Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=[CH:13][N:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:41]=[C:42]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)[CH2:43][NH:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:49][CH:48]=1)=[O:46]>CN(C=O)C.O>[Cl:10][C:11]1[C:16]([C:17]([N:62]2[CH2:61][CH2:60][N:59]([C:42](=[O:41])[CH2:43][NH:44][C:45]([C:47]3[CH:52]=[CH:51][C:50]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[CH:49][CH:48]=3)=[O:46])[CH2:64][CH2:63]2)=[O:19])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cccnc2Cl)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 37.9 %

Procedure:
DIPEA (179.7 mg, 0.24 mL, 1.39 mmol) was added to a stirred solution of 2-chloro-pyridine-3-carboxylic acid (48.6 mg, 0.37 mmol) in DMF (3 mL). HOBT (45.9 mg, 0.34 mmol) and EDCI (148.1 mg, 0.77 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (120 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 90% EtOAc in Hexane as eluent) to afford 65 mg (45.7% yield) of biphenyl-4-carboxylic acid {2-[4-(2-chloro-pyridine-3-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 99.71, 1H NMR (DMSO-d6): δ 8.7-8.6 (t, 1H), 8.5 (d, 1H), 8.0-7.9 (d, 3H), 7.84-7.7 (q, 4H), 7.6-7.46 (m, 3H), 7.44-7.36 (m, 1H), 4.26-4.3 (m, 2H), 3.8-3.58 (m, 4H), 3.58-3.46 (m, 2H), 3.28-3.12 (m, 2H).
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4].[O:10]1[C:14]2=[N:15][C:16]3[C:22](=[O:23])[O:21][C:19](=[O:20])[C:17]=3[CH:18]=[C:13]2[CH:12]=[CH:11]1.CCOCC>O1CCCC1>[C:3]([C:2]([NH:1][C:22]([C:16]1[N:15]=[C:14]2[O:10][CH:11]=[CH:12][C:13]2=[CH:18][C:17]=1[C:19]([OH:21])=[O:20])=[O:23])([CH3:9])[CH:6]([CH3:8])[CH3:7])(=[O:4])[NH2:5]
Reactant: O=C1OC(=O)c2nc3occc3cc21
Reactant: CC(C)C(C)(N)C(N)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C(C)(NC(=O)c1nc2occc2cc1C(=O)O)C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
2-Amino-2,3-dimethylbutyramide (2.1 g, 0.016 mol) is added to a stirred suspension of furo[2,3-b]pyridine-5,6-dicarboxylic acid anhydride (3.0 g, 0.016 mol) in tetrahydrofuran (7.5 mL) and the mixture allowed to stir at room temperature for 16 hours. The reaction mixture is then stirred at 60° C. for one hour, cooled to room temperature, ether added, and the solid filtered off and dried to give 5 g of 6-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]furo[2,3-b]pyridine-5-carboxylic acid mp 192°-196° C. (dec).
Reaction SMILES: [F-].[K+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10](=[O:12])=[O:11]>>[CH:5]1[C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=[C:3]([OH:9])[CH:4]=1
Reactant: Oc1ccccc1
Reactant: O=C=O
Agent: [F-]
Agent: [K+]
Product: O=C(O)c1ccc(O)cc1
Temperature: 120 °C
Yield: 10 %

Procedure:
Using apparatus 4, 10.3 g of KF and 4.3 g phenol were added to apparatus 4. The reactor was pressurized to 114 bar with CO2, the stirrer was set to 800 rpm, and heated at 120° C. for 86 h. Analysis by method 2 showed a yield of 10% PHBA and 5% SA.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:10])[C:8]=1[Br:9])[NH2:5].[N:11]([O-])=O.[Na+].O.O.Cl[Sn]Cl>O.Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:11])[CH:6]=[C:7]([Br:10])[C:8]=1[Br:9]
Reactant: Nc1cc(Br)c(Br)c(Br)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(Br)c(Br)c(Br)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
3,4,5-Tribromoaniline was obtained by the procedure of L. F. Tietze and T. Eicher (L. F. Tietze, T. Eicher. Reaktionen und Synthesen im organisch-chemischen Praktikum und Forschungslaboratorium. (1991) Georg Thieme Verlag, Stuttgart, N.Y.). 7.8 g (24 mmol) of 3,4,5-tribromoaniline were stirred with a solution of 6.5 mL of concentrated hydrochloric acid and 6.5 mL of water. The mixture was cooled to about −10° C. and at this temperature the solution of 2.76 g of NaNO2 in 11 mL of water was added for 20 min with intensive stiffing. The reaction mixture was stirred for 30 min at −10° C. Then the cooled solution of 16.2 g of SnCl2.2H2O in 17 mL of concentrated HCl was added dropwise at −10° C. to the suspension of diazocompound. The reaction mixture was kept at −10° C. for one hour and at 5° C. overnight. The obtained precipitate was filtered off and washed with water. The residue was resuspended in 50 mL of water and concentrated aqueous solution of NaOH was added to get alkaline medium. The 3,4,5-tribromophenylhydrazine was extracted with ether. Organic layer was dried with MgSO4 and ether was evaporated. Yield: 5.5 g (67%). 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 7.09 (2H, s, arom.), 7.34 (1H, s, NH), 4.19 (2H, d, NH2).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[C:4]([CH:19]=[O:20])[CH:3]=1.S(Cl)(Cl)=O.[CH3:25]O>>[CH3:25][O:15][C:14](=[O:16])[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][C:4]=2[CH:19]=[O:20])[CH:8]=1
Reactant: CO
Reactant: O=Cc1cc(Br)ccc1Oc1cccc(CC(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Temperature: 65 °C

Procedure:
To [3-(4-bromo-2-formyl-phenoxy)-phenyl]-acetic acid (1 g, 3.0 mmol) in MeOH (10 mL) was added thionyl chloride (0.43 mL, 6.0 mmol), and the reaction was heated to 65° C. for 2 hours, and then at room temperature overnight. The mixture was quenched with 1N aqueous NaOH and extracted three times with EtOAc, and the combined organic layers were washed with H2O, dried, and concentrated. The residue was purified by silica gel chromatography (20-40% EtOAc in hexanes) to give the desired product (0.7 g); as well as the acetal by-product.
Reaction SMILES: S(C)C.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH2:14][C:13](=O)[NH:12][C:11]=2[CH:17]=1)([O-:6])=[O:5]>C1COCC1>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH2:14][CH2:13][NH:12][C:11]=2[CH:17]=1)([O-:6])=[O:5]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Solvent: CSC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)NCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A solution of BH3.Me2S in THF (2 M, 7.75 mL, 15.5 mmol) was added dropwise to a suspension of 6-nitro-4H-benzo[1,4]oxazin-3-one (0.6 g, 3.1 mmol) in THF (10 mL). The mixture was stirred at room temperature overnight. The reaction was quenched with MeOH (5 mL) at 0° C. and then water (20 mL) was added. The mixture was extracted with Et2O and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine as a red solid (0.5 g, 89%), which was used without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:16])[C:10]2=[N+]=[N-])[C:7]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:3])[CH3:2].[CH2:24](B(CC)CC)[CH3:25].O>C1COCC1>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:16])[CH:10]2[CH2:24][CH3:25])[C:7]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(=[N+]=[N-])C2SC1
Reactant: CCB(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCC1C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CSC12
Temperature: -78 °C

Procedure:
A 2 liter, 3-necked round bottom flask fitted with 2 dropping funnels was charged with 200 ml THF and cooled to -78° C. under N2. One dropping funnel was charged with a solution of 6.33 g (15.3 mM] t-butyl 3-acetyloxymethyl-7-diazo-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate in 300 ml THF. The other funnel was charged with 32 ml 1M-triethylborane in THF, 1.2 ml H2O, and 300 ml THF. The funnels were adjusted so their contents were added to the flask at 2.5 ml/min and the temperature of the reaction mixture maintained at -78°. After the addition, the cooling bath was removed and the reaction mixture allowed to warm. When the temperature reached -45° C., 6.67 ml 30% H2O2 was added. At -15°, the reaction mixture was washed with 300 ml brine, the organic layer diluted with 300 ml CH2Cl2, washed with 300 ml brine, dried over MgSO4, filtered and stripped to give 7.46 g of yellow oil which was chromatographed on a flash column with CHCl3 /EtOAc (25:1) to yield 1.289 g (19%) t-butyl-3-acetyl-oxymethyl-7α-ethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate a 4:1 mixture of the α and β isomers. NMR(CDCl3): δ1.08, t (J=8 Hz), 3H; 1.50, s, 9H; 1.8, br, qt, 2H; 2.05, s, 3H; 3.1, brm, 1H; 3.4, d, 2H; 4.35, d (J=2Hz), 1H; 4.82, AB qt (J=12, 6Hz) 2H.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH3:11])[N+:7]([O-:10])=[CH:8][CH:9]=1)([O-])=O.C([Cl:15])(=O)C>C(OCC)(=O)C.C(Cl)(Cl)Cl>[Cl:15][C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[C:6]([CH3:11])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)cc[n+]1[O-]
Temperature: -12.5 °C
Reaction time: 0.25 h
Yield: 16.8 %

Procedure:
4-nitro-2-picoline N-oxide (20 g, 130 mmol) was added to acetyl chloride (120 ml, 1688 mmol) in a nitrogen atmosphere at −25° C. The mixture was stirred at −30 to 5° C. for 4 hours and 15 minutes. After the reaction mixture was diluted with ethyl acetate (about 150 ml) and chloroform (about 100 ml), the mixture was concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 200 g, elution solvent: heptane, heptane/ethyl acetate=75/25, 50/50, 25/75, ethyl acetate, ethyl acetate/methanol=20/1) to obtain the title compound (3.14 g) as brown oil. Simultaneously, a crude product (about 17 g) was obtained. The crude product thus obtained was further purified by silica gel column chromatography (NH silica gel: 300 g, elution solvent: heptane, heptane/ethyl acetate=75/25, 40/60, 25/75, ethyl acetate) to obtain the title compound (5.39 g) separately as brown oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:22])C=1.C(O)C>ClCCl.C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:22])=[CH:5][N:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ncc(Sc2cccnc2)s1
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1ncc(S(=O)c2cccnc2)s1
Yield: 37.2 %

Procedure:
To a mixture of 2-amino-5-(3-pyridylthio)thiazole (3.0 g) in a mixture of dichloromethane (100 ml) and chloroform (100 ml) was added dropwise the solution of 3-chloroperbenzoic acid (3.4 g) in dichloromethane (50 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for hours. The reaction mixture was washed with aqueous sodium bicarbonate and the aqueous layer was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was recrystallized from ethanol no give 2-amino-5-(3-pyridylsulfinyl)thiazole (1.2 g, yield: 37.2%). mp: 178°-179° C. IR (Nujol): 3300, 3150, 1630, 1580, 1520, 1485, 1325, 1220 cm-1NMR (DMSO-d6, 200 MHZ, ppm): 7.58-7.70 (1H, m), 7.80 (1H, s), 8.00 (2H, s), 7.98-8.05 (1H, m), 8.72 (2H, br s) Mass: M+1 226, M 225, m/e 209, 177, 147
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[O:14]=[C:11]1[NH:10][C:9]2[CH:15]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=2[O:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)CO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1COc2ccc(C(=O)O)cc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 260.6 %

Procedure:
To a solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester (3.13 g, 15.1 mmol) in THF/H2O (3:1; 76 mL) was added a LiOH (4 M in H2O; 19.0 mL, 75.5 mmol), and the solution was stirred at RT for 24 h. The solution was concentrated, diluted with H2O (50 mL), and acidified to pH<1 with conc. HCl. The resulting precipitate was collected by filtration afforded 7.6 g of the title compound contaminated with excess HCl and H2O. MS (ESI): exact mass calculated for C9H7NO4, 193.04; m/z found, 194.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 10.85 (br s, 1H), 7.50-7.47 (m, 2H), 6.99 (d, J=8.3, 1H), 4.63 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]([CH3:20])[C:7](=[CH:21]O)[C:6]2=[O:23].C([O-])(=O)C.[NH4+:28]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]([CH3:20])[C:7](=[CH:21][NH2:28])[C:6]2=[O:23]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CN)C1C
Yield: 46 %

Procedure:
The less polar diasteriomer from the reaction of racemic ethyl 6,7-dimethoxy-3-hydroxymethylene-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate with d-1-(1-naphthyl)ethylamine (see Example 18) was treated with ammonium acetate, according to the procedure of Example 19. This afforded a 46% yield of the title compound, m.p. 92°-95° C., [α]D25 = -91.52° (0.2% in CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:5][NH:6][CH2:7][CH2:8][OH:9].O1C[C@@H]1[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].[C:29]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:30]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:5][N:6]1[CH2:30][CH2:29][O:9][C@@H:8]([CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH2:7]1
Reactant: OCCNCc1ccc(Cl)c(Cl)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reaction time: 2.25 h
Yield: 69.9 %

Procedure:
A mixture of 2-[(3,4-dichlorobenzyl)amino]ethanol (2.038 g) and (S)-2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (2.032 g) in tetrahydrofuran (3.3 ml) was stirred and heated at reflux under nitrogen. After 21.5 h more tetrahydrofuran (12.5 ml) was added and the mixture was cooled to 3°. Triphenyl phosphine (2.793 g) was added and the mixture was stirred until all the solid had dissolved. Diisopropylazodicarboxylate (2.1 ml) was then added over 12 min maintaining the temperature at <7°. After 2.25 h the mixture was allowed to warm to 22°. After 5.3 h more triphenylphosphine (121 mg) and diisopropylazodicarboxylate (0.09 ml) were added. After 22.5 h the reaction mixture was concentrated to near dryness. Propan-2-ol (12 ml) was added and the concentration repeated, this was repeated once more. More propan-2-ol (12 ml) was added and the mixture was heated to 70°. After 0.5 h the slurry was cooled to 22° and then after a further 2 h the product was collected. The bed was washed with propan-2-ol (2×4 ml) and then dried in vacuo at 40° to give the title compound (2.622 g).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.CCN(CC)CC.[Cl:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]([C:30](Cl)=[O:31])[CH:25]=1>C(Cl)Cl>[Cl:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]([C:30]([NH:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:31])[CH:25]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(Cl)ncn1
Yield: 59.8 %

Procedure:
To a stirred and cooled (0° C.) solution of (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (7.15 g, 34.7 mmol) and Et3N (14.0 g, 138.8 mmol) in DCM (100 mL) was added 6-chloropyrimidine-4-carbonyl chloride (5.5 g, 34.7 mmol). After addition, the resulting mixture was stirred at 25° C. for 16 h, at which time LCMS showed the completion of the reaction. The solvent was evaporated and the residue purified by flash chromatography to give the (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide (7.2 g, yield: 60%). LCMS (m/z): 347.0 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.[CH3:31][C:32]1([CH3:40])[C:34]([CH3:36])([CH3:35])[CH:33]1[C:37](O)=[O:38]>CCOC(C)=O.C1COCC1.CCN(CC)CC>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:37]([CH:33]3[C:34]([CH3:36])([CH3:35])[C:32]3([CH3:40])[CH3:31])=[O:38])[S:8][C:4]=2[CH:3]=1
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: Nc1nc2ccc(F)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)C(C(=O)Nc2nc3ccc(F)cc3s2)C1(C)C

Procedure:
A mixture of 6-fluoro-benzothiazol-2-ylamine (1 equiv), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1 equiv), 1-hydroxybenzotniazole, triethylamine (1.1 equiv), and 2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.8 equiv) in 3:1 THF/Et3N (1 M) and were stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with 1 M aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated. Puried by silica gel chromatography afforded the title compound. MS (ESI+) m/z 293 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=1)[C:15]([OH:17])=[O:16].Cl>CN(C)C=O.O>[CH2:3]([O:10][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=1)[C:15]([OH:17])=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccnc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.6 %

Procedure:
To a suspension of sodium hydride (14.0 g) in N,N-dimethylformamide (250 mL) was added dropwise benzyl alcohol (20.6 g) under ice-cooling over 30 minutes and then added 2-chloroisonicotinic acid (25.0 g) thereto. The reaction solution was stirred at room temperature for 2 hours and then at 70° C. for 13 hours. The reaction solution was allowed to cool to room temperature, diluted with about decuple volumes of water, and then adjusted to pH 5 with 5N hydrochloric acid. The resulting crystals were collected by filtration and then washed with water and hexane to give the title compound as a colorless solid (12.6 g).
Reaction SMILES: [NH:1]([CH3:13])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(C)(C)C>C(O)(C)(C)C.[OH-].[Na+].O>[C:19]([N:1]([CH3:13])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:25]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CN[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.6 g of H-MePhe-OH are dissolved in a mixture of tert.-butanol, 25 ml of 10% aqueous KHCO3 solution and 5 ml of 4 N sodium hydroxide. 8 ml of di-tert.-butylcarbonate are added and the mixture stirred for 2 days at room temperature. The reaction mixture is diluted with ca. 100 ml of water and extracted with ether. The aqueous phase is acidified, with stirring to pH 2. The precipitated product is extracted with acetic acid, the extract washed with water and dried over Na2SO4. The liquid is evaporated and the product crystallised from ether/petroleum ether to yield Boc-MePhe-OH. M.P. 87°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH3:13][CH:14](O)[CH:15]=[CH2:16].COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:13]([CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: C=CC(C)O
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(OC)cc2C1=O
Yield: 55 %

Procedure:
A solution of 20.0 g of 6-methoxy-1-indanone, 31.3 ml of 3-buten-2-ol, 53.5 ml of 2,2-dimethoxypropane and 200 mg of p-toluenesulfonic acid in 200 ml of toluene was brought to boiling. The resulting methanol/acetone mixture was distilled off and the reaction solution was subsequently boiled under reflux overnight. After cooling, the solution was washed with 50 ml of saturated sodium hydrogen carbonate solution. The aqueous washing was extracted with 50 ml of ethyl acetate, the organic phases were combined, dried with magnesium sulfate and evaporated in a vacuum. Purification on silica gel (hexane/diethyl ether 5:1) yielded 13.6 g (55%) of (RS)-2-(2-buten-1-yl)-6-methoxy-1-indanone as a pale yellow oil.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][C@@:9]12[C@H:18]3[CH2:19][CH2:20][C@:21]4([CH3:32])[C:25]([C:26]5[CH:27]=[CH:28][CH:29]=[N:30][CH:31]=5)=[CH:24][CH2:23][C@H:22]4[C@@H:17]3[CH2:16][CH:15]=[C:14]1[CH2:13][C@@H](O)C[CH2:10]2.CO.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH3:6][C:5]([O:4][C@@H:1]1[CH2:13][C:14]2[C@@:9]([CH3:10])([C@@H:18]3[C@@H:17]([CH2:16][CH:15]=2)[C@@H:22]2[CH2:23][CH:24]=[C:25]([C:26]4[CH:27]=[CH:28][CH:29]=[N:30][CH:31]=4)[C@@:21]2([CH3:32])[CH2:20][CH2:19]3)[CH2:8][CH2:2]1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (70 g) is added to a suspension of Abiraterone (16 g) in ethyl acetate (48 mL) The mixture is heated to 70° C. until the reaction is complete (about 20 h); the temperature is then reduced to about 50° C. and methanol (28 mL) is added. The resulting mixture is maintained under stirring for 2 h, cooled to room temperature, and ethyl acetate (110 mL) and an aqueous solution of sodium carbonate (450 mL) are added. The phases are separated and the organic phase is treated with decolourising carbon. The organic phase is then concentrated under vacuum and the concentrate is taken up with acetonitrile (about 80 mL) to obtain a sandy solid, which is isolated by filtration (at 0-5° C.) and dried under vacuum at 40° C. for 8 h (about 15 g).