Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2].[CH3:18][CH2:19][CH:20]([NH2:24])[C:21]([OH:23])=[O:22].[OH-].[K+].Cl>O1CCCC1.O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:24][CH:20]([C:21]([OH:23])=[O:22])[CH2:19][CH3:18])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2]
Reactant: CCC(N)C(=O)O
Reactant: N#Cc1nc(Cl)c(-c2ccccc2)nc1C#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(Nc1nc(C#N)c(C#N)nc1-c1ccccc1)C(=O)O
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
2,3-Dicyano-5-chloro-6-phenylpyrazine (2.41 g; 0.01 mole) was dissolved in 30 ml of tetrahydrofuran, and with stirring at 15° to 20° C., a solution prepared from 2.04 g (0.02 mole) of DL-α-amino-n-butyric acid, 1.12 g (0.02 mole) of potassium hydroxide and 40 ml of water was added dropwise over the period of 5 minutes. The mixture was then sitrred at 30° C. for 30 minutes. After the reaction, the reactor was cooled with ice, and in the meanwhile, 2 ml of conc. hydrochloric acid was added to the reaction solution. The solution was then extracted with 100 ml of toluene. The toluene layer was washed with 50 ml of a saturated aqueous solution of sodium chloride and 50 ml of water, and the solvent was removed by concentration under reduced pressure to afford a yellowish white solid. Recrystallization of the solid from ethanol afforded 2.63 g (yield 86%) of 2,3-dicyano-5-(1-carboxy-n-propyl)amino-6-phenylpyrazine.
Reaction SMILES: [FH:1].C(=O)=O.CC(C)=O.[CH3:9][O:10][C:11]1[C:12]([N+:19]([O-:21])=[O:20])=[CH:13][C:14]([CH3:18])=[C:15]([CH:17]=1)N.N([O-])=O.[Na+]>N1C=CC=CC=1>[F:1][C:15]1[CH:17]=[C:11]([O:10][CH3:9])[C:12]([N+:19]([O-:21])=[O:20])=[CH:13][C:14]=1[CH3:18]
Reactant: F
Reactant: COc1cc(N)c(C)cc1[N+](=O)[O-]
Agent: O=C=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: COc1cc(F)c(C)cc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
Hydrogen fluoride (70%) in pyridine (47.4 ml, 0.48 mol) in a plastic separatory funnel was added dropwise over 20 min. to pyridine (16 mL) in a plastic bottle at −78° C. (dry ice/acetone bath) under nitrogen. Note: reaction was exothermic. After the addition was complete, the reaction was stirred for 10 min. at −78° C. 5-Methoxy-2-methyl-4-nitroaniline (9.11 g, 0.05 mol) was then added and the reaction mixture was stirred for an additional 10 min. at −78° C. Sodium nitrite (5.8 g, 0.08 mol) was then added and the reaction mixture was stirred an additional 10 min. at −78° C. The reaction mixture was allowed to warm to RT and then heated to 60° C. for 2 h. The reaction mixture was then allowed to cool to RT and an ice/water mixture (300 mL) was added. The resultant precipitates were collected by vacuum filtration, washed with water and dried under vacuum. The solid product was recrystallized from methylcyclohexane to give yellow crystals as the title product (5.8 g, 63%).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1>Cl>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[F:25])[NH:18][C:9]1[C:8]2[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([N:5]=[C:1]=[S:2])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: S=C(Cl)Cl
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N=C=S
Temperature: 25 °C
Reaction time: 16 h

Procedure:
After repetition of the previous steps, thiophosgene (0.5 ml) was added dropwise to a stirred solution of 6-amino4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline (1.65 g) in 2N aqueous hydrochloric acid (45 ml). The mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated and dried to give 4-(3-chloro-4-fluoroanilino)-6-isothiocyanato-7-methoxyquinazoline which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:2]3([CH3:1])[CH2:6][C:5]4[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=4[O:3]3)[CH2:17][CH2:18]2)=[O:28])=[CH:25][CH:24]=1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Reactant: O=C(O)c1ccc(Cl)cc1
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCN(C(=O)c3ccc(Cl)cc3)CC1)O2
Yield: 64 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and 4-chlorobenzoic acid, the procedure of Example 10, presented hereinafter, was otherwise followed to provide the title compound. Yield 64%.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][C:11]1[NH:15][C:14]2[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:13]=2[N:12]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][O:20][C:16]1[C:14]2[NH:15][C:11]([CH2:10][CH2:9][NH:7][CH3:6])=[N:12][C:13]=2[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc2nc(CCN(C)C(=O)OC(C)(C)C)[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCc1nc2cccc(OC)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
A solution of 1.5 g of [2-(7-methoxy-1H-benzoimidazol-2-yl)-ethyl]-methyl-carbamic acid tert.-butyl ester in 10 mL DCM was treated with 0.39 mL of TFA and stirred overnight at rt. The reaction mixture was concentrated in vacuo, redissolved in DCM and treated with diluted NaOH. After separation of the 2 phases the water phase was lyophilized to yield 380 mg of [2-(7-methoxy-1H-benzoimidazol-2-yl)-ethyl]-methyl-amine as beige solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[N+](C1C=CC(C([O:17][C@H:18]2[CH2:21][C@H:20]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]2)=O)=CC=1)([O-])=O>CO>[C:26]([O:25][C:23](=[O:24])[NH:22][C@H:20]1[CH2:21][C@H:18]([OH:17])[CH2:19]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Temperature: 100 °C
Yield: 46.3 %

Procedure:
To a mixture of potassium carbonate (5.24 mL, 87 mmol) and water (100 mL) and MeOH (400 mL), was added trans-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-nitrobenzoate (17.1 g, 50.8 mmol). The resulting mixture was heated to 100° C. for 2 h, cooled, and filtered. The filtrate was evaporated under vacuum to give the desired product tert-butyl(trans-3-hydroxycyclobutyl)carbamate (4.4 g, 23.50 mmol, 46.2% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.73 (br. s., 1 H), 4.39-4.58 (m, 1 H), 4.22 (br. s., 1 H), 2.10-2.48 (m, 5 H), 1.44 (s, 9 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][S:7][C:8]1[C:19]2[O:18][C:17]([CH3:21])([CH3:20])[O:16][C:15]=2[C:14]([C:22]([C:47]2[C:57]3[O:58][C:59]([CH3:62])([CH3:61])[O:60][C:56]=3[C:55]([S:63][CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66])=[C:49]3[O:50][C:51]([CH3:54])([CH3:53])[O:52][C:48]=23)([C:24]2[C:34]3[O:35][C:36]([CH3:39])([CH3:38])[O:37][C:33]=3[C:32]([S:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:26]3[O:27][C:28]([CH3:31])([CH3:30])[O:29][C:25]=23)O)=[C:13]2[C:9]=1[O:10][C:11]([CH3:71])([CH3:70])[O:12]2)=[O:5])[CH3:2].C[Si](Cl)(C)C.[I-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.C(OCC)C>[CH2:45]([O:44][C:42]([CH2:41][S:40][C:32]1[C:33]2[O:37][C:36]([CH3:38])([CH3:39])[O:35][C:34]=2[C:24]([CH:22]([C:14]2[C:15]3[O:16][C:17]([CH3:21])([CH3:20])[O:18][C:19]=3[C:8]([S:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:9]3[O:10][C:11]([CH3:70])([CH3:71])[O:12][C:13]=23)[C:47]2[C:57]3[O:58][C:59]([CH3:61])([CH3:62])[O:60][C:56]=3[C:55]([S:63][CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66])=[C:49]3[O:50][C:51]([CH3:53])([CH3:54])[O:52][C:48]=23)=[C:25]2[C:26]=1[O:27][C:28]([CH3:30])([CH3:31])[O:29]2)=[O:43])[CH3:46]
Reactant: CCOC(=O)CSc1c2c(c(C(O)(c3c4c(c(SCC(=O)OCC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(SCC(=O)OCC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [I-]
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)CSc1c2c(c(C(c3c4c(c(SCC(=O)OCC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(SCC(=O)OCC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2

Procedure:
Tris(8-ethoxycarbonylmethylthio-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxole-4-yl)methanol (1.06 g, 1.01 mmol (Example 27)) was added to a solution of trimethyl silylchloride (0.767 mL, 6.07 mmol) and sodium iodide (0.91 g, 6.07 mmol) in acetonitrile (50 mL) and stirred for ten minutes. Saturated sodium thiosulfate (30 mL) was added, followed by diethylether (70 mL), and the mixture was stirred for 10 minutes. The phases were separated and the organic phase was washed with water (30 mL). The organic phase was diluted with more ether (100 mL), since crystals had started to form in the funnel. The solution was kept in the freezer over night after drying (MgSO4) and filtration. The crystals formed were removed (impurity) and the solution evaporated to dryness. The product was purified by dissolving the substance at room temperature in diispropyl ether (E. Merck 118867, 30 mL), followed by bubbling with helium. The flask was stoppered and put in the refrigerator for two and a half hours. The product was collected by filtration (glass sinter no. 3), and the mother liquor was evaporated to approximately half the volume. The total yield after collecting the second crop was 640 mg (0.621 mmol, 61%).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([CH2:13][C:14]2[N:15]=[C:16]([NH2:19])[S:17][CH:18]=2)=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(OC(=O)CC)(=O)CC>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([CH2:13][C:14]2[N:15]=[C:16]([NH:19][C:11](=[O:12])[CH2:13][CH3:14])[S:17][CH:18]=2)=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nnc(NC(=O)Cc2csc(N)n2)s1
Agent: CCC(=O)OC(=O)CC
Product: CCC(=O)Nc1nc(CC(=O)Nc2nnc(C(C)(C)C)s2)cs1
Yield: 67.2 %

Procedure:
A mixture of 4.8 g (0.016 mole) of 4-(5-tert-butyl-1,3,4-thiadiazol-2-ylcarbamoylmethyl)-2-aminothiazole dissolved 20 ml of propionic anhydride was heated for one hour at 90°. The reaction solution was cooled and the precipitate was collected. The crude solid was recrystallized from chloroform-hexane. There was obtained 1.9 g of product, m.p. 210°-12°. N.M.R. (CDCl3) ∂ 1.1-1.4 (CH3, triplet), 1.4 [C(CH3)3 ], 2.3-2.7 (CH2, quartet), 3.9 (CH2, singlet), 6.8 (hetero-aromatic).
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl.C(OCC)(=O)C>CN(C=O)C>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc([N+](=O)[O-])cc3)CC2)n1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(N)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-4-{(1R,2S)-2-[2-(4-nitrophenoxy)ethyl]cyclopropyl}piperidine (353 mg, 0.881 mmol) in DMF (5 ml) was added at tin(II) chloride dihydrate (994 mg, 4.41 mmol) and the resulting mixture stirred at room temperature for 2 hours, then heated to 50° C. for 13 hours. Ethyl acetate (50 mL) was added and the solution washed with saturated aqueous sodium hydrogen carbonate followed by brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure (328 mg). The residue was purified by flash chromatography on silica gel using a 25 g column, eluting with 1 column volume of DCM, followed by a linear gradient of ethyl acetate in DCM from 0% to 100% over 15 column volumes, to afford the title compound. LCMS: retention 0.79 min/2.0 minute run: (ESI) m/z 371 [M+H]+.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[CH2:7][CH2:8][CH:9]=[C:10]([F:12])[F:11]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:4][CH2:7][CH2:8][CH:9]=[C:10]([F:12])[F:11])(=[S:3])[CH3:2]
Reactant: CC([O-])=S
Reactant: FC(F)=CCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: CC(=S)OCCC=C(F)F
Reaction time: 18 h
Yield: 38.9 %

Procedure:
Potassium thioacetate (1.98 g), 4-bromo-1,1-difluorobut-1-ene (3.0 g) and tetra-n-butylammonium bromide (0.3 g, catalyst) were stirred at the ambient temperature under nitrogen for 5 hours and stored for 18 hours. The mixture was distilled using a Kugelrohr apparatus to give 4,4-difluorobut-3-enyl thioacetate as a colourless liquid (1.12 g); 1H NMR δ 2.25(2H,m); 2.30(3H,s); 2.90(2H,t); 4.20(1H,m); (bp 115° C. at 120 mmHg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1.BrC1C=CC([C:22]([F:25])([F:24])[F:23])=CC=1>>[CH3:14][C@H:10]1[NH:11][CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][C:6]([C:22]([F:25])([F:24])[F:23])=[CH:7][CH:2]=2)[CH2:9]1
Reactant: C[C@@H]1CN(c2ccccc2F)CCN1
Reactant: FC(F)(F)c1ccc(Br)cc1
Product: C[C@@H]1CN(c2ccc(C(F)(F)F)cc2)CCN1

Procedure:
The title compound was prepared following the procedure of Intermediate 5, but starting from 1-bromo-4-trifluoromethylbenzene. Purification by flash chromatography (CHCl3/MeOH) gave the title compound as a pale yellow solid. M+(ESI): 245.2. HPLC (Condition A), Rt: 2.31 min (HPLC purity: 97.5%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O.Cl[CH2:15][C:16]([O:18][C:19](=O)[CH2:20]Cl)=O.O1C=CC=C1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:16]1[O:18][CH:19]=[CH:20][CH:15]=1)=[O:12])=[O:13]
Reactant: COC(=O)CCCCCCC(=O)O
Reactant: O=C(CCl)OC(=O)CCl
Solvent: c1ccoc1
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCC(=O)c1ccco1
Temperature: 50 °C
Reaction time: 6 h
Yield: 92.3 %

Procedure:
In 50 ml of toluene were dissolved 9.41 g (0.05 mole) of suberic acid monomethyl ester and 9.83 g (0.0575 mole) of monochloroacetic anhydride. To the resulting solution were added 4.43 g (0.065 mole) of furan and 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 50° C. for 6 hours. After completion of the reaction, the reaction solution was cooled and washed successively with of water, 5% aqueous sodium carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure and the resulting concentrated residue was purified by silica gel-filled column chromatography to obtain 11 g of 2-(7-methoxycarbonyl-1-oxoheptyl)furan.
Reaction SMILES: C([N:11]1[CH2:18][C:17](=[O:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.[BrH:20].CCOCC>C(O)(=O)C>[BrH:20].[O:19]=[C:17]1[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: O=C1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C1CN[C@H](C(=O)O)C1
Reaction time: 0.13 h

Procedure:
To 4.0 g. (0.015 mole) of N-carbobenzyloxy-4-keto-L-proline are added 20 ml. of hydrogen bromide in acetic acid (30-32%). The mixture is frequently swirled over a period of eight minutes. At the end of this period (effervescence has stopped), the yellow-orange solution is layered over with 25° of ether, triturating the gummy product. The ether is discarded and the resulting tacky solid is triturated with fresh ether and finally with 50 ml. of acetonitrile to give 4-keto-L-proline, hydrobromide as a crystalline solid weighing 2.7 g. (85%), m.p. 153°-155° (dec.,), [α]D26 -49° (c, 1% in water).
Reaction SMILES: [CH2:1]([S:6]([NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([NH:20]C(=O)C)[CH:12]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].O.[OH-].[Na+]>C(O)C>[CH2:1]([S:6]([NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([NH2:20])[CH:12]=1)(=[O:7])=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])c(NC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 47.5 °C
Reaction time: 6 h

Procedure:
The above partially purified product of N-(n-pentanesulfonyl)-3-(acetylamino)-4-nitrobenzamide was mixed with 300 ml of water and 500 ml of ethanol. Two-hundred grams of a 10%-sodium hydroxide aqueous solution were added thereto, and the mixture was stirred at 45 to 50° C. for 6 hours. The solvent (approx. 300 ml) was evaporated under reduced pressure. The resulting residue was neutralized with 10% hydrochloric acid aqueous solution and adjusted to pH 2 with diluted hydrochloric acid. The precipitated crystals were collected by filtration and dried to give 85.0 g of yellow crystals of N-(n-pentanesulfonyl)-3-amino-4-nitrobenzamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:25])[CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[C:17]=3[Cl:24])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[C:27]([CH3:36])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13](=[O:25])[CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:27]([CH3:36])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[C:18]([Cl:23])[C:17]=3[Cl:24])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(CCc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(Br)cc2)s1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(Br)cc3)s2)c(Cl)c1Cl

Procedure:
Tert-butyl 2-(4-(3-(5-(4-bromophenyl)thien-2-yl)-3-oxopropyl)-2,3-dichlorophenoxy)-2-methylpropanoate is prepared from 1-(5-(4-bromophenyl)thien-2-yl)-3-(2,3-dichloro-4-hydroxyphenyl)propan-1-one according to general procedure D, using 4 equivalents of tert-butyl bromoisobutyrate and 5 equivalents of potassium carbonate.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.S(Cl)(Cl)=O.C1(C[N:27]2CCC(C3C=CC(N)=CC=3)CC2)C=CC=CC=1.CC(NC(C)C)C>C(Cl)Cl.CN(C=O)C>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([NH2:27])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: Nc1ccc(C2CCN(Cc3ccccc3)CC2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: NC(=O)c1ccccc1-c1ccccc1
Yield: 253.5 %

Procedure:
2-Biphenylcarboxylic acid (0.25 mol) was dissolved in DCM (500 ml) and DMF (0.5 ml). Thionyl chloride (0.51 mol) was added dropwise. The mixture was stirred and refluxed for 1 hour under nitrogen flow. The solvent was evaporated. DCM (500 ml) was added twice. The solvent was evaporated twice. The residue was dissolved in DCM (200 ml) and then added dropwise at 0° C. to a mixture of 4-[1-(phenylmethyl)-4-piperidinyl]-benzenamine (0.25 mol) and N-(1-methylethyl)-2-propanamine (0.75 mol) in DCM (800 ml). The mixture was brought to room temperature and then stirred at room temperature overnight under nitrogen flow. The mixture was washed three times with water (800 ml). The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 125 g of [1,1′-biphenyl]-2-carboxamide, N-[4-[1-(phenylmethyl)-4-piperidinyl]phenyl]-(intermediate 39).
Reaction SMILES: [C-]#N.[Na+].[Cu][C:5]#[N:6].Br[C:8]1[C:9]([NH2:25])=[N:10][C:11]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:13]=1>CN(C)C=O>[NH2:25][C:9]1[C:8]([C:5]#[N:6])=[N:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:11]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:10]=1
Reactant: Nc1nc(-c2ccco2)c(-c2ccncc2)nc1Br
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1nc(-c2ccncc2)c(-c2ccco2)nc1N
Temperature: 120 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A mixture of sodium cyanide (21 mg, 0.42 mmol) and copper (I) cyanide (38 mg, 0.42 mmol) in anhydrous dimethylformamide (1.5 mL) was heated to 120° C. 3-Bromo-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 62, 90 mg, 0.28 mmol) was added in portions. After stirring at 120° C. for two hours, the mixture was cooled and evaporated. A 0.75M aqueous solution of sodium cyanide (6 mL) was added, stirred for 10 min at room temperature and partitioned between water and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4), and evaporated. Silica gel flash column chromatography (dichloromethane/methanol 98:2) furnished the title compound as a dark yellow solid (52 mg, 70%).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+].Cl.O>C(O)C>[C:17]([O:16][C:14]([NH:13][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C@@H:4]([OH:21])[CH2:3][OH:2])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CO
Temperature: 30 °C
Reaction time: 3 h

Procedure:
A solution of N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenylbutyric acid methyl ester 154.7 g dissolved in ethanol 300 ml was kept at 5-15° C. and mixed with sodium borohydride 24.6 g and stirred at 15-45° C. for 3 hrs. The reaction solution was cooled and adjusted with 3N-HCl to pH 2.5-3.5. Water was added to the resultant solution and then the obtained solution was cooled to 5° C. or lower to deposit crystals. The crystals were filtered, dissolved in ethyl acetate, and washed with aqueous 5% sodium bicarbonate solution to separate an organic phase, which was washed with aqueous 10% sodium chloride solution and concentrated under an reduced pressure to obtain the crude N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-butanol.
Reaction SMILES: [CH2:1]([C:9]1[N:10]=[C:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([S:21]CCC(OC)=O)=[CH:17][C:16]=2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:12][CH:13]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC([O-])(C)C.[K+].CS(O[CH:46]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=1)[CH:47]1[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]1)(=O)=O>>[CH2:1]([C:9]1[N:10]=[C:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([S:21][CH:46]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=3)[CH:47]3[CH2:48][CH2:49][N:50]([C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])[CH2:51][CH2:52]3)=[CH:17][C:16]=2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:12][CH:13]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(OS(C)(=O)=O)c2ccccn2)CC1
Reactant: COC(=O)CCSc1cnc(Nc2nc(CCc3ccccc3)cs2)c(Oc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(C(Sc2cnc(Nc3nc(CCc4ccccc4)cs3)c(Oc3ccccc3)c2)c2ccccn2)CC1

Procedure:
Prepared according to the method of Example 16 from methyl 3-(6-(4-phenethylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate, potassium 2-methylpropan-2-olate, and tert-butyl 4-((methylsulfonyloxy)(pyridin-2-yl)methyl)piperidine-1-carboxylate.
Reaction SMILES: O[C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:17]1CCCC1>>[OH:17][C:3]1([CH2:8][OH:10])[N:4]=[CH:5][CH:6]=[N:7][CH2:2]1
Reactant: O=C(O)c1nccnc1O
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC1(O)CN=CC=N1

Procedure:
3-Hydroxypyrazine-2-carboxylic acid is converted to the methyl ester and the ester is reduced with lithium aluminium hydride in tetrahydrofuran to give 3-hydroxy-3-hydroxymethylpyrazine. Treatment of 3-hydroxy-2-hydroxymethylpyrazine at room temperature with thionyl chloride gives 3-hydroxy-2-hydroxy-2chloromethylpyrazine and reacting this intermediate with cysteamine by the procedure of Example 62 gives 2-[(2-aminoethyl)thiomethyl]-3-hydroxypyrazine.