Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][C:17]1([O:50][CH3:51])[C:48](=[O:49])[N:19]2[C:20]([C:32]([O:34][CH:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])=[C:21]([CH2:24][S:25][C:26]3[N:30]([CH3:31])[N:29]=[N:28][N:27]=3)[CH2:22][S:23][C@H:18]12.[CH3:52][O:53][N:54]=[C:55]([C:59]1[N:60]=[N:61][S:62][CH:63]=1)[C:56](O)=[O:57]>O1CCCC1>[CH3:52][O:53][N:54]=[C:55]([C:59]1[N:60]=[N:61][S:62][CH:63]=1)[C:56]([NH:16][C:17]1([O:50][CH3:51])[C:48](=[O:49])[N:19]2[C:20]([C:32]([O:34][CH:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:33])=[C:21]([CH2:24][S:25][C:26]3[N:30]([CH3:31])[N:29]=[N:28][N:27]=3)[CH2:22][S:23][C@H:18]12)=[O:57]
Reactant: COC1(N)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nnnn3C)CS[C@@H]21
Reactant: CON=C(C(=O)O)c1csnn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1(OC)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nnnn3C)CS[C@@H]21)c1csnn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.1 %

Procedure:
Dicyclohexylcarbodiimide (0.99 g.) was added at ambient temperature to a solution of diphenylmethyl 7-amino-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (2.1 g.) in dry tetrahydrofuran (20 ml.) and then 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer) (0.9 g.) was added thereto at ambient temperature to give white precipitates. After stirring for 2 days at ambient temperature, the precipitates were filtered off and the filtrate was concentrated under reduced pressure to give brown oil. The oil was subjected to column chromatography on silica gel, eluted with a mixture of chloroform and ethyl acetate and the eluate was concentrated under reduced pressure to give diphenylmethyl 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (1.78 g.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:22])OC(C)(C)C)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].Cl[CH2:32][CH2:33][CH2:34]C(Cl)=O.[OH-].[Na+]>C(#N)C.O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]3[CH2:34][CH2:33][CH2:32][C:16]3=[O:22])[CH2:11]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C(Cl)CCCCl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Nc1ccc(N2CC[C@@H](N3CCCC3=O)C2)cc1
Reaction time: 2 h

Procedure:
tert-Butyl [1-(4-Nitrophenyl)pyrrolidin-3-yl]carbamate was treated by method G. The crude product (1.4 g) was dissolved in acetonitrile (20 ml) and mixed with trisodium phosphate (0.67 g) and 4-chlorobutyryl chloride (1.1 g). After 2 hours, sodium hydroxide (0.6 g) in water (10 ml) was added and the mixture was vigorously stirred. After 12 hours, the same amount of sodium hydroxide solution was again added, and the mixture was stirred for a further 24 hours. The concentrated reaction solution was partitioned between water and ethyl acetate, and the organic phase was dried and concentrated. The residue was hydrogenated by method B. This resulted in the product with the molecular weight of 245.33 (C14H19N3O); MS (ESI): 246 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.CS(O[CH2:18][CH:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:20])(=O)=O.CN(C)P(N(C)C)(N(C)C)=O.O>C(O)C>[O:21]([CH:19]([CH3:20])[CH2:18][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(COS(C)(=O)=O)Oc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCO
Solvent: O
Product: CC(CNc1ccc(C(=O)O)cc1)Oc1ccccc1
Temperature: 125 °C

Procedure:
A mixture of 33 g of ethyl p-aminobenzoate, 0.10 mole of 2-phenoxy-1-propanol O-methanesulfonate and 80 ml of hexamethylphosphoramide is heated at 125° C. for 18 hours. The mixture is chilled, poured into water and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and concentrated under vacuum to an oil. The oil is combined with 250 ml of ethanol-water (9:1) and 20 g of potassium hydroxide and the mixture refluxed for 3.5 hours. The mixture is acidified with concentrated hydrochloric acid, diluted with water and extracted with chloroform. The chloroform extracts are washed with water, dried (magnesium sulfate) and concentrated under vacuum to give an oil. Ethanol is added and the mixture chilled and filtered to give the product, mp 140°-144° C. Recrystallization gives the product as crystals, mp 145°-147° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:7]([C@H:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([CH3:27])=[CH:5]2.Cl(O)(=O)(=O)=O>C(OC(=O)C)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][S:13]([C:16]([F:18])([F:17])[F:19])(=[O:15])=[O:14])=[C:7]([C@H:20]([O:26][C:4]([CH3:9])([CH3:5])[CH3:3])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([CH3:27])=[CH:5]2
Reactant: CCOC(=O)[C@@H](O)c1c(C)cc2cc(Br)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Br)ccc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 2.5 h

Procedure:
To a solution of (S)-ethyl 2-(6-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (2 g, 4.26 mmol) in tert-butylacetate (30 mL) was added 70% perchloric acid (1.10 mL, 4.69 mmol). The reaction mixture was stirred for 2.5 hours and quenched with solid sodium bicarbonate and stirred for 45 minutes. Water and solid sodium bicarbonate were carefully added and stirred for another 15 minutes. The mixture was diluted with ethyl acetate, washed with saturated bicarbonate solution (2×), brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give the desired compound. 1H NMR (400 MHz, CDCl3) δ: 7.96 (s, 1H), 7.90 (d, J=10.2 Hz, 1H), 7.62 (d, J=9.2 Hz, 1H), 7.58 (s, 1H), 5.90 (s, 1H), 4.26-4.08 (m, 2H), 2.53 (s, 3H), 1.20 (s, 9H), 1.17 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:39][CH3:40])[CH2:38][N:10]3[C:11](=[O:37])[C@@H:12]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C@@H:20]4[CH2:25][C@@:21]4([C:26](O)=[O:27])[NH:22][C:23](=[O:24])[C@@H:9]3[CH2:8]2)=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:59]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[C:1]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:39][CH3:40])[CH2:38][N:10]3[C:11](=[O:37])[C@@H:12]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:35])([CH3:36])[CH3:34])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C@@H:20]4[CH2:25][C@@:21]4([C:26](=[O:27])[NH:65][S:62]([CH:59]4[CH2:61][CH2:60]4)(=[O:64])=[O:63])[NH:22][C:23](=[O:24])[C@@H:9]3[CH2:8]2)=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: CO[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: CO[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)NS(=O)(=O)C4CC4)C[C@H]3/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: CO[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CO[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)NS(=O)(=O)C4CC4)C[C@H]3C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-methoxy-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (50 mg, 0.079 mmol) and CDI (755 mg, 4.66 mmol) in tetrahydrofuran (5 mL) was heated at reflux for 1 h. It was then cooled to rt, and then cyclopropanesulfonamide (11.51 mg, 0.095 mmol) was added, followed by DBU (0.042 mL, 0.277 mmol). This reaction mixture was stirred at rt for 18 h, and then concentrated in vacuo to give the crude product as a light colored oil. Purification by preparative HPLC gave 15 mg (26%) of tert-butyl (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-14a-(cyclopropylsulfonylcarbamoyl)-2-methoxy-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5](=[CH:9][C:10]=1[F:11])[C:6]([OH:8])=O>C(OC(=O)C)(=O)C>[F:11][C:10]1[CH:9]=[C:5]2[C:6](=[O:8])[O:14][C:12](=[O:13])[C:4]2=[CH:3][C:2]=1[F:1]
Reactant: O=C(O)c1cc(F)c(F)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(F)c(F)cc21
Yield: 95 %

Procedure:
The title compound of Example 2 (28.2 g, 139.5 mmol) was suspended in 90 ml of acetic anhydride and heated to reflux for 2 hours. The reaction was evaporated to dryness to give 24.4 g of the title compound as crude product (95% yield). 1H NMR(CDCI3) : 7.73 (t). I.R.: 3025 (m), 1877 (m), 1794 (vs), 1505 (s) , 1220 (vs), 910 (s) , 780 (rs) cm-1.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18]C)=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[NH2:21][NH2:22]>C(O)C>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([NH:21][NH2:22])=[O:18])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(CCC(=O)OC)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCCCCOc1ccc(CCC(=O)NN)cc1

Procedure:
To a solution of methyl 3-(4-n-hexyloxyphenyl)propionate (1.18 g) in ethanol (10 ml) was added hydrazine monohydrate (1.08 ml) and the mixture was refluxed for 24 hours. After cooling, the solvent was removed under reduced pressure. Water was added and the precipitate was collected by filtration, washed with water and dried under reduced pressure to give 3-(4-n-hexyloxyphenyl)propionohydrazide (0.92 g).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH3:27].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:2]2[C:7](=[O:8])[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=2[CH3:27])=[CH:32][CH:31]=1
Reactant: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(Oc2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 26.6 %

Procedure:
A mixture of 4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.41 g), 4-methoxyphenol (0.13 g), 8 M potassium hydroxide solution (0.13 mL) and dimethyl sulfoxide (5 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.12 g, 28%).
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])=[C:12]([CH3:14])[CH3:13])[CH:3]=[CH2:4].N1C=CC=CC=1.P(Br)(Br)[Br:25]>CCCCCC>[Br:25][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])=[C:12]([CH3:14])[CH3:13]
Reactant: BrP(Br)Br
Reactant: C=CC(C)(O)CCC=C(C)CCC(C)=C(C)C
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(=CCBr)CCC=C(C)CCC(C)=C(C)C
Reaction time: 0.5 h

Procedure:
To a solution containing 223.9 g. of 3,7,10,11-tetramethyl-1,6,10-dodecatrien-3-ol in 570 ml. of hexane and 22.2 ml. of pyridine there was added dropwise at -7°C. over a period of two hours, 112 g. of phosphorous tribromide in 125 ml. of hexane. The resulting mixture was stirred for 30 minutes. After this, the reaction mixture was poured onto ice water and the reaction mixture was allowed to stand under constant stirring for 30 minutes. After 30 minutes, the reaction mixture was diluted with 1,000 ml. of hexane and the water layer was separated and the hexane layer was washed with water, aqueous sodium bicarbonate and finally with water. After washing, the hexane solution was dried over sodium sulfate and evaporated. There resulted 1-bromo-3,7,10,11-tetramethyl-2,6,10-dodecatriene.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:28]=[CH:27][C:12]([CH2:13][O:14][C:15](=[O:26])[C@@H:16]([NH:18]C(OC(C)(C)C)=O)[CH3:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=2[O:36][CH2:37][CH3:38])[N:3]=1.Cl>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15](=[O:26])[CH:16]([NH2:18])[CH3:17])=[CH:27][CH:28]=2)[CH:5]=[C:4]([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=2[O:36][CH2:37][CH3:38])[N:3]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(COC(=O)[C@H](C)NC(=O)OC(C)(C)C)cc2)nc(N)n1
Agent: Cl
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(COC(=O)C(C)N)cc2)nc(N)n1
Yield: 51 %

Procedure:
Following the method described in Example 64, (S)-2-tert-butoxycarbonylamino-propionic acid 4-[2-amino-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-4-ylamino]-benzyl ester and hydrogen chloride provided the title compound (51% yield).
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.[CH2:6]([O:8][C:9]([C:11]1[S:12][C:13](S(C)(=O)=O)=[C:14]([C:23]#[N:24])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)=[O:10])[CH3:7]>C(Cl)Cl>[CH2:6]([O:8][C:9]([C:11]1[S:12][C:13]([CH2:4][CH3:5])=[C:14]([C:23]#[N:24])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)=[O:10])[CH3:7]
Reactant: CC[Zn]CC
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1-c1ccc(I)cc1
Solvent: ClCCl
Product: CCOC(=O)c1sc(CC)c(C#N)c1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Add dropwise diethylzinc (1.0M in hexanes, 16 mmol) to a solution of 3-(4-iodophenyl)-4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid ethyl ester (2.78 mmol) in 15 mL of anhydrous CH2Cl2 and stir under nitrogen at room temperature for 5 days. Cool to 0° C. and carefully quench with ice followed by 10 mL of saturated NH4Cl. Filter the mixture through Celite and rinse the filter pad with 100 mL of CH2Cl2. Wash the combined organic layers with brine (1×20 mL), dry over Na2SO4, filter, and evaporate. Chromatograph (hexane:ethyl acetate 3:1) over silca gel to provide the title compound: MS (ES+, m/e): 412 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[C:14]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1>>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:23]1[CH2:24][CH2:25][N:20]([C:14]2[C:13]([CH3:12])=[CH:18][C:17]([CH3:19])=[CH:16][N:15]=2)[CH2:21][CH2:22]1)=[O:6]
Reactant: O=C(O)c1ccc(Cl)cc1Br
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Yield: 98.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 2-bromo-4-chlorobenzoic acid (2.09 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (1.7 g) described in Preparation Example 47, the title compound (3.58 g) was obtained.
Reaction SMILES: C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:19][NH:20][O:21][CH3:22].C(Cl)CCl.[CH2:27]([O:34][C:35]([NH:37][C:38]1[CH:39]=[C:40]([CH2:44][C:45]([OH:47])=O)[CH:41]=[CH:42][CH:43]=1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:22][O:21][N:20]([CH3:19])[C:45](=[O:47])[CH2:44][C:40]1[CH:39]=[C:38]([NH:37][C:35](=[O:36])[O:34][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)Cc1cccc(NC(=O)OCc2ccccc2)c1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CON(C)C(=O)Cc1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a suspension of 24.7 g (87 mmol) of (3-{[(benzyloxy)carbonyl]amino}phenyl)acetic acid in 200 mL of dichloromethane (from Step B) was added triethylamine (30.2 mL, 173 mmol) which resulted in some exotherming (+5° C.) and the suspension becoming a solution. After 10 min cooling, HOBt (13.2 g, 87 mmol), N,O-dimethylhydroxylamine HCl (8.5 g, 87 mmol) was added to the solution followed by EDC (16.6 g, 87 mmol) and the resulting mixture stirred at room temperature overnight under nitrogen atmosphere. The solution was transferred to a separatory funnel and washed with 1 M HCl which caused an emulsion. Methanol was added to break up the emulsion and the aqueous was partitioned off. The organics were dried over sodium sulfate, filtered and concentrated under vacuum. Recrystallization of the residue from 1000 mL of 70% hexane in ethyl acetate (heated to reflux and then cooled to room temperature overnight) afforded the title compound (21 g, 74%) as a white solid. LC-MS: m/z (ES) 329 (MH)+.
Reaction SMILES: BrC1C=C2C(=CC=1Cl)NC=C2C=O.Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][C:23]=1[Cl:24])[NH:20][CH:19]=[C:18]2[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[O:26].CC1(C)COB([C:39]2[CH:44]=[CH:43][C:42]([C:45]([CH3:49])([CH3:48])[CH2:46][OH:47])=[C:41]([O:50][CH3:51])[CH:40]=2)OC1.BrC1C=CC(C(C)(C)CO)=C(OC)C=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(O)C.C1(C)C=CC=CC=1>[Cl:24][C:23]1[CH:22]=[C:21]2[C:17]([C:18]([C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[O:26])=[CH:19][NH:20]2)=[CH:16][C:15]=1[C:39]1[CH:44]=[CH:43][C:42]([C:45]([CH3:49])([CH3:48])[CH2:46][OH:47])=[C:41]([O:50][CH3:51])[CH:40]=1
Reactant: COc1cc(B2OCC(C)(C)CO2)ccc1C(C)(C)CO
Reactant: CS(=O)(=O)NC(=O)c1c[nH]c2cc(Cl)c(Br)cc12
Agent: COc1cc(Br)ccc1C(C)(C)CO
Agent: O=C([O-])[O-]
Agent: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(-c2cc3c(C(=O)NS(C)(=O)=O)c[nH]c3cc2Cl)ccc1C(C)(C)CO
Temperature: 110 °C

Procedure:
A round bottomed flask was charged with a 1:1 mixture of 5-bromo-6-chloro-1H-indole-3-carbaldehyde and 5-bromo-6-chloro-N-(methylsulfonyl)-1H-indole-3-carboxamide (96 mg, 0.27 mmol) as prepared in step 1, 2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methoxyphenyl]-2-methylpropan-1-ol (40 mg, 0.14 mmol) (prepared from 2-(4-Bromo-2-methoxyphenyl)-2-methylpropan-1-ol in a manner similar to Example 8, Step 4), potassium carbonate solution (2.0M, 0.27 mL), toluene (0.75 mL), ethanol (0.28 mL), and THF (0.28 mL) then degassed with nitrogen for 5 minutes. PddppfCl2 was then added and the reaction heated to 110° C. for 3 hours. The reaction was then cooled to rt, diluted with water and ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate×3. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was then dissolved in DMSO and purified by reverse phase HPLC to provide the title compound as an ammonium salt (8.0 mg). MS (ES−): 449.1 (M−H)—HPLC retention time: 1.86 min, Waters XBridge C18, 5 μm, 4.6×50 mm, 0.03% NH4OH, 5-95% acetonitrile in water gradient over 4.0 min, hold at 95% acetonitrile in water to 5.0 min, flow 2.0 mL/min.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[K+]>O1CCCC1>[CH2:1]([N:8]1[CH2:4][CH2:3][CH:2]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:1]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CNC2CCN(Cc3ccccc3)C2)cc1
Reaction time: 24 h

Procedure:
1,000 g (5.34 mols) of 1-benzyl-Δ3 -pyrroline-2,5-dione are dissolved in 2.5 l of tetrahydrofuran, and 572 g (5.34 mols) of benzylamine are added with stirring at 10° to 20° C. The mixture is left to stand for 24 hours at room temperature, after which 360 g are removed from the resulting solution (3,848 g of total weight) and added to a solution of 38 g (1 mol) of lithium aluminum hydride in 380 ml of absolute dehydrated tetrahydrofuran. The mixture is refluxed for 20 hours, 500 ml of tetrahydrofuran, 38 g of water and 120 ml of tetrahydrofuran, 38 g of 10% strength potassium hydroxide solution and 114 g of water are then sucessively added to the mixture. The salts are filtered off with suction, washed with tetrahydrofuran, the filtrate is concentrated, and the residue is distilled.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH3:3].N12CCCN=C1CCCCC2.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH:43]([C:49](=O)[CH2:50][CH2:51][CH3:52])[C:44](OCC)=[O:45])=[CH:38][CH:37]=1)#[N:29].C(OCC)(=O)C>CCN(C1C=CC=CC=1)CC.O>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:44](=[O:45])[C:43]([CH2:42][C:39]3[CH:40]=[CH:41][C:36]([C:31]4[C:30]([C:28]#[N:29])=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:37][CH:38]=3)=[C:49]([CH2:50][CH2:51][CH3:52])[N:16]3[N:15]=[CH:14][CH:13]=[C:12]23)=[CH:9][CH:10]=1)[CH3:1]
Reactant: CC(C)Oc1ccc(Nc2ccn[nH]2)cc1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Solvent: CCN(CC)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)C)cc2)c2ccnn12
Yield: 88.8 %

Procedure:
N-[4-(1-Methylethoxy)phenyl]-1H-pyrazol-5-amine (0.37 g) and a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.051 mL) and ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.2 g) in diethylaniline (5 mL) were stirred at 180° C. for 1 hr. The mixture was allowed to cool, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.76 g, 89%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[Cl:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Zn]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[Cl:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2Cl)CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2Cl)CC1
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-chloronitrobenzene (2.40 g) in acetic acid (50 ml) was added zinc powder (5.60 g) in four portions at room temperature and the mixture was stirred for 2 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=1/1 as an eluant to give the desired compound (1.99 g, yield 87%) as an orange oil.