of 1-methylethyl((2S,4R)-1-acetyl-6-{5-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1,2,4-oxadiazol-3-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation, see Intermediate 76) (260 mg, 0.518 mmol) in 1,4-Dioxane (1 mL) was treated with HCl (4N in 1,4-dioxane, 1.00 mL, 4 mmol) and the resulting mixture was stirred at room temperature for 16 h. Et2O (10 mL) was then added and the precipitate formed was triturated then filtered off to give 1-methylethyl {(2S,4R)-1-acetyl-6-[5-(2-aminoethyl)-1,2,4-oxadiazol-3-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate hydrochloride (195 mg, 0.446 mmol, 86%) as an off white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:22]=O)=[CH:4][N:5]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:24][NH2:25].[BH4-].[Na+].CO>O1CCCC1>[F:1][C:2]1[C:3]([CH2:22][NH:25][CH3:24])=[CH:4][N:5]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN
Reactant: O=Cc1cn(S(=O)(=O)c2cccnc2)c(-c2ccccc2)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1cn(S(=O)(=O)c2cccnc2)c(-c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
4-Fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0.27 g) was dissolved in tetrahydrofuran (10 mL), a 2 mol/L solution (0.8 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 2 hr. Sodium borohydride (91 mg) and methanol (7 mL) were added, and the mixture was stirred at the same temperature for further 30 min. The reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane-ethyl acetate=19:1→0:1). The above-mentioned operation was repeated to give the title compound (0.22 g, yield 39%) as a colorless solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][C@@H:21]([CH3:25])[NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:26][O:27][CH2:28][CH2:29]Br.[H-].[Na+]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][C@@H:21]([CH3:25])[N:22]([CH2:29][CH2:28][O:27][CH3:26])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3C[C@@H](C)NC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: COCCN1C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3n2C[C@H]1C
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-3-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 14), 2-bromoethyl methyl ether and sodium hydride, to give the desired product as a colorless oil (49%).
Reaction SMILES: CP(C)C.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[I:23]C.O[CH2:26][CH:27]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C1COCC1>[I:23][CH2:26][CH:27]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCC(CO)NC(=O)OC(C)(C)C
Reactant: CI
Agent: CP(C)C
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCCCCCCCC(CI)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
Trimethylphosphine (1.0M, 1.33 mmol) was added dropwise to a stirred solution of (azodicarbonyl)dipiperidine [ADDP] (336 mg, 1.33 mmol) in abs. THF (25 ml) at 0° C. After 30 minutes, iodomethane (189 mg, 1.33 mmol) and tert-butyl N-[1-(R/S)-(hydroxy-methyl)undecyl]carbamate 46 (200 mg, 0.664 mmol) were added to the solution, which was subsequently stirred for 4 hours at room temperature. The precipitate was then filtered off and the solution evaporated to dryness. The residue was dissolved in ethyl acetate and the remaining hydrazide was precipitated from hexane and removed by filtration. Following evaporation, the residue was taken up in CH2Cl2 (50 ml), washed with water (2×25 ml) and with NaHCO3 (sat, aq) (1×25 ml), dried with MgSO4, filtered and evaporated. The residue was purified by column chromatography in hexane:ethyl acetate 4:1 (v/v) to give 62 (176 mg, 64%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[S:10])[NH2:9].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])=O>C1COCC1>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[S:10][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[N:9]=1
Reactant: COc1ccccc1C(=O)CBr
Reactant: COC(=O)CCCCC(N)=S
Solvent: C1CCOC1
Product: COC(=O)CCCCc1nc(-c2ccccc2OC)cs1
Temperature: 80 °C
Yield: 142.4 %

Procedure:
Add THF (125 mL, anhydrous) to a sealed vessel containing 5-thiocarbamoyl-pentanoic acid methyl ester (7.25 g, 41.4 mmol) and 2-bromo-2′-methoxyacetophenone (9.48 g, 41.4 mmol). Flush vessel with N2, seal, and heat at 80° C. overnight. Cool to room temperature, add EtOAc, wash with saturated aqueous NaHCO3 solution, brine, and backextract from each aqueous layer with EtOAc. Dry combined organic layers over MgSO4 and concentrate to get 18 grams of purple residue. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes to afford the title compound (9.7 g, 77%). TLC (30% EtOAc/hexanes) Rf=0.38. MS (IS) 306 (M+1)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1)[CH3:2].OS(O)(=O)=O.[CH3:18]O>>[CH2:1]([NH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:18])=[O:9])=[CH:6][N:5]=1)[CH3:2]
Reactant: CO
Reactant: CCNc1ccc(C(=O)O)cn1
Agent: O=S(=O)(O)O
Product: CCNc1ccc(C(=O)OC)cn1
Yield: 84 %

Procedure:
A suspension of 6-(ethylamino)nicotinic acid (50 g, 0.3 mol) in methanol (500 ml) was treated with concentrated H2SO4 (30 ml). The reaction was heated at reflux for 18 hours. The reaction mixture was then evaporated, poured into ice water (1 L) and adjusted to pH 8 with solid sodium hydrogen carbonate (foaming). The aqueous mixture was extracted with ethyl acetate (3×300 ml) and the organic layers combined, dried (MgSO4) and evaporated to give methyl 6-(ethylamino)nicotinoate as an off-white solid (45.5 g, 84%).
Reaction SMILES: C(O[C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)C.Cl.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([C:30]2[NH:34][N:33]=[N:32][N:31]=2)[CH:24]=1.C(N(CC)CC)C>C(#N)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:4]2[C:5](=[O:20])[C:6](=[O:19])[C:7]=2[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)=[C:25]([C:30]2[NH:34][N:33]=[N:32][N:31]=2)[CH:24]=1
Reactant: CCOc1c(Nc2cccc(C(F)(F)F)c2)c(=O)c1=O
Reactant: Nc1ccc(Br)cc1-c1nnn[nH]1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1c(Nc2cccc(C(F)(F)F)c2)c(Nc2ccc(Br)cc2-c2nnn[nH]2)c1=O

Procedure:
0.29 g of 3-ethoxy-4-(3-trifluoromethylphenylamino)-3-cyclobuten-1,2-dione in 25 mL of acetonitrile was added 0.28 g of 4-bromo-2-(1H-tetrazol-5-yl)-phenylamine hydrochloride and 0.1 g of triethylamine. The reaction mixture was heated at reflux for 62 hours, the reaction mixture was concentrated to an oil, the oil was dissolved in ethyl alcohol (96%), to this solution was added hydrochloric acid (4M) and a solid precipitated. The product was isolated by filtration, washed with water and dried by pulling air though it on a glass filter. Yield 0.26 g (56%) mp. 150-165° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.[CH2:31](NN)C>>[CH2:1]([N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1)[CH3:31]
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: CCNN
Product: CCn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting ethyl hydrazine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.35 (bs, 2H), 8.19 (d, J=8.3 Hz, 1 H), 8.07 (d, J=9.1 Hz, 1 H), 7.82 (d, J=7.9 Hz, 1H), 7.73 (t, J=8.3 Hz, 1H), 7.67 (d, J=8.3 Hz, 2 H), 7.62 (s, 1H), 7.55 (t, J=7.9 Hz, 1 H), 7.37 (d, J=9.1 Hz, 2H), 7.21 (bs, 2 H), 7.01 (d, J=8.7 Hz, 2H) 5.39 (s, 2H), 4.24 (q, J=7.5 Hz, 2H), 1.56 (t, J=7.5 Hz, 3H); MS: (M+H m/z=407.3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[CH3:11])=[CH:6][C:5]=1[NH2:14].[I:16]I>CCO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([I:16])[C:7]([C:10]([F:12])([F:13])[CH3:11])=[CH:6][C:5]=1[NH2:14]
Reactant: COC(=O)c1ccc(C(C)(F)F)cc1N
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1cc(I)c(C(C)(F)F)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A mixture of 2-amino-4-(1,1-difluoro-ethyl)-benzoic acid methyl ester (1.3 g, 6.04 mmol), I2 (1.53 g, 6.03 mmol) and Ag2SO4 (1.89 g, 6.03 mmol) in EtOH (40 mL) was stirred for 1 h at r.t. The suspension was then filtered and the filtrate diluted with EtOAc and washed once with a 10% aqueous Na2SO3. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 2-amino-4-(1,1-difluoro-ethyl)-5-iodo-benzoic acid methyl ester (1.98 g, 5.8 mmol, 96%) as a brown solid, ESI-MS: m/z 383 [M+CH3CN+H]+. rt 6.71 min
Reaction SMILES: C(N[C:6]1[C:11]2[C:12]([CH3:21])=[N:13][C:14]3[N:18]([CH2:19][CH3:20])[N:17]=[CH:16][C:15]=3[C:10]=2[N:9]2[N:22]=[C:23]([CH3:25])[CH:24]=[C:8]2[N:7]=1)CCC.[CH2:26]([CH2:28][NH2:29])[OH:27].CN(C)CCCO>>[NH2:29][CH2:28][CH2:26][O:27][C:6]1[C:11]2[C:12]([CH3:21])=[N:13][C:14]3[N:18]([CH2:19][CH3:20])[N:17]=[CH:16][C:15]=3[C:10]=2[N:9]2[N:22]=[C:23]([CH3:25])[CH:24]=[C:8]2[N:7]=1
Reactant: NCCO
Reactant: CCCCNc1nc2cc(C)nn2c2c1c(C)nc1c2cnn1CC
Agent: CN(C)CCCO
Product: CCn1ncc2c1nc(C)c1c(OCCN)nc3cc(C)nn3c12

Procedure:
By substituting the 5-chloro-2,6-dimethyl-8-ethyl-8H pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine obtained in Example 37 in the procedure of Example 21 and substituting ethanolamine for the 3-(dimethylamino)propanol, 5-(2-aminoethoxy)-2,6-dimethyl-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine is obtained.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1)[CH3:2].[Cl:10]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:10][C:4]1[CH:5]=[C:6]([CH:8]=[O:9])[S:7][C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1ccc(C=O)s1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1sc(C=O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of 5-ethyl-2-thiophenecarboxaldehyde (6.0 g) in N,N-dimethylformamide (60 ml) was added N-chlorosuccinimide (8.57 g), and the mixture was stirred at room temperature for 2 hours, and subsequently stirred under heating at 60° C. for 2 hours. N-chlorosuccinimide (4.00 g) was further added thereto, and the mixture was further stirred under heating at 60° C. for 2 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=33:1) to give 4-chloro-5-ethyl-2-thiophenecarboxaldehyde (3.1 g) as colorless oil. (2) The above 4-chloro-5-ethyl-2-thiophenecarboxaldehyde was treated in a manner similar to Reference Example 1 to give 3-bromo-1-(4-chloro-5-ethyl-2-thienylmethyl)benzene as yellow oil. APCI-Mass m/Z 347/349 (M+H+MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([CH2:21]Cl)[CH:18]=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[O:9][C:10]=1[CH3:11].[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([OH:40])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([O:40][CH2:21][C:19]2[CH:18]=[CH:17][C:3]([O:4][CH2:5][C:6]3[N:7]=[C:8]([C:12]4[O:13][CH:14]=[CH:15][CH:16]=4)[O:9][C:10]=3[CH3:11])=[C:2]([Cl:1])[CH:20]=2)=[N:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cc1Cl
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(Cl)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of 4-(2-chloro-4-chloromethylphenoxy)methyl-2-(2-furyl)-5-methyl-1,3-oxazole (2.00 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.45 g), potassium carbonate (0.82 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 1-benzyl-3-[(3-chloro-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (3.09 g, yield 96%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 153-154° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10](=O)[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:16].S(=O)(=O)(O)O>>[Cl:16][C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cnc(-c2ccccc2)c[nH]1
Agent: O=S(=O)(O)O
Product: Clc1cnc(-c2ccccc2)cn1

Procedure:
A mixture of 0.01 mol. of 5-phenylpyrazin-2(1H)one 8.0 ml. of POCl3 and a drop of concentrated sulfuric acid is refluxed for 4-5 hr. The solution is poured into 100 g. of ice. The title compound is isolated by filtration and recrystallized.