Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[C:4]([CH2:11]Cl)[CH:3]=1.[C-:13]#[N:14].[Na+].O>CS(C)=O>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[C:4]([CH2:11][C:13]#[N:14])[CH:3]=1
Reactant: [C-]#N
Reactant: ClCc1cc(Cl)c2c(c1)OCO2
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cc(Cl)c2c(c1)OCO2
Temperature: 40 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
A mixture of 4-chloro-6-(chloromethyl)benzo[d][1,3]dioxole (6.0 g, 29 mmol) and NaCN (1.6 g, 32 mmol) in DMSO (20 mL) was stirred at 40° C. for 1 h and was then poured into water. The mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure to afford 2-(7-chlorobenzo[d][1,3]dioxol-5-yl)acetonitrile (3.4 g, 58%). 1H NMR 67 6.81 (s, 1H), 6.71 (s, 1H), 6.07 (s, 2H), 3.64 (s, 2H). 13C-NMR δ149.2, 144.3, 124.4, 122.0, 117.4, 114.3, 107.0, 102.3, 23.1.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:37]=[CH:36][C:35]3[C:34]([CH3:39])([CH3:38])[CH2:33][CH2:32][C:31]([CH3:41])([CH3:40])[C:30]=3[CH:29]=2)O1>>[CH3:38][C:34]1([CH3:39])[CH2:33][CH2:32][C:31]([CH3:41])([CH3:40])[C:30]2[CH:29]=[C:28]([C:2]3[N:7]=[C:6]([N:8]4[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]4)[CH:5]=[CH:4][CH:3]=3)[CH:37]=[CH:36][C:35]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: OCCCNC1CCCN(c2cccc(Br)n2)CC1
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCC(NCCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS102 starting from 107 mg (0.323 mmol) of 3-[1-(6-bromopyridin-2-yl)azepan-4-ylamino]propan-1-ol and 123 mg (0.356 mmol) of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane. The crude product is purified by means of RP flash chromatography on C18 silica gel. The product is in the form of the hydrochloride.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][N:20]2[C:26]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)([CH2:31][CH3:32])[C:27]([O:29][CH3:30])=[O:28])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][N:20]2[C:26]([C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)([CH2:31][CH3:32])[C:27]([O:29][CH3:30])=[O:28]
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cc(F)cc21
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (4 mL) was added rapidly dropwise to a stirred solution of methyl 2-(4-(tert-butoxycarbonylamino)-6-fluoro-1H-indol-1-yl)-2-(4-chlorophenyl)butanoate (0.92 g, 2 mmol) in DCM (10 mL) at 0° C. After 1 h, the reaction was quenched by careful addition of saturated aqueous sodium bicarbonate, followed by extraction with ether. The organic layers were washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound. LC/MS m/z=361.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]2[N:29]=[N:30][N:31]([CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])[C:26]2=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]3[N:29]=[N:30][N:31]([CH2:32][C:33]([OH:35])([CH3:34])[CH3:36])[C:26]3=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(C)(O)Cn1nnc2nc(Cl)ccc21
Product: CC(C)(O)Cn1nnc2nc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)ccc21

Procedure:
The title compound was prepared as described in Example 1, Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (23 mg, 0.074 mmol) and 1-(5-chloro-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-2-methylpropan-2-ol (17 mg, 0.074 mmol) as starting materials.
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[S:15][CH3:16].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[C:19]=1[N+:25]([O-:27])=[O:26]>O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[C:19]=2[N+:25]([O-:27])=[O:26])=[CH:10][C:9]=1[S:15][CH3:16]
Reactant: CSc1cc(O)ccc1N
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1cc(Oc2ccnc(N)c2[N+](=O)[O-])ccc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.7 %

Procedure:
Method A2 Sodium hydride (148 mg) was added to dry DMSO (5.5 mL) and the mixture was stirred at RT for 20 minutes under Ar atmosphere. 4-amino-3-(methylthio)phenol (573 mg, 3.7 mmol) was added thereto, and the mixture stirred for 10 more minutes. Next, 4-Chloro-3-nitropyridin-2-amine (3.7 mmol) was added, and the mixture was heated to 100° C. and stirred for 3 hours. After cooling down, water was added, and the mixture extracted three times with EtOAc. The combined organic layers were washed first with a saturated aqueous sodium hydrogen carbonate solution then water, dried over MgSO4 and evaporated to afford the title compound (657 mg, 61%) was obtained after purification by chromatography on silica gel (EtOAc-DCM, 1:1) as a red brown solid (Rf 0.56, EtOAc-DCM, 1:1).
Reaction SMILES: [OH:1][C:2]1[N:3]2[C:7]([N:8]=[C:9]([CH3:11])[CH:10]=1)=[N:6][CH:5]=[N:4]2.[Br:12]Br.O>C(O)(=O)C>[Br:12][C:10]1[C:9]([CH3:11])=[N:8][C:7]2[N:3]([N:4]=[CH:5][N:6]=2)[C:2]=1[OH:1]
Reactant: Cc1cc(O)n2ncnc2n1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2ncnn2c(O)c1Br
Reaction time: 2 h
Yield: 83 %

Procedure:
A suspension of 4-hydroxy-6-methyl-1,3,3a,7-tetraazaindene (15.0 g, 0.1 mol) in acetic acid (100 ml) was treated dropwise at 20° C. with a solution of bromine (16.172 g, 0.102 mol) in acetic acid (20 ml). As the reaction progressed, the suspended crystals dissolved and new crystals of brominated product were formed. After about 2 hours, the reaction mixture was poured into water (250 ml) and crystals were collected by filtration. The crude product was purified by first converting into its sodium salt by dissolving 22 g in one liter of hot aqueous 0.2N sodium carbonate and then slowly acidifying with dilute hydrochloric acid. The unchanged starting material was converted into a soluble salt by addition of excess of triethylamine. Crystals were then collected and recrystallized from hot water to give 19 g (82%) of Compound TAI-4 as white needles, m.p.=269° C.
Reaction SMILES: [OH-].[Li+].[Cl:3][C@H:4]1[C@H:8]([CH2:9][CH2:10][CH2:11][C:12]2[S:16][C:15]([C:17]([O:19]C)=[O:18])=[CH:14][CH:13]=2)[C@@H:7](/[CH:21]=[CH:22]/[C@@H:23]([OH:30])[CH2:24][CH:25]([OH:29])[CH2:26][CH2:27][CH3:28])[C@H:6]([OH:31])[CH2:5]1.Cl>O.C1COCC1>[Cl:3][C@H:4]1[C@H:8]([CH2:9][CH2:10][CH2:11][C:12]2[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=2)[C@@H:7](/[CH:21]=[CH:22]/[C@@H:23]([OH:30])[CH2:24][CH:25]([OH:29])[CH2:26][CH2:27][CH3:28])[C@H:6]([OH:31])[CH2:5]1
Reactant: CCCC(O)C[C@H](O)/C=C/[C@@H]1[C@@H](CCCc2ccc(C(=O)OC)s2)[C@H](Cl)C[C@H]1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(O)C[C@H](O)/C=C/[C@@H]1[C@@H](CCCc2ccc(C(=O)O)s2)[C@H](Cl)C[C@H]1O
Reaction time: 24 h
Yield: 79.1 %

Procedure:
Lithium hydroxide (0.32 mL of a 0.5N solution in H2O, 0.16 mmol) was added to a solution of the ester 13 (36 mg, 0.081 mmol) in THF (0.64 mL) at 23° C. After stirring for 24 h the reaction mixture was acidified with 1N HCl and extracted with EtOAc. The organic portion was washed with brine (2×), dried (Na2SO4), filtered and concentrated in vacuo to provide 27.6 mg (79%) of the free acid 14 (see Scheme 1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][N+:10]=1[O-])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].CCOC(C)=O>C1COCC1.[Zn]>[C:1]([O:5][C:6]([N:8]([CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:9]1[N:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCN(C(=O)OC(C)(C)C)c1ccc(CC(=O)O)c[n+]1[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCN(C(=O)OC(C)(C)C)c1ccc(CC(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To 2-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)-5-(carboxymethyl)pyridine 1-oxide (0.78 g) in a mixture of THF (10 mL) and sat. NH4Cl (10 mL) was added Zinc dust (0.65 g). The reaction mixture was stirred at room temperature for overnight. EtOAc was then added and washed with water. The organic phase was dried and concentrated to afford the desired product (0.5 g).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=1.B1C2CCCC1CCC2.C1C[O:33]CC1>>[F:1][C:2]1[CH:18]=[C:17]([CH2:19][CH2:20][OH:33])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=1
Reactant: C=Cc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: OCCc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
To a solution of 2-(2-fluoro-4-vinylphenoxy)-6-(trifluoromethyl)pyridine (0.342 mL, 1.554 mmol) in THF (10 mL) was added 9-BBN (4.66 mL, 2.330 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (2 mL), followed by aq. NaOH (3 M, 4 mL), and 30% H2O2 (5 mL). The reaction mixture was stirred at 50° C. for 2 h. Then the THF and some water was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated and purified by flash chromatography to afford the title compound (183 mg, 39.1% yield) as a colorless oil. LCMS: rt=2.45 min
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[N:9][C:8]=1[N:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1.[Cl:20][C:21]1[C:26]([CH3:27])=[C:25](Cl)[N:24]=[CH:23][N:22]=1>C1COCC1>[Cl:20][C:21]1[C:26]([CH3:27])=[C:25]([O:19][CH:16]2[CH2:15][CH2:14][N:13]([C:8]3[N:9]=[CH:10][CH:11]=[CH:12][N:7]=3)[CH2:18][CH2:17]2)[N:24]=[CH:23][N:22]=1
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: OC1CCN(c2ncccn2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(Cl)ncnc1OC1CCN(c2ncccn2)CC1
Temperature: 30 °C
Reaction time: 5 h
Yield: 3.3 %

Procedure:
Potassium tert-butoxide (2.86 gm, 0.01397 moles) was added to an ice-cold solution of 1-(pyrimidin-2-yl)piperidin-4-ol (2.50 gm, 0.01397 moles) and 4,6-dichloro-5-methylpyrimidine (2.27 mg, 0.01397 moles) in dry THF (15 ml) and the reaction mixture was stirred for 5 hours at 30° C. The reaction mixture was poured into ice cold water, solid precipitated was filtered and dried under vacuum to obtain 140 mg of product.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[NH4+:6].[NH4+].[OH2:8]>>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[NH4+:6].[NH4+:6].[O:8]=[O:2]
Reactant: O
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: O=O

Procedure:
In FIG. 2, which shows a lactam preparation in which the rearrangement mixture is neutralized to ammonium sulfate, the letters A, B, D, and E denote similar devices to those in FIG. 1. The flows 1, 2, 3 and 4 are the same as those mentioned in FIG. 1. Neutralizing device B is fed with an amount of water through conduit 19 to keep the water concentration at the desired level. The extraction of lactam is effected in two extracting devices C1 and C2 that are connected by two conduits. After the neutralized reaction mixture supplied through conduit 4 has been separated into two liquid layers, the organic layer is passed through conduit 5 to extracting device C1 and the aqueous layer containing ammonium sulfate is passed through conduit 6 to extracting device C2. The organic solvent is supplied through conduit 9 and the lactam-laden solvent is discharged through conduit 7. Tar and water can be vented through conduit 8. The aqueous ammonium sulfate layer is passed through conduit 10 to decomposition device D, where it is decomposed by means of coke supplied through feed 18. The resulting gases containing ammonia and sulfur dioxide are passed through conduit 11 to neutralizing device B and the sulfur dioxide escaping from this device is passed through conduit 12 to installation E for the preparation of oleum, which is fed with water vapor formed in the decomposition of ammonium sulfate through conduit 16, with oxygen through conduit 15, and, if so required, with sulfur through conduit 20. The residual liquid components in device D are drained from the system through conduit 17 and a gas containing mainly carbon dioxide is removed through conduit 14.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13](O)[CH2:14][CH2:15]C.C(OC(C)C)(C)C>[Zn]>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCO
Reactant: COC(=O)CCc1ccccc1
Agent: [Zn]
Solvent: CC(C)OC(C)C
Product: CCCCOC(=O)CCc1ccccc1

Procedure:
Under a nitrogen atmosphere, a mixture of methyl 3-phenylpropionate (3.0 mmol), n-butanol (3.6 mmol), the zinc cluster obtained in the above-described Example 1 (0.0375 mmol), and diisopropyl ether (5.0 ml) was refluxed for 18 hours. As a result, butyl 3-phenylpropionate was obtained quantitatively.
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:15][CH:16]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:22]1[CH2:23][CH2:24][CH2:25][N:26]=[C:21]1[NH:20][C:19]([CH2:18][CH2:17][C:14]1[S:13][C:12]([C:10]([NH:9][CH2:8][C@H:7]([NH:28][S:29]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:37]=2)(=[O:30])=[O:31])[C:6]([OH:42])=[O:5])=[O:11])=[CH:16][CH:15]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)s1)NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccc(C(F)(F)F)cc2)C(=O)O)s1)NC1=NCCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 868.7 %

Procedure:
0.096 g (0.15 mmol) of the compound obtained in step b) were dissolved in dichloromethane (1 ml). Trifluoroacetic acid (1 ml) was added and the reaction mixture was stirred for 3 h at room temperature. After evaporation of the solvents lyophilization gave the title compound (0.75 g, 86%) as a white amorphous solid.
Reaction SMILES: [OH:1][C:2]([CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])([CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:9])[C:3](O)=[O:4].Cl.C([O:35][NH2:36])(C)(C)C.CN1CCOCC1>C(Cl)Cl>[OH:35][NH:36][C:3](=[O:4])[C:2]([OH:1])([CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:9]
Reactant: COc1ccc(C(=O)NCC(O)(CS(=O)(=O)c2ccc(OC)cc2)C(=O)O)cc1
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(C(=O)NCC(O)(CS(=O)(=O)c2ccc(OC)cc2)C(=O)NO)cc1
Reaction time: 6 h
Yield: 67.5 %

Procedure:
2-Hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(N-(4-methoxybenzenecarbonyl)amino)-propionic acid (100 mg, 0.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiilnide hydrochloride (68 mg, 0.35 mmol), O-tert-butylhydroxylamine hydrochloride (118 mg, 0.944 mmol), and 4-methylmorpholine (131 mg, 0.354 mmol) are dissolved in 20 mL of methylene chloride. The reaction mixture is stirred under nitrogen for 6 hours. The solvent is removed under reduced pressure, and the residue is dissolved in ethyl acetate. The organic layer is washed with 1N sodium hydrogen sulfate, 5% sodium bicarbonate, and saturated brine and dried over magnesium sulfate. The solvent is removed to yield 71 mg of white solid which is recrystallized from methanol. The tert-butyl protecting group is removed by treatment with 50% trifluoroacetic acid in methylene chloride for 24 hours. The solvents are removed, and the crude product is purified by reverse phase chromatography on a C18 Vydac column using a water-acetonitrile elution system to yield the title compound as a white solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:6]([OH:8])=O)[CH2:4][OH:5].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO>[CH2:9]([NH:16][C:6](=[O:8])[CH:3]([NH2:2])[CH2:4][OH:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: N[C@H](CO)C(=O)O
Agent: Cl
Solvent: CO
Product: NC(CO)C(=O)NCc1ccccc1

Procedure:
HCl (8.00 g, 219.4 mmol) was passed into MeOH (250 mL), and then D-serine ((R)-5) (20.00 g, 190.3 mmol) was added. The reaction solution was heated at reflux (18 h), then benzylamine (81.6 mL, 761 mmol) was added, and then the reaction mixture was heated for additional 18 h. The solvent was removed under reduced pressure, the insoluble salts were filtered, and the excess benzylamine was removed under high vacuum (Kugelrohr). The residue was dissolved in H2O (100 mL), and the product was extracted with CHCl3 (8×200 mL). The organic layers were combined and dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was triturated with Et2O (150 mL) and filtered to vie 10.0 g (27%) of the product as white solid: mp 74-78° C.; [α]23D (c=1, MeOH)=1.6°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[CH2:17][CH3:18])=[C:6]([N+:19]([O-])=O)[CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[CH2:17][CH3:18])=[C:6]([NH2:19])[CH:5]=1
Reactant: CCC1CCCCC1Nc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCC1CCCCC1Nc1ccc(C(=O)OC)cc1N
Reaction time: 4 h
Yield: 98.5 %

Procedure:
0.45 g 4-(2-Ethyl-cyclohexylamino)-3-nitro-benzoic acid methyl ester were dissolved in 60 ml methanol, 0.02 g of palladium on carbon (10%) were added and the mixture was hydrogenated at 5 bar for 4 h. The catalyst was removed by filtration over celite, the filtrate was concentrated to obtain 0.40 g (100%) of 3-Amino-4-(2-ethyl-cyclohexylamino)-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[CH:5]=1)=O.[NH2:12][O:13][CH2:14][C:15]([OH:17])=[O:16].C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][C:2](=[N:12][O:13][CH2:14][C:15]([OH:17])=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[CH:5]=1
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NOCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=NOCC(=O)O)c1ccc(Cl)c(Cl)c1

Procedure:
In the manner described in example 1, the above substance was obtained by boiling 4.73 g or 3,4-dichloroacetophenone, 2.74 g of hemihydrochloride of aminooxyacetic acid and 6.15 g of sodium acetate in 80% ethanol for one hour. After one crystallisation from a mixture of benzene and petroleum ether, the melting point was 128°-129° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:14][C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[C:3]1=[O:15])[CH2:10][CH2:9][CH2:8][CH2:7]3.[Al+3].[Cl-].[Cl-].[Cl-].[Br:20]Br.O>C(Cl)Cl>[Br:20][C:12]1[CH:13]=[C:4]2[C:3](=[O:15])[CH:2]([CH3:1])[CH2:14][C:5]2=[C:6]2[C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7]2
Reactant: CC1Cc2c(ccc3c2CCCC3)C1=O
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC1Cc2c(cc(Br)c3c2CCCC3)C1=O
Reaction time: 1 h

Procedure:
In a three-necked round-bottom 500 ml flask equipped with a reflux condenser, dropping funnel with pressure-equalizing, and mechanical stirrer a solution of 55.0 g (0.275 mol) of 2-methyl-1,2,6,7,8,9-hexahydro-3H-cyclopenta[a]naphthalen-3-one in 50 ml of CH2Cl2 was added dropwise with vigorous stirring for 1 h at −10° C. to a suspension of 92 g (0.69 mol) of AlCl3 in 100 ml of CH2Cl2. This mixture was stirred additionally for 1 h at this temperature; then 14.2 ml (44.0 g, 0.275 mol) of bromine was added dropwise with vigorous stirring for 1 h. The resulting mixture was stirred for 2 h at −10° C. and then overnight at ambient temperature, and, then, it was poured on 1000 cm3 of cold water. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether. The combined extract was washed with saturated aqueous Na2SO3 to eliminate bromine and with aqueous Na2CO3. It was then dried over K2CO3, and evaporated to dryness. Fractional distillation gave a yellowish liquid, b.p. 195-198° C./4 mm Hg. Yield 58.3 g (76%).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)C=CC=CC=1.[C:39]([C:41]1[NH:45][C:44]([CH2:46][CH2:47][CH3:48])=[N:43][C:42]=1[N:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[C:54](=[O:59])[C:55]([F:58])([F:57])[F:56])#[N:40].CN(C)C=O.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[C:39]([C:41]1[N:45]([CH2:25][C:22]2[CH:23]=[CH:24][C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[NH:8][N:9]=[N:10][N:11]=3)=[CH:20][CH:21]=2)[C:44]([CH2:46][CH2:47][CH3:48])=[N:43][C:42]=1[N:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[C:54](=[O:59])[C:55]([F:58])([F:56])[F:57])#[N:40]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C#N)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
N-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (Example 26, 2.1 g), 5-cyano-4-[2-(1-oxo-2,2,2-trifluoroethyl)-1H-pyrrol-1-yl]-2-propylimidazole (Example 18, 0.89 g), N,N-dimethylformamide (10 mL), and anhydrous K2CO3 (0.5 g) were stirred at room temperature under nitrogen atmosphere for 24 hours. Ethyl acetate (50 mL) was added and inorganic solids were removed by filtration. The filtrate was evaporated at reduced pressure and the major product was isolated by flash chromatography on silica gel (toluene acetonitrile 96:4) to afford the title compound in its triphenylmethyl-protected form (1.3 g). This material was dissolved in methanol (50 mL), treated with aqueous 10% citric acid (1.5 mL) and heated at reflux for 90 minutes. After cooling to room temperature, water (10 mL) and hexanes (100 mL) were added and the mixture was shaken vigorously. The methanol layer was separated, washed again with hexanes and evaporated. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated. The resulting gum was dissolved in ether, concentrated and allowed to stand overnight to give some seed crystals. The remaining gum was dissolved in tertbutyl methyl ether, seeded and diluted with diisopropyl ether. Crystallization gave the title product after filtration. MS (CI, CH4 +NH3) 531 (m+1).