Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7]/[C:8]/2=[CH:13]\[C:14](=[N:23]/[CH2:24][C:25](OCC)=[O:26])\[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1.Cl.C(OC(=O)CN)C>CCO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]1[C:25](=[O:26])[CH2:24][N:23]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[CH:13]=[C:8]12
Reactant: CCOC(=O)C/N=C(\C=C1/NCCc2c(OC)cccc21)c1cccc(OC)c1
Agent: CCOC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: COc1cccc(C2=NCC(=O)N3CCc4c(OC)cccc4C3=C2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
ethyl 2-((E)-((Z)-2-(5-methoxy-3,4-dihydroisoquinolin-1(2H)-ylidene)-1-(3-methoxyphenyl)ethylidene)amino)acetate. 1-2. A mixture of 1-1 (5.8 g, 18.81 mmol) and glycine ethyl ester hydrochloride (13.1 g, 94 mmol) in EtOH (200 mL) was heated to 100° C. and stirred for 2 h. The reaction was then cooled to RT and the mixture was concentrated in vacuo. The residue obtained was taken up in DCM and washed with a 1 M aq. solution of NaOH. The org. layer was then dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (7.0 g) as a brown oil that was used as it is in the next step. UPLC-MS: MS 395.3 (M+H+); UPLC rt 0.80 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:15][O:16][CH3:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[CH3:17][O:16][CH2:15][CH:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=1
Reactant: COCC(c1cccc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: COCC(c1cccc(C(F)(F)F)c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-[2-Methoxy-1 -(3-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.387 mmoles) in neat trifluoroacetic acid (3 mL) was stirred at room temperature for one hour. The mixture was concentrated to dryness and pumped on high vacuum to give 1-[2-Methoxy-1-(3-trifluoromethyl-phenyl)-ethyl]-piperazine trifluoroacetate as an oil. The material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][NH:7][C:8](=[NH:10])[NH2:9])=O>O>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]1[N:9]=[C:8]([NH2:10])[NH:7][N:6]=1
Reactant: N=C(N)NNC(=O)c1ccccc1Cl
Solvent: O
Product: Nc1nc(-c2ccccc2Cl)n[nH]1

Procedure:
A solution of 2-(2-chlorobenzoyl)hydrazinecarboximidamide (3 g, 14.1 mmol) in water (10 mL) was stirred for 4 h at 100° C. After the reaction was completed, the solids were collected by filtration, and washed with H2O (3×5 ml). This resulted in 1.5 g (55%) of 3-(2-chlorophenyl)-1H-1,2,4-triazol-5-amine as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1I.[CH:15]([Sn](CCCC)(CCCC)CCCC)=[CH2:16]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[CH:15]=[CH2:16]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1nc(Cl)c(Cl)c(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1c(C(=O)OC)nc(Cl)c(Cl)c1N
Yield: 184.6 %

Procedure:
Methyl 4-amino-5,6-dichloro-3-iodopicolinate (0.5 g, 1.4 mmol), vinyltributylstannane (530 μl, 0.57 mmol, 1.8 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.10 g, 0.1 mmol) were combined in nitrogen-deaerated 1,2-dichloroethane (10 mL). The reaction mixture was heated at reflux for 8 hours. The cooled reaction mixture was diluted with ethyl acetate (30 mL) and stirred with 15% KHF2 solution (10 mL) for 30 minutes. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (SiO2, ethyl acetate/hexane) to afford the title compound as a tan solid (0.26 g, 73%): mp 96-97° C.; 1H NMR (400 MHz, CDCl3) δ 6.85 (dd, J=18.1, 11.5 Hz, 1H), 5.72 (dd, J=11.5, 1.3 Hz, 1H), 5.53 (dd, J=18.1, 1.3 Hz, 1H), 5.19 (s, 2H), 3.91 (s, 3H); EIMS m/z 246 ([M−H)−].
Reaction SMILES: [CH3:1]/[C:2](=[CH:7]\[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)/[CH2:3][CH2:4][CH:5]=O.Cl.[NH2:16]O>C(O)C>[CH3:1]/[C:2](=[CH:7]\[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)/[CH2:3][CH2:4][C:5]#[N:16]
Reactant: NO
Reactant: C/C(=C\c1ccc(C)cc1)CCC=O
Agent: Cl
Solvent: CCO
Product: C/C(=C\c1ccc(C)cc1)CCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
(4E)-4-methyl-5-(4-methylphenyl)-4-pentenal (3.2 g, 0.017 mol) and hydroxylamine hydrochloride (1.77 g, 0.025 mol) were heated together in 95% ethyl alcohol (55 ml) at reflux for 4 hours. After cooling to room temperature, ethanol was removed on the rotavapor. The residue was stirred in diethyl ether (250 ml) for 30 minutes. The solid was filtered off, rinsed with diethyl ether and discarded. The filtrate was evaporated under vacuum. The product was purified by column chromatography on silica gel (eluent: heptane/ethyl acetate 11:1) followed by bulb-to-bulb distillation. 2.18 g of the desired compound were obtained (0.012 mol, 70% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([N+:25]([O-:27])=[O:26])[C:22]=1[O:23][CH3:24])[CH:18]=[O:19]>O1CCCC1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:19])[CH:20]=[C:21]([N+:25]([O-:27])=[O:26])[C:22]=1[O:23][CH3:24]
Reactant: Brc1ccccn1
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccccn2)cc([N+](=O)[O-])c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.76 ml of 2-bromopyridine dissolved in 30 ml of absolute tetrahydrofuran are treated -60° within 30 minutes with 19.2 ml of 1.6M n-butyl lithium solution (in hexane), whereupon the mixture is stirred at -60° for 30 minutes, 6.0 g of 3,4-dimethoxy-5-nitrobenzaldehyde dissolved in 50 ml of tetrahydrofuran are then added dropwise thereto at -40° within 30 minutes. The reaction mixture is warmed to 0° within 2 hours, poured into ice-water and extracted with ethyl acetate. The combined extracts are dried over sodium sulfate and evaporated, and the residue is chromatographed on 200 g of silica gel with ethyl acetate. There is obtained α-(3,4-dimethoxy-5-nitrophenyl)-2-pyridinemethanol as a brown oil.
Reaction SMILES: [CH:1]([SiH:4]([CH:14]([CH3:16])[CH3:15])[C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+].[NH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].Cl>>[CH:1]([SiH:4]([CH:14]([CH3:16])[CH3:15])[C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)[SiH](c1ccc(C(=O)Cl)cc1)C(C)C
Reactant: NCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)[SiH](c1ccc(C(=O)NCCCC(=O)O)cc1)C(C)C
Reaction time: 8 h
Yield: 65 %

Procedure:
4-diisopropylsilanylbenzoyl chloride (2) (1.7 g, 6.7 mmol) was added into 1N sodium hydroxide aqueous solution (9 mL) dissolving 4-aminobutanoic acid (910 mg. 8.94 mmol) and stirred for 8 hours. After the addition of 12N hydrochloric acid to the aqueous solution to reach pH 2, the solution was extracted with 400 mL of CH2Cl2 and an organic layer was then collected. The resulting organic layer was dehydrated with anhydrous sodium sulfate and filtered so that the resulting solvent was distilled out under a reduced pressure. A desired compound was then purified by silica gel column chromatography. After eluted with chloroform having 0-3% methanol gradient, the solvent was distilled out to give the desired compound as white solid (1.4 g, 65%). Its NMR data are as follows:
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C@@H:9]([NH:20]C(=O)OC(C)(C)C)[CH2:10][N:11]2[CH2:18][CH:17]3[O:19][CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][CH:35]=[CH:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:20][C@@H:9]([CH2:10][N:11]1[CH2:18][CH:17]2[O:19][CH:13]([CH2:14][N:15]([CH2:31][CH2:32][N:33]3[CH:37]=[CH:36][CH:35]=[CH:34]3)[CH2:16]2)[CH2:12]1)[CH2:8][O:7][C:6]1[CH:28]=[CH:29][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1ccc(C#N)cc1)CN1CC2CNCC(C1)O2
Reactant: BrCCn1cccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OC[C@@H](N)CN2CC3CN(CCn4cccc4)CC(C2)O3)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.7 %

Procedure:
A mixture of tert-butyl (1S)-2-(4-cyanophenoxy)-1-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylmethyl)ethylcarbamate (Preparation J; 100.62 mg, 0.25 mmol), 1-(2-bromoethyl)pyrrole (52.21 mg, 0.30 mmol) and TEA (37.9 mg, 0.375 mmol) in DMF (2.5 mL) was stirred at rt for 2 days and then at 50° C. for 1 day. The solvent was evaporated and the resulting residue dissolved in ethyl acetate (0.5 mL). Ethyl acetate saturated with gaseous hydrochloric acid (2 mL) was added, and the reaction mixture stirred for 1.5 h at rt. The solvent was evaporated and the resulting residue dissolved in a mixture of MeCN (2.5 mL) and H2O (0.13 mL). Potassium carbonate (100 mg, 0.72 mmol) was added, and the mixture stirred overnight at rt. The mixture was filtered and the filtrate concentrated in vacuo. The resulting crude product was dissolved in DCM (2 mL), which solution was added to a ion-exchange solid-phase extraction plug (CBA, 2 g). After 80 min, the product was eluted with DCM:MeCN (4×2 mL of 4:1), followed by DCM:MeOH:TEA (8:1:1), to give 89.7 mg (90.7%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[C:7]([Cl:13])[CH:6]=2.S(OCC)(O[CH2:18][CH3:19])(=O)=O>[OH-].[Na+]>[NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[S:12][CH2:18][CH3:19])=[CH:9][CH:8]=[C:7]([Cl:13])[CH:6]=2
Reactant: Nc1cnc2cc(Cl)ccc2c1S
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCSc1c(N)cnc2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
21.06 g (0.1 mole) of 3-amino-7-chloro-4-quinoline-thiol are dissolved in 100 ml of a 2 molar sodium hydroxide solution, whereupon 19.27 g (0.125 mole) of diethyl sulfate are added. The reaction mixture is heated to boiling for 2 hours, cooled to room temperature and extracted with dichloro ethane. The dichloro ethane solution is dried, clarified and evaporated. Thus 20.2 g of 3-amino-4-ethylthio-7-chloro-quinoline are obtained, yield 85%, m.p.: 105°-106° C. (after crystallization from methanol).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[N:30]([C:36]3[CH:41]=[CH:40][C:39]([O:42][Si](C(C)C)(C(C)C)C(C)C)=[CH:38][CH:37]=3)[C:31](=[O:35])[N:32]([CH2:33][CH3:34])[C:25]=12)(=[O:21])[CH3:20].[Cl-].[Cl-].[Ca+2]>>[C:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[N:30]([C:36]3[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=3)[C:31](=[O:35])[N:32]([CH2:33][CH3:34])[C:25]=12)(=[O:21])[CH3:20]
Reactant: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2nccc(COC(C)=O)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Ca+2]
Agent: [Cl-]
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(COC(C)=O)c21
Yield: 83.7 %

Procedure:
Tetrabutylammonium fluoride (1.241 ml) was added to a solution of [1-ethyl-2-oxo-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methyl acetate (300 mg) in THF(dry) (1 ml) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 30 min. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20%-100% EtOAc in hexane) to give [1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methyl acetate (170 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:18]C)=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)[CH3:2].Cl.C(Cl)(Cl)Cl.[OH-].[Na+]>C(OCC)(=O)C>[CH2:20]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)[CH3:21]
Reactant: CCN(CC)CCOCCc1ccc(OC)c(C(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCN(CC)CCOCCc1ccc(O)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
In 5.0 mL of ethyl acetate is dissolved 1.20 g of 1-(5-{2-[2-(diethylamino)ethoxy]ethyl}-2-methoxyphenyl)-1-ethanone, to which is added 1.1 mL of 3.7 mol/L solution of dry hydrogen chloride in ethyl acetate. The solvent is distilled off under reduced pressure. The residue is dissolved in 6.0 mL of methylene chloride, to which are successively added at an ice-cooled temperature 1.60 g of aluminum chloride and 0.70 g of sodium iodide. The mixture thus obtained is stirred at ambient temperature for 2 hours. Ice water and chloroform are added to the reaction mixture, pH is adjusted to 8.0 with 1.0 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. Thus, 1.10 g of 1-(5-{2-[2-(diethylamino)ethoxy]ethyl}-2-hydroxyphenyl)-1-ethanone is obtained as an oily product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[CH3:2].[C:15]([O:19][C:20]([N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][CH2:33][O:34][C:35]3[CH:36]=[C:37]4[C:41](=[CH:42][CH:43]=3)[NH:40][CH:39]=[CH:38]4)[N:30]=2)[CH2:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][CH2:33][O:34][C:35]3[CH:36]=[C:37]4[C:41](=[CH:42][CH:43]=3)[N:40]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH:39]=[CH:38]4)[N:30]=2)[CH2:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: CCOC(=O)C#Cc1cccc(Cl)c1
Product: CCOC(=O)C=C(c1cccc(Cl)c1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 90 %

Procedure:
The title compound was synthesized from (3-chloro-phenyl)-propynoic acid ethyl ester and 7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in 90% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) [E/Z mixture] δ 7.36–7.24 (m, 2H), 7.14–7.6.70 (m, 8H), 6.56 (s, 0.5H), 6.48 (m, 0.5H), 6.21 (s, 0.5H), 6.14 (s, 0.5H), 4.37 (m, 2H), 4.12 (q, 2H, J=6.8 Hz), 3.76 (m, 2H), 3.20 (t, 2H, J=6.8 Hz), 2.73 (t, 2H, J=6.8 Hz), 1.92 (m, 2H), 1.52 (s, 9H), 1.26 (t, 3H, J=7.2 Hz). Mass Spectrum (LCMS, ESI) calculated for C29H29ClN3O3 502.2 (M-Boc+1); found 502.4.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:19]([C:20]([CH2:22][OH:23])=[O:21])[C@:18]2([CH3:24])[C@H:4]([C@H:5]3[C@H:15]([C@@H:16]([OH:25])[CH2:17]2)[C@:14]2([CH3:26])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[C@@H:7]([F:27])[CH2:6]3)[CH2:3]1.[C:28]([NH:35][C@H:36]([C:40]([OH:42])=[O:41])[CH:37]([CH3:39])[CH3:38])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)(=O)C.CCCCCC>CN(C)C1C=CN=CC=1.ClCCl.O1CCOCC1>[OH:25][C@H:16]1[CH2:17][C@@:18]2([CH3:24])[C@@H:4]([CH2:3][C@@H:2]([CH3:1])[C@@H:19]2[C:20](=[O:21])[CH:22]([O:42][C:40](=[O:41])[C@@H:36]([NH:35][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH:37]([CH3:38])[CH3:39])[OH:23])[C@H:5]2[C@H:15]1[C@:14]1([CH3:26])[C:8]([C@@H:7]([F:27])[CH2:6]2)=[CH:9][C:10](=[O:11])[CH:12]=[CH:13]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)CO
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC(O)C(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Yield: 45.5 %

Procedure:
26 mmol of fluocortolone (FC) is reacted with 32 mmol of Boc-valine (Boc-Val-OH), 2.9 mmol of 4-dimethylaminopyridine and 34 mmol of dicyclohexylcarbodiimide in dichloromethane/dioxane 3:2. Chromatography (ethyl acetate/hexane 2:1): F1 9.3 g of pure product, F2 4.8 g of slightly contaminated product. (Total yield 92%) crystallization of F1 from ethyl acetate/hexane yields 7.0 g (46%) of (2S)-2-((1,1-dimethylethoxycarbonyl)-amino)-3-methyl-butyric acid [11β,21-dihydroxy-6α-fluoro-16α-methyl-3,20-dioxo-pregna-1,4-dien-21-yl] ester.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:22]=[CH:21][NH:20][N:19]=1>>[NH:20]1[CH:21]=[CH:22][C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)=[N:19]1
Reactant: Nc1cc[nH]n1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Product: c1ccc2c(c1)C[C@H]1CSC(=Nc3cc[nH]n3)N1C2
Yield: 51.7 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (18.2 g) and 3-aminopyrazole (8.3 g) as the starting materials, (S)-3-(pyrazol-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (7.0 g) is obtained in the form of white crystals, m.p.=161° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:37][C@@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[F:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:40]3[CH2:41][CH2:42][C@@H:38]([F:37])[CH2:39]3)=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:20][CH2:19]4)=[CH:29][CH:28]=1
Reactant: COCCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: F[C@@H]1CCNC1
Product: COCCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CC[C@@H](F)C3)nc1)C2

Procedure:
The title compound was prepared by the method of Example 20 using (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-(2-methoxyethoxymethyl)-4,4a,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene and (R)-3-fluoropyrrolidine. 1H NMR (400 MHz, CHCl3-d): δ 8.55-8.44 (m, 1H), 7.50-7.39 (m, 3H), 7.19-7.11 (m, 2H), 6.41 (d, 1H), 6.27 (d, 1H), 5.46 (s, 1H), 5.33 (s, 1H), 4.15 (dd, 1H), 3.87 (dd, 2H), 3.73 (d, 1H), 3.68-3.55 (m, 7H), 3.38 (s, 3H), 3.25 (d, 1H), 3.14 (d, 1H), 2.80-2.69 (m, 1H), 2.39-2.25 (m, 3H), 2.17-2.03 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:22])[O:18][CH2:19][CH2:20]Cl)[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].O>O1CCCC1>[O:22]=[C:17]1[N:16]([C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=2)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:20][CH2:19][O:18]1
Reactant: CC(C)(C)OC(=O)NCc1cccc(NC(=O)OCCCl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cccc(N2CCOC2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.20 g (3.65 mmol) 2-chloro-ethyl [3-(tert-butoxycarbonylamino-methyl)-phenyl]-carbamate and 0.850 g (7.58 mmol) potassium tert.butoxide are placed at 0° C. in 30 ml of tetrahydrofuran and the mixture is stirred for 3 hours at ambient temperature. Then the reaction mixture is added to water and extracted with dichloromethane. The organic phase is dried and evaporated to dryness. The residue is purified by chromatography.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:16])[CH:8]2[C:13](=[O:14])[CH:12]3[CH2:15][N:9]2[CH2:10][CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[C:17]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:16])[CH:8]2[CH:13]([OH:14])[CH:12]3[CH2:15][N:9]2[CH2:10][CH2:11]3)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1C2CCN(C2)C1C(O)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OC1C2CCN(C2)C1C(O)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-(Diphenylhydroxymethyl)-1-azabicyclo[2.2.1]heptan-3-one (210 mg) was dissolved in THF (5 ml) at -78° C. under argon. Lithium aluminium hydride (3 ml, 1.0M in ether) was added and the mixture stirred at -78° C. for 30 min, and then warmed to room temperature whereupon the reaction mixture became homogeneous. Water (0.1 ml) was added followed by sodium hydroxide (0.35 ml, 3N) and water (0.35 ml) affording a granular precipitate. Solid sodium sulphate was added, the mixture was filtered and the filtrate evaporated. The resulting diol was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([Cl:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:10])=[C:4]([Cl:9])[CH:3]=1
Reactant: Cc1ccc(Br)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: Clc1ccccc1
Product: Clc1cc(Br)ccc1CBr
Yield: 27.3 %

Procedure:
4-Bromo-2-chlorotoluene (7.02 g) and N-bromosuccinimide (6.07 g) was stirred in chlorobenzene (50 ml) under ultraviolet light at 100° C. for 18 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by medium-pressure liquid chromatography, eluting with iso-hexane, to give a colourless oil (2.65 g).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([O:15][C:16](=[O:21])[NH:17][CH2:18][CH2:19][NH2:20])([CH3:14])([CH3:13])[CH3:12]>C(Cl)(Cl)Cl>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Clc1nc2ccccc2o1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCNc1nc2ccccc2o1
Temperature: 125 °C
Reaction time: 5 h

Procedure:
A mixture of 2-chlorobenzoxazole (0.6 mL, 5.16 mmol) and N-(2-aminoethyl) carbamic acid tert-butyl ester (2.4328 g, 15.18 mmol)) was stirred in a preheated oil bath at 125° C. for 5 h, then held at room temperature overnight. The solidified mixture was dissolved in chloroform (125 mL), washed with aqueous sodium bicarbonate (2×150 mL), then brine (1×150). The organic layer was dried over sodium sulfate, then filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography, eluting with 60% ethyl acetate in heptane to yield tert-butyl 2-(benzo[d]oxazol-2-ylamino)ethylcarbamate as a beige powder.