Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[CH2:3][C:4]1[N:5]=[C:6]([C:15](O)([CH3:30])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[N:7](S(N(C)C)(=O)=O)[CH:8]=1.[OH-:34].[Na+].S(=O)(=O)(O)O.[C:41](#[N:43])[CH3:42]>>[CH3:32][C:2]([CH3:33])([CH3:1])[CH2:3][C:4]1[N:5]=[C:6]([C:15]([NH:43][C:41](=[O:34])[CH3:42])([CH3:30])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[NH:7][CH:8]=1
Reactant: CC#N
Reactant: [OH-]
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(-c2ccc(F)cn2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)NC(C)(Cc1ccc(-c2ccc(F)cn2)cc1)c1nc(CC(C)(C)C)c[nH]1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
4-(2,2-dimethylpropyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (for synthesis see Example 15) (20 mg, 0.042 mmol) was dissolved in sulfuric acid/acetonitrile (1:1) (2 mL). After stirring at 140° C. overnight, the reaction mixture was cooled to ambient temperature, neutralized with aqueous sodium hydroxide and extracted with chloroform. The combined organic extracts were dried (magnesium sulfate), filtered, and concentrated in vacuo to afford the title compound. (M+H) found: 409.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.CCCCCC.[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[CH3:21].Br[CH2:32][CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35].Cl>C1COCC1.O>[CH2:20]([O:22][C:23]([C:25]1([CH2:32][CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[CH3:21]
Reactant: CCC(CC)CBr
Reactant: CCOC(=O)C1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)C1(CC(CC)CC)CCCCC1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 78.7 %

Procedure:
To a solution of dicyclohexylamine (15.55 g, 85.77 mmol) in THF (90 mL) 1.6 M n-BuLi in hexane (48.0 mL, 76.8 mmol) was added with stirring over 50 min at temperature between −20° C. and −15° C. The orange suspension was stirred 10 min at −20° C. and then warmed up to 0° C. To this suspension a solution of cyclohexanecarboxylic acid ethyl ester (10.0 g, 64.0 mmol) in THF (30 mL) was added over 15 min at 0° C. The resulting solution was stirred 30 min at 0° C. then 1-bromo-2-ethylbutane (14.79 g, 89.6 mmol) in THF (37.5 mL) was added at the same temperature over 15 min. Stirring was continued 5 h at 0° C. and overnight at room temperature. At 5° C. cold water (25 mL) was added, followed by 2N HCl (60 mL). The white suspension was filtered and the filter cake was washed with water and ethyl acetate. The organic phase of the filtrate was washed with sat. aq. NaHCO3 and with aq. NaCl. The aqueous phases were extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate and concentrated. The crude product (16.0 g) was distilled at 60° C. (0.05 mbar) to give 12.1 g (79%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid ethyl ester as colorless oil, purity 97% (GC area) (cyclohexanecarboxylic acid dicyclohexylamide as impurity: not detectable in distilled product and 0.7% in crude product).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[N:20]=[C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]3[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([OH:34])[C:28]([CH3:36])([CH3:35])[CH2:27]3)[N:18]=[C:17]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH:42]3[CH2:47][C:46]([CH3:49])([CH3:48])[N:45]([OH:50])[C:44]([CH3:52])([CH3:51])[CH2:43]3)[N:16]=2)[CH2:4][C:3]1([CH3:54])[CH3:53].[CH2:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1>>[CH:55]1([O:50][N:45]2[C:44]([CH3:52])([CH3:51])[CH2:43][CH:42]([CH2:41][CH2:40][CH2:39][CH2:38][NH:37][C:17]3[N:16]=[C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:5]4[CH2:4][C:3]([CH3:54])([CH3:53])[N:2]([O:1][CH:55]5[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]5)[C:7]([CH3:9])([CH3:8])[CH2:6]4)[N:20]=[C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]4[CH2:31][C:30]([CH3:32])([CH3:33])[N:29]([O:34][CH:55]5[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]5)[C:28]([CH3:36])([CH3:35])[CH2:27]4)[N:18]=3)[CH2:47][C:46]2([CH3:49])[CH3:48])[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1
Reactant: CC1(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(O)C(C)(C)C3)nc(NCCCCC3CC(C)(C)N(O)C(C)(C)C3)n2)CC(C)(C)N1O
Reactant: C1CCCCC1
Product: CC1(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of 2,4,6-tris[N-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-s-triazine and cyclohexane following a procedure similar to that of Example 10.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccncc1Cl
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(Cl)c1ccncc1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-chloroisonicotinic acid (750 mg, 4.76 mmol, 1.0 eq) in 25 mL of toluene was added thionyl chloride (3.0 mL, 41.6 mmol, 8.7 eq) at room temperature. The reaction mixture was stirred at 100° C. for 3 hours. The mixture was concentrated under reduced pressure, dissolved in 25 mL of toluene and concentrated again to give crude 3-chloroisonicotinoyl chloride hydrochloride salt, which was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[O:13][C:14]([CH3:17])(C)C)(C)(C)C.[C]=O.[CH2:20]([OH:22])C>C(=[Ru])=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:1]1([CH2:7][C:20]([O:13][CH2:14][CH3:17])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CCO
Reactant: Cc1ccccc1
Agent: O=C=[Ru]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [C]=O
Product: CCOC(=O)Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 26.8 %

Procedure:
Toluene (1.38 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), carbonyl ruthenium (1.1 mg, 1 mol %), and Xantphos (2.9 mg) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 22 mg ethyl phenylacetate was obtained by column chromatography, in a yield of 27%. The ethyl phenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 17 mg product phenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 93%.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][NH+](C)C)[C:3]=1OC(NC)=O.[Cl-].[N-:18]=[C:19]=[O:20].[N-:21]=[C:22]=[O:23].O=[C:25]1[CH2:32][C:29](C)(C)[CH2:28][C:27](C)=[CH:26]1>>[CH:25]1[C:32]([CH2:8][C:4]2[CH:3]=[CH:2][C:7]([N:18]=[C:19]=[O:20])=[CH:6][CH:5]=2)=[CH:29][CH:28]=[C:27]([N:21]=[C:22]=[O:23])[CH:26]=1
Reactant: CNC(=O)Oc1c(C)cccc1C[NH+](C)C
Reactant: [N-]=C=O
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: [Cl-]
Product: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1

Procedure:
Vestanat T1890/100: isophoronediisocyanate trimer available from Evonik Degussa International AG.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Br:15][C:16]1[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][C:22](O)=O)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:26]=[CH:25][C:19](/[CH:20]=[CH:21]/[C:22]2[NH:1][C:2]3[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=3[N:8]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(Br)cc3)nc2n(CC)c1=O
Yield: 21.5 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.20 g (11.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.78 g (12.2 mmol) of 4-bromocinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 930 mg (yield 22%) of Compound 141 as yellow columns.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:28]([O:27][C:25](=[O:26])[NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)[CH3:29]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)N3CC

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid ethyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and ethyl chloroformate (84 μl, 0.89 mmol). The title compound was obtained as brown powder (100 mg, 32%).
Reaction SMILES: [CH2:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH2:16][C:17](=[O:27])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[CH:9]=1)[C:4]([O-:6])=[O:5])[CH3:2].[CH2:28](N)[CH2:29]N.[H][H]>C(O)C.C(OCC)(=O)C.[C].[Pd]>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH:3]([CH2:1][CH3:2])[C:4]([O:6][CH2:28][CH3:29])=[O:5])=[CH:9][C:10]=1[CH2:16][C:17](=[O:27])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26]
Reactant: NCCN
Reactant: CCC(=Cc1ccc(OC)c(CC(=O)Nc2ccc(Cl)cc2Cl)c1)C(=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(CC(=O)Nc2ccc(Cl)cc2Cl)c1

Procedure:
0.9 g of 2-ethyl-3-(4-methoxy-3-{2-oxo-2-[2,4-dichloroanilino]ethyl}phenyl)-2-propenoate was dissolved in 15 ml ethanol and 15 ml ethyl acetate, and 0.6 g of palladium-carbon poisoned with ethylene diamine was added. The reaction solution was stirred at room temperature for 5 hours in a hydrogen atmosphere, and then the palladium-carbon was filtered off, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 0.44 g of ethyl 2-(4-methoxy-3-{2-oxo-2-[2,4-dichloroanilino]ethyl}benzyl)butanoate as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[CH2:45]([N:47]([C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH3:57])[CH:52]=1)[CH2:48][CH2:49][NH2:50])[CH3:46]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:50][CH2:49][CH2:48][N:47]([CH2:45][CH3:46])[C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([CH3:57])[CH:52]=2)=[O:43])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CCN)c1cccc(C)c1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1[N+](=O)[O-])c1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (131 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1-ethyl-N1-(3-methylphenyl)-1,2-ethanediamine (78 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (110 mg, yield 69%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[N:14]([CH2:29][CH2:30][CH3:31])[C:13]=2[CH:32]=1.[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[N:14]([CH2:29][CH2:30][CH3:31])[C:13]=2[CH:32]=1)[CH2:39][C:35]1[N:34]([CH3:33])[CH:38]=[CH:37][N:36]=1
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCCc1nc2ccc(CNCc3ncc[nH]3)cc2n1CCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCCc1nc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2n1CCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
The compound (8.8 mg) obtained in Example 48-6 was dissolved in methanol (2.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (2.6 mg) and sodium cyanoborohydride (2.5 mg). After the solution was adjusted to pH 4 with acetic acid, the whole was stirred at room temperature for 18 hours. After the solvent was distilled off, the resultant was neutralized with a saturated aqueous sodium hydrogen carbonate solution and the whole was subjected to extraction with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (9.3 mg) of the subject compound as a white solid.
Reaction SMILES: CC[NH+]=[C:4]1[C:36]2C(=CC=C[CH:35]=2)[C:7](=[C:8](C2C=CC(N(CC)CC)=CC=2)[C:9]2C=[CH:13][C:12](N(CC)CC)=[CH:11][CH:10]=2)[CH:6]=[CH:5]1.[Cl-].C([O:50][S:51]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)(=[O:53])=[O:52])CCCCCCCCCCC.[Na]>O>[CH2:13]([C:59]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[S:51]([OH:50])(=[O:52])=[O:53])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:36][CH3:35]
Reactant: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Reactant: CC[NH+]=C1C=CC(=C(c2ccc(N(CC)CC)cc2)c2ccc(N(CC)CC)cc2)c2ccccc21
Agent: [Cl-]
Agent: [Na]
Solvent: O
Product: CCCCCCCCCCCCc1ccccc1S(=O)(=O)O

Procedure:
Into a solution prepared by dissolving 20 g of C.I. Basic Blue 7 (commercial name: Aizen Victoria Pure Blue, BOH, made by HODOGAYA CHEMICAL CO., LTD.) into 1.5 l of distilled water was added a solution prepared by dissolving 13 g of sodium dodecylbenzenesulfonate into 500 ml of distilled water. The formed precipitate was recovered and washed with water and dried to give a dodecylbenzenesulfonic acid salt of the dye.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[CH:19]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]1.[CH:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[OH:36][CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:19]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C1(C(O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.9 %

Procedure:
To a solution of diisopropylamine (1.203 mL, 8.44 mmol) in THF (10 mL) was added n-BuLi/hexane (3.38 mL, 8.44 mmol) dropwise at −78° C. The reaction mixture was stirred in the bath for 5 min and then stirred in ice bath for 30 min. The reaction mixture was added dropwise a solution of tert-butyl cyclopropanecarboxylate (1 g, 7.03 mmol) in THF (5 mL) at −78° C. The reaction mixture was stirred at −78° C. for 2 h. The solution of benzaldehyde (0.746 g, 7.03 mmol) in THF (2 mL) was added dropwise at −78° C. Then the solution was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with NH4Cl, then diluted with EtOAc. Then organic phase was washed with sat. NaHCO3, water, sat. NaCl, dried over anhydrous Na2SO4, and concentrated to yield an oil. The crude was purified by silica chromatography with 0-50% EtOAc/Hex to yield tert-butyl 1-(hydroxy(phenyl)methyl)cyclopropanecarboxylate (1.01 g, 57.8% yield) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.48-7.40 (m, 2H), 7.38-7.23 (m, 3H), 4.70 (d, J=7.5 Hz, 1H), 3.55 (d, J=7.8 Hz, 1H), 1.43-1.33 (m, 10H), 1.17 (ddd, J=9.6, 6.6, 3.9 Hz, 1H), 0.99-0.79 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[CH3:31].C(O)C>Cl.O>[CH:15]1([N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[CH3:31])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)C(=O)N2C
Yield: 48.8 %

Procedure:
A mixture of 0.03 g (0.0001 mole) of (rac)-2-chloro-9-cyclopentyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one, 0.015 g (0.0001 mole) of 4-amino-3-methylbenzoic acid, 0.3 mL of ethanol, 0.8 mL of water, and 1 drop of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.020 g of (rac)-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methyl-benzoic acid (I-7) as an off-white solid.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15]Br)=[CH:11][C:10]=1[CH3:19])C1C=CC=CC=1.[ClH:20].[CH2:21]([C:23]1[CH:36]=[CH:35][C:26]([CH2:27][C:28]2([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1)C.C(=O)([O-])[O-].[K+].[K+]>>[ClH:20].[OH:8][C:9]1[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][N:31]2[CH2:32][CH2:33][C:28]([OH:34])([CH2:27][C:26]3[CH:35]=[CH:36][C:23]([CH3:21])=[CH:24][CH:25]=3)[CH2:29][CH2:30]2)=[CH:11][C:10]=1[CH3:19]
Reactant: CCc1ccc(CC2(O)CCNCC2)cc1
Reactant: Cc1cc(OCCBr)ccc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(CC2(O)CCN(CCOc3ccc(O)c(C)c3)CC2)cc1

Procedure:
The title compound was prepared from 2-(4-benzyloxy-3-methylphenoxy)ethyl bromide (385 mg, 1.2 mmol), 4-(4-ethylbenzyl)-4-hydroxypiperidine hydrochloride (290 g, 1.2 mmol) and potassium carbonate (414 mg, 3 mmol) in two steps as white solid (200 mg): mp 90-94° C. (dec.). 1H NMR (CD3OD) 1.641 (m, 2 H), 1.859 (m, 2 H), 2.083 (5, 3 H), 2.224 (s, 3 H), 2.718 (s, 2 H), 3.260-3.423 (m, 6 H), 4.133 (m, 2 H), 6.585 (s, 2 H), 6.668 (s, 1 H), 7.035 (m, 4 H).
Reaction SMILES: C(OC([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:31])[CH:14]([NH:16][C:17](=[O:30])[C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=1)[CH3:15])=O)(C)(C)C.[O:32]=[C:33]1[O:37][CH:36]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43]C=2)[CH:35]([NH:47][C:48](C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=[O:49])[CH2:34]1>>[CH2:39]([O:38][CH:36]1[CH:35]([NH:47][C:48]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:31])[CH:14]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=2)[CH3:15])=[O:49])[CH2:34][C:33](=[O:32])[O:37]1)[C:40]1[CH:41]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(=O)Nc1c(Cl)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)OC(C)(C)C)cc1Cl
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(=O)Nc1c(Cl)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)NC2CC(=O)OC2OCc2ccccc2)cc1Cl
Yield: 72 %

Procedure:
Prepared from 1-[2-(4-acetylamino-3,5-dichloro-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester and syn-(2-benzyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 230 mg of title compound (72% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.36 (d, 0.6H), 1.47 (d, 2.4H), 1.68-2.47 (m, 4H), 2.23 (s, 3H), 2.60-3.15 (m, 2H), 3.40-3.90 (m, 2H), 4.15-4.95 (m, 5H), 5.68 (d, 0.8H), 5.84 (d, 0.2H), 7.20-7.98 (m, 7H). Analytical HPLC: 13.07 min. LC-MS (ES+): m/e=605.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.Cl[CH2:13][C:14]#[N:15].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH:6]([C:5]1[C:4]([CH3:11])=[CH:3][C:2]([O:1][CH2:13][C:14]#[N:15])=[CH:9][C:8]=1[CH3:10])=[O:7]
Reactant: N#CCCl
Reactant: Cc1cc(O)cc(C)c1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1cc(OCC#N)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-hydroxy-2,6-dimethyl-benzaldehyde (150 mg), chloroacetonitrile (0.1 mL), and Cs2CO3 (390 mg) in acetone (10 mL) was stirred at room temperature for 16 h. The mixture was concentrated, diluted with water, and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by column chromatography (SiO2, 3:1 hexane/EtOAc) gave (4-formyl-3,5-dimethyl-phenoxy)-acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[OH:12].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:12][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[CH3:8]
Reactant: Cc1c([N+](=O)[O-])ccc(O)c1Cl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
A solution of 2-chloro-3-methyl-4-nitrophenol (30.0g, 0.160 mol) in sieve-dried DMF (650 ml) was treated with sodium hydride (50%, 8.44g, 0.176 mol) and then benzyl bromide (30.1 g, 0.176 mol), while stirring at 0° C. The mixture was stirred at room temperature for 16 hours, then poured into 3 litres of water to precipitate an orange-coloured solid, which was recrystallised from ethanol to give 2-chloro-3-benzyloxy-6-nitrotoluene (31.3 g) m.p. 73°-74.5° C.
Reaction SMILES: COC1C=CC(C[N:8]([C:12]2([CH2:15][O:16][C:17]3[CH:26]=[C:25]4[C:20]([C:21]([O:27][C:28]5[CH:33]=[CH:32][C:31]([NH:34][C:35]([C:37]6([C:40](=[O:49])[NH:41]C7C=CC(F)=CC=7)[CH2:39][CH2:38]6)=[O:36])=[CH:30][C:29]=5[F:50])=[CH:22][CH:23]=[N:24]4)=[CH:19][C:18]=3OC)[CH2:14][CH2:13]2)C(=O)[O-])=CC=1.[C:55](O)([C:57]([F:60])(F)F)=O.C(Cl)Cl.[C:65]([O-:68])(O)=O.[Na+]>>[NH2:8][C:12]1([CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([O:27][C:28]4[CH:33]=[CH:32][C:31]([N:34]([C:12]5[CH:15]=[CH:55][C:57]([F:60])=[CH:14][CH:13]=5)[C:35]([C:37]5([C:40]([NH2:41])=[O:49])[CH2:39][CH2:38]5)=[O:36])=[CH:30][C:29]=4[F:50])=[CH:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:68][CH3:65])[CH2:14][CH2:13]1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C([O-])O
Reactant: COc1ccc(CN(C(=O)[O-])C2(COc3cc4nccc(Oc5ccc(NC(=O)C6(C(=O)Nc7ccc(F)cc7)CC6)cc5F)c4cc3OC)CC2)cc1
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1OCC1(N)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The product of Example 1 (2.1 g) was mixed with 10% TFA/DCM (50 ml) and stirred at 0° C. for 2 hours. Saturated NaHCO3 (80 ml) was added to the solution at 0° C. and the solution was further extracted with EtOAc twice. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated to give the titled compound for next step without further purification. Mass: (M+1), 575