Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=1[F:18].[NH2:19][C:20]1[C:21]([N:29]2[CH2:34][CH2:33][CH2:32][C@H:31]([NH:35]C(=O)OC(C)(C)C)[CH2:30]2)=[C:22]2[CH2:28][CH2:27][O:26][C:23]2=[N:24][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:35][C@H:31]1[CH2:32][CH2:33][CH2:34][N:29]([C:21]2[C:20]([NH:19][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:18])=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:14]=3)=[O:17])=[CH:25][N:24]=[C:23]3[O:26][CH2:27][CH2:28][C:22]=23)[CH2:30]1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCO3)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (15.0 mg, 0.0592 mmol), tert-butyl [(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (19.1 mg, 0.0571 mmol) and HATU (73.6 mg, 0.194 mmol), DMF (1.50 mL) was added, followed by DIPEA (84.8 mg, 0.656 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. DCM (2.0 mL) was added to the residue, followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.15% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (5.9 mg, 22%). LCMS calc. for C24H23F3N5O2 (M+H)+: m/z=470.2. found 470.2.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:21]2([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:27]([C:21]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:28])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Reactant: O=C(O)C1(c2ccccc2)CCCCC1
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(c2ccccc2)CCCCC1

Procedure:
The product from Example 92B and 1-phenylcyclohexanecarboxylic acid (Aldrich) were processed using the method described in Example 92C to afford the title compound. 1H NMR (DMSO-d6) δ 0.90 (t, J=7.3 Hz, 3H), 1.20-1.77 (m, 21H), 2.61-2.69 (m, 4H), 7.10-7.15 (m, 1H), 7.21-7.27 (m, 2H), 7.35-7.39 (m, 2H), 8.51 (s, 1H). MS (ESI+) m/z 399 (M+H)+. Anal. calcd. for C24H34N2OS: C, 72.32; H, 8.60; N, 7.03. Found: C, 72.24; H, 8.59; N, 7.10.
Reaction SMILES: ClC1C=CC(O)=CC=1.BrCC(SC1C(Cl)=CC=CC=1Cl)C[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.Br[CH2:28][CH2:29][C:30]([OH:32])=[O:31].N1C=CN=C1>>[N:13]1([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: Clc1cccc(Cl)c1SC(CBr)Cn1ccnc1
Reactant: O=C(O)CCBr
Agent: Oc1ccc(Cl)cc1
Agent: c1c[nH]cn1
Product: O=C(O)CCn1ccnc1

Procedure:
A mixture of 12.9 g of p-chlorophenol, 36.6 g of 1-bromo-2-(2,6-dichlorophenylthio)-3-(1-imidazolyl)propane [obtainable by reaction of 3-bromopropionic acid with imidazole to give 3-(1-imidazolyl)propionic acid, bromination to give 2-bromo-3-(1-imidazolyl)propionic acid, reaction with Na 2,6-dichlorothiophenolate to give 2-(2,6-dichlorophenylthio)-3-(1-imidazolyl)propionic acid, reduction with LiAlH4 to give the corresponding alcohol, and reaction with PBr3 ], 8 g of NaOH and 400 ml of ethanol is heated at 100° for 10 hours. The mixture is evaporated, worked up as usual and Ia of m.p. 175°-177° is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[C:16]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:25]3[O:24][CH:28]=[CH:27][CH:26]=3)=[CH:3][CH:4]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Oc1ccc(C(=C2CCCCCCC2)c2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCCCC2)c2ccc(-c3ccco3)cc2)cc1
Yield: 76 %

Procedure:
The procedure described for 202 was employed. A round-bottomed flask was charged with 4-[(4-bromophenyl)(cyclooctylidene)methyl]phenol (49) (0.150 g, 0.404 mmol), PdCl2(PPh3)2, (0.028 g, 0.40 mmol), 2-furanylboronic acid (0.090 g, 0.80 mmol), Na2CO3 (0.086 g, 0.808 mmol), and THF/H2O (4:1, 5 mL). The reaction mixture was refluxed for 10 h. Standard workup and purification by flash silica gel chromatography provided 110 mg (76%) of the title compound 203 as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.27 (s, 1H), 7.70 (d, J=0.9 Hz, 1H), 7.59 (d, J'6.0 Hz, 2H), 7.15 (d, J=6.3 Hz, 2H), 6.94 (d, J=6.6 Hz, 2H), 6.86 (d, J=2.4 Hz, 1H), 6.67 (d, J=6.3 Hz, 1H), 6.55 and 6.54 (dd, J1=2.4 Hz, J2=1.2 Hz, 1H), 2.48-2.47 (m, 4H), 1.60 (br s, 2H), 1.50-1.45 (m, 8H). 2.37 (br s, 4H), 1.62 (br s, 8H). LCMS (ESI): m/z 357 (M−H)−.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH2:7][CH3:8])[CH3:6].O>C(O)(=O)C>[N+:1]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH:5]([CH2:7][CH3:8])[CH3:6])[C:10]=1[OH:15])([O-:4])=[O:2]
Reactant: CCC(C)c1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CCC(C)c1cccc([N+](=O)[O-])c1O
Temperature: 0 °C
Yield: 48.1 %

Procedure:
A mixture comprising 290.6 g of 65% nitric acid and 800 g of glacial acetic acid is cooled to 0° C., and at 0° to 4° C. there is added in the course of 11/2 hours, with thorough stirring and with cooling, a solution of 375.6 g of sec-butylphenol in 375 g of glacial acetic acid. There results a dark solution which is stirred at 0° to 4° C. for a further one hour. The reaction mixture is subsequently stirred into 5000 ml of water and ice. The nitrating mixture is obtained as a dark oil which is extracted with 1500 ml of chloroform. The chloroform is distilled off, and steam is passed into the dark oil obtained. As distillate is obtained 235 g of 2-nitro-6-sec-butylphenol in the form of light-yellow oil.
Reaction SMILES: O[CH2:2][C:3]#[C:4][CH2:5][C:6]#[C:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].N1C=CC=CC=1.P(Br)(Br)[Br:23]>C(OCC)C>[Br:23][CH2:2][C:3]#[C:4][CH2:5][C:6]#[C:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: BrP(Br)Br
Reactant: CCCCCC#CCC#CCC#CCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCC#CCC#CCC#CCBr

Procedure:
6 g of 1-hydroxy-2,5,8-tetradecatriyne prepared above, dissolved in 30 cm3 of ethyl ether, are introduced into a round-bottomed flask equipped with an argon inlet. 0.05 cm3 of pyridine is added and 1 cm3 of phosphorus tribromide is added dropwise, and the mixture is then brought to reflux for 3 hours.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[N:9]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)[CH:10]=[C:11]([C:13]3[CH:27]=[CH:26][C:16]([O:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:15][CH:14]=3)[N:12]=2)[CH2:3][CH2:2]1.[CH:42](=O)[CH3:43].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:42]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[N:9]([C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=4)=[CH:32][CH:33]=3)[CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:26][CH:27]=3)[N:12]=2)[CH2:3][CH2:2]1)[CH3:43]
Reactant: CCN(CC)CCCOc1ccc(-c2cn(-c3ccc(Oc4ccc(Cl)cc4)cc3)c(CC3CCNCC3)n2)cc1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)CCCOc1ccc(-c2cn(-c3ccc(Oc4ccc(Cl)cc4)cc3)c(CC3CCN(CC)CC3)n2)cc1
Temperature: 25 °C

Procedure:
[3-(4-{2-(Piperidine-4-ylmethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine (Example 539) (0.1 mmol) was treated in anhydrous DCM (2 ml) with acetaldehyde (1.2 eq.,) followed by addition of Na(OAc)3BH (1.5 eq.). The reaction mixture was stirred at rt. Crude product was extracted into EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concenterated in vacuo to give desired product, which was purified by column chromatography on silica gel to afford 49 mg of Example 540.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.Cl.[NH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: COC(=O)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCNc1cc(Br)ccc1[N+](=O)[O-]
Yield: 0.1 %

Procedure:
A solution of 4-bromo-2-fluoro-1-nitrobenzene (10 g, 45.5 mol), methyl 3-aminopropanoate hydrochloride (6.4 g, 45.5 mol) and K2CO3 (19 g, 136.5 mol) in THF (250 mL) was heated at 100° C. for 4 hrs. The mixture was extracted with ethyl acetate (100 mL), washed with brine (150 mL), dried and concentrated to give the residue, which was purified by CombiFlash (PE:EA=2:1) to give methyl 3-((5-bromo-2-nitrophenyl)amino)propanoate (12 g, yield 88%). 1H NMR (300 MHz, CDCl3) δ 2.70-2.75 (t, J=6.6 Hz, 2H), 3.58-3.65 (m, 2H), 3.74 (s, 3H), 6.76-6.80 (m, 1H), 7.02-7.03 (d, J=2.1 Hz, 1H), 8.01-8.04 (d, J=9.0 Hz, 2H), 8.20-8.22 (br, 1H).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[C:34](O)=[O:35])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[C:34]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:35])=[CH:26][CH:27]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OCCO4)C[C@@H]3C[C@@H]32)c(-c2ccc(F)cc2)s1

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.35 min; [M+H]+=494.1.
Reaction SMILES: Br.Cl[C:3]1[CH:4]=[C:5]([CH3:13])[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.O>CN(C=O)C>[CH3:13][C:5]1[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=[C:3]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:4]=1
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Reactant: C1CCNC1
Agent: Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCCC2)nn2c(N)nnc12
Reaction time: 1.5 h

Procedure:
6-Chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 250 mg) was dissolved in DMF (2 ml) and admixed with pyrrolidine (2 ml). Thereafter, the reaction mixture was placed into the heating block at 80° C. with stirring for 1.5 h. Subsequently, the solvent was drawn off and the residue was admixed with a little water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. When the residue was dissolved in acetonitrile/water+0.05% TFA, a solid precipitated out, which was filtered off with suction and dried. 40 mg of 8-methyl-6-pyrrolidin-1-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine were obtained. The mother liquor was purified by means of preparative HPLC (met. A), and the clean product fractions were combined, freed of the acetonitrile under reduced pressure and freeze-dried. 11 mg of 8-methyl-6-pyrrolidin-1-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine were obtained as the trifluoroacetic acid salt. 8-Methyl-6-pyrrolidin-1-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][CH:13]([OH:16])[C:14]#[CH:15].CCN(CC)CC>[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]2[C:5]([CH:15]=[C:14]([CH:13]([OH:16])[CH3:12])[O:9][C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Br)ccc1I
Reactant: C#CC(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(O)c1cc2ccc(Br)cc2c(=O)o1
Temperature: 80 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
Part 2, Step A: A mixture of 5-bromo-2-iodobenzoic acid (12.6 g, 38.5 mmol), but-3-yn-2-ol (3.1 mL, 2.96 g, 42.4 mmol), ZnCl2 (5.2 g, 38.5 mmol), Pd(Ph3P)4 (2.23 g, 1.9 mmol), Et3N (16.0 mL, 11.7 g, 115.5 mmol) and DMF (80 mL) was stirred under argon at 80° C. for 2 hours. After removal of the volatiles under vacuum, the residue was chromatographed (silica gel, ethyl acetate in hexanes, 0-100%) to provide the intermediate 7-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one as a brown oil (7.5 g, 72%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.38-8.45 (1H, m), 7.81 (1H, dd, J=8.35, 2.05 Hz), 7.32 (1H, d, J=8.51 Hz), 6.52-6.59 (1H, m), 4.66 (1H, qd, J=6.52, 0.95 Hz), 1.54-1.60 (3H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[C:20](O)(=[O:22])[CH3:21].C(OC(=O)C)(=O)C>O>[C:20]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9]1)(=[O:22])[CH3:21]
Reactant: CC(=O)O
Reactant: O=C(O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)O)ccc21
Temperature: 80 °C
Yield: 100 %

Procedure:
To a flask containing 3-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (5.0 g, 0.02 mol) was added acetic acid (100 mL). The flask was placed under nitrogen and to the flask was added acetic anhydride (5.6 mL, 0.06 mol). The reaction refluxed at 80° C. for three hours. The flask was cooled to room temperature and the reaction was diluted with water. The product was collected by vacuum filtration and rinsed with additional amounts of water to yield the title compound (5.96 g, 100% yield) 1H NMR (DMSO-d6) δ 8.6 (s, 1H), 8.45–8.5 (d, 1H), 8.2–8.25 (d, 1H), 8.1 (m, 2H), 7.5 (t, 2H), 2.8 (s, 3H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=4[C:16]=3[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][C:28]#[N:29].[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:17]([C:16]1[C:15]2[CH:22]=[CH:23][CH:24]=[CH:25][C:14]=2[O:13][C:12]=1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:2]=[C:3]([O:26][CH2:27][C:28]1[NH:29][N:32]=[N:31][N:30]=1)[CH:4]=[CH:5]2)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)oc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCc1c(-c2ccc3cc(OCc4nnn[nH]4)ccc3c2)oc2ccccc12
Yield: 66.1 %

Procedure:
Following the procedure described in Step 6, of Example 1, the title compound was prepared from [1-bromo-6-(3-pentyl-benzofuran-2-yl)-naphthalen-2-yloxy]-acetonitrile (1.23 g, 2.75 mmol), sodium azide (1.8 g, 27.5 mmol) and ammonium chloride (1.45 g, 27.5 mmol) in DMF (30 mL). Crystallization from methanol afforded the title compound as an off-white solid (0.75 g), mp 192-194° C. Mass spectrum (+APCl, [M+H]+) m/z 491. 1HNMR (400 MHz, DMSO-d6): δ8.36 (d, 1H, J=1.5 Hz), 8.23-8.17 (m, 2H), 8.05 (dd, 1H, J=9.0, 1.7 Hz), 7.72-7.68 (m, 2H), 7.61 (m, 1H, J=8.1 Hz), 7.37-7.27 (m, 2H), 5.75 (s, 2H), 3.00 (t, 2H, J=7.8 Hz), 1.74-1.767 (m, 2H), 1.42-1.26 (m, 4H), and 0.84-0.80 ppm (m, 3H). Elemental Analysis for C25H24N4O2.0.75H2O: Calculated: C, 59.47; H, 4.89; N, 11.09. Found: C, 59.51; H, 4.6; N, 11.09.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16]Br)[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([O:26][C:27]([C:29]1[N:30]=[C:31]([SH:34])[NH:32][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[N:30]=[C:31]([S:34][CH2:16][C:14]2[N:15]=[C:11]([NH:10][C:8]([N:7]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:9])[S:12][CH:13]=2)[NH:32][CH:33]=1)=[O:28])[CH3:25]
Reactant: CCOC(=O)c1c[nH]c(S)n1
Reactant: O=C(Nc1nc(CBr)cs1)N(C1CCCCC1)C1CCCCC1
Product: CCOC(=O)c1c[nH]c(SCc2csc(NC(=O)N(C3CCCCC3)C3CCCCC3)n2)n1
Yield: 20 %

Procedure:
Prepared in 20% yield as described in general procedure (L) from 1,1-dicyclohexyl-3-(4-bromomethyl-thiazol-2-yl)urea and 2-mercapto-1H-imidazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:35])[C:11]2[CH:10]=[C:9]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])[S:8][C:7]=2[C:6]([CH3:34])([CH3:33])[CH2:5][CH2:4]1.[CH2:36]([O:38][C:39]([C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=1)=[O:40])[CH3:37]>C1OCCC1>[CH3:35][C:3]1([CH3:2])[C:11]2[CH:10]=[C:9]([C:12]([CH3:13])=[CH:45][C:44]3[CH:47]=[CH:48][C:41]([C:39]([O:38][CH2:36][CH3:37])=[O:40])=[CH:42][CH:43]=3)[S:8][C:7]=2[C:6]([CH3:34])([CH3:33])[CH2:5][CH2:4]1
Reactant: CC(c1cc2c(s1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C=C(C)c2cc3c(s2)C(C)(C)CCC3(C)C)cc1
Yield: 55.5 %

Procedure:
30 g of [1-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thien-2-yl)ethyl]triphenylphosphonium bromide and 9.5 g of 4-ethoxycarbonylbenzaldehyde are suspended in 300 ml of butylene oxide and the mixture is heated at reflux for 4 hours. The thus-obtained solution is concentrated to one third of the original volume in a water-jet vacuum, poured into 500 ml of a methanol/water mixture (6:4) and extracted several times with hexane. The organic phase is washed three times with water, dried over sodium sulphate and evaporated. There is obtained a light brownish oil which is purified by filtration over silica gel (eluting agent hexane/ether 19:1). After recrystallization from hexane, there are obtained 11.3 g of ethyl p-[2-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thien-2-yl)propenyl]-benzoate in the form of colorless crystals, m.p. 118°-120° C.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[C:1]1([C:7](=[N:14][C:15]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)([CH3:29])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1cncnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(N=C(c1ccccc1)c1ccccc1)c1cncnc1
Reaction time: 0.5 h

Procedure:
To a solution of 456 mg of ethyl [(diphenylmethylene)amino](pyrimidin-5-yl)acetate in 4.5 ml of DMF was added 69 mg of sodium hydride (55% mineral oil included) under ice-cooling, followed by stirring for 30 minutes. To the reaction mixture was added 0.1 ml of methyl iodide, followed by stirring at room temperature for 1.5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 224 mg of ethyl 2-[(diphenylmethylene)amino]-2-(pyrimidin-5-yl)propanoate.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H][H]>CC(O)=O.C(OCC)(=O)C.O=[Pt]=O>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH:4]2[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)n1ccc2ccncc21
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2CCNCC21
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.8 %

Procedure:
To a solution of tert-butyl 1H-pyrrolo[2,3-c]pyridine-1-carboxylate (0.5 g, 2.3 mmol) in AcOH (15 mL) was added PtO2 (0.25 g, 1.1 mmol). The mixture was treated with an atmosphere of hydrogen atmosphere (60 psi) and stirred for 12 h at rt. The suspension was filtered through a pad celite and concentrated in vacuo to afford a residue. The crude material was diluted with ethyl acetate (50 mL) and washed with sat. NaHCO3 (100 mL), the organic phase was separated, dried (Na2SO4) filtered and concentrated in vacuo to afford the title compound (0.53 g, 99% yield). 1H NMR (400 MHz, CDCl3) δ=6.07-5.58 (m, 1H), 4.03-3.68 (m, 1H), 3.57-3.22 (m, 3H), 3.05-2.66 (m, 2H), 2.49-2.19 (m, 1H), 1.96 (s, 4H), 1.77-1.64 (m, 1H), 1.45 (s, 9H). LC/MS (m/z): calc; d. For C12H22N2O2 (M+1H) 227. found 227.2.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[C:15]([CH3:16])=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[CH3:17])=[CH:6][CH:5]=1.[CH3:22][CH:23]([C:29]([CH3:31])=O)[C:24](OCC)=[O:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]([F:20])([F:21])[O:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[C:10]([CH3:17])=[C:11]3[C:12](=[CH:14][C:15]=2[CH3:16])[N:13]=[C:29]([CH3:31])[C:23]([CH3:22])=[C:24]3[OH:25])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Cc1cc(N)cc(C)c1Oc1ccc(OC(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1cc2nc(C)c(C)c(O)c2c(C)c1Oc1ccc(OC(F)(F)F)cc1
Yield: 130.1 %

Procedure:
A solution of 1.78 g of 4-(4-trifluoromethoxyphenoxy)-3,5-dimethylaniline, 1.92 g of ethyl 2-methylacetoacetate, and 1.14 g of p-toluenesulfonic acid dissolved in 61 mL of xylene was heated under reflux for 9 hr. This reaction solution was cooled, and the precipitated crystals were then collected by filtration and were washed with distilled water and n-hexane to give 2.94 g of 6-(4-trifluoromethoxyphenoxy)-4-hydroxy-2,3,5,7-tetramethyl-quinoline 2.26 g (yield 100%). A 1.14 g portion in the crystals thus obtained was stirred in 15 mL of acetic anhydride with heating at 120 to 125° C. for 2 hr. The reaction solution was concentrated, ethyl acetate was then added to the concentrate, the mixture was washed with saturated brine, and the solvent was then concentrated under the reduced pressure. The crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) to give 0.74 g of 4-acetoxy-6-(4-trifluoromethoxyphenoxy)-2,3,5,7-tetramethyl-quinoline (yield 58.4%).