Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].C([O:6][C:7](=O)[CH:8]=[CH:9][C@@H:10]1[CH2:14][C@H:13]([S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][N:11]1[C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])C>C(O)C>[CH2:38]([O:37][C:35]([N:11]1[CH2:12][C@@H:13]([S:15][C:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:14][C@H:10]1[CH:9]1[NH:3][NH:2][C:7](=[O:6])[CH2:8]1)=[O:36])[CH:39]=[CH2:40]
Reactant: NN
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1C=CC(=O)OCC
Solvent: CCO
Solvent: O
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1C1CC(=O)NN1
Reaction time: 1.5 h
Yield: 55.7 %

Procedure:
Hydrazine monohydrate (0.61 ml, 12.6 mmol) was dropwise added to a solution of 3-[(2S,4S)-N-allyloxycarbonyl-4-tritylthiopyrrolidin-2-yl]acrylic acid ethyl ester (1.53 g, 2.9 mmol) in ethanol (7.5 ml) under cooling with ice, and the mixture was stirred at the same temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, 2% methanol-chloroform) to obtain (2S,4S)-N-allyloxycarbonyl-2-(3-pyrazolidinon-5-yl)-4-tritylthiopyrrolidine (830 mg, yield: 51.1%). This compound was immediately dissolved in methylene chloride (10 ml). Then, triethylamine (0.24 ml, 1.7 mmol) and allyl chloroformate (0.18 ml 1.7 mmol) were dropwise added thereto under cooling with ice, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (50 ml). The organic layer was washed with water and a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, 1% methanol-chloroform) to obtain (2S,4S)-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-3-pyrazolidinon-5-yl)-4-tritylthiopyrrolidine (592 mg, yield: 62%).
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH3:28]>C1COCC1>[NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:10]([NH:12][C@H:13]([C:15]([NH2:28])=[O:17])[CH3:14])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Reactant: N
Solvent: C1CCOC1
Product: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(N)=O

Procedure:
The above described procedure was repeated using 5.65 g of Cbz-Phe-Ala-OH and excess anhydrous ammonia in THF to obtain 7.16 g of crude Cbz-Phe-Ala-NH2. The crude product was then subjected to hydrogenolysis in MeOH over 10% Pd/C to afford 3.42 g (95% yield) of Phe-Ala-NH2 as a yellow solid after flash chromatography (EtOAc-MeOH, 10:1). Characteristic analytical data are as follows: mp 95°-97° C.; RF 0.10 (1:2 MeOH:EtOAc); 1H NMR (300 MHz, CDCl3) δ7.80-7.72 (br, 1H, H--N), 7.35-7.18 (m, 5H, Ph), 6.58-6.45 (br, 1H, H--N), 5.70-5.60 (br, 1H, H--N), 4.46 (quint, J=7 Hz, 1H, Hα-(Ala)), 3.62 (dd, J=4, 9 Hz, 1H, Hα-(Phe)), 3.21 (dd, J=4, 11 Hz, 1H, Hβ-(Phe)), 2.72 (dd, J=9, 11 Hz, 1H, Hβ-(Phe)), 1.35 (d, J=7 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ175.3 (C=O), 174.8 (C=O), 137.6 (C-Ph), 129.4 (CH-Ph), 128.8 (CH-Ph), 127.0 (CH-Ph), 56.0 (CH-α), 48.0 (CH-α), 40.5 (CH2), 17.7 (CH3); [α]D25 -25.6° (C=1.90, EtOH).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][N:15]=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:32]CCl>C(O)C.O>[ClH:32].[CH:22](=[C:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C:16]1=[N:15][O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCON=C2CCCCC2=Cc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCON=C2CCCCC2=Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above ester (2.5 g, 6.5 mmol) was dissolved in ethanol (20 ml) and 4N sodium hydroxide (4.9 ml) was added. The mixture was stirred at ambient temperature for 3 h and excess concentrated hydrochloric acid was added followed by dichloromethane (300 ml) and water (15 ml). The phases were separated and the organic phase was dried (MgSO4) and the solvent evaporated in vacuo. The residue was re-evaporated with acetone and recrystallised from acetone (180 ml) to give 1.5 g of the title compound as a solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28](O)(=[O:32])[CH:29]([CH3:31])[CH3:30]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CC(C)C(=O)O
Agent: Cl
Product: CC(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (38 mg, 59%), MS (ISP) m/z=401.5 [(M+H)+], mp 203.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) isobutyric acid.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[BrH:12].CS(C)=O.[OH-].[Na+]>C(O)(=O)C>[Br:12][C:10]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1
Reactant: CC(C)(C)c1ccccc1N
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(Br)ccc1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
25 g (168 mmol) of 2-tert-butylaniline are placed in 300 ml of acetic acid. 450 ml of aqueous HBr at 48% are added and the mixture is then cooled to 0° C. 150 ml of DMSO are added dropwise, the mixture having been brought back to ambient temperature is stirred for 2 hours and it is then poured into ice-cold water and basified to pH 10 with 5N NaOH. It is extracted with diethyl ether and the organic phase is then dried and concentrated to dryness. The residue is column-purified (95/5 heptane/EtOAc). 25.2 g of 4-bromo-2-tert-butylphenylamine are obtained in the form of a yellow oil (yield=65%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:13]=[C:12]2[CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40])C1C=CC=CC=1>[Pd].CCOC(C)=O>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([Si:18]([CH:22]([CH3:23])[CH3:24])([CH:19]([CH3:20])[CH3:21])[CH:25]([CH3:27])[CH3:26])[CH:13]=[C:12]2[CH2:28][CH2:29][N:30]1[C:31](=[O:40])[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]1=[O:39]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(CCN2C(=O)c3ccccc3C2=O)c2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(CCN2C(=O)c3ccccc3C2=O)c2cc(O)ccc21

Procedure:
Combine 2-(2-(5-benzyloxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-dione and EtOAc (40 mL) and hydrogenated overnight with 1 g 5% Pd/C at atmospheric pressure. Filter through celite, concentrate to dryness, and chromatograph on silica gel eluting stepwise with a gradient 10% EtOAc in hexanes to 30% EtOAc in hexanes to give the title compound as a solid: FDMS 462 (M+1) Analysis for C27H24N2O3Si H2O: calcd: C, 69.55; H, 7.44; N, 6.01; Found: C, 69.44; H, 7.17; N, 6.00.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([C:34](=[O:35])[CH2:33][C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(N2CCN(C(=O)Cc3ccc(Cl)cc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.5 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) and 4-chlorophenylacetic acid (0.21 mmol) in DMF (2 ml) was added TBTU (0.21 mmol) followed by diisopropylethylamine (0.21 mmol, 35 μL). The reaction was stirred at room temperature for 24 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (44 mg) which was characterized by its mass spectrum: MS m/z (%): 511 ([M+H]+, 100).
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[C:8]([CH3:10])=[CH2:9].C(N(CC)CC)C>O>[C:13]([O:12][C:7](=[O:11])[CH:8]([CH3:10])[CH2:9][S:1][CH2:2][CH:3]([OH:4])[CH2:5][OH:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: OCC(O)CS
Reactant: C=C(C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CC(CSCC(O)CO)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
To thioglycerol (0.835 mI), t-butyl methacrylate (10 ml) and triethylamine (1 ml) were added, followed by stirring at 60° C. for 48 hours. After cooling and addition of water, the reaction mixture was extracted with chloroform. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off, to yield the title compound (2.11 g, yield 84%) as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[N:40]1[CH:45]=[CH:44][CH:43]=[N:42][C:41]=1[C:46]1([NH2:49])[CH2:48][CH2:47]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:49][C:46]1([C:41]2[N:42]=[CH:43][CH:44]=[CH:45][N:40]=2)[CH2:48][CH2:47]1)[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC1(c2ncccn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 80.1 %

Procedure:
To a suspension of the (S)-2-tert-Butoxycarbonylamino-propionic acid (43 mg, 0.23 mmol), HATU (99 mg, 0.26 mmol), and 1-Pyrimidin-2-yl-cyclopropylamine dihydrochloride (45 mg, 0.22 mmol) in CH2Cl2 (1.5 mL) was added triethylamine (0.12 mL, 0.87 mmol). The reaction was stirred at room temperature for 22 h, diluted with CH2Cl2 (7 mL) and then washed with saturated aqueous NaHCO3 (2×6 mL) and brine (1×6 mL). The organic phase was dried with MgSO4 and concentrated to afford 54 mg of [(S)-1-(1-Pyrimidin-2-yl-cyclopropylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester as white solid, m/z 307.56 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:31]([O-:33])=[O:32]>ClCCl>[N+:31]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:15]=1[NH:1][CH2:2][C:3]([CH3:5])([NH2:6])[CH3:4])=[CH:23][CH:22]=[C:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:20]=2)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1Cl
Reactant: CC(C)(N)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cc(-c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
A solution of 1,2-diamino-2-methylpropane (9.3 mL, 88.9 mmol) and triethylamine (5.0 mL, 35.5 mmol) in dichloromethane (100 mL) was cooled to 0° C. A solution of 4-chloro-3-nitro-7-phenylquinoline (5.06 g, 17.8 mmol) in dichloromethane (50 mL) was added over a period of 45 minutes, and then the reaction was allowed to warm to ambient temperature. The solution was washed sequentially with water (2×100 mL) and brine (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide N1-(3-nitro-7-phenylquinolin-4-yl)-2-methylpropane-1,2-diamine as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[CH2:34]([CH:36]([CH2:42][CH3:43])[C:37]([O:39][CH2:40]I)=[O:38])[CH3:35].C(OCC)(=O)C>CN(C)C(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH2:40][O:39][C:37](=[O:38])[CH:36]([CH2:42][CH3:43])[CH2:34][CH3:35])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:25]=[N:24][CH:23]=[N:22][CH:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C\c4cncnc4)CS[C@H]23)cs1
Reactant: CCC(CC)C(=O)OCI
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCC(CC)C(=O)OCOC(=O)C1=C(/C=C\c2cncnc2)CS[C@@H]2[C@H](NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12

Procedure:
The compound (100 mg) of Example 16 was dissolved in N,N-dimethylacetamide (2 ml), followed by the addition of 2-ethylbutanoyloxymethyl iodide (50 mg). They were reacted for 1 hour. Ethyl acetate (50 ml) was added. The resulting mixture was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. Ether was added to the residue and the resulting solid was collected by filtration, whereby the title compound (55 mg) was obtained.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)[C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[Cl:35]C1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[ClH:35].[Br:26][C:23]1[CH:24]=[CH:25][C:20]([CH:19]([O:18][CH:16]2[CH2:17][NH:14][CH2:15]2)[C:27]2[CH:28]=[CH:29][C:30]([Br:33])=[CH:31][CH:32]=2)=[CH:21][CH:22]=1
Reactant: Brc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Br)cc2)cc1
Reactant: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Agent: Cl
Product: Brc1ccc(C(OC2CNC2)c2ccc(Br)cc2)cc1

Procedure:
This material was prepared from 1-benzhydryl-3-(4,4′-dibromobenzhydryloxy)azetidine (85) using the procedure described for compound (9) (1.15 mg, 30%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=O)[O:27]C(C)(C)C)[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:33])[CH2:3][CH2:2]1.Cl.[C:35](OCC)(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:27])[CH3:35])[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:33])[CH2:2][CH2:3]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate (774 mg) was added 4 M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (570 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:15](Br)[CH:16]=[CH2:17].[Cl-].[NH4+]>C1COCC1.[Zn]>[CH2:17]([C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (10 g, 50.2 mmol), allyl bromide (10.8 mL, 124 mmol) in THF (10 mL), and saturated ammonium chloride solution (50 mL) was added Zn dust (6.5 g, 100 mmol) portionwise below 10° C. After addition was complete, the reaction mixture was stirred overnight, when TLC indicated consumption of s.m. The reaction mixture was diluted with water (50 mL) and acidified with several drops of 10% H2SO4 to pH=6. The reaction mixture was extracted with EtOAc (3×200 mL). The organic layers were combined and washed with a saturated solution of NaHCO3, brine and evaporated, to give the crude product which was purified by chromatography to give title compound 11B as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[CH2:14][C:15](=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:17]=[C:15]([CH3:16])[CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(=O)CBr
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCC(C)=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture comprising 74.6 g of methyl 4-hydroxyphenylacetate, 92.2 g of bromoacetone, 125 g of potassium carbonate and 750 ml of dimethylformamide was stirred at room temperature for 1 day. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. The resulting concentrate was mixed with water and then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate; the solvent was then removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:8 by volume mixture of ethyl acetate and benzene as the eluent, to give the title compound having an Rf=0.43 (thin layer chromatography over silica gel, using a 1:7 by volume mixture of ethyl acetate and benzene as the developing solvent).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[OH-].[Na+].O.C1C[O:21][CH2:20][CH2:19]1>CO>[CH2:20]([O:21][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1)[CH3:19]
Reactant: C1CCOC1
Reactant: COC(=O)c1cc2ncc(Cl)nc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1cnc2cc(C(=O)O)sc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of methyl 3-chlorothieno[2,3-b]pyrazine-6-carboxylate 92 (0.044 mmol, 10 mg) in methanol 250 uL and THF 250 uL was added sodium hydroxide 2N in water (0.219 mmol, 109 μA) and stirred overnight at rt. The reaction mixture was quenched in 2N HCl and extracted with CH2Cl2/methanol (9/1). The organic layer was dried and concentrated under reduced pressure to give 3-ethoxythieno[2,3-b]pyrazine-6-carboxylic acid 97 (9.3 mg, 100%).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:36])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:29]4[N:30]=[CH:31][C:32](N)=[N:33][CH:34]=4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N([O-])=[O:38].[Na+].OS(O)(=O)=O>C([O-])([O-])=O.[Na+].[Na+]>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:36])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:29]4[N:30]=[CH:31][C:32]([OH:38])=[N:33][CH:34]=4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: COc1cnc(-c2cnc(N)cn2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1cnc(-c2cnc(O)cn2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
1-(benzoyl)-4-[(4-methoxy-7-(2-amino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine (15 mg) and NaNO2 (10 mg) was added into a H2SO4 solution (0.1 ml of concentrated H2SO4 diluted with 0.3 ml of water). The reaction was stirred at room temperature for one hour. Then, the reaction mixture was neutralized with a saturated Na2CO3 solution (10 ml). The solvents were concentrated to give a residue which was purified using a Shimadzu automated preparative HPLC System to provide 4.2 mg of the desired compound, 1-(benzoyl)-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. 1H NMR (500 MHz, CD3OD) δ8.55 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.49 (m, 5H), 4.12 (s, 3H), 3.84-3.64 (m, 8H). MS m/z: (M+H)+ Calc'd for C25H23N6O5: 487.17; found 487.22. HPLC retention time: 1.13 minutes (column A).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:20](Cl)=[O:21])[C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[O:8][CH:7]([C:15]([Cl:18])([Cl:17])[Cl:16])[C:6]=2[CH:19]=1.[NH3:23]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:20]([NH2:23])=[O:21])[C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[O:8][CH:7]([C:15]([Cl:18])([Cl:17])[Cl:16])[C:6]=2[CH:19]=1
Reactant: Cc1cc(C(=O)Cl)c2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reactant: N
Solvent: CCO
Product: Cc1cc(C(N)=O)c2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2

Procedure:
A mixture of 6-methyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin-8-carbonyl chloride (2.0 g.) concentrated ammonia (10 ml.) and ethanol (10 ml.) was heated under reflux for 2 hours. A complete solution was not obtained, but the reaction mixture was cooled and filtered, and the solid product was washed with ethanol and dried, to give 6-methyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin-8-carboxamide, m.p. 281°-283° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:15]([C:14]2[CH:18]=[CH:19][C:11]([F:10])=[CH:12][CH:13]=2)=[O:16])=[C:5]([OH:9])[CH:4]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCc1cccc(O)c1
Product: CCc1ccc(C(=O)c2ccc(F)cc2)c(O)c1
Yield: 5.3 %

Procedure:
3-Ethylphenol (24.4 g) and 4-fluorobenzoyl chloride (34.9 g) were reacted together as in Example 2 giving three main fractions: B (11.4 g) 126°-129° C. at 0.07 mmHg; C (7.9 g), 129°-132° C. at 0.06 mmHg; D (5.9 g), 132°-150° C. at 0.06 mmHg, all containing ~ 80% of the required isomer. B (4.0 g) was separated by preparative thin layer chromatography to give the title compound (2.6 g), m.p. 44°-48° C. The same compound was obtained using the method of Example 4.