Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=[O:12].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[CH:18]1([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH:11]=[O:12])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
Caesium carbonate (214 g, 0.66 mol) was added to a mixture of 3-hydroxy-4-methoxybenzaldehyde (100 g, 0.66 mol) and cyclopentyl bromide (98 g, 0.66 mol) in anhydrous DMF (50 ml). The reaction mixture was stirred at RT for 16 h then treated with a further portion of cyclopentyl bromide (98 g, 0.66 mol) and caesium carbonate (214 g, 0.66 mol). After a further 6 h at RT, the mixture was filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (300 ml) and washed with sodium hydroxide solution (10%; 2×150 ml). The organic layer was dried (MgSO4), concentrated in vacuo, and distilled (150° C., 10-2 mbar) to afford the title compound (130 g) as a viscous colourless oil. (Found: C, 70.38; H, 7.48. C13H16O3 requires C, 70.89; H 7.32%); δH (CDCl3) 1.5-2.0 (8H, br m, CH2)4), 3.87 (3H, s, OMe), 4.80 (1H, br m, OCHCH2), 6.90 (1H, d, J 8.7 Hz. ArH ortho to OMe), 7.30-7.45 (2H, m. 2×ArH meta to OMe), and 9.77 (1 H, s, ArCHO).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[NH:19]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:19]3[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]3)[S:8][C:6]=2[N:7]=1
Reactant: OC1CCNC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: OC1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.1 %

Procedure:
To a solution of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde (1.1 g, 3.9 mmol) in 1,2-dichloroethane (20 mL) was added pyrrolidin-3-ol (5.4 mmol), and AcOH (3.9 mmol). After the reaction mixture stirred 10 min at room temperature, Na(OAc)3BH (4.6 mmol) was added then the mixture stirred 72 h at room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-20% MeOH in CH2Cl2) to afford 1-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)pyrrolidin-3-ol (0.5 g). MS (Q1) 355 (M)+
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH3:9])(=[O:7])=[O:6].[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[N:10]([CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH3:9])(=[O:7])=[O:6])=[N+:11]=[N-:12]
Reactant: CNS(=O)(=O)CCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)CCCN=[N+]=[N-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A mixture of 3-chloro-N-methylpropane-1-sulfonamide (29 mmol), NaN3 (29 mmol) in DMF (50 ml) was stirred at 100° C. for 2 h. The mixture was poured into 40 ml of brine. The mixture was extracted with ether (3×30 ml). The organic layers were combined and washed with 20 ml of brine. The organic layer was dried with Na2SO4, filtered and the filtrate was evaporated. Yield: 4.2 g (90% purity, 81% yield).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:27]1[C:28]2[C:35]([CH3:36])=[CH:34][S:33][C:29]=2[N:30]=[CH:31][N:32]=1>C(O)C>[O:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][CH:3]([NH:2][C:27]1[C:28]3[C:35]([CH3:36])=[CH:34][S:33][C:29]=3[N:30]=[CH:31][N:32]=1)[CH2:11]2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: NC1Cc2ccc(Oc3ccccc3)cc2C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1csc2ncnc(NC3Cc4ccc(Oc5ccccc5)cc4C3)c12
Yield: 39.4 %

Procedure:
Using 2-amino-5-phenoxyindan hydrochloride (99 mg, 0.36 mmol), ethanol (3 ml), triethylamine (92 μl, 0.66 mmol), and 4-chloro-5-methylthieno[2,3-d]pyrimidine (61 mg, 0.33 mmol), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (51 mg, 0.13 mmol) having the following physical properties:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:34][CH2:35][N:36]([CH2:39][C:40]([NH2:42])=[O:41])[CH2:37][CH:38]=2)=[CH:29][C:28]=1[O:43][CH3:44].C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:44][O:43][C:28]1[CH:29]=[C:30]([C:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]([NH2:42])=[O:41])[CH2:35][CH:34]=2)[CH:31]=[CH:32][C:27]=1[NH:26][C:15]1[N:14]=[CH:13][C:12]2=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:17]2[N:16]=1
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Reactant: COc1cc(C2=CCN(CC(N)=O)CC2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1cc(C2=CCN(CC(N)=O)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Into an 8-dram vial was added Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (210.0 mg, 0.5625 mmol), 2-[4-(4-Amino-3-methoxy-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetamide (180 mg, 0.69 mmol), N,N-Diisopropylethylamine (0.2940 mL, 1.688 mmol) and 1-Methoxy-2-propanol (2 mL, 20 mmol). The reaction mixture was heated at 100° C. overnight. After 18 h, the product, 2-(4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-acetamide, was isolated after purification with reverse phase prep-hplc (gilson) as a brown solid (46 mg, 17%). LCMS (E/I+) 582 (M+H). NMR 1H (DMSO-d6)-10.04 (br s, 1H), 8.97 (s, 1H), 8.15 (d, 1H, J=8.43 Hz), 7.96 (s, 1H), 7.80 (d, 1H, J=7.44 Hz), 7.72 (s, 2H), 7.48 (m, 1H), 7.23 (d, 1H, J=8.4 Hz), 7.13 (m, 2H0, 7.0-6.93 (m, 3H), 6.17 (s, 1H0, 4.01-3.2 (series of s, m along with the water peak, 12H), 2.78 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1C=O)(OC(C)(C)C)=O.C([Cl:18])(=O)C.[CH:19](OC)([O:22][CH3:23])[O:20][CH3:21]>CO>[ClH:18].[CH3:21][O:20][CH:19]([O:22][CH3:23])[C@@H:9]1[CH2:12][CH2:13][CH2:14][NH:8]1
Reactant: COC(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(OC)[C@@H]1CCCN1
Product: Cl
Temperature: 15 °C
Reaction time: 1 h

Procedure:
13.9 g Crude Boc-prolinal (70 mmol; Omega Chem, freshly distilled) were dissolved in 110 ml methanol and cooled to ˜15° C. A solution of 11.0 g (140 mmol) acetyl chloride in 30 ml methanol was added all at once and the yellowish solution was stirred at RT for 1 h (gas evolution). 66.9 g Trimethyl orthoformate (630 mmol) were now added and the reaction mixture was stirred at RT for 42 h. The solvent and the excess of the orthoester were removed by rotary evaporation (40° C./≧10 mbar) and the resulting 14.0 g beige, crystalline residue was crystallized from 300 ml hot ethyl acetate yielding after stirring at 0° C. for 17 h 8.9 g (70%) white needles, [α]D=−15.4 (CHCl3; c=1). 1H-NMR:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18]O)=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:31])CC>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][F:31])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(Nc1ccc(CCO)c(C(F)(F)F)c1)OCc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccc(CCF)c(C(F)(F)F)c1)OCc1ccccc1
Reaction time: 3 h
Yield: 45.1 %

Procedure:
[4-(2-Hydroxyethyl)-3-(trifluoromethyl)phenyl]carbamic acid benzyl ester (428 mg, 1.26 mmol) was dissolved in DCM (4 mL), and DAST (339 mL, 2.10 mmol) was added thereto. The resulting mixture was stirred for about 3 hours. The reaction solution was quenched with a saturated sodium bicarbonate solution, and then DCM (20 mL) was added thereto. 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=5:1) to give [4-(2-fluoroethyl)-3-(trifluoromethyl)phenyl]carbamic acid benzyl ester (194 mg, 45%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[CH2:24]O>>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[CH2:24][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: COc1cc(C)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-methoxy-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 3.37 (3H, s), 3.89 (3H, s), 5.23 (2H, s), 5.80 (1H, d, J=2.0 Hz), 6.76-6.79 (2H, m), 7.24-7.26 (1H, m), 7.37 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.58 (1H, d, J=1.6 Hz), 8.08 (1H, s), 8.70 (1H, d, J=4.4 Hz). [M+H] Calc'd for C18H16N4O2, 321; Found, 321.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:43](O)=[O:44])=[CH:24][C:25]=3[N:26]3[CH2:32][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:30][C:29]4[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:28]=4[C:27]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH:46]1([S:49]([NH2:52])(=[O:51])=[O:50])[CH2:48][CH2:47]1.C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:43](=[O:44])[NH:52][S:49]([CH:46]4[CH2:48][CH2:47]4)(=[O:51])=[O:50])=[CH:24][C:25]=3[N:26]3[CH2:32][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:30][C:29]4[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:28]=4[C:27]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)C4CC4)cc3n2C1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
1,1′-Carbonyldiimidazole (1.82 g, 11.2 mmol) was added to a slurry of 13-cyclohexyl-3-methoxy-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (3.85 g, 8.65 mmol) in THF (15 mL). The reaction mixture was heated at 60° C. for 1.5 h, cooled to rt, treated with cyclopropanesulfonamide (1.36 g, 11.2 mmol), stirred 10 min and then treated with the dropwise addition of a solution of DBU (2.0 mL, 13 mmol) in THF (3 mL). The reaction mixture was stirred at rt overnight, diluted with EtOAc (100 mL) and washed with H2O (˜30 mL), 1N HCl (aq.) (2×50 mL) and brine (˜30 mL). The combined aqueous layers were extracted with EtOAc (100 mL) and the organic layer was washed with 1N HCl (aq.) (˜50 mL). The combined organic layers were washed with brine (˜30 mL), dried (MgSO4), filtered and concentrated. The residue was stirred with Et2O (˜100 mL) for 2 h and the solids were collected by filtration, rinsed with Et2O and dried to yield methyl 13-cyclohexyl-10-((cyclopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate (4.24 g, 7.73 mmol, 89%) as a pale yellow solid which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 1.08-2.13 (m, 14H), 2.73-2.87 (m, 1H), 3.13-3.24 (m, 1H), 3.82 (s, 3H), 3.89 (s, 3H), 4.04-4.27 (m, 1H), 5.50-5.71 (m, 1H), 6.98 (d, J=2.6 Hz, 1H), 7.08 (dd, J=8.8, 2.6 Hz, 1H), 7.44 (dd, J=8.4, 1.1 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.80 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 8.11 (br s, 1H), 8.78 (br s, 1H). LCMS: m/e 549 (M+H)+, ret time 3.79 min, column B, 4 minute gradient.
Reaction SMILES: [NH3:1].[I:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1>CCOCC>[I:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:1])=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(Cl)Cc1ccc(I)cc1
Reactant: N
Solvent: CCOCC
Product: NC(=O)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Concentrated aqueous ammonia (density, 0.88 g/cm3) was added to a solution of 4-iodophenylacetyl chloride (2.80 g) in ether (30 ml) and the mixture was stirred at ambient temperature for 15 minutes. The product, 4-iodophenylacetamide, was obtained as a colourless crystalline solid (2.36 g), m.p: 200-204° C.; NMR: 3.34(2H,s), 6.87(H,bs), 7.44(2H,bs), 7.04-7.68(4H,AB); m/z 262(M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]([CH3:26])([CH3:25])[CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].[C:27]1([C:33]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:34][CH2:35][CH2:36][CH:37]=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)C.[BH4-].[Na+]>C(OCC)(=O)C.O>[CH2:23]([O:22][CH2:21][C:8]1[N:7]([CH2:6][C:5]([CH3:25])([O:4][CH2:3][CH2:2][NH:1][CH2:37][CH2:36][CH2:35][O:34][C:33]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:26])[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=1)[CH3:24]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCN
Reactant: O=CCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCNCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.9 %

Procedure:
1-(2-(2-Aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (50 mg, 140 μmol) and 3-(triphenylmethoxy)-propanal (CAN 67057-68-5; 44.3 mg, 140 μmol) were combined with ethanol (500 μL) to give a light yellow suspension. The mixture was stirred for 2 hours at room temperature. Afterwards sodium borohydride (5.82 mg, 154 μmol) was added and stirring at room temperature continued overnight. The mixture was stirred with water (2 mL) and ethyl acetate (5 mL), dried by passage through a ChemElut® cartridge and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel-NH2, 0% to 100% ethyl acetate in heptane) followed by another flash chromatography (silica gel, 0 to 10% methanol in ethyl acetate) to give the title compound (10 mg, 11%) as yellowish gum; LC-MS (UV peak area, ESI) 89%, 658.5 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8]/[CH:9]=[C:10](/[F:13])\[CH2:11]Br)([CH3:4])([CH3:3])[CH3:2].[CH:15]1([NH:21][C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C>CN(C=O)C.O>[CH:15]1([NH:21][C:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:11]/[C:10](/[F:13])=[CH:9]\[CH2:8][NH:7][C:6](=[O:14])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:25][CH:24]=2)=[O:30])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC/C=C(/F)CBr
Reactant: O=C(NC1CCCCC1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C=CCBr
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC/C=C(/F)COc1ccc(C(=O)NC2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A stirred solution of (E)-tert-butyl-N-(3-fluoro-4-bromobut-2-enyl)carbamate (3.48 g, 13 mmol), N-cyclohexyl-4-hydroxybenzamide (3.55 g, 16.2 mmol) and potassium carbonate (2.76 g, 20 mmol) in DMF (10 mL) under nitrogen was heated at 60° C. for 3 hours at which time TLC analysis showed no remaining allyl bromide. The reaction mixture was allowed to cool and then water (50 mL) added, causing a white precipitate to form. Stirred for 30 minutes, then filtered, washing with water to remove any remaining DMF from the filtercake. The precipitate was then taken up into dichloromethane (150 mL), filtered to remove any insolubles and then washed with NaOH solution (2 M; 20 mL) and brine (20 mL). Dried over MgSO4, filtered and the solvent removed under reduced pressure to afford the title compound as a white solid (4.23 g, 80%); 1H-NMR (400 MHz, CDCl3): δppm: 1.21-1.25 (3H, m), 1.40-1.46 (2H, m), 1.44 (9H, s), 1.61-1.69 (1H, m), 1.73-1.77 (2H, m), 2.01-2.05 (2H, m), 3.80 (2H, t, J 6.7 Hz), 3.96 (1H, m), 4.64 (1H, br s), 4.73 (2H, d, J 19.0 Hz), 5.46 (1H, dt J 18.9, 8.1 Hz), 5.81 (1H, br s), 6.96 (2H, d, J 8.3 Hz), 7.73 (2H, d, J 8.3 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[N:14]1([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:23]3[CH2:24][CH2:25][CH:20]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[CH2:21][CH2:22]3)=[CH:7][CH:6]=2)[CH:9]=1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Clc1ccc(-c2cccnc2)nn1
Product: c1cncc(-c2ccc(N3CCC(N4CCCCC4)CC3)nn2)c1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(pyridin-3-yl)-pyridazine and 4-piperidinopiperidine. 1H NMR (400 MHz, CD3OD) δ 9.47 (d, 1H), 9.11 (dt, 1H), 8.93 (d, 1H), 8.40 (d, 1H), 8.15 (q, 1H), 7.94 (d, 1H), 4.66 (d, 2H), 3.66 (m, 1H), 3.58 (d, 2H), 3.36 (t, 2H), 3.08 (t, 2H), 2.38 (d, 2H), 1.80-2.00 (m, 7H), 1.54 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(Br)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-bromophenol and N-{3-[1-(6-hydroxy-6-phenylhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 577.0 (M+H)+.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[Br:12]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:12][C:9]1[CH:10]=[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: CCC(C)c1ccc(O)cc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC(C)c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-sec-Butyl-phenol (3.0 g) is dissolved in chloroform and thereto is added bromine (1.02 ml) and the mixture is stirred at room temperature for 30 minutes. Thereto are added a saturated aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 2-bromo-4-sec-butyl-phenol (4.57 g). NMR (CDCl3): 0.81 (3H, t), 1.19 (3H, d), 1.56 (2H, m), 2.51 (1H, m), 5.33 (1H, s), 6.93 (1H, d), 7.02 (1H, d), 7.26 (1H, s).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:3]1.N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]1[C:25](=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CC1CCc2c(cccc2Oc2ccccc2)N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2cccc(Oc3ccccc3)c2CCC1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
A glass, screw-cap vial equipped with a magnetic stir bar was charged with a solution of rac-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline (0.050 g, 0.21 mmol) in dichloromethane (1 mL) and pyridine (0.051 mL, 0.630 mmol). The solution was cooled to 0° C. and acetyl chloride (0.015 mL, 0.210 mmol) was added. The ice bath was removed and the reaction mixture stirred at rt. After 10 min, the reaction mixture was diluted with dichloromethane and washed with 1 N aqueous hydrochloric acid solution (2×1 mL) followed by 5% aqueous sodium chloride solution (1 mL). The organic layer was concentrated to a yellow oil, which crystallized upon standing. The crude product was purified by preparative thin layer chromatography (1×1000 micron plate, eluting with 2:1 hexanes-ethyl acetate) to yield 1-(2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.0189 g, 32%) as a nearly colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.13 (d, J=6.60 Hz, 3 H), 1.36-1.55 (m, 1H), 2.11-2.27 (m, 4H), 2.36 (br s, 1H), 2.85 (dt, J=16.04, 6.09 Hz, 1H), 4.88 (br s, 1H), 6.76 (d, J=8.80 Hz, 1H), 6.89-6.96 (m, 2H), 6.96-7.04 (m, 1H), 7.04-7.11 (m, 1H), 7.12-7.19 (m, 1H), 7.29-7.37 (m, 2H). MS (ESI, pos. ion) m/z 282 [M+H]+.
Reaction SMILES: ClC(OC1C=C[C:8]([N+:11]([O-])=O)=CC=1)=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]([CH2:26][CH2:27][CH3:28])=[C:24]([C:29]([NH:31][CH:32]3[CH2:34][CH2:33]3)=[O:30])[N:23]=[N:22]2)=[CH:17][CH:16]=1.N.C(OCC)(=[O:38])C>ClCCl.CN(C)C1C=CN=CC=1.CO>[NH2:11][C:8]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]([CH2:26][CH2:27][CH3:28])=[C:24]([C:29]([NH:31][CH:32]3[CH2:33][CH2:34]3)=[O:30])[N:23]=[N:22]2)=[CH:17][CH:16]=1)=[O:38]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Reactant: CCOC(C)=O
Agent: CN(C)c1ccncc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(N)=O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 80 %

Procedure:
To a solution of 4-nitrophenyl chloroformate (1.06 g) in dichloromethane (15 ml) was added dropwise a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (1.0 g) obtained in Example 1d) and N,N-dimethylpyridin-4-amine (0.65 g) in dichloromethane (15 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 7 hr, a solution (2M, 18 ml) of ammonia in methanol was added, and the mixture was further stirred for 10 hr. Ethyl acetate was added to the reaction mixture, and the resulting insoluble material was collected by filtration and recrystallized from methanol/ethyl acetate to give the title compound as a colorless powder (0.91 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]1[O:13][CH:11]1[CH3:12]>CCOCC.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:10][CH:11]([OH:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC1CO1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
General Procedure FF: To a THF (5 mL) solution of 1.0 M of 4-chlorophenylmagnesium bromide in Et2O (10.0 mL) was added a solution of propylene oxide (0.87 g, 15 mmol) in THF (5 mL) at −78° C. under nitrogen and stirred. The mixture was slowly warmed to rt. The mixture was quenched with sat. aq NH4Cl (10 mL) and then extracted with EtOAc (50 mL). The organic phase was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to give the desired product as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ=1.23-1.26 (m, 3H), 1.44 (d, J=3.8 Hz, 1H), 2.65-2.80 (m, 2H), 3.97-4.07 (m, 1H), 7.14-7.18 (m, 2H), 7.28-7.32 (m, 2H).