Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH2:4]([O:6][C:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:9](=[C:10]([CH:26]=[O:27])[CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][CH2:16]2)[CH:8]=1)[CH3:5].[BH4-].[Na+]>O>[CH2:4]([O:6][C:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:9](=[C:10]([CH2:26][OH:27])[CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][CH2:16]2)[CH:8]=1)[CH3:5]
Reactant: CCOC1=CC2=C(C=O)C[C@H]3[C@@H]4CCC[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC1=CC2=C(CO)C[C@H]3[C@@H]4CCC[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In 30 ml. of ethanol are dissolved 1 g. of 3-ethoxy-6-formylandrosta-3,5-diene according to reaction (2), and while the solution is stirred at room temperature, 0.1 g. of sodium borohydride is added. After 20 minutes, the reaction mixture is poured into water and extracted with ether. Then, the extract is washed with water and dried with anhydrous sodium sulfate. Finally the solvent is concentrated, whereupon 1 g. of 3-ethoxy-6-hydroxymethylandrosta-3,5-diene is obtained as an oil.
Reaction SMILES: C([S:4][C@H:5]1[N:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:14])[C@@H:6]1[Cl:15])(=O)C.[N+]([O-])([O-])=O.[Ag+:20].C(N(CC)CC)C>CO>[Cl:15][C@@H:6]1[C@@H:5]([S-:4])[N:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:7]1=[O:14].[Ag+:20]
Reactant: COC(=O)CN1C(=O)[C@H](Cl)[C@H]1SC(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CN1C(=O)[C@H](Cl)[C@H]1[S-]
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
A solution of methyl [(3S,4R)-4-acetylthio-3-chloro-2-oxo-azetidin-1-yl]acetate (3.64 g, 0.0145 mol) in methanol (125 ml) was added with stirring in subdued light to a solution of silver nitrate (3.2 g, 0.0188 mol) in methanol (55 ml). Triethylamine (2.6 ml, 0.0187 mol) was then added with ice cooling, and the reaction was stirred for 1 hr at 5-10° C. followed by 40 minutes at room temperature. The mixture was filtered and the solid washed with methanol (x2) and hexane to yield the title compound, 4.19 g (92%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].F[C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([F:19])[C:10]=1[C:11]#[N:12].O>O1CCCC1>[F:19][C:13]1[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:9]([O:7][CH2:6][CH2:5][O:4][CH3:3])[C:10]=1[C:11]#[N:12]
Reactant: COc1cc(F)c(C#N)c(F)c1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1cc(OC)cc(F)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.4 %

Procedure:
Sodium hydride (60% in mineral oil, 0.88 g, 22 mmol) was added to 2-methoxyethanol (1.84 g, 24 mmol) in tetrahydrofuran (20 ml) and the mixture was stirred at room temperature for 20 minutes. 2,6-Difluoro-4-methoxy-benzonitrile (Mol. Cryst. Liq. Cryst. 1989, 172) (3.38 g, 20 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and the solution was extracted with dichloromethane (3×50 ml). The combined organic solutions were dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane as eluant (gradient from 0:100 to 3:97) to give the title compound (3.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28]Br)=[N:26][CH:27]=1.CN(C=O)C>C(#N)C>[Br:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][O:1][C:2]2[CH:7]=[N:6][N:5]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][O:9]3)[C:4](=[O:14])[CH:3]=2)=[N:26][CH:27]=1
Reactant: O=c1cc(O)cnn1C1CCCCO1
Reactant: BrCc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(Br)cn2)cnn1C1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3.29 g (16.7 mmol) 5-hydroxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (preparation 5a) in acetonitrile is added at RT subsequently 4.63 g (33.4 mmol) potassium-carbonate and 4.20 g (16.7 mmol) 5-bromo-2-bromomethyl-pyridine. The reaction mixture is stirred 3 h at RT and 5 mL DMF is added. The reaction mixture is stirred overnight and the solvent is evaporated. To the residue water and tert-butylmethylether is added. The precipitate is collected and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:21][C:13]4=[N:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:22])[NH:8][C:5]2=[N:6][CH:7]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH3:33][CH2:34]O>>[Br:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:21][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20][CH2:33][CH3:34])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:22])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncc(Br)cc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncc(Br)cc21
Temperature: 25 °C

Procedure:
To a solution of (6S)-5′-bromo-2′-oxo-1′,2′,5,7-tetrahydrospiro [cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (described in Intermediate 6) (6.00 g, 16.7 mmol) in EtOH (250 mL) was added concentrated sulfuric acid (2.22 mL, 41.6 mmol) and the resulting mixture was heated at reflux for 18 h. The reaction mixture was cooled to ambient temperature and the volume was reduced to about 80 mL under reduced pressure. The residual mixture was poured into saturated aqueous sodium bicarbonate (100 mL) and the mixture was extracted with EtOAc (2×150 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH 100:0 to 90:10, to give the title compound. MS: m/z=389.9 (M+1).
Reaction SMILES: [I:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O>>[I:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([Cl:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccoc1I
Product: O=C(Cl)c1ccoc1I
Temperature: 70 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To 2-iodofuran-3-carboxylic acid (6.21 g, 26.1 mmol) was added thionyl chloride (20 ml, 274 mmol). The solution was heated while stirring to 70° C. for 5 h. The mixture was reduced in vacuo and the residue azeotroped with toluene (2×30 ml) to afford the crude title compound (6.69 g, 100%), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl[C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=[C:13]([Cl:22])[CH:12]=1.Cl>CCO>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=[C:13]([Cl:22])[CH:12]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(Br)cc1F
Yield: 58 %

Procedure:
4-Bromo-2-fluoroaniline and ethyl 4,6-dichloronicotinate were reacted in a mixture of EtOH and conc. HCl as for example 33, step A. The resultant solid was isolated by filtration and washed with 10% Et2O/Hexane, to give ethyl 4-(4-bromo-2-fluoroanilino)-6-chloronicotinate (58%); m.p. (EtOH/water) 150-152° C. 1H NMR [400 MHz, CDCl3] δ 9.74 (br s, 1H), 8.81 (s, 1H), 7.41 (dd, J=9.6, 2.2 Hz, 1H), 7.38-7.35 (m, 1H), 7.25 (t, J=8.3 Hz, 1H), 6.71 (d, J=1.5 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). MS (FAB+) 375 (16%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(=O)([O-])[O-].[K+].[K+].[N+:20]([CH3:23])([O-:22])=[O:21]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([OH:13])[CH2:23][N+:20]([O-:22])=[O:21])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1c(Cl)cnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])CC(O)c1c(Cl)cnc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a brown clear solution of 3-chloroquinoline-4-carbaldehyde (A275-3) (0.362 g, 1.89 mmol) in THF (1.9 mL) at room temperature was added potassium carbonate (0.078 g, 0.566 mmol) and nitromethane (1.420 mL, 26.4 mmol). The brown homogeneous mixture was stirred at room temperature. After 4 h, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2×50 mL). The organic extract washed with saturated NaCl (1×50 mL), and dried over Na2SO4. The solution was filtered, concentrated in vacuo, and dried under high vacuum to give 1-(3-chloroquinolin-4-yl)-2-nitroethanol (A275-4) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.88-8.93 (1H, m), 8.73 (1H, dd, J=8.6, 0.8 Hz), 8.08 (1H, dd, J=8.4, 1.0 Hz), 7.82 (1H, ddd, J=8.4, 6.9, 1.5 Hz), 7.72 (1H, ddd, J=8.5, 6.9, 1.4 Hz), 6.91 (1H, dd, J=4.5, 1.0 Hz), 6.26 (1H, ddd, J=10.0, 4.6, 3.6 Hz), 5.03-5.12 (1H, m), 4.94-5.01 (1H, m); LC-MS (ESI) m/z 253.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)=[CH2:14]>>[Cl:1][C:2]1[N:3]([C:18]2[CH:19]=[CH:20][C:15]([CH:13]=[CH2:14])=[CH:16][CH:17]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: C=Cc1ccc(B(O)O)cc1
Product: C=Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Yield: 28 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-vinylphenylboronic acid as described in step-1 of Example 29 to afford 2-chloro-1-(4-vinylphenyl)-1H-indole-3-carboxaldehyde (28% yield) as a off white solid. ESI/MS 282 (M+H); RT 3.59 min; NMR 10.22 (1H, s); 8.36 (1H, d, J=6 Hz); 7.65 (2H, d); 7.37 (5H, m); 6.87 (1H, dd); 5.92 (1H, d, J=18 Hz); 5.45 (1H, d, J=12 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@H:28]([CH3:33])[C:29](OC)=[O:30])[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[CH3:34][NH:35][CH2:36][CH2:37][OH:38]>>[OH:38][CH2:37][CH2:36][N:35]([CH3:34])[C:29](=[O:30])[C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: CNCCO
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(=O)N(C)CCO
Yield: 79.9 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with 2-(methylamino)ethanol (0.35 ml, 4.3 mmol) to give the title compound as a solid (173 mg, 79%), except that the mixture was heated at 45° C. for 24 hours and purified on an HPLC column (C18, 5 microns, 19 mm diameter, 100 mm length) of a preparative HPLC-MS system eluting with a mixture of water and acetonitrile containing 2 g/l of ammonium carbonate (gradient). NMR Spectrum (2 rotamers) 1.60-1.63 (m, 3H), 3.18 and 2.93 (s, 3H), 3.41-3.65 (m, 4H), 5.01 and 4.75 (br s, 1H), 5.81 and 5.91 (q, 1H), 6.04 (s, 2H), 7.30-7.36 (m, 2H), 7.66 (s, 1H), 7.71-7.78 (m, 3H), 8.84-8.90 (m, 1H), 8.20 (s, 1H), 8.52 (s, 1H), 8.55 and 8.58 (s, 1H), 11.12 (br s, 1H); Mass spectrum MH+ 504.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9](=O)[C:8]3[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[K+]>C(O)CO>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8]3[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCc2c(Cl)cccc2-c2ccccc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Clc1cccc2c1CCCc1ccccc1-2
Temperature: 0 °C

Procedure:
Under a dry nitrogen atmosphere a stirred mixture of 8-chloro-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-5-one (2.6 grams, 0.011 mole), 85% hydrazine hydrate (5 ml, 0.1 mole), potassium hydroxide (4 grams, 0.071 mole) and ethylene glycol (30 ml) was heated at reflux for 1.5 hours. Sufficient volatiles were removed by distillation to increase the pot temperature to 200° while maintaining reflux. The two-phase reaction mixture was refluxed at that temperature for three hours. The mixture was cooled, poured into ice water, and the resultant mixture extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give a yellow oil. The oil was purified by distillation to give 4-chloro-6,7-dihydro-5H-dibenzo[a,c]cycloheptene (bp 119°-126°/0.15 mm).
Reaction SMILES: [CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:24]([O:26]C)=[O:25])[CH2:5][CH2:4]1)=[O:2].[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:24]([OH:26])=[O:25])[CH2:5][CH2:4]1)=[O:2]
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
In a mixture of THF and ethanol (1:1, v/v. 24.0 ml) was dissolved methyl 1-formyl-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (501 mg). To the solution was added 1N sodium hydroxide solution (15.0 ml), and the mixture was stirred at room temperature for 16 hours. The mixture was a little concentrated, and to the residue was added 1N hydrochloric acid to convert weakly acidic solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give 1-formyl-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (482 mg) as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[S:7](=[O:9])(=[O:8])[C@H:6]2[CH2:10][C:11]([CH3:23])([CH3:22])[O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:24])[N:4]=[C:3]1[N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CCOC(C)=O.CO.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][C:11]([CH3:23])([CH3:22])[CH2:10][C@@H:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:40])([CH3:1])[C:3]([N:25]([C:26]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:32])[C:33](=[O:34])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[N:4][C@:5]3([CH3:24])[C:14]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OC(C)(C)C[C@@H]2S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(N)ccc3OC(C)(C)C[C@@H]2S(=O)(=O)C1(C)C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of tert-butyl N-[(4aS,11bR)-3,3,6,6,11b-pentamethyl-10-nitro-4,4-dioxo-4a,5-dihydro-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (70 mg, 0.120 mmol) (Prepared following the procedure for Intermediate 31 (trans), Step 1 and 2) and 10% Pd/C (38.6 mg, 0.036 mmol) in EtOAc (1.1 mL) and MeOH (1.1 mL) was stirred under hydrogen atmosphere for 16 hours. The mixture was passed through a celite cake and rinsed with ethyl acetate and ethanol. The filtrate was concentrated in vacuo to afford the title compound (66 mg, 0.120 mmol, 100% yield) as a white foam. MS m/z=574.3 (M+Na).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=O)(C)(C)C>>[C:1]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccccc1
Product: O=C(c1ccccc1)N1CCNCC1

Procedure:
This was similarly prepared from benzoic acid (5.02 g) and 1-(tert-butoxycarbonyl)piperazine (7.66 g) and the title compound was isolated as a white solid (7.7 g, 82%). LCMS: Rt 0.51 min; m/z 191 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]1[N:20]=[C:19]([NH:21][C@H:22]2[C:31]3[C:26](=[C:27]([F:32])[CH:28]=[CH:29][CH:30]=3)[O:25][CH2:24][CH2:23]2)[C:18]([N+:33]([O-])=O)=[CH:17][N:16]=1>O.C1COCC1.[Ni]>[CH3:1][O:2][C:3]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]1[N:20]=[C:19]([NH:21][C@H:22]2[C:31]3[C:26](=[C:27]([F:32])[CH:28]=[CH:29][CH:30]=3)[O:25][CH2:24][CH2:23]2)[C:18]([NH2:33])=[CH:17][N:16]=1
Reactant: COc1ccc(CNc2cc(F)ccc2Nc2ncc([N+](=O)[O-])c(N[C@@H]3CCOc4c(F)cccc43)n2)c(OC)c1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNc2cc(F)ccc2Nc2ncc(N)c(N[C@@H]3CCOc4c(F)cccc43)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an Ar atmosphere, a catalytic amount of a Raney Ni solution in water was added to a solution of (R)—N2-(2-(2,4-dimethoxybenzylamino)-4-fluorophenyl)-N4-(8-fluorochroman-4-yl)-5-nitropyrimidine-2,4-diamine (21 mg) in THF. The flask was closed with a septum, evacuated under house vacuum and hydrogen added via balloon. The resulting suspension was stirred at RT for 2 hr, when the H2 balloon was removed, the mixture evacuated and filtered through a plug of celite, that was thoroughly rinsed with THF and MeOH, to yield (R)—N2-(2-(2,4-dimethoxybenzylamino)-4-fluorophenyl)-N4-(8-fluorochroman-4-yl)pyrimidine-2,4,5-triamine that was used directly.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)[N:17]=[C:16]2[OH:32]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([N:17]1[C:16](=[O:32])[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([O:12][CH3:11])[CH:14]=2)[N:18]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)=[O:10]
Reactant: O=C=Nc1ccccc1F
Reactant: COc1ccc2c(c1)c(O)nn2Cc1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(=O)n(C(=O)Nc1ccccc1F)n2Cc1cccc([N+](=O)[O-])c1

Procedure:
1.8 g (0.013 mol) of 2-fluorophenyl isocyanate are added to a solution of 3.0 g (0.01 mol) of 5-methoxy-1-(3-nitrobenzyl)-1H-indazol-3-ol in 100 ml of tetrahydrofuran and the mixture is heated under reflux for 4 hours. It is then concentrated to 20 ml, and the precipitate deposited is filtered off with suction and recrystallized from ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:10])[CH:6]=[C:4]([OH:5])[C:3]=1[OH:17].[O:18]1[C:20]([CH3:25])([CH2:21][CH2:22][CH:23]=[CH2:24])[CH2:19]1.N1CCCCC1>CCOCC>[OH:18][C:20]([CH3:25])([CH2:21][CH2:22][CH:23]=[CH2:24])[CH2:19][O:5][C:4]1[CH:6]=[C:7]([C:9]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:10])[CH:8]=[C:2]([CH3:1])[C:3]=1[OH:17]
Reactant: Cc1cc(C(C)(C)CC(C)(C)C)cc(O)c1O
Reactant: C=CCCC1(C)CO1
Solvent: CCOCC
Solvent: C1CCNCC1
Product: C=CCCC(C)(O)COc1cc(C(C)(C)CC(C)(C)C)cc(C)c1O
Temperature: 120 °C
Reaction time: 168 h
Yield: 25 %

Procedure:
A mixture of 10.5 g (44 mmole) of 3-methyl-5-t-octylcatechol, 11 g (90 mmole) of 1,2-epoxy-2-methyl-5-hexene and 0.75 ml of piperidine was heated at 120° C., with stirring, under nitrogen, for 7 days. The reaction mixture was cooled and dissolved in ether (300 ml), and the resulting solution was washed with water, followed by 1N hydrochloric acid, followed by saturated sodium chloride solution. The washed ethereal solution was dried (MgSO4) and evaporated in vacuo, and the residue was purified by column chromatography on silica gel, eluting with chloroform. This afforded a 25% yield of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH2:12]O)[CH:3]=1.C(N(CC)CC)C.S(Cl)([Cl:23])=O>ClCCl>[Cl:23][CH2:12][C:4]1[CH:3]=[C:2]([F:1])[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(F)c2c(c1)OCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1cc(CCl)cc2c1OCCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
To a solution of (8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methanol (0.84 g, 4.55 mmol) and triethylamine (960 μl, 4.84 mmol) in dichloromethane (20 mL) was slowly added thionyl chloride (400 μl, 5.47 mmol) at 0° C. The solution was stirred at 0° C. for 15 min then at rt for 3 h. Dichloromethane (80 mL) was added and the solution was washed with water (40 mL), saturated aqueous sodium bicarbonate (40 mL) then brine (40 mL) and dried over sodium sulfate. Filtration and concentration gave 7-(chloromethyl)-5-fluoro-2,3-dihydro-1,4-benzodioxine (0.92 g, quantitative yield) as a brown oil. The chloride was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:8]([C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=1[OH:17])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:8]([C:10]1[CH:15]=[C:14]([O:16][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH:13]=[CH:12][C:11]=1[OH:17])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)c1cc(O)ccc1O
Reactant: CC(C)CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)CCCCCCCOc1ccc(O)c(C(=O)Cc2ccccc2)c1
Temperature: 20 °C

Procedure:
A mixture of 40.1 parts of 2,5-dihydroxyphenyl benzyl ketone, 42.7 parts of isodecylbromide, 48.5 parts of potassium carbonate and 400 parts of dry acetone was stirred under reflux for 120 hours. On cooling to 20° C the inorganic salts were filtered off and the acetone filtrates evaporated to give a brown oil. This residue was dissolved in 200 parts of petroleum ether, filtered to remove insoluble matter, and then washed with 4 × 50 parts of N sodium hydroxide solution and finally with water. The petrol solution was dried and evaporated to yield 42.4 parts of 2-hydroxy-5-isodecyloxyphenyl benzyl ketone as a brown oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][N:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:22](=[O:33])[N:23]([CH2:26][C:27]3[N:28]=[CH:29][NH:30][C:31]=3[CH3:32])[CH2:24][CH2:25][C:14]1=2.C(N(CC)CC)C>ClCCl>[CH3:32][C:31]1[N:30]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH:29]=[N:28][C:27]=1[CH2:26][N:23]1[CH2:24][CH2:25][C:14]2[N:13]([CH3:12])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]=2[C:22]1=[O:33]
Reactant: Cc1[nH]cnc1CN1CCc2c(c3ccccc3n2C)C1=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CN2CCc3c(c4ccccc4n3C)C2=O)ncn1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of benzyl chloroformate (0.28 ml) in dichloromethane (10 ml) was added to a stirred solution of 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1one (294 mg) and triethylamine (0.4 ml) in dichloromethane (30 ml) at 20° under nitrogen, and the mixture was stirred overnight. It was then concentrated onto FCC silica and purified by FCC eluting with System A (200:8:1) to give the title compound (62 mg), t.l.c. (System A, 100:8:1) Rf 0.50.