Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:20]=2[C:28]#[N:29])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].[Cl-].[Ca+2].[Cl-].O>C(O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:30]=[CH:31][CH:32]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=3)[CH:17]=[CH:16][CH:15]=2)=[C:20]([C:28]#[N:29])[CH:21]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])cc3C#N)c2)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)cc3C#N)c2)c1
Temperature: 80 °C
Yield: 81.9 %

Procedure:
A suspension of 3-(1-cyano-1-methylethyl)-N-[3-(2-cyano-4-nitrophenoxy)phenyl]benzamide (4.18 g, 9.80 mmol), calcium chloride (3.43 g, 29.4 mmol) and reduced iron (2.73 g, 49.0 mmol) in ethanol (70 mL)/water (7 mL) was stirred with heating at 80° C. for 16 hr. The reaction mixture was cooled to room temperature, and insoluble material was filtered off through a pad of celite and washed with ethanol. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (200 mL×2) and saturated brine (200 mL×2), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (3.18 g, 82%) as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].[CH2:13]([Mg]Br)[CH2:14][CH:15]=[CH2:16]>>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1)([OH:5])[CH2:16][CH2:15][CH:14]=[CH2:13]
Reactant: O=C(CCCl)c1ccc(F)cc1
Reactant: C=CCC[Mg]Br
Product: C=CCCC(O)(CCCl)c1ccc(F)cc1

Procedure:
1-chloro-3-(4-fluorophenyl)hept-6-en-3-ol was prepared from 3-chloro-1-(4-fluorophenyl)propan-1-one and 3-butenylmagnesium bromide following a procedure analogous to that described in Example 110 Step 1.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[C:14]=2[CH3:20])=[CH:8][C:7]=1[CH3:21].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:15]2[C:14]([CH3:20])=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2C)cc1C
Reactant: Oc1ccc(Cl)cc1Oc1ccccc1
Product: Cc1cc(Oc2cccc(Oc3ccc(Cl)cc3Oc3ccccc3)c2C)ccc1CCC(=O)O
Yield: 9 %

Procedure:
3-[4-(3-bromo-2-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester is reacted with 4-chloro-2-phenoxy-phenol as in Example 18 to afford 0.031 g (9%) of the title compound. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H25O5Cl 488, found 489 and 491 (M+1 and M+3, 100%).
Reaction SMILES: O=S1(=O)CCC(NCC[NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)C1.Cl[CH2:51][CH2:52][N:53]1[CH2:59][C:55]2([CH2:58][O:57][CH2:56]2)[CH2:54]1>>[CH2:58]1[C:55]2([CH2:59][N:53]([CH2:52][CH2:51][NH:10][C@:11]34[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]3[C@@H:13]3[C@@:26]([CH3:29])([CH2:27][CH2:28]4)[C@@:25]4([CH3:30])[C@@H:16]([C@:17]5([CH3:42])[C@@H:22]([CH2:23][CH2:24]4)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]4[CH:34]=[CH:35][C:36]([C:37]([OH:39])=[O:38])=[CH:40][CH:41]=4)=[CH:19][CH2:18]5)[CH2:15][CH2:14]3)[CH2:54]2)[CH2:56][O:57]1
Reactant: ClCCN1CC2(COC2)C1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNC3CCS(=O)(=O)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CC4(COC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1,1-dioxidotetrahydrothiophen-3-yl)amino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 6-(2-chloroethyl)-2-oxa-6-azaspiro[3.3]heptane (prepared as described below) as the alkylating reagent in Step 3. The product was isolated as a white solid (1.1 mg, 18%). LCMS: m/e 655.53 (M+H)+, 2.29 min (method 11). 1H NMR (500 MHz, Acetic) δ 8.04 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 5.37 (d, J=4.9 Hz, 1H), 4.93 (s., 4H), 4.86 (s, 1H), 4.75 (br. s., 1H), 4.71-4.32 (m, 4H), 4.05-3.86 (m, 2H), 3.70-3.40 (m, 2H), 3.00-2.66 (m, 1H), 2.25-1.05 (m, 22H), 1.76 (s, 3H), 1.18 (s, 3H), 1.13 (s, 3H), 1.08 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [CH:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:20]=1[C:21]([N:23]=[C:24]=[O:25])=[O:22].CN(C=O)C>O>[CH3:31][O:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:19]([O:18][CH3:17])[C:20]=1[C:21]([NH:23][C:24]([NH:16][C:13]1[CH:12]=[N:11][C:10]([S:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)(=[O:8])=[O:9])=[CH:15][CH:14]=1)=[O:25])=[O:22]
Reactant: COc1cccc(OC)c1C(=O)N=C=O
Reactant: Nc1ccc(S(=O)(=O)C2CCCCC2)nc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(OC)c1C(=O)NC(=O)Nc1ccc(S(=O)(=O)C2CCCCC2)nc1

Procedure:
2-Cyclohexylsulfonyl-5-aminopyridine (1.0 gram) and 2,6-dimethoxybenzoyl isocyanate (0.9 gram) were mixed in 50 ml. of DMF and stirred at room temperature overnight (about 18 hours). The reaction mixture was then poured into water and filtered to separate the product. It was crystallized from ethyl acetate-hexanes, yield 0.5 gram, m.p., 123°-125° C.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]3[CH:33]=[C:32]4[C:27]([CH2:28][CH2:29][NH:30][CH2:31]4)=[CH:26][CH:25]=3)[N:21]=[C:20]([NH2:34])[N:19]=2)[CH2:14][CH2:13]1>>[NH2:34][C:20]1[N:21]=[C:22]([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][N:30]([C:8]([NH:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:9])[CH2:31]3)=[CH:26][CH:25]=2)[CH:23]=[C:18]([N:15]2[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]2)[N:19]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)NC3CCCCC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5 starting from cyclohexylisocyanate and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=450.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([OH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].IC.[C:20]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([O:17][CH3:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1oc2ccc(Br)c(O)c2c1C
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2ccc(Br)c(OC)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To 200 mg (0.67 mmol) of 5-bromo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 0.5 mL of iodomethane, 200 mg of K2CO3 and 2 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent in vacuo gave 185 mg (88% yield) of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C=CC=CC=1>C(O)C>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:3][CH:4]=3
Reactant: Cc1ccc(-n2c3ccc(Br)cc3c3cc(Br)ccc32)cc1
Reactant: OB(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-n2c3ccc(Br)cc3c3cc(-c4ccccc4)ccc32)cc1
Yield: 51.7 %

Procedure:
3,6-Dibromo-N-(4-methylphenyl)carbazole (6.23 g) and phenylboronic acid (2.01 g) were added to a solvent mixture of toluene (60 mL) and ethanol (15 mL), followed by bubbling with nitrogen. Then, tetrakistriphenylphosphine palladium (290 mg) and 21.2% aqueous sodium carbonate solution (15.0 g) were added to the mixture, and the resultant mixture was refluxed under nitrogen flow for 5 hours. The mixture was diluted with toluene. The toluene layer was washed with water and dried and the toluene was evaporated. The residue was treated through silica gel column chromatography (eluent: toluene/hexane=1/4 (by mass)), to thereby obtain 3.20 g of 3-bromo-6-phenyl-N-(4-methylphenyl)carbazole as colorless powder.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:13][C:14]1[C:15](Cl)=[N:16][CH:17]=[C:18]([CH:22]=1)[C:19]([OH:21])=[O:20].CC(C)([O-])C.[K+]>CS(C)=O.C(OCC)(=O)C.Cl>[C:1]12([CH2:11][O:12][C:15]3[C:14]([Cl:13])=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1
Temperature: 80 °C
Yield: 42 %

Procedure:
A mixture of 1-adamantylmethanol (5.32 g, 32.00 mmol), 5,6-dichloronicotinic acid (6.14 g, 32.00 mmol) and potassium tert-butoxide (8.3 g, 73.60 mmol) in anhydrous dimethyl sulfoxide (100 mL) was heated to 80° C. under nitrogen for 1 h. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (500 mL) and 1.0 M aqueous hydrochloric acid (300 mL). The layers were separated and the organic layer was washed with 1.0 M aqueous hydrochloric acid (100 mL), brine (2×100 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was triturated with diethyl ether to afford the title compound as a white solid (4.32 g, 42%); 1H NMR (300 MHz, DMSO-d6) 13.23 (br s, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 3.95 (s, 1H), 2.00-1.88 (m, 3H), 1.71-1.50 (m, 12H); MS (ES−) m/z: 320.3, 322.3 (M−1).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[NH:14][CH:13]=[CH:12][N:10]3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[CH2:22]([O:21][C:19]([CH2:18][N:14]1[C:9]2[N:10]([N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[CH:12]=[CH:13]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: c1ccc(-c2cc3[nH]ccn3n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccn2nc(-c3ccccc3)cc12
Reaction time: 1 h

Procedure:
A solution of 0.4 g of 6-phenyl-1H-imidazo[1,2-b]pyrazole in 10 ml of dimethylformamide was slowly added dropwise, whilst stirring at room temperature, to 96 mg of a 55% w/w suspension of sodium hydride in mineral oil, which was itself suspended in 10 ml of dimethylformamide, and then the mixture was stirred for a further 1 hour. At the end of this time, 0.24 ml of ethyl bromoacetate and 10 ml of dimethylformamide were added, and then the whole mixture was stirred at room temperature for 3 hours. The reaction mixture was then partitioned between ethyl acetate and water, and then the organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified first by column chromatography through silica gel, eluted with a 1:1 by volume mixture of ethyl acetate and hexane, and then by recrystallization from a mixture of ethyl acetate and hexane, to give 0.38 g of the title compound in the form of plates melting at 85°-87° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClC(Cl)C>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([C:29]3[C:30]([O:36][CH3:37])=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:28]=3[O:27][CH3:26])[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1cc(OC)cc(OC)c1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COc1cc(OC)c(-c2nc(Nc3ccc(OC)c(Cl)c3)nc(NC3CCCCCC3)n2)c(OC)c1
Temperature: 80 °C

Procedure:
A mixture of compound 133 (0.5 grams), 1,3,5-trimethoxybenzene (0.2 grams) and AlCl3 (0.2 grams) in dichloroethane (10 mL) was stirred under nitrogen atmosphere. It was then heated at 80° C. for 3 hours. The reaction mixture was poured into ice-cold water (50 mL), extracted with chloroform and the organic layer was washed with water followed by concentration. The residue thus obtained was purified by column chromatography using petroleum ether-ethyl acetate to afford the N-(3-Chloro-4-methoxy-phenyl)-N′-cycloheptyl-6-(2,4,6-trimethoxy-phenyl)-[1,3,5]triazine-2,4-diamine.
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)C.[H-].[Na+].[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][CH2:24][CH2:25]Br)([CH3:19])([CH3:18])[CH3:17]>CS(C)=O>[CH2:16]([O:20][C:21](=[O:27])[CH2:4][CH:5]([C:6]1[CH:7]=[CH:8][C:9]([Br:12])=[CH:10][CH:11]=1)[CH2:25][CH2:24][CH2:23][NH:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:27])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)CC(CCCNC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reaction time: 0.05 h
Yield: 137.7 %

Procedure:
A solution of (4-bromo-phenyl)-acetic acid ethyl ester (2.31 g, 9.50 mmol) in dimethylsulfoxide (6 mL) was added to the suspension of sodium hydride (407 mg, 60% in oil, 10.17 mmol) and stirred 3 min. A solution of (3-bromo-propyl)-carbamic acid tert-butyl ester (2.03 g, 8.52 mmol) in dimethylsulfoxide (6 mL) was added to the solution and stirred at 50° C. for 30 min. The resulting solution was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried by passing through Celite column, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting ethyl acetate/hexane (4/1 to 3/1, v/v) to afford 3-(4-Bromo-phenyl)-6-tert-butoxycarbonylamino-hexanoic acid ethyl ester (2.43 g, 74%).
Reaction SMILES: [OH:1][C@@:2]([CH3:11])([CH2:9][OH:10])[C:3](N(OC)C)=[O:4].[OH2:12].[OH-].[Li+:14]>CO>[OH:1][C@@:2]([CH3:11])([CH2:9][OH:10])[C:3]([O-:4])=[O:12].[Li+:14]
Reactant: CON(C)C(=O)[C@@](C)(O)CO
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: C[C@](O)(CO)C(=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.2 %

Procedure:
To a solution of the compound prepared in Example 130(a) (565 mg) in methanol (7.0 mL) was added lithium hydroxide monohydrate (146 mg) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to give the title compound (446 mg) having the following physical data.
Reaction SMILES: C1(C[C@H]([NH:15][C:16](=[O:49])[C@@H:17]([NH:31][C:32](=[O:48])[C@@H:33]([CH2:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:18][C:19]2[N:20](C(OC(C)(C)C)=O)[CH:21]=[N:22][CH:23]=2)C(O)C[N+]([O-])=O)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:44][C:43]([CH3:46])([CH3:45])[C:42](=[O:47])[CH2:41][C@@H:33]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:32]([NH:31][CH:17]([CH2:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)[C:16]([NH2:15])=[O:49])=[O:48]
Reactant: CC(C)(C)OC(=O)n1cncc1C[C@H](NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1)C(=O)N[C@@H](CC1CCCCC1)C(O)C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)C(=O)C[C@@H](Cc1ccccc1)C(=O)NC(Cc1c[nH]cn1)C(N)=O

Procedure:
In an analogous manner to that described in Example 4 by cleaving off the Boc protecting group from (S)-N-[(1S, 2RS)-1-(cyclohexylmethyl)-2-hydroxy-3-nitropropyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]-3-t-butoxycarbonylimidazole-4-propionamide with potassium carbonate in methanol and subsequently purifying by chromatography on 50 g of silica gel using a 200:10:1 mixture of methylene chloride, methanol and ammonia as the eluting agent there were obtained the two epimeric compounds (S)-N-[(1S,2S or R)-1-(cyclohexylmethyl)-2-hydroxy-3-nitropropyl]-α-[(R)-α-(3 3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4-propionamide and (S)-N[(1S,2R or S)-1-(cyclohexylmethyl)-2-hydroxy-3-nitropropyl]-α-[(R)-α-(3.3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4-propionamide, in both cases as a foam, MS (each): 584 (M+H)+.
Reaction SMILES: O[CH:2]([CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[CH2:3][CH2:4][CH2:5][CH3:6].C(O)(=O)C(O)=O>C1(C)C=CC=CC=1>[CH:2](=[C:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(O)C1CCCC1=O
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Product: CCCCC=C1CCCC1=O
Yield: 83.1 %

Procedure:
In a 300 ml four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were placed 2-(1-hydroxypentyl)cyclopentanone (70 g) synthesized in Reference Example 1, oxalic acid (0.7 g) and toluene (140 ml), and the whole was refluxed to allow dehydration to proceed. The formed water was removed and the reaction was continued until water was not formed any more (about 2.5 hours). The reaction mixture was washed with water and the layers were separated from each other. The resulting organic layer was further washed with saturated brine and separated. The organic layer was evaporated on a rotary evaporator under reduced pressure to recover toluene and unreacted cyclopentanone, whereby a crude product (63 g) was obtained. The product was distilled using a Widmer distillation apparatus to obtain 52 g of 2-pentylidenecyclopentanone (boiling point: 92° C./533 Pa).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=2)=[C:9]([CH3:22])[CH:8]=1)=[O:5])[CH3:2].[CH2:23]([N:25]1[CH2:30][CH2:29][C:28]2([C:41]3[C:33](=[CH:34][C:35]4[CH2:36][CH2:37][NH:38][C:39]=4[CH:40]=3)[O:32][CH2:31]2)[CH2:27][CH2:26]1)[CH3:24]>>[CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([N:38]3[C:39]4[CH:40]=[C:41]5[C:28]6([CH2:31][O:32][C:33]5=[CH:34][C:35]=4[CH2:36][CH2:37]3)[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27]6)=[O:20])=[CH:15][CH:14]=2)=[C:9]([CH3:22])[CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Reactant: CCN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: CCOC(=O)Nc1ccc(-c2ccc(C(=O)N3CCc4cc5c(cc43)C3(CCN(CC)CC3)CO5)cc2)c(C)c1
Yield: 61 %

Procedure:
This compound was prepared from 4'-(ethoxycarbonylamino)-2'-methylbiphenyl-4-carboxylic acid (D61) and 1'-ethyl-2,3,6,7-tetrahydrosprio[furo[2,3-f]indole-3,4'-piperidine] (D109), following the procedure of Example 29. This gave the title compound (61%) as a straw coloured foam, which was converted to its hydrochloride salt.
Reaction SMILES: [C:1]([CH:6]1[CH2:15][CH2:14][C:13]2[NH:12][C:11](=[O:16])[N:10]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])[N:19]=[C:9]3[C:8]=2[CH2:7]1)([O:3]CC)=[O:2].Cl>[OH-].[Na+]>[C:1]([CH:6]1[CH2:15][CH2:14][C:13]2[NH:12][C:11](=[O:16])[N:10]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])[N:19]=[C:9]3[C:8]=2[CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
To 20 mL of 1N NaOH was added 9-Carboethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (400 mg). After the solid dissolved, the mixture was stirred for 40 minutes at 60° C., cooled and the pH adjusted to 3 with concentrated HCl. The solid was collected and dried to yield 9-Carboxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (Compound 17), m.p.>325° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15](O)=[O:16])[CH:5]=[CH:4][C:3]1=2.[CH3:19][NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1>>[CH3:19][N:20]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[C:15](=[O:16])[CH2:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:1])([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1
Reactant: CC1(C)CCC(C)(C)c2cc(CC(=O)O)ccc21
Reactant: CNc1ccc(C(=O)OC)cc1
Product: COC(=O)c1ccc(N(C)C(=O)Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 53.4 %

Procedure:
In a manner similar to Example 4(c), by reaction of 2.46 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetic acid with 1.65 g (10 mmol) of methyl 4-methylaminobenzoate, 2.1 g (54%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:13][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(C)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(Br)c1ccccc1
Temperature: 25 °C

Procedure:
A carbon tetrachloride (150 mL) solution of the intermediate from Step A (10.39 g, 66.6 mmol), N-bromosuccinimide (14.22 g, 80 mmol) and AIBN (0.547 g, 3.33 mmol) was heated to reflux. After 4 hours the reaction solution was cooled to room temperature and the mixture filtered. The filtrate was concentrated and the residue purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR (500 MHz, CHCl3-d): δ 7.59-7.53 (m, 2H); 7.37-7.30 (m, 3H); 3.80 (s, 3H); 2.31 (s, 3H).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15]([CH2:19][C:20](Cl)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>O1CCCC1>[CH3:16][C:15]([CH3:18])([CH3:17])[CH2:19][C:20]([NH:14][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:21]
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)CC(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 53.7 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (1.1 g, 6.0 mmol), t-butylacetyl chloride (0.93 mL, 6.6 mmol), and triethylamine (2.6 mL, 18 mmol) in tetrahydrofuran (11 mL) provided 3,3-dimethyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-butyramide (0.92 g). Mp 164-165° C.; Anal. Calcd. for C18H23NO2: C, 75.76; H, 8.12; N, 4.91; Found: C, 75.62; H, 8.18; N, 5.00.