Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][NH:3]1.[H-].[Na+].[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][C:22]=1[Cl:29].O>CN(C)C=O>[Cl:29][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:21]=1[Br:20])[CH2:25][N:3]1[N:4]=[C:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]1=[O:1]
Reactant: CCOC(=O)Cc1n[nH]c(=O)c2ccccc12
Reactant: Clc1cc(CBr)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1nn(Cc2ccc(Br)c(Cl)c2)c(=O)c2ccccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
A mixture of ethyl 1,2-dihydro-1-oxophthalazin-4-ylacetate (11.5 g.) and sodium hydride (2.7 g.; 50% w/w dispersion in mineral oil) in dimethylformamide (125 ml.) was stirred at 60° C. for 1 hour under nitrogen. The solution obtained was cooled to room temperature and then 4-bromo-3-chlorobenzyl bromide (15.0 g.) was added, and the mixture stirred at 60° C. for 2 hours. After cooling to 25° C. the reaction mixture was poured into water (500 ml.). The aqueous mixture obtained was extracted with ethyl acetate (400 ml.). The extracts were washed with water, dried (MgSO4), and evaporated to give a solid, which was crystallised from propan-2-ol to yield ethyl 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetate (7.3 g.), m.p. 142°-145° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH2:27][C:28]([CH3:31])([OH:30])[CH3:29]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:26][CH2:27][C:28]([OH:30])([CH3:31])[CH3:29])=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(O)CN
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(C)(O)CNC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 1-amino-2-methyl-propan-2-ol and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]([C@@H:22]1[C@@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C@H:28]([OH:40])[C@@H:27]([CH2:41][OH:42])[O:26][C@H:23]1[S:24][CH3:25])=[N+:20]=[N-:21]>CN(C)C1C=CN=CC=1.ClCCCl.C(Cl)(Cl)Cl>[N:19]([C@@H:22]1[C@@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C@H:28]([OH:40])[C@@H:27]([CH2:41][O:42][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:26][C@H:23]1[S:24][CH3:25])=[N+:20]=[N-:21]
Reactant: COc1ccc(CO[C@H]2[C@H](O)[C@@H](CO)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CO[C@H]2[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A mixture of t-butyldiphenylsilyl chloride (8.66 g, 31.53 mmol), 4-dimethylaminopyridine (5.12 g, 42.04 mmol) and methyl 2-azido-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (9) (7.21 g, 21.02 mmol) in dry 1,2-dichloroethane (100 mL) was stirred at 80° C. for 2 hours. The resulting clear solution was cooled to room temperature, diluted with CHCl3 (300 mL), washed with H2O (3×200 mL), brine solution (200 mL), dried over MgSO4 and evaporated. The residue was purified by chromatography using hexane—ether 2:1 as the mobile phase to give methyl 2 -azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl-1-thio-β-D glucopyranoside (10) (9.73 g, 80%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](C2CC2)[C:5]2[O:12][C:9]3([CH2:11][CH2:10]3)[CH2:8][C:7](C)(C)[C:6]=2[CH:15]=1.O1CCCC1.C([Li])(C)(C)C.CCCCC.[C:34](=[O:36])=[O:35]>CCCCCC.C(OCC)(=O)C>[C:9]12([CH:8]=[CH:7][C:6]3[CH:15]=[C:2]([C:34]([OH:36])=[O:35])[CH:3]=[CH:4][C:5]=3[O:12]1)[CH2:10][CH2:11]2
Reactant: O=C=O
Reactant: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(Br)cc21
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=C(O)c1ccc2c(c1)C=CC1(CC1)O2

Procedure:
Following general procedure R and using 6-bromo-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 42, 0.45 g, 1.48 mmol), anhydrous tetrahydrofuran (5 mL), 1.7M solution of tert-butyl lithium solution in pentane (1.74 mL, 2.96 mmol) and carbon dioxide generated from dry ice, followed by flash column chromatography over silica gel (230-400 mesh) using 50% ethyl acetate in hexane as the eluent, the title compound was obtained as a white solid (0.34 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:10]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[CH2:33](I)[CH3:34]>>[CH2:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:29]=2)[C:10]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1)[CH3:34]
Reactant: CCI
Reactant: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N)cc1)c1ccc(C(C)C)cc1)CCC2
Product: CCNc1ccc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 162 using N-[(4-aminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.33 g) and ethyl iodide (0.07 mL) as starting materials, N-[(4-ethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.29 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:13][CH2:14][CH2:15][CH2:16]Br.FC(F)(F)C1C=CC(C2(C#N)CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:10]#[N:11])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: BrCCCCBr
Agent: N#CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: N#CC1(c2ccc(Cl)c(Cl)c2)CCCC1

Procedure:
1-(3,4-dichlorophenyl)cyclopentanecarbonitrile (481) was synthesized from 2-(3,4-dichlorophenyl)acetonitrile (480) and 1,4-dibromobutane following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbonitrile (237).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.C1CCCCC1.Cl.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1>C(O)(=O)C>[Br:16][C:17]1[CH:22]=[C:21]2[C:20](=[CH:19][CH:18]=1)[NH:23][C:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][C:4]2=1
Reactant: CC1CCC(=O)CC1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: C1CCCCC1
Solvent: CC(=O)O
Product: CC1CCc2[nH]c3ccc(Br)cc3c2C1
Yield: 74.2 %

Procedure:
To a solution of 4-methylcyclohexanone (5.47 mL, 44.6 mmol), cyclohexane (70 mL) and glacial acetic acid (50 mL) was added 4-bromophenylhydrazine hydrochloride (10.0 g, 44.6 mmol) and the reaction mixture was refluxed for 23 h under a nitrogen atmosphere. The cooled reaction mixture was filtered and the filtrate was evaporated. Diethyl ether was added and the mixture was washed with a saturated sodium bicarbonate solution and then water; the ether solution was dried and evaporated. The crude product was recrystallised from ethanol over an ice bath, filtered, washed with cold PS and dried in vacuo to afford 6-bromo-3-methyl-1,2,3,4-tetrahydrocarbazole (8.73 g, 33.1 mmol, 74%) as an off-white solid, mp 108-110° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][CH3:17])[C:10]=1[CH2:18][C:19]([N:21]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[N:22]=[C:23]([S:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:24]([O:26]CC)=O)=[O:20])[CH3:8].Cl>C1COCC1>[CH2:7]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][CH3:17])[C:10]=1[C:18]1[C:19](=[O:20])[N:21]([CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:22]=[C:23]([S:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:24]=1[OH:26])[CH3:8]
Reactant: CCCCCCCCCCCCSC(=NN(Cc1ccccc1)C(=O)Cc1c(CC)cc(C)cc1CC)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCSc1nn(Cc2ccccc2)c(=O)c(-c2c(CC)cc(C)cc2CC)c1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.9 %

Procedure:
To a solution of potassium t-butoxide (12.4 g, 110 mmol) in dry THF (80 ml) was added a solution of ethyl 2-[2-(2,6-diethyl-4-methylphenyl)acetyl-2-benzylhydrazono]-2-(dodecylthio)acetate (16.4 g, 27.6 mmol) in dry THF (20 ml) dropwise at room temperature over 20 minutes. After being stirred for 10 minutes at room temperature, 1N hydrochloric acid (200 ml) was added, and extracted with tert-butyl methyl ether 2 times. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 1.48 g of Compound (I-12-1) (yield: 13%) as solid and 2.71 g of 4-(2,6-diethyl-4-methylphenyl)-6-dodecylthio-5-hydroxy-2-benzyl-3(2H)-pyridazinone and Compound (I-12-1-B) (yield: 17%) as oil.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:4]([C:15]([O:17]C)=[O:16])[CH2:3]1.[OH-].[Li+]>C1COCC1.CO.O>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C:2]([F:1])([F:19])[CH2:3][CH:4]1[C:15]([OH:17])=[O:16])=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)C1CC(F)(F)CCN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(F)(F)CC1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butyl 2-methyl 4,4-difluoropiperidine-1,2-dicarboxylate, 13e, (4.6 g, 16.5 mmol) in THF (18 mL), methanol (18 mL) and H2O (9 mL) was added lithium hydroxide (3.45 g, 82.22 mmol). The reaction mixture was stirred at room temperature for 1 hour. All volatiles were removed under reduced pressure. The residue was diluted with a slight amount of water and ether. The layers were separated and the organic phase was discarded. The aqueous phase was acidified to pH 3 with the addition of aqueous saturated KHSO4 solution. The product was extracted with EtOAc. The organic phase was washed with water, dried over MgSO4, filtered and evaporated to dryness. The resulting product was used without further purification.
Reaction SMILES: [NH:1]([C:44](OCC1C=CC=CC=1)=[O:45])[C@@H:2]([C:20]([NH:22][C@H:23]([C:31]([N:33]([CH3:43])[CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[NH:54]([C:71]([O:73][CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)=[O:72])[C@H:55](C(O)=O)[CH2:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[CH:59][CH:58]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CO.[Pd]>[NH:54]([C:71]([O:73][CH2:74][C:75]1[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=1)=[O:72])[C@H:55]([C:44]([NH:1][C@@H:2]([C:20]([NH:22][C@H:23]([C:31]([N:33]([CH3:43])[CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:11])=[O:10])=[O:45])[CH2:56][C:57]1[CH:58]=[CH:59][C:60]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[CH:61][CH:62]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)N(C)CCC(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)[C@H](Cc2ccc(OC(C)(C)C)cc2)NC(=O)OCc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)N(C)CCC(=O)OC(C)(C)C)cc1
Temperature: -10 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
Z-D-Arg(Tos)-Phe-MeβAla-O-t-Bu (31.9 g, 41.0 mmol) was dissolved in methanol (200 ml), and added with 5% Pd-C (water content: 50%, 32 g) as catalyst, and catalytic reduction was carried out for four hours to remove the protective group. After the catalyst was removed by filtration, the solvent was evaporated under reduced pressure, and then the residue was dissolved in dimethylformamide (100 ml). Z-Tyr(t-Bu)-OH (13.7 g, 36.9 mmol) and 1-hydroxybenzotriazole (5.54 g, 41.0 mmol) were dissolved in the solution. This solution was cooled to −10° C., added with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.86 g, 41.0 mmol), and then stirred at −10° C. for one hour and further at room temperature for 20 hours. After the solvent was evaporated under reduced pressure, the reaction mixture was added with ethyl acetate (100 ml), and washed with 1N hydrochloric acid and then with saturated aqueous sodium hydrogencarbonate. The solvent was concentrated under reduced pressure to obtain an oily product, which was purified by silica gel column chromatography (chloroform: methanol=40:1 (v/v)) to obtain 27.8 g of Z-Tyr(t-Bu)-DArg(Tos)-Phe-MeβAla-O-t-Bu as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(Cl)(C(Cl)=O)=O.[N:20]1[CH:25]=[CH:24]C=[CH:22][CH:21]=1.C(NCC)C>C(Cl)Cl.CC(OCC)=O>[CH2:21]([N:20]([CH2:25][CH3:24])[C:5](=[O:7])[C:4]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[CH3:22]
Reactant: COc1ccc(OC)c(C(=O)O)c1
Reactant: c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCNCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1cc(OC)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a stirred solution of 2,5-dimethoxybenzoic acid (6.61 g, 36.3 mmol) in 50 ml of CH2Cl2 was added a solution of (COCl)2 in CH2Cl2 (2.0M, 20 ml, 40.0 mmol) at 0° C. under argon. After addition of catalytic amount of pyridine (0.2 ml) an evolution of gas was observed. The reaction was warmed up to room temperature and stirred for 3 hours. The volatile were removed and the residue was dissolved in 300 ml of diethyl ether. Diethylamine (5.26 ml, 50.8 mmol) was introduced dropwise at 0° C. under argon. The resulting mixture was stirred at room temperature for another 3 hours, and then quenched with saturated K2CO3 solution. The organic layer was washed with 2N NaOH and water, dried over MgSO4, filtered and then evaporated. Flash chromatography of the residue with CH2Cl2 and CH3CO2Et (1:1) provided pure title compound (8.34 g, 35.1 mmol) in 97% yield as white solid. 1H NMR (CDCl3) δ:1.05 (3H, t, J=7.1 Hz), 1.24 (3H, t, J=7.1 Hz), 3.16 (2H, q, J=7.1 Hz), 3.56 (2H, m), 3.77 (3H, s), 3.78 (3H, s), 6.77 (1H, m), 6.84 (2H, m).
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([Cl:37])[CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)=[O:17])[CH2:12][CH2:11]1)=O)(C)(C)C>Cl.C(OCC)(=O)C>[ClH:37].[NH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([Cl:37])[CH:33]=4)[CH:28]=3)(=[O:25])=[O:26])[CH2:20][CH2:19]2)=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(trans-4-tert-butoxycarbonylaminomethylcyclohexane-1-carbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine (0. 7g) and 4 N HCl-ethyl acetate (10 ml) was stirred at room temperature for 1 hour, and the precipitated crystals of the title compound (0.48g) were filtered.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15]([CH3:18])(=O)=O)[N:3]=1.[CH2:19](S)[CH2:20][CH2:21]C.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([S:15][CH2:18][CH2:19][CH2:20][CH3:21])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CCCCS
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCCCSc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, butylmercaptan and DBU in DME. ES-MS m/e (%): 275 (M+H+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH:11](O)[CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].C1C=CC=CC=1.C(Cl)(Cl)[Cl:27].S(Cl)(Cl)=O>N1C=CC=CC=1.O>[Cl:27][CH:11]1[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8][C:7]2[CH:18]=[CH:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[CH2:12]1
Reactant: ClC(Cl)Cl
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(O)c1ccccc1S2
Solvent: c1ccncc1
Solvent: O
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)CC(Cl)c1ccccc1S2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
124 g of 10,11-dihydro-2-nitro-dibenzo[b,f]thiepin-10-ol are suspended in 69.5 ml of pyridine, 615 ml of benzene and 350 ml of chloroform and the mixture is treated dropwise with stirring at 0° C with 53 ml of thionyl chloride. The mixture is stirred overnight at room temperature and then for a further 30 minutes at 35°-40° C, cooled and diluted with water. The organic phase is washed successively with water and aqueous sodium bicarbonate solution, dired over magnesium sulphate and evaporated. There is obtained 10-chloro-10,11-dihydro-2-nitro-dibenzo[b,f]thiepin of melting point 74°-77° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(COc2ccc(C(C)=O)c(O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2′,4′-Dihydroxyacetophenone (11.71 g, 0.077 mol), 4-methoxybenzyl chloride (10.44 ml, 0.077 mol), anhydrous potassium carbonate (11.75 g, 0.085 mol) and potassium iodide (12.78 g, 0.077 mol) are heated together in refluxing dry acetone (80 ml) for 4 hours. The mixture is then cooled to room temperature, poured into water (250 ml) and extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts are combined, washed with saturated brine (100 ml), dried (MgSO4), filtered and concentrated, until crystallization commences. After standing at 4° C. for 16 h, the crystals are recovered by filtration, washed with cold ethyl acetate and then with n-hexane and dried.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[O:21][CH:20]([CH3:22])[CH2:19][C:18]2=[C:23]([NH2:25])[CH:24]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[C:1]1([CH2:7][O:8][C:9](=[O:10])[NH:25][C:23]2[C:18]3[CH2:19][CH:20]([CH3:22])[O:21][C:17]=3[CH:16]=[C:15]([O:14][CH3:13])[CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(N)c2c(c1)OC(C)C2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1cc(NC(=O)OCc2ccccc2)c2c(c1)OC(C)C2
Reaction time: 2 h
Yield: 88.5 %

Procedure:
0.65 grams of phenylmethylchlorocarbonate are dripped at 5° C. into a stirred mixture containing 0.7 grams of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine hydrochloride, 5 cc of 2N NaOH and 10 cc of chloroform. When the addition is terminated vigorous stirring is continued for one hour at the same temperature and for two hours at room temperature. Then the organic phase is separated, washed with water, dried over Na2SO4 and concentrated to dryness. The obtained residue crystallized twice from ethyl ether-petroleum ether yields 0.9 grams (88 percent of theoretical) of (2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl)carbamic acid phenylmethyl ester which melts at 82°-83° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH3:16][N:17]([CH3:35])[C:18]1[C:23]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:16][N:17]([CH3:35])[C:18]1[C:23]([CH2:24][N:25]([C:26]2[CH:27]=[CH:28][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:30][CH:31]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CC(C)c1ccc(NCc2cccnc2N(C)C)cc1
Product: COc1ccc2c(c1)C(C(=O)N(Cc1cccnc1N(C)C)c1ccc(C(C)C)cc1)CCC2
Yield: 85.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and [(2-dimethylaminopyridin-3-yl)methyl](4-isopropylphenyl)amine (0.40 g) as starting materials, N-[(2-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.58 g) was obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13](=[O:22])[CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.[BH4-].[Na+].O>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH:13]([OH:22])[CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(CCc1cccnc1)CCc1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC(CCc1cccnc1)CCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
5-(2-Naphthyl)-1-(3-pyridyl)-3-pentanone (0.327 g) and sodium borohydride were dissolved in ethanol (30 ml) and stirred overnight at room temperature. Water was added to the solution and the mixture extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate:dichloromethane (2:1) to yield the title compound as a white solid (0.117 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])[N:6]=[CH:5][N:4]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]([CH2:30][C@H:31]([OH:36])[C:32]([F:35])([F:34])[F:33])[C:26](=[O:29])[NH:27][N:28]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]([CH2:30][C@H:31]([OH:36])[C:32]([F:34])([F:35])[F:33])[C:26](=[O:29])[N:27]([CH2:2][C:3]3[CH:8]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=4[Cl:16])[N:6]=[CH:5][N:4]=3)[N:28]=2)=[CH:20][CH:19]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: Clc1cccc(-c2cc(CBr)ncn2)c1Cl
Product: O=c1n(Cc2cc(-c3cccc(Cl)c3Cl)ncn2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of the compound in Example 94, 23 mg (0.07 mmol) of the compound from Example 84A and 24 mg (0.08 mmol) of the compound from Example 5A were reacted with one another. This gave 29 mg (66% of theory) of the target compound.