Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=O)C.NC1C=C(S(O)(=O)=O)C2C=CC=C(S(O)(=O)=[O:27])C=2C=1>O>[OH:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:9])=[O:27]
Reactant: Nc1cc(S(=O)(=O)O)c2cccc(S(=O)(=O)O)c2c1
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1C
Solvent: O
Product: Cc1c(O)cccc1C(=O)O

Procedure:
The process according to the invention for the preparation of 3-acetoxy-2-methylbenzoyl chloride avoids these disadvantages. It comprises reacting an alkali metal salt of 3-aminonaphthalene-1,5-di-sulfonic acid with alkali metal hydroxide and water in the weight ratio 1:(1 to 1.6):(l to 1.6) at 220 to 320° C. to give the dialkali metal salt of 3-hydroxy-2-methylbenzoic acid, separating off insoluble constituents from the reaction mixture, then adjusting the reaction mixture to a pH of 11.5 to 13.5 by addition of acid and reacting it with acetic anhydride at -5 to 25° C., precipitating the 3-acetoxy-2-methylbenzoic acid by addition of acid, separating off the 3-acetoxy-2-methylbenzoic acid and reacting it with an inorganic acid chloride to give 3-acetoxy-2-methylbenzoyl chloride.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH:8][CH:9]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[CH2:10][SH:11].C(NC(C)C)(C)C>>[Cl:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][CH2:12][CH:9]1[O:8][C:4](=[O:5])[CH:3]([CH2:2][C:1]([OH:6])=[O:7])[S:11][CH2:10]1
Reactant: O=C1C=CC(=O)O1
Reactant: OC(CS)COc1cccc(Cl)c1
Solvent: CC(C)NC(C)C
Product: O=C(O)CC1SCC(COc2cccc(Cl)c2)OC1=O

Procedure:
Analogously to Example 1, from maleic acid anhydride and 2-hydroxy-3-m-chlorophenoxypropane-1-thiol in the presence of diisopropylamine and the usual working up of the reaction mixture, 6-m-chlorophenoxymethyl-2-oxo-1,4-oxathiane-3-acetic acid is obtained. It is separated into two isomers using chromatographic purification:
Reaction SMILES: ClC1C=CC=CC=1NC(=O)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=NC=1.[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43](=[O:70])[NH:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:59]=[C:58]3[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([O:64]C)=[O:63])[C:57]3=[O:60])=[CH:53][CH:52]=2)=[CH:47][C:46]=1[F:69]>>[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43](=[O:70])[NH:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:59]=[C:58]3[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([OH:64])=[O:63])[C:57]3=[O:60])=[CH:53][CH:52]=2)=[CH:47][C:46]=1[F:69]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)c(F)c3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)c(F)c3)cc2C1=O
Yield: 85 %

Procedure:
The compound of example 442 was prepared analogous to the compound of example 394 by hydrolysis of the compound of example 441.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][C:12]([Cl:19])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C(COC)OC>C(OCC)(=O)C.O>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][C:12]([Cl:19])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: O
Product: Clc1nc2c(c(-c3ccccc3)n1)CCN(Cc1ccccc1)C2
Temperature: 80 °C
Yield: 31.9 %

Procedure:
To a round bottomed flask containing 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (578 mg, 1.96 mmol) was added phenylboronic acid (260 mg, 2.13 mmol), dichloro-((bis-diphenylphosphino)ferrocenyl)-palladium (II) (complex with methylene chloride, 160 mg, 0.32 mmol), triethylamine (600 μL, 4.3 mmol), dimethoxyethane (20 mL), and water (0.5 mL). The reaction mixture was heated to 80° C. for 14 h, then cooled to rt and diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The material was purified by flash column chromatography to afford 7-benzyl-2-chloro-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (210 mg, 32%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:25])[C:16]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[N:17][O:18][CH3:19])[C:12](=[O:26])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10].P(OC[C@H]1[O:45][C@@H:44]([N:46]2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.P([O-])([O-])(OC(=O)N)=O.S([O-])([O-])(=O)=O.[Mg+2].Cl>[Cl-].[Mn+2].[Cl-]>[C:44]([O:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:25])[C:16]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[N:17][O:18][CH3:19])[C:12](=[O:26])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10])(=[O:45])[NH2:46]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Agent: [Mn+2]
Agent: Cl
Agent: NC(=O)OP(=O)([O-])[O-]
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 3 h
Yield: 34.4 %

Procedure:
(6R,7R)-3-Hydroxymethyl-7-[2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (syn isomer) (40 mg), ATP (300 mg), carbamoyl phosphate (150 mg), magnesium sulphate (20 mg) and manganese chloride (20 mg) were added to a portion of the 0-transcarbamoylase solution (50 ml) prepared in Example 8 and the final volume made up to 100 ml at a pH of 6.75. The mixture was incubated at 28° for 3 hours and was then acidified by addition of conc. hydrochloric acid (2.5 ml), left for 10 mins. and extracted with ethyl acetate. The ethyl acetate layer was back extracted with 0.1 M sodium bicarbonate which was then acidified and re-extracted with ethyl acetate. This extract was dried under reduced pressure and the solid triturated with diethyl ether to afford title compound (15.3 mg) as a dry powder, E1 cm1% 405 (273 nm). The n.m.r. spectrum resembled that of an authentic sample of title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].N[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.N1C=CN=C1>O1CCOCC1>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:6]2[C:5](=[O:15])[C:4]3[C:8](=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH2:1])[CH:3]=3)[C:7]2=[O:14])[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Agent: c1c[nH]cn1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)c3cc(N)c([N+](=O)[O-])cc3C2=O)CC1
Temperature: 140 °C
Yield: 53.5 %

Procedure:
A mixture of 5-amino-6-nitro-isoindole-1,3-dione (2.07 g, 10 mmol), tert-butyl 4-amino-piperidine-1-carboxylate (2.5 g, 12 mmol), imidazole (1.63 g, 24 mmol) in dioxane (100 mL) was sealed in a ChemGlass heavy wall pressure flask. After it was heated at 140° C. for 72 h, the reaction mixture was evaporated to dryness at 95° C. (the bath temperature) under reduced pressure. The chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (320:10:1) afforded the title compound (2.09 g, 54%). 1H NMR (CDCl3) δ 1.49 (s, 9H), 1.73 (m, 2H), 2.38 (m, 2H), 2.80 (m, 2H), 4.20-4.31 (3H), 7.03 (br s, 2H, NH), 7.34 (s, 1H), 8.61 (s, 1H); ESI-MS m/z 391.5 (MH+). 2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[CH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[CH2:15]([C:17]([O-:19])=[O:18])[CH3:16].C(O)(=O)C.[I:24]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:24][C:7]1[CH:6]=[CH:5][C:4]2[NH:3][C:2](=[O:1])[C:11]3[NH:12][CH:13]=[CH:14][C:10]=3[C:9]=2[CH:8]=1.[CH2:15]([C:17]([O-:19])=[O:18])[CH3:16]
Reactant: O=c1[nH]c2ccccc2c2cc[nH]c12
Reactant: II
Agent: [Ag+2]
Agent: CCC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.7 %

Procedure:
1.49 g (4.7 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate cocrystallized with one equivalent of acetic acid is added to a suspension of 1.61 g (5.17 mmol) of diiodine and 1.31 g (5.17 mmol) of silver sulfate in anhydrous ethanol (100 mL). The reaction mixture is stirred at room temperature for 6 hours then the solvents are evaporated under vacuum. The residue is taken up in water and the product is extracted copiously with a mixture of ethyl acetate/methanol 95/5. The organic phases are dried over magnesium sulfate, filtered on celite and evaporated under vacuum to give 1.4 g (78%) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([CH:16]=[N:17][OH:18])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19]NC(=O)CCC(N)=O>CN(C)C=O>[OH:18][N:17]=[C:16]([Cl:19])[C:10]1[O:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]=1[C:12]([F:13])([F:14])[F:15]
Reactant: ON=Cc1onc(-c2ccccc2)c1C(F)(F)F
Reactant: NC(=O)CCC(=O)NCl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbaldehyde oxime (Intermediate I-12C, 0.34 g, 1.327 mmol) in N,N-dimethylformamide (1 mL) was added N-chlorosuccinamide (0.177 g, 1.327 mmol) in batches over a period of 2 min. at room temperature. The reaction mixture was stirred at room temperature for 30 min. An additional 0.09 g of N-chlorosuccinamide was added in one lot at room temperature and the contents were stirred for 20 min. The reaction mixture was partitioned between ethyl acetate (20 mL) and brine (2×20 mL). The ethyl acetate layer was dried over sodium sulfate and purified by silica gel column chromatography using hexane/ethyl acetate to yield N-hydroxy-3-phenyl-4-(trifluoromethyl)isoxazole-5-carbimidoyl chloride (0.250 g, 0.860 mmol, 64.8% yield) as a white solid. LC/MS M+1=291.2.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[C:12]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=3)C(=O)[O:18][N:17]=2)=[N:13][O:14][N:15]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Cl:28][C:23]1[CH:22]=[C:21]([NH:20][C:16]([C:12]2[C:11]([CH2:10][CH2:9][NH:8][S:31]([CH3:30])(=[O:33])=[O:32])=[N:15][O:14][N:13]=2)=[N:17][OH:18])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: NCCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)NCCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a solution of 3-[4-(2-aminoethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one trifluoroacetate (16.0 mg, 0.037 mmol) in DCM (1.0 mL) was added TEA (15 μL, 0.11 mmol) and methanesulfonyl chloride (4.2 μL, 0.055 mmol). The resulting mixture was stirred at rt for 1 h and then the solvent was removed under reduced pressure. The residue was dissolve in MeOH (1 mL) and 2.0 M sodium hydroxide in water (0.10 mL) was added. After stirring for 4 h, the reaction solution was diluted with MeOH and a few drop of acetic acid and then purified by preparative LCMS to give the desired product as a white solid (14.1 mg, 78.3%). MF═C12H13ClFN5O4S; LCMS calculated C12H14ClFN5O4S(M+H)+: m/z=377.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][C:7]=1[O:8][CH3:9].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH2:21][C:20]3[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=3)[CH2:12][CH2:11]2)=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1nc(N2CCNCC2)ccc1Br
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(CN2CCN(c3ccc(Br)c(OC)n3)CC2)cc1OC
Temperature: 25 °C

Procedure:
A quantity of 0.1 g (0.4 mmole, 1 eq) of 1-(5-Bromo-6-methoxy-pyridin-2-yl)-piperazine and 0.061 g (0.4 mmole, 1 eq) of 3,4-dimethoxybenzaldehyde is dissolved in 5 mL of anhydrous toluene, and 3 drops of glacial acetic acid is added. An excess of NaBH(OAc)3 is added to the solution and stirred at room temperature under a nitrogen atmosphere until no starting material is detectable by TLC. At that time the reaction is quenched with saturated aqueous NaHCO3 and extracted with ethyl acetate. The ethyl acetate extracts are dried over anhydrous MgSO4 and concentrated in vacuo. The residue is chromatographed on SiO2 with 10% CH3OH (2M NH3)/CH2Cl2 to afford 1-(5-bromo-6-methoxypyridin-2-yl)-4-(3,4-dimethoxybenzyl)piperazine (compound 1). Analysis: 1H NMR (400 MHz, DMSO): 7.71 (1H, d), 7.36 (1H, s), 7.05 (2H, m), 6.39 (1H, d), 4.38 (4H, m), 3.80 (9H, m), 3.39 (4H, m), 3.02 (2H, m). MS (LC-MS): Calculated for C19H24BrN3O3 422.32, found 436.3424.31 (M+2).
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[N:14]([CH3:15])[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([S:24](=[O:29])(=[O:28])[N:25]([CH3:27])[CH3:26])[CH:18]=3)(O)[CH2:12][S:11]2)=[C:5]([O:30][CH3:31])[CH:4]=1>C(O)=O>[BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[N:14]([CH3:15])[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([S:24](=[O:29])(=[O:28])[N:25]([CH3:26])[CH3:27])[CH:18]=3)=[CH:12][S:11]2)=[C:5]([O:30][CH3:31])[CH:4]=1
Reactant: COc1cc(Cl)ccc1N=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)N(C)C)c2)N1C
Agent: Br
Solvent: O=CO
Product: COc1cc(Cl)ccc1N=c1scc(-c2ccc(Cl)c(S(=O)(=O)N(C)C)c2)n1C

Procedure:
Obtained by a procedure analogous to that indicated in Example 1 (b), from 2-(4-chloro-2-methoxyphenyl-imino)-4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methylthiazolidin-4-ol hydrobromide, by boiling for 30 minutes in formic acid, then distilling off the solvent, treating the residue with ethyl acetate or diisopropyl ether and filtering off the solid. Melting point 244° C. (with decomposition).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:37]=[CH:36][C:24]2[CH2:25][CH2:26][N:27]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:28][CH2:29][C:23]=2[C:22]=1OS(C(F)(F)F)(=O)=O.COC(=O)C1C=CC(CN)=CC=1>C1(C)C=CC=CC=1.O>[Cl:20][C:21]1[CH:37]=[CH:36][C:24]2[CH2:25][CH2:26][N:27]([C:30](=[O:35])[C:31]([F:32])([F:34])[F:33])[CH2:28][CH2:29][C:23]=2[C:22]=1[NH:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([O:3][CH3:2])=[O:13])=[CH:6][CH:7]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1

Procedure:
Treat 4-aminomethyl-benzoic acid methyl ester hydrochloride (0.2 g, 0.71 mmol) with K2CO3 (1.0 g, 0.71 mmol) in a mixture of toluene/water (1:1, 2 mL). Separate the organic layer, dry over anhydrous Na2SO4 and use as a toluene solution for the next step. Use a method similar to the General Procedure 5-2, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.1 g, 0.24 mmol) and 4-aminomethyl-benzoic acid methyl ester (0.2 g, 0.71 mmol) to give 7-chloro-6-(4-methoxycarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.O[C:14]1[C:22]2N=NN[C:18]=2[CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.C[N:33]([CH:35]=[O:36])C>>[C:35]([NH2:33])(=[O:36])[C:14]1[CH:22]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1

Procedure:
Ester compound 3 is converted to the free carboxylic acid, and is then reacted with substituted aniline compound 4 to yield an arylamide of formula 5. For example, LiOH is added to a stirred solution of 3 in a mixture of solvents. The volatiles are removed under vacuum, and the residue is diluted with water and acidified to about pH 3. The resulting solids are filtered, washed with water and dried under vacuum to furnish a carboxylic acid intermediate. The intermediate is dissolved in a solvent such as DMF and the mixture is stirred to prepare a solution. To the stirred solution is added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) followed by hydroxybenzotriazole (HOBt). After stirring, diisopropyl ethyl amine is added and stirred. Then substituted aniline 4 (representative of substituted aryl or heteroaryl) is added, and the reaction mixture is stirred. The solvent is removed under vacuum. The residue is diluted with water and stirred. The resulting solids are filtered and purified through column chromatography to provide benzamide compound 5.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH:16]2[CH:11]([CH2:12][CH2:13][NH:14][CH2:15]2)[CH2:10]1)=[O:8].Cl[C:24]1[N:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[N:25]=1.ClC1C=NC2C(=CC=CC=2)N=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[C@@H:16]2[C@@H:11]([CH2:12][CH2:13][N:14]([C:24]3[N:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[N:25]=3)[CH2:15]2)[CH2:10]1)=[O:8]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CCNCC21
Reactant: Cc1cc(C)nc(Cl)n1
Agent: Clc1cnc2ccccc2n1
Product: Cc1cc(C)nc(N2CC[C@H]3CN(C(=O)c4ccccc4-c4ccccc4)[C@H]3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S) biphenyl-2-yl-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-methanone for biphenyl-2-yl-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-methanone and 2-chloro-4,6-dimethyl-pyrimidine for 2-chloro quinoxaline. MS (ESI) mass calcd. for C25H26N4O, 398.50; m/z found 399.2 [M+H]+. 1H NMR (CDCl3): 7.54-7.31 (m, 7H), 7.25-7.11 (m, 2H), 6.33-6.23 (m 1H), 4.64-4.36 (0.5H), 4.00-3.39 (m, 5H), 3.25-2.85 (m, 1.25H), 2.60-2.37 (m, 1.25H), 2.33 (s, 3H), 2.25 (s, 3H), 2.00-1.37 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:47][C:48]#[N:49].P([O-])([O-])(O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:47][C:48]#[N:49])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)NCCC3)cc1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CC#N)CCC3)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 85.9 %

Procedure:
A solution of 2.50 g (4.05 mmol) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [example 1(c)] and 0.968 g (8.10 mmol, 2.0 equiv.) of bromoacetonitrile in 15 ml of toluene and 2 ml of N-methyl pyrrolidone was treated with 2.88 g (20.27 mmol, 5.0 equiv.) of anhydrous disodium hydrogen phosphate. The suspension was stirred for 18 h at 50° C., allowed to cool to room temperature, poured into 100 ml of an ice/water mixture and extracted three times with 200 ml of ethyl acetate. The combined organic phases were washed twice with 50 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus obtained crude product was purified by chromatography on silica gel using a 10:1 v/v mixture of dichloromethane and ethyl acetate as eluent to yield 2.28 g (3.48 mmol, 85.9% of theory) of (3R,4R)-3-(1-cyanomethyl-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 656 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[NH:17][C:16]([CH:18]=[C:19]4[N:54]=[C:22]([C:23]([CH:35]([CH2:45][CH2:46][O:47][P:48]([O:52]C)([O:50]C)=[O:49])[CH2:36][CH2:37][O:38][P:39]([O:43]C)([O:41]C)=[O:40])=[C:24]5[NH:34][C:27](=[CH:28][C:29]6[CH:30]=[CH:31][C:32]=2[N:33]=6)[CH:26]=[CH:25]5)[CH:21]=[CH:20]4)=[CH:15][CH:14]=3)=[CH:8][CH:7]=1)([OH:3])=[O:2].[Si](Br)(C)(C)C>C(Cl)Cl>[C:1]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:13]3[NH:17][C:16]([CH:18]=[C:19]4[N:54]=[C:22]([C:23]([CH:35]([CH2:36][CH2:37][O:38][P:39]([OH:43])([OH:41])=[O:40])[CH2:45][CH2:46][O:47][P:48]([OH:52])([OH:50])=[O:49])=[C:24]5[NH:34][C:27](=[CH:28][C:29]6[CH:30]=[CH:31][C:32]=2[N:33]=6)[CH:26]=[CH:25]5)[CH:21]=[CH:20]4)=[CH:15][CH:14]=3)=[CH:10][CH:11]=1)([OH:3])=[O:2]
Reactant: COP(=O)(OC)OCCC(CCOP(=O)(OC)OC)c1c2nc(cc3ccc([nH]3)c(-c3ccc(OCC(=O)O)cc3)c3nc(cc4ccc1[nH]4)C=C3)C=C2
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=C(O)COc1ccc(-c2c3nc(cc4ccc([nH]4)c(C(CCOP(=O)(O)O)CCOP(=O)(O)O)c4nc(cc5ccc2[nH]5)C=C4)C=C3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
A sample of thoroughly dried 13a (11.8 mg, 0.015 mmol) was dissolved in dry CH2Cl2 (2.0 mL) and then treated with TMS-Br (100 μL, 0.760 mmol). The reaction mixture was stirred at room temperature for 3 h under argon. The solvents were evaporated at reduced pressure. The residue was dissolved in MeOH (3.0 mL). The solution was stirred for 1 h at room temperature. The volatile components were evaporated. The solid residue was dissolved in ˜0.2 mL aqueous NaOH (15 wt %), and the sample was diluted to ˜3 mL with water. The sample was chromatographed (silica C-18, water/MeOH, 0→50%) to afford a dark red solid (8.2 mg, 76%): 1H NMR δ (D2O) 3.61 (m, 4H), 3.95 (m, 2H), 4.33 (m, 2H), 5.04 (s, 2H), 5.89 (m, 1H), 7.57 (d, J=7.8 Hz, 2H), 7.94-7.97 (m, 2H), 8.91 (m, 2H), 9.28-9.34 (m, 2H), 9.78-9.82 (m, 2H), 10.24-10.33 (m, 4H); ESI-MS obsd (+) 362.1 (M+2H)2+, 723.1 (M+H)+, 745.1 (M+Na)+ (−) 721.1 (M−H)−, calcd 722.15 (M, M=C33H32N4O11P2); λabs 402, 506 nm; λem (λexc 402 mm) 628, 688 nm; HPLC (20% B, 1.5 mL/min, tR=2.22 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.[N:17]([Sn](C)(C)C)=[N+:18]=[N-:19]>C1(C)C=CC=CC=1>[C:11]1([C:3]2[CH:4]=[C:5]([CH2:8][C:9]3[NH:19][N:18]=[N:17][N:10]=3)[CH:6]=[CH:7][C:2]=2[NH2:1])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#CCc1ccc(N)c(C2=CCCCC2)c1
Solvent: Cc1ccccc1
Product: Nc1ccc(Cc2nnn[nH]2)cc1C1=CCCCC1

Procedure:
The title compound was prepared from (4-amino-3-cyclohex-1-enyl-phenyl)-acetonitrile (as prepared in the previous step, 103 mg, 0.485 mmol) and azidotrimethylstannane (105 mg, 0.510 mmol) in toluene (4 mL) according to the procedure in Example 52, step (c) and then further purified by preparative TLC (10% MeOH—CHCl3) to afford 40 mg (39%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C14H17N5, 256.1 (M+H), found 256.1.