Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@H:14]([OH:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)c2ccccc21
Solvent: ClCCl
Solvent: CO
Product: O=C(OCc1ccccc1)N1CC[C@H](O)c2ccccc21
Reaction time: 0.25 h
Yield: 393.6 %

Procedure:
To a mixture of 0.5 mL of (R)-2-methyl-CES-oxazaborolidine solution and 3 mL of dichloromethane was added dropwise 0.07 mL of 1.0M borane-dimethylsulfide complex at 25° C., and the mixture was stirred at the same temperature for 15 minutes. To the solution was added dropwise a solution of 141 mg of 1-benzyloxycarbonyl-4-oxo-1,2,3,4-tetrahydroquinoline in 2.5 mL of dichloromethane over about 10 minutes. Furthermore, to the reaction solution were added 0.07 mL of 1.0M borane-dimethylsulfide complex and a solution of 141 mg of 1-benzyloxycarbonyl-4-oxo-1,2,3,4-tetrahydroquinoline in 2.5 mL of dichloromethane alternately with total 4 times. To the reaction solution was added dropwise 1 mL of methanol, and the reaction solution was concentrated. To the resulting residue were added 10 mL of dichloromethane and 10 mL of phthalate buffer (pH4.0), and the aqueous layer was removed, and then water was added. The organic layer was separated, dried over magnesium sulfate, and then filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography on silica gel (solvent; n-hexan/ethyl acetate=4/1) to give 559 mg of (4S)-1-benzyloxycarbonyl-4-hydroxy-1,2,3,4-tetrahydroquinoline (yield: 99%, optical purity: 96% ee).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH:24]1([CH2:27][NH2:28])[CH2:26][CH2:25]1.CCN(CC)CC>CCO>[CH:24]1([CH2:27][NH:28][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:9][C:10]([F:12])([F:11])[F:13])[CH2:14][C:15]([F:18])([F:16])[F:17])=[O:7])=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])[CH2:26][CH2:25]1
Reactant: NCC1CC1
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(c1ccc(NCC2CC2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (100 mg, 0.287 mmol) and cyclopropylmethyl amine (0.030 mL, 0.344 mmol) in 3 mL of EtOH containing Et3N (0.080 mL, 0.574 mmol). The product was purified by flash chromatography on silica gel using 4:1/hexanes:EtOAc as eluent. Yield: 91 mg (80%); 1H NMR (CDCl3) 0.35 (m, 2H), 0.70 (m, 2H), 1.21 (m, 1H), 3.21 (m, 2H), 4.25 (q, J=8.59 Hz, 4H), 6.91 (d, J=8.98 Hz, 1H), 7.54 (d, J=8.79 Hz, 1H), 8.30 (s, 1H), 8.35 (s, 1H); MS (ESI) 400.19 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[O:18][CH3:19].[C:20](OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:17])[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH2:20])[CH:5]=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(=O)Cc2ccccc2)c(Cl)c1Cl
Product: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Acetic anhydride (150 ml.) is added dropwise to a suspension of 2,3-dichloro-4-phenylacetylanisole (8.95 g., 30.3 mmol) in 15.3 ml. of N,N,N'N'-tetramethylenediaminomethane under an atmosphere of argon with icebath cooling. The reaction mixture stirred at 25° for 2 hrs. and poured into ice-water affords 11.9 g. of beige solid. An ethereal solution of the solid is washed with hydrochloric acid, water and then dried over magnesium sulfate. Removal of the solvent under reduced pressure provides 8.77 g. (94% yield) of 2,3-dichloro-4-(2-phenylacryloyl)anisole, m.p. 83.5°-86°.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:20][CH2:21][C:22]([O:24][CH2:25]C)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1.C(O)(=O)C>CO>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])(=[O:12])=[O:13])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Reaction time: 40 h

Procedure:
A solution of 130.15 g of sodium methoxide in 2.4 l methanol is added at room temperature to a solution of 5469 g of ethyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate in 52.3 l of methanol. The mixture is stirred for 40 h under nitrogen. Glacial acetic acid (145.5 g) is added and the reaction mixture is evaporated to dryness at 60° and 3 mm Hg (=4.00 mbar). The residue is dissolved in 40 l of ethyl acetate, the solution is washed with dilute sodium bicarbonate solution and then with 5% sodium bisulfite, dried over sodium sulfate, treated with charcoal and evaporated to dryness to yield crude methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate (compound of example 4a).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH2:31][C:32]([NH:34][NH2:35])=[O:33].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.C1COCC1>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:34]([C:32](=[O:33])[CH2:31][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][N:25]=3)[NH2:35])=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:1])[F:23])[CH:8]=1
Reactant: NNC(=O)Cc1cnccn1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NN(C(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)C(=O)Cc1cnccn1
Temperature: -60 °C
Reaction time: 1 h
Yield: 6.1 %

Procedure:
In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.3 g, 1.0 eq.) was dissolved in EtOAc:THF (15 mL; 2:1) and cooled to −60° C. where 2-(pyrazin-2-yl)acetohydrazide (0.129 g, 1.1 eq.) was introduced. T3P (50% in EtOAc) (1.01 mL, 2 eq.) was added dropwise followed by DIPEA (0.35 mL, 2.5 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(2-(pyrazin-2-yl)acetyl)acrylohydrazide (0.025 g, yield: 5%).
Reaction SMILES: C(O[C:6](=[O:28])[NH:7][C@H:8]1[CH2:16][O:15]C(=O)[C@H](CC2C=CC=CC=2)[C@@H:12]([OH:25])[C@H:11]([CH3:26])[O:10][C:9]1=[O:27])(C)(C)C.[OH:29][C:30]1[C:31](C(O)=O)=[N:32][CH:33]=[CH:34][C:35]=1[O:36][CH3:37].N1C=CC=CC=1C(N)=[O:48].O.[OH-].[Li+]>CO>[OH:29][C:30]1[C:31]([C:6]([NH:7][C@@H:8]2[C@@H:16]([OH:15])[C@H:26]([OH:48])[C@@H:11]([CH2:12][OH:25])[O:10][C@@H:9]2[OH:27])=[O:28])=[N:32][CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: NC(=O)c1ccccn1
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@H](Cc2ccccc2)[C@H]1O
Reactant: COc1ccnc(C(=O)O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccnc(C(=O)N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
1,3,4,6-Tetra-O-acetyl-2-amino-2-deoxy-alpha-D-glucopyranose (151) and 3-hydroxy-4-methoxypicolinic acid were coupled together using standard coupling procedure C. To a solution of the resulting picolinamide (0.19 g, 0.38 mmol) in 6 mL of methanol was added lithium hydroxide monohydrate (0.92 mmol, 40 mg). The reaction mixture was stirred at room temperature overnight. The solution was neutralized by the addition of DOWEX® 5×8-100 acidic resin (0.5 g). The mixture was filtered and concentrated to afford the title compound (110 mg, 88%).
Reaction SMILES: [Cl-:1].N[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1S.[CH2:10]([Cl:12])Cl>>[CH:7]1[CH:6]=[CH:5][C:4]([C:10]([Cl:12])([C:3]2[C:8]([Cl:1])=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:3][CH:8]=1
Reactant: [Cl-]
Reactant: Nc1ccccc1S
Reactant: ClCCl
Product: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 g of 2-chlorotrytyl chloride resin (1.66 mmol/g, 1 eq) was allowed to swell in methylene chloride for 3-5 min, 1.162 mmol of N,N-diisopropylethylaminem (0.202 ml, 0.7 eq) and 1.66 mmol of aminothiophenol (0.178 ml, 1 eq) were added thereto, and the mixture was gently stirred for 3 hr at room temperature. Then, the resin was filtered and washed with a mixture of methylene chloride, methanol and N,N-diisopropylethylamine (85:10:5 v/v/v) to obtain 2-chlorotrityl resin loaded with 0.332 mmol/g of 2-aminobenzenethiol. The loaded 2-chlorotrityl resin 200 mg was suspended in 5-6 ml of N,N-dimethylformamide, 0.996 mmol of benzoyl chloride (0.116 ml, 3 eq) and the mmol of N,N-diisopropylethylamine (0.173 ml, 3 eq) were added thereto, and the mixture was shaken for 3 hr at room temperature. Then, the resin was filtered and washed with 5×10 ml N,N-dimethylformamide and 5×10 ml methylene chloride. The resin still remaining on the filter was then treated with 20 ml portions of 65% trifluoroacetic acid/methylene chloride and 5% triethylsilane/methylene chloride. The obtained filtrates were concentrated in a vacuum to obtain an oily residue, which was dissolved in 10 ml of N,N-dimethylformamide/methanol (9:1 v/v) containing 0.2 mmol of dithiothreitol (0.031 g). After 3 hr of standing at room temperature, the mixture was extracted with ether, washed with water, dried and concentrated in a vacuum to obtain the title compound as a white powder.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2[C:18]([CH2:27][N:28]3[C@@H:32]([CH3:33])[C@@H:31]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([O:40][C:41]([F:44])([F:43])[F:42])[CH:35]=4)[O:30][C:29]3=[O:45])=[N:19][C:20](S(C)(=O)=O)=[N:21][CH:22]=2)[C:12]([O:15][CH3:16])=[N:13][CH:14]=1.Cl.[F:47][CH:48]1[CH2:51][NH:50][CH2:49]1.Cl>C(OCC)(=O)C.C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2[C:18]([CH2:27][N:28]3[C@@H:32]([CH3:33])[C@@H:31]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([O:40][C:41]([F:44])([F:43])[F:42])[CH:35]=4)[O:30][C:29]3=[O:45])=[N:19][C:20]([N:50]3[CH2:51][CH:48]([F:47])[CH2:49]3)=[N:21][CH:22]=2)[C:12]([O:15][CH3:16])=[N:13][CH:14]=1
Reactant: FC1CNC1
Reactant: COc1ncc(Cl)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cccc(OC(F)(F)F)c2)[C@@H]1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ncc(Cl)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cccc(OC(F)(F)F)c2)[C@@H]1C
Temperature: 60 °C

Procedure:
Triethylamine (0.499 mL, 3.58 mmol) was added to a THF (5 mL) solution of (4S,5R)-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-5-[3-(trifluoromethoxy)phenyl]-1,3-oxazolidin-2-one (Step A, 410 mg, 0.716 mmol) and 3-fluoroazetidine hydrochloride (300 mg, 2.69 mmol). The reaction was placed in an oil bath and heated for 20 minutes at 60° C. LCMS showed complete conversion to product. The reaction was diluted with ethyl acetate (50 mL) and poured into 0.1N HCl solution (50 mL). The ethyl acetate layer was washed with brine (50 mL), dried over sodium sulfate, filtered and the filtrate was concentrated on rotary evaporator. The crude isolate was purified by silica gel chromatography, eluting with a 0-50% ethyl acetate/hexanes linear gradient followed by a hold at 50% ethyl acetate/hexanes to give the title compound as a pale yellow solid. LCMS (M+H)+: 568.3. 1H NMR (500 MHz, CDCl3): δ 8.21 (d, J=2.3 Hz, 1H), 8.14 (s, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.25 (m, 2H), 7.15 (s, 1H), 5.59 (d, J=8.4 Hz, 1H), 5.55 (m, 0.5H), 5.44 (m, 0.5H), 4.66 (d, J=17.1 Hz, 1H), 4.61 (m, 2H), 4.43 (m, 2H), 4.32 (m, 1H), 4.03 (d, J=17.5 Hz, 1H), 3.96 (s, 3H), 0.75 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][C:17]#[N:18])=[C:11]([F:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][NH2:22]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([NH2:18])[NH:22][N:21]=2)=[C:11]([F:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: N#CCC(=O)c1ccc(OCc2ccccc2)cc1F
Solvent: CCO
Product: Nc1cc(-c2ccc(OCc3ccccc3)cc2F)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
3-(4-(Benzyloxy)-2-fluorophenyl)-3-oxopropanenitrile (1.7 g, 6.3 mmol) was dissolved in ethanol (21 mL), and then hydrazine (0.22 mL, 6.9 mmol) was added. The reaction mixture was stirred at room temperature for about one hour, and the progress of the reaction was followed by thin-layer chromatography. If no progress had been made, the temperature was gradually increased until the reaction began proceeding. As soon as the reaction appeared complete by thin-layer chromatography, the crude material was concentrated in vacuo and purified by chromatography to provide the title compound 97% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12]([C:18]1[C:23]([CH2:24]O[Si](C(C)(C)C)(C)C)=[CH:22][CH:21]=[CH:20][N:19]=1)([OH:17])[CH2:13]2.[F-].C([N+:45](CCCC)(CCCC)CCCC)CCC>>[NH2:45][CH2:24][C:23]1[C:18]([C:12]2([OH:17])[CH2:11][CH:10]3[N:9]([CH:8]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[Cl:39])[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccnc1C1(O)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: NCc1cccnc1C1(O)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl

Procedure:
Follow the procedure of Step 4 of Example 15, using the product from Step 3 (12.3 g, 21.1 mmol) and tetrabutylamonium fluoride (11 g, 42.2 mmol) to give the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][CH:18]3[CH:13]([CH:14]([NH2:21])[CH2:15][CH2:16][CH2:17]3)[CH2:12]2)=[CH:4][CH:3]=1.[C:22]([C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1)(=[O:24])[CH3:23].CO>O1CCCC1>[C:22]([C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH:21][CH:14]2[CH:13]3[CH:18]([CH2:19][CH2:20][N:11]([CH2:10][CH2:9][CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:12]3)[CH2:17][CH2:16][CH2:15]2)=[O:33])[CH:28]=[CH:29][CH:30]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)c1cccc(N=C=O)c1
Reactant: NC1CCCC2CCN(CCCc3ccc(F)cc3)CC12
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1cccc(NC(=O)NC2CCCC3CCN(CCCc4ccc(F)cc4)CC32)c1
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
A solution of (4aSR,8SR,8aRS)-2-[3-(4-fluorophenyl)propyl]decahydroisoquinolin-8-amine (15 mg, 50 μmol) in tetrahydrofuran (1 mL) was treated with 3-acetylphenylisocyanate (8.3 mg, 50 mmol). The mixture was stirred for 30 minutes, then treated with methanol (0.5 mL). The mixture was concentrated under vacuum to provide a residue. The residue was purified by flash column chromatography, eluting with 5% triethylamine/ethyl acetate, to provide a white solid (11.4 mg, 49%). 1H NMR (300 MHz, CDCl3) δ7.80 (s, 1H), 7.78 (d, J=8 Hz, 1H), 7.70 (s, 1H), 7.50 (d, J=8 Hz, 1H), 7.29 (t, J=8 Hz, 1H), 7.00 (m, 2H), 6.83 (m, 2H), 5.16 (d, J=10 Hz, 1H), 3.61 (m, 1H), 3.42 (m, 1H), 3.08 (m, 1H), 2.94 (m, 1H), 2.53 (s, 3H), 2.47 (t, J=8 Hz, 2H), 2.4-2.2 (m, 2H), 1.9-1.5 (m, 8H), 1.4-0.8 (m, 5H). Mass spec (ES+) m/z 452.3 (M+H+, 100%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:10][N@@:9]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])(=O)=O.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>O1CCCC1.CS(C)=O>[CH2:21]([N:28]1[CH2:6][CH2:7][C@H:8]([NH:9][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)[N@]2CC2CCOS(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)[N@@]2CC2CCOS(C)(=O)=O)cc1
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N[C@H]2CCN(Cc3ccccc3)C2)cc1

Procedure:
(S)-2-(2'-Methanesulfonyloxyethyl)-1-(p-toluenesulfonyl)aziridine, 3, (54.5 g) was dissolved in warm tetrahydrofuran (50 mL) and the solution added dropwise over 20 minutes to a solution of benzylamine (40 g) and triethylamine (40 g) in dimethyl sulfoxide (250 mL) at 75° to 85° C. The resulting solution was heated another 2.5 hours at 75° to 85° C. and then concentrated under vacuum to remove tetrahydrofuran and dimethyl sulfoxide. The residue was dissolved in toluene (300 mL) and cautiously treated with 10 g of dry ice followed by 1.0N NaOH (150 mL). The layers were separated and the toluene layer treated cautiously with more dry ice (3 g) followed by 20 mL 1.0N NaOH. This carbon dioxide--NaOH extraction procedure was repeated three more times and the resulting toluene solution concentrated under vacuum to give (S)-1-benzyl-3-(p-toluenesulfonylamino)pyrrolidine, 4, as an amber oil. The oil was dissolved in warm (60° -70° C.) toluene (15 mL) and a solution (30 mL) of isopropyl alcohol saturated with hydrogen chloride gas was added. The solution was stirred and cooled to -5° C. where it was maintained for 3 hours. The solid product was collected and washed with isopropyl alcohol and ether and vacuum dried to give (S)-1-benzyl-3-(p-toluenesulfonylamino)pyrrolidine hydrochloride as an off-white solid (46.5 g, 74% combined yield for Steps 3 and 4). A portion was recrystallized from isopropyl alcohol: mp 179°-181° C.
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:11]#[C:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:12])=[CH:16][CH:15]=1
Reactant: C#CCCCCCCCCCO
Reactant: Clc1ccc(I)cc1
Product: OCCCCCCCCCC#Cc1ccc(Cl)cc1

Procedure:
In a manner described in Example 18 above, 10-undecyn-1-ol was reacted with 1-chloro-4-iodobenzene to give the title compound; NMR (CDCl3) δ 1.21-1.50 (m, 10H), 1.50-1.65 (m, 4H), 2.36-2.41 (m, 2H), 3.61-3.66 (m, 2H), 7.16-7.31 (m, 4H).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5](=[O:19])[O:4]1.Cl[C:21]1[N:26]=[CH:25][C:24]([C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:22]1[CH:23]=[C:24]([C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH:25]=[N:26][C:21]=1[N:16]1[CH2:17][CH2:18][CH:13]([N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:3]([CH3:2])[O:4][C:5]2=[O:19])[CH2:14][CH2:15]1
Reactant: Cl
Reactant: CC1OC(=O)N(C2CCNCC2)c2ccccc21
Reactant: CC(C)NC(=O)c1ccc(Cl)nc1
Product: CC(C)NC(=O)c1cnc(N2CCC(N3C(=O)OC(C)c4ccccc43)CC2)c(Cl)c1

Procedure:
The title compound was prepared from the product of step (ii) (0.36 g) and the product from example 117 step (i) (0.466 g) using the method of example 115 step (ii). Yield 0.112 g
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([NH2:20])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1.[C:22](C1NC=CN=1)(C1NC=CN=1)=[O:23].[NH:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[NH:42][C:41]2=[O:50])[CH2:36][CH2:35]1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH:4]([NH:20][C:22]([N:34]1[CH2:35][CH2:36][CH:37]([N:40]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[NH:42][C:41]2=[O:50])[CH2:38][CH2:39]1)=[O:23])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: COC(=O)C(N)Cc1ccc(OCc2ccccc2)nc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)nc1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-amino-3-(6-benzyloxy-pyridin-3-yl)-propionic acid methyl ester (60 mg, 0.21 mmol) in methylene chloride (1 mL, 0° C.) was added carbonyl diimidazole (34 mg, 1.0 equiv.). After 15 min, a solution of 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (58 mg, 1.2 equiv.) in methylene chloride (0.5 mL) was added via canula. The ice bath was removed and stirring continued overnight. The reaction was concentrated and purified by column chromatography to give 59 mg (52%). Mass spec.: 544.49 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=2)[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][N:30]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OCc3ccccc3)c2)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OCc3ccccc3)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of 951 mg (4.86 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 1.997 g (5.35 mmol) [2-(3-benzyloxy-phenyl)-ethyl]-(4-tert-butyl-benzyl)-amine in 50 ml DMF, were added 1.6 ml (14.58 mmol) N-methylmorpholine and 2.77 g TBTU (7.29 mmol) at rt. After stirring for 16 h at rt, the reaction mixture was diluted with 300 ml water and extracted with EtOAc (2×). The combined organic phases were washed with twice 200 ml water and 100 ml brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (90 g silica gel; heptane/EtOAc 9:1 then 4:1) to give 2.41 g of 5-chloro-1H-indole-7-carboxylic acid [2-(3-benzyloxy-phenyl)-ethyl]-(4-tert-butyl-benzyl)-amide as a light yellow solid (88%). MS (ISP) 551.3 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[Cl:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([S:38]([NH:41][CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:40])=[O:39])[CH:32]=[CH:31]2>>[ClH:27].[Cl:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([S:38]([NH:41][CH:42]1[CH2:47][CH2:46][N:45]([C:17]([C:15]3[S:14][C:11]4[CH2:12][CH2:13][NH:8][CH2:9][C:10]=4[CH:16]=3)=[O:19])[CH2:44][CH2:43]1)(=[O:39])=[O:40])[CH:32]=[CH:31]2
Reactant: O=S(=O)(NC1CCNCC1)c1ccc2cc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C(=O)O)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(c1cc2c(s1)CCNC2)N1CCC(NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
In a similar manner to Example 4 except for the use of 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-carboxylic acid and 4-[(6-chloronaphthalen-2-yl)sulfonamido]piperidine trifluoroacetate as the raw materials, the reaction was conducted, whereby the title compound was obtained.