Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH2:30]C=C)[C:15](=[O:29])[C@H:16]([NH:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)[CH2:17][CH:18]=[CH2:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.CCOC(C)=O>[Cl:28][C:23]1[CH:22]=[C:21]([NH:20][C@@H:16]2[CH2:17][CH:18]=[CH:19][CH2:30][N:14]([C@@H:10]3[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]3)[C:15]2=[O:29])[CH:26]=[C:25]([F:27])[CH:24]=1
Reactant: C=CC[C@@H](Nc1cc(F)cc(Cl)c1)C(=O)N(CC=C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N2CC=CC[C@@H](Nc3cc(F)cc(Cl)c3)C2=O)C1
Temperature: 25 °C

Procedure:
A solution of (R)-3-{allyl-[(R)-2-(3-chloro-5-fluoro-phenylamino)-pent-4-enoyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (0.65 g, 1.4 mmol) in DCM (50 mL) was degassed and purged with argon. To the solution was added Grubb's 2nd generation catalyst (0.12 g, 0.13 mmol) and the mixture was refluxed for 90 minutes. After the solution was cooled to rt, the solvent was removed under reduced pressure to afford a solid which was dissolved in EtOAc. The organic phase was washed with brine, a solution of NaHCO3, dried (MgSO4), filtered and concentrated in vacuo to afford a residue which was purified by silica gel chromatography (gradient hexanes:EtOAc 0-70%). LCMS, m/z 381.9 [M−tBu]+.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([O:18][CH3:19])[C:12]([O:20][CH3:21])=[CH:11][CH:10]=1)=O)(C)(C)C.[ClH:22].O1CCOCC1>>[ClH:22].[NH2:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([O:18][CH3:19])[C:12]([O:20][CH3:21])=[CH:11][CH:10]=1
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(C(=O)O)c1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(N)c(C(=O)O)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
6-((tert-Butoxycarbonyl)amino)-2,3-dimethoxybenzoic acid (39 g, 131 mmol) was treated with HCl in dioxane (4N, 300 mL, 1200 mmol) at r.t. and the mixture was stirred at r.t. for 3 h. LCMS indicated completion of the reaction. The solid was collected by filtration, washed with ethyl ether and dried to afford 6-amino-2,3-dimethoxybenzoic acid, Hydrochloride (28.5 g, 120 mmol, 91% yield) as a white solid. LCMS: (M+H)+: 198.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([O:13][CH3:14])[CH:5]=1>CO.C1COCC1.[C].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:13][CH3:14])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N)c(OC)c1
Temperature: 25 °C
Yield: 104.1 %

Procedure:
To a solution of 3-methoxy-4-nitrobenzoic acid methyl ester (150 g) in methanol (600 mL) and THF (300 mL), 10% palladium-carbon (15 g) was added and the reaction mixture was agitated at 50° C. to 64° C. under hydrogen pressure of 0.9 MPa(s) for 6.5 hours. After allowing cool the reaction solution to room temperature, 134 g of the title compound was obtained by filtering the reaction solution on celite and condensing the obtained filtrate under reduced pressure. The physical properties was in agreement with the reported values (CAS#41608-64-4).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH:5]=1.N([O-])=O.[Na+].[N-]=[N+]=[N-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH3:3][C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]2[N:20]=[C:15]3[C:14]([CH:19]=[CH:18][CH:17]=[CH:16]3)=[C:6]2[CH:5]=1
Reactant: Cc1cc(-c2ccccc2N)nc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc2c3ccccc3nn2c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
9 ml of conc. hydrochloric acid are added to a suspension, cooled to 0° C., of 90.5 g (332 mmol) of 2-(4-methylquinolin-2-yl)phenylamine hydrochloride in 1300 ml of ice-water and 1000 ml of toluene in an open 10 l beaker, and a solution of 24.1 g (352 mmol) of sodium nitrite in 100 ml of water is then added dropwise, during which the temperature is kept below +5° C. When the addition is complete, the mixture is stirred for a further 20 min., a solution of 24.9 g (382 mmol) of sodium azide in 500 ml of ice-water is then allowed to run in slowly with vigorous stirring (note: evolution of gas, foaming!), and the mixture is then stirred further until the evolution of gas is complete. After warming to room temperature, the reaction mixture is rendered slightly alkaline using saturated sodium carbonate solution, the organic phase is separated off, washed once with 500 ml of water and once with 500 ml of saturated sodium chloride solution, dried over a mixture of sodium carbonate and magnesium sulfate, the desiccant is filtered off, and the filtrate is slowly heated to reflux under argon (care: evolution of gas from about 80° C.). After 8 h under reflux, the mixture is allowed to cool, filtered through 800 g of alumina (basic, activity grade 1), rinsed with 2000 ml of toluene, and the filtrate is then evaporated to dryness in vacuo. The yellow oil obtained in this way is recrystallised twice from about 300 ml of ethanol. The solid obtained in this way is freed from readily volatile and non-volatile secondary components by fractional sublimation (p about 1×10−5 mbar, T about 180° C.). Yield: 48.8 g (210 mmol), 63%, purity: about 99.5% (NMR).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1>ClCCCl>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[C:17]3[C:12](=[CH:13][C:14]([Cl:20])=[C:15]([O:18][CH3:19])[CH:16]=3)[NH:11][C:6]=2[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(=O)c3c(Cl)ccc([N+](=O)[O-])c3[nH]c2cc1Cl

Procedure:
A mixture of 17 g of 6-chloro-2-[(3-chloro-4-methoxyphenyl)amino]-3-nitrobenzoic acid, 35 ml of phosphorus oxychloride, 1 ml of N,N-dimethylaniline and 150 ml 1,2-dichloroethane was heated under reflux for 45 minutes. The resulting solid was collected by filtration from the hot reaction mixture and was washed with chloroform to provide 1,6-dichloro-7-methoxy-4-nitro-9(10H)-acridinone, mp 284°-285° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([NH2:18])=[O:17])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([Sn](CCCC)(CCCC)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1)CCC.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[C:2]1[S:6][C:5]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([NH2:18])=[O:17])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1cccc2[nH]c(-c3ccc(Br)s3)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2[nH]c(-c3ccc(-c4ccccn4)s3)nc12

Procedure:
A mixture of EXAMPLE 10A (184 mg), tri-ortho-tolylphosphine (52 mg), tris(dibenzylidineacetone)dipalladium(0) (52 mg), 2-(tri-n-butylstannyl)pyridine (420 mg) and triethylamine (238 L) in DMF (5 mL) was heated at 75° C. overnight. The mixture was cooled, diluted with dichloromethane and flash chromatographed (with 0-15% methanol in 2:1 ethyl acetate/hexane). Additional purification by HPLC (Zorbax, C-18, Mobile phase A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile; 0-100% gradient) provided the title compound. 1H NMR (DMSO-d6) δ 7.34-7.39 (m, 2H), 7.74-7.76 (m, 2H), 7.86-7.95 (m, 3H), 8.00-8.05 (m, 1H), 8.02 (s, 1H), 8.60 (d, J=4.6 Hz, 1H), 9.04 (brs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:24](=[O:25])[CH2:23][C:22](=[O:26])[NH:21][C:20]4[C:27]5[C:32]([CH:33]=[CH:34][C:19]3=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:35](=O)([O-])[O-].[K+].[K+].CI>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]([C:12]2[CH:13]=[CH:14][C:15]([N:18]3[C:24](=[O:25])[CH2:23][C:22](=[O:26])[NH:21][C:20]4[C:27]5[C:32]([CH:33]=[CH:34][C:19]3=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:16][CH:17]=2)[CH3:35])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3cccc(Br)c3)cc2)c2ccc3ccccc3c2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CN(c1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1)S(=O)(=O)c1cccc(Br)c1
Yield: 72.7 %

Procedure:
By using 3-bromo-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide (78 mg, 0.145 mmol) obtained in Example 147, potassium carbonate (22 mg, 0.159 mmol), and methyl iodide (11 μL, 0.177 mmol), the title compound (58 mg, yield 73%) was obtained in the same manner as that of Example 152.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:30][CH3:31])[C:5]([N+:27]([O-])=O)=[C:6]([N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.[NH4+].[Cl-].CO.C1COCC1>[Zn].C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:30][CH3:31])[C:5]([NH2:27])=[C:6]([N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: CNc1cc(Br)cc(N(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O=CO
Solvent: C1CCOC1
Product: CNc1cc(Br)cc(N(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-Bromo-N,N-bis-(4-methoxy-benzyl)-N′-methyl-2-nitro-benzene-1,3-diamine (170 mmol), NH4Cl (2038 mmol) and Zn (2034 mmol) in 1:1 MeOH/THF (1 L) was stirred at room temperature for 1 h. The mixture was cooled to 0° C. and HCOOH (20 mL) was added slowly. The mixture was allowed to reach room temperature and stirred for 1 h. The mixture was filtered and combined with another one obtained following the procedure described above. The resulting mixture was concentrated. The residue was dissolved in DCM. The organic mixture was washed (sat. NH4Cl), dried (Na2SO4) and concentrated to afford the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([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:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reaction time: 8 h

Procedure:
Pd/C (10%; 510 mg) was added to a solution of tert-butyl 4-(4-nitrophenoxy)piperidine-1-carboxylate (A111) (2.21 g, 6.86 mmol) in methanol (30 mL) and the resulting mixture was stirred under a hydrogen atmosphere overnight. The mixture was filtered through Celite and the filtrate concentrated under reduced pressure to afford the title compound A112 (1.13 g, 56%); 1H NMR (300 MHz, CDCl3); δ 6.68 (d, J=8.8 Hz, 2H), 6.52 (d, J=8.7 Hz, 2H), 4.17 (m, 1H), 3.63 (m, 4H), 3.20 (m, 2H), 1.78 (m, 2H), 1.61 (m, 2H), 1.40 (s, 9H). LCMS-B: rt 5.05 min; m/z 293.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]O)=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)([O-:3])=[O:2].CCN(S(F)(F)[F:24])CC>C(Cl)Cl>[F:24][CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:14]([F:17])([F:16])[F:15]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=[N+]([O-])c1ccc(CCCO)c(C(F)(F)F)c1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCCF)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
3-(4-Nitro-2-(trifluoromethyl)phenyl)propan-1-ol (450 mg, 1.8 mmol) was dissolved in DCM (10 mL), and DAST (0.4 mL, 3.03 mmol) was added thereto under ice-cooling. The mixture was stirred at 0° C. for 1 hour. The reaction solution was quenched with a saturated sodium bicarbonate solution. The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=9:1) to give 1-(3-fluoropropyl)-4-nitro-2-(trifluoromethyl)benzene (300 mg, 66%) as a light-yellow oil.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.BrC1C=C2C(=CC=1)C(C)(C)C[CH:37]=[C:36]2[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[C:51]([CH3:54])([CH3:53])[CH3:52]>>[C:51]([C:46]1[CH:47]=[CH:48][C:49]([C:36]2[C:45]3[CH:50]=[C:49](/[C:27](/[Si:28]([CH3:29])([CH3:30])[CH3:31])=[CH:26]/[C:23]4[CH:22]=[CH:21][C:20]([CH2:19][OH:18])=[CH:25][CH:24]=4)[CH:48]=[CH:47][C:46]=3[C:51]([CH3:53])([CH3:52])[CH2:54][CH:37]=2)=[CH:50][CH:45]=1)([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)c1ccccc1C1=CCC(C)(C)c2ccc(Br)cc21
Reactant: CC(C)(C)[Si](OCc1ccc(C#C[Si](C)(C)C)cc1)(c1ccccc1)c1ccccc1
Product: CC(C)(C)c1ccc(C2=CCC(C)(C)c3ccc(/C(=C/c4ccc(CO)cc4)[Si](C)(C)C)cc32)cc1

Procedure:
Following General Procedure A, 4-[(trimethylsilyl)ethynyl]benzyl tert-butyldiphenylsilyl ether and 6-bromo-4-(tert-butylphenyl)-1,1-dimethyl-1,2-dihydronaphthalene (which can be prepared by the procedure described in Klein, et al., U.S. Pat. No. 5,952,345) were coupled to give the title compound (Compound 29). PNMR (300 MHz, CDCl3): δ0.0 (s, 9 H), 1.48 (s, 6 H), 1.51 (s, 9 H), 2.49 (d, J=4.8 Hz, 2 H), 4.82 (d, J=4.8 Hz, 2 H), 6.13 (t, J=4.8 Hz, 1 H), 7.00 (d, J=1.7 Hz, 1 H), 7.22 (dd, J=1.7, 7.9 Hz, 1 H), 7.30-7.50 (m, 8 H), 7.55 (d, J=8.8 Hz, H).
Reaction SMILES: [OH:1][P:2]([O:5][P:6]([O:9][P:10]([OH:13])([OH:12])=[O:11])([OH:8])=[O:7])(=[O:4])[OH:3].[N+]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)([O-])=O.[NH2:26]C1C=C2C(=CC=1)NC=C2>>[OH:13][P:10]([O:9][P:6]([O:5][P:2]([OH:4])([OH:3])=[O:1])([OH:8])=[O:7])(=[O:11])[OH:12].[NH2:26][C:21]1[NH:22][C:23]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:25][CH:24]=2
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: O=P(O)(O)OP(=O)(O)OP(=O)(O)O
Product: Nc1cc2ccccc2[nH]1

Procedure:
Amino-indole triphosphate was prepared from 5-nitro-indole triphosphate by hydrogenation reaction. The extinction coefficient for 5-amino-indole is 5830 M−1 cm−1 at 270 nm.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)C.C1(NC2CCCCCC2)CCCCC1.NC1SC=NC=1.C(OC(=O)CS)C>>[CH:22]1([N:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:29])=[O:3])=[CH:8][N:9]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCCCC2)C2CCCCC2)s1
Agent: C1CCCC(NC2CCCCC2)CC1
Agent: CCOC(=O)CS
Agent: Nc1cncs1
Product: O=C(O)CSc1cnc(NC(=O)N(C2CCCCCC2)C2CCCCC2)s1

Procedure:
[2-(3-Cycloheptyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid ethyl ester prepared as described in general procedure (A) using cyclohexyl-cycloheptylamine and 5-aminothiazole-2-mercaptoacetic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: C(N1[CH2:13][CH2:12][NH:11][CH2:10]C1)(OC(C)(C)C)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[N:32][NH:33][CH:34]=3)=[CH:26][CH:25]=2)[CH:22]=O)=[CH:17][CH:16]=1.N1CCC1>>[N:11]1([CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[N:32][NH:33][CH:34]=3)=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[CH2:10][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=CC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Agent: C1CNC1
Product: Clc1ccc(C(CN2CCC2)c2ccc(-c3cn[nH]c3)cc2)cc1

Procedure:
By following the procedure described in Example 33B but replacing bis-(4-chloro-phenyl)-acetaldehyde and N-BOC-piperazine with (4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-acetaldehyde and azetidine, the title compound was obtained. LC/MS: (PS-B3) Rt 2.99 [M+H]+ 338.09. 1H NMR (Me-d3-OD) δ 3.57-3.60 (1H, m), 3.63-3.70 (2H, m), 3.71-3.77 (1H, m), 4.01 (2H, m), 4.14 (2H, m), 4.40 (1H, t), 7.40 (4H, br s), 7.49 (2H, d), 7.73 (2H, d), 8.69 (2H, br s).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=1[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:6]([F:12])=[CH:7][CH:8]=[CH:9][C:10]=3[F:11])[N:29]=2)=[CH:26][C:25]=1[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:35][N:34]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1F)S(=O)(=O)c1ccccc1
Reactant: N#Cc1ccc(Cl)c(Oc2ccc(C(F)(F)F)cn2)c1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2F)nc1-c1ccc(Cl)c(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2,6-difluorobenzohydrazonoyl chloride (0.90 g), 4-chloro-3-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (0.90 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexaneethyl acetate as eluent to give 0.30 g of desired compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:10].[CH2:11]([O:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH3:12].C([N-]C(C)C)(C)C.[Li+]>CN(C)P(N(C)C)(N(C)C)=O>[CH3:16][C:15]([CH3:17])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:10])[C:14]([O:13][CH2:11][CH3:12])=[O:18]
Reactant: CCOC(=O)C(C)C
Reactant: BrCCCCCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(C)(C)CCCCCCCCBr
Yield: 16.5 %

Procedure:
Using the method described in Example 5(i), 1,8-dibromooctane (27.2 g, 0.1 mol) and ethylisobutyrate (10.44 g, 0.09 mol) were reacted in the presence of lithium diisopropylamide (67 ml, 0.1 mol) and hexamethylphosphoramide (22 g) to give the title compound (4.56 g) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C(C#N)(C)=O.[Na+].[I-].Cl[Si:21]([CH3:24])([CH3:23])[CH3:22]>>[CH3:22][Si:21]([CH3:24])([CH3:23])[O:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCCc2cc(O)ccc21
Agent: CC(=O)C#N
Agent: [I-]
Agent: [Na+]
Product: C[Si](C)(C)OC1=CCCc2cc(O[Si](C)(C)C)ccc21
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of 6-hydroxytetralone (0.972 g, 6.0 mmol) in 10 mL of freshly distilled AcCN at room temperature was added sequentially dry NaI (2.25 g, 15 mmol), TEA (2.10 mL, 15 mmol), and chlorotrimethylsilane (1.92 mL, 15 mmol). After stirring for 1 hour, the reaction was quenched with the addition of a cold solution of saturated ammonium chloride and the reaction was extracted into Et2O (2×100 mL). The combined extracts were washed with ice cold water and then dried, filtered, and concentrated in vacuo to afford 1.53 g of the title compound as a colorless oil which was used for further reaction without purification.
Reaction SMILES: [C:1]1([C:7]2([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][N:25]=[C:26]=[O:27]>C1C=CC=CC=1>[CH3:24][NH:25][C:26]([N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[CH2:12][CH2:11]1)=[O:27]
Reactant: CN=C=O
Reactant: FC(F)(F)c1cccc(OC2(c3ccccc3)CCNCC2)c1
Solvent: c1ccccc1
Product: CNC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
To a solution of 2.22 g of 4-phenyl-4-(3-trifluoromethylphenoxy)piperidine in 50 ml of benzene was added 0.40 g of methyl isocyanate. The reaction mixture was stirred at room temperature for 2.5 hours. Evaporation of the volatile afforded an oil which was purified by means of high pressure liquid chromatography (silica gel; elution with 50% ethyl acetate/dichloromethane) to yield 2.04 g (77%) of 1-(N-methylamino)carbonyl-4-phenyl-4-(3-trifluoromethylphenoxy)piperidine, m.p. 124°-127° C.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[NH:6][C:7](=O)[C:8]3[CH:13]=[N:12][CH:11]=[CH:10][C:9]=3[N:4]2[N:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:7]1[C:8]2[CH:13]=[N:12][CH:11]=[CH:10][C:9]=2[N:4]2[N:3]=[C:2]([CH3:1])[CH:15]=[C:5]2[N:6]=1
Reactant: Cc1cc2[nH]c(=O)c3cnccc3n2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc2nc(Cl)c3cnccc3n2n1

Procedure:
200 g. of 2-methylpyrazolo[1,5-a]pyrido[3,4-e]-pyrimidin-5(4H)-one of Example 1c are refluxed with 800 ml. of phosphorus oxychloride overnight. The excess phosphorus oxychloride is removed in vacuo and the oily residue decomposed by pouring on ice. The acidic aqueous solution is made alkaline with sodium hydroxide. The precipitated 5-chloro-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidine is filtered off, yield: 143 g. (66%); m.p. 169.8° (ethyl acetate).
Reaction SMILES: COC([C:5]1[C:9](=[O:10])[O:8][CH2:7][C:6]=1O)=O.[Cl:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][CH:22]([F:24])[F:23])=[CH:15][CH:14]=1.S([O-])(O)(=O)=O.[K+].O>C(#N)CCC.ClCCl>[Cl:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:21][CH:22]([F:24])[F:23])[C:6]2[CH2:7][O:8][C:9](=[O:10])[CH:5]=2)=[CH:15][CH:14]=1
Reactant: FC(F)CNCc1ccc(Cl)nc1
Reactant: COC(=O)C1=C(O)COC1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCCC#N
Solvent: ClCCl
Solvent: O
Product: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)F)CO1
Temperature: 120 °C
Reaction time: 3 h
Yield: 108.8 %

Procedure:
To a suspension of 5.2 g of 4-(methoxycarbonyl)-5-oxo-2,5-dihydrofuran-3-ol and 5 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethylamine in 70 ml of butyronitrile are added, at room temperature. 4.5 g of potassium hydrogensulphate. The mixture is stirred at a temperature of 120° C. for 3 hours. Subsequently, the mixture is cooled to room temperature and admixed with 60 ml of water and 60 ml of dichloromethane. The organic phase is removed and the aqueous phase is extracted twice with 30 ml each time of methylene chloride. The combined organic phases are concentrated to dryness. 7.6 g of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one are obtained in a purity of 85% (this corresponds to 94% yield).
Reaction SMILES: BrCC.[CH:4]#[C:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:11](Br)[CH:12]=[CH2:13].Cl>CCOCC.Cl[Cu]>[CH2:4]=[CH:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: C=CCBr
Reactant: C#CCCCCC
Agent: Cl[Cu]
Agent: Cl
Solvent: CCOCC
Solvent: CCBr
Product: C=CCC#CCCCCC
Yield: 70 %

Procedure:
A solution of bromoethane (43.6 g, 400 mmol) in Et2O (280 ml) was added dropwise to a suspension of Mg (9.6 g, 400 mmol) in Et2O (140 ml). After 3 hours a solution of 1-heptyne (35.0 g, 360 mmol) in Et2O (140 ml) was added dropwise to the reaction medium. After 90 minutes at reflux, CuCl (1.8 g, 18.2 mmol) was added to the cold reaction mixture and after 15 minutes a solution of allyl bromide (48.4 g, 400 mmol) in Et2O (140 ml) was added dropwise. After 18 hours at reflux, the cold reaction mixture was poured onto 10% aqueous HCl (320 ml) at 0° C. The aqueous phase was extracted with Et2O, then the organic phase was washed with H2O, dried (MgSO4), concentrated and distilled through a Vigreux column (65915 mbar) to afford the pure desired compound (70%).