Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>O>[C:28]([O:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
4-(N,N-Diphenylamino)benzyl alcohol (5.94 g, 0.0216 mol), pyridine (16 mL) and acetic anhydride (11.4 mL) were mixed in a three-neck flask equipped with a condenser and addition funnel. The resulting mixture was stirred overnight at room temperature. Deionized water (50 mL) was then added and the resulting mixture stirred for 2 hours. The product was obtained by filtration, and recrystallized from hexane to yield the desired product (6.52 g, 95%). m.p. 105-6° C.; 1H NMR δ: 2.10 (s, 3H, CH3), 5.04 (s, 2H, CH2), 7.0-7.4 (m, 14H, phenyl). Analysis: Calculated for C19H17NO2: C, 79.46%; H, 6.03%; N, 4.41%. Found: C, 79.37 %; H, 5.72 %; N, 4.41%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:42](=[O:48])[O:43][C:44](Cl)(Cl)Cl)Cl.[Cl:50][C:51]1[CH:56]=[CH:55][C:54]([S:57][CH2:58][CH2:59]CO)=[C:53]([CH3:62])[CH:52]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:42](=[O:48])[O:43][CH2:44][CH2:59][CH2:58][S:57][C:54]1[CH:55]=[CH:56][C:51]([Cl:50])=[CH:52][C:53]=1[CH3:62]
Reactant: Cc1cc(Cl)ccc1SCCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCCSc4ccc(Cl)cc4C)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Yield: 53.1 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (75 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (120 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-[4-chloro-2-methylphenyl]sulfanyl-1-propanol (80 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (69 mg, yield 50%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH2:12][NH:13][CH3:14].[C:15]([OH:19])(=O)[CH:16]=[CH2:17].C1C=CC2N(O)N=NC=2C=1.O.[CH2:31]1CC[CH:34]([N:37]=[C:38]=[N:39]C2CCCCC2)[CH2:33][CH2:32]1>CN(C=O)C.C(Cl)Cl>[NH2:39][C:38]1[N:37]=[CH:34][C:33](/[CH:17]=[CH:16]/[C:15]([N:13]([CH2:12][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([C:4]=2[CH3:11])=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH3:14])=[O:19])=[CH:32][CH:31]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C=CC(=O)O
Reactant: CNCc1c(C)c2ccccc2n1C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Cc1c(CN(C)C(=O)/C=C/c2ccc(N)nc2)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
To a stirred solution of 1,3-dimethyl-2-(methylaminomethyl)-1H-indole (0.6 g, 3.2 mmole) in 1:1 DMF/CH2Cl2 (25 mL) was added (E)-3-6-aminopyridin-3-yl)acrylic acid (0.50 g, 3 mmole), HOBt.H2O (0.43 g, 3.2 mmole), and DCC (0.66 g, 3.2 mmole). After stirring at RT for 16 hr the reaction was concentrated under vacuum. Purification by flash chromatography on silica gel (3% methanol/CHCl3) gave the title compound (0.83 g, 83%) as an off-white solid: LCMS (ES) m/e 335.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C@@H:8]12[C:17](=O)[O:16][C:14](=[O:15])[C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13]2.CS(O)(=O)=O>C1(C)C(C)=CC=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:14](=[O:15])[CH:9]3[CH:8]([CH2:13][CH2:12][CH2:11][CH2:10]3)[C:17]2=[O:16])=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Product: O=C1C2CCCCC2C(=O)N1c1ccncc1
Reaction time: 18 h

Procedure:
The starting material is prepared as follows: The mixture of 23.5 g of 4-aminopyridine, 38.5 g of cis-1,2-cyclohexanedicarboxylic acid anhydride and 400 ml of xylene is refluxed for 42 hours while stirring and separating the water formed. After the first half-hour, and after 18 hours, 1 ml of methane sulfonic acid is added to the mixture. It is filtered hot, the crystals formed after cooling are filtered off and recrystallized from isopropanol, to yield the 2-(4-pyridyl)-hexahydroisoindole-1,3-dione melting at 165°-168°.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.Cl>C(OC)(C)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:21][C:20]([C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)=[O:22]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Yield: 93.3 %

Procedure:
Ethyl trifluoroacetate (23.52 g, 166 mmol) was placed in a 500 mL three-necked round bottom flask, and dissolved in methyl tert-butyl ether (75 mL). To the stirred solution was added 25% sodium methoxide (40 mL, 177 mmol) via an addition funnel over a 2 minute period. Next 4′-chloroacetophenone (23.21 g, 150 mmol) was dissolved in methyl tert-butyl ether (20 mL), and added to the reaction dropwise over 5 minutes. After stirring overnight (15.75 hours), 3N HCl (70 mL) was added. The organic layer was collected, washed with brine (75 mL), dried over MgSO4, filtered, and concentrated in vacuo to give a 35.09 g of yellow-orange solid. The solid was recrystallized from iso-octane to give 31.96 g (85%) of the dione: mp 60-67° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([O:11][CH2:12][CH3:13])=[O:10]>>[CH2:12]([O:11][C:9](=[O:10])[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:19]=1)[CH3:13]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: Clc1ccnc(Cl)n1
Product: CCOC(=O)c1cccc(-c2ccnc(Cl)n2)c1

Procedure:
2,4 dichloropyrimidine was coupled to 3-carboethoxyphenylboronic acid following procedure A. LC-MS showed the product to be >95% pure and to have the expected M+H+ of 195.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12](F)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([O:41][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:19]=[CH:20][C:2]([Br:1])=[CH:3][CH:4]=3)=[CH:10][C:11]=2[N+:16]([O-:18])=[O:17])=[CH:39][CH:40]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 8639.2 %

Procedure:
The product from Example 247a (0.89 g, 2.63 mmol) was mixed with cesium carbonate (0.85 g, 2.63 mmol) and 4-benzyloxyphenol (0.53 g, 2.63 mmol) in DMF (10 mL) and stirred at room temperature a total of sixty hours. The reaction mixture was diluted with ethyl acetate (100 ml) and treated with 2N HCl (20 ml). The organic layer was separated and washed with 2N NaOH, 2, 10% sodium chloride and dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was evaporated under vacuum leaving the title compound as a yellow solid (118 g, 86%).
Reaction SMILES: [C:1]([C:4]1[C:5](O)=[C:6]([Cl:11])[CH:7]=[C:8]([OH:10])[CH:9]=1)(=[O:3])[CH3:2].[Cl:13][C:14]([Cl:18])=[CH:15][CH2:16]Cl.[C:19](=[O:22])([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[C:1]([C:4]1[C:5]([O:22][CH2:19][CH:15]=[C:14]([Cl:18])[Cl:13])=[C:6]([Cl:11])[CH:7]=[C:8]([O:10][CH2:16][CH:15]=[C:14]([Cl:18])[Cl:13])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc(O)cc(Cl)c1O
Reactant: ClCC=C(Cl)Cl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1OCC=C(Cl)Cl

Procedure:
2.9 g of 3-acetyl-1-chloro-2,5-dihydroxybenzene were dissolved in 29 ml of acetone, and 3.39 g of 1,1,3-trichloropropene, 4.3 g of potassium carbonate and 0.7 g of sodium iodide were added. The mixture was heated under reflux for 5 hours (monitored by TLC). The reaction mixture was then allowed to cool and concentrated using a rotary evaporator, and the resulting crude product was subjected to chromatographic purification. Yield: 6.1 g (99%)
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH:12](Br)[CH2:13][Br:14])(=O)C.[O-]CC.[Na+].C(Cl)(Cl)Cl>C(O)C>[Br:14][CH2:13][CH:12]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:11]1
Reactant: CC(=O)Oc1ccccc1CC(Br)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: BrCC1Cc2ccccc2O1
Temperature: 0 °C
Yield: 65.7 %

Procedure:
340 mg (1.0 mmol) of compound 001B, which had been prepared in Step B, was dissolved in 3 ml of ethanol, followed by cooling to 0° C. To the resultant solution was dropwise added 1.2 ml (1.2 mmol) of a 1N solution of sodium ethoxide in ethanol and then, the resultant mixture was stirred at 0° C. for 2 hours to effect a reaction. To the resultant reaction mixture was added 20 ml of chloroform to obtain a mixture. The obtained mixture was successively washed with 20 ml of a 10% aqueous citric acid solution, 20 ml of water and 20 ml of saturated saline, to thereby form a chloroform layer containing the desired compound 001C, followed by separation of the chloroform layer. The chloroform layer thus separated was dehydrated by means of a Whatman 1PS filter paper and then, concentrated in vacuo to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was applied to a column of 10 g of silica gel (Art. 9385, manufactured and sold by E. Merck, Darmstadt, Germany) and eluted with a mixed solvent of hexane-ethyl acetate (30:1), to thereby obtain 140 mg of compound 001C as a transparent oily substance (yield: 66%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=3[Cl:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1Cl
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(Cl)cc3Cl)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2,4-dichloro-phenyl)-acrylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([Cl:10])[CH:3]=1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:12])=[C:4]([Cl:10])[CH:3]=1
Reactant: OCc1ccc(Br)cc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(Br)ccc1CBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a magnetically stirring solution of (4-bromo-2-chloro-phenyl)-methanol (2.80 g, 12.67 mmol) from step 1 above in CH2Cl2 (60.0 mL) under argon at 0° C., was added carbon tetrabromide (4.41 g, 13.30 mmol) followed by triphenylphosphine (3.48 g, 13.30 mmol). The resulting mixture was stirred for 4 hours at room temperature. The resulting reaction mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography (10% EtOAc in Hexanes) to yield the intermediate bromide as a clear oil (3.59 g, 100%). 1H NMR (400 MHz, CDCl3): δ 4.53 (s, 2H), 7.29 (d, J=8.2 Hz, 1H), 7.39 (dd, J=8.2, 1.9 Hz, 1 H), 7.56 (d, J=1.9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([Cl:13])=[CH:4][CH:3]=1.Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:13][C:5]1[C:6]2[CH2:7][C:8]([CH3:11])([CH3:12])[O:9][C:10]=2[C:2]([N:1]=[C:15]=[O:16])=[CH:3][CH:4]=1
Reactant: CC1(C)Cc2c(Cl)ccc(N)c2O1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(Cl)ccc(N=C=O)c2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 1.97 g (0.010 mole) of 7-amino-4-chloro-2,3-dihydro-2,2-dimethylbenzofuran in 60 mL of toluene was added slowly 1.2 mL (0.010 mole) of trichloromethyl chloroformate. This mixture was stirred at ambient temperature for one hour and then was heated at reflux for approximately 16 hours. At the conclusion of this period the solvent was evaporated from the reaction mixture under reduced pressure, leaving 2.23 g of 4-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-yl isocyanate as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH2:9][CH3:10])=[N:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[CH2:23]([N:25](CC)CC)[CH3:24].C(Cl)(=O)C>C1C=CC=CC=1.C(O)C>[CH2:9]([N:8]1[C:7]2=[N:6][C:5]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=[C:2]2[N:25]=[C:23]1[CH3:24])[CH3:10]
Reactant: CCN(CC)CC
Reactant: CCNc1nc(-c2ccccc2)c(-c2ccccc2)nc1Cl
Solvent: CCO
Solvent: CC(=O)Cl
Solvent: c1ccccc1
Product: CCn1c(C)nc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 15 °C

Procedure:
2-Chloro-3-ethylamino-5,6-diphenylpyrazine, (3.10 g, 0.01 moles) is dissolved in benzene (50 ml) and then triethylamine (1.29 g, 0.013 moles) and acetyl chloride (1.00 g, 0.013 moles) are added. The solution is refluxed 41/2 hours, cooled to 15° C and filtrate. The filtrate is diluted with ethanol (3 ml), warmed briefly at 50° C and then all volatile materials evaporated. The resultant brown oil is treated with liquid ammonia (17 g) in ethanol (60 ml) in a bomb at 165° C for 12 hours. The solution is diluted with water (200 ml), cooled and the yellow precipitate filtered off. The solid is triturated with boiling 50% aqueous methanol, filtered, and the filtrate chilled. The product is collected by filtration. Yield 0.45 g (14%). It is recrystallized from benzene-heptane, m.p. 178.5°-180° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.[CH2:28]([N:35]1[CH2:39][C@@H:38]2[C@@H:40]([NH2:43])[CH2:41][CH2:42][C@@H:37]2[CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:28]([N:35]1[CH2:39][C@@H:38]2[C@@H:40]([NH:43][C:14](=[O:16])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:41][CH2:42][C@@H:37]2[CH2:36]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-(tert-Butoxycarbonyl)-L-leucine (0.374 g, 1.617 mmol), 1-hydroxybenzotriazole hydrate (0.248 g, 1.617 mmol), and (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 (0.318 g, 1.470 mmol) were combined in dichloromethane (3.0 mL). After 20 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.286 mL, 1.617 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction was quenched with water and extracted with dichloromethane (2×2 mL), and the extracts were applied directly to a 25 g silica gel cartridge and purified with a gradient of 5-40% acetone/hexanes over 30 minutes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.61-8.64 (m, 1H), 7.96-7.99 (m, 1H), 7.42-7.44 (m, 2H), 7.36 (t, J=7.4 Hz, 2H), 7.28 (d, J=7.3 Hz, 1H), 4.65-4.73 (m, 1H), 4.37-4.45 (m, 1H), 3.59 (d, J=13.1 Hz, 1H), 3.43 (d, J=13.1 Hz, 1H), 2.81-2.84 (m, 1H), 2.55-2.58 (m, 1H), 2.44-2.54 (m, 2H), 2.24-2.36 (m, 2H), 2.02-2.13 (m, 1H), 1.78-1.94 (m, 4H), 1.53-1.66 (m, 1H), 1.50 (s, 9H), 1.26-1.43 (m, 1H), 0.87 (d, J=5.5 Hz, 3H), 0.83-0.85 (m, 3H); MS (ESI+) m/z 430 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][O:32][C:31]([CH3:36])([CH3:35])[CH2:30]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][O:32][C:31]([CH3:35])([CH3:36])[CH2:30]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: CC1(C)CC(CCCBr)CCO1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCOC(C)(C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 224 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(3-bromopropyl)-2,2-dimethyltetrahydro-2H-pyran.
Reaction SMILES: C(S([C:6]1[N:15]=[C:14]2[C:9]([C:10](=[O:24])[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][N:13]2[CH2:16][CH2:17][F:18])=[CH:8][C:7]=1[F:25])(=O)=O)C.[C:26]([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)(=[O:28])[CH3:27].C(N(CC)CC)C>C(O)C>[C:26]([NH:29][CH:30]1[CH2:34][CH2:33][N:32]([C:6]2[N:15]=[C:14]3[C:9]([C:10](=[O:24])[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][N:13]3[CH2:16][CH2:17][F:18])=[CH:8][C:7]=2[F:25])[CH2:31]1)(=[O:28])[CH3:27]
Reactant: CC(=O)NC1CCNC1
Reactant: CCOC(=O)c1cn(CCF)c2nc(S(=O)(=O)CC)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cn(CCF)c2nc(N3CCC(NC(C)=O)C3)c(F)cc2c1=O
Yield: 77.8 %

Procedure:
A mixture of ethyl 7-ethylsulfonyl-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (19.8 g) obtained according to the Reference Example 2, 3-acetylaminopyrrolidine (10.2 g), triethylamine (7.4 ml), and ethanol (400 ml) was heated under reflux for 2 hours. After cooling, the resulting crystals were collected by filtration, and recrystallized from chloroform-ethanol to give 16.8 g of ethyl 7-(3-acetylamino-1-pyrrolidinyl)-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate melting at 269°-270° C. A solution of the above ester (15.0 g) in 20% hydrochloric acid (100 ml) was heated under reflux for 4 hours. After cooling, ethanol (100 ml) was added to the mixture and the resulting crystals were collected by filtration. The crystals were dissolved in hot water (100 ml) and treated with charcoal. The filtrate was adjusted to pH 8.5-9.0 by addition of aqueous 27% ammonia, and the resulting crystals were collected by filtration, washed with water, and dried to give 9.3 g of the compound 3, m.p. 251°-255° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.Cl.[NH2:43][C@H:44]1[CH2:49][CH2:48][C@H:47]([OH:50])[CH2:46][CH2:45]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:43][C@H:44]5[CH2:49][CH2:48][C@H:47]([OH:50])[CH2:46][CH2:45]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@H]2CC[C@H](O)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.08 g (0.18 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.13 mL (0.72 mmole) of ethyldiisopropyl amine and 0.030 g (0.20 mmole) of trans-4-amino-cyclohexanol hydrochloride in 2.0 mL of dimethylformamide was added 0.085 g (0.2 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.077 g of trans-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-hydroxy-cyclohexyl)-3-methoxy-benzamide (I-69) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[OH:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:20]1([S:26]([O:8][N:9]2[C:10](=[O:19])[C:11]3=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]3[C:13]2=[O:14])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OS(=O)(=O)c1ccccc1
Reaction time: 24 h
Yield: 86.2 %

Procedure:
A dichloromethane (50 ml) solution of triethylamine (3.1 g, 0.0306 mole) was slowly added to a stirred dichloromethane (50 ml) suspension of N-hydroxyphthalimide (5.0 g, 0.0306 mole) and benzenesulfonyl chloride (5.4 g, 0.0306 mole) at ice-bath temperature. The stirred reaction mixture was kept at ambient temperature for about 24 hours. The product was partitioned between dichloromethane and distilled water and the dichloromethane extract was dried with magnesium sulfate. Solvent was removed under reduced pressure and the residue was crystallized with ethyl acetate-n-pentane (2:1 v/v) to give 8.0 g (87%) of colorless crystals; mp 186°; mass spectrum M+ 303 (calcd. M+ 303).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:17][C:16]([S:18](O)(=[O:20])=[O:19])=[CH:15][CH:14]=2)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]1.C1C=CC=CC=1.S(Cl)([Cl:34])=O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:17][C:16]([S:18]([Cl:34])(=[O:20])=[O:19])=[CH:15][CH:14]=2)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]1
Reactant: O=S(=O)(O)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)s1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)s1

Procedure:
5-(1-(2-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophene-2-sulfonic acid (˜3.2 mmol from previous step) was combined with benzene (5.0 mL) in a reaction vial. This mixture was treated with thionyl chloride (5.0 mL, 69 mmol) and a catalytic amount of dimethylformamide (0.1 mL). The reaction was then heated to reflux in an oil bath. After refluxing for 1 hour the reaction mixture was concentrated under reduced pressure to afford a yellow oil that partially solidified under reduced pressure. This crude material was purified by flash column chromatography eluting with a gradient from 10% to 30% EtOAc/hexane. Product-containing fractions were collected and concentrated to afford 5-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophene-2-sulfonyl chloride as a pale yellow oil. The mostly pure material was carried on to subsequent transformations without further purification.