Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4](Cl)=[O:5].[CH3:14][OH:15]>>[CH3:14][O:15][C:4](=[O:5])[C:3]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1]
Reactant: CO
Reactant: O=C(Cl)c1c(Cl)cccc1[N+](=O)[O-]
Product: COC(=O)c1c(Cl)cccc1[N+](=O)[O-]

Procedure:
18.9 gm (86 mmols) of 2-chloro-6-nitro-benzoic acid chloride were added dropwise over a period of 10 minutes to 100 ml of methanol. The reaction mixture was refluxed for 4 hours and then evaporated in vacuo. The residue was treated with a little ice-cold methanol and filtered off.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:20]=[C:19]([F:21])[C:18]3[O:17][C:16]4[C:11](=[CH:12][C:13]([C:22]5[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=5)=[CH:14][CH:15]=4)[C@@:10]4([CH2:32][O:31][C:30]([NH2:33])=[N:29]4)[C:9]=3[CH:8]=2)[CH2:3][CH2:2]1>[Pd].CO>[F:21][C:19]1[C:18]2[O:17][C:16]3[C:11](=[CH:12][C:13]([C:22]4[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:14][CH:15]=3)[C@@:10]3([CH2:32][O:31][C:30]([NH2:33])=[N:29]3)[C:9]=2[CH:8]=[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:20]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Agent: [Pd]
Solvent: CO
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(C3CCOCC3)cc12
Reaction time: 8 h

Procedure:
(S)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (30 mg, 0.067 mmol) and palladium on carbon (7.14 mg, 0.067 mmol) were combined in 10 ml of MeOH and stirred under an atmosphere of hydrogen overnight. The solution was filtered and concentrated to afford (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(tetrahydro-2H-pyran-4-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[SH:11].[OH-].[Na+].Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1S
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1SCc1ccccn1
Yield: 73.7 %

Procedure:
2-methyl-4-nitrobenzenethiol (3.0 g) was dissolved in THF (60 ml), and to this solution was added aqueous solution of sodium hydroxide (2.1 g, 15 ml) and then, 2-(chloromethyl)pyridine hydrochloride (3.5 g), and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 2-[[(2-methyl-4-nitrophenyl)sulfanyl]methyl]pyridine (3.4 g).
Reaction SMILES: O=C1[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])O1.[C:12](#[N:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C:12]2[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:19]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccccc1
Reactant: CCOC(=O)c1nsc(=O)o1
Product: CCOC(=O)c1nsc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 3 %

Procedure:
A mixture of ethyl 2-oxo-1,3,4-oxathiazole-5-carboxylate (U.S. Publication No. 2005/0096362) (1.5 g, 8.56 mmol) and benzonitrile (4.37 ml, 42.8 mmol) in 1,2-dichrlotobenzene (15.42 ml, 137 mmol) was heated to 160° C. for 4 days. The reaction was then cooled down to RT and the solvent was evaporated by heated the reaction at 75° C. at maximum vacuum. The residue was purified on silica gel chromatography (100% CH2Cl2 to 3% EtOAc in CH2Cl2) to provide the title material (0.064 g, 3%). LC (Method B): 2.021 min. HRMS (ESI) calcd for C11H11N2O2S [M+H]+ m/z 235.0541. found 235. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.01-8.09 (m, 1H), 7.49-7.59 (m, 2H), 4.56 (q, J=7.17 Hz, 1H), 1.50 (t, J=7.24 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=2)[O:10][CH:11]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:12]2[CH2:16][CH:15]([OH:17])[CH2:14][N:13]2[C:18](=[O:48])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:5][CH:4]=1.[C:63]1(=[O:69])[O:68][C:66](=[O:67])[CH2:65][CH2:64]1>>[CH3:62][O:61][C:58]1[CH:57]=[CH:56][C:55]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:10][CH:11]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:12]2[N:13]([C:18](=[O:48])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:14][CH:15]([O:17][C:63](=[O:69])[CH2:64][CH2:65][C:66]([OH:68])=[O:67])[CH2:16]2)=[CH:60][CH:59]=1
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)NCCCCCC(=O)N1CC(OC(=O)CCC(=O)O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1

Procedure:
Using the above described procedure, the amide 102h (2.56 g, 3 mmol) was treated with succinic anhydride and after work-up the amide was isolated as a foam (2.8 g, 99%) and this was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:11][O:12][C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH3:10])[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]([O:12][CH3:11])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNCC
Reactant: COC(=O)CCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCCCN(CC)C(=O)CCCCC(=O)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3.2 gms of the N-heptyl-N-ethylamine in 96 ml of CH2Cl2 are added 5.7 ml of Et3 followed by 3.63 ml of hexanedioic acid monochloride monomethyl ester. This mixture is stirred at room temperature for 18 hours; and after concentrating under vacuum, the residue obtained is partitioned between ethyl acetate and an aqueous 2N HCl solution. The organic layer is separated and washed with aqueous saturated NaHCO3, then brine, and dried over MgSO4. Following filtration and concentration under vacuum, the residue is flash chromatographed on normal phase silica gel using a 3/1 ratio of hexane and ethyl acetate to yield N-heptyl-N-ethyladipamic acid, methyl ester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:2]1.N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[CH3:17][S:18]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCc1ccsc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCCc1ccsc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.2 %

Procedure:
To a solution of 1.05 g (6.7×10-3 mol) of 4-(3-thienyl)-butanol in 25 ml of dry, freshly distilled pyridine was added 0.85 g (1.1 equiv.) of methane-sulfonyl chloride at 25° C. The addition was gradual and carried out over a several minute period. The reaction mixture was stirred for 6 hr at room temperature and quenched by pouring into a separtory funnel containing water-HCl and ether. The layers were separated and the aqueous layer was extracted once with 10% hydrochloric acid, followed by extraction with water and drying with Na2SO4. Evaporation of the solvent afforded 1.51 g of a light brown oil (95% yield), tlc (CHCl3) showed a single spot. El. Anal. Calcd. for C9H14 O3S2 : C, 46.13; H, 6.02; S, 27.36. Found: C, 45.92; H, 5.94; S, 27.15. Nmr (CDCl3, δ rel TMS) 2.0-1.5 brs, 4H; 2.67 brt, 2H; 2.97s, 3H; 4.22t, 2H; 7.07-6.80d, 2H; 7.37-7.13, 1H.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].Cl[CH2:11][CH:12]=O>CCO>[Br:1][C:2]1[C:3]2[N:4]([CH:11]=[CH:12][N:9]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1nnc(Cl)cc1Br
Reactant: O=CCCl
Solvent: CCO
Product: Clc1cc(Br)c2nccn2n1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-bromo-6-chloropyridazin-3-amine (D-2) (16 g, 77.3 mmol, 1.0 eq) in EtOH (200 mL), 2-chloroacetaldehyde (45% in water, 67.4 g, 386.6 mmol, 5.0 eq) is added and the resulting mixture is stirred at reflux overnight. The mixture is allowed to cool to RT and concentrated in vacuo to remove EtOH. The residue is slurried in acetone. The solid is collected by filtration and washed with acetone. The solid is suspended in water, neutralized with aqueous ammonia to adjust the pH to 8 at 0-5° C. and then extracted with ethyl acetate (2×150 mL). The combined layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the product, 8-bromo-6-chloroimidazo[1,2-b]pyridazine (D-3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1.[H-].[Na+].Cl[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][C:26]=1[O:34][CH3:35]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][C:26]=3[O:34][CH3:35])=[CH:8][S:7][C:6]=2[CH:17]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Clc1ccc2c(Nc3ccncc3)csc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN(c1ccncc1)c1csc2cc(Cl)ccc12
Temperature: 45 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
6-Chloro-3-(4-pyridinylamino)benzo[b]thiophene (4 g, 15 mmol) was added portionwise as a powder to a suspension of sodium hydride (60% oil dispersion, 0.7 g, 18 mmol, washed with heptane) in 50 mL of dimethylformamide. After the anion formation was completed, 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4 g, 16 mmol) was added. The reaction mixture was stirred two hours at 45° C., and then was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution, and then was dried (anhydrous magnesium sulfate), filtered and concentrated to 8 g of a dark oil. Elution through silica with 10% methanol in ethyl acetate via flash column chromatography afforded 4.1 g of a brown oil. Elution of this oil three times through silica with ethyl acetate via flash column chromatography afforded 3.0 g of a waxy solid. Recrystallization from acetonitrile afforded 2.1 g of white crystals, mp 148-149° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](O)(=[O:17])[CH:10]([CH:12]([C:14](O)=[O:15])[OH:13])[OH:11]>C1(C)C(C)=CC=CC=1>[CH2:1]([N:8]1[C:14](=[O:15])[C@@H:12]([OH:13])[C@H:10]([OH:11])[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C1[C@@H](O)[C@H](O)C(=O)N1Cc1ccccc1
Yield: 77.5 %

Procedure:
Benzylamine (75 g, 0.70 mol) and (−)-tartaric acid (100 g, 700 mol) were heated in boiling xylene (1.0 L) in a Dean-Stark apparatus. After cooling, the product was collected, washed with acetone, and recrystallized from EtOH to afford the product (120 g, 77%). 1H NMR (300 MHz, CDCl3) δ 7.39-7.20 (5H, m), 6.27 (2H, d), 4.58 (1H, d), 4.52 (1H, d), 4.38 (2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=[CH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=CC1CCN(C(=O)OCc2ccccc2)CC1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(CCC1CCN(C(=O)OCc2ccccc2)CC1)c1ccccc1
Reaction time: 3.5 h
Yield: 100.1 %

Procedure:
1-(Benzyloxycarbonyl)-4-(3-oxo-3-phenylprop-1-enyl)piperidine (0.95 g, 2.7 mmol, from EXAMPLE 154, Step A) was hydrogenated using 5% Pd/C (10 mg) in 95% ethanol (20 mL) at atmospheric pressure. After 3.5 h, the mixture was filtered and the catalyst was washed with 95% ethanol. Evaporation of the filtrate gave 0.95 g of 1-(benzyloxycarbonyl)-4-(3-oxo-3-phenylpropyl)piperidine as a colorless syrup.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[C:8]([NH:10][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(N)nn1Cc1ccc(OC)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(NCc2ccc(F)cc2)nn1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
In a round bottom flask, 5-amino-2-(4-methoxy-benzyl)-2H-pyrazole-3-carboxylic acid methyl ester (109, 1.4 g, 5.4 mmol) was combined with 4-fluoro-benzaldehyde (110, 0.565 mL, 5.36 mmol), trifluoroacetic acid (2.06 mL, 26.8 mmol), triethylsilane (4.28 mL, 26.8 mmol) and 50 mL of acetonitrile. The reaction was stirred at room temperature for 15 minutes, then concentrated under vacuum, combined with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The residue was recrystallized from a mixture of ethyl acetate and hexane to provide the desired compound (111, 1.6 g). 1H NMR was consistent with the compound structure.
Reaction SMILES: [BH4-].[Na+].[O:3]([C:10]1[CH:22]=[CH:21][C:13]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.CO>[O:3]([C:10]1[CH:22]=[CH:21][C:13]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[OH:20])=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCCC1Oc1ccc(Oc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1CCCC1Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 3.78 g of sodium borohydride in 10 ml of water is added at room temperature to a solution of 8.04 g of 2-(4-phenoxyphenoxy)-cyclopentan-1-one in 60 ml of methanol. The reaction mixture is stirred for 15 hours at room temperature and then concentrated under reduced pressure. The residue is poured into ice-water and extracted with ether. The organic phase is washed twice with saturated sodium chloride solution, dried over sodium sulphate and concentrated by rotary evaporation. Fractional distillation of the residue yields 2-(4-phenoxyphenoxy)-cyclopentan-1-ol as a colourless oil with a boiling point of 181°-185° C./0.001 torr.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[C:12]([O:49][CH3:50])=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:15]=[C:14]2[C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[CH3:50][O:49][C:12]1[C:11]([NH2:10])=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14]([C:39]1[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=1)=[N:15][N:16]2[C:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1c(NC(=O)OCc2ccccc2)ccc2c1c(-c1ccc3ccccc3c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1c(N)ccc2c1c(-c1ccc3ccccc3c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 67.7 %

Procedure:
466 mg of (4-methoxy-3-naphthalen-2-yl-1-trityl-1H-indazol-5-yl)-carbamic acid benzyl ester obtained in Production Example II-38-a was dissolved in 20 ml of a 1:1 solvent mixture of ethyl acetate and methanol. 300 mg of 10% palladium-carbon was added and the mixture was subjected to catalytic hydrogenation at room temperature and normal atmospheric pressure. The reaction mixture was filtered through Celite, and the solvent was removed, to give 252 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([C:24](=[O:25])[C:23]3[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:28][CH:27]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc2c(c1)Cc1ccccc1CN2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Cc2cc(Cl)ccc21
Yield: 68.9 %

Procedure:
A mixture of 2.05 g of 2-chloro-6,11-dihydro-5H-dibenz[b,e]azepine, 2.15 g of 4-nitrobenzoyl chloride, 1.50 g of N,N-diisopropylethylamine, 54 mg of 4-(dimethylamino)pyridine in 15 ml of dichloromethane is refluxed for 18 hours. The mixture is cooled and washed with H2O, 1N HCl, 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated and the residue recrystallized from dichloromethane-hexane to give 2.33 g of crystals, m.p. 198°-201° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:15].[C:16]([O:20][C:21](=[O:34])[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH:30](Cl)[CH:31]=O)[CH:24]=1)([CH3:19])([CH3:18])[CH3:17]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:30]([CH2:29][C:25]4[CH:24]=[C:23]([NH:22][C:21](=[O:34])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])[CH:28]=[CH:27][CH:26]=4)=[CH:31][N:14]=3)[N:13]=2)=[CH:4][C:3]=1[F:15]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CC(Cl)C=O)c1
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(Cc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)c1
Temperature: 105 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (19 mg, 0.070 mmol) and tert-butyl[3-(2-chloro-3-oxopropyl)phenyl]carbamate (20 mg, 0.070 mmol) in ethanol (0.4 mL) was stirred overnight at 105° C. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=498.0/500.0.
Reaction SMILES: [ClH:1].C[C:3]1C=C2[C:6]([NH:7]C=C2CCN)=[C:5](Br)[CH:4]=1.Cl.[CH3:17][C:18]1[CH:19]=[C:20]([NH:25]N)[CH:21]=[C:22]([CH3:24])[CH:23]=1>>[ClH:1].[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]2[C:19]=1[C:4]([CH2:5][CH2:6][NH2:7])=[CH:3][NH:25]2
Reactant: Cc1cc(C)cc(NN)c1
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Agent: Cl
Product: Cc1cc(C)c2c(CCN)c[nH]c2c1

Procedure:
4,6-Dimethyltryptamine hydrochloride was prepared (1.06 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 3,5-dimethylphenylhydrazine hydrochloride (7.65 g) as starting material.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6]([CH3:9])[NH:7][O:8][C:4]=2[CH:3]=1.C([Li])CCC.[C:17](=[O:19])=[O:18].O>C1COCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6]([CH3:9])[NH:7][O:8][C:4]=2[C:3]=1[C:17]([OH:19])=[O:18]
Reactant: CC1NOc2cc(F)ccc21
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1NOc2c1ccc(F)c2C(=O)O
Reaction time: 1 h

Procedure:
A stirred solution of 6-fluoro-3-methyl-1,2(2H)-benzisoxazole (5.5 g, 0.037 mole) in THF (100 mL) was cooled in a dry ice-acetone bath, and 2.5 M n-butyllithium in hexanes (16 mL, 0.040 mole) was added dropwise. Upon completion of addition, the reaction mixture was stirred for one hour. The reaction mixture was then exposed to a CO2 atmosphere where it stirred for three hours. After this time, the reaction mixture was poured into water. The mixture was washed with ether, acidified with hydrochloric acid, and then extracted repeatedly with ether. The combine extracts were washed with water, dried with magnesium sulfate and concentrated yielding 4.5 grams of [6-fluoro-3-methyl-1,2(2H)-benzisoxazol-7-yl]carboxylic acid. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:2]=[CH2:3].B(F)(F)F.[CH3:20]COCC>CO>[CH2:1]([NH:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH2:7][CH2:8][C:9]([O:11][CH3:20])=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCNc1ccccc1CCC(=O)O
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: C=CCNc1ccccc1CCC(=O)OC
Temperature: 0 °C

Procedure:
A solution of 50.5 g. of 2-(allylamino)hydrocinnamic acid and 34.4 ml. of boron trifluoride etherate in 200 ml. of methanol is stirred under reflux for 44 hours, allowed to cool, and poured into 1.20 liters of ice-cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzene-ethanol to yield methyl 2-(allylamino)hydrocinnamate.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][NH:17][C:18]([CH3:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH:21]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:22]([C:31](N[C@@H](C(NCC(O)=O)=O)CCSC)=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1>CN(C=O)C>[NH:21]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@@H:22]([C:31]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][NH:17][C:18]([CH3:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4])=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CN
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Using H-Gly-Phe-NHNH-COCH3 (0.44 g) and BOC-(D)-Phe-ONB (0.68 g), the desired compound (0.68 g) is obtained in a similar manner to (III) of Example 45, m.p. 208°-209° C., [α]D23 +3.3°(c=0.45, DMF), Rf1 =0.51.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[C:16]([CH3:19])=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCCC1>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])=[CH:14][C:15]=1[CH:20]1[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccc(N)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 77.2 %

Procedure:
Benzyl chloroformate (95%, 4.52 mL, 30.1 mmol) was added dropwise to a stirred mixture of tert-butyl 4-(3-amino-6-methylphenyl)piperidinecarboxylate (6.99 g, 24.1 mmol) and K2CO3 (3.66 g, 26.4 mmol) in tetrahydrofuran (350 mL) and stirred under nitrogen for 18 h. CH2Cl2 was added to the reaction mixture, washed with NaHCO3 solution (saturated), followed by water, then dried over Na2SO4 and concentrated in vacuo to give an oil. Purification by flash column chromatography (eluent: cyclohexane:EtOAc (87:13)) gave tert-butyl 4-{2-methyl-5-[(phenylmethoxy)carbonylamino]phenyl}piperidinecarboxylate (7.90 g, 77.1% yield) as a white foam. ESMS m/e: 425.0 (M+H)+.