Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].C(N(CC)CC)C>ClCCl>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(CCO)CC2)cc1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 415 μL (3.38 mmol) of 1-piperazineethanol in 20 mL of dichloromethane were added 500 mg (2.26 mmol) of 4-nitrobenzenesulfonyl chloride and 472 μL (3.38 mmol) of triethylamine under ice cooling, and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was diluted with dichloromethane and the organic layer was washed with water, saturated sodium bicarbonate aqueous solution and saturated saline solution and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to give 670 mg (94%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[C:8](Cl)(Cl)=[O:9]>C(OCC)(=O)C>[Br:7][C:4]1[S:3][C:2]([N:1]=[C:8]=[O:9])=[N:6][CH:5]=1
Reactant: Nc1ncc(Br)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1ncc(Br)s1
Reaction time: 3 h

Procedure:
2-Amino-5-bromothiazole (19.0 grams) and a saturated solution of phosgene in ethyl acetate (200 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture was cooled and filtered to recover the desired product 5-bromothiazol-2-yl isocyanate dimer as a fine yellow powder.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH2:11].Cl[C:13]1[N:14]=[N+:15]([O-:26])[C:16]2[CH:25]=[C:24]3[C:20]([CH2:21][CH2:22][CH2:23]3)=[CH:19][C:17]=2[N:18]=1>COCCOC>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH:11][C:13]1[N:14]=[N+:15]([O-:26])[C:16]2[CH:25]=[C:24]3[C:20]([CH2:21][CH2:22][CH2:23]3)=[CH:19][C:17]=2[N:18]=1
Reactant: CC1CCCC(C)N1CCN
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Solvent: COCCOC
Product: CC1CCCC(C)N1CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Yield: 81.4 %

Procedure:
2-(2,6-Dimethyl-1-piperidinyl)ethylamine (280) (0.66 g, 4.3 mmol) was added to a stirred solution of chloride 21 (314 mg, 1.4 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 3 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 38 (389 mg, 80%) as a yellow solid: mp (MeOH) 173-175° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.38 (s, 1H, H-5), 5.47 (br s, 1H, NH), 3.50-3.55 (m, 2H, CH2N), 2.96-3.03 (m, 4H, CH2N, CH2), 2.87-2.91 (m, 2H, CH2), 2.48-2.57 (m, 2H, CH2N), 2.10-2.18 (m, 2H, CH2), 1.64-1.69 (m, 1H, CH2), 1.53-1.58 (m, 2H, CH2), 1.33-1.38 (m, 1H, CH2), 1.24-1.31 (m, 2H, CH2), 1.20 (d, J=6.3 Hz, 6H, 2×CH3); 13C NMR δ 158.8, 154.5, 148.8, 143.2, 129.8, 120.6, 114.7, 57.2 (2), 47.5, 39.4, 34.3, 33.1 (2), 32.3, 25.8, 24.4, 21.7 (2). Anal. calcd for C19H27N5O: C, 66.8; H, 8.0; N, 20.5. Found: C, 66.8; H, 7.8; N, 20.6%.
Reaction SMILES: C(N1CCN(C2N=C(Br)C=C3C=CSC=23)CC1)C.[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:41]=[CH:40][C:39]([C@H:42]4[CH2:47][C@H:46]([O:48]C(=O)C)[CH2:45][CH2:44][O:43]4)=[CH:38][CH:37]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:23][CH2:22]1)[CH3:20].[ClH:52]>C(OCC)(=O)C>[ClH:52].[ClH:52].[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:37]=[CH:38][C:39]([C@H:42]4[CH2:47][C@H:46]([OH:48])[CH2:45][CH2:44][O:43]4)=[CH:40][CH:41]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:23][CH2:22]1)[CH3:20]
Reactant: CCN1CCN(c2nc(-c3ccc([C@H]4C[C@H](OC(C)=O)CCO4)cc3)cc3ccsc23)CC1
Agent: CCN1CCN(c2nc(Br)cc3ccsc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc([C@H]4C[C@H](O)CCO4)cc3)cc3ccsc23)CC1
Reaction time: 1 h

Procedure:
The resulting compound and 7-(1-ethylpiperazin-4-yl)-5-bromothieno[2,3-c]pyridine (0.21 g) were reacted in the same manner as in Example 300-4, to give a reaction solution containing 7-(4-ethylpiperazin-1-yl)-5-[4-(trans-4-acetoxytetrahydropyran-2-yl)phenyl]thieno[2,3-c]pyridine. To the resulting reaction solution were added ethyl acetate and 2N hydrochloric acid, and the resulting insoluble matters were filtered off. The aqueous layer was separated, while the organic layer was extracted with 2N hydrochloric acid. The aqueous layers were combined and washed with ethyl acetate twice. The pH of the solution was adjusted to pH 10 by adding a 8N aqueous solution of sodium hydroxide thereto, and then the solution was extracted with ethyl acetate twice. The extract was washed with brine, dried over magnesium sulfate and the solvent was evaporated. Methanol (10 ml) was added to the resulting residue and dissolved, followed by the addition of a 5N aqueous solution of sodium hydroxide solution (1 ml). The resulting solution was left as it was at room temperature for 1 hr, and then the solvent evaporated. Water was added thereto, and then the mixture was extracted with ethyl acetate thrice. The extract was washed with brine, dried over magnesium sulfate, and then the solvent was evaporated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate/n-hexane system), to give 0.18 g of the free compound of the title compound as a colorless amorphous.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:27]=1)=[C:5]([CH3:20])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][C@H:15]([CH3:19])[CH2:14]1)=[N:7]2.[CH3:34][N:35]=[C:36]=[O:37]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:27]=1)=[C:5]([CH3:20])[C:6]([N:13]1[CH2:18][CH2:17][N:16]([C:36]([NH:35][CH3:34])=[O:37])[C@H:15]([CH3:19])[CH2:14]1)=[N:7]2
Reactant: CN=C=O
Reactant: Cc1c(N2CCN[C@H](C)C2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: CNC(=O)N1CCN(c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)C[C@H]1C

Procedure:
Prepared according to Procedure N using (R)-5,7-difluoro-3-methyl-2-(3-methylpiperazin-1-yl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine (50.0 mg, 0.11 mmol) and methylisocyanate to give (R)-4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-N,2-dimethylpiperazine-1-carboxamide. 1H NMR (CDCl3) δ ppm 7.93 (1H, d, J=2.5 Hz), 7.68 (1H, d, J=2.3 Hz), 7.27-7.33 (1H, m), 6.92 (1H, d, J=12.7 Hz), 6.79 (1H, ddd, J=13.8, 8.8, 2.6 Hz), 6.58 (1H, t, J=2.3 Hz), 4.58 (1H, q, J=4.3 Hz), 4.16-4.29 (1H, m), 3.78-3.92 (5H, m), 3.68-3.78 (1H, m), 3.54-3.64 (1H, m), 3.36 (1H, td, J=12.4, 3.3 Hz), 3.11-3.25 (5H, m), 2.95 (1H, td, J=12.4, 3.4 Hz), 2.85 (3H, d, J=4.5 Hz), 2.09 (3H, s), 1.30 (3H, d, J=6.7 Hz). Mass Spectrum (ESI) m/e=512.3 (M+1).
Reaction SMILES: [O-2].[Al+3].[O-2].[O-2].[Al+3].[N+:6]([C:9]1[CH:10]=[C:11]2[C:16](=[O:17])[NH:15][C:13](=[O:14])[C:12]2=[CH:18][CH:19]=1)([O-])=O.[H][H].[N+](C1C=CC=C2C(NC(=O)C=12)=O)([O-])=O>N.O[V](=O)=O.[Pd].CO>[NH2:6][C:9]1[CH:10]=[C:11]2[C:16](=[O:17])[NH:15][C:13](=[O:14])[C:12]2=[CH:18][CH:19]=1
Reactant: [H][H]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Agent: O=[V](=O)O
Agent: [Pd]
Agent: N
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)NC2=O
Temperature: 25 °C
Reaction time: 43 h
Yield: 100 %

Procedure:
0.002 g of ammonium vanadate and 4 g of aluminium oxide granules containing 0.5% by weight of metallic palladium and having a particle size of 3.2 mm (from Acros Organics) are added to a suspension consisting of 250 ml of methanol and 9.6 g of 4-nitrophthalimide. After displacing the air with nitrogen, the latter is replaced by hydrogen at atmospheric pressure and the suspension is stirred at room temperature for 43 hours. During this time, 97.6% of the theoretical amount of hydrogen, based on the nitrophthalimide, is absorbed. The resulting suspension is then sieved through a sieve having a mesh width of 1 mm. The material remaining on the sieve is washed with methanol and the methanol is subsequently removed from the combined methanol phases by means of a rotary evaporator. Drying at 60° C. under reduced pressure (125 mbar) gives 8.1 g (100%) of 4-aminophthalimide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:26])([F:25])[F:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[B-](F)(F)(F)[F:28].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:25])([F:26])[F:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[CH:17]([F:28])[CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: F[B-](F)(F)F
Reactant: O=C1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: O=C1c2ccc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)cc2CC1F
Temperature: 25 °C

Procedure:
To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2,3-dihydro-1H-inden-1-one (0.5 g, 1.24 mmol) in acetonitrile (20 mL), was added Selectfluor® (0.52 g, 1.48 mmol) and the reaction was heated to reflux temperature for 16 h. The reaction mixture was cooled to ambient temperature, concentrated under reduced pressure and diluted with CH2Cl2. The solution was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in petroleum ether) to afford the title compound as a pale yellow semi solid (0.1 g, 24%): 1H NMR (400 MHz, CDCl3) δ 7.80 (m, 1H), 7.48 (m, 2H), 7.32 (m, 2H), 6.65 (d, J=16.0 Hz, 1H), 6.54 (dd, J=16.0, 8.0 Hz, 1H), 5.38 (m, 1H), 4.18 (m, 1H), 3.62 (m, 1H), 3.32 (m, 1H); ESIMS m/z 419.06 ([M−H]−); IR (thin film) 1728, 1114, 817 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.Cl.[NH2:12][OH:13]>CO.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[N:12][OH:13]
Reactant: NO
Reactant: Cc1ccc(C=O)cc1Cl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(C=NO)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
In a solution of 5.0 g of 3-chloro-4-methylbenzaldehyde in 40 mL of methanol and 30 mL of water, 4.7 g of hydroxylamine hydrochloride was added, and stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was diluted with 70 mL of ethyl acetate, washed with water (30 mL×1), and then dehydrated with and dried over saturated sodium chloride and anhydrous sodium sulfate in that order, and the solvent was distilled off under reduced pressure to obtain 5.1 g of the aimed product as white crystal. The resulting product was used as such without purification for the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]3[O:32][CH:33]=[CH:34][N:35]=3)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([C:31]5[O:32][CH:33]=[CH:34][N:35]=5)=[CH:28][CH:29]=4)[CH:24]=[CH:23]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: c1coc(-c2ccc3[nH]ccc3c2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(-c5ncco5)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and 2-(1H-indol-5-yl)oxazole (intermediate-67).
Reaction SMILES: O.CC([NH:6][S:7]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[S:22][CH3:23])(=[O:9])=[O:8])(C)C>FC(F)(F)C(O)=O>[CH3:23][S:22][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]=1[S:7]([NH2:6])(=[O:9])=[O:8]
Reactant: CSc1cccc(-c2ccccc2)c1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CSc1cccc(-c2ccccc2)c1S(N)(=O)=O
Yield: 77.6 %

Procedure:
In a mixture of 75 ml trifluoroacetic acid plus 2 ml water was dissolved 10 g (0.030 mol) of N-(1,1-dimethylethyl)-2-(methylthio)-6-phenylbenzenesulfonamide and heated to 85°. After 15 minutes the mixture was cooled and evaporated, then diluted with water and extracted with methylene chloride. The methylene chloride was washed with saturated sodium bicarbonate solution, dried (MgSO4), evaporated in vacuo and crystallized from ether/hexanes to afford 6.5 g of the title compound, m.p. 167°-168°.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)[CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[CH3:33][CH:34]([CH3:38])[C:35](=[O:37])[CH3:36].[Cl-].[NH4+]>O1CCCC1>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:14]=[C:15]([C:35]([OH:37])([CH:34]([CH3:38])[CH3:33])[CH3:36])[CH:16]=[CH:17][CH:18]=2)[CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)C(C)C
Reactant: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)C(C)(O)c1cccc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: -40 °C
Yield: 43.3 %

Procedure:
Compound 78 (2.00 g; 5.78 mmol) was dissolved in tetrahydrofuran (20 ml). While the solution was stirred at −40° C. under nitrogen atmosphere, n-butyl lithium in n-hexane (1.56 M: 3.7 ml; 5.8 mmol) was added dropwise. After completion of the addition, the mixture was cooled to −75° C., an 3-methyl-2-butanone (2.00 g) in a small amount of tetrahydrofuran was added dropwise thereto. The resultant mixture was gradually brought to room temperature, and the reaction was stopped by dropwise addition of saturated aqueous ammonium chloride solution, followed by extraction with diethyl ether (100 ml). The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 0.86 g of the target compound as brown oily matter (yield: 43.3%).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=O)[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2=[CH:22][S:23][CH:24]=[C:4]2[C:3]1=O.B.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2=[CH:22][S:23][CH:24]=[C:4]2[CH2:3]1
Reactant: CN1C(=O)c2cscc2N(C(=O)Cc2ccccc2)c2ccccc21
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1Cc2cscc2N(CCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of 6.0 g. of 4,9-dihydro-9-methyl-4-phenylacetyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. of dried tetrahydrofuran, cooled in an ice bath, is added 125 ml. of 1 M borane in tetrahydrofuran, dropwise over 10 minutes. The mixture is stirred at room temperature for one hour, refluxed for 6 hours and then stirred at room temperature for 16 hours. The reaction is decomposed by the addition of 50 ml. of 6 N hydrochloric acid and then 75 ml. of 5 N sodium hydroxide is added. Most of the solvent is evaporated, the residue is extracted with methylene chloride and the extract is evaporated to an oil. This oil is dissolved in hot hexane, filtered through diatomaceous earth and evaporated to an oil which crystallizes giving the desired product as colorless crystals, mp. 53°-56° C.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[C:5]([C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=1[OH:21])[CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])([CH3:8])([CH3:7])[CH3:6].Cl.C([O-])(O)=O.[Na+]>O.CO.C(Cl)Cl.O1CCOCC1>[C:5]([C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=1[OH:21])[CH2:12][C@@H:13]([C:15]([O:17][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:16])[NH2:14])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)c1cc(C[C@H](N)C(=O)O)ccc1O
Reactant: C=C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a 250 mL round bottomed flask equipped with a magnetic stirrer were added 30 mL of isobutylene (condensed at −78° C.), 1.30 g of 3-tert-butyl-L-tyrosine.HCl, 60 mL of 1,4-dioxane, and 0.5 mL of concentrated H2SO2. The flask was sealed with a rubber septum and wired shut. After stirring at RT for 18 h, the flask was vented and the contents poured into a solution of 10 g of NaHCO3 in 150 mL of water. The mixture was subjected to rotary evaporation to remove isobutylene. An emulsion resulted which was extracted with EtOAc (4×40 mL). The combined extracts were washed with 5% aqueous NaHCO3 (3×50 mL), dried over anhydrous MgSO4, and concentrated to give a light yellow foam. Analysis of the product by tlc (SiO2, 95:5 CH2Cl2:MeOH) indicated major and minor components at Rf=0.45 and 0.49 respectively. The Rf=0.45 product was isolated by flash chromatography on silica gel (95:5 CH2Cl2:MeOH) to afford 0.61 g (44%) of tert-butyl 3-tert-butyl-L-tyrosinate as a white foam, m.p. 43-52° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[O:17]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH2:19][CH:18]1[CH2:27][NH2:28]>>[O:17]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH2:19][CH:18]1[CH2:27][NH:28][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: NCC1COc2ccccc2O1
Product: Oc1cccc(Nc2nc(NCC3COc4ccccc4O3)ncc2F)c1

Procedure:
In like manner to the preparation of N4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine were reacted to give N2-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 19.26 min.; purity: 96.2%; MS (m/e): 369.08 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:43]=[CH:42][C:32]([C:33]([NH:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:34])=[C:31]([F:44])[CH:30]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:43]=[CH:42][C:32]([C:33]([NH:35][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)=[O:34])=[C:31]([F:44])[CH:30]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(C(=O)NC2CCCCC2)c(F)c1
Product: O=C(NC1CCCCC1)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1F

Procedure:
Use a method similar to the General Procedure 5-2 to react 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 mg, 1.17 mmol) with 4-aminomethyl-N-cyclohexyl-2-fluoro-benzamide (441 mg, 1.76 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (20:1, 10:1, 7:1 and 5:1) to give 7-chloro-6-[4-(cyclohexylaminocarbonyl-)3-fluoro-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12]([CH:15]=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:22][C:23]#[N:24]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21](/[C:22](=[CH:15]/[C:12]2[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=4[CH:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)/[C:23]#[N:24])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1cc2ccccc2c2ccccc12
Product: COc1ccc(/C(C#N)=C/c2cc3ccccc3c3ccccc23)cc1OC
Yield: 63 %

Procedure:
Phenanthrene-9-aldehyde (250 mg) was condensed with 3,4-dimethoxybenzyl cyanide (214 mg) through Method A (production step 2), to thereby yield the target product (yield: 278 mg, 63%).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C@@H:12]([OH:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][CH2:3]2.CC(=O)[C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)[C@H](CC(O)CC2)CC3)CC1>>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][CH2:3]2
Reactant: C[C@@]12CCC[C@H]1[C@@H]1CC[C@@H]3C[C@H](O)CC[C@]3(C)[C@H]1CC2
Agent: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: C[C@@]12CCC[C@H]1[C@@H]1CC[C@@H]3CC(=O)CC[C@]3(C)[C@H]1CC2
Yield: 98.8 %

Procedure:
Using the same process, 5β-androstane-3α-ol and 5α-pregnane-3-ol -20-one were oxidized to obtain a 98.8% yield of 5β-androstane-3-one and a 94.3% yield of 5α-pregnane-3,20 -dione respectively.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)[CH:4]=[CH:3][C:2]=1[C:15](=O)[CH3:16].C([O-])(=O)C.[NH4+:22].N.O.[OH-].[Na+]>[Zn]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)[CH:4]=[CH:3][C:2]=1[CH:15]([NH2:22])[CH3:16]
Reactant: [NH4+]
Reactant: CC(=O)c1ccc2ccc3ccccc3c2n1
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: O
Product: CC(N)c1ccc2ccc3ccccc3c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
A solution of the oxime of 1-(benzo[h]quinolin-2yl)ethanone (2.60 g, 11.0 mmol) and ammonium acetate (1.05 g, 13.6 mmol) in a mixture consisting of 30% NH3/H2O/96% EtOH (39.5/26.3/26.3 ml) was stirred at ambient temperature for 30 minutes. Zinc in powder form (3.95 g, 60.4 mmol) was then added in small portions (at ambient temperature) over a period of 2 hours, and the resulting mixture was heated under reflux for 3 hours. The grey precipitate formed was filtered off under reduced pressure and the solvent was evaporated to give a residue that was alkalized with 10% NaOH, and extracted with Et2O (3×30 ml). The organic phases were combined, dried over anhydrous Na2SO4 and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography using MeOH as eluent to give 1.88 g (77% yield) of 1-(benzo[h]quinolin-2-yl)ethanamine in the form of an orange coloured oil.