Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH2:11][N:10]([CH2:23][CH2:24][C:25](=[N:27][OH:28])[NH2:26])[C:9]2=[O:29])=[CH:4][CH:3]=1.[CH:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH2:11][N:10]([CH2:23][CH2:24][C:25](=[N:27][O:28][C:36]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:37])[NH2:26])[C:9]2=[O:29])=[CH:4][CH:3]=1
Reactant: NC(CCN1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Cl)cc2)C1=O)=NO
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(CCN1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Cl)cc2)C1=O)=NOC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-3-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)-N′-hydroxypropanimidamide (28.7 mg, 0.067 mmol) is dissolved in dichloromethane (2 mL). Cyclohexanecarbonyl chloride (14.8 mg, 0.10 mmol) and diisopropyl ethylamine (26.3 mg, 0.20 mmol) are then added. The reaction is stirred for 3 h at room temperature. The reaction is diluted with ethyl acetate followed by quenching with sat. sodium bicarbonate solution. The organic layer is washed with brine and dried with MgSO4. The solvents is removed under vacuum to afford crude (S)-3-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N′-(cyclohexanecarbonyloxy)propanimidamide which is used directly in the next step without further purification. HPLC-MS calculated for C26H29ClF3N4O3 (M+H+) 537.1, found 537.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([SH:23])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1>CC(C)=O>[C:43]([O:42][C:40]([N:37]1[CH2:38][CH2:39][CH:34]([CH2:33][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:24][CH3:25])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)[CH2:35][CH2:36]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)(C)c2cnc(SCC3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 4 h
Yield: 90 %

Procedure:
To a suspension of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (0.557 g, 1.48 mmol) and K2CO3 (0.306 g, 2.22 mmol) in acetone (4 mL) was added tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (0.431 g, 1.55 mmol). The reaction was heated at reflux. After 4 h, the reaction was concentrated and purified by column chromatography using Hex:EtOAc as eluents to afford the title compound (0.765 g) as a white solid. MS (EI) m/z 574 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][N:37]([C:45]([CH3:49])([CH3:48])[CH:46]=O)[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41].N1CCCCC1>O1CCOCC1.CC(O)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:49][C:45]([N:37]([CH3:36])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:46])[CH3:48])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CN(C(=O)OC(C)(C)C)C(C)(C)C=O
Solvent: C1CCNCC1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CN(C(=O)OC(C)(C)C)C(C)(C)C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 110 °C
Reaction time: 6 h
Yield: 18.3 %

Procedure:
To a solution of 3-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (236 mg, 0.5 mmol, 1 equiv) and tert-butyl methyl(2-methyl-1-oxopropan-2-yl)carbamate (2.01 g, 10 mmol, 20 equiv) in dioxane (30 mL) was added 0.5 mL piperidine, 1 drop AcOH and 2 g of 4A molecular sieves. The resulting mixture was stirred for 6 h at 110° C. The solids was filtered out, the filtrate was diluted with 50 mL of EA, washed with brine, dried over Na2SO4, concentrated. The residue was purified on silica gel column (EA to EA/MeOH 10/1) to give 60 mg of tert-butyl 5-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl(methyl)carbamate as white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]([NH:18][OH:19])=[NH:17])[N:3]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[O:19][N:18]=[C:16]([C:4]2[N:5]=[C:6]([N:8]([CH3:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:7]=[C:2]([NH2:1])[N:3]=2)[N:17]=1
Reactant: O=C(Cl)c1ccco1
Reactant: CN(c1ccccc1)c1nc(N)nc(C(=N)NO)n1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccco3)n2)n1

Procedure:
To a suspension of 4-amino-N-hydroxy-6-(methyl-phenyl-amino)-[1,3,5]triazine-2-carboxamidine (Intermediate 1, 95 mg, 0.37 mmol) in anhydrous toluene (3 mL) and anhydrous pyridine (1 mL) was added 2-furoyl chloride (53 mg, 0.41 mmol) in a solution of anhydrous toluene (3 mL) at 0 C in a sealed tube under an atmosphere of nitrogen.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>CN1CCCC1=O.CCOCC>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10]([N:26]3[CH2:25][CH2:24][NH:23][CH:22]([CH3:21])[CH2:27]3)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(N3CCNC(C)C3)c(F)c21
Reaction time: 18 h

Procedure:
A 289 mg portion of 1-ethyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was dissolved in 3 ml of 1-methyl-2-pyrrolidone. A 390 mg portion of 2-methyl piperazine was added, the mixture was stirred for 18 hours and then diluted with ether. The solid was collected, washed with hexane, dried and recrystallized from dichloromethane-acetone, giving 240 mg of solid. This solid was purified by chromatography, eluting with a gradient of chloroform-methanol-water and then a gradient of chloroform-methanol-water-acetic acid. The active fractions were combined and partitioned between dilute sodium bicarbonate and dichloromethane. The organic layer was dried and evaporated. The solid was recrystallized from dichloromethane-hexane, giving 100 mg of the desired product as off-white crystals, mp 220°-222° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6]1.I[CH2:16][CH3:17]>CN(C=O)C>[CH2:16]([O:3][CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6]1)[CH3:17]
Reactant: CCI
Reactant: CCOC(=O)C1=NOC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC1CC(C(=O)OCC)=NO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
Sodium hydride (0.141 g; 3.51 mmol) was added to a solution of ethyl 5-(hydroxymethyl)-4,5-dihydroisoxazole-3-carboxylate (0.338 g; 1.76 mmol) in DMF (3 mL) in an ice bath. The mixture was stirred for 10 min before addition of iodoethane (0.430 mL; 5.27 mmol). The ice bath was removed and the mixture was stirred at room temperature for 2 h. After evaporation, the residue was partitioned between brine and dichloromethane and the solution extracted with dichloromethane. Organic extracts were evaporated and the residue was purified by flash chromatography on silica gel (eluent: 1-6% ethyl acetate in dichloromethane) to afford 0.142 g (40%) of ethyl 5-(ethoxymethyl)-4,5-dihydroisoxazole-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][N:8]=[C:7]2O.P(Cl)(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][N:8]=[C:7]2[Cl:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c(Br)cccc12
Product: Clc1ncnc2c(Br)cccc12
Reaction time: 0.08 h
Yield: 99.6 %

Procedure:
A suspension of 8-bromoquinazolin-4-ol (410 mg, 1.822 mmol) in phosphorous oxychloride (15.000 mL, 161 mmol) was heated to reflux. After refluxing 45 min, a clear, amber solution was observed. Refluxed an additional 30 min, concentrated in-vacuo, and concentrated 2× from methylene chloride to remove residual phosphorous oxychloride. The residue was taken up in ethyl acetate (50 mL), treated with the careful addition of saturated sodium bicarbonate, and this mixture was stirred for 5 minutes, until gas evolution had ceased. The layers were separated, the and the aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phases were washed with saturated sodium bicarbonate, water, and saturated sodium chloride, dried over sodium sulfate, and concentrated in-vacuo to yield the title compound (442 mg, 1.815 mmol, 100% yield) as a tan powder which was used as-is in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:14]([O-])=O)=[C:4]([NH:9][C:10](=[O:13])[O:11][CH3:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>O.CO.C1COCC1>[NH2:14][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[NH:9][C:10](=[O:13])[O:11][CH3:12]
Reactant: COC(=O)Nc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Nc1cc(Cl)cc(Cl)c1N
Yield: 42.5 %

Procedure:
Methyl (3,5-dichloro-2-nitrophenyl)carbamate (79 mg, 0.3 mmol) prepared in Step 1 was added with THF (1.5 mL, 0.2 M), followed by stirring. In a separate vial, sodium hydrosulfite (603 mg, 2.7 mmol, 9.0 eq) and sodium bicarbonate (227 mg, 2.7 mmol, 9.0 eq) were dissolved in H2O (3 mL, 0.1 M), and the solution thus obtained was added to a solution of methyl (3,5-dichloro-2-nitrophenyl)carbamate. MeOH (0.5 mL) was added to the solution, and the mixture was subjected to a reaction at room temperature for 2 hours. Upon completion of the reaction, THF and MeOH were removed by distillation under reduced pressure, and the residue thus obtained was extracted with ethyl acetate (30 mL x 2), dried over MgSO4, and concentrated under reduced pressure. Subsequently, the residue was purified by silica gel column chromatography (EtOAc/Hex=1:4) to obtain the title compound (30 mg, yield: 43%).
Reaction SMILES: [I:1][C:2]1[NH:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[C:3]=1[CH2:4][CH2:5][NH2:6].[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1.CC1NC2C=CC(OC)=CC=2C=1CCNC(C)=O>C1COCC1>[I:1][C:2]1[NH:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[C:3]=1[CH2:4][CH2:5][NH:6][C:19]([CH:16]1[CH2:18][CH2:17]1)=[O:20]
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc2[nH]c(I)c(CCN)c2c1
Agent: COc1ccc2[nH]c(C)c(CCNC(C)=O)c2c1
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(I)c(CCNC(=O)C3CC3)c2c1

Procedure:
A solution of 2-iodo-5-methoxytryptamine (0.316 g, 1 mmol), in THF (3 mL) and TEA (0.14 mL) was acylated with cyclopropanecarbonyl chloride (0.09 mL) at room temperature for 1.5 h using the procedure described for 4a. The desired product 4m was obtained as amorphous solid (0.34 g, 89% yield), IR νmax :3450, 3300, 1650. 1H NMR: 0.71(m, 2H, CH2cyclopropyl), 0.96(m, 2H, CH2cyclopropyl), 1.21(m, 1H, cyclopropyl-CH), 2.90(t, 2H, β -CH2), 3.55(q, 2H, α-CH2), 3.85(s, 3H, OCH3), 5.62(br s, 1H, NH), 6.78-7.27(m, 3Harom), 8.21(br s, 1H, NHindole).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.C[NH:17][C:18](=[NH:20])S.[OH-].[Na+]>O>[C:18]([NH:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[NH:17])[NH2:20]
Reactant: CNC(=N)S
Reactant: NNC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N=C(N)NNC(=O)c1ccccc1
Yield: 61.4 %

Procedure:
A solution of benzoic acid hydrazide (10.3 g), methylisothiourea sulfate (21.0 g), sodium hydroxide (3.12 g) and water (150 ml) was stirred for 99 hours at room temperature. The resulting solid was collected by filtration and washed with water to give 8.28 g of a white solid (yield 61%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[NH2:7][C:8]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30].Cl>O.O1CCOCC1>[Cl:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([NH:7][S:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([C:29]([F:32])([F:30])[F:31])[CH:21]=2)(=[O:27])=[O:26])[CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Yield: 64.6 %

Procedure:
To a solution of Na2CO3 (11.7 g, 110.7 mmol) in water (50 mL) and 1,4-dioxane (50 mL) at 60° C. was added 2-amino-4-chloro-benzoic acid (5.0 g, 29.14 mmol) followed by 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (20.15 g, 72.48 mmol) in 3 portions and heated the resulting reaction mixture at 80° C. for 4 hours. 2N HCl Was added until the reaction mixture became acidic (pH=˜2) and obtained white solid was filtered, washed with water, dried under high vacuum to obtain title compound (7.8 g) in 65% yield. MS (ES) M+Na expected 436.0, found 435.8.
Reaction SMILES: [CH3:1][CH:2](CC)[O-].[CH3:6][CH:7](CC)[O-].[CH3:11][CH:12](CC)[O-].[Al+3:16].C([O:19][C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23])C>CCCCCCC>[CH2:1]([CH2:24][C:22](=[O:23])[CH2:21][C:20]([O-:19])=[O:25])[CH3:2].[CH2:6]([CH2:24][C:22](=[O:23])[CH2:21][C:20]([O-:19])=[O:25])[CH3:7].[CH2:11]([CH2:24][C:22](=[O:23])[CH2:21][C:20]([O-:19])=[O:25])[CH3:12].[Al+3:16]
Reactant: CCC(C)[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: [Al+3]
Solvent: CCCCCCC
Product: CCCC(=O)CC(=O)[O-]
Yield: 99.2 %

Procedure:
To a flask containing 50.02 g of a mixture of heptane isomers was added 31.0 g (0.125 mol) of aluminium tris(sec-butoxide). To this was added with stirring, 48.37 g (0.376 mol) of ethylacetoacetate. After stirring the liquor was transferred to a rotary evaporator flask and the volatile sec-butanol and heptanes (78.66 g) were removed under vacuum leaving aluminium tris(ethylacetoacetate) (51.23 g, 0.124 mol).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:23](=[O:24])[N:22]([CH3:25])[C:14]3[N:15]=[C:16](S(C)=O)[N:17]=[CH:18][C:13]=3[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2.Cl[C:37]1C=CC(N)=CC=1>>[NH:32]1[C:33]2[C:29](=[CH:28][C:27]([NH:26][C:16]3[N:17]=[CH:18][C:13]4[CH:12]=[C:11]([S:8]([C:5]5[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=5)(=[O:10])=[O:9])[C:23](=[O:24])[N:22]([CH2:25][CH3:37])[C:14]=4[N:15]=3)=[CH:35][CH:34]=2)[CH:30]=[CH:31]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cn1c(=O)c(S(=O)(=O)c2ccc(Cl)cc2)cc2cnc(S(C)=O)nc21
Product: CCn1c(=O)c(S(=O)(=O)c2ccccc2)cc2cnc(Nc3ccc4[nH]ccc4c3)nc21

Procedure:
The title compound was prepared according to the procedure of Example 3, substituting 8-ethyl-2-(methylsulfinyl)-6-(phenylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one for 6-(4-chlorophenylsulfonyl)-8-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one, and 5-aminoindole for 4-chloroaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH3:21])[C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[O:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])=[CH:4][C:3]=1[C:24]1[CH:25]=[N:26][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:29]=1[C:30]#[N:31].[CH:36]1([O:42][C:43](=[O:48])[O:44][CH:45](Cl)[CH3:46])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(N(CC)CC)C.[Na+].[I-]>CN(C=O)C.C(OCC)(=O)C>[CH:36]1([O:42][C:43]([O:44][CH:45]([O:15][C:14](=[O:16])[CH2:13][CH2:12][O:11][C:10]2[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=2[N:8]([C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([Cl:1])=[C:3]([C:24]3[CH:25]=[N:26][C:27]([C:32]([F:35])([F:33])[F:34])=[CH:28][C:29]=3[C:30]#[N:31])[CH:4]=2)[CH3:21])[CH3:46])=[O:48])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)O
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(OC(=O)CCOc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)OC(=O)OC1CCCCC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of 3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid 11-4 (500 mg, 0.95 mmol), carbonic acid 1-chloroethyl cyclohexyl ester (393 mg, 1.9 mmol), triethylamine (399 μL, 2.85 mmol), and NaI (142.5 mg, 0.95 mmol) in DMF (5 mL) were stirred at 60° C. for 1 day. Ethyl acetate was added and the mixture was washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified via silica gel flash column chromatography eluting with 20% ethyl acetate in hexane to afford 3-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid 1-cyclohexyloxycarbonyloxy-ethyl ester 37-1. MS [M+H]+: 674.2; tR=35.7 min (method 5).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:28](OCC)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al].[Li]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:28][OH:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccccc1
Agent: [Al]
Agent: [Li]
Product: OCc1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from ethyl 1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indole-2-Carboxylate (step 3 of Example 1) and lithium aluminum in substantially the same manner, as described in step 1 of Example 21. The product was obtained as a white solid, mp: 108–109° C. Mass spectrum (ESI, [M+H]+) m/z 398. 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.76 (d, 2H, J=8.86 Hz), 7.42–7.36 (m, 4H) 7.29 (d, 1H, J=7.03 Hz), 7.27 (d, 1H, J=7.63 Hz), 7.23–7.20 (m, 1H), 7.06 (d, 2H, J=7.03 Hz), 6.52 (s, 1H), 5.50 (s, 2H), 5.36 (t, 1H), and 4.60 ppm (d, 2H).
Reaction SMILES: [CH2:1]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[N:15]([O-])=O.[Na+].[OH-].[Na+].[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[OH:27][C:21]1[CH:26]=[CH:25][C:24]([N:15]=[N:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:13][CH:12]=2)=[CH:23][CH:22]=1
Reactant: CCCCCCc1ccc(N)cc1
Reactant: O=N[O-]
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCc1ccc(N=Nc2ccc(O)cc2)cc1
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
30.1 g (0.17 M) of 4-hexylaniline was cooled to 0° C. or below, 85 g of 10% aqueous hydrochloric acid solution was added, and then a solution of 11.6 g of sodium nitrite in 68 g of water was added. During the addition, the mixture was cooled so as not to exceed 0° C. After the addition, the mixture was allowed to react for 30 minutes, transferred into a dropping funnel and added dropwise into 170 g of an 8% NaOH aqueous solution containing 16 g of phenol held at 5° C. or below. After the addition, the mixture was stirred for 0.5 hour, and then 10% hydrochloric acid aqueous solution was added thereto until a pH of 5-6 to precipitate the reaction product. The precipitate was separated by filtration, washed with water and dried overnight under reduced pressure. After the drying, the product was washed with 500 ml of petroleum ether and further dried under reduced pressure to obtain 29.6 g (0.10 M) of 4-hydroxy-4'-hexylazobenzene. The yield was 59%.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Br:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Br:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: Clc1cc(Br)cc2c1NCC2
Reactant: CC[C@H](COC)n1cc(Br)nc(Br)c1=O
Product: CC[C@H](COC)n1cc(Br)nc(N2CCc3cc(Br)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 118° C.; 1H NMR (300 MHz, CDCl3): δ 7.31 (s, 1 H), 7.24 (s, 1 H), 7.13 (s, 1 H), 4.98-4.90 (m, 1 H), 4.32 (t, J=7.9 Hz, 2 H), 3.66 (dd, J=10.7, 5.9 Hz, 1 H), 3.55 (dd, J=10.6, 3.3 Hz, 1 H), 3.35 (s, 3 H), 3.13 (t, J=7.9 Hz, 2 H), 1.85-1.74 (m, 2 H), 0.93 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C17H19N3O2Br2Cl (M+H)+: 489.0543; Found m/z 489.9534.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([S:59](Cl)(=[O:61])=[O:60])=[CH:55][CH:54]=1>>[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([S:59]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:16])(=[O:61])=[O:60])=[CH:55][CH:54]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 38 %

Procedure:
Nα-tert-butoxycarbonyl-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 4-chlorobenzenesulfonyl chloride as described in example 2, affording the title compound in 38% yield.
Reaction SMILES: O[C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[CH:4][CH:3]=1.CC1(C)CCC(C)(C)C2C=C(C=CC(Cl)=O)C=CC1=2.[CH3:33][C:34]1([CH3:60])[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[C:40]2[CH:39]=[C:38]([CH:46]=[CH:47][C:48]([O:50]C3C=CC=CC=3C([O-])=O)=[O:49])[CH:37]=[CH:36][C:35]1=2>>[CH3:33][C:34]1([CH3:60])[CH2:43][CH2:42][C:41]([CH3:44])([CH3:45])[C:40]2[CH:39]=[C:38](/[CH:46]=[CH:47]/[C:48]([O:50][C:12]3[CH:13]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[O:49])[CH:37]=[CH:36][C:35]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Oc3ccccc3C(=O)[O-])ccc21
Reactant: C=CCOC(=O)c1ccc(O)cc1
Agent: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Cl)ccc21
Product: C=CCOC(=O)c1ccccc1OC(=O)/C=C/c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a similar manner to that of Example 11(b), by reaction of 710 mg (4 mmol) of allyl 4-hydroxybenzoate with 1 g (3.62 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acryloyl chloride obtained in Example 1(c), 500 mg (33%) of allyl E)-2-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)acryloyloxy]benzoate, with a melting point of 92-3° C., are obtained.