Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[C:8]([F:12])[C:9]=1[CH2:10][OH:11].[CH:14]1([CH2:17]Br)[CH2:16][CH2:15]1>CN(C)C=O>[CH:14]1([CH2:17][O:13][C:6]2[CH:5]=[C:4]([F:3])[C:9]([CH2:10][OH:11])=[C:8]([F:12])[CH:7]=2)[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: OCc1c(F)cc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCc1c(F)cc(OCC2CC2)cc1F
Reaction time: 24 h
Yield: 134 %

Procedure:
Sodium hydride (82 mg, 55%, 1.87 mM) was added to a solution of 3,5-difluoro-4-hydroxymethyl-phenol (300 mg, 1.87 mM) in dimethylformamide (4 mL). After 1 h stirring at room temperature cyclopropylmethylbromide (135 mg, 1.87 mM) was added and stirring continued for 24 h. The mixture was partitioned between water and diethylether. Organic phases were pooled, washed with brine and dried with MgSO4 to yield after evaporation a yellow oil (673 mg). This residue was purified by column chromatography (silica gel; n-hexane/ethylacetate gradient) to yield 287 mg (71%) of the product as a yellowish oil. MS (EI): 214.1 (M)+.
Reaction SMILES: N1C=CC=CC=1.CN(C)C=O.S(Cl)([Cl:14])=O.O[CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@H:41]([NH:42][C:43](=[O:51])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:40](=[O:52])[N:22]2[C:23]=1[C:24]([O:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O1CCCC1>[Cl:14][CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@@H:41]([NH:42][C:43](=[O:51])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:40](=[O:52])[N:22]2[C:23]=1[C:24]([O:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]
Reactant: O=S(Cl)Cl
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)N[C@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reaction time: 0.17 h

Procedure:
24 ml (0.3 mole) of pyridine, 400 ul of dimethylformamide and 21.6 ml (0.3 mole) of thionyl chloride are added to a solution of 103 g (0.2 mole) of benzhydryl 3-hydroxymethyl-7β-phenylacetamido-3-cephem-4-carboxylate (prepared, for example, in accordance with Helv. Chim. Acta 57, 2044 (1974)) in 3.5 l of absolute tetrahydrofuran, while cooling with ice. After 10 minutes, the mixture is concentrated on a rotary evaporator, the residue is taken up in 2 l of ethyl acetate and the mixture is extracted by shaking twice with sodium bicarbonate solution and once with water. The organic phase is extracted by stirring with 50 g each of kieselguhr and active charcoal and the extract is filtered with suction over a frit covered with silica gel. The filtrate is then dried over magnesium sulphate and concentrated, the residue is taken up in 200 ml of methylene chloride and the product is precipitated with petroleum ether.
Reaction SMILES: [Cl:1]Cl.[CH3:3][N:4]([CH2:9][CH2:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([CH3:8])([CH3:7])[CH3:6]>C(O)(=O)C>[CH3:3][N:4]([CH2:9][CH2:10][CH:11]([C:18]1[CH:23]=[C:22]([Cl:1])[CH:21]=[CH:20][C:19]=1[OH:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(CCC(c1ccccc1)c1ccccc1O)C(C)(C)C
Reactant: ClCl
Solvent: CC(=O)O
Product: CN(CCC(c1ccccc1)c1cc(Cl)ccc1O)C(C)(C)C

Procedure:
A solution of chlorine (7,1 g, 0,10 mol) in acetic acid (500 ml) is added dropwise to a stirred solution of N-methyl-N-tert.butyl-3-(2-hydroxyphenyl)-3 -phenylpropylamine (29.7 g. 0.10 mol) in acetic acid (200 ml) with stirring. After 2 h the solvent is distilled off under reduced pressure and the crude hydrochloride left is recrystallized from 2-propanol. Melting point 260° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1.[OH:14][C:15]1[CH:37]=[CH:36][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]([O:27]CC)=[O:26])[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:21]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:30]1([C:22]2[C:23]([C:25]([OH:27])=[O:26])=[CH:24][N:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:2][C:3]4[N:4]=[C:5]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[S:6][CH:7]=4)=[CH:37][CH:36]=3)[N:21]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CCOC(=O)c1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A mixture of 4-chloromethyl-2-phenylthiazole (1.19 g), ethyl 1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-carboxylate (1.65 g), potassium carbonate (1.18 g) and N,N-dimethylformamide (25 ml) was stirred overnight at 80° C. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. A mixture of the residue, potassium hydroxide (0.93 g) and ethanol (50 ml) was refluxed for 5 hours. After the reaction solvent was removed under reduced pressure, water was added to the reaction mixture, then the mixture was acidified with 1N hydrochloric acid. The crystals obtained were collected by filtration to yield 3-phenyl-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-1H-pyrazol-4-carboxylic acid (1.82 g, yield: 76%). This was recrystallized from acetone-hexane. Melting point: 119–120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([NH2:15])=[CH:13][C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([F:34])=[CH:30][C:31]=2[F:33])[N:26]=[C:25]([C:35]2[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=2)[C:24]=1[CH3:42].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:33][C:31]1[CH:30]=[C:29]([F:34])[CH:28]=[C:27]2[C:32]=1[C:23]([NH:15][C:14]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:10][CH:11]=[C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:13]=1)=[C:24]([CH3:42])[C:25]([C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1)=[N:26]2
Reactant: COc1ccc(-c2ncc(N3CCOCC3)cc2N)cc1
Reactant: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2ncc(N3CCOCC3)cc2Nc2c(C)c(-c3cc(C)ccn3)nc3cc(F)cc(F)c23)cc1
Temperature: 100 °C
Reaction time: 19 h

Procedure:
A mixture of 2-(4-methoxyphenyl)-5-morpholinopyridin-3-amine (60.3 mg, 0.21 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (52.0 mg, 0.17 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (14.7 mg, 0.031 mmol), tris(dibenzylideneacetone)dipalladium (0) (6.8 mg, 7.43 μmol), and sodium tert-butoxide (42.9 mg, 0.45 mmol) in dry toluene (1.5 mL) was degassed by nitrogen. The resulting reaction was heated to 100° C. and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (10-40% EtOAc in hexanes) to afford a >80% pure light yellow film that was triturated with isopropanol to afford a light yellow solid as 5,7-difluoro-N-(2-(4-methoxyphenyl)-5-morpholinopyridin-3-yl)-3-methyl-2-(4-methylpyridin-2-yl)-quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.54 (1H, d, J=5.1 Hz), 8.00 (1H, d, J=2.3 Hz), 7.81 (4H, m), 7.61 (1H, d, J=9.6 Hz), 7.20 (1H, d, J=4.7 Hz), 7.10 (4H, m), 6.53 (1H, d, J=2.3 Hz), 3.99 (7H, m), 3.26 (4H, m), 2.48 (3H, s), 2.21 (3H, s). Mass Spectrum (pos.) m/e: 554.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:13]3[C:23]([OH:25])=[O:24])[CH2:4][CH2:3]1.[CH3:32][Si](C=[N+]=[N-])(C)C.O>CO.C(Cl)Cl>[CH3:32][O:24][C:23]([C:13]1[N:14]2[C:10]([CH:9]([O:8][CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15]2)=[N:11][C:12]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:25]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CN1CCC(OC2c3ccccc3CCn3c2nc(-c2ccccc2)c3C(=O)O)CC1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c(-c2ccccc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene-1-carboxylic acid (example 256B) (50 mg, 0.120 mmole) in MeOH (2 mL) is added a 2M solution of trimethylsilyldiazomethane in CH2Cl2 (0.2 mL). After 2 hours, as the reaction is only partial, a 2M solution of trimethylsilyldiazomethane in CH2Cl2 (0.2 mL) is added and the reaction mixture is heated at 45° C. overnight. Water is added and the aqueous phase is extracted with AcOEt. The organic phase is dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH) from (100:0) to (95:5) to give 4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene-1-carboxylic acid methyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[O:34][C:33]([Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])=[N:32][CH:31]=1)CCC.CN(C)C=O>O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH:3]=[C:2]([C:30]3[O:34][C:33]([Si:35]([CH:39]([CH3:41])[CH3:40])([CH:42]([CH3:44])[CH3:43])[CH:36]([CH3:37])[CH3:38])=[N:32][CH:31]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc([Si](C(C)C)(C(C)C)C(C)C)o1
Reactant: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](c1ncc(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)o1)(C(C)C)C(C)C
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 65.9 %

Procedure:
150 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine (Example 9), 246 mg of 5-(tributylstannyl)-2-(triisopropylsilyl) oxazole (synthesized according to the method described in WO2007/17096), and 25 mg of tetrakis(triphenylphosphine) palladium were added in turn to 5 ml of degassed dimethylformamide, and then the mixture was stirred at 100° C. for 2.5 hours under argon atmosphere. 246 mg of 5-(tributylstannyl)-2-(triisopropylsilyl) oxazole was added thereto, and the mixture was further stirred for four hours. The reaction solution was diluted with water, and then subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 153 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)-6-[2-(tri isopropylsilyl) oxazol-5-yl]pyrimidine-2,4-diamine as pale orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:17]#[N:18])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:2].[ClH:20]>C(O)C.[Pt]=O>[ClH:20].[CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:17][NH2:18])[CH3:2]
Reactant: CCOC(=O)C(C#N)Cc1cccc2ccccc12
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(CN)Cc1cccc2ccccc12

Procedure:
A solution of 6.22 g of 2-cyano-3-(1-naphthyl)propionic acid ethyl ester and 50 ml of a 2N-hydrochloric acid in 300 ml of ethanol was hydrogenated over 600 mg of platinum oxide under atmospheric pressure. After filtration of the catalyst, the filtrate was concentrated under reduced pressure, and water was added to the residue. The mixture was washed with diethyl ether to remove neutral materials. The aqueous layer was neutralized by adding sodium bicarbonate, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. An absolute ethanol solution containing hydrogen chloride was added to the organic layer. The organic layer was concentrated under reduced pressure, and hexane was added to the residue, and the resulting precipitates were collected by filtration to obtain 3.20 g of 3-amino-2-(1-naphthylmethyl)propionic acid ethyl ester hydrochloride as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C(=O)C)=[CH:18][CH:17]=1)[O:14][CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CCO>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][C@@H:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[O:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H](CNC(=O)OCc1ccccc1)c1ccc(OC(C)=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CO[C@@H](CNC(=O)OCc1ccccc1)c1ccc(O)cc1
Temperature: 24 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
To a solution of 6c (132 mg, 0.35 mmol) in EtOH (5 mL) 0.469 g of a freshly prepared solution of potassium hydroxide (253.2 mg in 5.013 g H2O, 0.045M, 1.1eq.) was added. The mixture was stirred at 23-25° C. for 1 h (completion monitored by TLC) and neutralized with 0.1% HCl (neutral by pH indicator paper). Solvent was evaporated in vacuo and the residue dissolved in ethyl acetate and flash filtered through a pad of silica gel to remove inorganic impurities. The silica gel was washed with ethyl acetate, fractions combined and solvent evaporated in vacuo to afford 107 mg (92%) of 6e.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(OC1C=C[CH:23]=[C:22]2[C:17]=1C=CC=[N:21]2)C=C.C(C1C=CC2N=CC=CC=2C=1O)C=C.C1(O)C=CC=CC=1.C(C1C(OCC2C=CC=CC=2)=C2C(=CC=1)N=CC=C2)C=C.C(OC1C(CC(O)CO)=CC=C2C=1C=CC=N2)C1C=CC=CC=1.CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.BrCC([O-])=O.[H-].[Na+]>CC1C=CC(C)=CC=1.Br.C(O)(=O)C>[O:1]1[C:2]2=[C:3]3[C:8](=[CH:9][CH:10]=[C:11]2[CH2:23][CH:22]([NH2:21])[CH2:17]1)[N:7]=[CH:6][CH:5]=[CH:4]3
Reactant: Oc1cccc2ncccc12
Reactant: C=CCOc1cccc2ncccc12
Agent: Br
Agent: C=CCc1ccc2ncccc2c1O
Agent: C=CCc1ccc2ncccc2c1OCc1ccccc1
Solvent: Cc1ccc(C)cc1
Solvent: CC(=O)O
Solvent: Oc1ccccc1
Product: NC1COc2c(ccc3ncccc23)C1

Procedure:
The 3,4-dihydro-2H-pyrano[2,3-f]quinolin-3-amine 1b is prepared according to Scheme III. The commercially available 5-hydroxyquinoline 13 is first protected with an allyl group, and the resulting 5-allyloxyquinoline 14 subjected to Claisen rearrangement by heating in p-xylene to generate 6-allyl-quinolin-5-ol 15. The resulting phenol is protected with a suitable protecting group, such as benzyl, and the resulting product 16, 6-allyl-5-benzyloxy-quinoline converted to the 3-(5-benzyloxy-quinoline-6-yl)-propane-1,2-diol 17 using the Sharpless Catalytic Asymmetric Dihydroxylation reagent, AD-mix-α. The diol is then converted to the bromoacetate 18 upon heating in 30% HBr in acetic acid, simultaneously cleaving the benzyl protecting group. Cyclization to 19 is achieved under basic conditions using sodium hydride. Cleavage of the acetyl group under basic conditions produced 20, 3,4-dihydro-2H-pyrano[2,3f]quinolin-3-ol quantitatively. The tosylate 21 is then generated using p-toluenesulfonyl chloride in pyridine, and converted to the azide 22 with sodium azide in DMF. The azide is finally reduced by treatment with triphenylphosphine in THF-H2O to provide the 3,4-dihydro-2H-pyrano[2,3-f]quinolin-3-amine 1b suitable for the preparation of some of the derivatives claimed in this invention.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:27])/[CH:18]=[CH:19]\[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21]>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:18]([CH2:19][C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[C:17]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOC(=O)/C=C\C(=O)OCCCC
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Product: CCCCOC(=O)CC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)OCCCC

Procedure:
The procedure of Example 1 is repeated using 11.92 grams of 2, 6-di-tert-butyl-4-mercaptophenol, 11.41 grams of di-n-butyl maleate, and 0.5 gram of triethylamine. The product is purified by dry column chromatography to give a clear syrup.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C1COCC1>[C:36]([NH:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)(=[O:38])[CH3:37]
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(CN)ccc4c23)cccc1N1Cc2ccccc2C1=O
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3cccc(N4Cc5ccccc5C4=O)c3C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
A solution of crude 7-(aminomethyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 33-1, 60 mg, 0.065 mmol) and TEA (23 μL, 0.163 mmol) in THF (1.3 mL) was treated with acetic anhydride (7.4 μL, 0.078 mmol) and the mixture was stirred at rt overnight. The mixture was concentrated and the residue was purified by preparative HPLC. The appropriate effluent fractions were concentrated and the residue was partitioned between NaHCO3 (aq) and EtOAc. The organic phase was washed with brine, dried and concentrated to provide 7-(acetamidomethyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as an off-white solid (12 mg, 36%). 1H NMR (400 MHz, DMSO-d6) δ 11.51 (1H, s), 8.29-8.45 (1H, m), 8.18 (1H, br. s.), 8.01 (1H, d, J=7.9 Hz), 7.81 (1H, d, J=7.5 Hz), 7.69 (2H, d, J=4.0 Hz), 7.60-7.65 (2H, m), 7.57 (1H, ddd, J=7.9, 4.2, 4.0 Hz), 7.50 (2H, t, J=7.8 Hz), 7.34 (1H, dd, J=7.7, 1.1 Hz), 6.94-7.06 (2H, m), 6.87 (1H, dd, J=8.3, 1.4 Hz), 4.90-5.04 (2H, m), 4.35 (2H, t, J=5.2 Hz), 1.89 (3H, s), 1.84 (3H, s). Mass spectrum m/z 503.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl.[CH3:10][N:11]([CH2:13][CH2:14]Cl)[CH3:12].[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>C(C(C)=O)C>[CH3:10][N:11]([CH2:13][CH2:14][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:12]
Reactant: CN(C)CCCl
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CN(C)CCOc1ccc(Br)cc1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A mixture of 4-bromophenol (5.0 g, 28.9 mmol), 2-(N, N-dimethylamino)ethyl chloride, hydrochloride (6.24 g, 43.4 mmol), sodium iodide (600 mg, 4 mmol), cesium carbonate (28 g, 86.7 mmol) and methyl ethyl ketone (120 ml) was heated to reflux for 4 h. After cooling to r.t., the mixture was filtered and washed with acetone. The combined filtrates were concentrated in vacuo, and the residue was chromatographed on silica gel (dichloromethane/methanol 95:5 to 90:10) to give a pale yellow liquid. Bulb-to-bulb distillation (80-84° C./0.05 mmHg) afforded the title compound (5.19 g, 74%) as a colorless liquid.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([CH3:12])=[C:7]([C:9]([CH3:11])=O)[N:8]=1)[CH2:2][CH3:3].[C:13](OCC)(=[O:16])[NH:14][NH2:15]>C(O)(=O)C.C(O)CCC>[CH3:11][C:9]1[C:7]2[N:8]([C:4]([CH2:1][CH2:2][CH3:3])=[N:5][C:6]=2[CH3:12])[C:13](=[O:16])[NH:14][N:15]=1
Reactant: CCOC(=O)NN
Reactant: CCCc1nc(C(C)=O)c(C)[nH]1
Solvent: CCCCO
Solvent: CC(=O)O
Product: CCCc1nc(C)c2c(C)n[nH]c(=O)n12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 59.7 g. of methyl 2-n-propyl-5-methyl-4-imidazolyl ketone, 41.14 g. of ethyl carbazate, 200 ml. of n-butanol and 4 drops of glacial acetic acid is warmed until solution is complete and then heated under reflux for 5 hours. The solution is concentrated in vacuo to an oily residue, 250 ml. of diphenyl ether are added and the resulting solution is heated with stirring in an oil bath for 30 minutes after the start of gas evolution. The temperature is maintained as closely as possible to the point at which gas evolution starts (150°-250°C.). The reaction is removed from the oil bath, cooled to 50° C. and diluted with 1-2 volumes hexane. The product is collected, washed with petroleum ether and then dissolved in 200 ml. of chloroform. This solution is filtered through 250 ml. of Magnesol® followed by an 800 ml. chloroform wash. The filtrate is concentrated in vacuo and the residue is recrystallized from 250 ml. of ethyl acetate, giving 48.2 g. of the desired product as off-white crystals, m.p. 154°-155° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4]([CH3:14])[N:3]=1.[C:15]1([N:21]2[CH:25]=[CH:24][C:23](=[O:26])[NH:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.CCOCC>[CH3:14][C:4]1[N:5]=[C:6]([CH3:13])[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([O:26][C:23]2[CH:24]=[CH:25][N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:22]=2)[N:3]=1
Reactant: O=c1ccn(-c2ccccc2)[nH]1
Reactant: COC(=O)Cc1c(C)nc(C)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc(C)nc1Oc1ccn(-c2ccccc2)n1

Procedure:
A mixture of methyl (4-chloro-2,6-dimethyl-5-pyrimidinyl)-acetate (5.0 g, 23 mmol), 1-phenyl-1H-pyrazol-3-on (3.73 g, 23 mmol), potassium carbonate (5,5 g, 40 mmol) in dimethylformamide (30 ml) is heated at +120° C. for 2 hours. Addition of water, extraction with ether and drying gives the intermediate methyl 2-[2,4-dimethyl-6-(1-phenyl-1H-pyrazol-3-yloxy)-pyrimidin-5-yl]-acetate as a yellow oil.