Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH2:9]O)=[CH:5][CH:4]=1.S([Cl:17])([CH3:16])(=O)=O.C([N:20]([CH2:23][CH3:24])CC)C>C1C=CC=CC=1>[ClH:17].[CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH2:9][NH:20][CH:23]([CH3:24])[CH3:16])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CSc1ccc(OCCO)cc1
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Product: CSc1ccc(OCCNC(C)C)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 22.2 g (0.121 mole) of 2-[4-(methylthio)phenoxy]ethanol (from preparation 35), 16.41 g (0.143 mole) of mesyl chloride and an excess of triethylamine in 800 ml of benzene was stirred at room temperature for 2 hours. The mixture was extracted with water and then with dilute sodium hydroxide. The benzene solution was dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was dissolved in 300 ml of isopropylamine, and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was dissolved in methylene chloride. The methylene chloride solution was extracted with dilute sodium hydroxide and then with dilute sulfuric acid. The acidic extract was made basic with 50% sodium hydroxide, and the basic solution was extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give the free base of the product as an oil. The free base was convreted to the hydrochloride salt, and the salt was recrystallized from methanol-diethyl ether to give 23.9 g (76%) of the product as a white, crystalline solid, m.p. 183.5°-185° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:60][CH3:61])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[C:53]([CH3:58])=[N:54][CH:55]=[CH:56][CH:57]=2)[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:43](=[O:44])[C@@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[C:53]([CH3:58])=[N:54][CH:55]=[CH:56][CH:57]=2)[C:47]1=[O:59])[CH:41]([CH3:40])[CH2:60][CH3:61])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccnc2C)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2cccnc2C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
A solution containing the product from Example 2C (1.1 g, 2.07 mmol) in THF (20 mL) was treated with the product from Example 15C (0.87 g, 2.07 mmol), DEPBT (0.93 g, 3.11 mmol), and N,N-diisopropylethylamine (1.8 mL, 10.33 mmol), stirred at 25° C. for 3 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with a gradient starting with 0-100% ethyl acetate/dichloromethane, followed by 0-10% methanol in ethyl acetate to give the title compound (1.17 g, 69% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (m, 18 H), 1.29 (m, 1 H), 1.53 (m, 2 H), 1.80 (m, 1 H), 2.48 (s, 3 H), 2.72 (m, 3 H), 2.96 (m, 3 H), 3.50 (s, 3 H), 3.65 (m, 1 H), 3.84 (d, J=9.93 Hz, 1 H), 3.94 (d, J=11.03 Hz, 1 H), 4.15 (m, 2 H), 4.32 (s, 2 H), 4.67 (d, J=7.35 Hz, 1 H), 6.64 (d, J=9.93 Hz, 1 H), 7.09 (m, 5 H), 7.22 (m, 3 H), 7.31 (m, 2 H), 7.52 (dd, J=7.72, 1.47 Hz, 1 H), 7.86 (m, 5 H), 8.36 (dd, J=4.78, 1.47 Hz, 1 H), 8.63 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[CH3:21].Cl[C:36]1[N:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:33][C:2]([F:1])([F:34])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:36]2[N:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][N:37]=2)=[CH:8][C:7]=1[CH3:21]
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ncc(C(F)(F)F)cn3)cc2C)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A reaction mixture of methyl 4-((4,4,4-trifluoro-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)amino)benzoate (0.300 g) obtained in Example 10, step A, 2-chloro-5-(trifluoromethyl)pyrimidine (0.108 g), tetrakistriphenylphosphinepalladium (0.0726 g), sodium carbonate (0.200 g), DME (3 mL) and water (1 mL) was stirred at 130° C. for 1 hr under microwave irradiation under a nitrogen atmosphere. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.259 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2OC(=O)[S:12][N:11]=2)=[CH:4][CH:3]=1.[S:16]([C:26]#[N:27])([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].CCCCC>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:27]=[C:26]([S:16]([C:19]3[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[S:12][N:11]=2)=[CH:6][CH:7]=1
Reactant: O=c1oc(CCc2ccc(Cl)cc2)ns1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Solvent: CCCCC
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(S(=O)(=O)c2nc(CCc3ccc(Cl)cc3)ns2)cc1
Yield: 64.7 %

Procedure:
10.90 g (45.1 mmol) of 5-[2-(4-chlorophenyl)ethyl]-1,3,4-oxathiazol-2-one and 8.58 g (47.4 mmol) of tosyl cyanide are stirred in 11 ml of 1,2-dichlorobenzene at 160° C. for 1 h. Subsequently, the reaction mixture is cooled and treated with 10 ml of pentane, and the precipitate is filtered off and dried under vacuum. 11.06 g of product are obtained (99.9% purity, 64.7% yield, log P (pH 2.3)=4.62).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]12(O)[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>ClCCl.O.C(O)(=O)C>[C:12]12([C:8]3[C:9]([OH:11])=[CH:10][C:2]([OH:1])=[C:3]([CH:7]=3)[C:4]([OH:6])=[O:5])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1ccc(O)cc1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(C23CC4CC(CC(C4)C2)C3)c(O)cc1O
Yield: 51 %

Procedure:
2,4-Dihydroxybenzoic acid (9.24 g) and 1-adamantanol (9.14 g) are dissolved in dichloromethane (200 mL) and then stirred. After adding acetic acid (17.1 mL) mixed with concentrated sulfuric acid (3.3 mL) dropwise, the mixture is stirred at room temperature for 12 hours. After adding water (200 mL), sodium bicarbonate is added until the pH of the solution becomes 6. The produced solid is filtered to obtain 8.82 g of 5-adamantan-1-yl-2,4-dihydroxybenzoic acid as solid of a light color.
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([O:33][CH3:34])[CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21]>>[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([O:33][CH3:34])[CH:24]=1)[CH2:19][C:20]([O:22][CH3:2])=[O:21]
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Reactant: COc1cc(C(N)CC(=O)O)ccc1OC(C)C
Product: COC(=O)CC(N)c1ccc(OC(C)C)c(OC)c1

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)-propionic acid was substituted with 3-amino-3-(3-methoxy-4-isopropoxy-phenyl)propionic acid. 1H NMR (CDCl3): δ 6.82-6.89 (m, 3H), 4.44-4.51 (m, 1H), 4.35 (t, 1H, J=5 Hz), 3.83 (s, 3H), 3.66 (s, 3H), 2.62 (d, 2H, J=5 Hz), 1.81 (s, 2H), 1.33 (d, 6H, J=5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([N+:20]([O-])=O)=[C:9]([C:11]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][C:14]=2I)=[O:12])[CH:10]=1.ClC1C=CC(CC2C=CC([N+]([O-])=O)=C(C(C3N(C)N=CC=3I)=O)C=2)=CC=1>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:20][C:14]3[CH:15]=[N:16][N:17]([CH3:18])[C:13]=3[C:11](=[O:12])[C:9]=2[CH:10]=1
Reactant: Cn1ncc(I)c1C(=O)c1cc(Cc2ccccc2Cl)ccc1[N+](=O)[O-]
Agent: Cn1ncc(I)c1C(=O)c1cc(Cc2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Product: Cn1ncc2[nH]c3ccc(Cc4ccccc4Cl)cc3c(=O)c21

Procedure:
The title compound was prepared according to the procedure of step 5 in EXAMPLE 13 using [5-(2-chlorobenzyl)-2-nitrophenyl](4-iodo-1-methyl-1H-pyrazol-5-yl)methanone (EXAMPLE 15, step 3), instead of [5-(4-chlorobenzyl)-2-nitrophenyl](4-iodo-1-methyl-1H-pyrazol-5-yl)methanone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:22])[CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]2[CH2:33][O:34][CH2:35][CH:29]2[CH2:28]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH:30]5[CH2:33][O:34][CH2:35][CH:29]5[CH2:28]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1O
Reactant: ClCCCN1CCC2COCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OCCCN1CCC2COCC2C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A mixture of 4-((4-bromo-2-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (225 mg, 0.62 mmol, 1 eq), 5-(3-chloropropyl)octahydrofuro[3,4-c]pyridine (151 mg, 0.74 mmol, 1.2 eq) and K2CO3 (171 mg, 1.24 mmol, 2 eq) in DMF (10 mL) was stirred at 80° C. overnight and cooled to room temperature. To this, CH2Cl2 (50 mL) was added. The mixture was washed with brine (20 mL×3) and water (20 mL×2), then dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a yellow solid (199 mg, 60.50%), HPLC: 98.32%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 531.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.69-1.73 (2H, m), 2.41-2.46 (3H, m), 2.64-2.66 (2H, m), 2.68-2.70 (3H, m), 2.75-2.82 (2H, m), 3.00-3.03 (3H, m), 3.06-3.10 (2H, m), 3.81-3.85 (2H, m), 4.23-4.27 (2H, m), 7.06-7.12 (1H, m), 7.21 (1H, s), 7.68-7.79 (2H, m), 7.87 (1H, s), 8.06-8.11 (1H, m), 8.65 (1H, s) ppm.
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:22]1COCC1.[H-].[Na+].CI>O>[CH2:1]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([O:21][CH3:22])[CH:15]=[CH:14]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C1CCOC1
Reactant: CCCCCCCCCCc1ccc2cc(O)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCCCCCCCCCc1ccc2cc(OC)ccc2c1
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, 6-n-decyl-2-hydroxynaphthalene (5.68 g, 20 mmol) and a THF (200 ml) solution of 55% NaH (oil dispersion, 880 mg, 20 mmol) were stirred at room temperature for 40 minutes. CH3I (1.48 ml, 24 mmol) was added to the mixed solution, and the mixed solution was heated under reflux for 12 hours. Water (20 ml) was added to the mixture at 0° C., and the mixture was washed with saline water. Organic layers were combined, and dried with MgSO4, and condensed with an evaporator. The condensed solution was recrystallized from methanol to obtain 6-n-decyl-2-methoxynaphthalene (compound (3)-64) (5.0 g, 85%) as a white solid.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([NH2:18])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:19]1[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[N:21][CH:20]=1>>[CH:1]1([C:6]2[CH:7]=[C:8]([NH:18][C:25]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)=[O:26])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: O=C(O)c1cncnc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1)c1cncnc1
Yield: 19 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 1c) (100 mg, 0.38 mmol) and pyrimidine-5-carboxylic acid (41 mg, 0.33 mmol) as starting materials. The title compound (23 mg, 15.7%) was isolated as off white solid; MS (ESI): 367 [M+H]+.
Reaction SMILES: C(C1C2[O:10]C(C)=CC=2C(NC(=O)C(C)(C)C)=CC=1)#N.Cl.NC1C2CCCCC=2C(C#N)=CC=1.[OH:34][C@H:35]1[C@@H:42]2[N:38]([C:39](=[O:56])[N:40]([C:44]3[C:53]4[CH2:52][CH2:51][CH2:50]C[C:48]=4[C:47]([C:54]#[N:55])=[CH:46][CH:45]=3)[C:41]2=[O:43])[CH2:37][CH2:36]1>>[OH:34][C@H:35]1[C@@H:42]2[N:38]([C:39](=[O:56])[N:40]([C:44]3[C:53]4[CH:52]=[C:51]([CH3:50])[O:10][C:48]=4[C:47]([C:54]#[N:55])=[CH:46][CH:45]=3)[C:41]2=[O:43])[CH2:37][CH2:36]1
Reactant: Cc1cc2c(NC(=O)C(C)(C)C)ccc(C#N)c2o1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Agent: Cl
Agent: N#Cc1ccc(N)c2c1CCCC2
Product: Cc1cc2c(N3C(=O)[C@@H]4[C@H](O)CCN4C3=O)ccc(C#N)c2o1

Procedure:
The title compound was prepared from compound 10E by procedures analogous to those described in Experiment 2 (2D to 2F). HPLC: 99% at 4.2 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O—10% MeOH—0.1% H3PO4 and B=10% H2O—90% MeOH—0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). Chiral HPLC: retention time=10.99 min (99%); Conditions: OD (4.6×250 mm); Eluted with 25% isopropanol in hexane for 30 min at 1 mL/min. MS (ES) m/z 312 [M+1]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][CH2:12]Cl.[C:14]([O:18][C:19]([N:21]1[CH2:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])[CH2:23][C:22]1([CH3:36])[CH3:35])=[O:20])([CH3:17])([CH3:16])[CH3:15].O>C(Cl)Cl>[C:14]([O:18][C:19]([N:21]1[CH2:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:10][O:11][CH3:12])[CH2:23][C:22]1([CH3:36])[CH3:35])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: COCCl
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2O)CC1(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccccc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
0.72 ml of diisopropylethylamine (4.10 mmol) and 0.16 ml of methoxymethyl chloride (2.05 mmol) were added to a solution of 400 mg of 4-(2-hydroxyphenyl)-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (10d) (1.36 mmol) in methylene chloride (14 ml), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=1/1) to obtain 497 mg of 2,2-dimethyl-4-(2-methoxymethoxyphenyl)-5-oxopiperazine-1-carboxylic acid t-butyl ester (yield: quant.).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[O:9][C:10]3[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>CO.O1CCCC1>[CH:1]1([CH:6]([C:8]2[O:9][C:10]3[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])[OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)C2CCCC2)oc2c(F)cc(F)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(O)C2CCCC2)oc2c(F)cc(F)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
Cyclopentyl(5,7-difluoro-3-methyl-1-benzofuran-2-yl)methanone (1.24 g) synthesized above was dissolved in methanol (4 mL)-tetrahydrofuran (20 mL), and sodium tetrahydroborate (90%)(355 mg) was added to the solution at 0° C. The reaction mixture was stirred at 0° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (1.18 g, 100%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][N:32]3C(=O)C4=CC=CC=C4C3=O)[C:6]=2[CH:43]=1.O.NN.O>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][NH2:32])[C:6]=2[CH:43]=1
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(CCN3C(=O)c4ccccc4C3=O)c3cc(Cl)ccc32)cn1)c1ccccc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)nc2)c2ccc(Cl)cc21
Yield: 35.3 %

Procedure:
To a solution of 7-chloro-5-(2-phthalimidoethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.8 g) in ethanol (50 ml) is added hydrazine monohydrate (0.19 ml), and the mixture is refluxed for 4 hours. The mixture is cooled, and thereto is added water. The mixture is extracted with dichloromethane, and the extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-aminoethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g) as colorless amorphous.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[C:20]([O:22][CH3:23])=[O:21].[C:24](Cl)(=[O:26])[CH3:25].Cl>O1CCOCC1.N1C=CC=CC=1>[C:24]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[C:20]([O:22][CH3:23])=[O:21])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 315 mg(1 mmole) of 4-(2-aminophenyl)-2,6-dimethyl-3,5-bis(methoxycarbonyl)-1,4-dihydropyridine [J. Am. Chem. Soc., 71, 4003 (1949)] in 1 ml of dioxane and 1 ml of pyridine a solution of 0.18 g of acetylchloride in 1 ml of dioxane was added drop-wise during 20 minutes in a temperature range of 0° to 10° C., then the mixture was stirred for 40 minutes at this temperature and for 3 hours at room temperature, thereafter it was poured into 10 ml of aqueous 10% hydrochloric acid. The precipitate formed was filtered, washed with water and dried. Yield 350 g (97.5%), m.p. 284° to 285° C. (ethanol).
Reaction SMILES: [CH2:1]([S:8][CH:9]1[N:12]([CH2:13][C:14]([OH:16])=O)[C:11](=[O:17])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43]>CN(C)C=O>[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:14](=[O:16])[CH2:13][N:12]1[CH:9]([S:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][C:11]1=[O:17]
Reactant: O=C(O)CN1C(=O)CC1SCc1ccccc1
Reactant: NCCCCCCc1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)CC1SCc1ccccc1)NCCCCCCc1ccc(F)cc1F
Yield: 73 %

Procedure:
Sequential treatment of (4-benzylthio-2-oxoazetidin-1-yl)acetic acid with 1-cyclohexyl-3-(2-morpholinethyl)carbodiimide metho-p-toluenesulfonate and 6-(2,4-difluorophenyl)hexylamine in dimethyl formamide by the method described for Example 29 gave the title compound as a colourless solid, m.p. 65-66° C., in 73% yield 1H NMR δ (CDCl3) 1.3-1.36 (4H, m, 4×CH2), 1.50-1.60 (4H, m, 4×CH2), 2.58 (2H, t, J=7.6 Hz, PhCH2), 2.93, 2.97 (1H, dd, J=2.4, 15.6 Hz, H3), 3.23 (2H, m, NHCH2), 3.35, 3.39 (1H, dd, J=5.2, 15.2 Hz, H3), 3.57, 3.71 (each 1H, d, J=16.4 Hz, NCH2), 3.81 (2H, s, SOCH2), 4.80 (1H, m, H4), 6.02 (1H, m, HH), 6.76-7.33 (8H, m, 2Ph--H); νc=o 1774 cm-1Found: C, 64.5; H, 6.3; N, 6.5%, C24H28F2N2O2S requires: C, 64.6; H, 6.3; N, 6.3%
Reaction SMILES: C1(C2C3C([N:20]4[CH2:25][CH2:24][CH2:23][C@H:22]([C:26](=[O:36])[CH2:27][P:28]([O:33][CH2:34][CH3:35])([O:30][CH2:31][CH3:32])=[O:29])[C@@H:21]4[C:37]([O:39][CH2:40]C)=[O:38])=CC=CC=3C3C2=CC=CC=3)C=CC=CC=1.FC(F)(F)C(O)=O>C(#N)C.O>[CH2:31]([O:30][P:28]([CH2:27][C:26]([C@H:22]1[CH2:23][CH2:24][CH2:25][NH:20][C@H:21]1[C:37]([O:39][CH3:40])=[O:38])=[O:36])([O:33][CH2:34][CH3:35])=[O:29])[CH3:32]
Reactant: CCOC(=O)[C@H]1[C@@H](C(=O)CP(=O)(OCC)OCC)CCCN1c1cccc2c1C(c1ccccc1)c1ccccc1-2
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOP(=O)(CC(=O)[C@H]1CCCN[C@H]1C(=O)OC)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve N-(9-phenylfluorenyl)-3(S)-[(diethoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, ethyl ester (1 g) in acetonitrile (7 mL) and water (1 mL). Cool to 0° C. and add, by dropwise addition, trifluoroacetic acid (7 mL). Stir at 0° C. for 1 hour then warm to room temperature over 1 hour. Extract into ethyl acetate (10×100 mL) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [O:1]=[C:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)[CH:3]=[CH2:4].C(N(CC)CC)C.[SH:25][C:26]1[CH:27]=[C:28]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:29]([OH:38])=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:31]=1>CO>[OH:38][C:29]1[C:28]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:27][C:26]([S:25][CH2:4][CH2:3][C:2]([N:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][CH2:10]2)=[O:1])=[CH:31][C:30]=1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C=CC(=O)N1CCN(Cc2ccccc2)CC1
Reactant: Oc1c(-c2ccccc2)cc(S)cc1-c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(CCSc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1)N1CCN(Cc2ccccc2)CC1
Reaction time: 12 h
Yield: 29.5 %

Procedure:
Following the procedure of Example 4, 1-(1-oxo-2-propenyl-4-phenylmethyl)piperazine (Example 6) (2.30 g, 0.01 mole) was dissolved in methanol (150 ml) and triethylamine (1 ml) added to the solution. The solution was flushed with argon several times, 5'-mercapto [1,1':3',1"-terphenyl]-2'-ol (2.77 g, 0.01 mole) added and the reaction stirred for 12 hours. The solvent was removed and the product isolated by chromatography to yield 1.5 g of product after drying in vacuo.