Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2O.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=[CH:10][CH:9]=1
Reactant: COc1cccc2c(O)ccnc12
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cccc2c(Cl)ccnc12
Yield: 72.3 %

Procedure:
Compound 16 (2.65 g, 15.1 mmol) was dissolved in POCl3 (4.2 ml, 45.3 mmol) under nitrogen atmosphere and refluxed for 2 h. It was then cooled and concentrated under vacuum. The solid concentrate was taken in a beaker with 200 ml water neutralized with NaHCO3 powder and extracted with EtOAc. The solution was dried over Na2SO4, filtered, and concentrated. This crude product was then purified through column chromatography using ethyl acetate to get 17 as brown solid (2.113 g, 72%). 1H NMR (400 MHz, CDCl3) δ ppm 4.079 (s, 3H), 7.08-7.1 (d, 1H, J=8 Hz), 7.49-7.56 (m, 2H), 7.76-7.78 (d, 1H, J=8 Hz), 8.76-8.77 (d, 1H, J=4 Hz).
Reaction SMILES: C(Cl)(=O)C1C=CC(C(Cl)=O)=CC=1.[CH3:13][O:14][C:15](=[O:26])[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1.O[Li].O>ClCCl.CO>[CH3:13][O:14][C:15](=[O:26])[C:16]1[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: O=C(Cl)c1ccc(C(=O)Cl)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 20.3 g (100 mmol) terephthaloyl chloride in 100 ml dichloromethane was added to 100 ml anhydrous methanol at 0° C. The reaction was left 1.5 h at rt. The reaction mixture was evaporated and the residue was dissolved dichloromethane. The organic phase was washed with saturated NaHCO3 aq. The organic phase was dried and evaporated. Yield 18.3 g (94.2 mmol, 94%). A solution of 18.3 g (94.2 mmol) of terephthalic acid dimethyl ester and 3.96 g (94.2 mmol) LiOH.H2O in anhydrous methanol (did not dissolve completely) was stirred for 5 d at rt. The solvent was evaporated and the product was dissolved in water. The aqueous phase was washed with dichloromethane. The aqueous phase was made acidic with 2 M HCl aq. The product precipitated from the aqueous phase. The product was filtered off and dried in vacuo. The product was dissolved in 1 L dry ethanol, and thereafter 4 l water was added slowly while stirring. The product precipitated slowly overnight at +4°C. The product was filtered and dried in vacuo. Yield 8.61 g (48 mmol, 51%)
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Mn]([O-])(=O)(=O)=[O:24].[K+]>O.C(Cl)Cl>[CH2:6]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:13]([OH:24])=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCCCCCCC(CO)CCCCCC
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCC(CCCCCC)C(=O)O
Temperature: 25 °C

Procedure:
Concentrated sulphuric acid (100 g) was diluted with water (750 ml) and this solution was cooled to room temperature and added to a solution of 2-hexyldecanol (242 g) in methylene chloride (600 ml). The solutions were stirred together beneath a reflux condenser and solid potassium permanganate was added in portions during 5 hours so as to maintain gentle boiling of the methylene chloride. The mixture was filtered to remove precipitate manganese dioxide, and the organic layer was separated and washed with water. The solvent was distilled leaving 2-hexyldecanoic acid (222 g) as a nearly colourless oil.
Reaction SMILES: [Cl:1][C@H:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.[C:15]1([C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N+]=[N-])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:1][C@H:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([O:12][CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12
Reactant: CC1=C(C(=O)O)N2C(=O)[C@H](Cl)[C@H]2SC1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Cl)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
The 7α-chloro-3-methyl-3-cephem-4-carboxylic acid (10.0 g, 0.0428 mol) was dissolved in methylene chloride (200 ml), and diphenyldiazomethane (10.8 g, 0.0557 mol) dissolved in methylene chloride (50 ml) was added dropwise over 30 minutes. The mixture was stirred at room temperature for two hours. Solvent was removed under reduced pressure and the product was purified over silica column using hexane-ethyl acetate mixture to yield benzhydryl 7α-chloro-3-methyl-3-cephem-4-carboxylate (7.8 g, 45.6%). NMR (CDCl3) δ 2.1 (s, 3H, CH3), 3.25 (bs, 2H, H-2), 4.70 (bs, 1H), 4.75 (bs, 1H), 7.0 (s, 1H, CHPh2), 7.3-7.7 (m, 10H, aromatic).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:23])[CH2:6][NH:7][C:8](=[O:22])[CH2:9][NH:10][C:11](=[O:21])[C@H:12]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[NH2:13])[CH3:3].C(N(CC)C(C)C)(C)C.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39].CO>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:23])[CH2:6][NH:7][C:8](=[O:22])[CH2:9][NH:10][C:11](=[O:21])[C@H:12]([CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[NH:13][C:38]([C:34]1[O:33][CH:37]=[CH:36][CH:35]=1)=[O:39])[CH3:3]
Reactant: CCOC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1CCCCC1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)CNC(=O)[C@H](CC1CCCCC1)NC(=O)c1ccco1
Yield: 98.2 %

Procedure:
To a solution of 90.1 mg (0.258 mmol) of β-cyclohexyl-L-alanyl-glycyl-glycine ethyl ester hydrochloride in methylenechloride (1 mL), 100.0 mg (0.774 mmol) of N,N-diisopropylethylamine and 37.2 mg (0.285 mmol) of 2-furoyl chloride were added with stirring under ice cooling and the reaction mixture was stirred for 0.5 hour. Methanol (0.2 mL) was added and the reaction mixture was stirred at room temperature, and then concentrated under reduced pressure. Chloroform (25 mL) was added to the residue, and then the mixture was washed with 0.5M hydrochloric acid (3×5 mL) and 5% aqueous sodium hydrogencarbonate solution (3×5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby 127 mg of the crude product was obtained. The crude product was purified by silica gel column chromatography [silica gel 7.5 g, chloroform, methanol-chloroform (1:100)], to give 103.2 mg of 2-furoyl-β-cyclohexyl-L-alanyl-glycyl-glycine ethyl ester as a colorless oil (yield 98%)
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16](O)=O)=[CH:12][N:13]=2)CCCC1.[CH:28]1([NH:35][CH:36]2[CH2:41][CH2:40][CH:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:38][CH2:37]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C([O:50][C:51](=[O:61])CCSC1SC(N)=NC=1)C>>[CH:28]1([N:35]([CH:36]2[CH2:41][CH2:40][CH:39]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:38][CH2:37]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][CH2:16][C:51]([OH:61])=[O:50])=[CH:12][N:13]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CCOC(=O)CCSc1cnc(N)s1
Reactant: c1ccc(C2CCC(NC3CCCCCC3)CC2)cc1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Product: O=C(O)CCSc1cnc(NC(=O)N(C2CCCCCC2)C2CCC(c3ccccc3)CC2)s1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cycloheptyl-(4-phenyl-cyclohexyl)-amine and 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[F:14][C:15]1[C:21](F)=[CH:20][C:18]([NH2:19])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1.O>CN(C=O)C>[F:14][C:15]1[C:21]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:20][C:18]([NH2:19])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1
Reactant: OCCCCN1CCCCC1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(OCCCCN2CCCCC2)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 24 h

Procedure:
382 mg of sodium hydride (60% in suspension in oil) are added in small portions, over two hours, to a solution of 4-piperidin-1-ylbutan-1-ol in 10 mL of DMF, cooled to 0° C. with an ice bath. A solution of 4,5-difluoro-2-nitroaniline in 5 mL of N,N-dimethylformamide is then added dropwise. The medium is stirred at ambient temperature for 24 hours. 60 mL of distilled water are added and the reaction medium is extracted with 3×30 mL of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum in a rotary evaporator. The reaction crude is purified by flash chromatography on an Intelliflash apparatus with an Analogix RS-12 silica cartridge, with a 100% to 85/15 dichloromethane/-methanol elution gradient. 700 mg of 4-fluoro-2-nitro-5-(4-piperidin-1-ylbutoxy)phenylamine are isolated in the form of a red oil. 1H NMR (300 MHz, DMSO-d6, δ in ppm): from 1.29 to 1.62 (m, 8H); 1.75 (m, 2H); 2.28 (m, 6H); 4.07 (t, J=6.5 Hz, 2H); 6.62 (d, J=7.5 Hz, 1H); 7.48 (broad s, 2H); 7.74 (d, J=12.0 Hz, 1H).
Reaction SMILES: C[Mg]I.COC(=O)/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1.[Cl-].[NH4+].C([O:27]CC)C>O1CCCC1>[CH3:7][CH:8]([OH:27])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1
Reactant: CCOCC
Reactant: COC(=O)/C=C/c1ccc(Cc2cccnc2)cc1
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Cc2cccnc2)cc1

Procedure:
Under an atomsphere of nitrogen, 1.5 ml of a 3M solution of methylmagnesium iodide in diethyl ether were added to a solution of 830 mg of the aldehyde(prepared as described in Reference Example 1) in 20 ml of tetrahydrofuran at -70° C., the mixture was allowed to warm from -70° C. to room temperature over a period of one hour with stirring, poured into a saturated aqueous solution of ammonium chloride, and extracted with diethyl ether. The extract was washed with water, and a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:1) as eluent to give 547 mg of the title compound having the following physical characteristics:
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][CH2:22][CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])C)[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38]1(S(CC2C(C(O)=O)=C(O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.C(OC(NC(C)CO)=O)(C)(C)C>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][CH2:22][CH:23]([NH:24][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH3:38])[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCN(C)C(=O)OC(C)(C)C
Agent: CC(CO)NC(=O)OC(C)(C)C
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCC(C)NC(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 125, starting from methyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 114) and 2-(N-t-butoxycarbonylamino)-1-propanol as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.ClC1C(C(F)(F)F)=CC=CN=1.[Cl-:22].[Al+3].[Cl-:24].[Cl-:25]>>[Cl:1][C:2]1[C:3]([C:4]([Cl:25])([Cl:24])[Cl:22])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: [Cl-]
Agent: FC(F)(F)c1cccnc1Cl
Agent: [Al+3]
Product: Clc1ncccc1C(Cl)(Cl)Cl

Procedure:
The process according to claim 4 wherein 2-chloronicotinic acid is produced by reacting 2-chloro-3-trifluoromethyl pyridine with aluminum chloride to obtain 2-chloro-3-trichloromethyl pyridine and then hydrolyzing the 2-chloro-3-trichloromethyl pyridine in the presence of sulfuric acid or phosphoric acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([CH3:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[ClH:22].Cl.NCC1C=CC2C(=CC=CC=2)N=1>COCCOC>[Cl:22][C:6]1[C:5]([CH3:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Cl
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1-c1ccco1
Agent: NCc1ccc2ccccc2n1
Solvent: COCCOC
Product: Cc1c(Cl)nc(N)nc1-c1ccco1
Temperature: 80 °C
Yield: 49.6 %

Procedure:
To a stirred solution of 250 mg (0.77 mmol) trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-methyl-pyrimidin-4-yl ester in 10 ml DME was added 489 mg (2.12 mmol) 2-(aminomethyl)quinoline dihydrochloride and the mixture heated at 80° C. for 16 hours. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate/hexane 4/1) followed by trituration in ether/hexane afforded 80 mg (50%) 4-chloro-6-furan-2-yl-5-methyl-pyrimidin-2-ylamine as a white crystalline solid. ES-MS m/e (%): 212 (M{37Cl}+H+, 50), 210 (M{35Cl}+H+, 100).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C1N=CN([C:25]([N:27]2[CH:31]=N[CH:29]=[CH:28]2)=[O:26])C=1.CCN(C(C)C)C(C)C.[F:41][C:42]1[CH:43]=[C:44]([C@@H:48]([C@@H:57]2CCCN[CH2:58]2)[O:49][CH2:50][CH2:51][NH:52][C:53](=[O:56])[O:54][CH3:55])[CH:45]=[CH:46][CH:47]=1>C(Cl)Cl>[CH:14]1([CH2:13][C@H:2]([NH:1][C:25]([N:27]2[CH2:28][CH2:29][CH2:58][C@@H:57]([C@H:48]([C:44]3[CH:45]=[CH:46][CH:47]=[C:42]([F:41])[CH:43]=3)[O:49][CH2:50][CH2:51][NH:52][C:53](=[O:56])[O:54][CH3:55])[CH2:31]2)=[O:26])[CH2:3][N:4]([CH3:12])[C:5]([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:11])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CN(C[C@@H](N)CC1CCCCC1)C(=O)OC(C)(C)C
Reactant: COC(=O)NCCO[C@@H](c1cccc(F)c1)[C@@H]1CCCNC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NCCO[C@@H](c1cccc(F)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To a solution of tert-butyl (S)-2-amino-3-cyclohexylpropylmethylcarbamate (65 mg, 0.24 mmol) and CDI (40 mg, 0.24 mmol) in anhydrous CH2Cl2 (5 mL) cooled in an ice bath was added DIEA (104 mg, 0.81 mmol). After addition, the mixture was stirred for 1 h at 0° C., a solution of methyl 2-((R)-(3-fluorophenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate (50 mg, 0.16 mmol) in anhydrous CH2Cl2 (5 mL) was added dropwise. The reaction mixture was allowed to warm to rt and stirred overnight. After the reaction was complete, the solvent was removed in vacuo. The product was purified by preparative tlc to afford the desired isomer of methyl 2-((R)—((R)-1-((S)-1-cyclohexyl-3-(N-methyl-N-(t-butoxycarbonyl)amino)propan-2-ylcarbamoyl)piperidin-3-yl)(3-fluorophenyl)methoxy)ethylcarbamate (50 mg, 52% yield). MS (E/Z): 607 (M+H+).
Reaction SMILES: [N+](C1C=CC(C[CH:9]([O:16][CH:17](CC2C=CC([N+]([O-])=O)=C(OC)C=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=CC=1OC)([O-])=O.[C:40]([O-:43])(=O)C.[NH4+:44]>CO.[Zn]>[CH2:17]([O:16][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:44])=[C:14]([O:43][CH3:40])[CH:15]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: [NH4+]
Reactant: COc1cc(CC(OC(Cc2ccc([N+](=O)[O-])c(OC)c2)c2ccccc2)c2ccccc2)ccc1[N+](=O)[O-]
Reactant: CC(=O)[O-]
Agent: [Zn]
Solvent: CO
Product: COc1cc(COCc2ccccc2)ccc1N
Reaction time: 1 h

Procedure:
A solution of 4-nitro-3-methoxybenzylbenzyl ether (2.2 g, 8.1 mmol) and ammonium acetate (2.46 g, 32 mmol, 4 eq.) in 30 mL MeOH was stirred at 0° C. and 1.3 g (20 mmol, 2.5 eq.) of zinc dust was added in several portions. After 1 h, the reaction mixture was partitioned between 40 mL water and 40 mL ethyl acetate. The organic phase was dried over MgSO4 and concentrated. The residue was used directly in next step without further purification. 1H NMR (400 MHz, CDCl3): δ7.35 (m, 5H), 6.82 (s, 1H), 6.77 (d, J=6.3 Hz, 1H). 6.67 (d, J=7.8 Hz, 1H), 4.51 (s, 2H), 4.45 (s, 2H), 3.85 (s, 3H), 3.79 (s, 2H). MS ESI-pos, M+1=244.2.
Reaction SMILES: [CH2:1]=O.[CH3:3][NH:4][CH3:5].[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2.[OH-].[K+]>O1CCOCC1.C(O)(=O)C>[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:8]=1[C:18]1[NH:19][C:20]2[C:25]([C:26]=1[CH2:3][N:4]([CH3:1])[CH3:5])=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: C=O
Reactant: Cc1onc(-c2ccccc2)c1-c1cc2ccccc2[nH]1
Reactant: CNC
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1-c1[nH]c2ccccc2c1CN(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 20.6 ml. (0.24 mole) 37% aqueous formaldehyde, 18 ml. (0.12 mole) 40% aqueous dimethylamine and 80 ml. acetic acid is cooled to 0° and treated by dropwise addition with 25.5 g. (0.113 mole) 2-(5-methyl-3-phenyl-4-isoxazolyl)-indole in a solution of 45 ml. acetic acid and 125 ml. dioxane. After addition is complete the mixture is stirred for 1 hour at room temperature and poured onto 500 ml. ice-water. The resulting solution is made basic with 20% potassium hydroxide and then extracted with methylene chloride. The methylene chloride is washed with water, brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 2-(5-methyl-3-phenyl-4-isoxazolyl)-3-(dimethylaminomethyl)-indole.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:31](OC(N1C[C@@H]2CC[C@H]1CN2)=O)(C)(C)[CH3:32].N1(CC2C=CC([C@@H]3OC4=NC=CC=C4OC3)=CC=2)CCNCC1>>[C@H:10]12[CH2:32][CH2:31][C@H:13]([NH:8][CH2:9]1)[CH2:12][N:11]2[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[O:30][C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[O:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H]1CN2
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Agent: c1cnc2c(c1)OC[C@H](c1ccc(CN3CCNCC3)cc1)O2
Product: c1cnc2c(c1)OC[C@H](c1ccc(CN3C[C@@H]4CC[C@H]3CN4)cc1)O2

Procedure:
The title product JJ is prepared from compound JJ-1 (prepared from Intermediate C and (1S,4S)-2,5-diaza-bicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester according to General Method J) according to the procedure used to synthesize Intermediate S.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:24](O)=[O:25].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1)=[O:25]
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: CCOC(=O)c1ccc(Oc2ccc(N)cn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2ccc(NC(=O)c3ccc(C)c(C)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of ethyl 4-(5-aminopyridin-2-yloxy)benzoate (14.15 g, 54.8 mmol) in DMF (100 mL) were added 3,4-dimethylbenzoic acid (8.23 g, 54.8 mmol), 1-hydroxybenzotriazole monohydrate (8.4 g, 54.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.6 g, 65.7 mmol) under ice cooling, and then stirred for 30 minutes under ice cooling and for 17 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added water (200 mL), and extracted with ethyl acetate (250 mL). The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby yield 16.15 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:25]([O:29][C:30]([N:32]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:41][CH:40]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)cc2)CC1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (1.0 g, 3.90 mmol), methylene chloride (50 mL), and a catalytic amount of DMF was stirred under argon, and oxalyl chloride (2M in methylene chloride, 2 mL, 4.0 mmol) was dripped into the mixture over 5 min. The mixture was stirred at room temperature for 1.0 hr and the reaction was concentrated to dryness. Benzene was added and the solution was evaporated to dryness again. The white-yellow solid was re-dissolved in methylene chloride (30 mL) and dripped, under argon, into a solution of 4-(4-amino-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.2 g, 4.0 mmol), and triethylamine (0.6 g, 5.8 mmol) in methylene chloride (50 mL). The reaction was stirred at room temperature for 0.5 hr then concentrated and the residue was taken up in EtOAc (100 mL) and washed with saturated ammonium chloride (100 mL), brine (100 mL) and dried with anhydrous sodium sulfate. The solvent was removed and the residue was purified on a flash column chromatography with EtOAc/hexanes to afford 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.65 g, 83% yield) as a white solid. ES-MS for C27H29F3N4O4 calcd. (m/e) 530, observed 531 (M+H).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])C(=O)C2=CC=CC=C12.O.NN>C(O)C.C(Cl)(Cl)Cl>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1cccc(OCCCCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: COC(=O)c1cccc(OCCCCN)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 115.3 %

Procedure:
Methyl 3-(4-phthalimidobutoxy)benzoate (6.60 g, 18.68 mmol) was dissolved in 50 mL of ethanol and reacted with hydrazine monohydrate (1.87 g, 37.36 mmol). Following stirring at 80° C. for 1 hour, the resulting mixture was diluted with chloroform, then washed with a saturated sodium bicarbonate solution, water, and brine, and dried with sodium sulfate. The resulting reaction solution was concentrated under reduced pressure to give a white crystal (4.81 g). The white crystal was directly used in subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1>[Pd].CCOC(C)=O>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc([N+](=O)[O-])c(N)cc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N)c(N)cc1Cl
Product: Cl
Reaction time: 1 h

Procedure:
To a solution of EtOAc (25 mL) and 5-chloro-4-methoxy-2-nitro-phenylamine (1.6 g, 7.9 mmol) under argon is added 5% Pd/C (0.5 g). The reaction mixture is hydrogenated at 50 psi for 1 hour. The mixture is filtered under N2 through Celite into a solution of 1 N HCl/Et2O in EtOAc, and the pad is washed with additional EtOAc. The resulting precipitate is filtered off to provide a white solid.