Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:7][C:6](=O)[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:15]>O=P(Cl)(Cl)Cl>[Cl:15][C:6]1[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][C:2]([CH3:13])([CH3:1])[N:7]=1
Reactant: CC1(C)NC(=O)c2ccccc2O1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)N=C(Cl)c2ccccc2O1
Reaction time: 8 h
Yield: 45.6 %

Procedure:
To a solution of 2,2-dimethyl-2H-benzo[e][1,3]oxazin-4(3H)-one (100 g, 0.56 mol) in POCl3 (500 mL) was added PCl5 (170 g, 0.84 mol) at the room temperature. The mixture was hearted at 60° C. overnight. The solvent was removed by distillation under atmospheric pressure and the residue was distilled under reduced pressure (85-86° C., 2.5 mmHg) to give 4-chloro-2,2-dimethyl-2H-benzo[e][1,3]oxazine (50 g, 45%). 1H NMR (400 MHz, CDCl3) δ 7.55 (dd, J=1.6, 8.4 Hz, 1H), 7.38 (dt, J=1.6, 8.0 Hz 1H), 6.95 (t, J=6.8 Hz 1H), 6.79 (d, J=8.0 Hz 1H), 1.61 (s, 6H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]([CH2:21][CH:22]([CH3:24])[CH3:23])[N:13]=[C:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[C:15]2[F:20].B(Br)(Br)Br.C1CCCCC=1>>[F:20][C:15]1[C:14]2[C:19](=[C:11]([C:4]3[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=3[OH:2])[N:12]([CH2:21][CH:22]([CH3:24])[CH3:23])[N:13]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(-c2c3cccc(F)c3nn2CC(C)C)c(OC)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CC(C)Cn1nc2c(F)cccc2c1-c1ccc(O)cc1O
Yield: 79.9 %

Procedure:
Prepared according to Method D step C from 3-(2,4-dimethoxyphenyl)-7-fluoro-2-isobutyl-2H-indazole (0.036 g, 0.1 mmol), boron tribromide (0.083 mL, 0.9 mmol) and 1.0 mL of cyclohexene to give the product (0.024 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].C([O:18][CH2:19][CH2:20][O:21][C:22](=[O:26])[C:23]([CH3:25])=[CH2:24])(=O)CCC([O-])=O.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[CH3:25][C:23]([C:22]([O:21][CH2:20][CH2:19][OH:18])=[O:26])=[CH2:24]
Reactant: C=C(C)C(=O)OCCOC(=O)CCC(=O)[O-]
Agent: COC(=O)C1CCOCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)OCCO
Temperature: 80 °C

Procedure:
A 1 L three neck flask equipped with a mechanical stirrer, condenser, thermocouple, and addition funnel was charged with THPE GE (112.5 g), mono-2-(methacryloyloxy)ethyl succinate (218.3 g), triethylamine (1.2 g), and Prostab® 5415 (0.2 g,). The mixture was heated to 80° C. for 7.5 hr to obtain a pale yellow mixture. The mixture was dissolved in 1250 mL of ethyl acetate, extracted with 500 mL of water followed by 500 mL of saturated sodium bicarbonate solution. The solution was dried with anhydrous sodium sulphate, then added to 1 liter of silica gel (Merck silica gel 60), and the solvent was removed. The silica gel containing the compound was then added to a column with 2500 g of silica gel and was eluted with a mixture of hexanes and ethyl acetate to isolate a purified fraction of the desired compound, THPE GE Su HEMA. 1H NMR (500 MHz, CDCl3) δ 1.93 (s, 9H), 2.08 (s, 3H), 2.61-2.7 (m, 12H), 3.84-4.2 (m, 15H), 4.3-4.4 (m, 12H), 5.6 (m, 3H), 6.1 (m, 3H), 6.75 (m, 6 H), 6.98 (m, 6H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[NH2:9][C:10]1[N:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>>[CH2:5]([O:4][C:2](=[O:3])[NH:9][C:10]1[N:15]=[N:14][C:13]([N:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[CH2:20][CH2:21]2)=[CH:12][CH:11]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)COC(=O)Cl
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: CC(C)COC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 7, making variations only as required to use 2-methylpropyl chloroformate in place of n-butyl chloroformate to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (47% yield). 1H NMR (500 MHz, CDCl3) δ 8.09, 7.73, 7.65, 7.63, 7.55, 7.36, 7.04, 3.96, 3.95-4.02, 3.88-3.94, 3.61-3.65, 3.52-3.56, 3.32, 1.94-2.04, 0.96. MS (ES+) m/z 452 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(C3C4=NON=C4C=CC=3OC2)C1=O.[F:44][CH:45]([F:53])[C:46]1[O:50][C:49]([CH2:51]O)=[CH:48][CH:47]=1.Cl.CO>>[F:44][CH:45]([F:53])[C:46]1[O:50][C:49]([CH2:51][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[CH:48][CH:47]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: OCc1ccc(C(F)F)o1
Agent: Cl
Agent: O=C1Nc2ccccc2C12COc1ccc3nonc3c12
Solvent: CO
Product: O=C1N(Cc2ccc(C(F)F)o2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure described in EXAMPLE 11.107 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one and (5-(difluoromethyl)furan-2-yl)methanol to replace 3-trifluoromethyl-pyridin-2-yl)methanol hydrochloride, 1′-{[5-(difluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (35%) as a colorless solid: mp 173-175° C.; 1H NMR (300 MHz, CDCl3) δ7.33-7.25 (m, 1H), 7.21-7.14 (m, 1H), 7.11-6.96 (m, 2H), 6.63-6.58 (m, 1H), 6.57 (t, JH-F=54.3 Hz, 1H), 6.50 (s, 1H), 6.37-6.34 (m, 1H), 6.20 (s, 1H), 5.04 (d, J=16.2 Hz, 1H), 4.94-4.83 (m, 2H), 4.65 (d, J=9.0 Hz, 1H), 4.23-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.1, 155.2, 151.1 (t, JC-F=2.2 Hz), 146.5, 144.6, 141.5, 138.3, 132.1, 128.9, 123.9, 123.7, 120.8, 111.5, 111.3 (t, JC-F=4.1 Hz), 109.2, 108.9, 108.2 (t, JC-F=233.6 Hz), 99.4, 80.0, 64.5, 63.9, 57.9, 37.0; MS (ES+) m/z 425.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:37][CH3:38])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH:16]3[CH2:34][OH:35])=[O:14])=[CH:8][C:7]=2[CH:36]=1.[H-].[Na+].[CH2:41](I)[CH3:42]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([O:37][CH3:38])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=4)[CH2:17][CH:16]3[CH2:34][O:35][CH2:41][CH3:42])=[O:14])=[CH:8][C:7]=2[CH:36]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1CO)=C2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC1CN(Cc2cc(OC)c(OC)c(OC)c2)CCN1C(=O)C1=Cc2cc(OC)c(OC)cc2CCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)piperazine-2-methanol (500 mg) obtained by the method in Working Example 19 and N,N-dimethylformamide (3 ml) is cooled to 0° C., to which is added, in limited amounts, 60% oily sodium hydride (80 mg). The reaction mixture is stirred for 30 minutes and then cooled to -20° C., followed by adding thereto dropwise a mixture of ethyl iodide (200 mg) and N,N-dimethylformamide (1 ml). After stirring for 4 hours at -20° C., the reaction mixture is poured into ice-water, followed by extraction with methylene chloride. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent:ethyl acetate-hexane-methanol=50:45:5) to give 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -2-ethoxymethyl-4-(3,4,5trimethoxybenzyl)piperazine as a colorless oily product (420 mg). This product is dissolved in ethyl acetate and converted to its hydrochloride with 4N HCl (ethyl acetate solution). To the mixture is added ethyl ether, and left standing to give the hydrochloride as colorless crystals, m.p. 169-171° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:34]([C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)([O-:36])=[O:35].CCOC(/N=N/C(OCC)=O)=O.Cl>C1COCC1.CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:41](=[O:42])[C:40]2[CH:39]=[CH:38][C:37]([N+:34]([O-:36])=[O:35])=[CH:45][CH:44]=2)[CH2:10][CH:9]1[CH3:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CC(O)CN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
The 4-hydroxy-2-methyl-pyrrolidine-1-carboxylic acid t-butyl ester (300.00 mg, 1.49 mmol) and triphenyl phosphine (512.54, 1.95 mmol) were dissolved in anhydrous THF and added to a mixture of para-nitrobenzoic acid (249.00 mg, 1.49 mmol) and DEAD (268.00 mg, 1.54 mmol, 0.24 mL) in anhydrous THF at 0EC under argon. The mixture was stirred for 1 h at 0EC. After 1 h the TLC indicated no starting material remained and the reaction mixture was poured into a 1N HCl solution and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine then dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (2:1 hexane-ethyl acetate) Yield 391.54 mg. 1H NMR (CDCl3, 300 MHz): δ 1.39 (d, J=9 Hz, 3H), 1.49 (s, 9H), 1.99 (d, J=15 Hz, 1H), 2.24-2.33 (m, 1H), 3.62-3.71 (m, 1H), 3.82 (dd, J=7, 12 Hz, 1H), 4.13 (bs, 1H), 5.52-5.56 (m, 1H), 8.20-8.35 (m, A2B2), 4H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:29])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH:17]=[CH:18]2)[C@@H:13]([Cl:27])[CH2:12]3)[CH2:9][C@H:8]1[CH3:28])(=[O:3])[CH3:2].BrN1C(=[O:36])CCC1=O.Cl(O)(=O)(=O)=O>O1CCOCC1>[C:1]([O:4][CH2:5][C:6](=[O:29])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]4([O:36][C@H:22]4[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH:17]=[CH:18]2)[C@@H:13]([Cl:27])[CH2:12]3)[CH2:9][C@H:8]1[CH3:28])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1COCCO1
Product: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
A solution of 12.0 g of 21-acetoxy-6α-chloro-16α-methyl-1,4,9(11)-pregnatriene-3,20-dione in 120 ml of dioxane is stirred at room temperature after adding 11.1 g of N-bromosuccinimide and 60 ml of 10% perchloric acid and, after 60 minutes, poured into ice water. The thus-precipitated product is filtered off, washed with water, dried in the air, and dissovled in 215 ml of ethanol. After adding 29 g of potassium acetate, the solution is heated for 8 hours to 60° C. under argon. Then the mixture is concentrated to a volume of 60 ml under vacuum, and stirred into ice water. The precipitated product is isolated and chromatographed on silica gel. With 8-9% acetone-hexane, after recrystallization from acetone-diisopropyl ether, 5.2 g of 21-acetoxy-6α-chloro-9,11β-epoxy-16α-methyl-9β-pregna-1,4-diene-3,20-dione is obtained, m.p. 189° C. [α]D25 =+57° (chloroform).
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C@@H:6]1[C@@H:11]2[CH2:12][CH2:13][N:8]([CH:9]([CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]2=O)[CH2:7]1)=[O:5])[CH3:2].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:33]=1[CH2:34][NH2:35].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C.O>[CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C@@H:6]1[C@@H:11]2[CH2:12][CH2:13][N:8]([C@@H:9]([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:10]2[NH:35][CH2:34][C:33]2[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:32]=2[O:31][CH3:30])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)[C@H]1CN2CC[C@@H]1C(=O)C2C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(OC)c(CN)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCN(CC)C(=O)[C@H]1CN2CC[C@@H]1[C@H](NCc1cc(OC)ccc1OC)[C@@H]2C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
A mixture of 23 (3.9 g, 10 mmol), 2,5-dimethoxybenzyl amine (1.9 g, 11 mmol) (Acta. Chem. Scand., 25. p. 2629 (1971)) and camphor sulfonic acid (120 mg) in toluene (40 ml) was heated at reflux with removal of water for 8 hours and then the solvent was removed. The residue was dissolved in small amount of THF (c.a. 5 ml) and this solution was added to a solution of sodium triacetoxyborohydride (5.3 g, 25 mmol) in acetic acid (100 ml) at room temperature. The mixture was stirred at room temperature for 4 hours and the solvent was removed. Water (25 ml) was added and the mixture was neutralized with NaHCO3 and extracted with EtOAc three times. The clude was purified by recrystallization from EtOAc to give 24 (2.4 g, 4.4 mmol, 44%).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:6]1.[OH-].[Li+]>CO.O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:7]2[N:8]([CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:14])[F:15])[C:9](=[O:10])[N:5]([CH2:4][C:3]([OH:25])=[O:2])[N:6]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The enantiomerically pure ester from Example 227A (265 mg, 0.70 mmol) is dissolved in 14 ml methanol and treated with 2.8 ml of a 1 M solution of lithium hydroxide in water. The mixture is stirred for 1 hr at RT and then freed of methanol on the rotary evaporator. The residue is diluted with 200 ml water and extracted once with dichloromethane. This organic phase is discarded. The aqueous phase is slowly acidified to pH 2 with 1 N hydrochloric acid. The product is extracted three times with dichloromethane, the combined organic phases are dried over sodium sulphate and the solvent removed on the rotary evaporator. The residue is dried under high vacuum. 142 mg (56% of theory) of the title compound are thus obtained. Since the aqueous phase still contains more product, it is evaporated to dryness on the rotary evaporator, and the residue is dissolved in a little DMSO and purified by preparative HPLC (Method 20). A further 71 mg (28% of theory) of the pure title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.OC1CCC(C(C2CCC(O)CC2)(C)C)CC1>>[O:1]=[C:2]1[CH2:3][CH2:4][CH:5]([C:8]([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)([CH3:10])[CH3:9])[CH2:6][CH2:7]1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CC(C)(C1CCC(O)CC1)C1CCC(O)CC1
Product: CC(C)(C1CCC(=O)CC1)C1CCC(=O)CC1

Procedure:
The process described in Japanese Patent Laid-Open Publication No. 59742/1992, however, has a problem of using expensive alicyclic diol. If 2,2-bis(4-hydroxyphenyl)propane that is relatively inexpensive is used as a starting material, reactions of two steps, namely, hydrogenation reaction of 2,2-bis(4-hydroxyphenyl)propane and oxidation reaction of 2,2-bis(4-hydroxycyclohexyl)propane obtained by the hydrogenation reaction, must be conducted to produce 2,2-bis(4-oxocyclohexyl)propane, so that the process becomes complicated.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[SH:7])(=[O:3])[CH3:2].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(N(CC)CC)C>ClCCl>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[S:7][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](S)[C@H]1OC(C)=O
Reactant: CCCCCCCCCCCCCCCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCS[C@H]1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 48 h
Yield: 55.1 %

Procedure:
A solution of 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranose (2.0 g, 6.5 mmol) and 1-bromohexadecane (2.0 g, 6.5 mmol) in dichloromethane (40 ml) containing triethylamine (1 ml) is kept under nitrogen for 2 days at room temperature. The reaction is worked up in the usual manner to give a syrup which is put on a silica gel column and eluted with 2-5% ethyl acetate in chloroform. The desired fractions are pooled and concentrated to dryness. Crystallization from aqueous ethanol gives hexadecyl 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranoside (1.9 g, 55%), m.p. 49°-50°, [α]D +9° (c, 1.5, chloroform).
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=CC=2)=CC=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)[CH:40]=[CH:41][CH:42]=1>>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:50][CH:51]=2)[CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(OC)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Product: COc1cccc(NC(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)c1
Yield: 96 %

Procedure:
The compound of example 26 was prepared analogous to compound of example 8 by hydrolysis of compound of example 25.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14].[Br:21][C:22]1[CH:23]=[CH:24][C:25](F)=[N:26][CH:27]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:11][O:12][C:13]([C:15]1([C:25]2[CH:24]=[CH:23][C:22]([Br:21])=[CH:27][N:26]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14]
Reactant: Fc1ccc(Br)cn1
Reactant: COC(=O)C1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccc(Br)cn2)CCOCC1
Yield: 69.4 %

Procedure:
1.0 M Tetrahydrofuran solution (28 ml) of lithium bis(trimethylsilyl)amide was added dropwise to a solution of tetrahydro-2H-pyrane-4-carboxylic acid methyl ester (2.87 g) in tetrahydrofuran (40 ml) at −78° C., and the mixture was stirred at the same temperature for an hour. And then a solution of 5-bromo-2-fluoropyridine (3.5 g) was added dropwise, and the reaction mixture was stirred at room temperature for two hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 4-(5-bromopyridin-2-yl)tetrahydro-2H-pyrane-4-carboxylic acid methyl ester (4.14 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1.[ClH:24]>CO>[ClH:24].[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C@@H:9]([NH:15][C@H:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3N[C@@H](C)c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1ccc2[nH]c3c(c2c1)CCC[C@@H]3N[C@@H](C)c1ccccc1

Procedure:
(1S)-6-Methyl-N-[(1S)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared by separation of diastereomeric 6-methyl-N-[(1S)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine by SFC (Berger Amino, 8% methanol, 1500 psi, 40° C., 2 mL/min, retention time: 8.7 min.) The oil obtained was converted to the HCl salt to give a white solid. [α]25=−133.5 (c 0.20, MeOH); 1H-NMR (CD3OD): δ 7.63 (d, J=7.6 Hz, 2H), 7.55-7.46 (m, 3H), 7.29 (d, J=8.0 Hz, 1H), 7.27 (s, 1H), 7.02 (d, J=8.4 Hz, 1H), 4.75 (q, J=7.2 Hz, 1H), 4.43 (m, 1H), 2.85 (dt, J=16.4 Hz, J=4.0 Hz, 1H), 2.67 (dt, J=16.4 Hz, J=4.0 Hz, 1H), 2.40 (s, 3H), 2.11-1.96 (m, 4H), 1.71 (d, J=7.2 Hz, 3H); MS m/z 184 (M−121).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:11]([C:15]#[N:16])C([O-])=O)[CH2:6][CH2:5]2.[C-:17]#[N:18].[K+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH2:11][C:15]#[N:16])([C:17]#[N:18])[CH2:6][CH2:5]2
Reactant: N#CC(C(=O)[O-])=C1CCc2cc(Br)ccc21
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCC1(C#N)CCc2cc(Br)ccc21
Temperature: 65 °C
Reaction time: 20 h
Yield: 70.6 %

Procedure:
To a solution of ethyl (2E/Z))-(5-bromo-2,3-dihydro-1H-inden-1-ylidene)(cyano)ethanoate (Prep1, 3.1 g, 10.15 mmol) in ethanol (23 mL) a solution of KCN (1.65 g, 2.5 eq) in water (6 mL) was added and the reaction mixture was warmed to 65° C. and stirred for ˜16-24 h. Then the solvent was removed under reduced pressure, the crude was treated with ether and water. Crystallization from ethanol gave the title compound (1.87 g, y=70%).
Reaction SMILES: BrC[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16](=[O:22])[CH2:17][O:18][C:19](=[O:21])[CH3:20])=[CH:6][CH:5]=1.[C:23]([O:27][C:28]([NH:30][C:31]([CH3:49])([CH3:48])[CH2:32][C:33]([NH:35][C@@H:36]1[CH2:42][CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[NH:38][C:37]1=[O:47])=[O:34])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:19]([O:18][CH2:17][C:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([CH2:3][N:38]2[C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[CH2:41][CH2:42][C@@H:36]([NH:35][C:33](=[O:34])[CH2:32][C:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:25])([CH3:24])[CH3:26])([CH3:48])[CH3:49])[C:37]2=[O:47])=[CH:9][CH:8]=1)=[O:22])(=[O:21])[CH3:20]
Reactant: CC(=O)OCC(=O)c1ccccc1-c1ccc(CCBr)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Product: CC(=O)OCC(=O)c1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1

Procedure:
Prepared from 4'-bromoethyl-2-(acetoxyacetyl) -1,1'-biphenyl and 3-t-butoxycarbonylamino-3-methyl -N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 57, Step A) by the procedure described in Example 69, Step D. 1H NMR (200 MHz,CDCl3): 1.33 (s,6H), 1.39 (s,9H), 1.87 (m,1H), 2.03 (s,3H), 2.35-2.70 (m,5H), 4.36 (s,2H), 4.51 (m,1H), 4.85 (d,15 Hz,1H), 5.28 (d,15 Hz,1H), 6.66 (m,1H), 7.1-7.6 (m,12H).