Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C.CCCCCC.CCOCC>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:12])[C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)C(=O)c1ccc(F)cc1
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(=O)C(=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-fluorophenyl glyoxylic acid (100 mg, 0.595 mmol) in ethyl ether (5 ml) was added trimethylsilyl diazomethane (2 M/hexane, 1 ml) at 0° C. TLC showed reaction was complete after 1 h. The ether was evaporated to leave a yellow oil. Chromatography with hexane/ether (95:5) gave methyl 4-fluorophenylglyoxalate as a pale yellow oil (75 mg). 500 MHz 13C NMR (CDCl3): δ 184.11; 167.85; 165.79; 163.59; 133.04; 132.96; 128.97; 116.33; 116.16; 115.90; 115.72; 52.85.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@@H:12](O)[C@H:11]([CH3:16])[O:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.P([N:64]=[N+:65]=[N-:66])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O>C1COCC1>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:64]=[N+:65]=[N-:66])[C@H:11]([CH3:16])[O:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H]1O[C@H](O[Si](C)(C)C(C)(C)C)CC[C@H]1O
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H]1O[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1N=[N+]=[N-]
Reaction time: 18 h
Yield: 56 %

Procedure:
To a solution of the alcohol from step 3 herein (62 mg, 0.25 mmol) in dry THF (2.5 ml), at room temperature, under argon, were added successively Ph3P (66 mg, 1 eq.), DEAD (40 μl, 1 eq.) and (PhO)2 PON3 (54 μl, 1 eq.) and the solution was stirred for 18 hours. The THF was evaporated and the crude oil was purified by flash chromatography (silica gel, 95:5 hexanes/EtOAc) to give 38 mg (56%) of the titled azide as a clear oil.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.[CH2:21]([O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])[CH3:22].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:21]([O:23][C:24](=[O:31])[CH:25]([NH:26][C:16]([C@@H:11]1[CH2:12][S:13][CH2:14][CH2:15][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=1)(=[O:8])=[O:9])=[O:18])[CH2:27][CH:28]([CH3:29])[CH3:30])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C(CC(C)C)NC(=O)[C@@H]1CSCCN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.3 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.215 g (1.1 mmol) of L-leucine ethyl ester hydrochlorid, 0.227 g (1.2 mmol) of DCC and 0.122 g (1 mmol) of DMAP were dissolved in 30 mL of CH2Cl2, 0.2 ml (1.4 mmol) of TEA was added. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: CH2Cl2:CH3Cl=1:1) to obtain the product as a oil (0.36 g).
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][NH:8][N:7]=1)([O-:5])=[O:4].CCN(C(C)C)C(C)C.Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26]>CN(C=O)C.CC(=O)OCC.O>[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[N:7]=1)([O-:5])=[O:4]
Reactant: CC(=O)CCCCBr
Reactant: O=[N+]([O-])c1cn[nH]n1
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)CCCCn1ncc([N+](=O)[O-])n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 4-nitro-2H-[1,2,3]triazole (114 mg, 1.00 mmol) in DMF (1.0 mL) was treated with DIPEA (0.34 mL, 2.00 mmol). After 30 min, a solution of 6-bromo-hexan-2-one (179 mg, 1.00 mmol) in DMF (1.0 mL) was added and the reaction mixture was stirred for 24 h at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (2:1 hept-EA) gave the title compound as a yellow oil: TLC:rf (2:1 hept-EA)=0.26. LC-MS-conditions 02: tR=0.86 min.
Reaction SMILES: Cl.[O:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[S:17][C:16]([C:18]4([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[CH:5][N:4]=[CH:3]1.C(N(CC)CC)C.Cl[C:43]([O:45][CH2:46][CH:47]1[C:59]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:53]2[C:48]1=[CH:49][CH:50]=[CH:51][CH:52]=2)=[O:44]>C(Cl)(Cl)Cl.CN(C)C=O>[CH:58]1[C:59]2[CH:47]([CH2:46][O:45][C:43]([N:21]3[CH2:20][CH2:19][C:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:16]4[S:17][C:13]([C:10]5[CH:9]=[CH:8][C:7]([C:6]6[O:2][CH:3]=[N:4][CH:5]=6)=[CH:12][CH:11]=5)=[CH:14][CH:15]=4)[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22]3)=[O:44])[C:48]3[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:54]=2[CH:55]=[CH:56][CH:57]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)CC1(c2ccc(-c3ccc(-c4cnco4)cc3)s2)CCNCCS1(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)CC1(c2ccc(-c3ccc(-c4cnco4)cc3)s2)CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CCS1(=O)=O
Reaction time: 0.5 h
Yield: 102 %

Procedure:
To a mixture of tert-butyl 2-(7-(5-(4-(5-oxazolyl)phenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetate hydrochloride (4.2 g) and triethylamine (2.43 g) in a mixture of chloroform (24 ml) and N,N-dimethylformamide (12 ml) was added dropwise a solution of 9-fluorenylmethyl chloroformate (2.28 g) in chloroform (5 ml) under ice-cooling. After being stirred for 30 minutes, the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with water, a saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo to give tert-butyl 2-[4-(9-fluorenylmethoxycarbonyl)-7-(5-(4-(5-oxazolyl)phenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetate (5.8 g) as an amorphous powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:40])([CH3:39])[CH2:31][O:32]C1CCCCO1)([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:25])([CH3:24])[CH2:16][O:17]C1CCCCO1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)C>Cl.O>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:39])([CH3:40])[CH2:31][OH:32])([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:24])([CH3:25])[CH2:16][OH:17])[C:4]([O:3][CH2:1][CH3:2])=[O:41])[CH3:10]
Reactant: CCOC(=O)C(CCCCC(C)(C)COC1CCCCO1)(CCCCC(C)(C)COC1CCCCO1)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CCCCC(C)(C)CO)(CCCCC(C)(C)CO)C(=O)OCC
Yield: 83.5 %

Procedure:
A solution of 2,2-bis-[5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]-malonic acid diethyl ester (2.92 g, 5 mmol) in concentrated HCl (2.4 mL) and water (1.6 mL) was refluxed for 1 h. Ethanol (8.2 mL) was added and the reaction mixture was heated to reflux for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with diethyl ether (3×20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), and dried over Na2SO4. The solution was concentrated to furnish 2,2-bis(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid diethyl ester (1.74 g, 84%). 1H NMR (300 MHz, CDCl3/TMS): (ppm) 4.13 (q, J=7.2 Hz, 4H), 3.25 (s, 4H), 2.42 (s, 2H), 1.90-1.75 (m, 4H), 1.30-1.12 (m, 18H), 0.84 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): (ppm) 172.0, 71.7, 60.9, 57.4, 38.2, 34.9, 32.1, 24.8, 24.0, 23.7, 14.0.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH:15]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: Cc1ccccc1C(Cl)Cn1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.64 g of methyl 4-mercaptobenzoate was dissolved in 10.4 ml of dry dimethylformamide, and 424 mg of a 55% w/w suspension of sodium hydride in mineral oil were added, whilst ice-cooling. The resulting mixture was then stirred at room temperature for 30 minutes. 12 ml of dry dimethylformamide containing 2.15 g of 1-[2-chloro-2-(2-methylphenyl)ethyl]imidazole were added to the resulting solution, and the mixture was heated at a temperature between 60° and 70° C. for 5.5 hours. At the end of this time, the resulting solution was treated and purified by the same procedure as described in Example 1, to give 2.62 g of the title compound as an oil.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CCCCCC.[CH3:19][CH:20]([CH2:25][CH2:26][CH2:27][CH3:28])[C:21](OC)=[O:22].[Cl-].[NH4+]>C1COCC1.O>[CH3:19][CH:20]([CH2:25][CH2:26][CH2:27][CH3:28])[C:21](=[O:22])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCCC(C)C(=O)OC
Reactant: COP(C)(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(C)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of dimethyl methylphosphonate (60 g, 485 mmol) in 600 ml THF was cooled to −78° C. and treated with a 2.5 M solution n-butyl lithium in hexane (194 mL, 485 mmol). After 30 min, the reaction was treated with a solution of methyl 2-methylhexanoate (14 g, 97 mmol) in THF (40 mL). The reaction was stirred for 1 h at −78° C. The reaction was treated with a saturated aqueous ammonium chloride solution (200 mL) and allowed to warm to ambient temperature. The solution was diluted with water and extracted with ether. The combined organic layers were washed with brine, dried, and concentrated. Purification by normal phase chromatography using a gradient of ethyl acetate in hexane gave dimethyl (3-methyl-2-oxoheptyl)phosphonate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][C:7]=1[O:16][CH3:17].[OH-].[Na+].Cl>CO>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[O:16][CH3:17]
Reactant: COC(=O)c1ccc(OCCCCl)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)ccc1OCCCCl
Temperature: 40 °C
Yield: 95 %

Procedure:
In a 300 mL volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed 18.2 g (69.7 mmol) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate (purity: 98 wt. %) prepared by procedures similar to the procedures of Reference Example III-3, 69.7 mL of an aqueous sodium hydroxide (2 mol/L), and 69.7 mL of methanol. The resulting mixture was heated to 40° C. for 4 hours in an argon gas atmosphere. After the reaction was complete, the reaction mixture was cooled to 10° C. and neutralized by 69.7 mL of hydrochloric acid (2 mol/L), to precipitate a crystalline product. The crystalline product was collected by filtration and dried under reduced pressure. There was obtained 16.2 g (isolated yield: 93.8%, purity: 99% in terms of area percentage determined by high performance liquid chromatography) of 4-(3-chloropropoxy)-3-methoxybenzoic acid as a white crystalline product.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O=[C:12]1[CH2:29][CH2:28][C:15]2([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:14][CH2:13]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:12]2[CH2:29][CH2:28][C:15]3([CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:19][CH2:20]3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCC(N3CCN(C(C)(C)C)CC3)CC2)CC1
Reaction time: 0.08 h

Procedure:
1-tert-Butylpiperazine (0.21 g, 1.49 mmol) was added to tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (see product of step (v) of the synthesis of amine AMN-06) (0.4 g, 1.49 mmol) and triethylamine (0.52 ml, 3.74 mmol) in methylene chloride (9.6 ml). The mixture was stirred for 5 min and sodium triacetoxyborohydride (0.44 g, 2.09 mmol) was then added and the mixture was stirred at room temperature overnight. Sat. NaHCO3 solution was added and, after separation of the phases, the organic phase was washed with sat. NaCl solution (2×), dried over sodium sulfate and concentrated in vacuo. Yield: 0.27 g (45%)
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH:2]1[C:5]([NH2:7])=O.[Cl:8][CH2:9][C:10](Cl)=[O:11]>>[Cl:8][CH2:9][C:10]([N:1]1[CH2:4][CH2:3][C@H:2]1[C:5]#[N:7])=[O:11]
Reactant: O=C(Cl)CCl
Reactant: NC(=O)C1CCN1
Product: N#C[C@@H]1CCN1C(=O)CCl
Yield: 43.9 %

Procedure:
In a similar procedure as employed in the Intermediate Example 1, the azetidine-2-carboxylic acid amide (161 mg) obtained above was reacted with chloroacetyl chloride (200 mg) and then subjected to dehydration reaction to give the title compound (112 mg, Y.:44%).
Reaction SMILES: [CH3:1][C:2]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:4][C:2]([CH:5]1[CH2:6][CH2:7][CH:8]([CH:11]=[O:12])[CH2:9][CH2:10]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)C1CCC(CO)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)C1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of 4-(1,1-dimethylethyl)cyclohexanemethanol (1.0 g, 5.9 mmol) in CH2Cl2 (distilled from CaH2) (43 mL) were added at room temperature under argon anhydrous NaOAc (3.84 g, 46.8 mmol). After stirring at room temperature for 5 minutes pyridinium chlorochromate (3.84 g, 17.8 mmol) was added and after stirring for 1 h at room temperature, the reaction was quenched by addition of ethyl ether (200 mL). The crude reaction was filtered through a Fluorasil column to give crude 4-(1,1-dimethylethyl)cyclohexanecarboxaldehyde (0.862 g, 5.12 mmol) as a mixture of trans and cis isomer in 87% yield.
Reaction SMILES: [OH:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>>[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([O:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18])=[O:25]
Reactant: O=C(Cl)c1ccco1
Reactant: CC1=C2C[C@@]3(C)C(=CC[C@H](O)[C@@H]3C)C=C2OC1=O
Product: CC1=C2C[C@@]3(C)C(=CC[C@H](OC(=O)c4ccco4)[C@@H]3C)C=C2OC1=O

Procedure:
The title compound was prepared in the same manner as in Example B2, except that the compound prepared in Example B1 was reacted with 2-furoyl chloride.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)C[CH2:12][O:11][CH2:10]1)C1C=CC=CC=1.NCC1(N(CC2C=CC=CC=2)CC2C=CC=CC=2)C[O:51][CH2:50]1>>[NH2:8][C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][C:36]([O:51][CH3:50])=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:10][O:11][CH2:12]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Product: COc1ccc2c(c1)S(=O)(=O)CCN(c1cc(NCC3(N)COC3)c3ccccc3n1)C2

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloroquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloroquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 455, 1H NMR (400 MHz, CD3OD) δ ppm 7.91-7.74 (m, 2 H), 7.58-7.38 (m, 3 H), 7.22-7.03 (m, 2 H), 6.23 (s, 1 H), 5.12 (brs, 2 H), 4.70-4.46 (m, 6 H), 3.81 (s, 3 H), 3.70 (s, 2 H), 3.65-3.52 (m, 2 H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[C:17]([NH:29][CH3:30])[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31]I>>[CH2:1]([N:8]([C:9]1[CH:10]=[C:11]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[C:17]([NH:29][CH3:30])[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1nc(-c2cccc(NCc3ccccc3)c2)c2cc(OC)c(OC)cc2n1
Reactant: CI
Product: CNc1nc(-c2cccc(N(C)Cc3ccccc3)c2)c2cc(OC)c(OC)cc2n1
Yield: 33.8 %

Procedure:
Starting from 100 mg of 4-(3-benzylaminophenyl)-6,7-dimethoxy-2-methylaminoquinazoline obtained in Example 38 and 71.0 mg of methyl iodide, 35.0 mg of the title compound was obtained as a pale yellow oil in the same manner as in Example 38.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:21][C:22]([O:24]C)=O)[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=[O:8])(=O)C.C(SCC(CC(OC)=O)C([N:34]1CCC[C@H]1C(O)=O)=O)(=O)C>>[SH:4][CH2:5][CH:6]([CH2:21][C:22](=[O:24])[NH2:34])[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=[O:8]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)C(CS)CC(N)=O)C(=O)O

Procedure:
By substituting Nα -[3-(acetylthio)-2-(methoxycarbonylmethyl)propanoyl]-L-arginine for the 1-[3-(acetylthio)-2-(methoxycarbonylmethyl)propanoyl]-L-proline in the procedure of Example 6A, and then isolating the product with Dowex 50 resin as described in the procedure of Example 17, Nα -[3-mercapto-2-(carbamoylmethyl)propanoyl]-L-arginine is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:18])=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[CH:10]=2)=[O:5])[CH3:2].IC.[CH3:21]COC(C)=O.CCCCCC>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:18][CH3:21])=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1c(O)nc2cc(F)ccc2c1C
Solvent: CI
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)c1c(OC)nc2cc(F)ccc2c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a stirred solution of 2.30 g (9.24 mmol) 7-fluoro-2-hydroxy-4-methylquinoline-3-carboxylic acid ethyl ester in DCM (60 ml) were added 6.36 g (23.1 mmol) Ag2CO3 and 1.44 ml (23.1 mmol) iodomethane at RT. The reaction mixture was stirred at RT for 16 h. Then the mixture was filtered through celite and the filtrate was concentrated in vacuum. After CC (EtOAc/hexane 1:4) of the residue, 1.50 g (5.70 mmol, 62%) 7-fluoro-2-methoxy-4-methylquinoline-3-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:25])=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[CH2:12][N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=O)[C:10](=[O:21])[CH:9]=1)[CH3:2].[CH3:26][C:27]1([CH3:39])[O:31][C@H:30]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]2)[CH2:29][O:28]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:26][C:27]1([CH3:39])[O:31][C@H:30]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH:38][C:14](=[O:16])[C@@H:13]([N:11]3[CH2:12][C:8]([O:7][C:6]4[CH:22]=[CH:23][CH:24]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=4[F:25])=[CH:9][C:10]3=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:34]2)[CH2:29][O:28]1
Reactant: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Temperature: 0 °C
Yield: 87.3 %

Procedure:
To a solution of (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 114, 570 mg, 1.62 mmol) in N,N-dimethylformamide (10 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 382 mg, 1.94 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.43 g, 3.23 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.417 g, 3.23 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g, 10% to 80% ethyl acetate/hexanes) which afforded (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.750 g, 87%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=1)[CH2:19][N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]2([OH:26])[CH2:22][CH2:21][N:20]([CH2:19][C:18]3[CH:27]=[CH:28][CH:29]=[C:16]([O:15][CH3:14])[CH:17]=3)[CH2:25][CH2:24]2)=[CH:3][CH:4]=1
Reactant: COc1cccc(CN2CCC(=O)CC2)c1
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(CN2CCC(O)(c3ccc(Cl)cc3)CC2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To 1-bromo-4-chlorobenzene (397 mg, 2.07 mmol) in tetrahydrofuran (10 mL), at −78° C., was added n-butyllithium (0.91 mL of a 2.5 M solution in hexanes, 2.3 mmol) dropwise. After 0.5 h, a solution of the ketone (500 mg, 2.28 mmol) from Step B above in tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 1.5 h and then warmed to 0° C. After 1 h, the reaction mixture was quenched with saturated ammonium chloride (5 mL) and warmed to ambient temperature. The mixture was diluted with ethyl acetate (50 mL) and washed with saturated ammonium chloride (20 mL), water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (5% ethyl acetate/methylene chloride to ethyl acetate) gave 4-(4-chlorophenyl)-1-(3-methoxybenzyl)piperidin-4-ol (370 mg, 53%) as a colorless oil: 1H NMR (DMSO-d6, 500 MHz) δ 7.50 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.24-7.21 (m, 1H), 6.90-6.89 (m, 2H), 6.81-6.79 (m, 1H), 4.87 (s, 1H), 3.74 (s, 3H), 3.47 (s, 2H), 2.61-2.59 (m, 2H), 2.43-2.38 (m, 2H), 1.94-1.87 (m, 2H), 1.57-1.54 (m, 2H).