Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.[O:31]=[C:32]1[NH:37][C@H:36](C(O)=O)[CH2:35][CH2:34][CH2:33]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([CH:36]2[NH:37][C:32](=[O:31])[CH2:33][CH2:34][CH2:35]2)=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: O=C1CCC[C@@H](C(=O)O)N1
Reactant: COc1cc(Cl)cc(OC)c1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: COc1cc(Cl)cc(OC)c1C1CCCC(=O)N1
Temperature: 100 °C

Procedure:
A mixture of commercially available 1-chloro-3,5-dimethoxybenzene (1.243 g; 6.98 mmol), P2O5(991 mg; 6.98 mmol), and methanesulfonic acid (5.659 g; 58.89 mmol) was treated with commercially available (S)-6-oxopiperidine-2-carboxylic acid (1.000 g; 6.98 mmol), and the resulting mixture was heated to 100° C. for 30 min. After cooling to rt, water was added, and the resulting solution was extracted with DCM. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by preparative HPLC afforded 6-(4-chloro-2,6-dimethoxyphenyl)piperidin-2-one as a colorless solid. LC-MS (conditions E): tR=0.61 min.; [M+H]+: 270.26 g/mol.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([F:12])[C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1.[C-:13]#[N:14].[Na+].O>CS(C)=O>[F:12][C:5]1[C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=[C:3]([CH2:2][C:13]#[N:14])[CH:4]=1
Reactant: [C-]#N
Reactant: Fc1cc(CCl)cc2c1OCO2
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cc(F)c2c(c1)OCO2
Temperature: 30 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
A mixture of 6-chloromethyl-4-fluoro-benzo[1,3]dioxole (0.80 g, 4.3 mmol) and NaCN (417 mg, 8.51 mmol) in DMSO (20 mL) was stirred at 30° C. for 1 h and was then poured into water. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/E.A.=10/1) to afford 2-(7-fluorobenzo[d][1,3]dioxol-5-yl)acetonitrile (530 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 6.68-6.64 (m, 2H), 6.05 (s, 2H), 3.65 (s, 2H). 13C-NMR δ151.1, 146.2, 134.1, 124.2, 117.5, 110.4, 104.8, 102.8, 23.3.
Reaction SMILES: [C:1]1([O:7][S:8](=[O:11])(=[O:10])[NH2:9])[CH:6]=[CH:5]C=CC=1.[CH:12]1(O)[CH2:14][CH2:13]1>>[CH:12]1([NH:9][S:8](=[O:11])(=[O:10])[O-:7])[CH2:14][CH2:13]1.[CH:1]1([O:7][S:8](=[O:11])(=[O:10])[NH2:9])[CH2:5][CH2:6]1
Reactant: NS(=O)(=O)Oc1ccccc1
Reactant: OC1CC1
Product: NS(=O)(=O)OC1CC1
Product: O=S(=O)([O-])NC1CC1

Procedure:
Cyclopropylsulfamate was synthesized according to the method presented in the synthesis of sulfamic acid phenyl ester in Example 1 with the exception of utilizing cyclopropanol (synthesized by methods reported in JOC 1980, 45, 4129-35) to obtain sulfamic acid cyclopropyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH3:20][O:21][CH2:22][CH:23]([NH2:26])[CH2:24][CH3:25]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH:23]([CH2:22][O:21][CH3:20])[CH2:24][CH3:25])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: CCC(N)COC
Product: CCOC(=O)c1cnc2c(N)cccc2c1NC(CC)COC
Yield: 80 %

Procedure:
The compound prepared in Example 3 was reacted with 1-methoxy-2-aminobutane according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 80%).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@@H:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=C[CH:22]=1.[NH+]1C=CC=CC=1.[OH2:33]>CN(C=O)C>[C:10]([O:11][CH3:22])(=[O:33])[CH2:9][C@H:7]([CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1])[CH3:8]
Reactant: c1cc[nH+]cc1
Reactant: CC(C)=CCC[C@H](C)CCO
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](C)CCC=C(C)C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a solution of 10.0 g (64.1 mmol) of (S)-(-)-citronellol 29 (Aldrich, 98% e.e.) in 150 ml of dry DMF is added 84.4 g (224 mmol) of pyridinium dichromate (PDC), and the mixture is stirred overnight. The reaction mixture is poured into 1.5 l of water, and extracted with toluene twice. The extract is washed with water, and then extracted with 1N aqueous solution of sodium hydroxide to separate the carboxylic acid. The aqueous layer is acidified with 5N hydrochloric acid to pH 2, and extracted with ethyl acetate again. The ethyl acetate extract is washed with water, a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. To a solution of residue in 100 ml of ether is added an ethereal solution of diazomethane at 0° C. until the yellow color persists. The reaction mixture is distilled under reduced pressure to give 7.53 g of the desired methyl ester 30 as an oil in 63.9% yield.
Reaction SMILES: [N:1]1([CH:6]=[CH:7][C:8]#N)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1(C=CCC)CCCC1.C(O)(=O)C.[ClH:23]>C(Cl)(Cl)Cl>[Cl:23][C:6]1[CH:7]=[CH:8][C:4]([CH2:3][CH3:2])=[CH:5][N:1]=1
Reactant: Cl
Reactant: N#CC=CN1CCCC1
Agent: CCC=CN1CCCC1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
19.3 g of β-pyrrolidino-acrylonitrile were added at -10° C. to 30 g of pyrrolidino-butene from A4 in 50 ml of chloroform. The mixture was allowed to warmto RT, and 50 ml of acetic acid were added dropwise. After stirring at RT for 15 hours, the mixture was cooled to -10° C., and dry hydrogen chloride gas was introduced. Aqueous workup gave 2-chloro-5-ethylpyridine as the main product.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:19]1[C:26]2[CH2:25][CH2:24][CH2:23][N+:22]=2[CH2:21][CH2:20]1>CCOCC.CCCCC>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([C:26]23[CH2:25][CH2:24][CH2:23][N:22]2[CH2:21][CH2:20][CH2:19]3)=[CH:3][CH:4]=1
Reactant: C1CC2=[N+](C1)CCC2
Reactant: Cc1ccc(I)cn1
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCCCC
Solvent: CCOCC
Product: Cc1ccc(C23CCCN2CCC3)cn1
Temperature: -95 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
5-Iodo-2-methylpyridine (345 mg, 1.39 mmol) was dissolved in Et2O and cooled to -95° C. A solution of 2.5M t-BuLi (1.7M in pentane, 1.8 mL, 3.06 mmol) in pentane was added dropwise. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (435 mg, 2.1 mmol) was added, and the reaction mixture was allowed to warm to -10° C. with stirring for 2 hours. The cold bath was removed, 2N HCl was added, and the phases were separated. The aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 95:5) to afford the title compound as an oil (126 mg, 45%): 1H NMR (CDCl3, 300 MHz) δ1.57-1.71 (m, 2H), 1.77-2.05 (m, 6H), 2.52 (s, 3H), 2.64-2.72 (m, 2H), 3.12-3.19 (m, 2H), 7.05 (d, J=8.1 Hz, 1H), 7.71 (dd, J=8.1, 2.6 Hz, 1H), 8.56 (d, J=2.6 Hz, 1H); MS (CI/NH3) m/z: 203 (M+H)+.
Reaction SMILES: [CH3:1][S-:2].[Na+].C(N(CC)CC)C.[O:11]1[CH:16]2[CH:12]1[C:13](=O)[CH2:14][C:15]2([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[O:17][Si](C)(C)C.[Cl-].[NH4+]>CO>[CH3:1][S:2][C:13]1[C:12](=[O:11])[CH2:16][C:15]([OH:17])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:14]=1
Reactant: C[S-]
Reactant: CCCCCCCCC1(O[Si](C)(C)C)CC(=O)C2OC21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCCCCCC1(O)C=C(SC)C(=O)C1

Procedure:
A solution of 910 mg of sodium thiomethoxide dissolved in 100 ml of methanol was stirred under ice-cooling and stirring for 15 minutes. Triethylamine (6 ml) was added, and after the mixture was stirred for 10 minutes, a solution of the above crude oil of 2,3-epoxy-4-octyl-4-trimethylsilyloxycyclopentanone in 15 ml of methanol was added dropwise. After the mixture was stirred for 6 hours, the reaction mixture was poured onto saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude oil of 2-methylthio-4-hydroxy-4-octyl-2-cyclopentenone.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([O:11][C:12]1[CH:29]=[CH:28][C:27]2[C@@H:26]3[C@H:17]([C@H:18]4[C@@:22]([CH2:24][CH2:25]3)([CH3:23])[C:21](=[O:30])[CH:20]=[CH:19]4)[C@H:16]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[CH2:15][C:14]=2[CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.[Cu]I>[CH2:4]([O:11][C:12]1[CH:29]=[CH:28][C:27]2[C@@H:26]3[C@H:17]([C@H:18]4[C@@:22]([CH2:24][CH2:25]3)([CH3:23])[C:21](=[O:30])[CH2:20][C@H:19]4[CH3:1])[C@H:16]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[CH2:15][C:14]=2[CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[Mg]Br
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC2=O
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1CC(=O)[C@@]2(C)CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5.35 g of copper(I) iodide is added to an ice-cooled solution of 11.9 ml of a 3-molar methylmagnesium bromide solution in 68 ml of tetrahydrofuran under a nitrogen stream. Then, a solution of 4.26 g of 3-benzyloxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one (see Example 6b) in 50 ml of tetrahydrofuran is added in drops and stirred for 30 minutes at a bath temperature of 0° C. Then, the excess reagent is decomposed with saturated ammonium chloride solution, diluted with ethyl acetate, washed with ammonium chloride solution and water, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/acetone. 3.6 g of 3-benzyloxy-7α-(5-hydroxypentyl)-15β-methyl-estra-1,3,5(10)-trien-17-one is obtained as oil. [α]D22 =+66.4°(c=0.515% in chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][C:19]#[N:20]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17](/[C:18](=[CH:6]/[C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)/[C:19]#[N:20])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1OC
Yield: 89.4 %

Procedure:
3,4-Dimethoxybenzaldehyde (1.00 g) and 3,4-dimethoxybenzyl cyanide (1.07 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (1.75 g, yield: 89%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14](SC2C=CC=CC=2)=[C:13]([CH:22]([CH3:24])[CH3:23])[N:12]=[C:11]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:27]1[CH:32]=[CH:31][CH:30]=[C:29](C(OO)=O)[CH:28]=1.[S:37]([O-:41])([O-])(=[O:39])=S.[Na+].[Na+].[Na]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([S:37]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:41])=[O:39])=[C:13]([CH:22]([CH3:23])[CH3:24])[N:12]=[C:11]1[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])([O-])=S
Reactant: Cc1nc(C(C)C)c(Sc2ccccc2)n1COCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Product: Cc1nc(C(C)C)c(S(=O)(=O)c2ccccc2)n1COCc1ccccc1

Procedure:
To a solution of 1 g of 1-benzyloxymethyl-4-isopropyl-2-methyl-5-phenylthio-imidazole (2.8 mmol) in 40 ml of methylene chloride is added 1.84 g of m-chloroperbenzoic acid (10.7 mmol) under ice cooling, and the resultant mixture is stirred at room temperature. Six hours later, the reaction mixture is mixed with aqueous sodium thiosulfate and aqueous sodium hydrogenecarbonate and extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed on a column of silica gel, eluting with ethyl acetate/n-hexane (1:1) to give 580 mg of the objective 1-benzyloxymethyl-4-isopropyl-2-methyl-5-phenylsulfonyl-imidazole as crystals melting at mp. 116°-117° C. Yield, 53%.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O1CCC[CH2:22]1.[OH2:26].Cl>C(OCC)(=O)C>[OH:26][CH2:22][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: C1CCOC1
Reactant: O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)CO

Procedure:
A mixture of about 96.5 g of octadecanoic acid chloride and about 205.06 g of tris-trimethylsilyloxyethylene was heated at about 110°-115° C. for about 2 hours. Another about 65 g of tris-trimethylsilyloxyethylene was added and heating was continued for about one more hour. The solution was poured slowly into a mixture of about 300 ml of tetrahydrofuran, about 300 ml of water and about 50 ml of concentrated hydrochloric acid with vigorous stirring (exothermic). The mixture was stirred at reflux for about 15 minutes and then diluted with about 1000 ml ethyl acetate. The water layer was separated from the hot mixture. The ethyl acetate layer was kept hot (about 0° C.), and saturated aqueous sodium bicarbonate was added. The resulting mixture was stirred for about 10 minutes. The organic layer was separated, dried, evaporated and recrystallized from methanol, giving about 81.3 g of the desired title compound as a white solid, mp 78°-80° C.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:17]([C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26]([CH2:28][CH:29]([CH3:34])[CH2:30][C:31](O)=[O:32])=[O:27])=[N:23][CH:24]=1)#[N:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:17]([C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:27])[CH2:28][CH:29]([CH3:34])[CH2:30][C:31]([NH:16][C:12]2[CH:13]=[CH:14][C:15]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([C:10]=3[CH:11]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)=[O:32])=[N:23][CH:24]=1)#[N:18]
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cn1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CC(=O)Nc3ccc(C#N)cn3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.2 %

Procedure:
To a solution of 9-ethyl-9H-carbazol-3-ylamine (306.5 mg, 1.457 mmol) in DMF (7 mL) were added the compound obtained in Step 1 (300 mg, 1.215 mmol), HATU (554.14 mg, 1.457 mmol) and DIPEA (0.632 mL, 3.644 mmol) at room temperature, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate (2×50 mL). The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound (220 mg, 41.21%) as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C@H:10]([NH:19][C:20]([C:22]2([CH2:27][CH:28]([CH2:32][C:33]([NH:35][CH:36]([CH3:38])[CH3:37])=[O:34])[C:29]([OH:31])=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:9]1=[O:39])([CH3:4])([CH3:3])[CH3:2].[CH3:41][O:42][CH2:43][CH2:44][O:45][CH2:46]Cl.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:41][O:42][CH2:43][CH2:44][O:45][CH2:46][C:28]([CH2:27][C:22]1([C:20]([NH:19][C@H:10]2[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:40])[C:9]2=[O:39])=[O:21])[CH2:26][CH2:25][CH2:24][CH2:23]1)([CH2:32][C:33]([NH:35][CH:36]([CH3:37])[CH3:38])=[O:34])[C:29]([OH:31])=[O:30]
Reactant: COCCOCCl
Reactant: CC(C)NC(=O)CC(CC1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCC(CC(=O)NC(C)C)(CC1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1)C(=O)O
Reaction time: 8 h

Procedure:
300 mg 2-{[1-({[(3S)-1-(2-tert. butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-(isopropylamino)-4-oxobutyric acid (for preparation see Example 12) was dissolved in 5 ml dichloromethane. 33 mg DMAP, 74 μl methoxyethoxymethyl chloride and 90 μl triethylamine were added to this receiving solution. The reaction mixture was stirred overnight, then diluted with 5 ml dichloromethane and the organic phase was washed in succession once each with 3 ml dilute aqueous KHSO4 solution and saturated aqueous common salt solution. The organic phase was dried over magnesium sulfate, the solvent was largely evaporated at reduced pressure and the remaining residue was chromatographed on silica gel (mobile phase: EA/cyclohexane 2:1 v/v). Drying the product fractions in an oil pump vacuum yielded 191 g of the title compound, MS: [M+H]+: 646; m/z: 590, 540, 484, 425.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(Cl)Cl>[S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCNC(=O)OC(C)(C)C)cc1
Yield: 81.8 %

Procedure:
3-t-Butoxycarbonylaminopropanol (10.0 g) is dissolved in methylene chloride (100 ml) and thereto are added triethylamine (8.66 g) and tosyl chloride (16.3 g) with stirring under ice cooling. The mixture is stirred at room temperature overnight. The reaction mixture is concentrated and the residue is dissolved in water-ethyl acetate, and the organic layer is separated, washed with an aqueous saturated saline solution, dried over sodium sulfate, and then distilled off the solvent. The residue is purified with a silica gel column chromatography to give 3-t-butoxycarbonylaminopropyl tosylate (15.37 g) as pale yellow oil.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1Cl)(=[O:3])[CH3:2].[K].[Cl:26][C:27]1[CH:28]=[N:29][C:30](=[O:33])[NH:31][CH:32]=1>CN(C)C=O>[C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[N:31]1[CH:32]=[C:27]([Cl:26])[CH:28]=[N:29][C:30]1=[O:33])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1C(Cl)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=c1ncc(Cl)c[nH]1
Agent: [K]
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1C(n2cc(Cl)cnc2=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
2-Desoxy-2-acetylamino-3,4,6-tri-O-actyl-D-glucopyranosylchloride (0.01 mol) and the potassium salt of 5-chloropyrimid-2-one (0.008 mol) were heated together in dimethylformamide (60 ml) with stirring at 80° C. for 24 hours. The solvent was then evaporated at reduced pressure (1 mm Hg) and the residue was extracted with chloroform (120 ml). The chloroform solution was washed with aqueous 1 N NaOH (2×3 ml) and water (3 ml) before drying (Mg SO4). Evaporation left the title compound which was further purified by trituration with ether and recrystallization from a small volume of methanol; yield 50%, m.p. 165°-167° C. when the sample is heated rapidly. (Found: C, 47.00; H, 4.82. Calc. for C18H22ClN3O9: : C, 47.02; H, 4.82)
Reaction SMILES: BrBr.[S-:3][C:4]#[N:5].[Na+].[NH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[N:11]=[C:10]([C:24]#[N:25])[CH:9]=1.O>CO>[NH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[Cl:23])[N:11]=[C:10]([C:24]#[N:25])[C:9]=1[S:3][C:4]#[N:5]
Reactant: N#Cc1cc(N)n(-c2ccc(C(F)(F)F)cc2Cl)n1
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CSc1c(C#N)nn(-c2ccc(C(F)(F)F)cc2Cl)c1N
Temperature: 20 °C
Yield: 91.2 %

Procedure:
Bromine (0.5 ml) was added over 10 minutes to a stirred solution of sodium thiocyanate (1.7 g) in anhydrous methanol at −65° C. A solution of 5-amino-1-(2-chloro-4-(trifluoromethyl)phenyl]-1-H-pyrazole-3-carbonitrile (1.5 g) in anhydrous methanol was added over 10-minutes and the stirred mixture allowed to warm to 20° C. over 16-hours. After pouring into water the precipitate was collected and dried to give 5-amino-1-[2-chloro-4-(trifluoromethyl)phenyl]-4-thiocyanato-1H-pyrazole-3-carbonitrile (1.64 g). HPLC (C-18 column, eluting with 3:1 CH3CN/H2O at 1.0 ml/min.) showed the compound as a peak of 86.6% area at 5.11 minutes.
Reaction SMILES: [CH2:1]([C@@:4]1([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:33][CH3:34])[CH2:25][NH:26][S:27]([CH:30]2[CH2:32][CH2:31]2)(=[O:29])=[O:28])[C:5]1=[O:35])[CH:2]=[CH2:3].[H-].[Na+].I[CH3:47]>C1COCC1>[CH2:1]([C@@:4]1([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:33][CH3:34])[CH2:25][N:26]([CH3:47])[S:27]([CH:30]2[CH2:31][CH2:32]2)(=[O:28])=[O:29])[C:5]1=[O:35])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C2CC2)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O

Procedure:
A solution of N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-1-yl)butyl)cyclopropanesulfonamide (Example 414, Step C, 1.5 g, 2.253 mmol) in THF was treated with sodium hydride (60% dispersion in mineral oil, 6.76 mmol) and iodomethane (0.280 ml, 4.51 mmol) at room temperature for 3 hours. The reaction mixture was quenched with HCl (1N) and diluted with DCM. The organic extract was washed with satd NaCl and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an oil. The product was purified by chromatography through a RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (4 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to provide the title compound as an oil.
Reaction SMILES: [CH2:1]([CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:9]([NH2:11])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH2:24]=O>>[CH2:1]([CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:9]([NH:11][CH2:24][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[S:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: NC(=S)C(Cc1ccccc1)c1ccccn1
Reactant: C=O
Product: S=C(NCN1CCOCC1)C(Cc1ccccc1)c1ccccn1

Procedure:
By the procedure of Example 14, 2-benzyl-2-(2-pyridyl)thioacetamide is reacted with morpholine and formaldehyde to give 2-benzyl-N-morpholinomethyl-2-(2-pyridyl)thioacetamide.