Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:32])[CH2:8][O:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C@@H:19]([CH2:20][CH2:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:32])[CH2:8][O:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][C@@H:19]1[CH2:20][CH2:21][CH:22]([OH:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH:6][CH2:7][CH2:8][O:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C@@H:19]([CH2:20][CH2:21][CH:22]([OH:30])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]
Reactant: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1CCC(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1CCC(O)Cc1ccccc1
Product: O=C1CCC[C@H](CCC(O)Cc2ccccc2)N1CC#CCOCCO
Yield: 86 %
Yield: 14 %

Procedure:
Sodium borohydride (4.4 mg, 0.12 mmol) followed by MeOH (0.2 mL) was added to a solution of {4-[(R)-2-oxo-6-(3-oxo-4-phenyl-butyl)-piperidin-1-yl]-but-2-ynyloxy}-acetic acid methyl ester (15 mg, 0.039 mmol) in CH2Cl2 (0.6 mL) at 0° C. After 5 min at 0° C. the reaction was quenched with aqueous HCl (0.2 M, 5 mL). The reaction mixture was extracted with CH2Cl2 (3×5 mL), then the combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→5% MeOH/CH2Cl2) afforded 13 mg (86%) of {4-[(R)-2-(3-hydroxy-4-phenyl-butyl)-6-oxo-piperidin-1-yl]-but-2-ynyloxy}-acetic acid methyl ester and 2 mg (14%) of (R)-1-[4-(2-hydroxy-ethoxy)-but-2-ynyl]-6-(3-hydroxy-4-phenyl-butyl)-piperidin-2-one.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[CH2:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH:18]1([CH:4]([C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6])[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrC1CCCC1
Reactant: CCCCOC(=O)CC(=O)OCCCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)C(C(=O)OCCCC)C1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
A 0.5-liter three-neck flask equipped with a stirrer was purged with nitrogen gas, and 7.2 g (0.3 mols) of sodium hydride and 250 ml of dewatered tetrahydrofuran were put thereinto in a nitrogen stream atmosphere. With stirring, the mixture was cooled to 0° C., and, while its temperature was kept cooled, 66 ml (0.3 mols) of di-n-butyl malonate was dropwise added thereto over a period of 30 minutes. After the addition, the mixture was heated up to room temperature, and 32 ml of cyclopentyl bromide was dropwise added thereto, and refluxed for 5 hours. After this was cooled to room temperature, 10 g of sodium hydride and 32 ml of cyclopentyl bromide were added thereto, and refluxed further for 8 hours. The resulting reaction mixture was washed with 200 ml of water, and subjected to distillation under reduced pressure to obtain 20 g of di-n-butyl cyclopentylmalonate. The yield was 23.5%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH:26]([CH3:28])[CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.BrC1[S:38][C:39]2[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:38][C:39]4[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=4[N:41]=3)[CH2:14][C@H:13]2[NH:25][CH:26]([CH3:27])[CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(C)C)nc1Cl
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc2nc(N3CC[C@@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NC(C)C)C3)sc12
Yield: 28.1 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl trans(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(isopropylamino)piperidine-1-carboxylate obtained in Example (211a) (20.0 mg, 0.048 mmol), 4 N hydrochloric acid/1,4-dioxane (2 mL), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (15 mg, 0.053 mmol) and sodium carbonate (51 mg, 0.483 mmol), to obtain 7 mg of the title compound (28%) as a colorless solid.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][OH:8])(=[O:4])=[O:3].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:27][C:28]1[CH:47]=[CH:46][C:31]([NH:32][C:33]2[C:42]3[C:37](=[CH:38][C:39](O)=[C:40]([O:43][CH3:44])[CH:41]=3)[N:36]=[CH:35][N:34]=2)=[C:30]([F:48])[CH:29]=1.C(P(CCCC)CCCC)CCC.Cl>C(Cl)Cl.CC(C)=O.CO.C(Cl)Cl>[ClH:27].[Cl:27][C:28]1[CH:47]=[CH:46][C:31]([NH:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[C:40]([O:43][CH3:44])[CH:41]=3)[N:36]=[CH:35][N:34]=2)=[C:30]([F:48])[CH:29]=1
Reactant: CS(=O)(=O)CCCO
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: Cl
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCS(C)(=O)=O
Reaction time: 18 h
Yield: 57.2 %

Procedure:
3-(Methylsulphonyl)propan-1-ol (0.6 g, 4.3 mmol) followed by 1,1′-(azodicarbonyl)dipiperidine (4.2 g, 16 mmol) in portions were added to a stirred solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.5 g, 4.7 mmol), (prepared as described for the starting material in Example 2), and tributylphosphine (4.0 ml, 16 mmol) in methylene chloride (50 ml) under nitrogen. The mixture was stirred for 18 hours, the resulting precipitate was collected by filtration and dried to give crude product (1.36g). The solvent was removed from the filtrate by evaporation and the residue was purified by column chromatography eluting with methylene chloride/methanol (a gradient from 100/0 to 90/10). The semi-purified product was triturated with acetone and the solid product collected by filtration and dried to give further crude product (0.53 g). The filtrate from the trituration was repurified by column chromatography as before to give freer crude product (0.23 g). The crude products were combined and dissolved in acetone/methanol/methylene chloride and ethereal hydrogen chloride (6 ml of a 1M solution) added. The precipitated product was collected by filtration and recrystalilsed from methanol/methylene chloride/hexane to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3(methylsulphonyl)propoxy)quinazoline hydrochloride (640 mg, 29%).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[N:9]=[C:8]([OH:16])[CH:7]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].F[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1.OC1N=CC=CC=1C([O-])=O>CN(C=O)C>[CH:1]([O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[N:9]=[C:8]([O:16][C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[CH:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cc(O)nc(OC(C)C)c1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: O=C([O-])c1cccnc1O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(Oc2ccc(C#N)cc2)nc(OC(C)C)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
2-Hydroxy-6-isopropoxy-isonicotinic acid isopropyl ester (0.5 g, 2.09 mmol) and 0.577 g (4.18 mmol) potassium carbonate was dissolved in 5 ml of dry DMF. 0.25 g (2.09 mmol) of 4-fluorobenzonitrile, dissolved in 5 ml of DMF, was added to the stirred solution of hydroxynicotinate over a period of 15 min and then the contents of the reaction flask were stirred overnight at 100° C. Reaction mixture was concentrated and the residue was dissolved in 100 ml of ethylacetate and washed with water. Ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 0.3 g of required product which was used for the next step without further purification. 1H NMR (CDCl3): δ 1.2 (6H, d), 1.35 (6H, d), 4.8 (1H, m), 5.25 (1H, m), 7.2 (3H, m), 7.7 (3H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[N:15]=[C:14]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C1C(=O)N([I:38])C(=O)C1.O>CC(O)=O.C(Cl)Cl.C(Cl)Cl>[I:38][C:13]1[C:14]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[N:15][N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[C:12]=1[NH:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-c2cc(Nc3ccc(C)cc3C(=O)O)n(-c3ccccc3C)n2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(-c2nn(-c3ccccc3C)c(Nc3ccc(C)cc3C(=O)O)c2I)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.4 %

Procedure:
To a solution of 5-methyl-2-{[1-(2-methylphenyl)-3-(4-methylphenyl)-1H-pyrazol-5-yl]amino}benzoic acid (Example 65), (49.5 mg, 0.13 mmol) in AcOH/DCM (1:1, v/v) (2 mL) was added a solution of NIS (28 mg, 0.13 mmol) in DCM (1 mL). The reaction was stirred at rt for 3 h. Water (1 mL) was added to the reaction mixture. The water layer was extracted with DCM (2 mL), and the combined organic layers were washed with sodium sulfite and brine, and concentrated under reduced pressure. The crude product was subjected to HPLC purification with a gradient elution from 30% to 95% acetonitrile in water to afford 9.1 mg (14%) of the title compound. 1H NMR (300 MHz, CD2Cl2) δ 8.88 (s, 1H), 7.85 (d, 2H), 7.74 (s, 1H), 7.18-7.32 (m, 7H), 6.58 (d, 1H), 2.41 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H). ES-MS m/z 524.1 (MH+); HPLC RT (min) 4.35.
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]1[C@@:39]2([CH3:40])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:41])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:34])[CH2:21][C:22]#[C:23][C:24]([O:27]C2CCCCO2)([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:42]C2CCCCO2)[CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[OH:7][C@@H:8]1[C@@:39]2([CH3:40])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:41])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:34])[CH2:21][C:22]#[C:23][C:24]([OH:27])([CH3:25])[CH3:26])[CH2:11][C@@H:10]([OH:42])[CH2:9]1
Reactant: C[C@H](CC#CC(C)(C)OC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: C[C@H](CC#CC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A solution of 1.0 g (1.5 mmol) of 1α,3β,25-tris[(tetrahydro-2H-pyran-2-yl)oxyl]-cholest-5-en-23-yne in 14 ml of methanol was treated with 50 mg of p-toluenesulphonic acid monohydrate, and the mixture was left at room temperature for 1 hour. 16 ml of water was added dropwise while stirring. The separated material was filtered off under suction and dried. After chromatography on 60 g of silica gel with hexane/ether (1:1) and ethyl acetate, there was obtained 0.49 g (79%) of crystalline 1α,3β,25-trihydroxy-cholest-5-en-23yne of melting point 204°-206° C. Recrystallization of a sample from acetone gave crystals of melting point 205°-206° C.; [α]D25 =-12.6° (c=0.5 in methanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH:7]=S(C)C)([CH3:4])([CH3:3])[CH3:2].[CH3:12][C:13](=[O:16])[CH:14]=[CH2:15]>ClCCl>[C:1]([O:5][C:6]([C@@H:7]1[CH2:15][C@H:14]1[C:13](=[O:16])[CH3:12])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(C)=CC(=O)OC(C)(C)C
Reactant: C=CC(C)=O
Solvent: ClCCl
Product: CC(=O)[C@@H]1C[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (dimethyl-λ4-sulfanylidene)-acetic acid tert-butyl ester (6.3 g, 35.7 mmol) (CAS 195453-96-4; K. Saigo et al., J. Org. Chem. 2006, 71, 1633-1639) in dichloromethane (36 ml) was treated dropwise at 15° C. with but-3-en-2-one (2.64 g, 3.1 ml, 35.7 mmol) keeping the internal temperature below 27° C. The yellow mixture was stirred overnight at room temperature. For the workup, all volatiles were evaporated to give a yellow oil. The crude oil was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 80:20 as the eluent. The (1R,2R)-rel-2-acetyl-cyclopropanecarboxylic acid tert-butylester was obtained as a colorless oil (5.48 g, 83% yield). MS (ISP): m/z=185.0 [M+H]+.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]1([CH2:14][OH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:17][O:18][C:19](=[O:26])[C:20]([CH2:23][CH2:24][CH3:25])(C)[NH2:21].C(N(CC)CC)C.Cl.[Cl-].[Na+]>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:26])[CH:20]([NH:21][S:2]([NH:5][C:6]([O:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])(=[O:4])=[O:3])[CH2:23][CH2:24][CH3:25]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCCC(C)(N)C(=O)OC
Reactant: OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(NS(=O)(=O)NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Yield: 35 %

Procedure:
To a stirred solution of 15.4 9 ml (0. 178 mol) of chlorosulfonyl isocyanate in methylene chloride was added phenylmethanol (18.5 ml, 0.178 mol) at 0°-5° C. After stirring the above cold solution at this temperature, a solution of 34.9 g (0.192 mol) of 2-propyl-DL-alanine methyl ester hydrochloride in 350 ml of methylene chloride containing triethylamine (73.86 ml, 0.532 mol) was added, and the resulting mixture was stirred for 17 hours allowing the mixture to warm to room temperature. To the reaction mixture was added 500 ml of 10% aq. HCl solution saturated with sodium chloride, and the organic layer was separated. The aqueous layer was extracted with methylene chloride (2×100 ml) and the combined organic layer was dried over magnesium sulfate, concentrated in vacuo, and the residual brown oil was purified by flash chromatography (30% ethyl acetate in hexane) followed by crystallization from ether/hexane to afford 22.35 g (35%) of N-(carbobenzyloxyaminosulfonyl)-2-propyl-DL-alanine methyl ester (Formula XIV: R=CH3 ; R1 =propyl; R2 =CH3 ; R3 =H) as a white solid, m.p. 97°-99° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[C:12]([OH:14])[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].C([O:20][C:21]([C:23]1([NH:28][C:29]([CH:31]2[CH2:35][CH:34](O)[CH2:33][CH:32]2[C:37](=[O:46])[N:38]([CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=[CH2:45])[CH3:39])=[O:30])[CH2:25][CH:24]1C=C)=[O:22])C>>[CH2:1]([O:3][C:4]1[N:13]=[C:12]([O:14][CH:34]2[CH2:35][CH:31]3[CH:32]([C:37](=[O:46])[N:38]([CH3:39])[CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=[CH:45][CH:25]4[C:23]([C:21]([OH:20])=[O:22])([NH:28][C:29]3=[O:30])[CH2:24]4)[CH2:33]2)[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Reactant: CCOc1nc(O)c2ccc(OC)c(C)c2n1
Product: CCOc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1

Procedure:
Reaction of the quinazolinol (148) and the alcohol (143) according to the procedure described in examples 144-146, gave the title compound m/z=567 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][CH:10]([CH3:18])[N:9]2[CH:19]=1)([O:3][CH2:4][CH3:5])=[O:2].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].[OH-].[Na+]>CC(C)=O.O>[C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]([CH3:18])[N:9]2[CH:19]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1cc2n(c1)C(C)Nc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2n(c1)C(C)N(C(=O)OCC)c1ccccc1-2

Procedure:
A solution of the product of Example XXXVIII (3.0 g, 0.0117 m) and ethyl chloroformate (12.6 g, 0.117 m) in acetone (50 ml) and H2O (50 ml) was treated with NaOH (0.21 ml aq. 30%) and the mixture refluxed for 1 hr. The acetone was removed in vacuo and the aqueous residue cooled in ice-bath. A solid formed and this was filtered, washed with water, and dried in vacuo. The crude product (3.4 g) was crystallized from methanol (25 ml) to afford the desired product; m.p. 125°-127°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21]>>[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(F)c(F)c1
Reactant: Clc1ncnc2ccc(-n3ccnc3)cc12
Product: Fc1ccc(Nc2ncnc3ccc(-n4ccnc4)cc23)cc1F
Yield: 35 %

Procedure:
Using an analogous procedure to that described in Example 4, 4-chloro-6-(1-imidazolyl)quinazoline was reacted with 3,4-difluoroaniline to give 4-(3,4-difluoroanilino)-6-(1-imidazolyl)quinazoline in 35% yield, NMR Spectrum: (CD3SOCD3) 7.2 (s, 1H), 7.4-7.7 (m, 3H), 7.95 (d, 1H), 8.1 (m, 1H), 8.2 (m, 1H), 8.4 (s, 1H), 8.65 (s, 1H), 8.7 (d, 1H), 9.7 (broad s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][NH:27][CH3:28]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][C:23]([N:27]([CH3:28])[CH3:26])=[O:25])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCCCC(=O)O)cc2C1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)CCCOc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2
Reaction time: 0.75 h
Yield: 92.1 %

Procedure:
(S)-4-[2-(tert-Butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yloxy]butyric acid (399 mg) was dissolved in tetrahydrofuran (5 ml), and N,N'-carbonyldiimidazole (204 mg) was added to the solution under ice-cooling with stirring. After reaction for 2 hours, a solution of dimethylamine (1.40 g) in tetrahydrofuran (2 ml) was added to the reaction mixture under ice-cooling with stirring. After reaction for 45 minutes and then at room temperature for 45 minutes, the reaction mixture was concentrated in vacuo. Water was added to the resulting residue and the mixture was extracted with diethyl ether. The extract was washed with 10% aqueous citric acid solution, water, a saturated aqueous sodium bicarbonate solution and water successively, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give (S)-4-[2-(tert-butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylbutyramide (396 mg) having a melting point of 97-101° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(NC(C)C)(C)C.[Li].CN(C)CCN(C)C.I[CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36]>C1COCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:8][C:6]([NH:5][CH:4]([CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:3]([O:2][CH3:1])=[O:16])=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CNC(=O)OCc1ccccc1
Reactant: C[Si](C)(C)CI
Agent: CN(C)CCN(C)C
Agent: [Li]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C[Si](C)(C)C)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
A solution of 5.58 g (25 mmol) of N-benzyloxycarbonyl glycine methyl ester in dry THF (70 ml) is added dropwise to a solution at -78° C. of lithium diisopropylamine (8.76 ml, 62.5 mmol) and tetramethylethylene diamine (9.43 ml, 62.5 mmol) in dry THF (100 ml), under nitrogen. After the addition is complete, the solution is stirred for 2 hours at -78° C., then 15 minutes at -30° C. and cooled to -78° C. A solution of 5.36 g (25 mmol) of iodomethyl-trimethylsilane in dry hexamethylphosphoramide (39 ml) is added dropwise to the resultant syrupy mixture. After the addition is complete, the reaction mixture is warmed up to -50° C., kept at this temperature for 1 hour and cooled to -78° C., just before hydrolysis. The reaction mixture is quenched by addition of water and ammonium chloride and diluted with ether. The organic layer is washed with 1N potassium hydrogen sulfate, twice with water and dried over sodium sulfate. The solvent is evaporated and the residue obtained (8.03 g) is purified by flash chromatography (silica gel,ethyl acetate/petroleum ether: 2/8). 4.30 g of the title compound are obtained (yield: 56%) (colorless oil). Rf : 0.51 (ethyl acetate/petroleum ether: 2/8).
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])C.ClC(Cl)(O[C:25](=[O:31])OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH:8]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:25](=[O:31])[N:16]([CH:17]2[CH2:18][CH2:10][CH2:9][CH2:8][CH2:13]2)[CH:19]2[CH2:20][CH2:3][CH2:2][CH2:1][CH2:6]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCN(CC)CC
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C(N(C1CCCCC1)C1CCCCC1)N(C1CCCCC1)C1CCCCC1
Reaction time: 8 h

Procedure:
A solution of dicyclohexylamine (3.9 mL, 19 mmol) and triethylamine (6 mL, 43 mmol) in THF (64 mL) was added dropwise to a stirred solution of triphosgene (1.99 g, 6.7 mmol) in THF (35 mL) at room temperature. The reaction mixture was stirred overnight. Then, a solution of dicyclohexylamine (3.9 mL, 18 mmol) and triethylamine (6 mL, 43 mmol) in THF (37 mL) was added. The reaction mixture was stirred overnight at reflux temperature. The reaction mixture was filtered and the filtrate was evaporated to dryness, yielding tetracyclohexylurea as a yellow solid. Yield: 4.5 g (65%). A solution of oxalyl chloride in dichloromethane (1.1 mL, 13 mmol) was added to a stirred solution of the urea (4.5 g, 11 mmol) in THF (50 mL). The reaction mixture was evaporated to dryness after overnight heating to reflux. A solution of ammonia in methanol (5 mL, 35 mmol, 7 M) was added to a solution of the formed solid in THF (40 mL). The reaction mixture was heated to reflux overnight and evaporated to dryness. The product was neutralized and treated with aqueous sodium hydroxide solution. The organic layer was extracted with diethyl ether and dried over magnesium sulfate. Crystallization from hexanes yielded the desired guanidine as a brown solid. Yield: 2.9 g (64%). 13C NMR (CDCl3, 75 MHz): δ 25.4, 26.2, 31.8, 58.0, 156.2 ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:24][C:10]3=[CH:11][C:12]4[C:13]([CH3:23])([CH3:22])[C:14](=[O:21])[N:15]([CH:18]([CH3:20])[CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>>[CH:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:28]([CH:25]5[CH2:27][CH2:26]5)=[O:29])=[CH:6][NH:5][N:4]=4)[NH:24][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:23])[C:14]1=[O:21])([CH3:19])[CH3:20]
Reactant: CC(C)N1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)C1CC1
Product: CC(C)N1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)C4CC4)nc3cc21

Procedure:
Cyclopropanecarboxylic acid[3-(5-isopropyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-isopropyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (325 mg, 0.90 mmol) and cyclopropanecarbonyl chloride (92 μl, 0.99 mmol). The title compound was obtained as dark green powder (85 mg, 22%).