Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2=[C:17]3[C:4]=1[CH2:5][CH:6](O)[N:7]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:8]3=[N:9][CH:10]=[N:11]2.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:7]2[CH:6]=[CH:5][C:4]3[C:17]4[C:8]2=[N:9][CH:10]=[N:11][C:12]=4[CH:13]=[C:14]([O:15][CH3:16])[C:3]=3[O:2][CH3:1])=[CH:19][CH:20]=1
Reactant: COc1cc2ncnc3c2c(c1OC)CC(O)N3c1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc3c2c(c1OC)C=CN3c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7,8-dimethoxy-4-(4-chloro-phenyl)-5,6-dihydro-4H-1,3,4-triaza-phenalen-5-ol (140 mg, 0.39 mmol) (from Example 21, Step A, supra) and triethylamine (0.32 mL, 2.33 mmol) in dichloromethane (50 mL) at 0° C. was added methanesulfonyl chloride (0.12 mL, 1.55 mmol) (Aldrich). The reaction solution was the stirred at room temperature for 2 hours. The solution was then concentrated, the residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:1:0.01) as eluent to give the desired 4-(4-chloro-phenyl)-7,8-dimethoxy-4H-1,3,4-triaza-phenalene as a yellow solid. (Yield 47 mg, 55%).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:25]([Cl:28])=[N:26][CH:27]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH4+].[Cl-]>CN(C=O)C>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:21][C:22]3[CH:23]=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:25]([Cl:28])=[N:26][CH:27]=3)=[N:3][CH:4]=[C:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:6]=2)[N:9]=1
Reactant: COCCOc1cnc(F)c(-c2nc(C)nc(N)n2)c1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCCOc1cnc(Nc2cnc(Cl)c(NS(C)(=O)=O)c2)c(-c2nc(C)nc(N)n2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To a stirred mixture of 4-(2-fluoro-5-(2-methoxyethoxy)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.105 g, 0.376 mmol) and N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (Example 330 step 2, 0.0977 g, 0.441 mmol) in DMF (1 mL) in 5 mL microwave vial, NaHMDS (Aldrich, 1 M in THF, 1.20 mL, 1.20 mmol) was added slowly at 0° C. The dark brown mixture was stirred at 0° C. for 30 min. Additional NaHMDS (0.5 mL) was added at 0° C. and the stirring was continued at 0° C. for 30 min. The reaction mixture was poured into 30 mL of sat'd NH4Cl and stirred for 30 min. The resulting yellow solid was collected via filtration and washed with copious amount of water and air-dried to afford N-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(2-methoxyethoxy)pyridin-2-ylamino)-2-chloropyridin-3-yl)methanesulfonamide (0.120 g, 66% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.96 (s, 1H) 9.62 (s, 1H) 8.61 (d, J=19.95 Hz, 2H) 8.44 (d, J=2.74 Hz, 1H) 8.21 (d, J=2.54 Hz, 1H) 7.75-8.01 (m, 2H) 4.12-4.27 (m, 2H) 3.69 (d, J=4.30 Hz, 2H) 3.33 (br. s., 3H) 3.13 (s, 3H) 2.45 (s, 3H). m/z (ESI, positive ion): 481.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[CH:3]=1.B(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+].Cl>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 14.8 g 4-bromo-1-chloro-2-(4-methoxy-benzyl)-benzene in 150 ml dichloromethane is cooled in an ice bath. Then 50 ml of a 1 M solution of boron tribromide in dichloromethane are added, and the solution is stirred for 2 h at ambient temperature. The solution is then cooled in an ice bath again, and saturated potassium carbonate solution is added dropwise. At ambient temperature the mixture is adjusted with aqueous 1 M hydrochloric acid to a pH of 1, the organic phase is separated off and the aqueous phase is extracted another three times with ethyl acetate. The combined organic phases are dried over sodium sulfate, and the solvent is removed completely.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Br[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C.CC(=O)OCC.O>C1COCC1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: BrC1CCCCC1
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(C2CCCCC2)cn1
Yield: 22.9 %

Procedure:
A solution of 60.1 mg (0.23 mmol) of the compound from example 1g, 37.7 mg (0.23 mmol) of bromocyclohexane and 100 μl of triethylamine in 1 ml of absolute THF was treated in a microwave at 170° C. for 40 min. The reaction solution was then taken up in a little EA/water (1:1), and the phases were separated off, dried over Na2SO4, filtered and evaporated to dryness. Purification by chromatography on RP silica gel with CH3CN/water/0.1% TFA as mobile phase and freeze-drying of the combined product fractions afforded 18.0 mg of the desired compound as bistrifluoroacetate in the form of an amorphous solid.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][C@H:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1C(C1C=CC=CC=1)(C1C=CC=CC=1)O>>[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:2]1[C:10]2[O:9][CH2:8][C@H:7]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:3]=1[CH3:29]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccco1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccco1)OC[C@@H]2c1ccc(C(C)C)cc1
Yield: 6 %

Procedure:
Using (−)-N-((3R)-7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 51 and 2-furyl(diphenyl)methanol, the title compound was obtained in the same manner as in Example 107. Yield: 6%. Melting point: 214-217° C. (ethyl acetate-hexane).
Reaction SMILES: CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][C:7]1[C:12]2[CH:13]([CH3:24])[CH:14]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:15]([CH3:18])([CH3:17])[O:16][C:11]=2[CH:10]=[C:9]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:8]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:6][C:7]1[C:12]2[CH:13]([CH3:24])[CH:14]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:15]([CH3:18])([CH3:17])[O:16][C:11]=2[CH:10]=[C:9]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:8]=1
Reactant: CCCCCc1cc2c(c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c1)C(C)C(CCC(=O)O)C(C)(C)O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCC(=O)O)C2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
A solution of 1.0 g (1.75 mmol) of 5-[[(1,1-Dimethylethyl)-diphenylsilyl]oxy]-3,4-dihydro-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanoic acid in anhy. THF under argon was treated with 2.09 mL (2.09 mmol) of a 1M solution of tetrabutylammonium fluoride in THF (Aldrich). After stirring at RT for 1 hr the reaction was evaporated under reduced pressure and the residue subjected to column chromatography on flash-grade silica gel, eluting with 5% MeOH-CHCl3. The fractions containing product were combined and evaporated under reduced pressure to give 395 mg (67%) of 3,4-Dihydro-5-hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanoic acid as a tan-colored foam. MA: Calc for C20H30 O4.0.2H2O: C, 71.06; H, 9.06; O, 19.29. Found: C, 70.93; H, 8.95; O, 19.27.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]([CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:7]2=[O:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N12CCCN=C1CCCCC2.[C:58]([NH2:62])([CH3:61])([CH3:60])[CH3:59]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:62][C:58]([CH3:61])([CH3:60])[CH3:59])[N:8]([CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:7]2=[O:19]
Reactant: CS(=O)(=O)CCn1c(=O)[nH]c2c(Br)cccc2c1=O
Reactant: CC(C)(C)N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1CCS(C)(=O)=O
Temperature: 40 °C
Reaction time: 4 h
Yield: 38.9 %

Procedure:
A glass microwave reaction vessel was charged with 8-bromo-3-(2-(methylsulfonyl)ethyl)quinazoline-2,4(1H,3H)-dione (200 mg, 0.576 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (382 mg, 0.864 mmol, Sigma Aldrich) in DMF (2 mL) followed by 1,8-diazabicyclo-[5.4.0]undec-7-ene (0.172 mL, 1.152 mmol, Sigma Aldrich). The reaction mixture was stirred for 5 min. tert-butylamine (0.30 mL, 2.88 mmol) was added. The reaction was stirred at 40° C. for 4 h. The mixture was diluted with EtOAc (30 mL) and washed with water, brine, dried (MgSO4), filtered and concentrated. The residue was purified with silica gel chromatography (eluted with 0-10% EtOAc in DCM) to give 8-bromo-2-(tert-butylamino)-3-(2-(methylsulfonyl)ethyl)quinazolin-4(3H)-one (516c; 90 mg, 0.224 mmol, 39% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 402 (M+1).
Reaction SMILES: [F:1][C:2]([F:34])([CH2:31][CH2:32][OH:33])[C:3]([F:30])([F:29])[C:4]([F:28])([F:27])[C:5]([F:26])([F:25])[C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12]>[Pd]>[CH2:11]([O:33][CH2:32][CH2:31][C:2]([F:34])([F:1])[C:3]([F:29])([F:30])[C:4]([F:27])([F:28])[C:5]([F:25])([F:26])[C:6]([F:24])([F:23])[C:7]([F:21])([F:22])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:31][CH3:32]
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd]
Product: CCCCCCCCCCCCOCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 193.3 %

Procedure:
In the same manner as in Example 1, except that 2-(perfluorodecyl)ethanol 16.9 g (0.03 mol) was used instead of 2-(perfluorooctyl)ethanol and the amount of 5% Pd-C (pH 6.8) to be added was 0.34 g, reaction was carried out to obtain the objective dodecyl{2-(perfluorodecyl)ethyl}ether 21.1 g (0.029 mol) as a white solid. Isolation yield was 96%.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:14][C:13]3[C:8](=[C:9]([Cl:18])[C:10]([Cl:17])=[C:11]([S:15][CH3:16])[CH:12]=3)[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:22]I>COCCOC>[CH:1]1([C:6]2([CH3:22])[CH2:14][C:13]3[C:8](=[C:9]([Cl:18])[C:10]([Cl:17])=[C:11]([S:15][CH3:16])[CH:12]=3)[C:7]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CI
Reactant: CSc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)C2
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2

Procedure:
2-Cyclopentyl-2-methyl-5-methylthio-6,7-dichloro-1-indanone is prepared following substantially the same procedure described in Example 10, Step D, using the following substances: 2-cyclopentyl-5-methylthio-6,7-dichloro-1-indanone (7.9 g., 0.025 mole), 1,2-dimethoxyethane (200 ml.), sodium hydride (660 mg., 0.0275 mole) and methyl iodide (7.5 ml.).
Reaction SMILES: Cl.[CH:2]([NH:5][CH:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12)([CH3:4])[CH3:3].[CH2:27](Br)[CH:28]=[CH2:29].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:2]([N:5]([CH:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12)[CH2:29][CH:28]=[CH2:27])([CH3:3])[CH3:4]
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)NC(C)C)=C21
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=CCN(C(C)C)C(C)CC1=C2c3ccc(OC)cc3CCC2CCNC1=O

Procedure:
The mixture of 7.58 g of slow moving 1-(2-isopropylaminopropyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one hydrochloride, 4.8 g of allyl bromide, 5.5 g of potassium carbonate and 100 ml of anhydrous ethanol is refluxed for 3 hours. The mixture is recharged with 2.4 g of allyl bromide and 2.75 g of potassium carbonate and refluxed overnight. It is evaporated, water is added to the residue and the mixture extracted with chloroform. The extract is evaporated, the residue crystallized from petroleum ether and recrystallized from ethyl acetate to yield the 1-[2-(N-isopropyl-N-allylamino)propyl]-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one, melting at 168°-170°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][C:12]1[C:17]([CH3:18])=[C:16]([O:19][CH2:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=1[C@@H:23]([N:25]1[CH2:30][C@@H:29]2[CH2:31][C@H:26]1[CH2:27][NH:28]2)[CH3:24]>C(Cl)Cl.C([O-])(O)=O.[Na+].[OH-].[Na+]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:28]2[CH2:27][C@@H:26]3[CH2:31][C@H:29]2[CH2:30][N:25]3[C@H:23]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:17]([CH3:18])[C:12]=2[CH3:11])[CH3:24])=[O:7])=[CH:9][CH:10]=1
Reactant: CCCOc1ccc([C@H](C)N2C[C@@H]3C[C@H]2CN3)c(C)c1C
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCOc1ccc([C@H](C)N2C[C@@H]3C[C@H]2CN3C(=O)c2ccc(Cl)nc2)c(C)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-chloronicotinoyl chloride (151 mg, 0.86 mmol) in 2 mL CH2Cl2 is added to a mixture of (1S,4S)-2-((S)-1-(2,3-dimethyl-4-propoxyphenyl)ethyl)-2,5-diaza-bicyclo[2.2.1]heptane in 5 mL of CH2Cl2 and aqueous NaHCO3 (saturated solution, 3 mL). The mixture is stirred vigorously at room temperature for 1 h. The mixture is then diluted with 1N NaOH (5 mL) and extracted CH2Cl2 (2×25 mL). The combined extracts are dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material is purified by flash chromatography on silicagel, eluting with CHCl3-MeOH (40:1 to 20:1) to afford the title compound. LC/MS: 428 (M+1).
Reaction SMILES: C(OC[C@H](C1C(Br)=[C:17]2[C:22](=CC=1C)[N:21]=[C:20](CN(C)C)[CH:19]=[CH:18]2)OC(C)(C)C)(=O)C(C)(C)C.[C:31]([O:35][C@@H:36]([C:45]1[C:46]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)=[C:47]2[C:52](=[CH:53][C:54]=1[CH3:55])[N+:51]([O-])=[C:50]([CH3:57])[CH:49]=[CH:48]2)[CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:34])([CH3:33])[CH3:32].N1CCCCC1>>[C:39]([O:38][CH2:37][C@@H:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])[C:45]1[C:46]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)=[C:47]2[C:52](=[CH:53][C:54]=1[CH3:55])[N:51]=[C:50]([CH2:57][N:21]1[CH2:22][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH:49]=[CH:48]2)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]
Reactant: Cc1cc2nc(CN(C)C)ccc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cc1cc2c(ccc(C)[n+]2[O-])c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Solvent: C1CCNCC1
Product: Cc1cc2nc(CN3CCCCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1-ylmethyl)quinolin-6-yl)ethyl pivalate was prepared following the procedure used to prepare compound (S)-2-(5-bromo-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)-2-tert-butoxyethyl pivalate of Example 9, except that (S)-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline 1-oxide was used instead of (S)-5-bromo-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-2,7-dimethylquinoline 1-oxide, and piperidine was used instead of N,N-dimethylamine solution. LCMS-ESI+ (m/z): 551.3, 553.3 (M+H)+.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=[CH:9][C:2]=12.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:11][CH2:10][C:7]1[CH:8]=[CH:9][C:2]2[C:3]([CH:6]=1)=[N:4][O:5][N:1]=2)(=[O:22])=[O:21]
Reactant: OCc1ccc2nonc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc2nonc2c1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 99.7 %

Procedure:
5-Benzofurazanmethanol (0.6 g, 4 mmol) and triethylamine (0.84 mmol, 0.61 g, 6 mmol) were dissolved in dichloromethane (20 ml) and cooled to -20° C. Methanesulfonyl chloride (0.37 ml, 0.55 g, 4.8 mmol) was added dropwise and the mixture was stirred at -20° C. for 20 minutes, diluted with dichloromethane (30 ml), washed with water (30 ml), dried (Na2SO4), and evaporated under reduced pressure to give the benzofurazan as a white solid (0.91 g, 99%).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[S:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[C:10]=2[CH3:18])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+].[OH-].[Na+].Cl>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)C.C(O)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[C:9]2[S:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[C:10]=2[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)C2CCCCC2)sc2cnccc12
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)sc2cnccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
To a mixture of cyclohexyl(3-methylthieno[2,3-c]pyridin-2-yl)methanone (628 mg) synthesized above, methyl 4-aminobenzoate (402 mg), triethylamine (2.70 mL) and methylene chloride (10 mL) was added titanium (IV) chloride (318 μL), and the mixture was stirred under argon atmosphere overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (30 mL) of the obtained oil in tetrahydrofuran were added acetic acid (277 μL) and sodium cyanoborohydride (304 mg), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, the organic solvent was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give an orange solid. To a mixture of the obtained solid, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5.00 mL), and the mixture was stirred with heating under reflux for 4 hr. 1N Hydrochloric acid (5.00 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40-100% ethyl acetate/hexane) to give the title object compound (202 mg, 22%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:50])=[C:32]([CH:49]=1)[O:33][C:34]1[CH:35]=[CH:36][C:37]2[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]3[CH2:48][CH2:47]3)=[O:45])[N:42]=2)[N:39]=1>CN(C)C=O.CN1CCCC1=O>[C:1]([C:3]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([CH3:50])=[C:32]([O:33][C:34]3[CH:35]=[CH:36][C:37]4[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]5[CH2:48][CH2:47]5)=[O:45])[N:42]=4)[N:39]=3)[CH:49]=2)=[O:12])[CH2:4][CH2:5][CH2:6]1)#[N:2]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CCC1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CCC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 64.4 %

Procedure:
Using 3-(1-cyanocyclobutyl)benzoic acid (110 mg, 0.56 mmol), oxalyl chloride (60 μL, 0.70 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N-methylpyrrolidone (3.0 mL) as starting materials and in the same manner as in Example 335, the title compound (150 mg, 64%) was obtained as a white powder.
Reaction SMILES: FC(F)(F)C(O)=O.CC(C)(OC([N:14]1[CH2:19][CH2:18][CH:17]([N:20]([CH3:30])[C:21]2[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:16][CH2:15]1)=O)C.[OH-].[Na+]>C(Cl)Cl>[CH3:30][N:20]([CH:17]1[CH2:18][CH2:19][NH:14][CH2:15][CH2:16]1)[C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: CN(c1ncccc1[N+](=O)[O-])C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(c1ncccc1[N+](=O)[O-])C1CCNCC1
Reaction time: 17 h

Procedure:
Trifluoroacetic acid (13.0 ml) is added to a solution of 1-((1,1-dimethylethoxy)-carbonyl)-4-(N-methyl-N-(3-nitro-2-pyridinyl)amino)piperidine (PREPARATION 49) in methylene chloride (100 ml) with cooling to -78°. The mixture is warmed to 20°-25°, stirred 17 hrs, cooled to 0° and basified to pH 12 with 5% sodium hydroxide. The phases are separated and the aqueous phase is extracted with methylene chloride (2×50 ml). The combined organic phases are dried over sodium sulfate and concentrated to give the title compound, mp 115.5°-117°.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[NH2:15][OH:16]>CO.C(OCC)(=O)C.[Pt]>[CH2:1]([N:15]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC=O
Reactant: NO
Agent: [Pt]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCN(O)CCCCCCCCCCCC
Yield: 50.9 %

Procedure:
A solution of dodecanal (9.2 g, 50 mmol) and hydroxylamine hydrochloride (3.8 g, 54 mmol) in 75 ml of methanol and 10 ml of ethyl acetate is shaken under hydrogen at 40-45 psi (2.8-3.15 Kg/cm2) for five hours at room temperature in the presence of a catalytic amount of 5% platinum on carbon (450 mg). The reaction mixture is then filtered through CELITE filter agent. The filtrate is concentrated and the residue is treated with a saturated aqueous potassium carbonate solution till the pH is over 10. A white solid is isolated by filtration and is recrystallized from methanol to provide 4.7 g (51% yield) of the title compound as a white solid melting at 88° C.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH:30]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])([CH3:32])[CH3:31]>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][NH:33][CH:30]([CH3:32])[CH3:31])=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Reactant: CC(C)NCCCCCN
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCCNC(C)C)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N1-Isopropyl-pentane-1,5-diamine by the procedure analogous to Example 6. HPLC ret. time: 3.4 minutes. 1H NMR (300 MHz, CD3OD) δ 7.20 (dd, 1H, J=5.7, 9.0 Hz), 7.06 (dd, 1H, J=6.3, 10 Hz), 5.47 (s, 2H), 3.23 (t, 2H, J=6.6 Hz), 2.93 (s, 1H, J=6.3 Hz), 2.70 (m, 2H), 2.27 (d, 3H, J=1.8 Hz), 1.7-1.5 (m, 4H), 1.5-1.3 (m, 2H), 1.11 (d, 6H, J=6.6 Hz) ppm; MS (APCl, m/z): 470 [M+H]+.