Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([CH3:24])[N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].Cl[CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31]>C(O)(C)C.[OH-].[Na+].O>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([CH3:24])[N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[O:26][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(CC(C)C)cc(C)n3)n2)cc(C)c1O
Reactant: OC[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1cc(-c2noc(-c3cc(CC(C)C)cc(C)n3)n2)cc(C)c1OC[C@@H](O)CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.4 %

Procedure:
To a solution of 2-ethyl-4-[5-(4-isobutyl-6-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (41 mg, 0.116 mmol) in isopropanol (3 mL) and 3 N aq. NaOH (0.4 mL), (S)-3-chloro-1,2-propanediol (66 mg, 0.577 mmol) is added. The mixture is stirred at 65° C. for 16 h before another portion of (S)-3-chloro-1,2-propanediol (66 mg, 0.577 mmol) and 3 N aq. NaOH (0.4 mL) is added. Stirring is continued at 65° C. for 24 h. The mixture is cooled to rt, diluted with water, and repeatedly extracted with diethyl ether. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC using DCM:methanol 9:1 to give the title compound (16 mg) as a colourless oil; LC-MS: tR=1.02 min, [M+H]+=426.17.
Reaction SMILES: [CH3:1][CH:2]([OH:13])[CH2:3][O:4][CH:5]([CH2:7][O:8][CH:9]([CH2:11][OH:12])[CH3:10])[CH3:6].[C:14]([O:19]C(=O)C(C)=C)(=[O:18])[C:15]([CH3:17])=[CH2:16]>O1CCCC1>[C:14]([OH:19])(=[O:18])[C:15]([CH3:17])=[CH2:16].[CH3:1][CH:2]([OH:13])[CH2:3][O:4][CH:5]([CH2:7][O:8][CH:9]([CH2:11][OH:12])[CH3:10])[CH3:6]
Reactant: C=C(C)C(=O)OC(=O)C(=C)C
Agent: CC(O)COC(C)COC(C)CO
Solvent: C1CCOC1
Product: C=C(C)C(=O)O

Procedure:
In a 0.5 L separable flask, 0.1 mol of tripropylene glycol and 0.1 mol of methacrylic anhydride were mixed in anhydrous tetrahydrofuran. After stirring the mixture for a while, the internal pressure of the container was reduced to volatile the content and the material was distilled off to obtain tripropylene glycol monomethacrylate.
Reaction SMILES: [CH:1]1([N:4]([CH:31]2[CH2:33][CH2:32]2)[C:5]([C:7]2[N:28]([CH2:29][CH3:30])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][CH:22]=[C:23]([C:25]([OH:27])=O)[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:34][N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:36].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>CN(C=O)C>[CH:1]1([N:4]([CH:31]2[CH2:32][CH2:33]2)[C:5]([C:7]2[N:28]([CH2:29][CH3:30])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][CH:22]=[C:23]([C:25]([N:35]([CH3:36])[CH3:34])=[O:27])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C(=O)O)cs3)nc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C(=O)N(C)C)cs3)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
To 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-4-carboxylic acid (example 12A, 44 mg, 0.095 mmol) in DMF (2 ml) was added HATU (108 mg, 0.284 mmol), DIPEA (0.066 mL, 0.378 mmol), and dimethylamine (0.013 mL, 0.189 mmol). The reaction was stirred at rt for 3 h, then the solvent was removed in vacuo. The residue was purified by preparative HPLC to give 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-4-ylamino)-N,N-dimethylthiazole-4-carboxamide (10 mg, 21% yield) as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(OCC)(=O)C>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCN(c2cccc(O)c2)CC1
Reaction time: 14 h

Procedure:
1-(3-Hydroxyphenyl)piperazine (200 mg) was dissolved in tetrahydrofuran (10 ml), the solution was added with saturated aqueous sodium hydrogencarbonate (10 ml) and benzyl chloroformate (176 μl) at room temperature, and the mixture was stirred for 14 hours. The reaction mixture was added with ethyl acetate for extraction, and the organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (342 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]2[C:18]([CH2:21][OH:22])=[CH:19][N:20]=[C:15]2[C@H:14]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:13][CH2:12]1.I[CH3:32]>O1CCCC1>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]2[C:18]([CH2:21][O:22][CH3:32])=[CH:19][N:20]=[C:15]2[C@H:14]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CO)cnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 44.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 25.0 mg, 0.61 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (160 mg, 0.41 mmol) and iodomethane (51.0 μL, 0.81 mmol) in tetrahydrofuran (2 mL) at 0° C. After 3 h, the reaction was quenched with water and the mixture was extracted with dichloromethane (3×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (75 mg). MS 408.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)CCCl
Reactant: Oc1ccc2c(Cl)nccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CN(C)CCOc1ccc2c(Cl)nccc2c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 120.6 %

Procedure:
To a solution of 1-chloro-isoquinolin-6-ol (300 mg, 1.67 mmol) in acetonitrile (16 ml) was added (2-Chloro-ethyl)-dimethyl-amine (289 mg, 2.0 mmol) and cesium carbonate (1.2 g, 3.67 mmol). The reaction was stirred at 65° C. overnight. The solvent was removed and the residue dissolved in ethyl acetate. The organic solution was washed with saturated sodium bicarbonate, dried over magnesium sulfate and concentrated. The crude product was purified using reverse phase HPLC to afford 505 mg (83%) of [2-(1-chloro-isoquinolin-6-yloxy)-ethyl]-dimethyl-amine as a white amorphous solid. LCMS found 251.04 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([O:9][CH2:10]OC(C2C=CC=CC=2)=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si]([Cl:24])(C)(C)C.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]([O:9][CH2:10][Cl:24])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OCOC(=O)c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(OCCl)c1ccccc1
Yield: 35 %

Procedure:
1-acetoxy-1-bromoacetone was extremely difficult or impossible to make by the standard preparation of 1-acyloxyalkyl bromide compounds, since the standard route would require preparation of pure anhydrous pyruvaldehyde, CH3COCHO, to be reacted with acetyl bromide. Anhydrous pyruvaldehyde is extremely hygroscopic, unstable, and prone to polymerization. All the above preparations of 1-acyloxyalkyl halides carried out with trimethylsilyl bromide and a catalytic quantity of anhydrous zinc chloride at room temperature overnight; if the starting 1,1-diester was solid, a chlorinated solvent (CH2Cl2, CHCl3, or CCl4) was added to make a homogeneous reaction mixture. Products were characterized by boiling point, NMR, and halide titration. Different Lewis acids were tested in the case of methylene dibenzoate. ZnCl2, ZnI2, ZrCl4, and SnCl4 all proved effective, AlCl3 less so. BF3.Et2O and Cu2Br2 were ineffective. 1-acyloxyalkyl chlorides can also be obtained by this general procedure, though more vigorous conditions are required and lower yields result. Thus C6H5COOCH2OCOC6H5 and Me3SiCl reacted in CCl4 with AlCl3 catalysis at 100° (sealed vessel) for 60 hrs. and gave a 35% yield of C6H5COOCH2Cl.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH3:3].[N:25]1([C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH2:1]([NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:28]2[CH2:29][CH2:30][N:25]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)[CH2:26][CH2:27]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH3:3]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CCCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: CCCNC(=O)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(propyl)-amide and 2-(piperazin-1-yl)-quinoline.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].Cl[C:7]1[S:8][C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=1>C(O)C>[CH2:2]([O:1][C:7]1[S:8][C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:10]([C:12]([F:14])([F:13])[F:15])[N:11]=1)[CH3:3]
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1sc(OCC)nc1C(F)(F)F
Temperature: 80 °C
Yield: 78 %

Procedure:
To a cold (0° C.) solution of sodium ethoxide, prepared from 0.46 g (0.02 mole) of sodium and 40 ml. of dried ethanol, was added 5.2 g (0.02 mole) of ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate. A precipitate formed immediately. The reaction mixture was heated to 80° C. and then poured into ice water. The precipitate was collected to give 4.2 g (78%) of the desired product as a white solid, m.p. 30.5°-31.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34].CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:33]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[O:25][CH3:24])=[O:34]
Reactant: COc1ccccc1N=C=O
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Reaction time: 1 h
Yield: 54 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was dissolved in chloroform (5 ml), and 2-methoxyphenyl isocyanate (24 μl) was then added to the solution. The mixture was stirred at 60 C for one hr. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 39 mg (yield 54%) of the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[NH:7][C:8](=[O:13])[NH:9][C:10](=O)[CH:11]=1)(=O)[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:10]1[CH:11]=[C:6]2[CH:5]=[N:4][CH:1]([CH3:2])[N:7]2[C:8](=[O:13])[N:9]=1
Reactant: CC(=O)NCc1cc(=O)[nH]c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CC1N=Cc2cc(Cl)nc(=O)n21

Procedure:
A suspension of 6.63 g (36.2 mmole) of 4-acetylaminomethylpyrimidine-2,6-dione in 250 ml of phosphorous oxychloride was heated at reflux for 20 hours, and was then cooled and evaporated. The residue was added to about 700 ml of cold saturated sodium bicarbonate solution. To the resulting mixture was added 200 ml of chloroform and sufficient solid sodium bicarbonate to neutralize the mixture. The solid was separated by filtration, and the filtrate was saved for Part B. The solid was washed with water and ethanol, and was then recrystallized from ethanol to provide yellow solid 7-chloro-3-methylimidazo[1,5-c]pyrimidin-5-one, m.p. 239° C. (dec.). Analysis: Calculated for C7H6ClN3O; %C, 45.8; %H, 3.3; %N, 22.9; Found: %C, 45.8; %H, 3.1; %N, 22.8.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=[O:31])OC3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:31])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)N1CCCC1

Procedure:
Pyrrolidine-1-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-yl-methyl)-amide was prepared starting from intermediate M and pyrrolidine. MS calcd. for C21H21ClN3O2 [(M+H)+] 382.1, obsd. 381.9.
Reaction SMILES: [Br-].[C:2]1([P+:8]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:14][C:13]3[CH:15]=[CH:16][C:17]4[C:22]([C:12]=3[C:11]3[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=5[CH:29]=[CH:30][C:10]=3[CH2:9]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:37].[Na+]>C(O)C>[C:2]1([P:8]([CH2:9][C:10]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:11]=2[C:12]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:13]=2[CH3:14])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:37])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc([P+]2(c3ccccc3)Cc3ccc4ccccc4c3-c3c(ccc4ccccc34)C2)cc1
Reactant: [OH-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2ccccc2c1-c1c(CP(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Reaction time: 4 h

Procedure:
4 g (7.3 mmol) of 4,4-diphenyl-4,5-dihydro-3H-dinaphtho-[2,1-c:1',2'-e]phosphepinium bromide are suspended in a mixture of 80 ml of 2N sodium hydroxide solution and 30 ml of ethanol and heated to boiling for 4 hours. The reaction solution is subsequently evaporated to dryness at 12 torr/40° C. The residue is taken up in 80 ml of dichloromethane and extracted twice with 30 ml of water each time. The organic phase is dried over sodium sulfate and evaporated to dryness at 12 torr/40° C. This gives colorless crystals (melting point: 199.5° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH:15]4[CH2:16][CH:12]([CH2:13][CH2:14]4)[C:11]=13)[O:8][C:7]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])([CH3:17])[CH2:6][CH2:5]2.[OH-].[Na+].[CH2:25](Br)[CH:26]=[C:27]([CH3:29])[CH3:28].Cl>CCOC(C)=O>[OH:1][C:2]1[C:3]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])=[C:4]2[C:9](=[C:10]3[CH:15]4[CH2:16][CH:12]([CH2:13][CH2:14]4)[C:11]=13)[O:8][C:7]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])([CH3:17])[CH2:6][CH2:5]2
Reactant: CC(C)=CCBr
Reactant: CC1(CCC(=O)O)CCc2cc(O)c3c(c2O1)C1CCC3C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)=CCc1c(O)c2c(c3c1CCC(C)(CCC(=O)O)O3)C1CCC2C1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of 3-(6-hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl)-propionic acid, (2.39 mmol) in 1M aq. NaOH (4.8 mL, 4.8 mmol) was cooled to 0° C., and treated with prenyl bromide (0.277 mL, 2.39 mmol). Following stirring for 7 h at ambient temperature the reaction mixture was made slightly acidic with 0.5M HCl and shaken with EtOAc. The organic phase was evaporated yielding 1. The mixture was subjected to column chromatography on silica gel (SiO2: hexane:EtOAc, 85:15 v/v eluting yielded 3-[6-hydroxy-2-methyl-5-(3-methyl-but-2-enyl)-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl]-propionic acid 1H-NMR (300 MHz, CDCl3) δ (ppm): 5.17 (t, J=6, 1H), 3.54 (br s, 1H), 3.49 (br s, 1H), 3.18-3.37 (m, 2H), 2.70 (t, J=7, 2H), 2.49-2.62 (m, 2H), 1.60-2.07 (m, 13H), 1.39-1.48 (m, 1H), 1.05-1.32 (m, 5H). 13C-NMR (75 MHz CDCl3) δ (ppm): 180.1, 141.1, 133.9, 133.3, 132.9, 122.9, 122.3, 117.4, 73.2, 49.0, 48.9, 40.0, 39.8, 33.6, 32.0, 28.7, 26.7, 25.9, 25.6, 23.8, 233.2, 20.5, 18.0. MS ESI-Pos m/z371.2 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[N:10]([CH2:16][CH3:17])[CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27]/[CH:28]=[C:29]1/[C:30]2[CH:43]=[C:42]([C:44]([OH:47])([CH3:46])[CH3:45])[CH:41]=[CH:40][C:31]=2[O:32][CH2:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][C:35]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[N:10]([CH2:16][CH3:17])[CH:11]2[CH2:15][CH2:14][N:13]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Reactant: CCN(C(=O)Nc1ccc(Cl)cc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN(C(=O)Nc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(4-chloro-phenyl)-1-ethyl-1-pyrrolidin-3-yl-urea (0.21 g, 0.8 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.16 g, 0.8 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) and the resulting mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by flash chromatography on silica using gradient elution from ethyl acetate/methanol (5%) to ethyl acetate/methanol (10%) to give the desired product as yellow solid. 1H-NMR (CDCl3) δ: 1.05 (3H, t), 1.40 (6H, s), 1.80 (1H, m), 2.20–2.40 (3H, m), 2.50–3.00 (8H, m), 3.40 (4H, q and m), 4.20 (1H, m), 5.20 (2H, br, s), 6.20 (1H, t), 6.65(1H, d), 7.00 (2H, dd), 7.20–7.40 (5H, m), 7.70 (1H, dd), 8.50 (1H, dd) 9.80 (1H, br s). ESI-MS m/z: 561 (M+1), UV retention time: 1.45 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([N+:11]([O-])=O)=[CH:6][N:5]=1>C1COCC1.[Pd]>[NH2:10][C:8]1[C:7]([NH2:11])=[CH:6][N:5]=[C:4]([C:3]([O:2][CH3:1])=[O:14])[CH:9]=1
Reactant: COC(=O)c1cc(N)c([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(N)cn1

Procedure:
Prepared analogously to example 83d by hydrogenation of methyl-4-amino-5-nitropicolinate using palladium/charcoal 10% in THF.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[NH2:28][OH:29].O>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]([NH:28][OH:29])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(CC(=O)NO)N2Cc3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A mixture of 3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (15.0 g, 42.7 mmol) and N,N′-carbonyldiimidazole (7.27 g, 44.8 mmol) in tetrahydrofuran (50 mL) under nitrogen was stirred at room temperature for 2 hours. To the resulting solution was added hydroxylamine hydrochloride (3.86 g, 55.5 mmol). The resulting suspension was stirred for 18 hours. To the suspension was added water (150 mL) and stirring was continued for 1 hour. The suspension was filtered, the solid was washed with water (5×30 mL) and ether (2×20 mL), and then was dried in a vacuum oven overnight (60° C., <1 torr) to give 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propion-amide as a white solid (13.0 g, 82% yield): mp, 167-168° C.; 1H NMR (DMSO-d6) δ1.29 (t, J=6.9 Hz, 3H, CH3) 2.81-2.86 (m, 2H, CH2), 3.72 (s, 3H, CH3), 3.96-4.04 (m,2H, CH2), 4.13 (d, J=17.5 Hz, 1H, CHH), 4.54 (d, J=17.5 Hz, 1H, NCHH), 5.73 (t, J=7.9 Hz, 1H, NCH), 6.84-6.92 (m, 3H, Ar), 7.43-7.68 (m, 4H, Ar), 8.83 (br.s, 1H, OH), 10.61 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.68, 35.04, 46.22, 51.20, 55.44, 63.73, 111.85, 112.19, 119.21, 122.78, 123.43, 127.83, 131.29, 131.85, 132.27, 141.67, 147.85, 148.42, 165.99, 166.82. Anal. Calcd for C20H22N2O5: C, 64.85; H, 5.99; N, 7.56. Found: C, 64.73; H, 6.17; N, 7.36.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:26][CH3:27])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH:24]=C)[CH:17]=4)=[N:14][NH:13][C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1.[O:28]1CCCC1.O=[O+][O-].[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH3:1][O:2][C:3]1[C:4]([O:26][CH3:27])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH2:24][OH:28])[CH:17]=4)=[N:14][NH:13][C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1
Reactant: C1CCOC1
Reactant: C=Cc1cc(-c2n[nH]c3cnc4cc(OC)c(OC)cc4c23)ccc1C#N
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc2ncc3[nH]nc(-c4ccc(C#N)c(CO)c4)c3c2cc1OC
Temperature: 78 °C
Reaction time: 0.33 h

Procedure:
4-(7,8-Dimethoxy-3H-pyrazolo[3,4-c]quinolin-1-yl)-2-vinylbenzonitrile (247 mg, 693 μmol) is dissolved in N,N-dimethylformamide (1.5 ml), tetrahydrofuran (6.0 ml) and ethanol (9.0 ml) and cooled to (−) 78° C. The reaction solution is subsequently treated with ozone (oxygen flow of ozone generator 50 l/h) for 4 min, nitrogen is then passed through (2 min). After LC-MS check (aldehyde intermediate), NaBH4 (24 mg, 624 μmol) is added, and the reaction mixture is stirred at (−)78° C. for 20 min. The cold bath is subsequently removed, so that the reaction solution warms to room temperature. For purification, the mixture is extracted with ethyl acetate and semi-saturated sodium chloride solution. The organic phase is dried over Na2SO4, filtered with suction and evaporated to dryness at 40° C. in vacuo. The residue is purified by chromatography (pHPLC, solvent gradient water/1-30% by vol. of acetonitrile, 0.1% by vol. of formic acid), and the product fractions are lyophilised, giving 4-(7,8-dimethoxy-3H-pyrazolo[3,4-c]quinolin-1-yl)-2-hydroxymethylbenzonitrile (46 mg, 128 μmol) as a solid. MS: 361.4 (M+H+), TLC (HPTLC): Rf=0.38 (ethyl acetate/ethanol 8:1, parts by volume).