Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]([O:8]C)=O.[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]2[CH:34]=[C:33]([N:35]([CH3:37])[CH3:36])[S:32][C:31]=2[CH:38]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([C:34]2[C:30]3[CH:29]=[CH:28][C:27]([O:26][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:38][C:31]=3[S:32][C:33]=2[N:35]([CH3:37])[CH3:36])=[O:8])[CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CN(C)c1cc2ccc(OCc3ccccc3)cc2s1
Reactant: COC(=O)c1ccc(CN2CCCC2)c(OC)c1
Product: COc1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Yield: 80 %

Procedure:
Following essentially the procedure of Example 208, Part B, the title compound was prepared from methyl 3-methoxy-4-[(1-pyrrolidinyl)methyl]benzoate (Example 139, Part B) and 6-benzyloxy-2-dimethylaminobenzo[b]thiophene in 80% yield.
Reaction SMILES: O=C(NCCCC[C@@H](C(OC(C)(C)C)=O)NC(=O)N[C@H:20]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:21][CH2:22][C:23]([O:25]CC1C=CC=CC=1)=[O:24])OCC1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[Pd]>[C:36]([O:35][C:33](=[O:34])[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 325.7 %

Procedure:
A suspension of (9S,13S)-15-benzyl 13,9-di-tert-butyl 3,11-dioxo-1-phenyl-2-oxa-4,10,12-triazapentadecane-9,13,15-tricarboxylate (4.30 g, 6.64 mmol), 10% Pd/C (1.0 g) and ammonium formate (4.0 g) in EtOH (70 mL) under a empty balloon was stirred at room temperature overnight. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The solvent was evaporated to give (S)-4-(3-(S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)-5-tert-butoxy-5-oxopentanoic acid (4.07 g, 70%) which was used without further purification. ESMS m/z: 432.3 (M/2+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][CH2:24][CH3:25])=[CH:11][C:6]=2[O:5][C:4]([C:26]#[N:27])=[CH:3]1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][CH2:24][CH3:25])=[CH:11][C:6]=2[O:5][C:4]([C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:3]1
Reactant: CCCc1ccccc1OCCCOc1ccc2c(=O)cc(C#N)oc2c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCc1ccccc1OCCCOc1ccc2c(=O)cc(-c3nnn[nH]3)oc2c1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A mixture of 38.1 parts of 4-oxo-7-(3-[2-propylphenoxy]-propoxy)-4H-1-benzopyran-2-carbonitrile, 7.52 parts of sodium azide, 6.16 parts of ammonium chloride and 5,000 parts of dimethylformamide was stirred at 80° C for 15 hours. The reaction mixture was cooled and 2,000 parts of 2N hydrochloric acid were added to give a yellow solid which was collected. This product was dissolved in hot 3% sodium bicarbonate solution and the hot solution filtered and then cooled. The solid obtained was collected, washed with water and slurried with 500 parts of 2N hydrochloric acid. The resulting solid was collected, washed with water, dried and crystallised from acetone to give 18.4 parts of 5-(4-oxo-7-[3-{2-propylphenoxy}-propoxy]-4H-1-benzopyran-2-yl)-tetrazole m.pt. 191°-193°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([O:22]C(C)C)=[O:21])[N:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.[Li+].[OH-].C(OCC)(=O)C>C1COCC1.O.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=[O:21])[N:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1
Reactant: CC(C)OC(=O)/C=C\n1cnc(-c2cc(Cl)cc(OC(F)(F)F)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)/C=C\n1cnc(-c2cc(Cl)cc(OC(F)(F)F)c2)n1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
In a 100 mL, 3-neck round-bottomed flask equipped with nitrogen inlet, and a rubber septum, (Z)-isopropyl 3-(3-(3-chloro-5-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-1-yl)acrylate (0.750 g, 1.0 eq.) was dissolved in THF (30 mL, 40 V) and H2O (30 mL, 40 V). The reaction mixture was added LiOH (0.419 g, 5 eq.). The reaction mixture was stirred at room temperature. The progress of the reaction was followed by TLC analysis on silica gel with 20% ethyl acetate in hexane as mobile phase. Reaction mixture was Quenched in 500 ml water and made acidic by dilute HCl. The aqueous layer was extracted with ethyl acetate. The organic layer were washed with Brine solution, dried over NaSO4 and distilled under reduce pressure to obtain 0.620 g (93.23%) crude material.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8](O)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38].CCCCCCC>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([Cl:38])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)OC(C)(C)C
Temperature: 4 °C
Reaction time: 0.75 h
Yield: 88.9 %

Procedure:
A solution of 374 g (1.48 mol) (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 1.6 l CH2Cl2 was treated with 680 g (2.6 mol) triphenylphosphine, cooled to 3-5° C. and treated in 10 min with 1.24 l (12.8 mol) CCl4, after 2 h at this temperature cooling was stopped, the reaction temperature raised during 2 h to 35° C. It was cooled down to 20° C. and stirred for further 45 min. After addition of 4 l of n-heptane, the reaction was evaporated to 2.9 l , cooled to 0° C., filtered, the residue was treated twice the same way, the third time by dissolving the residue again in 2 l of CH2Cl2. The solvents were evaporated and filtered through silica gel with hexane/tert.-butyl-methylether 9:1 as eluent. Evaporation of the solvents gave 347 g (89%) of (2S,4S)-4-Chloro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, MS: 246 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5]Cl.CC(C)=O.[I-:19].[Na+]>CCOCC>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5][I:19]
Reactant: [I-]
Reactant: COc1ccc(CCl)c(OC)c1OC
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: COc1ccc(CI)c(OC)c1OC
Temperature: 25 °C
Reaction time: 2.75 h

Procedure:
46.64 g (215.2 mmol) of 2,3,4-trimethoxybenzyl chloride in 466 ml of abs. acetone are treated with 156.7 g (4.86 equivalents) of sodium iodide, and this mixture is stirred at RT for 2.75 h while excluding light The reaction mixture is treated with approximately 3 l of (cold) ether, and the organic phase is washed once with 10% sodium thiophosphate solution and twice with saline (both kinds of solutions being cold). The combined aqueous phases are reextracted with ether. The combined organic phases are dried over Na2SO4 and evaporated on a RE at approximately 30° C. The residue, which is the desired title compound, is dried again under HV and subjected to further processing as a crude product. 1H-NMR (200 MHz, CDCl3): 7.03 and 6.59 (each d; each 1H); 4.47 (s, 2H); 4.05, 3.85 and 3.84 (each s, each 3H).
Reaction SMILES: Br[C:2]1[C:3]([C:19]([O:21][CH3:22])=[O:20])=[N:4][C:5]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])=[CH:6][N:7]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:2]1[C:3]([C:19]([O:21][CH3:22])=[O:20])=[N:4][C:5]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1Br
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1-c1ccc(Cl)cc1Cl
Temperature: 85 °C
Yield: 59.1 %

Procedure:
Charge a Kimble vial with methyl 3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate (0.45 g, 1.14 mmol), Pd(PPh3)4 (198 mg, 0.17 mmol), and 2,4-dichlorophenylboronic acid (325 mg, 1.71 mmol). Flush with N2 and add DMF (4 mL) and 2 M Na2CO3 (1.1 mL). The resulting mixture was heated at 85° C. overnight. The mixture was diluted with sat. aq. NaHCO3. Extract with Et2O. The organic extract was dried over MgSO4, filtered and concentrated. Purify by biotage MPLC (90 g column, 30% ethyl acetate/hexanes) to afford 290 mg (59%) of methyl 3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate as a solid: 1H NMR (CDCl3) δ 3.06-3.09, 3.27-3.32, 3.80, 4.09-4.15, 4.84, 5.58, 7.28-7.49, 8.25; MS (ESI+) for C21H17Cl2N3O3 m/z 430 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:22])[NH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3)=[CH:4][CH:3]=1.C(O)(=[O:25])C.C(OO)(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:22])[NH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3=[O:25])=[CH:6][CH:7]=1
Reactant: O=c1[nH]cc2c(c1-c1ccc(Cl)cc1)Nc1ccccc1S2
Reactant: CC(=O)O
Agent: CC(=O)OO
Solvent: O
Product: O=c1[nH]cc2c(c1-c1ccc(Cl)cc1)Nc1ccccc1S2=O

Procedure:
To 3 parts of the product of the process described in Example 14, 4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one, suspended in 5 parts acetic acid is added and 1 part 40% peracetic acid. After ten minutes reaction time, water is added to the now homogeneous reaction mixture and the precipitate which forms is collected and recrystallized from aqueous DMF to yield white needles of 4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one 10 oxide, melting above 310°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH:5]=[N:6][CH:7]=1.FC(F)(F)C(O)=O.ClCCl>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cncc(Br)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: NCc1cncc(Br)c1
Yield: 87.7 %

Procedure:
The product of Example 18A (0.98 g, 2.53 mmol) was treated with trifluoroacetic acid and dichloromethane (1:1 v/v, 20 mL) for 2 hours at room temperature. The solvent was removed by rotary evaporation and the resulting oil was chased with benzene/dichloromethane (3 times) to give a waxy solid. The salt was dissolved in anhydrous methanol (20 mL) and stirred with Amberlite IRA-400(OH), resin (10 g) for 2 hrs. The resin was removed by vacuum filtration and thoroughly washed with dry methanol. The filtrate was concentrated by rotary evaporation to give the title compound (0.415 g, 88%). MS (DCI/NH3) M/z 187/189 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 3.73 (s, 2H), 8.02 (t, J=2.02 Hz, 1H), 8.50 (d, J=1.47 Hz, 1H), 8.53 (d, J=2.21 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([SH:7])=[N:4][CH:3]=1.[O-:8][C:9]#[N:10].[Na+].O1CCCC1.Cl>O.C(O)(=O)C.C(OCC)(=O)C>[NH:1]([C:2]1[S:6][C:5]([SH:7])=[N:4][CH:3]=1)[C:9]([NH2:10])=[O:8]
Reactant: Nc1cnc(S)s1
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NC(=O)Nc1cnc(S)s1
Reaction time: 2 h
Yield: 6.6 %

Procedure:
To a mixture of 5-amino-2-mercaptothiazole (6.61 g) in water (34 ml) and acetic acid (17 ml) was added a solution of sodium cyanate (6.50 g) in water (55 ml) at 35° C. After stirring at the same temperature for 2 hours, the solution was poured into a mixture of water, tetrahydrofuran and ethyl acetate, and adjusted to pH 3.0 with 1N-hydrochloric acid. The separated organic layer was washed with saturated sodium chloride solution (×2), dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to give 5-ureido-2-mercaptothiazole (577 mg).
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1>>[CH3:17][N:4]1[C:3]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[C:2]([C:35]2[CH:36]=[N:31][CH:32]=[N:33][CH:34]=2)[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1
Reactant: OB(O)c1cncnc1
Reactant: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(4-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 104) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as colorless amorphous solid. MS: 485.3 (MH+).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:34])[C:11]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15](=[O:28])[C:14]=12)C1C=CC=CC=1.[ClH:35]>C(O)(=O)C>[ClH:35].[OH:8][C:9]1[C:10](=[O:34])[C:11]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15](=[O:28])[C:14]=12
Reactant: O=C1c2c(OCc3ccccc3)c(=O)c(-c3nccs3)cn2CCN1CCCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C1c2c(O)c(=O)c(-c3nccs3)cn2CCN1CCCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 9-benzyloxy-2-(3-phenylpropyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (27 mg) in acetic acid (1 ml) was added conc. aqueous hydrochloric acid (0.5 ml) and the mixture was stirred at 90° C. for 2 hr. The solvent was evaporated and ethyl acetate was added to the residue. The obtained solid was collected by filtration to give 9-hydroxy-2-(3-phenylpropyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (25 mg).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9](B(O)O)[CH2:10][CH3:11]>>[CH2:9]([C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1)[CH2:10][CH3:11]
Reactant: O=Cc1ccc(Br)s1
Reactant: CCCB(O)O
Product: CCCc1ccc(C=O)s1
Yield: 28.7 %

Procedure:
The compound was synthesized as in Example 3.1 using 5-bromothiophene-2-carbaldehyde (250 mg, 1.31 mmol) in place of 5-bromo-2-formylfuran and propylboronic acid (190 mg, 2.16 mmol) in place of hexylboronic acid to give 5-propylthiophene-2-carbaldehyde (58 mg, 29%). Used without further characterization.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C:16]([O:18]C)=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>CO>[C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COC(=O)/C=C/CCCCCNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCC/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.2 %

Procedure:
A solution of 10.7 g (39.4 mmoles) of (8) in 30 mL methanol was chilled in an ice bath and 59 mL of 1N sodium hydroxide was added. The ice bath was removed and the mixture was stirred at room temperature for 20 h. After evaporation of most of the methanol, the solution was acidified to pH 3 with 1N potassium bisulfate. The mixture was extracted with ether, and washed with water and brine. After drying over sodium sulfate and removal of solvent in vacuo, the residue was crystallized from ether-hexane to provide 9.55 g of the title compound (9), mp 76°-78° C. Anal. Calcd. for C13H23NO4 : C, 60.68; H, 9.01; N, 5.44. Found: C, 60.50; H, 9:00; N, 5.40.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([OH:25])[C@@:10]2([N:22]=[N+]=[N-])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:5])C>CC(O)=O.O.[Pd]>[NH2:22][C@@:10]1([C:12]([OH:14])=[O:13])[C@H:9]([OH:25])[CH2:8][C@@H:7]2[C@H:11]1[C@H:6]2[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1O)[C@@H]2C(=O)O
Temperature: 23 °C
Yield: 86.8 %

Procedure:
A solution of (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VII-1) (1.55 g, 4.49 mmol) in HOAc (20 mL) and H2O (5 mL) was hydrogenated in the presence of Pd/C (100 mg, 10% Pd/C) at 23° C. for 18 h. The catalyst was removed by filtration, the filter cake washed with 50% aqueous acetic acid. After removal of the solvent in vacuum, the beige residue was refluxed in 10% HCl (55 mL) for 4 h. The solution was cooled to 23° C., filtered, washed with water and evaporated to dryness. The remaining pale yellow solid was dissolved in EtOH (45 mL) and propylene oxide (24 mL) and refluxed for 15 min, whereupon the amino acid precipiated. After cooling to 23° C., the product was filtered off, washed with ether and dried to give (1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid (I-A) (784 mg, 87%) as a white solid. 1H-NMR (250 MHz, D2O) □1.87 (1H, t, J=3.1 Hz), 2.15-2.26 (3H, m), 2.38 (1H, dd, J=13.0, 7.6 Hz), 3.97 (1H, dd,J=8.6,7.4 Hz); MS[ISP]202 (M+H+); mp>250° C.; □D20 +7.41° (c=1.01, H2O).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=2)=[CH:4][N:3]=1.C([O-])([O-])=[O:22].[K+].[K+].OO.O>CS(C)=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:22])=[CH:15][N:14]=2)=[CH:4][N:3]=1
Reactant: Cc1ncc(Oc2ccc(C#N)cn2)c2ccccc12
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ncc(Oc2ccc(C(N)=O)cn2)c2ccccc12

Procedure:
To a solution of 6-(1-methylisoquinolin-4-yloxy)nicotinonitrile (Preparation 18) (200 mg, 0.77 mmol) in DMSO (5 mL) was added K2CO3 (53 mg, 0.38 mmol) and H2O2 (30% w/v, 120 μL, 1.1 mmol). After 1 h water (20 mL) was added and the mixture extracted with EtOAc (3×50 mL). The organic phase was washed with water (2×30 mL), NaHCO3 (30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (0.5 NH3: 5 MeOH: 95 DCM) to give the title compound: RT=2.11 min; m/z (ES+)=280.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12]Br)([CH2:5]3)[CH2:3]1)[CH2:9]2.[I:14][C:15]1[CH:16]=[N:17][NH:18][CH:19]=1.[H-].[Na+]>CN(C)C=O>[Br:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][N:17]4[CH:16]=[C:15]([I:14])[CH:19]=[N:18]4)([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: BrCC12CC3CC(CC(Br)(C3)C1)C2
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: BrC12CC3CC(C1)CC(Cn1cc(I)cn1)(C3)C2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 1-bromo-3-(bromomethyl)-adamantane (1.0 g) and 4-iodopyrazole (0.63 g) in N,N-dimethylformamide (10 mL) was cooled to 0° C. To this solution was added 60% sodium hydride (0.20 g). The solution was stirred at 65° C. overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed three times with water, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: C(OO)(=[O:3])C.OO.S(=O)(=O)(O)O.[C:13]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].C([O-])(=O)C.[Na+]>S(=O)(=O)(O)O.C(Cl)(Cl)Cl.O.C(O)(=O)C>[C:13]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[O:3][CH2:22]2)=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: CC(=O)OO
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(C2CO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Commercially available peracetic acid (57 g) produced by the oxidation of acetic acid with hydrogen peroxide using sulfuric acid as catalyst, and containing about 35 wt % of peracetic acid, about 19 wt % of water, about 0.6 wt % of hydrogen peroxide, about 1 wt % of sulfuric acid, and the remainder acetic acid, is mixed with chloroform (250 ml) and transferred to a separatory funnel. The upper aqueous layer is discarded and the chloroform layer is dried over magnesium sulfate and filtered to yield a solution containing about 37 wt % of peracetic acid, about 0.6% wt of hydrogen peroxide, and the remainder acetic acid. No more than a trace of sulfuric acid or water is detectable. The solution is added dropwise to an ice cold solution of 4-acetoxystyrene (24.3 g, 0.15 mol) in chloroform (150 ml) containing sodium acetate (5.0 g). After the addition of peracetic acid solution, the reaction mixture is warmed up to room temperature and stirred overnight. The reaction mixture is washed with water (3×200 ml) and saturated sodium bicarbonate solution (3×200 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated in-vacuo to afford an oil characterized by NMR analysis as 4-acetoxystyrene oxide (26.2 g, 98% yield).
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[N:23][CH:24]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[N:23][CH:24]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)nc2)C2CCCCC2)sc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
To a mixture of ethyl 3-{[(5-{[cyclohexyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}pyridin-2-yl)carbonyl](methyl)amino}propanoate (141 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (112 mg, 84%) as a white solid.