Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][C@@H:4]1[O:8][CH2:7][O:6][C@@H:5]1[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].S([N:28]=[N+:29]=[N-])(C1C=CC(C)=CC=1)(=O)=O.CCN(CC)CC>C(#N)C>[CH3:17][C:2]([CH3:1])=[CH:3][C@@H:4]1[O:8][CH2:7][O:6][C@@H:5]1[C:9](=[O:16])[C:10](=[N+:28]=[N-:29])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)[C@H]1OCO[C@H]1C=C(C)C
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=[N+]=[N-])C(=O)[C@H]1OCO[C@H]1C=C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a stirred solution of keto ester 110 (4.84 g, 20 mmol) in acetonitrile (40 mL) was successively added tosyl azide (4.13 g, 21 mmol) and Et3N (4.4 g, 40 mmol). The resulting reaction mixture was concentrated after stirring for 30 min at room temperature. The diazo derivative was purified by column chromatography (silica gel; hexanes:EtOAc, 95:5) to furnish 112 (3.75 g, 70%) as an oil; IR (neat) 2141, 1713 cm−1; [α]25D=+81.0° (c 2.02, CHCl3); 1H NMR (CDCl3) δ5.77 (ddd, 1 H, J=17.3, 10.1, 7.3 Hz), 5.70 (d, 1 H, J=7.6 Hz), 5.45 (dm, 1 H, J=17.1 Hz), 5.30 (dm, 1 H, J=10.2 Hz), 5.05 (t, 1 H, J=7.5 Hz), 4.36 (q, 2 H, J=7.1 Hz), 1.74 (s, 3 H), 1.51 (s, 3 H), 1.41 (t, 3 H, J=7.1 Hz); FAB MS m/z (relative intensity) 269 (MH+, 86). This compound was used for the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[CH2:29]Br)[CH3:26]>CN(C=O)C>[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[CH2:29][NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:26]
Reactant: NCCCCCCOCCCCc1ccccc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(CNCCCCCCOCCCCc1ccccc1)OCC
Reaction time: 20 h
Yield: 42.6 %

Procedure:
To a solution of 2.77 g (11.12 mmol) 6-(4-phenylbutoxy)hexylamine in 20 ml DMF is added 1.54 g (11.16 mmol) K2CO3 and 1.68 g (11.17 mmol) bromoacetaldehyde diethylacetal. After allowing the mixture to stand for 20 hr at 80° C., DMF is distilled off at reduced pressure, and the resulting crude product in 30 ml CH2Cl2 is washed with 30 ml H2O. The CH2Cl2 phase is dried on anhydrous Na2SO4, concentrated to dryness and the residue is purified by column chromatography on silica gel (gradient CH2Cl2/AcOEt 1:1 to AcOEt), thereby yielding 1.73 g (42.6 %) N-diethoxyethyl-6-(4-phenylbutoxy)hexylamine as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:11]2[CH:12]=[CH:13][C:14]([CH:19]([C:34]3[CH:39]=[CH:38][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=3)[CH2:20][C@H:21]3[CH2:25][CH2:24][C:23](=[O:26])[N:22]3C(OC(C)(C)C)=O)=[N:15][C:16]=2[O:17][CH3:18])[CH2:10][CH2:9]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:8]1([C:11]2[CH:12]=[CH:13][C:14]([CH:19]([C:34]3[CH:39]=[CH:38][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=3)[CH2:20][C@@H:21]3[NH:22][C:23](=[O:26])[CH2:24][CH2:25]3)=[N:15][C:16]=2[O:17][CH3:18])[CH2:10][CH2:9]1
Reactant: COc1nc(C(C[C@H]2CCC(=O)N2C(=O)OC(C)(C)C)c2ccc(C(C)C)cc2)ccc1C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(C(C[C@H]2CCC(=O)N2)c2ccc(C(C)C)cc2)ccc1C1CC1
Yield: 105.8 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl (2R)-2-{2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-[4-(propan-2-yl)phenyl]ethyl}-5-oxopyrrolidine-1-carboxylate (211 mg) in methylene chloride (2 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 75 minutes. Saturated aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure to give (5R)-5-{2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-[4-(propan-2-yl)phenyl]ethyl}pyrrolidin-2-one (176.5 mg, quant.).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:15][CH2:16][CH3:17])[NH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:4])[CH3:3].[C:18]([NH:22][C:23]([C:25]1[C:26]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=2)=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CC(C)([O-])C.[K+]>>[C:18]([NH:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][N:8]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:2]([OH:1])([CH3:4])[CH3:3])[N:6]=[C:7]2[CH2:15][CH2:16][CH3:17])=[CH:33][CH:32]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)NC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)NC(C)(C)C)cc1
Yield: 67.1 %

Procedure:
Following a procedure similar to that described in Example 68(a), but using 4.16 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9), 6.00 g of N-t-butyl-4'-bromomethylbiphenyl-2-carboxamide (prepared as described in Preparation 38) and 2.14 g of potassium t-butoxide, 5.87 g of the title compound was obtained as crystals, melting at 145°-146° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([Cl:31])=[CH:19][C:18]=1[C:32]1[CH:36]=[CH:35][NH:34][N:33]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>ClCCl>[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([Cl:31])=[CH:19][C:18]=1[C:32]1[C:36]([Br:1])=[CH:35][NH:34][N:33]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1cc(-c2cc[nH]n2)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: Clc1cc(-c2n[nH]cc2Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
N-Bromosuccinimide (4.70 g, 26 mmol) was added in portions over 5 minutes to a stirred solution of 3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-1H-pyrazole (10.29 g 26 mmol) in dichloromethane (200 ml). The reaction mixture was stirred at ambient temperature for 2 hours then water (200 ml) was added and vigorous stirring continued for 10 minutes. The phases were separated and the organic phase was washed with water (3×100 ml), saturated aqueous sodium chloride solution (2×100mi) and dried over sodium sulphate. The mixture was filtered and filtrate solvents were removed in vacuo to afford an off-white solid, which was triturated with ethyl acetate/hexane (1:20) mixture to give 3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-bromo-1H-pyrazole (11.80 g, 97%) as off-white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19](Cl)=[O:20]>ClC1C=CC=CC=1>[F:14][C:12]([F:15])([F:13])[O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:19](=[O:20])[C:18]3[C:17]([F:16])=[CH:25][CH:24]=[CH:23][C:22]=3[F:26])[S:3][C:4]=2[CH:10]=1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: Clc1ccccc1
Product: O=C(Nc1nc2ccc(OC(F)(F)F)cc2s1)c1c(F)cccc1F
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A mixture composed of 2-amino-6-trifluoromethoxybenzothiazole (2.34 g), 2,6-difluorobenzoylchloride (1.8 g) and chlorobenzene (20 ml) was boil for 1 hour. The hot reaction mixture was filtered and cooled to 10°-20° C. The resulting crystals were collected by filtration and washed with n-hexane (20 ml) to give N-(6-trifluoromethoxybenzothiazol-2-yl)-2,6-difluorobenzamide (3.15 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.CC1C=CC(S(O[C@H:28]2[CH2:32][CH2:31][O:30][CH2:29]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C@@H:28]3[CH2:32][CH2:31][O:30][CH2:29]3)=[CH:11][CH:10]=2)[O:5]1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCOC2)cc1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(O[C@@H]3CCOC3)cc2)OC1(C)C
Temperature: 85 °C
Yield: 29.5 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (6.3 g, 28.5 mmole), (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (6.8 g, 28 mmol) and K2CO3 (8.0 g, 58 mmole) in DMF (25 mL) was heated at 85° C. for 15 h. The reaction mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, elute: 5% ethyl acetate in hexane) to give the title compound (2.4 g, 30% yield). MS (ESI) m/z: Calc. 290.1 (M+). Found: 291.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:9]=[N:10][NH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])=[C:4]([N+:20]([O-])=O)[CH:3]=1>C(O)C.C(Cl)(Cl)Cl.O=[Pt]=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:9]=[N:10][NH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])=[C:4]([NH2:20])[CH:3]=1
Reactant: CCOC(=O)c1[nH]nnc1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1[nH]nnc1C(=O)c1ccc(Cl)cc1N
Reaction time: 19 h
Yield: 108.4 %

Procedure:
A suspension of PtO2 (541.6 mg) in ethanol (50 mL) was shaken under hydrogen (40 psi) in a PARR™ hydrogenator for 19 hours. A solution of ethyl 4-(4-chloro-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate (1.014 g, 3.124 mmol) in chloroform (10 mL)/ethanol (200 mL) was then added to the reaction mixture and shaking on the PARR™ hydrogenator at 51 psi was continued. After 3 hours the reaction mixture was filtered through a pad of CELITE™, washing with ethanol. The filtrate was concentrated under vacuum (0.3 torr) to afford 0.998 g (108%) of crude title compound as a bright yellow foam.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]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>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([NH:30][C:27]3[CH:28]=[N:29][C:24]([N:21]4[CH2:20][CH2:19][O:18][CH2:23][CH2:22]4)=[CH:25][CH:26]=3)=[O:17])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: Cc1cc(-c2ccc(CC(=O)O)cc2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCOCC4)nc3)cc2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)acetic acid 73-1 (40 mg, 0.18 mmol), 6-morpholinopyridin-3-amine (40 mg, 0.22 mmol) and HATU (80 mg, 0.21 mmol) in 2 mL DMF was added DIEA (104 μL, 0.6 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give the title compound 73 as white solid. MS m/z 389.19 (M+1); 1H NMR 400 MHz (DMSO-d6) δ11.30(s, 1H), 8.82(d, 1H, J=6.4 Hz), 8.57(d, 1H, J=2.4 Hz), 8.35(m, 1H), 8.24(dd, 1H, J1=6.4 Hz, J2=1.6 Hz), 8.19(dd, 1H, J1=10.0 Hz, J2=2.8 Hz), 8.02(m, 2H), 7.63(m, 2H), 7.42(d, 2H, J=9.6 Hz), 3.87(s, 2H), 3.75(m, 4H), 3.66(m, 4H), 2.80(s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([CH2:14][CH2:15][NH2:16])[N:13]=2)=[CH:5][CH:4]=1.[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29](O)=[O:30])[N:20]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][CH:11]=[C:12]([CH2:14][CH2:15][NH:16][C:29](=[O:30])[C:28]3[CH:32]=[C:24]([C:21]4[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=4)[CH:25]=[N:26][CH:27]=3)[N:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(CCN)co2)cc1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: COc1ccc(-c2nc(CCNC(=O)c3cncc(-c4noc(C(F)(F)F)n4)c3)co2)cc1
Yield: 19 %

Procedure:
This compound was synthesized from 2-(2-(4-methoxyphenyl)oxazol-4-yl)ethanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (35 mg, yield 19%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.47 (m, 1H), 9.34 (m, 1H), 8.90-8.89 (t, J=2.0 Hz, 1H), 8.08-8.06 (m, 1H), 8.03-8.00 (d, J=8.8 Hz, 2H), 7.55 (s, 1H), 6.99-6.97 (d, J=8.8 Hz, 2H), 3.88 (s, 3H), 3.87-3.84 (m, 2H), 2.96-2.93 (t, J=5.9 Hz, 2H). MS (ESI) m/z: Calculated for C21H16F3N5O4: 459.12. found: 460.1 (M+H)+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][O:10][CH2:11]/[C:12](/[CH3:27])=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH3:28].CCCCCC>CC(O)C>[NH2:28]/[C:3](/[CH3:5])=[CH:2]\[C:1]([O:7][CH2:8][CH2:9][O:10][CH2:11]/[C:12](/[CH3:27])=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)=[O:6]
Reactant: N
Reactant: CC(=O)CC(=O)OCCOC/C(C)=C/c1ccc(Cc2cccnc2)cc1
Solvent: CCCCCC
Solvent: CC(C)O
Product: C/C(N)=C/C(=O)OCCOC/C(C)=C/c1ccc(Cc2cccnc2)cc1
Yield: 80.2 %

Procedure:
In 8 ml of 2-propanol was dissolved 2.0 g of 2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]ethyl acetoacetate, and ammonia gas was introduced into the resulting solution for 2 hours with ice-cooling. And, the solution was subjected to reaction at room temperature for 15 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and to the residue thus obtained were added 2 ml of 2-propanol and 8 ml of n-hexane, after which the resulting mixture was stirred. The crystals thus precipitated were collected by filtration to obtain 1.6 g (yield 80.2%) of 2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]ethyl 3-aminocrotonate.
Reaction SMILES: [Br-:1].[C:2]([CH2:5][CH2:6][N+:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][C:8]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)[CH3:3]>CS(C)=O>[Br-:1].[CH3:3][C:2]1[CH2:5][CH2:6][N+:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][C:8]=2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)CC[n+]1c(Cc2ccccc2)sc2ccccc21
Agent: [Br-]
Solvent: CS(C)=O
Product: CC1=C(c2ccccc2)c2sc3ccccc3[n+]2CC1
Yield: 30 %

Procedure:
1,2-Dihydro-3-methyl-4-phenylpyrido[2,1-b]benzothiazolium bromide is prepared by reacting 3-(2-acetylethyl)-2-benzylbenzothiazolium bromide (1.0 g.) dissolved in 25 ml. of dimethyl sulfoxide. The reaction mixture is heated to reflux for several minutes and cooled. The resulting tan solid precipitate is filtered, washed with ether and dried to give 0.7 g. (72% yield) of product having a melting point of 208°-210° C. 1,2-Dihydro-3-methyl-4-phenylpyrido[2,1-b]benzothiazolium bromide (1.0 g.) is heated in 15 ml. of dimethylsulfoxide to 160° C and held for several minutes. As the mixture cools, 5 ml. each of ether and ethanol are added, precipitating some of the starting material. The addition of more ether causes the slow crystallization of the product, which on recrystallization from ethanol, is obtained in 30% yield (0.3 g.). The product has a melting point of 285°-287° C with decomposition. The NMR spectrum verifies a completely aromatic ring system. When this example is repeated, except that 3-(2-acetylethyl)-2-methylbenzothiazolium bromide is used as the starting material, there is obtained, in somewhat lower yield, 3-methylpyrido[2,1-b]benzothiazolium bromide, which is a useful intermediate in preparing dyes in accordance with this invention.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:12]O)[C:8]2=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=[O:23])=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:9]=1[C:8]([OH:11])=[O:23])#[N:12]
Reactant: Cc1ccc2c(c1)C(=O)C(=NO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(CC#N)c(C(=O)O)c1
Temperature: 50 °C
Yield: 44.1 %

Procedure:
6-Methyl-2-hydroxyimino-1-indanone (37 g) and sodium hydroxide (19.7 g) were dissolved in water (287 mL), and p-toluenesulfonyl chloride (44.3 g) was added with stirring at 50° C. After the completion of the reaction, aqueous citric acid solution was added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated. Ether was added to the precipitated crystals, and the crystals were collected by filtration to give 2-cyanomethyl-5-methylbenzoic acid (16.3 g).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]([N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)[C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.S(OCC)(O[CH2:33][CH3:34])(=O)=O>O.CS(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16]/[C:17](/[N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)=[C:18](/[O:23][CH2:33][CH3:34])\[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)C(Oc1ccc(-c2ccc(Cl)cc2)cc1)n1ccnc1
Reactant: CCOS(=O)(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCO/C(=C(/Oc1ccc(-c2ccc(Cl)cc2)cc1)n1ccnc1)C(C)(C)C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
6 g of potassium hydroxide, dissolved in a little water, are added dropwise to 36.85 g (0.1 mole) of 1-(4'-chloro-4-biphenylyloxy)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-one in 50 ml of dimethylsulphoxide. The mixture is subsequently stirred for a short time and 16 g (0.11 mole) of diethyl sulphate are then added dropwise. During this addition, the temperature of the reaction mixture is kept at about 40° C. and thereafter it was kept at 80° C. for 1/2 hour. It was allowed to cool, water is added and the crystalline precipitate is filtered off and recrystallised from petroleum ether. 22 g (50% of theory) of (E)-1-(4'-chloro-4-biphenylyloxy)-3,3-dimethyl-2-ethoxy-1-(imidazol-1-yl)-1-butene of melting point of 112°-113° C. are obtained.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:15][N:16]=2)[CH:9]=[CH:10][CH:11]=1.S(=O)(=O)(O)O>CC(C)=O>[F:26][C:23]([F:24])([F:25])[C:20]1[CH:21]=[CH:22][C:17]([C:14]2[O:13][C:12]([C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=3)[CH:2]=[O:1])=[N:16][N:15]=2)=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1ccc(-c2nnc(-c3cccc(C4OCCO4)c3)o2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=Cc1cccc(-c2nnc(-c3ccc(C(F)(F)F)cc3)o2)c1
Yield: 99.4 %

Procedure:
A mixture of 2-[3-(1,3-dioxolan-2-yl)phenyl]-5-(4-trifluoromethylphenyl)-1,3,4-oxadiazole (4.10 g), 0.5 M sulfuric acid (30 ml) and acetone (100 ml) was heated under reflux for 1 hr. After cooling, the reaction mixture was concentrated, and the residue was diluted with ethyl acetate. This solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-[5-(4-trifluoromethylphenyl)-1,3,4-oxadiazol-2-yl]benzaldehyde (3.58 g, yield 99%). Recrystallization from hexane-ethyl acetate gave colorless-prism crystals. melting point: 129–130° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:30][O:31][CH2:32][CH3:33])[N:18]([CH2:19][C:20]([NH:23][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])([CH3:22])[CH3:21])[C:14]=2[C:13]2[CH:12]=[CH:11][C:10]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:9][C:8]=2[N:7]=1.C(N(CC)CC)C>ClCCl>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:30][O:31][CH2:32][CH3:33])[N:18]([CH2:19][C:20]([NH:23][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])([CH3:21])[CH3:22])[C:14]=2[C:13]2[CH:12]=[CH:11][C:10]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:1](=[O:3])[CH3:2])=[CH:9][C:8]=2[N:7]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCCCCCN)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCNC(C)=O)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.6 %

Procedure:
Acetyl chloride (180 μL, 2.53 mmol) was added to a stirred solution of N-{2-[4-amino-7-[(6-aminohexyl)oxy]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea (prepared as described in Parts A-H of Example 369, 1.18 g, 2.30 mmol) and triethylamine (0.64 mL, 4.60 mmol) in dichloromethane (100 mL) at 0° C. After approximately 20 minutes, the solution was allowed to warm to room temperature and was stirred overnight. The solution was transferred to a separatory funnel and washed with water (2×). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, elution with 10% methanol in dichloromethane) to yield 0.34 g of N-(6-{[4-amino-2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexyl)acetamide as a tan solid, mp 90-110° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[O:11][C:12]([C:16]([O:18]CC)=O)=[CH:13][C:14](=[O:15])[C:3]1=2.[NH3:21]>C(O)C>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[O:11][C:12]([C:16]([NH2:21])=[O:18])=[CH:13][C:14](=[O:15])[C:3]1=2
Reactant: CCOC(=O)c1cc(=O)c2c(o1)c1ccccc1n2C
Reactant: N
Solvent: CCO
Product: Cn1c2ccccc2c2oc(C(N)=O)cc(=O)c21
Temperature: 25 °C

Procedure:
A suspension of 11.0 g (40.7 mmole) of ethyl 4,5-dihydro-5-methyl-4-oxopyrano[3,2-b]indole-2-carboxylate in 500 ml ethanol was stirred in ice while gaseous ammonia was added until the reaction mixture temperature reached 20° C. (ca. 10 min). The ice bath was removed, and stirring at room temperature was continued for a total of 24 hr. The light yellow solid was filtered and washed with a little cold ethanol. Recrystallization from 50% aqueous DMF gave light yellow needles of mp >295° C.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[CH:21][CH:20]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Product: COc1ccc(/C=C/C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)cc1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(4-methoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.06 min; [M+H]+=388.10.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][CH:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)[CH2:11][NH:10]1.C(Cl)(Cl)Cl.ClCCl.[CH:38](OCC)=[O:39]>>[CH:38]([N:10]1[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)=[CH:13][CH:9]1[CH2:8][S:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:39]
Reactant: CCOC=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CC(CSc4ncccn4)NC3)cc2)C(=O)O1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CC(CSc4ncccn4)N(C=O)C3)cc2)C(=O)O1
Reaction time: 2 h
Yield: 20 %

Procedure:
The amine (Reference Example 7, 0.048 g, 0.11 mM) was refluxed in ethyl formate (3 ml). After 2 hours, chloroform (1 ml) and dichloromethane (1 ml) was added to solublise the precipitate. After 70 hours the solution was evaporated and the residue dissolved in acetonitrile/EtOAc (1:1) and the precipitate removed by filtration. The mother liquor was purified by Isolute chromatography (using as eluant a mixture increasing in polarity from 50% to 70% MeCN in EtOAc) to give after trituration with diethyl ether the title product (0.010 g, 20%).