Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[Na+].CN(C)C=O.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:29][C:28](=[O:30])[CH2:27][C:26](=[O:31])[N:25]([CH3:32])[C:24]=2[CH:33]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S(OCC)(OCC)(=O)=O>C(OCC)(=O)C.O>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:29]([CH2:1][CH3:2])[C:28](=[O:30])[CH2:27][C:26](=[O:31])[N:25]([CH3:32])[C:24]=2[CH:33]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)[O-]
Reactant: CN1C(=O)CC(=O)Nc2ccc(OCc3ccccc3)cc21
Agent: CCOS(=O)(=O)OCC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1C(=O)CC(=O)N(C)c2cc(OCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Sodium t-butoxide (330 mg, 3.43 mmol) was added to a N,N-dimethylformamide (5 mL) solution of 8-benzyloxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.01 g, 3.4 mmol) under ice cooling, and the mixture was stirred under ice cooling for 30 minutes. Thereafter, diethyl sulfate (0.51 mL, 3.69 mmol) was added, and the mixture was stirred for 6 hours under ice cooling. Water was added to the reaction solution, and ethyl acetate (20 mL) extraction was performed. The resulting organic layer was washed with water, and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from 50% ethanol (9 mL). Precipitated crystals were collected by filtration, washed with 50% ethanol, and dried at 60° C., thereby obtaining 760 mg of light-yellow, powdery 7-benzyloxy-1-ethyl-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (yield: 69%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]1[O:10][CH:8]1[CH3:9].CN(CCO)C.C1(C=CC(O)=CC=1)O>[N+](C)([O-])=O>[C:1]([O:6][CH2:7][CH:8]([OH:10])[CH3:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC1CO1
Reactant: C=C(C)C(=O)O
Agent: CN(C)CCO
Agent: Oc1ccc(O)cc1
Solvent: C[N+](=O)[O-]
Product: C=C(C)C(=O)OCC(C)O

Procedure:
2-hydroxypropyl methacrylate was prepared in the same apparatus and in the same manner as described in Example 1 by reaction of a mixture of 1000 g/hr methacrylic acid, 887 g/hr propylene oxide, 37 g/hr N,N-dimethylaminoethanol, 5 g/hr nitromethane and 1 g/hr hydroquinone at a temperature of 100° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[C:30]1([S:40](Cl)(=[O:42])=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>>[C:30]1([S:40]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]4[C:15]([C:20]5[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=5)=[CH:16][CH:17]=[CH:18][CH:19]=4)=[O:13])[CH:6]=3)[CH2:1]2)(=[O:42])=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: O=C(Nc1ccc2c(c1)CCNC2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Product: O=C(Nc1ccc2c(c1)CCN(S(=O)(=O)c1cccc3ccccc13)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydroisoquinolin6-yl]-amide was prepared by METHOD D reacting compound II with naphthalene-1-sulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.Cl[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[CH2:18][CH2:17]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=4)[CH2:18][CH2:17]3)[CH:8]=2)[N:3]=1
Reactant: Oc1ccc2nc(Cl)cnc2c1
Reactant: Cc1ccc(N2CCC(CCCl)CC2)nn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCC(CCOc3ccc4nc(Cl)cnc4c3)CC2)nn1
Yield: 61.5 %

Procedure:
A mixture of 2-chloro-6-hydroxyquinoxaline (52 mg, 288 μmol), 3-[-4-(2-chloroethyl)-1-piperidinyl]-6-methylpyridazine (76 mg, 317 μmol), potassium iodide (53 mg, 317 μmol) and potassium carbonate (199 mg, 1.44 mmol) in anhydrous dimethylformamide (2 ml) was heated at 90° under an Argon atmosphere for 2 days. Tlc (silica; ethyl acetate) showed new polar material. Removal of the solvent under high vacuum and then chromatography on silica (5 g; eluent: 30% hexane in ethyl acetate) gave the product as a white solid 68 mg (61%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([NH2:31])=[CH:26][CH:25]=2)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([NH:31][C:2]1[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=1)=[CH:26][CH:25]=2)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: CCOC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2[nH]1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 2-ethoxycarbony-5-aminoindole gave N2-(2-ethoxycarbonylindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.95 (d, 1H), 7.84 (d, 1H, J=3.9 Hz), 7.34 (s, 1H), 7.33 (d, 1H, J=1.8 Hz), 7.22-7.19 (m, 2H), 7.11-7.05 (m, 2H), 6.55 (m, 1H), 4.62 (s, 2H), 4.38 (q, 1H, J=6.9 Hz), 1.40 9t, 3H, J=7.5 Hz).
Reaction SMILES: [CH2:1]([Li])CCC.CN(CCN(C)C)C.[C:14]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[N:26][CH:27]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CI>CCCCCC.O>[C:14]([NH:21][C:22]1[C:23]([CH3:1])=[CH:24][C:25]([O:28][CH3:29])=[N:26][CH:27]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: [Li]CCCC
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cn1
Agent: CN(C)CCN(C)C
Solvent: O
Solvent: CI
Solvent: CCCCCC
Product: COc1cc(C)c(NC(=O)OC(C)(C)C)cn1
Reaction time: 4 h

Procedure:
41.7 ml of 1.6M n-butyllithium in hexane and 7.7 g of TMEDA are added, under nitrogen, to 5 g of 5-(N-Boc-amino)-2-methoxypyridine, at −60° C. The medium turns yellow. The mixture is left stirring for 4 hours, allowing the temperature to return to −10° C., and a pale yellow. precipitate forms. The mixture is recooled to −40° C. and 4.7 g of methyl iodide are then added. The medium is allowed to return to RT and is then poured into water and extracted with EtOAc, and the extracts are dried and evaporated. The residue is chromatographed on silica, eluting with cyclohexane/EtOAc (85/15; v/v).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]([CH3:21])([CH3:20])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([OH:19])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:26]1[N:33]=[CH:32][CH:31]=[CH:30][C:27]=1[C:28]#[N:29].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]([CH3:21])([CH3:20])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([O:19][C:26]3[C:27]([C:28]#[N:29])=[CH:30][CH:31]=[CH:32][N:33]=3)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cccnc1Cl
Reactant: CC(C)(Cc1c[nH]c2c(O)cccc12)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(Cc1c[nH]c2c(Oc3ncccc3C#N)cccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 95.7 %

Procedure:
To a solution of [2-(7-Hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (274 mg, 0.900 mmol) in dimethylformamide (15 mL) is added sodium hydride (26 mg, 1.07 mmol). The mixture is stirred at ambient temperature for 25 minutes under nitrogen. 2-Chloro-nicotinonitrile (187 mg, 1.35 mmol) is added and the mixture is heated in an oil bath to eighty degrees Celsius for 15 hours, under nitrogen. Water (50 ml) is added to quench the reaction and the mixture is extracted three times with 50 mL of ethyl acetate. The organic layers are combined and washed twice with 50 mL of 1.00 N sodium hydroxide. The organic layer is dried with sodium sulfate, filtered and the solvent evaporated. The residue is dissolved in dichloromethane and purified using silica gel chromatography (6% 2M ammonia in methanol, 94% dichloromethane used as mobile phase) to give 350 mg (96%) of {2-[7-(3-cyano-pyridin-2-yloxy)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester. FDMS m/e=407 (M++1).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:21](O)=[O:22])=[C:6]2[C:20]=1[C:10]1[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:13][C:9]=1[CH2:8][CH2:7]2.[C:24](Cl)(=O)[C:25](Cl)=O.C[N:31](C)C=O>O1CCCC1>[CH2:24]([NH:31][C:21]([C:5]1[S:4][C:3]([S:2][CH3:1])=[C:20]2[C:10]3[N:11]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[S:13][C:9]=3[CH2:8][CH2:7][C:6]=12)=[O:22])[CH3:25]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Reactant: CSc1sc(C(=O)O)c2c1-c1nc(-c3ccccc3)sc1CC2
Solvent: C1CCOC1
Product: CCNC(=O)c1sc(SC)c2c1CCc1sc(-c3ccccc3)nc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
4,5-Dihydro-8-methylthio-2-phenylthieno[3,4-e]benzothiazole-6-carboxylic acid (0.43 g) was suspended in tetrahydrofuran (15 ml); oxalyl chloride (0.23 g) and then N,N-dimethylformamide (6 μl) were added. After this mixture was stirred at room temperature for 2 hours, it was concentrated under reduced pressure. The residue was suspended in tetrahydrofuran (5 ml) and cooled with ice; a 70% aqueous solution of ethylamine (4.0 ml) was added. After the reaction mixture was stirred at room temperature for 1 hour, it was poured over water (150 ml) and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield N-ethyl-4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzothiazole-6-carboxamide (0.35 g, 76%), which was then recrystallized from chloroform-ethanol. Yellow needles. Melting point 211-212° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][C:20]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:6][CH:7]=2)[CH2:12][CH2:13][CH3:14])=[CH:25][CH:24]=1)=[O:21]
Reactant: CCC[C@H](Oc1ccc(C(=O)OC)cc1)c1ccc(CC(C)C)cc1
Reactant: Cc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC[C@H](Oc1ccc(C(=O)Cc2ccccn2)cc1)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-[1-(S)-(4-isobutylphenyl)-butoxy]benzoate (283 mg) and 2-methylpyridine (0.09 ml) in tetrahydrofuran (5 ml) was added 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.7 ml) at 0° C. The mixture was stirred for 18 hours at room temperature. Acetic acid (0.18 ml) and ethyl acetate (15 ml) was added to the mixture. The mixture was washed with water and aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1) to give 4-[1-(S)-(4-isobutylphenyl)butoxy]phenyl 2-pyridylmethyl ketone as a yellow oil (216 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(N(CC)CC)C.[C:44](Cl)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCCC1>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][C:44](=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)c4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
A stirred solution of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (110 mg, 0.22 mmol) in dry tetrahydrofuran (20 ml) was treated with triethylamine (0.1 ml, 0.72 mmol) and the mixture heated gently until all components had dissolved. The solution was then cooled to room temperature, treated with a solution of benzoyl chloride (28 mg, 0.20 mmol) in dry tetrahydrofuran (2 ml) and the mixture stirred for 1.5 hr. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (95:5), to give the product which was then triturated with a mixture of diethyl ether and pentane, filtered off and dried to afford the title compound as a solid (80 mg). MS: 595 (MH+).
Reaction SMILES: [CH:1]1([C:4](=O)[CH3:5])[CH2:3][CH2:2]1.[CH3:7][C:8]([S:11]([NH2:13])=[O:12])([CH3:10])[CH3:9]>C1COCC1>[CH:1]1(/[C:4](=[N:13]/[S:11]([C:8]([CH3:10])([CH3:9])[CH3:7])=[O:12])/[CH3:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)S(N)=O
Reactant: CC(=O)C1CC1
Solvent: C1CCOC1
Product: C/C(=N\S(=O)C(C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
A mixture of 1-cyclopropylethanone (1 g, 12 mmol), 2-methylpropane-2-sulfinamide (1.7 g, 14 mmol), Ti(OEt)4 (5.5 g, 24 mmol) in 10 mL of THF was heated at reflux with stirring overnight. The mixture was cooled to room temperature, solvent was removed under reduced pressure and the crude residue was purified by column chromatography (silica gel, 200-300 mesh, petroleum ether and ethyl acetate (3:1, v/v) to give (E)-N-(1-cyclopropylethylidene)-2-methylpropane-2-sulfinamide (0.6 g, 27%) as clear oil. MS: (M+H)+=188.2; 1H NMR (300 MHz, CDCl3): δ 2.36 (s, 3H), 1.69 (m, 1H), 1.18 (s, 9H), 1.07-0.89 (m, 4H).
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]([C:18](=[O:38])[C@H:19]([CH3:37])[NH:20][C@H:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(C)(C)C.[BrH:40].C(O)(=O)C.C(OCC)C>C(O)(=O)C>[BrH:40].[BrH:40].[CH2:35]([O:34][C:32]([C@@H:21]([NH:20][C@H:19]([C:18]([N:8]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[CH2:7][C:6]([OH:39])=[O:5])=[O:38])[CH3:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]1)=[O:33])[CH3:36]
Reactant: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@@H](C)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 0.5 h

Procedure:
In 2 ml of acetic acid is dissolved 0.3 g of N-[N-[(S)-5-(4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-N-(indan-2-yl)glycine tert-butyl ester, and 1 ml of hydrogen bromide-acetic acid solution is added to the solution, followed by standing at room temperature for 30 minutes. 50 ml of ethyl ether is added to the reaction solution, followed by shaking, and the supernatant layer is removed by decantation. The precipitate is collected and dried under reduced pressure to give 0.3 g of N-[N-[(S)-1-ethoxycarbonyl-5-(4-piperidyl)pentyl]-L-alanyl]-N-(indan-2-yl)glycine.dihydrobromide as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>CN(C)C=O.C(O)C>[CH2:22]([N:24]([CH2:25][CH3:26])[CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:10][CH:11]=1)[CH3:23]
Reactant: CCNCC
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCN(CC)C[C@@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and diethylamine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=359.
Reaction SMILES: C([S:4][C@@H:5]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:6]([NH:8][CH2:9][C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]([OH:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][C:17]=2[F:31])[C:13]([O:32][CH2:33][CH3:34])=[N:12][C:11]=1[CH2:35][CH3:36])=[O:7])(=O)C.C(S)[C@@H](O)[C@H](O)CS.CC(O)=O.O>CO>[CH2:33]([O:32][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]([OH:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][C:17]=2[F:31])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C@@H:5]([SH:4])[CH2:37][CH:38]([CH3:39])[CH3:40])=[C:11]([CH2:35][CH3:36])[N:12]=1)[CH3:34]
Reactant: CCOc1nc(CC)c(CNC(=O)[C@H](CC(C)C)SC(C)=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1F
Agent: O[C@H](CS)[C@H](O)CS
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCOc1nc(CC)c(CNC(=O)[C@@H](S)CC(C)C)n1Cc1ccc(-c2ccccc2C(=O)O)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
Crystalline 4′-{5-[((S)-2-acetylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylic acid (2.3 g, 4 mmol, 1 eq.) and DTT (62 mg, 0.4 mmol, 0.1 eq.) was dissolved in MeOH (30 mL). The resulting solution was degassed with nitrogen (3 times) and cooled at 0° C. NaOMe (25% in MeOH, 1.7 mL) was added and the mixture was stirred at 0° C. for 30 minutes. AcOH (3 g, 50 mmol, 4 eq.) was added to quench the reaction at 0° C. The mixture was warmed to 20° C. Deionized water (10 mL) was added slowly. The mixture was stirred at 20° C. for 3 hours and then stirred at 4° C. for 1 hour until precipitates were formed. The solids were filtered and washed with MeOH/H2O (2:1; 30 mL), then dried under nitrogen at 20° C. for 48 hours to yield the title crystalline compound (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:13]1[CH:21]=[CH:20][C:16]([N:17]([CH3:19])[CH3:18])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:21]=[CH:20][C:16]([N:17]([CH3:19])[CH3:18])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: Clc1ccnc2ccccc12
Reactant: CN(C)c1ccc(Br)cc1
Product: CN(C)c1ccc(-c2cc(Cl)c3ccccc3n2)cc1

Procedure:
The title compound, MS: m/e=282 (M+), was prepared from 4-chloro-quinoline and 4-bromo-N,N-dimethylaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=3)[S:10][C:11]=2[C:12]2[N:16](COCC[Si](C)(C)C)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=3)[S:10][C:11]=2[C:12]2[NH:13][CH:14]=[N:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cc(-c2nc(Cc3ccc(Cl)cc3)c(-c3ncnn3COCC[Si](C)(C)C)s2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2nc(Cc3ccc(Cl)cc3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
To a solution of N-{4-[4-(4-chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-5-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.112 g, 0.207 mmol) in dichloromethane (2.0 mL) at room temperature was added trifluoroacetic acid (3.1 mL, 40 mmol). The mixture was then stirred at room temperature for 4 hours. The solvent was evaporated and the excess trifluoroacetic acid was removed by azeotroping with toluene. Column chromatography was performed to yield the title compound (0.0520 g, 61%). LCMS: (FA) ES+ , 411. 1H NMR (400 MHz, d6-DMSO) δ: 14.46 (s, 1H), 10.69 (s, 1H), 8.80-8.73 (m, 1H), 8.64-8.60 (m, 1H), 8.43-8.37 (m, 1H), 7.59-7.54 (m, 1H), 7.37-7.28 (m, 4H), 4.66 (s, 2H), 2.12 (s, 3H).
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:4]([NH:5][C:6]1=[O:7])[C:3](=[O:10])[NH:2]2.[H-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O.C(OCC)C>[CH2:13]([N:2]1[C:3](=[O:10])[CH:4]2[CH2:8][CH2:9][CH:1]1[C:6](=[O:7])[N:5]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1NC2CCC1NC2=O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1C2CCC(C(=O)N2Cc2ccccc2)N1Cc1ccccc1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A hot solution of 36.6 g (0.262 mole) of 2,5-diazabicyclo[2.2.2]octane-3,6-dione in 800 ml dry dimethylformamide was added rapidly from a dropping funnel to 12.5 g (0.52 mole) of oil-free sodium hydride. After stirring for 1 hour, the mixture was chilled and treated with 67.5 ml (0.59 mole) benzyl chloride during a period of a few minutes. After stirring at room temperature for 18 hours, 1 liter of water was added cautiously, and the mixture was extracted with chloroform. The extracts were washed with water, dried with sodium sulfate, and evaporated to dryness to yield a crystalline residue. Trituration in diethyl ether provided 77.0 g (91%) of product as colorless needles, melting point 168°-170°C.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.[N:39]1([C:43](=O)[CH2:44]Cl)[CH2:42][CH2:41][CH2:40]1>>[N:39]1([CH2:43][CH2:44][O:1][C:2]2[CH:38]=[CH:37][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=3[CH:20]3[CH2:29][CH2:28][C:27]4[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=4[CH2:21]3)=[CH:4][CH:3]=2)[CH2:42][CH2:41][CH2:40]1
Reactant: O=C(CCl)N1CCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN3CCC3)cc2)c1
Yield: 8.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (27 mg) and 1-azetidin-1-yl-2-chloroethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.3 mg) was obtained.