Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=C[C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)C(=CC(=O)C=C2)CC3)CC1.[CH3:23][C@@:24]12[C@H:34]3[C@@H:35]([OH:48])[CH2:36][C@:37]4([CH:46]=[O:47])[C@@H:41]([C:42]([CH2:44][OH:45])=[O:43])[CH2:40][CH2:39][C@H:38]4[C@@H:33]3[CH2:32][CH2:31][C:30]1=[CH:29][C:27](=[O:28])[CH2:26][CH2:25]2>>[CH3:23][C@@:24]12[C@H:34]3[C@@H:35]([OH:48])[CH2:36][C@:37]4([CH2:46][OH:47])[C@@H:41]([C:42]([CH2:44][OH:45])=[O:43])[CH2:40][CH2:39][C@H:38]4[C@@H:33]3[CH2:32][CH2:31][C:30]1=[CH:29][C:27](=[O:28])[CH2:26][CH2:25]2
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C=O)[C@@H](C(=O)CO)CC[C@@H]12
Agent: C=C[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(CO)[C@@H](C(=O)CO)CC[C@@H]12

Procedure:
Commercially available 1,4-pregnendiene-3-one was incubated with aldosterone-producing adrenal tissue and Δ1 18-hydroxycorticosterone isolated chromatographically. The diol was then converted to the 11β,18-oxido derivative by refluxing for 30 minutes in ethylene dichloride containing p-toluenesulfonic acid in the same manner described in connection with Example 1 above.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:4]([N:14]([CH3:16])[CH3:15])[CH:3]=1.[C:17]([C:19]1[N:23]([CH3:24])[C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:17]([C:19]1[N:23]([CH3:24])[C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:4]([N:14]([CH3:16])[CH3:15])[CH:3]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CN(C)c1cc(Br)ccc1S(=O)(=O)N(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CN(C)c1cc(-c2ccc(C#N)n2C)ccc1S(=O)(=O)N(C)C
Reaction time: 16 h
Yield: 14.3 %

Procedure:
According to general procedure B, 4-bromo-2-(dimethylamino)-N,N-dimethylbenzenesulfonamide (180 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(dimethylamino)-N,N-dimethylbenzenesulfonamide (28 mg, 14%) was provided after purification. MS (ESI) m/z 332. HPLC purity 100.0% at 210-370 nm, 9.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=O.C1(=O)C2C(=CC=CC=2)CC1>O>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH:2]([CH3:1])[C:3]2=[O:5])=[CH:8][CH:9]=1
Reactant: COc1ccc(CC(C)C(=O)O)cc1
Agent: O=C1CCc2ccccc21
Solvent: O
Product: COc1ccc2c(c1)C(=O)C(C)C2

Procedure:
Alternatively, the same compound can be obtained by adding α-methyl-β-(p-methoxylphenyl)propionic acid (15 g.) to 170 g. of polyphosphoric acid at 50° and heating the mixture at 83-90° for two hours. The syrup is poured into iced water. The mixture is stirred for one-half hour, and is extracted with ether (3×). The etheral solution is washed with water (2×) and 5% NaHCO3 (5×) until all acidic material has been removed, and is dried over sodium sulfate. Evaporation of the solution gives 9.1 g. of the indanone as a pale yellow oil.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22]2[C:23]3[N:24]([C:28]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=4)=[CH:29][N:30]=3)[CH:25]=[CH:26][N:27]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:40][O:39][C:33]1[CH:32]=[C:31]([C:28]2[N:24]3[CH:25]=[CH:26][N:27]=[C:22]([NH:21][CH2:20][C:17]4[CH:16]=[CH:15][C:14]([CH2:13][OH:12])=[CH:19][CH:18]=4)[C:23]3=[N:30][CH:29]=2)[CH:36]=[CH:35][C:34]=1[O:37][CH3:38]
Reactant: COC(=O)c1ccc(CNc2nccn3c(-c4ccc(OC)c(OC)c4)cnc23)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COc1ccc(-c2cnc3c(NCc4ccc(CO)cc4)nccn23)cc1OC
Reaction time: 1 h

Procedure:
Diisobutylaluminium hydride (1 ml, 1.0 mmol, 1 M solution in dichloromethane) was added dropwise to a solution of 4-{[3-(3,4-dimethoxy-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-methyl}-benzoic acid methyl ester (0.10 g, 0.24 mmol) in dichloromethane (1 mL) at ambient temperature. The reaction mixture was stirred for 1 hour then diluted with dichloromethane (50 ml) and washed with 1 M aqueous potassium sodium tartarate solution (30 mL) and water (30 mL). The organic layer was dried with magnesium sulphate, filtered and concentrated in vaccuo. The crude material was purified by column chromatography using 1:1 dichloromethane:ethyl acetate as eluent. The product, (4-{[3-(3,4-Dimethoxy-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-methyl}-phenyl)-methanol, is obtained as a white solid (35 mg, 37%) (LC-MS m/z 391 [M+H]+).
Reaction SMILES: [C:1]([N:9]1[CH2:23][C@@H:22]([OH:24])[CH2:21][C@H:10]1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:32]([S:35](Cl)(=[O:37])=[O:36])([CH3:34])[CH3:33].O.[OH-].[Li+]>ClCCl.C(OCC)(=O)C.O.C1COCC1>[C:1]([N:9]1[CH2:23][C@@H:22]([O:24][S:35]([CH:32]([CH3:34])[CH3:33])(=[O:37])=[O:36])[CH2:21][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)O[C@H]1C[C@@H](C(=O)O)N(C(=O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
A solution of (cis)-1-benzoyl-4-hydroxy-L-proline, benzyl ester (500 mg, 1.54 mmole) and triethylamine (322 μl, 2.31 mmole) in dichloromethane (10 ml) was stirred under argon at -10° C. and treated dropwise with isopropylsulfonyl chloride (190 μl, 1.69 mmole). The reaction was warmed to 0° C. over 3 hours and treated with additional triethylamine (30 μl) and isopropylsulfonyl chloride (45 μl). The reaction was stirred at room temperature overnight and diluted with ethyl acetate and washed with 1M HCl, sodium bicarbonate solution, and brine and dried (sodium sulfate). Filtration followed by evaporation afforded an oil which was treated with THF. Evaporation was followed by redissolving the oily residue in 10% aqueous THF (8 ml). The resulting solution was treated with lithium hydroxide monohydrate (129 mg, 3.08 mmole) dissolved in 3 ml of water. The resulting mixture was stirred under argon at room temperature for 2 hours, concentrated in vacuo, and diluted with water. The pH was adjusted to 8 and the aqueous solution was washed with ethyl acetate. The aqueous layer was acidified to pH 2 with HCl and extracted with dichloromethane. The extracts were washed with brine, dried (sodium sulfate), filtered and concentrated. The crude product was recrystallized from methanol-ethyl acetate to afford 413 mg (78%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)(=O)=O)=CC=1>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(CCC2COc3ccccc3C2)CC1
Reaction time: 16 h
Yield: 97.1 %

Procedure:
First 3.76 g (24 mmol) of piperidine-4-carboxylic acid ethyl ester and then 3.1 g (24 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 3.98 g (12 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 50 ml of absolute diemthylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction by shaking is carried out with diethyl ether. The combined organic phases are extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 3.8 g (100%) of crude product are obtained which are chromatographed on 200 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 3.7 g (97.3%) of 1-[2-(chroman-3-yl)ethyl]piperidine-4-carboxylic acid ethyl ester are then obtained in the form of a colourless oil. The 1-[2-chroman-3-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 182°-186°.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:22]=[CH:21][C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH:15]=1.[Cl:23]NC(=O)CCC(N)=O>C1COCC1.CCCCCC>[Br:13][C:14]1[CH:22]=[CH:21][C:17]2[S:18][C:19]([Cl:23])=[CH:20][C:16]=2[CH:15]=1
Reactant: Brc1ccc2sccc2c1
Reactant: NC(=O)CCC(=O)NCl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Clc1cc2cc(Br)ccc2s1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
n-Butyl lithium (0.64 ml, 1.2 mmol) was added drop wise to a solution of diisopropyl amine (0.25 mL, 1.5 mmol) in dry THF at −78° C. under nitrogen atmosphere over a period of 5 minutes. The reaction mixture was stirred at −20° C. for 30 minutes. To this was added 5-bromo-benzo[b]thiophene (200 mg, 0.938 mmol) in dry THF at −78° C., continued stirring for a further 30 minutes at −78° C., followed by the addition of N-chlorosuccinamide (225 mg, 1.68 mmol) in dry THF at −78° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (100% hexane). The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was dried over sodium sulfate and concentrated to afford the crude product. Purification by column chromatography on silica gel (100% hexane) afforded 70 mg of the product (30% yield).
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(Cl)Cl>C1COCC1>[C:16]([NH:15][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)([NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:1]
Reactant: O=C1CCC(=O)N1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 2 h

Procedure:
FMOC-(O-t-Butyl)tyr-val (1.0 gm, 1.8 mMole) and N-hydroxysuccinimide (210 mg, 1.8 mMole) were dissolved in 40 ml THF under nitrogen at 0.C. Dicyclohexylcarbodiimide (DCC) was added as a methylene chloride solution (0.5M, 3.6 ml, 1.8 mMole) and the reaction mixture was incubated for 2 hours with stirring, then stored overnight at 4° C. TLC showed incomplete reaction, so additional DCC was added (0.45 mMole), and the reaction mixture incubated at room temperature for one day. Dicyclohexylurea (DCU) formed was filtered and the filtrate concentrated to a solid, which was triturated with 4% sodium bicarbonate. The solid was filtered, washed with water dried, then crystallized from chloroform/petroleum ether. A white solid was obtained on filtration and air drying. Yield: 761 mg (65%); Rf: 0.75 [chloroform/methanol 9:1 (silica)]. Elemental analysis for C37H41N3O8.0.5H2O calculated: C, 66.85; H, 6.37; observed C, 67.04; H, 6.85.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[CH:6]=1)=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].P(O)(O)(O)=O.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([C:39]1[C:40]([CH:45]=[C:46](O)[C:47]2[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=2)=[N:41][CH:42]=[CH:43][CH:44]=1)=[O:38].[OH-].[Na+]>CS(C)=O.C(Cl)Cl>[F:18][C:15]([F:16])([F:17])[C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:8]=1)[CH2:4][N:1]1[C:46]([C:47]2[CH:48]=[CH:49][N:50]=[CH:51][CH:52]=2)=[C:45]([C:40]2[C:39]([C:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[Cl:30])=[O:38])=[CH:44][CH:43]=[CH:42][N:41]=2)[N:3]=[N:2]1
Reactant: [N-]=[N+]=NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(c1ccccc1Cl)c1cccnc1C=C(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(c1ccccc1Cl)c1cccnc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Temperature: 40 °C
Reaction time: 22 h

Procedure:
Add 1-azidomethyl-3,5-bistrifluoromethylbenzene (3.73 g, 13.8 mmol) and potassium carbonate (5.73 g, 41.4 mmol) to a solution of (2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone phosphate (6.0 g, 13.8 mmol) in DMSO (16 mL). Heat to 40° C. and stir for approximately 20-24 h. Cool the reaction mixture to ambient temperature, and add the mixture to CH2Cl2 (75 mL) and 1 N NaOH (75 mL). Separate the layers, and extract the aqueous layer with CH2Cl2 (50 mL). Separate the layers, combine the organic layers and extract the combined organic layers with 1 N NaOH (2×50 mL). Add MgSO4 and acid-washed carbon (1.2 g), stir for 20 min and filter through Celite®. Concentrate the filtrate to a total weight of approximately 25 g. Add heptane (75 mL) dropwise over approximately 45 min. Seed the solution with the title compound if necessary. Stir the resulting slurry for 1 h and then filter to obtain the title compound. Dry the title compound, then add it to isopropanol (36 mL). Heat the mixture until the solid dissolves (approx. 65° C.). Allow the solution to cool to ambient temperature. Stir the resulting slurry for approximately 3 hours. Cool the slurry in an ice/water bath and stir for 2 h. Filter and dry to afford the title compound as a white solid. MS(IS) 588 (M+1). TLC (3% MeOH/CH2Cl2) Rf=0.17. 1H NMR (400 MHz, CDCl3): 5.46 (s, 2H); 7.19 (m, 5H); 7.36 (dd, 1H, J=4.9, 7.8); 7.45 (s, 2H); 7.59 (m, 1H); 7.83 (s, 1H); 7.93 (dd, 1H, J=1.5, 7.8); 8.56 (dd, 1H, J=1.5, 4.9); 8.70 (d, 2H, J=5.9).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:19][C:20]1([F:25])[CH2:22][CH:21]1[CH2:23]I>CN1C(=O)CCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[C:9](=[O:11])[N:10]([CH2:23][CH:21]3[CH2:22][C:20]3([F:25])[F:19])[C:5]2=[CH:4][CH:3]=1
Reactant: FC1(F)CC1CI
Reactant: Cn1c(=O)[nH]c2ccc(Cl)nc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CC2CC2(F)F)c2ccc(Cl)nc21
Temperature: 100 °C

Procedure:
5-Chloro-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1-3, 516 mg, 2.81 mmol) and cesium carbonate (4.97 g, 15.26 mmol) were added to a round bottom flask and suspended in NMP (4.6 mL) under nitrogen. 1,1-Difluoro-2-(iodomethyl)cyclopropane (481 μL, 5.06 mmol) was added to the suspension and then heated to 100° C. in microwave reactor for 10 min. Following this duration, the reaction was cooled to room temperature and suspended in ethyl acetate and sodium bicarbonate. The suspension was washed with sodium bicarbonate, brine(×5), dried over sodium sulfate, filtered, and concentrated. The mixture was purified using reverse-phase chromatography (5-95% 0.1% TFA in H2O:acetonitrile) to give 5-chloro-1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (6-1) as an off-white solid. MS m/z (M+H): calculated=274.0553; observed=274.0551.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C1COCC1.[OH-].[Na+].Cl>C(O)C>[Br:1][C:2]1[C:3]2[N:4]([C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CCOC(=O)c1cnc2c(Br)cc(C(F)(F)F)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cnc2c(Br)cc(C(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
To a mixture of ethyl 8-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate (490 mg) in a mixed solvent of THF (9 mL) and ethanol (3 mL) was added 8N aqueous sodium hydroxide solution (273 μL), and the mixture was stirred at room temperature for 1.5 hr, and then at 50° C. for 1 hr. The reaction solution was neutralized with 6N hydrochloric acid under ice-cooling, and the obtained solid was collected by filtration, and washed with water and IPE to give the title compound (380 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].S(Cl)([Cl:19])(=O)=O>CCCCCCC>[Cl:19][C:2]([CH3:15])([CH3:1])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)C(=O)c1cccc2ccccc12
Solvent: CCCCCCC
Product: CC(C)(Cl)C(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Methyl-1-(1-naphthalenyl)-1-propanone (30.0 g, 0.15 mole) was dissolved in heptane (10 ml), and sulfuryl chloride (30 g, 0.22 mole) was added at once. After about 5 min gas evolution occurred. After 3 h of stirring at room temperature the reaction mixture was concentrated. The concentrate was dissolved in heptane (200 ml) and washed with 150 ml of a 2 wt % aqueous sodium bicarbonate solution. After drying over magnesium sulfate the solvent was removed under reduced pressure. The yield of 2-chloro-2-methyl-1-(1-naphthalenyl)-1-propanone was 34.5 g or 98%.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][C:10]2[CH:11]=[C:12]([C:18](=[O:20])[CH3:19])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])C(=O)C2=CC=CC=C12.Cl>CO.O1CCCC1>[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([C:18](=[O:20])[CH3:19])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(C(C)=O)cc1CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(C(C)=O)cc1CN
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.8 %

Procedure:
Hydrazine hydrate (3.06 g) was added to a suspension of 3'-phthalimidomethyl-4'-methoxyacetophenone (15.74 g) in methanol (150 ml) and tetrahydrofuran (150 ml) at room temperature and the mixture was stirred at room temperature for 24 hours. Dilute hydrochloric acid (conc. hydrochloric acid (5 ml) in water (100 ml)) was added slowly to the mixture with cooling and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated. Water (100 ml) was added thereto and the mixture was alkalized to pH 10 with 30% aqueous potassium carbonate solution and extracted with ethyl acetate (300 ml). The extract was dried with magnesium sulfate. The solvent was removed under reduced pressure to afford 3'-aminomethyl-4'-methoxyacetophenone (4.45 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[C:28]([CH3:29])=[CH:27][C:24]([CH:25]=O)=[CH:23][C:22]=1[CH3:30].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[C:28]([CH3:29])=[CH:27][C:24]([C:25]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:23][C:22]=1[CH3:30]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C=O)cc(C)c1OCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCCO)c(C)c3)nc2c1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (497 mg, 2.53 mmol) and 4-(4-hydroxybutoxy)-3,5-dimethyl benzaldehyde (660 mg, 2.53 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (58.5 wt %, 496 mg, 2.79 mmol) and p-TSA (96 mg, 0.50 mmol) were added and the reaction mixture was heated at 115° C. for 16 hours and then cooled to room temperature. The solvent was removed under reduced pressure. Water (100 mL) was added and stirred for 1 hour at room temperature. The solid separated was filtered and dried. The solid was further washed with diethyl ether to give product 2-[4-(4-hydroxy-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as a white solid. Yield: 1.69 g (82%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH3:13])[C:5]([OH:7])=[O:6].[C:14](OCC)(OCC)(OCC)[CH3:15]>CCO>[CH2:12]([N:11]1[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=[C:14]1[CH3:15])[CH3:13]
Reactant: CCNc1ccc(C(=O)O)cc1N
Reactant: CCOC(C)(OCC)OCC
Solvent: CCO
Product: CCn1c(C)nc2cc(C(=O)O)ccc21
Temperature: 25 °C

Procedure:
A mixture of 1.4 g (7.7 mmol) of the title B compound, 3-amino-4-ethylamino-benzoic acid and 15 mL (104 mmol) of triethyl orthoacetate in 20 mL of EtOH is refluxed for 7 h. The reaction mixture is allowed to cool to RT and the precipitated solid is collected by filtration, washed with EtOH (2×), then with methyl-t-butylether (MTBE) and dried in vacuo to give 1-ethyl-2-methyl-1H-benzoimidazole-5-carboxylic acid as a grey solid: mp>250° C.; 1H-NMR (DMSO-d6) δ 12.65 (s, 1H), 8.11 (s, 1H), 7.82 (dd, 1H), 7.59 (d, J=8.46, 1H), 4.26 (q, 2H), 2.57 (s, 3H), 1.30 (t, 3H); [M−1]−=203.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:28][CH2:29][CH3:30])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([Br:31])=[CH:6][C:5]=2[N:4]=1.[OH-].[Na+]>C(O)C>[NH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[C:11]2[C:10]3[CH:9]=[CH:8][C:7]([Br:31])=[CH:6][C:5]=3[N:4]=[C:3]([NH2:2])[C:12]=2[N:13]=[C:14]1[CH2:28][CH2:29][CH3:30]
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN
Reaction time: 0.5 h

Procedure:
Concentrated hydrochloric acid (˜15 mL) was added to a suspension of tert-butyl [4-(4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (3.19 g, 6.7 mmol) in ethanol (6.4 mL), and the reaction was stirred for 30 minutes. The reaction was adjusted to pH 13 with the addition of 50% aqueous sodium hydroxide. A precipitate formed, was isolated by filtration, washed with 1% sodium carbonate, and dried overnight on the filter funnel to provide 1-(4-aminobutyl)-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine, which contained some water.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]3[NH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:12]=23)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[C:32](OC(=O)C)(=[O:34])[CH3:33]>O.O1CCOCC1>[C:32]([N:23]1[CH2:24][CH2:25][N:20]([C:19]2[C:12]3[C:13](=[N:14][CH:15]=[N:16][C:11]=3[NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[NH:17][N:18]=2)[CH2:21][CH2:22]1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Clc1cccc(Nc2ncnc3[nH]nc(N4CCNCC4)c23)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)CC1

Procedure:
Analogously to Example 26, 100 mg (0.248 mmol) of 4-(3-chlorophenylamino)-3-(piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine dihydrochloride and 103 mg (0.74 mmol) of potassium carbonate in 10 ml of water are reacted with 38 mg (0.37 mmol) of acetic anhydride in 10 ml of dioxane to form 3-(4-acetyl-piperazin-1-yl)-4-(3-chlorophenylamino)-1H-pyrazolo(3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)=10.8; FAB-MS: (M+H)+=372.