Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[C:17]2[Cl:23].N1C=CC=CC=1>O>[Cl:23][C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([NH:13][S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])[CH:15]=2)[NH:19][N:18]=1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1ccc2[nH]nc(Cl)c2c1)c1ccc(Cl)c(Cl)c1
Yield: 4.7 %

Procedure:
N-(3-Chloro-1H-indazol-5-yl)-3,4-dichlorobenzenesulfonamide can be obtained in the following way: a solution of 1.1 g of 3,4-dichlorobenzenesulfonyl chloride is added dropwise to a solution, cooled to 0° C. of 0.75 g of 5-amino-3-chloro-1H-indazole and of 14 ml of pyridine. After reacting for 10 minutes at a temperature in the region of 0° C. and 2 hours 30 minutes at a temperature in the region of 20° C., 50 ml of distilled water are added to the reaction medium. The medium is extracted with 50 ml and 25 ml of ethyl acetate. The organic phase is subsequently dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. The residue thus obtained is purified by chromatography on a silica column with a dichloromethane/methanol (99/1 by volume) mixture as eluent. The yellow oil thus obtained is again purified by chromatography on a silica column with dichloromethane as eluent. 0.08 g of N-(3-chloro-1H-indazol-5-yl)-3,4-dichlorobenzenesulfonamide is thus obtained in the form of a thick white oil (analysis C13H8Cl3N3O2S % calculated C, 41.46; H, 2.14; Cl, 28.24; N, 11.16; O, 8.50; S, 8.51% found C, 41.43; H, 2.58; N, 10.81; S, 7.84).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.C([N:26]=[C:27]=[S:28])(=O)C1C=CC=CC=1.[OH-].[Li+].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=1)=O.Cl>C1COCC1.O>[Br:41][C:38]1[CH:39]=[CH:40][C:35]([C:33]2[N:26]=[C:27]([NH:1][CH:2]3[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]3)[S:28][CH:32]=2)=[CH:36][CH:37]=1
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)C1CCC(Nc2nc(-c3ccc(Br)cc3)cs2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
cis-4-Amino-1-cyclohexanecarboxylic acid (1.43 g, 10 mmol) was suspended in THF (30 mL) and triethylamine (1.31 mL, 9.5 mmol) was added, followed by benzoylisothio-cyanate (1.36 mL, 10 mmol). The mixture was heated to reflux for 2 h, cooled, and stirred for 48 h. Lithium hydroxide (1N aqueous solution, 20 mL, 20 mmol) was added, the mixture was heated to reflux for 1 h, and the mixture was then cooled to 25° C. 2-Bromo-1-(4-bromo-phenyl)-ethanone (2.78 g, 10 mmol) was added, the mixture was heated to reflux for 1 h, and the mixture was then cooled to 25° C. The mixture was diluted with water, acidified with 2N HCl, and extracted with ethyl acetate. The organics were combined and washed with brine, dried over MgSO4, and concentrated. Flashing with 25% acetone in hexane with 0.5% acetic acid gave the intermediate 4-[4-(4-bromophenyl)-thiazol-2-ylamino]-cyclohexanecarboxylic acid (0.38 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28]=[O:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][OH:13])=[O:9].[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:28][OH:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][OH:13])=[O:9]
Reactant: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCO)C1c1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(CO)NC(C)=C(C(=O)OCCO)C1c1ccccc1[N+](=O)[O-]
Yield: 49.3 %

Procedure:
To a solution of 2-hydroxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (2.0 g) in ethanol (40 ml) was added bit-by-bit sodium borohydride (113.5 mg) at 5° C. under stirring. The mixture was further stirred at 5° C. for 30 minutes and acidified weakly with 50% acetic acid. After removal of the ethanol, to the residue was added water, and the mixture was made slightly alkaline with an aqueous solution of sodium bicarbonate, allowed to stand and then filtered, when it became clear. The precipitate (1.58 g) was collected by filtration and recrystallized from a mixture of ethanol and diisopropyl ether to give yellowish-orange granules (0.99 g) of 2-hydroxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 167° to 169° C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[NH:11][C:10](=[O:20])[CH:9]=1.O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:3][CH2:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[NH:11][C:10](=[O:20])[CH:9]=1
Reactant: COc1ccc2[nH]c(=O)cc(CCO)c2c1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc2[nH]c(=O)cc(CCCl)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
3.4 ml (46.6 mmol) of thionyl chloride are added while stirring at room temperature to a suspension of 3.11 g (14.2 mmol) of 4-(2-hydroxyethyl)-6-methoxy-2(1H)-quinolone in 50 ml of chloroform and 3 drops of dimethylformamide. The suspension is heated to reflux for 14 hours (total solubilization). After cooling to room temperature, 50 ml of water are added dropwise to the reaction medium and the mixture is left stirring for 30 minutes. The organic phase is recovered, separated after settling has taken place, washed with water, dried over magnesium sulphate and filtered. The filtrate is concentrated under vacuum. 3.2 g of a pale yellow solid are obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C:3](=O)[CH2:4][CH3:5].[CH3:9][C@@H:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>C1C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[C:11]1([C@H:10]([NH:17][C@H:3]([CH2:4][CH3:5])[C:2]([CH3:8])([CH3:7])[CH3:1])[CH3:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCC(=O)C(C)(C)C
Reactant: C[C@@H](N)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC[C@@H](N[C@H](C)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
To a cooled solution (0°) of 4,4-dimethyl-3-pentanone (106 g, 0.928 mol) and (R)-α-methylbenzylamine (111 g, 0.916 mol) in benzene (1 L), a solution of TiCl4 (50.5 mL, 0.461 mol) in benzene (200 mL) was added at a rate that kept the temperature of the mixture below 10°. Thereafter, the mixture was stirred mechanically for 3 h at 40°, cooled to room temperature (20°-22°) and filtered through diatomaceous earth. The diatomaceous earth was washed with Et2O. The combined filtrate and wash was concentrated. The residue was dissolved in dry MeOH (2 L). The solution was cooled to 0° and NaBH4 (20 g, 0.53 mol) was added portionwise while maintaining the temperature of the mixture below 5°. The methanol was evaporated. The residue was dissolved in Et2O. The solution was washed with brine, dried (MgSO4) and concentrated to give a reddish oil (a 18:1 mixture of diastereoisomers as indicated by NMR). The oil was purified by flash chromatography (SiO2, eluent: EtOAc/hexane, 7:93) to afford N-(1(R)-phenylethyl)-1(R)-ethyl-2,2-dimethylpropylamine as a liquid (110 g, 54% yield). This material was dissolved in hexane (1.5 L). 1N HCl in E2O (550 mL) was added to the solution over a period of 15 min. The resulting white solid was collected on a filter and then washed with hexane to provide N-(1(R)-phenylethyl)-1(R)-ethyl-2,2-dimethylpropylamine hydrochloride (125 g, 97% yield). 1H NMR(CDCl3) δ7.79-7.74 (m, 2H), 7.48-7.30 (m, 3H), 4.49-4.31 (m, 1H), 2.44-2.36 (m, 1H), 2.23 (d, J=6.5 Hz, 3H), 1.95-1.54 (m, 2H), 1.14 (s, 9H), 0.55 (t, J=7.5 Hz, 3H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.[F:23][C:24]([F:35])([F:34])[C:25]1[C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[NH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:35][C:24]([F:23])([F:34])[C:25]1[C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[N:27]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]3)[N:26]=1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(CO)cc2C1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Cn3nc(C(F)(F)F)c4c3CCCC4)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.1 %

Procedure:
(S)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (23 mg, 0.086 mmol) was dissolved in DCM (5 mL) and thionyl chloride (51 mg, 0.43 mmol) was added. The reaction mixture was stirred at room temperature for 1 h before being concentrated to dryness. The whole was dissolved in DMF (2 mL) to this was added 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (25 mg, 0.086 mmol) followed by potassium carbonate (24 mg, 0.172 mmol). The reaction mixture was heated to 65° C. for 3 h before being quenched with water (2 mL) and the organics extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Purification by preparative basic HPLC gave the title compound (1.2 mg, 2.7 μmol, 2.9%). MS (ESI): m/z [M+H]+ 442.2
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1.CCO.[ClH:31]>[Fe].O>[ClH:31].[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[CH:5]=[C:4]([CH3:27])[N:3]=[C:2]([NH2:1])[N:7]=3)=[CH:14][CH:13]=2)=[O:26])=[CH:18][CH:19]=1
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cc2)nc(N)n1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cc3)cc2)nc(N)n1
Yield: 90 %

Procedure:
To a refluxing suspension of amide E4 (2.10 g, 5.77 mmol) in 2:1 EtOH:H2O (100 mL) were sequentially added Fe dust (1.29 g, 23.09 mol) and c.HCl (1-2 mL), and the resulting mixture was refluxed for 24 h. After this time, the hot reaction mixture was filtered through a pad of Celite, and solvent was removed under reduced pressure. The resulting residue was crystallized from MeOH:EtOAc to afford amine E5 (in two batches) as a cream-coloured amorphous solid (1.94 g, 90%). 1H NMR [(CD3)2SO]): 2.27 [s, 3H, ArCH3], 6.16 [br s, 2H, ArNH2], 6.75 [d, J=8.36 Hz, 2H, ArNH2], 7.74 [m, 8H, ArH], 9.90 [br s, 1H ArH], 10.55 [br s, 1H, ArNHAr], 12.58 [br s, 1H, ArC(O)NH]. LCMS (APCI+): 335 (100%).
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[CH2:4].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10](S(O)(=O)=O)=[CH:9][CH:8]=1.CO[C:20]1[CH:26]=CC(O)=C[CH:21]=1>C1(C)C=CC=CC=1>[C:2]([O:6][CH:12]([CH2:7][CH3:17])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:21][CH2:20][CH3:26])(=[O:5])[CH:3]=[CH2:4]
Reactant: C=CC(=O)O
Reactant: COc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CC(=O)OC(CC)CCCCCCC
Reaction time: 2 h
Yield: 70 %

Procedure:
In a 10-liter separable flask equipped with a stirrer, a condenser and a water separator, 2700 g of tricyclo[5.2.1.02,6 ]deca-8-ol, 1588 g of acrylic acid, 2700 g of toluene, 135 g of p-toluenesulfonic acid, and 0.64 g of hydroquinone monomethyl ether were placed and reacted at 115° C. with stirring for 2 hours while removing the water generated out of the system. Then, the reaction solution was taken out of the flask and then subjected to distillation to remove low boiling point components. Then, 15 g of hydroquinone monomethyl ether was added to the resulting solution and distillation under reduced pressure was conducted to isolate a distillate having a boiling point of 87°-92° C. under 0.7 mmHg. The distillate was washed with an aqueous solution of 2% KOH, washed with water, dehydrated and filtered to give tricyclo[5.2.1.02,6 ]deca-8-yl acrylate (hereinafter referred to as "TCD-AA") in 70% yield and 99.5% purity.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8]([OH:10])=O.C(N(CC)CC)C.C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8]([N:32]=[N+:33]=[N-:34])=[O:10]
Reactant: O=C(O)/C=C/c1ccco1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)/C=C/c1ccco1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.4 %

Procedure:
To a mixture of (2E)-3-(2-furyl)acrylic acid (660 g, 4.78 mol) and triethylamine (800 mL, 5.74 mol) in tetrahydrofuran (960 mL) was added diphenylphosphoryl azide (1.13 L, 5.26 mol) under ice-cooling. After stirring at room temperature for 4 hr, the reaction solution was poured into a mixture of ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with methanol to give the title compound (580 g, yield 74%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][N:6]1[C:15](=[O:16])[CH2:14][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][C:7]1=[O:17].[CH3:18][S:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C(N(C(C)C)CC)(C)C>CC#N>[CH3:18][S:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][O:5][N:6]3[C:15](=[O:16])[CH2:14][C:9]4([CH2:13][CH2:12][CH2:11][CH2:10]4)[CH2:8][C:7]3=[O:17])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CC2(CCCC2)CC(=O)N1OCCCBr
Reactant: CSc1cccc(N2CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CSc1cccc(N2CCN(CCCON3C(=O)CC4(CCCC4)CC3=O)CC2)c1

Procedure:
A mixture of 8-(3-bromopropyloxy)-8-azaspiro[4.5]decan-7,9-dione (4.0 g), 1-(3-methylthiophenyl)piperazine (2.75 g) and diisopropylethylamine (4.6 ml) was stirred in 100 ml of dry CH3CN at room temperature under N2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13](=[O:14])[N:12]([CH2:15][C@H:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[N:10]2)[CH:5]=[N:6][CH:7]=1.[Cl:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:11]2[N:12]([CH2:15][C@H:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[C:13](=[O:14])[N:9]([CH2:8][C:4]3[CH:5]=[N:6][CH:7]=[C:2]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:29])[C:35]=4[Cl:36])[CH:3]=3)[N:10]=2)=[CH:23][CH:24]=1
Reactant: O=c1n(Cc2cncc(Br)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: OB(O)c1cccc(Cl)c1Cl
Product: O=c1n(Cc2cncc(-c3cccc(Cl)c3Cl)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of the compound in Example 86, 34 mg (0.07 mmol) of the compound from Example 29A and 20 mg (0.10 mmol) of 2,3-dichlorophenylboronic acid were reacted with one another. This gave 26 mg (69% of theory) of the target compound.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:33]=[CH:32][CH:31]=[CH:30][C:6]=2[C:7]=1[C:8]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13]([O:22]C)=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)=[O:9])[CH3:2].B(Br)(Br)Br.C(Cl)Cl.C(=O)=O.CC(C)=O>C(Cl)Cl>[CH2:1]([C:3]1[O:4][C:5]2[CH:33]=[CH:32][CH:31]=[CH:30][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:13]([OH:22])=[C:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:11]=1)=[O:9])[CH3:2]
Reactant: CCc1oc2ccccc2c1C(=O)c1cc(-c2ccccc2)c(OC)c(-c2ccccc2)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCc1oc2ccccc2c1C(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83 %

Procedure:
At −78° C., to a stirred solution of (2-ethyl-benzofuran-3-yl)-(2′-methoxy-[1,1′;3′,1″]terphenyl-5′-yl)-methanone (1.07 g, 2.47 mmol) in CH2Cl2 (10.1 mL) was added dropwise 1M boron tribromide/ CH2Cl2 (5.2 mL). After the addition was complete, the dry ice/acetone bath was replaced with an ice water bath and the reaction was stirred for 72 h, eventually warming to ambient temperature. The reaction was carefully quenched with crushed ice, diluted with H2O (16 mL) and extracted with ether. The ethereal extracts were dried (MgSO4) and concentrated. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 0.86 g, (83%) of the title compound as a white solid, mp 142-143° C. 1H NMR (DMSO-d6) δ1.24 (t, 3H), 2.90 (quartet, 2H), 7.28-7.66 (m, 16H), 9.37 (s, 1H). IR (KBr) 3200, 2950, 1625, 1560 and 1175 cm−1. mass spectrum (EI), m/z 418 (M+). Anal. Calcd. for C29H22O3.0.35H2O: C, 82.00; H, 5.39; N, 0.00. Found: C, 82.06; H, 5.40; N, 0.07.
Reaction SMILES: C(OC(C1CCCN1C(=O)C(NC(=O)[C:18]1[CH:23]=[CH:22][C:21](N)=[C:20]([Cl:25])[CH:19]=1)C)=O)(C)(C)C.[O:28]=[C:29]1[O:33][CH:32]([O:34][CH2:35]CC2C=CC=CC=2)[CH:31]([NH:43][C:44]([CH:46]2[CH2:50][CH2:49][CH2:48][N:47]2[C:51](=[O:65])[CH:52]([NH:54][C:55](=[O:64])[C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([Cl:63])[CH:57]=2)[CH3:53])=[O:45])[CH2:30]1>>[Cl:25][C:20]1[CH:21]=[CH:22][C:23]([CH2:35][O:34][CH:32]2[CH:31]([NH:43][C:44]([CH:46]3[CH2:50][CH2:49][CH2:48][N:47]3[C:51](=[O:65])[CH:52]([NH:54][C:55](=[O:64])[C:56]3[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([Cl:63])[CH:57]=3)[CH3:53])=[O:45])[CH2:30][C:29](=[O:28])[O:33]2)=[CH:18][CH:19]=1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccc(Cl)cc1
Yield: 65 %

Procedure:
Prepared from 97a and syn-[2-(4-chloro-benzyloxy)-5-oxo-tetrahydro-furan-3-yl]-carbamic acid allyl ester following the method used for 98a to afford 154 mg (65% yield) of the title compound as a pale pink solid. HPLC (C18 column) 10.597 min; 1H-NMR (500 MHz, CDCl3) δ 1.14 (d, J=6.8 Hz, 0.75H), 1.34 (d, J=6.8 Hz, 2.25H), 1.6 (br, 0.25H), 1.91 (m, 1H), 2.03 (m, 1H), 2.10 (m, 1H), 2.29 (m, 0.75H), 2.40 (dd, J=17.3, 10.3 Hz, 0.75H), 2.51 (m, 0.25H), 2.82 (dd, J=17.3, 8.5 Hz, 0.75H), 3.08 (dd, J=17.9, 10.9 Hz, 0.25H), 3.58 (m, 1H), 3.72 (dd, J=16.5, 8.7 Hz, 0.75H), 4.10 (m, 0.25H), 4.22 (d, J=8.0 Hz, 0.25H), 4.39 (d, J=10.8 Hz, 0.25H), 4.54 (dd, J=9.1, 2.9 Hz, 0.75H), 4.60 (d, J=11.9 Hz, 0.75H), 4.68 (m, 1H), 4.85 (d, J=11.7 Hz, 0.75H), 4.86 (m, 1H), 5.49 (d, J=5.2 Hz, 0.75H), 5.81 (d, J=5.2 Hz, 0.25H), 6.2 (br, 0.25H), 6.74 (m, 2H), 7.05 (d, J=8.5 Hz, 0.5H), 7.17 (d, J=8.4 Hz, 0.5H), 7.30 (m, 3.25H), 7.48 (dd, J=8.4, 2.0 Hz, 0.75H), 7.56 (d, J=1.9 Hz, 0.25H), 7.73 (d, J=1.9 Hz, 0.75H), 8.42 (d, J=5.7 Hz, 0.25H) ppm; LC-MS (ES+) m/e=563, 565 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3]O.[BrH:16]>>[Br:16][CH2:3][CH:2]([CH3:1])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CCCC(C)CCCC(C)CO
Reactant: Br
Product: CC(C)CCCC(C)CCCC(C)CBr

Procedure:
A 21.44 g (0.10 mol) portion of (±)-2,6,10-trimethylundecan-1-ol was stirred and heated to 140° C as HBr gas was bubbled through the liquid for 4.0 hr. The two-phase mixture was cooled, diluted with petroleum ether (B.P. 30°-60° C) and washed with H 2 O, saturated aqueous NaHCO 3 solution and brine. The solution was filtered through 100 g of Woelm neutral alumina III, stripped of solvent, and distilled to give (±)-1-bromo- 2,6,10-trimethylundecane as a colorless liquid: bp 97°-99° C/0.10 mmHg.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:7][CH2:6]2.[Cl:20][CH2:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[ClH:20].[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH2:21][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:7][CH2:6]2
Reactant: Oc1ccc2c(c1)CCC(CN1CCCCC1)C2
Reactant: ClCc1nc2ccccc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2sc(COc3ccc4c(c3)CCC(CN3CCCCC3)C4)nc2c1
Temperature: 60 °C
Reaction time: 7 h
Yield: 50.6 %

Procedure:
To a solution of 6-hydroxy-2-piperidinomethyltetralin hydrochloride (205 mg, Reference Example 19) and 2-chloromethylbenzothiazole (183 mg) in DMF (10 ml) was added potassium carbonate (327 mg) and the reaction mixture was stirred at room temperature for 4 days and further at 60° C. for 7 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate:methanol=10:1), alumina column chromatography (eluent: ethyl acetate:hexane=1:4) and converted into its hydrochloride, which was recrystallized from methanol-ethyl acetate to obtain the titled compound (158 mg).
Reaction SMILES: [C:1]1([C:7]2([CH2:10][NH2:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.[Pt]>[CH:1]1([C:7]([CH3:9])([CH3:8])[CH2:10][NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: NCC1(c2ccccc2)CC1
Agent: [Pt]
Solvent: CC(=O)O
Product: CC(C)(CN)C1CCCCC1

Procedure:
{1-(1-Phenylcyclopropyl)}methylamine (205 mg, 1.1 mmole) was hydrogenated using platinum-black (410 mg) in 20 mL of acetic acid under 4 atmospheres of hydrogen for 3 days. The same conditions were repeated 3 times to complete the reaction. 2-Cyclohexyl-2-methylpropylamine was isolated as an acetic acid salt in quantitative yield. This material (28.5 mg, 0.12 mmole) was coupled with Example 4 (100 mg, 0.1 mmole) by the EDC and HOBT method followed by deprotection and purification to afford pure title compound (51 mg, 47%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:10][CH:9]2[CH:4]([CH:5]3[CH2:11][CH:8]2[O:7][NH:6]3)[O:3]1>[Pd].CO>[NH2:6][C@H:5]1[C@@H:4]2[O:3][C:2]([CH3:1])([CH3:12])[O:10][C@@H:9]2[C@@H:8]([OH:7])[CH2:11]1
Reactant: CC1(C)OC2C3CC(ON3)C2O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)C[C@H]2N
Temperature: 20 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Under a presurrized hydrogen atmosphere (3 atm), a suspension of 4,4-dimethyl-3,5,8-trioxa-9-aza-tricyclo[5.2.1.02,6]decane (16.7 g, 97.55 mmol, 1.00 equiv.), 10% palladium on carbon (1.67 g), and methanol (250 mL) was stirred at about 20° C. for about 60 minutes. After filtering the solution, the resulting filtrate was concentrated in vacuo to give the title product as a white solid (16.8 g; yield=99%). MS: m/z=174 (MH)+.