Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:10]([C:16]([O:18][CH3:19])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7].[F:29][C:30]1[CH:43]=[CH:42][C:33]([C:34]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[O:35])=[CH:32][CH:31]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(OCC)(=O)C>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([CH:36]2[CH2:41][CH2:40][N:39]([CH2:2][CH2:3][CH2:4][O:5][C:6]([C:8]3[CH:9]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=4)[C:10]([C:16]([O:18][CH3:19])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=3[CH3:14])=[O:7])[CH2:38][CH2:37]2)=[O:35])=[CH:42][CH:43]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCl)C1c1cccc([N+](=O)[O-])c1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCN2CCC(C(=O)c3ccc(F)cc3)CC2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
A mixture of 16.4 g of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl ester 3-chloropropyl ester and 16.6 g of 4-(p-fluorobenzoyl)-piperidine is kept for 1 hour under argon in a bath heated to 145°. After cooling, 100 ml of ethyl acetate and 50 ml of 2N hydrochloric acid are added and the mixture is stirred until the reaction mass has completely dissolved. The partly oily aqueous-acidic phase is adjusted to pH 10 with 50% potassium carbonate solution; methylene chloride is added and the whole is filtered with suction. The methylene chloride phase of the filtrate is separated off and concentrated by evaporation and the residue is dissolved in ethyl acetate; the solution is dried over sodium sulphate and filtered. Filtration is then carried out over 1 kg of silica gel Merck 9385 using a hexane/ethyl acetate/methanol mixture (4:2:0.5) as eluant. The 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl ester 3-[4-(p-fluorobenzoyl)-piperidino]-propyl ester obtained after working up is converted by means of ethereal hydrogen chloride solution into the hydrochloride which, after recrystallisation from isopropanol, melts at 198°-205° with the evolution of gas.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:12]=1[CH2:13]O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1.C1C=CC(P([N:45]=[N+:46]=[N-:47])(C2C=CC=CC=2)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:12]=1[CH2:13][N:45]=[N+:46]=[N-:47])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 2-(1-(tert-butyloxycarbonylamino)ethyl)-5-chlorobenzyl alcohol from the previous step (0.475 g, 1.67 mmol) in toluene (20.0 mL) at ambient temperature under nitrogen atmosphere was added DBU (0.26 mL g, 1.74 mmol) and DPPA (0.43 mL, 2.0 mmol). The mixture was stirred at ambient temperature for 72 h. The reaction was concentrated in vacuo then partitioned between EtOAc and water. The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue purified by flash silica gel chromatography using dichloromethane as an eluent. 2-(1-(tert-butyloxycarbonylamino)ethyl)-5-chlorobenzylazide was obtained as a yellow oil after concentration of desired fractions in vacuo (0.53 g; HPLC RT=3.71 min, method A).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][C:10]([C:12]1[CH:22]=[CH:21][C:15]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][CH:13]=1)=[O:11])C1C=CC=CC=1.O.Cl.[H][H]>[Pd].CO>[NH2:8][CH2:9][CH:10]([C:12]1[CH:22]=[CH:21][C:15]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][CH:13]=1)[OH:11]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(C(O)CN)cc1

Procedure:
4'-(2-Dibenzylaminoacetyl)methanesulfonanilide (XXVI) (32.7 g) and Pd/C catalyst (1.5 g) were combined in MeOH (200 ml), H2O (25 ml), and concentrated HCl (6.6 ml) and shaken for 24 hours at 35° C. and 3 atmospheres pressure of hydrogen gas in a Parr hydrogenator, by which time three equivalents of hydrogen had been consumed. The catalyst was filtered off and the filtrate was evaporated to a white solid, which was recrystallized twice from 2-PrOH/H2O. This yielded 4.3 g of Compound (XXV).HCl, m.p. 178°-180°, whose elemental analysis for C, H, and N, NMR, and mass spectra were consistent with the indicated structure.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([O:13]CC2C=CC=CC=2)=[CH:8][C:7]=1[CH3:21])[CH2:2][CH2:3][CH3:4].[H][H]>CO.[Pd]>[CH2:1]([O:5][C:6]1[C:7]([CH3:21])=[CH:8][C:9]([OH:13])=[C:10]([CH3:12])[CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCOc1cc(C)c(OCc2ccccc2)cc1C
Agent: [Pd]
Solvent: CO
Product: CCCCOc1cc(C)c(O)cc1C

Procedure:
A solution of 11.2 g (39.5 mmol) of 1 butoxy-2,5-dimethyl-4-(phenylmethoxy)benzene (Example L) in 100 mL of methanol containing 1 g of 20% palladium on carbon is shaken under three atmospheres of hydrogen for 1 hour. The catalyst is removed and the solvent evaporated in vacuo to afford 7.6 g of the title compound; mp 43°-45° C.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[C:25]([CH:37]([CH3:39])[CH3:38])[N:24]=1>>[CH:37]([C:25]1[N:24]=[C:23]([N:18]2[CH2:19][CH2:20][CH:15]([N:5]3[C:6](=[O:14])[C:7]4[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=4)[N:3]([CH3:2])[C:4]3=[O:21])[CH2:16][CH2:17]2)[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=1)([CH3:39])[CH3:38]
Reactant: COc1cc2nc(C(C)C)nc(Cl)c2cc1OC
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Product: COc1cc2nc(C(C)C)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 10 %

Procedure:
The procedure similar to that described in Example 40 was repeated, except that 354.0 mg (1.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 4-chloro-2-isopropyl-6,7-dimethoxyquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. As a result, 50.3 mg (yield: 10%) of Compound 83 was obtained as white crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH2:9])[CH:2]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([S:23]([CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])(=[O:25])=[O:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH:9][C:37]([C:36]2[CH:35]=[CH:34][C:33]([C:29]3[O:30][C:31]([CH3:32])=[C:27]([CH2:26][S:23]([CH:20]4[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:16])[CH2:18][CH2:19]4)(=[O:24])=[O:25])[N:28]=3)=[CH:41][CH:40]=2)=[O:38])[CH:2]=1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NCCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccc(C(=O)NCCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 97.8 %

Procedure:
To a solution of 2-(pyridin-3-yl)ethanamine (940 mg, 7.70 mmol, 5.00 equiv), 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoic acid (700 mg, 1.51 mmol, 1.00 equiv), HOBt (250 mg, 1.85 mmol, 1.20 equiv), EDCI (350 mg, 1.83 mmol, 1.20 equiv) in N,N-dimethylformamide (20 mL) at 30° C. was added triethylamine (460 mg, 4.55 mmol, 3.00 equiv) dropwise with stirring. The reaction mixture was stirred at 30° C. overnight and then quenched by the addition of 30 mL of water/ice. The precipitate was collected by filtration, washed with water and dried in a vacuum oven to give 840 mg (98%) of tert-butyl 4-((2-(4-((2-(pyridin-3-yl)ethyl)carbamoyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylate as a yellow solid. LC-MS: (ES, m/z): 569 [M+H]+, 469, 361, 320, 169, 126. 1HNMR (400 MHz, DMSO-d6, ppm) δ 8.73 (s, 1H), 8.50-8.45 (d, 2H), 7.99-7.94 (d, 5H), 7.74 (s, 1H), 7.38 (s, 1H), 4.54 (s, 3H), 4.07 (s, 3H), 3.54 (s, 3H), 2.90 (m, 6H), 2.50-2.45 (s, 6H), 2.11 (s, 3H), 1.48-1.41 (s, 16H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][CH2:10][Cl:11].[C:12]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])([CH3:14])[CH3:13]>C1CCCCC1>[C:12]([N:16]([CH2:8][CH2:9][CH2:10][Cl:11])[C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: ClCCCBr
Reactant: CC(C)(C)NC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Product: CC(C)(C)N(CCCCl)C(C)(C)C
Reaction time: 20 h
Yield: 50.8 %

Procedure:
To a stirred suspension of K2CO3 (200 g, 1.5 mole) in cyclohexane 200 mL and 1-bromo-3-chloropropane (540 gms, 3.4 mole) is added dropwise over a period of 1 h at 20C di-t-butyl amine (289 g, 2.24 mole). After complete addition the reaction is allowed to stir for an additional 20 h. The crude reaction mixture is filtered and then washed with saturated NaCl (3×100 mL). The organic phase is extracted with 3N HCl (3×100 mL). The resulting aqueous phase, containing the desired product as the hydrochloric salt, is washed with hexanes (3×100 mL) to remove any residual BCP. The aqueous phase is subsequently basified with 50 wt % NaOH and extracted with cyclohexane (3×100 mL). After solvent removal 234 g (51% yield) of the title compound is isolated as a yellow oil.
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[C:5]2[N:6]([C:10](I)=[C:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)[CH:7]=[CH:8][CH:9]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]2=[C:23]([CH:39]=1)[O:24][CH2:25][C:26]1[CH:36]=[C:35]([CH:37]=[O:38])[CH:34]=[CH:33][C:27]=1/[C:28]/2=[C:29](/[CH3:32])\[C:30]#[N:31]>>[F:1][CH:2]([F:17])[O:3][C:4]1[C:5]2[N:6]([C:10]([CH:37]([OH:38])[C:35]3[CH:34]=[CH:33][C:27]4/[C:28](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:22]5[CH:21]=[CH:20][C:19]([F:18])=[CH:39][C:23]=5[O:24][CH2:25][C:26]=4[CH:36]=3)=[C:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)c1nc2c(OC(F)F)cccn2c1I
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C(C)C)nc4c(OC(F)F)cccn34)cc2COc2cc(F)ccc21
Yield: 96.5 %

Procedure:
[step 3] Using 8-(difluoromethoxy)-3-iodo-2-isopropylimidazo[1,2-a]pyridine (600 mg, 1.71 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (250 mg, 0.85 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8A, step 3, (E)-2-(8-{[8-(difluoromethoxy)-2-isopropylimidazo[1,2-a]pyridin-3-yl](hydroxy)methyl}-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (426 mg, 96%) was obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)#[N:7].[OH-].[Na+].CN([CH:22]=[O:23])C>>[CH:22]([C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:6]#[N:7])[CH:9]=2)[NH:13][CH:12]=1)=[O:23]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2[nH]cc(C=O)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add phosphorous oxychloride (11.76 g, 76.67 mmol) dropwise to DMF (24.3 ml) wile maintaining the temperature at less than 10° C. Warm to ambient temperature and stir for 15 minutes at ambient temperature. Add dropwise 5-cyanoindole (10.00 g, 70.34 mmol) as a solution in DMF (30 ml) while keeping the temperature below 35°. After 1 hour, pour the reaction mixture into ice/water (300 ml) and then add 5N NaOH (54 ml) with stirring Add slowly an additional amount of 5N NaOH (19.7 ml) and then heated to 90° for 1 minute and then cooled to ambient temperature to give a precipitate. Filter the precipitate and washed with water and dry to give the title compound: mp 248-250° C. MS (ACPI): m/e 171.0 (M+1). Analysis for C10H6N2O: Calcd: C, 70.58; H, 3.55; N, 16.46. found: C, 70.41; H, 3.53; N, 16.33.
Reaction SMILES: [CH2:1]([CH:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:6]([O:8][CH3:9])=[O:7])[C:2]#[C:3][CH3:4].[Li+].CC([N-]C(C)C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:36])(=O)=O)=CC=1>C1COCC1>[CH2:1]([C:5]([F:36])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:6]([O:8][CH3:9])=[O:7])[C:2]#[C:3][CH3:4]
Reactant: CC#CCC(CCCCCCCC)C(=O)OC
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC#CCC(F)(CCCCCCCC)C(=O)OC
Temperature: 25 °C

Procedure:
This ester was again deprotonated with LDA in THF, as described above, and at −78° C. a solution of N-fluoro benzenesulfonimide (1.1 equivalents) in THF was added dropwise. The mixture was allowed to warm to room temperature, quenched with saturated ammonium chloride solution, and worked up as above. Chromatography on silica gel with 5% ethyl acetate in hexane provided methyl 2-(2-butynyl)-2-fluorodecanoate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:27]1([CH2:32][CH2:33][C:34](Cl)=[O:35])[CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[CH:27]1([CH2:32][CH2:33][C:34]([NH:14][NH:13][C:11]([N:10]2[CH2:9][C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=3[O:6][C:5]3[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]2=3)=[O:12])=[O:35])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=C(Cl)CCC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CCC1CCCC1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution containing 2.9 parts of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazide, 50 parts by volume of acetonitrile and excess aqueous potassium carbonate is added 1.6 parts of 3-cyclopentylpropionyl chloride and the resulting reaction mixture is stirred at room temperature for about 2 days. The solvent is stripped under reduced pressure and the resulting residue is purified by chromatography on a silica gel column, using ethyl acetate-benzene solutions as the eluants. The 5% ethyl acetate in benzene eluate, after removal of the solvents, affords 1-(3-cyclopentylpropionyl)-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine, characterized by the following structural formula ##SPC6##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1/[CH:13]=[CH:14]/[C:15]([O:17]CC)=O>Cl.O1CCOCC1>[F:10][C:9]([F:12])([F:11])[O:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:15](=[O:17])[CH:14]=[CH:13]2
Reactant: CCOC(=O)/C=C/c1cc(OC(F)(F)F)ccc1N
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc2cc(OC(F)(F)F)ccc2[nH]1
Temperature: 100 °C

Procedure:
To a stirring mixture of (E)-ethyl 3-(2-amino-5-(trifluoromethoxy)phenyl)acrylate (2.2 mmol) in 4N HCl in dioxane (25 mL) was added concentrated HCl (2 mL). The resulting mixture was warmed to 100° C. overnight. The reaction mixture was cooled to rt and then slowly quenched with a cold saturated NaHCO3 solution until pH>7. The product was extracted with EtOAc and used without further purification. Retention time (min)=1.804, method [1], MS(ESI) 230.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH3:10])[CH:7]=1.[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:18][O:12][C:11](=[O:13])[C:9]([CH3:10])([CH3:14])[NH:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(C)(Nc1cc(Cl)ccc1[N+](=O)[O-])C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(C)(C)Nc1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A mixture of N-(5-chloro-2-nitrophenyl)-2-methylalanine (X, EXAMPLE 10, 22.3 g, DMF (260 ml), potassium carbonate (35.6 g), and iodomethane (26.9 ml) is stirred at 20°-25° for 16 hr. Aqueous workup (ether, water and saline washes, drying over magnesium sulfate) gives the title compound, mp 87°-89°; IR (Nujol) 3349, 2954, 2925, 1737, 1606, 1489, 1330, 1263, 1230, 1149 and 752 cm-1 ; NMR (CDCl3) 8.48, 8.15, 6.65, 6.54, 3.77 and 1.69 δ; MS (EI) 272 and 213 m/z.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:23])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:11]([CH3:14])[C:12]=1O.[NH2:24][NH2:25]>C(O)C>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:10]2[C:9](=[O:23])[NH:24][N:25]=[C:12]([CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:11]=2[CH3:14])[CH:20]=[CH:19][CH:18]=1
Reactant: NN
Reactant: COc1cccc(C2=C(C)C(O)=C(c3ccccc3F)C2=O)c1
Solvent: CCO
Product: COc1cccc(-c2c(C)c(Cc3ccccc3F)n[nH]c2=O)c1

Procedure:
A solution of 2-(2-fluorophenyl)-3-hydroxy-4-methyl-5-(3-methoxyphenyl)-2,4-cyclopentadienone (310 mg, 1 mmol) and hydrazine (0.2 mL) in ethanol (5 mL) was heated at reflux for 30 minutes. The resulting solution was concentrated in vacuo and the residue was dissolved in dichloromethane, dried over sodium sulfate, filtered and concentrated in vacuo to give the desired compound as a colorless oil. 1H NMR (CDCl3): 2.14 (s, 3H), 3.27 (d, J=13.8 Hz, 1H), 3.43 (d, J=13.8 Hz, 1H), 6.70–7.25 (m, 8H); MS: 325 (MH+).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:11][CH:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NC1CCc2cc(Cl)ccc21
Product: Clc1ccc2c(c1)CCC2Nc1nc2ccccc2[nH]1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and racemic 1-amino-5-chloroindane (prepared by Procedure B from 5-chloro-1-indanone) by Procedure A (30 min at 170° C.). The product was isolated by preparative LCMS to give the title compound as the free base and as a mixture of enantiomers (white solid, mp 242-243° C.). MS(ES+) m/z 284 ([M+1]+, 100). 1NMR (DMSO-d6) δ 1.92 (m, 1H), 2.55 (m, 1H), 2.83 (m, 1H), 2.95 (m, 1H), 5.32 (m, 1H), 6.81-6.97 (m, 3H), 7.10-7.21 (m, 3H), 10 7.26-7.33 (m, 2H), 10.8 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]([O:30][C@@H:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[CH3:39])[CH3:32])=[O:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Li+].Cl>O>[CH3:26][C:23]1[C:22]([NH:27][C:28]([O:30][C@@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[CH3:32])=[O:29])=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccccc4C)cc3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccccc1[C@@H](C)OC(=O)Nc1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)O)CC3)cc2)cc1
Temperature: 25 °C

Procedure:
To 1-{4′-[3-methyl-4-((R)-1-o-tolyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.36 mmol) in 2:1 MeOH:H2O was added lithium hydroxide (1.1 mmol), and the reaction was stirred at room temperature until no starting material was seen by analytical LCMS. The mixture was acidified with 1N aqueous HCl and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated to give the title compound.
Reaction SMILES: [N+](=[CH2:3])=[N-].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([S:19]([CH2:21][C:22]([OH:24])=[O:23])=[O:20])[CH3:18])=[CH:13][CH:12]=1>CCOCC>[CH3:3][O:23][C:22](=[O:24])[CH2:21][S:19]([CH:17]([C:14]1[CH:15]=[CH:16][C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[F:4])=[CH:12][CH:13]=1)[CH3:18])=[O:20]
Reactant: C=[N+]=[N-]
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Solvent: CCOCC
Product: COC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1

Procedure:
A solution of 320 mgm (7.6 millimols) of diazomethane (prepared from 2.14 gm of p-toluenesulfonyl-methylnitrosoamide in 30 ml of ether and 0.4 gm of potassium hydroxide in 10 ml of 96% ethanol and subsequent distillation) was added, while stirring, to a suspension of 2.3 gm (7.5 millimols) of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid (m.p.: 164°-165° C.) in 20 ml of ether. The acid dissolved, accompanied by nitrogen evolution. After the reaction was finished, the mixture was evaporated, and the residue was recrystallized from benzene cyclohexane (1/5). Yield: 2.0 gm (83.5% of theory); m.p.: 75°-77° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:42])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH:32]=[C:31]([CH2:33][O:34]C3CCCCO3)[CH:30]=[N:29]2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]4)[CH:23]=3)[CH2:20][C:19](=[O:42])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cc(COC4CCCCO4)cn3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3cc(CO)cn3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-dimethylamino-2-(3-oxo-3-{3-[4-(tetrahydro-pyran-2-yloxymethyl)-pyrazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert.-butyl ester (Example M58) (642 mg, 1.05 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (365 mg).
Reaction SMILES: CO[C:3](=[O:44])[C:4]1[C:5](=[CH:10][C:11]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:32][CH:31]=2)=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH:13]=1)[C:6](OC)=[O:7].[NH3:45]>C(O)CO>[CH2:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:12]2[CH:13]=[C:4]3[C:3](=[O:44])[NH:45][C:6](=[O:7])[C:5]3=[CH:10][C:11]=2[NH:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:34][CH:35]=2)=[CH:20][CH:19]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc(Nc2ccc(OCc3ccccc3)cc2)c(Nc2ccc(OCc3ccccc3)cc2)cc1C(=O)OC
Reactant: N
Solvent: OCCO
Product: O=C1NC(=O)c2cc(Nc3ccc(OCc4ccccc4)cc3)c(Nc3ccc(OCc4ccccc4)cc3)cc21
Reaction time: 16 h

Procedure:
Analogously to Example 1, 294.4 mg (0.5 mmol) of 4,5-bis(4-benzyloxy-anilino)phthalic acid dimethyl ester in 22 ml of ethylene glycol are heated at 120°, ammonia gas being passed through the mixture, with stirring, for 16 hours. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with dichloromethane/methanol 50:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of red crystals, m.p.187°-189° C., FAB-MS: 542 [M+ +H].