Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[CH3:13][S:12][C:9]1[N:8]=[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Oc1ccccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ncc(C(=O)O)c(Oc2ccccc2C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a solution of 7.0 g (23.0 mmol) 2-methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid ethyl ester in 50 ml ethanol a solution of 1.37 g (34.50 mmol) sodiumhydroxide in 30 ml water was added and the resulting mixture was stirred 1 h at RT. The pH of the solution was adjusted to 1 with 25% HCl. The mixture was extracted twice with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and evaporated. The resulting solid was triturated twice with 10 ml diisopropylether, filtered off and dried to give 3.00 g (47%) 2-methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid as a colorless solid, MS (ISN): 257.1 (M-H)−.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][NH:19][CH:20]3[C:28]4[C:23](=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[C:37]([N:19]([CH:20]1[C:28]2[C:23](=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)[CH2:18][C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: COc1cccc2c1CCC2NCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc2c1CCC2N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)C(C)=O
Reaction time: 1.5 h

Procedure:
To a solution of 1-(4,5-diphenyloxazol-2-yl)methylamino-2,3-dihydro-4-methoxy-1H-indene (0.22 g) and pyridine (0.2 ml) in dichloromethane (5 ml) was added acetyl chloride (0.15 ml) at 0° C. The mixture was stirred for 1.5 hours at the same temperature and partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water, sat. NaHCO3, and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give 1-[N-acetyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.08 g).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C1C=CC=CC=1.O[C:16]1[N:21]=C(O)[CH:19]=[C:18]([CH2:23][CH3:24])[N:17]=1.Cl[CH2:26][Cl:27]>>[Cl:3][C:16]1[N:21]=[C:26]([Cl:27])[CH:19]=[C:18]([CH2:23][CH3:24])[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClCCl
Reactant: CCc1cc(O)nc(O)n1
Solvent: CN(C)c1ccccc1
Product: CCc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A mixture of phosphorous oxychloride(43 ml), N,N-dimethyl aniline(6.6 ml) and 2,4-dihydroxy-6-ethyl pyrimidine(11.12 g, 79.3 mmol) prepared in the above Step 2 was heated to reflux for 6 hours. The reaction mixture was cooled to a room temperature and diluted with dichloromethane. The diluted solution was added slowly to ice water, while maintaining the temperature of the reaction system below 10° C. and the mixture was extracted with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate and concentrated to give 13.10 g of the titled compound as an oily form. (Yield: 93.3%)
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][C@@H:9]([OH:12])[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[OH2:5].[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][C@H:9]([O:12][C:42]3[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=3)[C@H:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:7]2)=[O:5])[CH2:2][CH2:3]1.[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][C@H:9]([O:45][C:42]3[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=3)[C@H:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(C1CC1)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: O
Product: O=C(C1CC1)N1CC[C@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 1.1 g of trans-1-cyclopropylcarbonyl-3-phenyl-4-piperidinol, 1.3 g of triphenylphosphine, 0.55 g of p-fluorophenol and 23 ml of dry benzene is added dropwise at 4° C. under nitrogen a solution of 0.86 g of diethyl azodicarboxylate in 23 ml of benzene. After stirring overnight at room temperature the solid is filtered off, washed well with benzene, and the filtrate concentrated in vacuo to a gum. The gum is taken up in about 25 ml of ether and the solution kept in a stoppered flask overnight. The colorless crystals which formed are filtered, washed well with ether, and the filtrate is diluted with ether to a volume of 50 ml. The solution is washed with 10% sodium hydroxide solution (2×10 ml) and 20 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to an oil weighing 2.27 g. This material is chromatographed on 115 g of silica gel, using ether as solvent. The product is obtained as a colorless oil which partially crystallized under high vacuum. The oily material is dissolved in about 20 ml of boiling cyclohexane and filtered hot. The filtrate is allowed to cool and stand at room temperature for 3 days, cooled and filtered to give product as a colorless solid, mp 84°-87° C. (softens 82° C.).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.Cl.[CH2:16]([S:18]([N:21]1[CH2:25][CH2:24][N:23]([C:26](Cl)=[O:27])[C:22]1=[O:29])(=[O:20])=[O:19])[CH3:17]>O1CCOCC1>[CH2:16]([S:18]([N:21]1[CH2:25][CH2:24][N:23]([C:26]([NH:14][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[C:11]([OH:13])=[O:12])=[O:27])[C:22]1=[O:29])(=[O:20])=[O:19])[CH3:17]
Reactant: CCS(=O)(=O)N1CCN(C(=O)Cl)C1=O
Reactant: NC(C(=O)O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCN(C(=O)NC(C(=O)O)c2ccc(Cl)cc2)C1=O

Procedure:
Sufficient concentrated sodium hydroxide solution just to dissolve the acid was added to a suspension of 11.0 parts by weight of p-chloro-α-aminophenylacetic acid in 110 parts by volume of 50% strength aqueous dioxane. Dilute hydrochloric acid was then added with stirring until a pH of 7.5-8.0 was reached. 13.0 parts by weight of 3-ethylsulphonyl-imidazolidin-2-one-1-carbonyl chloride were then added in portions at about 0° C and the pH of the mixture was maintained at 7.5-8.0 by means of dilute sodium hydroxide solution. Thereafter the mixture was stirred further for as long as an occasional addition of sodium hydroxide solution was still necessary to maintain the pH of 7.5-8.0. .ltorsim.The bulk of the dioxane was then removed in vacuo at pH 6.5, about 200 parts by volume of water were added, the mixture was extracted once with ether at pH 9.0 (the ether extract being discarded) and covered with fresh ether, and the pH was brought to 0.5 with stirring. The organic phase was then separated off, washed, dried and completely evaporated in vacuo. The residue was dissolved in hot ethyl acetate; thereafter the same amount of benzene and petroleum ether was added until there is turbidity which (only just) disappears again, and the mixture was left to crystallize.
Reaction SMILES: ClC1C(Cl)=CC(NC2C3C(=CC(OCCOCC[O:29][S:30]([CH3:33])(=O)=[O:31])=C([N+]([O-])=O)C=3)N=CN=2)=C(F)C=1.[Cl:35][C:36]1[C:41]([Cl:42])=[CH:40][C:39]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][C:50]([O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][OH:75])=[C:51]([N+:54]([O-:56])=[O:55])[CH:52]=3)[N:47]=[CH:46][N:45]=2)=[C:38]([F:76])[CH:37]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl>[Cl:35][C:36]1[C:41]([Cl:42])=[CH:40][C:39]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][C:50]([O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][S:30]([CH3:33])(=[O:31])=[O:29])=[C:51]([N+:54]([O-:56])=[O:55])[CH:52]=3)[N:47]=[CH:46][N:45]=2)=[C:38]([F:76])[CH:37]=1
Reactant: CS(=O)(=O)OCCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCOCCOCCOCCOCCO
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCCOCCOCCOCCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1[N+](=O)[O-]

Procedure:
Compound 32c was prepared as described hereinabove for Compound 32a, using Compound 29c (0.067 gram, 0.1 mmol), methanesulfonyl chloride (0.036 gram, 0.32 mmol) and triethylamine (0.053 gram, 0.53 mmol) in dichloromethane (6.7 ml), yielding 0.02 gram of the product (26% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:3]=1/[CH:4]=[N:5]/O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][C:3]=1[C:4]#[N:5]
Reactant: O/N=C/c1cc(OC(F)(F)F)ccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cc(OC(F)(F)F)ccc1F
Yield: 82.6 %

Procedure:
To a solution of E-2-fluoro-5-trifluoromethoxy-benzaldehyde oxime (47.5 g, 213 mmol) in THF (400 mL) was added triethylamine (65.0 mL, 466 mmol). The mixture was cooled in an ice bath and trifluoroacetic anhydride (32.8 mL, 236 mmol) was added at such a rate that the temperature was kept <30° C. After 1 h at rt all volatiles were evaporated (40° C., 200 mbar). The oily residue was partitioned (ether/water), the organic phase was dried over sodium sulfate and concentrated. Distillation (24 mbar, T=80-83° C.) afforded the title compound (36.1 g, 83%) that was sufficiently pure to be used in the next step. MS: m/e=205 [M]+.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:25][CH:26]1[CH2:27][CH2:28]1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1ccc2ncccc2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-cyclopropylpropanamide (80 mg, 0.301 mmol), 6-aminoquinoline (60 mg, 0.416 mmol), K2CO3 (65 mg, 0.471 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give a crude (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (130 mg). The crude (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (130 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (35 mg). MS 392.2 (M+H); UV 203.6, 266.4, 299.0, 358.5 nm; t 0.406 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH3:34])=[C:16]([CH:22]4[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]4)[C:17]([F:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.Cl.O1CCOCC1>C(Cl)Cl>[ClH:20].[NH:24]1[CH2:23][CH:22]([C:16]2[C:15]([O:33][CH3:34])=[C:14]([CH:12]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([CH3:11])=[N:9]3)[CH3:13])[CH:19]=[C:18]([Cl:20])[C:17]=2[F:21])[CH2:25]1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1

Procedure:
A mixture of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate (14 mg, 0.028 mmol) in methylene chloride (0.2 mL) was treated with 4.0 M hydrogen chloride in dioxane (0.2 mL, 0.8 mmol) at room temperature for 1 hour and then the solvent removed to give 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine HCl salt. To a mixture of the crude HCl salt in acetonitrile (0.1 mL)/methanol (0.1 mL)/tetrahydrofuran (0.1 mL) was added N,N-diisopropylethylamine (0.1 mL, 0.6 mmol), followed by acetone (0.050 mL, 0.68 mmol). The mixture was stirred for 30 minutes before the addition of sodium triacetoxyborohydride (0.030 g, 0.14 mmol). The reaction was stirred at room temperature overnight, then quenched and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product as TFA salt. The product was isolated as a racemic mixture. LCMS calculated for C21H27ClFN6O (M+H)+: m/z=433.2; Found: 433.1.
Reaction SMILES: ClC1C=CC=CC=1C(Cl)=O.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[CH:15]=[CH:14][C:13]=1[C:19]1[C:24]([C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[CH:23][N:22]=[C:21]([NH:30][CH2:31][CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][N:35]=2)[N:20]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:19]1[C:24]([C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[CH:23][N:22]=[C:21]([NH:30][CH2:31][CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][N:35]=2)[N:20]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Agent: O=C(Cl)c1ccccc1Cl
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccccc3Cl)n2)nc1

Procedure:
[4-(2-chlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 2-chlorobenzoyl chloride using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9](Cl)[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:9]1[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([CH3:1])[CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Product: Cc1cc(NCc2ccccc2)c(S(C)(=O)=O)cc1C(=O)O

Procedure:
in stage c) 2-methyl-4-chloro-5-methylsulfonylbenzoic acid is reacted with benzylamine to give 4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid,
Reaction SMILES: N1C=CC=CC=1.[OH:7][C:8]1[CH:9]=[CH:10][C:11]([C:19](=[O:27])[CH:20]([NH:23][CH:24]([CH3:26])[CH3:25])[CH2:21][CH3:22])=[C:12]2[C:17]=1[NH:16][C:15](=[O:18])[CH:14]=[CH:13]2.[C:28]([Cl:33])(=[O:32])[CH:29]([CH3:31])[CH3:30]>C(OCC)C>[ClH:33].[C:28]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:19](=[O:27])[CH:20]([NH:23][CH:24]([CH3:26])[CH3:25])[CH2:21][CH3:22])=[C:12]2[C:17]=1[NH:16][C:15](=[O:18])[CH:14]=[CH:13]2)(=[O:32])[CH:29]([CH3:31])[CH3:30]
Reactant: CCC(NC(C)C)C(=O)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: CC(C)C(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC(NC(C)C)C(=O)c1ccc(OC(=O)C(C)C)c2[nH]c(=O)ccc12
Product: Cl
Temperature: 0 °C

Procedure:
50 ml of pyridine was added to 2.5 g of 8-hydroxy-5-(α-isopropylaminobutyryl)carbostyril, and 5 ml of isobutyryl chloride was added dropwise to the mixture while cooling with ice-water and stirring followed by stirring for 2 hours. After addition of about 500 ml of diethyl ether, the precipitate formed was washed with diethyl ether and stirred in a small amount of cold water. The precipitate was separated by filtration, washed successively with a small amount of water, acetone and diethyl ether to obtain a crystalline product which was then recrystallized from acetone to obtain 2.1 g of 8-isobutyryloxy-5-(α-Isopropylaminobutyryl)carbostyril hydrochloride having a melting point of 231°-233° C. (with decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH:30](O)(C)C>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:13][CH:12]=3)=[O:5])([CH3:30])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(OCc4ccccc4)cc3c2c1COC
Reactant: CC(C)O
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Yield: 80 %

Procedure:
1.4 g (3.6 mmol) of 6-benzyloxy-4-methoxymethyl -β-carboline-3-carboxylic acid ethyl ester is boiled under reflux for 2 hours in 100 ml of isopropanol with 0.7 ml (2.2 mmol) of titanium tetraisopropoxide. After concentration, the mixture is taken up in 80 ml of 1N hydrochloric acid and extracted by shaking with 250 ml of ethyl acetate. The ethyl acetate phase is washed with a small amount of water, dried, filtered, and concentrated. After chromatography over silica gel with methylene chloride:acetone=4:1 as the eluent, the 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, mp 150°-151° C., is obtained in an 80% yield.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1)[CH3:2].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([NH:16][CH3:17])[N:10]=1>O1CCOCC1.C([O-])(O)=O.[Na+]>[Cl:8][C:9]1[CH:14]=[C:13]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[CH2:1][CH3:2])[N:12]=[C:11]([NH:16][CH3:17])[N:10]=1
Reactant: CC[C@@H]1CCCN1
Reactant: CNc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC[C@@H]1CCCN1c1cc(Cl)nc(NC)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of (2R)-2-ethylpyrrolidine (0.8 g, 5.90 mmol) and 4,6-dichloro-N-methyl-2-pyrimidinamine (0.997 g, 5.60 mmol) in 1,4-dioxane (40 mL) and saturated aqueous NaHCO3 (20 mL) was stirred overnight at 100° C. into a sealed tube. The reaction mixture was poured onto water (˜400 mL). A white precipitate was formed. The aqueous mixture was filtered, and the white solid was washed with water (˜100 mL). The wet solid was dried overnight on vacuum at 40° C. to afford the title compound (1.19 g). LC-MS (ES) m/z=241 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[C:12]1(OB(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>CN(C=O)C.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>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]([CH3:11])=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1)([O-:10])=[O:9]
Reactant: OB(O)Oc1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1-c1ccccc1
Temperature: 100 °C
Yield: 57.7 %

Procedure:
2-Bromo-4-nitrotoluene (2.16 g, 10.00 mmol) and phenylboric acid (1.46 g, 12.00 mmol) were dissolved in anhydrous DMF (25 mL) under nitrogen. To this mixture was added Pd(Ph3P)4 (0.58 g, 5%). The mixture was heated at 100° C. overnight. The solution was poured onto 1N HCl and extracted with Et2O. The crude product was chromatographed on silica gel using hexanes as eluent. After recrystallization from ethanol, the desired product (1.23 g) was obtained as pale orange needles: m.p. 69-71° C.; 1H NMR (CDCl3) d 2.36 (3H, s), 7.29-7.40 (2H, m), 7.41-7.49 (5H, m), 8.07-8.10 (2H, m); 13C NMR (CDCl3) d 20.68, 121.96, 124.51, 127.78, 128.41, 128.83, 131.06, 139.06, 139.44, 142.97, 143.48, 146.05; Anal. Calc. for C13H11NO2, C: 73.26, H: 5.20, N: 6.57; Found, C: 73.10, H: 5.12, N: 6.50; m/z (EI) 213; HRMS Calc. for C13H11NO2, 213.0790; Found, 213.0793.
Reaction SMILES: [Br:1][Si](C)(C)C.[NH:6](C(OC(C)(C)C)=O)[C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][NH2:9].[OH:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][NH-:27])=[CH:23][CH:22]=1.O>C(Cl)Cl>[NH2:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][NH2:9].[BrH:1].[OH:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][NH-:27])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Reactant: C[Si](C)(C)Br
Agent: [NH-]CCc1ccc(O)cc1
Solvent: O
Solvent: ClCCl
Product: Br
Product: NC[C@H](N)C(=O)O
Reaction time: 18 h

Procedure:
Bromotrimethylsilane (0.46 mL, 3.5 mmol) was added to a stirred solution of 7a (0.57 g, 1.4 mmol) in dry CH2Cl2 at 20° C., and stirring was continued for 18 h. Water (5 mL) was added, and the mixture was stirred vigorously for 30 min. The aqueous layer was removed, and the organic phase was extracted again with H2O (5 mL). Freeze-drying of the combined aqueous phase provided the hydrobromide salt 7b as a colorless solid (0.54 g, 99%), which was used without further purification. A sample was crystallized from CH2Cl2-hexane: mp 79-81° C.; IR (neat) νmax 3275, 2980, 1640, 1515, 1235, 830 cm−1; 1H NMR (CD3OD, 300 MHz) δ 6.95 (d, J=8.4 Hz, 2H), 6.60 (d, J=8.4 Hz, 2H), 3.47 (m, 1H), 3.41 (s, 3H), 3.25-3.02 (m, 5H), 2.72-2.62 (m, 2H), 2.33 (m, 1H), 1.88-1.76 (m, 2H), 1.72-1.64 (m, 2H), 1.13 (d, J=7.2 Hz, 3H); 13C NMR (CD3OD, 125.5 MHz) δ 175.6, 157.0, 131.0, 130.8, 116.2, 81.6, 62.9, 61.8, 46.5, 45.5, 41.3, 35.2, 24.1, 23.9, 15.5; HRMS (APCI) m/z 307.2026 [(M−HBr)+H]+ (calcd for C17H27N2O3, 307.2022).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[C:14]([CH2:20][CH3:21])[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1>>[CH2:20]([C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]2[C:4]3[CH:3]=[C:2]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=1)[CH3:21]
Reactant: OB(O)c1cccnc1
Reactant: CCc1nc2c(N)nc3ccc(Br)cc3c2n1CC(C)C
Product: CCc1nc2c(N)nc3ccc(-c4cccnc4)cc3c2n1CC(C)C

Procedure:
8-Bromo-2-ethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and pyridine-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (5%-7% methanol in CH2Cl2 gradient) followed by recrystallization from isopropanol afforded 2-ethyl-1-isobutyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as white crystals, m.p.>250° C.
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[NH2:6][CH2:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12]>CN(C)C=O>[ClH:3].[NH2:6][CH2:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([O:13][CH2:11][CH2:10][CH2:9][CH:8]=[CH2:7])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: C=CCCCOC(=O)CCC(=O)CN
Yield: 47 %

Procedure:
To 1 ml of thionyl chloride (SOCl2) were added 3 drops of N,N-dimethylformamide (DMF) with stirring. Following the addition of 5-aminolevulinic acid hydrochloride (ALA.HCl, 200 mg, 1.19 mmol), the solution was stirred for 12 hours at room temperature. Concentration in a vacuum was conducted before the addition of 4-pentenol. Then, the reaction mixture was stirred for 1.5 hours at room temperature, followed by purification by silica gel chromatography to afford 4-pentenyl 5-aminolevulinate hydrochloride at a yield of 47%.