Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.CS(O)(=O)=O.[NH2:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:5]([C:6]#[N:7])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:16]3[C:15](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:14]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Reactant: N#CCC(=O)C1CC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
Into a glass flask having an internal volume of 50 mL, equipped with a stirring apparatus, a thermometer and a reflux condenser, 0.72 g (6.6 mmol) of 3-cyclopropyl-3-oxopropanenitrile, 1.92 g (6.0 mmol) of 2-amino-4′-fluorobenzophenone methanesulfonate having a purity of 97.3% and 10 mL of toluene were put in an atmosphere of nitrogen, and reaction was carried out at 80° C. for 2 hours. After completion of the reaction, the reaction liquid was cooled to room temperature, 7.0 mL (7.0 mmol) of a 1 mol/L sodium hydroxide aqueous solution was added thereto to make the reaction liquid basic, followed by liquid separation, and the obtained organic layer was analyzed by high performance liquid chromatography (absolute quantitative analysis), whereupon 1.70 g (yield: 98%) of 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carbonitrile was formed.
Reaction SMILES: CCCCCC.[H-].[Na+].[Br:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[CH3:18].[CH3:19][O:20][CH2:21]Cl>O1CCCC1.[OH-].[Na+]>[Br:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:19][O:20][CH3:21])=[CH:12][C:11]=1[CH3:18]
Reactant: COCCl
Reactant: Cc1cc(O)cc(C)c1Br
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1cc(C)c(Br)c(C)c1
Temperature: 0 °C
Reaction time: 0.01 h
Yield: 73.6 %

Procedure:
Under nitrogen atmosphere, hexane (50 mL) was added to sodium hydride (50% in oil, 12.6 g, 264 mmol). The mixture was stirred for 30 sec, and stood still, and the supernatant was removed. Tetrahydrofuran (460 mL) was added thereto, and the mixture was cooled to 0° C. A solution of 4-bromo-3,5-dimethylphenol (53.0 g, 264 mmol) in tetrahydrofuran (50 mL) was added slowly dropwise. After completion of the dropwise addition, and the mixture was stirred at 0° C. for 10 min, allowed to warm to room temperature, and was stirred for 20 min. Then, chloromethyl methyl ether (22.3 g, 277 mmol) was added slowly at room temperature, and the mixture was stirred for 24 hr. The reaction mixture was diluted with 1 M aqueous sodium hydroxide solution (80 mL). Tetrahydrofuran was evaporated under reduced pressure, and the residue was extracted with diethyl ether. The extract was washed successively with 2 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-10:90) to give the title compound (47.6 g, yield 74%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]([CH:22]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=3)[CH:5]=[CH:4][C:3]1=2.[H][H]>CO.O1CCOCC1.[Pd]>[CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:22][CH:23]([C:24]([O:26][CH3:27])=[O:25])[C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)C(=Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)OC
Yield: 95.6 %

Procedure:
To a solution of dimethyl 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]benzylidenemalonate (2.55 g, 5.47 mmol) in a mixture of methanol (20 ml) and 1,4-dioxane (150 ml) is added 5% palladium on charcoal (1.20 g). Then the mixture is stirred under an atmosphere of hydrogen at room temperature until hydrogen uptake ceased. The solution is filtered through Celite, and the filtrate is evaporated under a vacuum. The residue is crystallized from ethyl acetate to give the title compound (2.45 g, 96%). HRMS calcd for C28H36O6: 468.5902. Found: 468.5905. MA calcd for C28H36O6: C, 71.77%; H, 7.74%. Found: C, 71.52%; H, 7.76%.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([I:18])=[C:14]([OH:19])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[C:22]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([I:18])=[C:14]([O:19][CH3:22])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2ccc(I)c(O)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(I)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
To 748 mg (2 mmol) of 5-iodo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 1.42 g (10 mmol) of iodomethane, 553 mg (4 mmol) of K2CO3 and 10 mL of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent in vacuo gave 790 mg (100% yield) 5-iodo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a pale brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=1)=[O:7])[CH3:2]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CCOc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccccc1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-ethoxy--benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Ethoxy-N-(4-nitro-3-trifluromethyl-phenyl)-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[N:3]=1.[CH3:13][N:14]1[C:18](=[O:19])[CH:17]([CH3:20])[NH:16][C:15]1=[O:21]>>[CH3:13][N:14]1[C:18](=[O:19])[CH:17]([CH3:20])[N:16]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[N:3]=2)[C:15]1=[O:21]
Reactant: COC(=O)c1ccc(Br)nc1C
Reactant: CC1NC(=O)N(C)C1=O
Product: COC(=O)c1ccc(N2C(=O)N(C)C(=O)C2C)nc1C
Yield: 16.4 %

Procedure:
Using methyl 6-bromo-2-methylnicotinate (96 mg) and 3,5-dimethylimidazolidine-2,4-dione (107 mg) described in Preparation Example 217 and by the reaction and treatment in the same manner as in Preparation Example 48, the title compound (19 mg) was obtained.
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:2][N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:15]([O:19][C:20](ON=C(C1C=CC=CC=1)C#N)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCOCC1.O>[C:15]([O:19][C:20]([N:6]1[CH2:7][CH2:8][N:3]([CH2:2][CH2:1][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH2:4][CH2:5]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: C1CN(CCN2CCNCC2)CCN1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(CCN2CCNCC2)CC1

Procedure:
1,1'-ethylenedipiperazine (1.98 g, 10 mmol) is dissolved in 20 mL of dioxane: water (1:1) mixture and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (2.46 g, 10 mmol) is added. The mixture is then stirred until no starting material is detected on thin layer chromatography. The obtained mixture is fractionally separated by silica gel chromatography, followed by RP-HPLC to obtain N-[4-tert-butoxycarbonylpiperazino]ethyl-piperazine. Following the procedure of Example 6, but replacing 1-benzylpiperazine with N-[4-tert-butoxycarbonylpiperazino]ethyl-piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), N-[4-tert-butoxycarbonylpiperazino]ethyl-piperazine (1.817 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5, followed by a carefully deprotection of N-tert-butoxycarbonyl group with 10% trifiuoroacetic acid to obtain the pure title compound.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[O:15](S(C(F)(F)F)(=O)=O)[S:16]([C:19]([F:22])([F:21])[F:20])(=O)=[O:17]>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[S:16]([O:7][C:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH:2]=1)(=[O:17])=[O:15]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CCCC(=O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1C=C(OS(=O)(=O)C(F)(F)F)CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of cyclohexane-1,3-dione (1 equiv) in DCM (0.4M) was added Na2CO3 (1.0 equiv.) and cooled to 0° C. Added Tf2O (1.0 equiv.) in DCM (5M) dropwise over 1 hr at room temperature under a nitrogen atmosphere. Upon addition, the reaction was stirred for 2 hr (dark red solution). The solution was filtered and to the filtrate was added saturated NaHCO3 (carefully), then extracted the organics, dried with brine, then Na2SO4, and concentrated. The crude was purified via SiO2 column chromatography eluting with DCM and hexanes (1:1) or alternatively via a neutral alumina plug eluting with DCM to afford 3-oxocyclohex-1-enyl trifluoromethanesulfonate in 30% or 67% yield respectively. The triflate decomposes upon storage and should be used immediately for the next reaction. LC/MS=244.9/286.0 (M+H and M+CH3CN); Rt=0.88 min.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Br>CC(C)=O>[Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:27][C:26]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:25]=1[F:24]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: O=c1c(Br)c(O)ccn1Cc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1c(Br)c(OCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-1-(3-fluorobenzyl)-4-hydroxy-1H-pyridin-2-one (0.20 g, 0.67) and K2CO3 (0.27 g, 1.34 mmol) in acetone (10 mL) was added 2,4-difluorobenzyl bromide (0.16 g, 0.8 mmol), and the reaction mixture was heated at reflux for 1 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with water and then brine, dried (Na2SO4), filtered and concentrated under reduced pressure. 1H NMR (300 MHz, CDCl3) δ 7.65-7.55 (m, 1H), 7.40-7.25 (m, 2H), 7.15-6.80 (m, 5H), 6.14 (d, J=8 Hz, 1H), 5.22 (s, 2H), 5.16 (s, 2H). ES HRMS m/z 424.0159 (M+H C19H14BrF3NO2 requires 424.0155).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1F.[C:15]([O:19][C:20](=[O:25])[NH:21][CH2:22][CH2:23][NH2:24])([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:24][CH2:23][CH2:22][NH:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:25]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(NCCNC(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.8 %

Procedure:
To a stirred solution of 2-fluoro-6-nitro-benzoic acid methyl ester (0.35 g, 0.00176 mol) in DMF (8 mL) under nitrogen was added (2-amino-ethyl)-carbamic acid tertbutyl ester (0.28 g, 0.00176 mol) and potassium carbonate (0.49 g, 0.0035 mol). The reaction mixture was stirred at room temperature for 48 h. The reaction solvent was removed and the resulting oil redissolved in ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The reaction mixture was purified by ISCO chromatography on silica gel (20 g column) using 10-50% ethyl acetate-hexane to give 2-(2-tert-Butoxycarbonylamino-ethylamino)-6-nitro-benzoic acid methyl ester (0.59 g, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.48 (t, 1H, J=8 Hz), 7.11 (m, 2H), 7.00 (m, 1H), 6.52 (m, 1H), 3.77 (s, 3H), 3.24 (m, 2H), 3.11 (m, 2H), 1.44 (s, 9H); MS (m/e) 340 (M+1).
Reaction SMILES: [OH:1][C:2]1([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=3)[CH:10]2O)[CH2:4][CH2:3]1.Cl.O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[OH:18][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C:2]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)([OH:1])[CH2:3][CH2:4]3)[CH2:17]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(CC2(O)CCN(CC3Cc4cc(O)ccc4C3O)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(CC2(O)CCN(CC3=Cc4ccc(O)cc4C3)CC2)cc1
Yield: 100 %

Procedure:
(1RS,2RS) and (1RS, 2SR)-2-[4-hydroxy-4-(4-methyl-benzyl)-piperidine-1-ylmethyl]-indan-1,5-diol (310 mg, 0.84 mmol) and ethanolic HCl (5 eq.) was heated in EtOAc (30 ml) at 65° C. for 1.5 hr. Distilled H2O (30 ml) and 10% NaHCO3 (30 ml) was added and the mixture shaken, the aqueous phase was further extracted with EtOAc (2×20 ml) and the combined organic extracts were washed with satd. NaCl solution (30 ml), dried (Na2SO4) and filtered. Evaporation of the solvent afforded 1-(6-hydroxy-1H-inden-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol as a beige solid (308 mg, 0.84 mmol, 100%) Mp. 154-157° C., MS m/e=350.2 (M+H+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([OH:29])[C@:7]1([OH:28])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C:22](=[O:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O.O>[CH3:2][C:1]([O:4][CH2:5][C:6]([C@:7]1([OH:28])[C@@:24]2([CH3:25])[CH2:23][C:22]([C@@H:21]3[C@:19]4([CH3:20])[C:14](=[CH:15][C:16]([CH2:17][CH2:18]4)=[O:27])[CH2:13][CH2:12][C@H:11]3[C@@H:10]2[CH2:9][CH2:8]1)=[O:26])=[O:29])=[O:3]
Reactant: CC(=O)OCC(O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3C(=O)C[C@@]21C
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3C(=O)C[C@@]21C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
A solution of 21-acetoxy-17,20-dihydroxy-pregn-4-en-3,11-dione (730 mg, 1.81 mmol) and o-iodoxybenzoic acid I (1 g, 3.57 mmol) in DMSO (7 ml) was stirred at 50° C. for 3 h. The solution was then diluted with water (10 ml), stirred for 10 min, filtered and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine and dried over sodium sulfate. The organic solvent was distilled under vacuum. The residue was crystallised from ethanol to give 676 mg (93%) of cortisone acetate, mp 238°-240° C. (lit. 238°-240° C.)
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:17])[CH2:12][N:11]([CH3:27])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>ClCCl>[CH2:1]([N:8]1[CH2:14][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:28](=[O:30])[CH3:29])[N:19]=2)=[O:17])[CH2:12][N:11]([CH3:27])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCN(Cc2ccccc2)CC(NC(=O)c2n[nH]c3ccccc23)C1
Solvent: ClCCl
Product: CC(=O)n1nc(C(=O)NC2CN(C)CCN(Cc3ccccc3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
To a solution of N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide (1.0 g) in dichloromethane (10 ml), acetic anhydride (0.56 g) is added; and the mixture is stirred at 25° C. for 16 hours. The reaction mixture is washed with saturated sodium bicarbonate and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution of acetone. Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (0.92 g) as an oil. The free base thus obtained is converted to the fumarate 1/4 hydrate of the title compound in a usual manner, m.p. 166°-168° C. (recrystallized from ethanol).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][NH:20]3)=[C:16]([NH2:23])[N:15]=2)=[N:6]1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.ClC(Cl)(Cl)S(O[CH2:52][C:53]([F:56])([F:55])[F:54])(=O)=O>CN(C)C=O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[CH2:52][C:53]([F:56])([F:55])[F:54])=[C:16]([NH2:23])[N:15]=2)=[N:6]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]cnc12
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1ncn2CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45 %

Procedure:
100 mg (0.278 mmol) of the compound from example 58 and 76 mg (0.278 mmol) of BEMP were initially charged in 3 ml of dimethylformamide, a solution of 78 mg (0.266 mmol) of 2,2,2-trifluoroethyl trichloromethanesulfonate in 2 ml of dimethylformamide was added dropwise at 0° C. within 10 min and the mixture was stirred at RT for 20 min The product was precipitated by adding water, filtered off with suction and purified by means of preparative HPLC (eluent: acetonitrile/water with 0.05% trifluoroacetic acid, gradient 20:80→50:50). 53 mg of the title compound were obtained (43% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH3:15])[CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[Br:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[Br:34][CH2:35][C:36]([N:11]1[CH2:12][CH:13]([CH:14]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=2)[CH3:15])[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10]1)=[O:37]
Reactant: CC(Oc1ccc(C(F)(F)F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(C(F)(F)F)cc1)C1CN(C(=O)CBr)CC1c1ccc(Cl)c(Cl)c1
Yield: 84.5 %

Procedure:
To a stirred solution of (3RS,4SR)-3-(3,4-dichloro-phenyl)-4-[(RS)-1-(4-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine (XV-B-1) 0.25 g (0.62 mmol) in CH2Cl2 (30 mL) at RT, 0.10 ml (0.74 mmol) of Et3N and 0.062 mL (0.74 mmol) of bromo-acetyl chloride were added. Stirring was continued over night and then concentrated under vacuo. The crude residue was dissolved in EtOAc, washed with H2O. The organic phase was dried over Na2SO4 and the product was purified by flash chromatography (SiO2, EtOAc) to yield the title product 0.275 g (85%) as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C@H:22]3[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]3)=[CH:18][CH:17]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.CO>C1COCC1>[OH:8][C:9]1[CH:14]=[N:13][C:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C@H:22]3[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]3)=[CH:20][CH:21]=2)=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3ncc(OCc4ccccc4)cn3)cc2)C1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3ncc(O)cn3)cc2)C1
Yield: 107.3 %

Procedure:
(R)-tert-Butyl 2-(4-(5-(benzyloxy)pyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (0.36 g) was combined with MeOH (15 ml) and THF (5 ml) to give a light brown solution. The mixture was degassed by bubbling through argon for several minutes. Palladium on charcoal (41.4 mg, 10%) was added. The reaction mixture was then stirred under a balloon filled with argon overnight. The reaction mixture was then filtered through celite and concentrated in vacuo to afford (R)-tert-butyl 2-(4-(5-hydroxypyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (311 mg, quant.) as a light brown foam which was used in the next step without further purification. MS (ISP): 373.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.C1C(=O)N([Cl:23])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:5]2[C:10]([Cl:23])=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Clc1nc(NC2CCC2)c2cc[nH]c2n1
Solvent: ClCCl
Product: Clc1nc(NC2CCC2)c2c(Cl)c[nH]c2n1
Yield: 19.4 %

Procedure:
To a suspension of 2-chloro-N-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (102 mg, 0.460 mmol) in CH2Cl2 (5 mL) at room temperature, NCS (68 mg, 0.51 mmol) was added. The mixture was stirred at reflux for 18 h. After being concentrated in vacuo, the residue was purified by HPLC to give 2,5-dichloro-N-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (23 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:26]([C:25]3[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccc(F)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 54.2 %

Procedure:
In a similar fashion to compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (100.00 mg, 0.29568 mmol), 4-Fluorobenzaldehyde (40.4 mg, 0.325 mmol), and Ammonium acetate (45.6 mg, 0.591 mmol) were reacted to yield 70.9 mg (54%) of the title compound. (300 MHz, DMSO-d6) 13.42 (s, 1H), 8.06 (s, 1H), 7.99 (d, J=8 Hz, 1H), 7.90 (d, J=11 Hz, 1H), 7.76 (s, 1H), 7.61 (m, 1H), 7.33 (m, 1H), 7.24 (m, 2H) 6.39 (s, 2H), 5.21 (t, J=17 Hz, 8.5 Hz, 1H), 2.89 (s, 1H), 2.78 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz, 1H). MS=444 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C(OC(=O)C)(=O)C>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccncc1
Reactant: COc1ccc(C=O)cc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C=Cc2ccncc2)cc1

Procedure:
A mixture of 4-picoline (280 g, 3.0 moles), p-methoxybenzaldehyde (410 g, 3.0 moles), and 500 ml. of acetic anhydride is refluxed for 24 hours, cooled, evaporated in vacuo, and the residue taken up in water and basified with 10% NaOH. The solid is filtered and crystallized from ethanol and water to give 350 g (55%) of the crude base. Recrystallization gives pure 4-(p-methoxystyryl)-pyridine, mp 128°-130°.