Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[CH:6][C:5]=1[NH:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=1.CO.[OH-].[Li+]>O1CCCC1>[C:20]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][C:17](/[CH:16]=[N:15]/[O:14][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[C:5]([NH:29][C:30](=[O:42])[C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:40])([F:41])[F:39])=[CH:33][CH:32]=3)[CH:6]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCCCO/N=C/c2ccc(-c3ccccc3)cc2)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(OCCCO/N=C/c2ccc(-c3ccccc3)cc2)ccc1C(=O)O)c1ccc(OC(F)(F)F)cc1
Reaction time: 2 h
Yield: 96.4 %

Procedure:
This compound was produced using similar methods as those used in Step 6, example 28, starting with 4-[3-({[(1E)-1,1′-biphenyl-4-ylmethylidene]amino}oxy)propoxy]-2-{[4-(trifluoromethoxy)benzoyl]amino}benzoic acid methyl ester (0.31 g, 0.52 mmol), 1:1 methanol:tetrahydrofuran (10 mL) and 4N aqueous lithium hydroxide solution (0.39 mL). The crude material was crystallized from hot chloroform (10 mL) by the addition of room temperature hexanes (100 mL), and allowing the mixture to sit for 2 hours. The product was isolated and then triturated with hexanes to give 4-[3-({[(1E)-1,1′-biphenyl-4-ylmethylidene]amino}oxy)propoxy]-2-{[4-(trifluoromethoxy)benzoyl]amino}benzoic acid (0.29 g, 95%) as a white solid. mp=194.5-195.5° C. 1H NMR (500 MHz, DMSO-d6); δ 13.49 (bs, 1H), 12.46 (s, 1H), 8.40 (s, 1H), 8.31 (s, 1H), 8.05 (d, 2H), 8.00 (d, 1H), 7.70-7.66 (m, 6H), 7.58 (d, 2H), 7.46 (t, 2H), 7.37(t, 1H), 6.81 (d, 1H), 4.31 (t, 2H), 4.22 (t, 2H), 2.18 (m, 2H). Mass spec (MW 578.54); (ES+) m/z 577.43 Elemental analysis; Calculated for C31H25F3N2O6: C, 64.36; H, 4.36; N, 4.84. Found: C, 63.78; H, 4.18; N, 4.77.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[C:3]=1[O:21][CH3:22].[CH2:23](Br)[CH2:24][CH2:25][CH3:26].[OH-].[K+]>CO>[CH2:23]([N:9]1[CH2:8][CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:5]=[C:4]([O:19][CH3:20])[C:3]([O:21][CH3:22])=[C:2]([Cl:1])[C:12]=2[CH2:11][CH2:10]1)[CH2:24][CH2:25][CH3:26]
Reactant: COc1cc2c(c(Cl)c1OC)CCNCC2c1ccccc1
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCN1CCc2c(cc(OC)c(OC)c2Cl)C(c2ccccc2)C1

Procedure:
A mixture of 4.5 g of 6-chloro-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 0.02 ml of n-butyl bromide and 0.02 mol of potassium hydroxide is dissolved in 120 ml of dry methanol and refluxed for 48 hours. The reaction mixture is evaporated to dryness, taken up in ethyl acetate and filtered to remove inorganic salts. The filtrate is washed with water, dried and evaporated to give 3-n-butyl-6-chloro-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([OH:16])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-])=O>CO.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]([NH2:13])[C:10]([OH:16])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1cc(O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)c1cc(O)c(N)cc1N

Procedure:
A solution of 2,4-dinitro-5-hydroxybenzamide (4.00 g, 0.018 mmol) in MeOH/EtOAc (1:1, 50 mL) is hydrogenated over 5% Pd/C at 60 psi for 3 h to give 2,4-diamino-5-hydroxybenzamide, which is used directly. Formic acid (50 mL) is added and the solution is heated under reflux for 48 h. then the volatiles are removed under reduced pressure. The residue is triturated with EtOAc to give crude 4-oxo-3H-oxazolo[5,4-g]quinazoline(3.27 g, 97%) as a tan powder which is used directly.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:33]5[C:28]([O:27][CH3:26])=[N:29][CH:30]=[CH:31][CH:32]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COc1ncccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ncccc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)ccc1C
Temperature: 120 °C

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (110 mg, 0.300 mmol) was dissolved in 3 mL of 1,2-dimethoxyethane (DME) in a microwave reactor tube. 2-Methoxypyridin-3-ylboronic acid (59.6 mg, 0.390 mmol), 0.4 mL of an aqueous 2 M potassium carbonate solution, and tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4, 34.7 mg, 0.0300 mmol) were added and the reaction mixture was heated at 120° C. in a microwave reactor for 20 minutes. The resulting material was cooled to room temperature, filtered, and the layers were separated. The crude product was evaporated to dryness, dissolved in 1 mL of N,N-dimethylformamide, and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 439.1. found 440.1 (M+1)+. Retention time 1.94 minutes.
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])[CH:8]=1.C([O-])(O)=O.[Na+].[CH3:29][CH2:30]O>>[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([CH3:23])([CH3:22])[C:19]([O:21][CH2:29][CH3:30])=[O:20])[CH:8]=1
Reactant: CCO
Reactant: CC(C)(C(=O)O)c1cc(N)n(-c2ccccc2)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)c1cc(N)n(-c2ccccc2)n1
Temperature: 45 °C
Yield: 91 %

Procedure:
Cone. H2SO4 (0.5 mL) was added to a solution of 2-(5-amino-1-phenyl-1 H-pyrazol-3-yl)-2-methylpropanoic acid (0.7 g, 28.5 mmol) in EtOH (10 mL) and the reaction was heated at 45° C. for 2 h. The reaction solution was neutralized with aq NaHCO3 and then extracted with EtOAc (3×20 mL). The combined extracts were washed with aq NaHCO3 solution, dried (Na2SO4), and concentrated in vacuo to give ethyl 2-(5-amino-1-phenyl-1 H-pyrazol-3-yl)-2-methylpropanoate (710 mg, 91% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.62 (d, δ 7.6 Hz, 2 H), 7.52 (t, J=7.6 Hz, 2 H), 7.35 (t, J=7.6 Hz, 1 H), 5.47 (s, 1 H), 5.35 (br s, 2 H), 4.12 (q, J= 7.2 Hz, 2 H), 1.50 (s, 6 H), 1.22 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 274.1(M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>CO>[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:14][CH:11]1[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: Cc1cccc(C=O)c1C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(CNC2CC2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,3-dimethylbenzaldehyde (1 eq.), cyclopropylamine (1.2 eq.) and sodium bicarbonate (1.5 eq.) were heated at reflux in MeOH (0.5 M) for 1 h. The reaction mixture was then cooled in ice and sodium borohydride (1.2 eq.) was introduced portionwise. Following the completion of addition, the reaction mixture was warmed to RT and stirred at RT for 1 h. The volatiles were then removed in vacuo and the resulting residue was partitioned between H2O and CH2Cl2. The organic layer was separated, washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a light yellow oil.
Reaction SMILES: [OH-].[Na+].O.C(=O)([O-])O.[Na+].Br[CH2:10][CH2:11]Br.[OH:13][C:14]1[C:19]([CH2:20][CH2:21][OH:22])=[C:18]([CH3:23])[N:17]=[C:16]([SH:24])[N:15]=1>CC(O)C>[OH:22][CH2:21][CH2:20][C:19]1[C:14](=[O:13])[N:15]2[CH2:10][CH2:11][S:24][C:16]2=[N:17][C:18]=1[CH3:23]
Reactant: BrCCBr
Reactant: Cc1nc(S)nc(O)c1CCO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1nc2n(c(=O)c1CCO)CCS2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 40 parts of sodium hydroxide in 500 parts of water were added 400 parts of 2-propanol. In this mixture were dissolved 186.23 parts of 4-hydroxy-2-mercapto-6-methyl-5-pyrimidineethanol. The resulting solution was added dropwise, during a 2.66 hours period, to a stirred and refluxing mixture of 210 parts of sodium hydrogen carbonate, 1635 parts of 1,2-dibromoethane and 1600 parts of 2-propanol. Upon completion, stirring was continued for 2 hours at reflux temperature. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was stirred three times in 750 parts of trichloromethane at room temperature. The trichloromethanephases were evaporated and the residue was crystallized from 300 parts of a mixture of trichloromethane and methanol (85:15 by volume) and 100 parts of hexane. The product was filtered off, washed with 2,2'-oxybispropane and dried in vacuo for 3 hours at 60° C., yielding 51 parts of 2,3-dihydro-6-(2-hydroxyethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one. The mother-liquor was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was boiled in 50 parts of a mixture of trichloromethane and methanol (85:15 by volume). After the addition of 50 parts of hexane, the whole was stirred to room temperature. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 17 parts of 2,3-dihydro-6-(2-hydroxyethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:12]2[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[N:16]=2)([OH:11])[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:43]2[CH:44]=[N:45][NH:46][CH:47]=2)O1.O>CN(C)C=O.O>[CH3:21][C:18]([CH3:22])([CH2:19][CH3:20])[CH2:17][C:15]1[N:16]=[C:12]([C:9]([OH:11])([CH3:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:43]3[CH:44]=[N:45][NH:46][CH:47]=3)=[CH:3][CH:4]=2)[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(Br)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3cn[nH]c3)cc2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (57 mg, 0.07 mmol) was added to a degassed, ambient temperature solution of 2-[2-(4-bromophenyl)-1-hydroxy-1-methylethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (329 mg, 0.70 mmol), sodium carbonate (222 mg, 2.1 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (217 mg, 1.4 mmol) in N,N-dimethylformamide/water (2:1) (30 mL). After stirring at 80° C. overnight, the reaction mixture was cooled, poured into water and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[4-(1H-pyrazol-4-yl)phenyl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12]2)=[CH:7][CH:6]=1)C=C.C(N(CC)[C:23]1[CH:28]=CC=C[CH:24]=1)C.Cl>>[CH2:28]([C:14]1[C:5]([OH:4])=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:10]=[CH:9]2)[CH:23]=[CH2:24]
Reactant: C=CCOc1ccc2ccc(C(=O)OCC)cc2c1
Reactant: CCN(CC)c1ccccc1
Agent: Cl
Product: C=CCc1c(O)ccc2ccc(C(=O)OCC)cc12

Procedure:
Ethyl 7-allyloxynaphthalene-2-carboxylate (6.2 g) was heated in refluxing N,N-diethylaniline for 2 hours. The solution was cooled, treated with dilute hydrochloric acid and extracted with ethyl acetate, which was then washed with dilute hydrochloric acid, and water, dried and evaporated to a solid. Crystallisation from benzene/petroleum ether (b.p. 40-60) afforded ethyl 8-allyl-7-hydroxynaphthalene-2-carboxylate (4.5 g), m.p. 115°-116°.
Reaction SMILES: [NH:1]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH:2]1[CH3:3].[OH-].[Na+].[C:14](Cl)([Cl:16])=[O:15]>C(OCC)C.O>[Cl:16][C:14]([N:1]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH:2]1[CH3:3])=[O:15]
Reactant: CC1CCC2CCCCC2N1
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC1CCC2CCCCC2N1C(=O)Cl

Procedure:
A mixture of 15 g decahydro-quinaldine dissolved in 200 ml of diethylether and 4 g of sodium hydroxide in 50 ml of water is reacted while stirring and cooling at -5° to 0° with 10 g of phosgene. An ethereal solution of 1-chlorocarbonyl-2-methyl-decahydro-quinoline is obtained. When an aqueous solution of 8.4 g of sodium ethylmercaptide is added to the ethereal solution at room temperature with stirring, 16 g of an almost colorless oil are obtained. The physical constants of this oil coincide with those of the compound of Example 1.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][S:9][C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH:13]=[CH:12][N:11]=2)=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.Cl>CO>[C:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][S:9][C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:12][N:11]=2)=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2nccc(OCC(=O)OCC)n2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(CSc2nccc(OCC(=O)O)n2)ccc(C(C)=O)c1O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 35.8 %

Procedure:
In 2 ml of 90% methanol was dissolved 0.06 g of ethyl [[2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-pyrimidin-4-yl]oxy]acetate obtained in Example 15 with heating at 60° C. Further 1 ml of a 1N aqueous sodium hydroxide solution was added to the solution followed by stirring at 60° C. for 15 minutes. An aqueous sodium hydroxide solution and ethyl acetate were added to the reaction mixture to fractionate. The aqueous phase was made acidic with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and then dried over anhydrous magnesium sulfate. The solvent was then distilled off. The thus obtained solid was recrystallized from isopropyl alcohol to give 0.02 g of [[2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-pyrimidin-4-yl]oxy]acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:14])[CH:5]2[CH:10]([C:11](=[O:13])[CH:12]=1)[CH2:9][CH:8]=[CH:7][CH2:6]2.N#N.Cl>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([OH:13])[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[C:4]=1[OH:14]
Reactant: COC1=CC(=O)C2CC=CCC2C1=O
Agent: Cl
Agent: N#N
Solvent: CO
Product: COc1cc(O)c2c(c1O)CC=CC2
Temperature: 25 °C

Procedure:
A solution of 2-methoxy-4a,5,8,8a-tetrahydronaphthalene-1,4-dione (55, 542 mg, 2.82 mmol) in MeOH (50 mL) was purged with a stream of N2 for 5 min with stirring at rt. With continued N2 purging, solid K2 CO3 (390 mg, 2.82 mmol, Baker) was added to the stirred solution. The solution immediately turned yellow. The reaction was allowed to stir for 15 min at rt under N2, after which it was brown. To this there was added a dilute HCl solution (10% concd HCl, 90% H2O, 50 mL) in one portion. The MeOH was removed in vacuo to give a colorless suspension. The suspended material was collected by filtration, washed with a dilute acid solution (as above, 4×6 mL) and dried in vacuo to yield a fluffy colorless solid (444 mg, 82%, pure by 1H NMR analysis (unstable on TLC)); mp 142.5°-144° C. (confirmed), lit. (Cavill et al., supra) 123°-124° C. (benzene/petroleum ether);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[C:12]([Cl:22])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccccc2)cc(C(=O)Cl)c1
Reaction time: 0.5 h

Procedure:
3-(Benzyloxy)-5-methoxybenzoic acid (162) (2.57 g, 0.01 mmol) and thionyl chloride (4.80 g, 0.04 mmol) were suspended in 200 mL of dry toluene. The reaction mixture was stirred for 30 min and then dimethyl formamide (3 drops) was added. The mixture was stirred for 24 h and then evaporated to dryness. The residue was directly used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]([NH2:24])=[O:23])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7](CC3C=CC=CC=3)[C:6]=2[N:21]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:22]([NH2:24])=[O:23])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:21]=1
Reactant: NC(=O)c1cc2c3ccccc3n(Cc3ccccc3)c2nc1N
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Temperature: 95 °C
Reaction time: 6 h

Procedure:
To a solution of 2-amino-9-benzyl-9H-pyrido[2,3-b]indole-3-carboxamide (vii-a, 1.01 g, 319 mmol) in benzene (30 mL) was added AlCl3 (1.10 g, 8.25 mmol), and the reaction was heated to 95° C. under atmosphere of Ar. After 6 h, the reaction was cooled to 0° C., quenched with water (75 mL) and poured into a separatory funnel containing EtOAc (200 mL). The mixture was washed with 1N NaOH (2×200 mL) and the organic layer was dried over sodium sulfate, filtered and concentrated to yield 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide as a light brown solid (5, 319 mg, 44%). NH4OAc Standard conditions. DAD Retention Time=5.10 min. M+H=227. 1H NMR (300 MHz, DMSO-d6): δ 11.33 (br s, 1H), 8.68 (s, 1H), 7.85 (br s, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.44 (br s, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.24 (dd, J=7.3, 7.3 Hz, 1H), 7.12 (dd, J=7.9, 7.9 Hz, 1H).
Reaction SMILES: [C:1]1([N:7]2[CH2:13][CH2:12][C:11]([C:14]([C:38](OC(C)(C)C)=[O:39])([C:16](=[O:37])[C@H:17]([CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:36])[NH2:35])[N:18]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH3:19])[NH2:15])=[CH:10][CH:9]([CH2:45][C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[C:8]2=[O:56])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1.C(N(CC)CC)C.C(Cl)(=O)[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1>>[C:1]1([N:7]2[CH2:13][CH2:12][C:11]([C:14]([C:38](=[O:39])[C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)([C:16](=[O:37])[C@H:17]([CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:36])[NH2:35])[N:18]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[CH3:19])[NH2:15])=[CH:10][CH:9]([CH2:45][C:46]([O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:47])[C:8]2=[O:56])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N(C)[C@@H](CCCNC(=N)N)C(=O)C(N)(C(=O)OC(C)(C)C)C2=CC(CC(=O)OCc3ccccc3)C(=O)N(c3ccccc3)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N(C)[C@@H](CCCNC(=N)N)C(=O)C(N)(C(=O)c2ccccc2)C2=CC(CC(=O)OCc3ccccc3)C(=O)N(c3ccccc3)CC2)cc1
Yield: 60.9 %

Procedure:
Compound (16) (69 mg, 0.087 mmol) from above was treated with anhydrous HCl/dioxane (5 mL) at room temperature for 4 h. The reaction mixture was then evaporated at reduced pressure and then re-evaporated at reduced pressure 2× from toluene to remove any excess HCl. The residue was dissolved in N,N-dimethylformamide (5 mL) and treated with triethylamine (24 μL, 0.174 mmol) and benzoyl chloride (20 μL, 0.174 mmol) at room temperature for 18 h. The reaction mixture was then evaporated under high vacuum and the residue was purified by flash chromatography (silica gel, 2.5×20 cm, 2% methanol in chloroform) to yield the title compound (17) (42 mg, 61%) as an inseparable mixture of diastereoisomers. Compound (17): TLC Rf 0.58 (silica gel, 9:1 chloroform: methanol).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[O:8][N:7]=1)=O)C.C(O)C.[BH4-].[Na+]>C1COCC1>[OH:3][CH2:4][C:6]1[CH:10]=[C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[O:8][N:7]=1
Reactant: CCOC(=O)c1cc(-c2ncccn2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1cc(-c2ncccn2)on1
Temperature: 30 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-(3-ethoxycarbonyl-isoxazol-5-yl)-pyrimidine (35 gm) in 2:1 v/v ethanol:THF mixture (525 ml) was added sodium borohydride (7.5 gm) in lots at 0° C. It was stirred at 30° C. temperature over a period of 4 h. The reaction mixture was evaporated under vacuum to provide a residue and to the residue, (150 ml) was added. The suspension was extracted with ethyl acetate (4.5 ltr). Combined organic layers was washed with water and concentrated under vacuum to provide crude mass in 23 gm quantity, which was recrystallized from ethanol to provide the title compound in 15.1 gm quantity (53%) as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[CH3:15])=[O:6])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[CH3:3][C:2]([CH3:16])([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:10][C:9]=1[CH3:15])=[O:6])[CH3:1]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(O)ccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a 200 mL round bottomed flask with a stirring bar, and an argon inlet was added 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenol (5.00 g, 22.39 mmol), Cs2CO3 (14.59 g, 44.78 mmol), DMF (50 mL), and ethyl bromoacetate (2.61 mL, 23.51 mmol). This mixture was stirred vigorously at ambient temperature for 24 h. The mixture was filtered through a frit and the DMF was removed under high vacuum. The residue was dissolved in EtOAc (300 mL) and washed with H2O (2×) and brine (1×). Drying (MgSO4), filtration, and removal of the solvent in vacuo gave a solid. This material was triturated with 5% Et2O-hexane, the solid was collected by filtration and dried in vacuo to give 5.40 g (78%) of ethyl 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenoxyacetate as a white, crystalline solid.