Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=O)[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18].N1CCCCC1>C(O)C>[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][C:10]2=[O:16])[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18]
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4)c32)c1CCCN1CCN(C)CC1
Temperature: 70 °C
Yield: 29.3 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (41.9 mg, 0.20 mmol) and 5-formyl-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (64.2 mg, 0.20 mmol) in ethanol (1 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at 70° C. for over-night. The solvent was evaporated and the residue was purified on a silica gel column eluting with MeOH—CH2CL2 1:9 to provide 2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-5-(2-oxo-4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid ethyl ester as a yellow solid (30 mg, 29%).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C@H:19]2[CH2:23][C@@H:22]([C:24](O)=[O:25])[C@H:21]([C:27](=[O:32])[NH:28][CH2:29][C:30]#[N:31])[CH2:20]2)(=[O:18])=[O:17])=[C:12]([CH3:33])[CH:11]=1>>[C:30]([CH2:29][NH:28][C:27]([C@@H:21]1[CH2:20][C@@H:19]([S:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][C:12]=2[CH3:33])(=[O:17])=[O:18])[CH2:23][C@H:22]1[C:24]([N:4]1[CH2:5][C@@H:6]([CH3:8])[O:7][C@@H:2]([CH3:1])[CH2:3]1)=[O:25])=[O:32])#[N:31]
Reactant: Cc1cc(Cl)ccc1S(=O)(=O)[C@H]1C[C@@H](C(=O)O)[C@H](C(=O)NCC#N)C1
Reactant: C[C@@H]1CNC[C@H](C)O1
Product: Cc1cc(Cl)ccc1S(=O)(=O)[C@@H]1C[C@@H](C(=O)NCC#N)[C@H](C(=O)N2C[C@@H](C)O[C@@H](C)C2)C1

Procedure:
The title compound was prepared in analogy to example 11 using cis-2,6-dimethymorpholine instead of 2-oxa-6-aza-spiro[3.3]heptan and (1R,2R,4R)-4-(4-chloro-2-methyl-benzenesulfonyl)-2-(cyanomethyl-carbamoyl)-cyclopentanecarboxylic acid instead of (1R,2R,4R)-4-benzenesulfonyl-2-(1-cyano-cyclopropylcarbamoyl)-cyclopentanecarboxylic acid. Colorless oil. MS: 480.0 (M−H)−.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15](=[S:17])[NH2:16])=[CH:11]2.[C:32]([O:37][CH2:38][CH3:39])(=[O:36])[C:33]#[C:34][CH3:35].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][N:20]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:17][CH:34]([CH2:33][C:32]([O:37][CH2:38][CH3:39])=[O:36])[CH2:35][N:16]=1)=[CH:11]2
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(N)=S)[nH]c12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC(COC)COC)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 13 h
Yield: 55 %

Procedure:
A mixture of 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carbothioamide (1.69 g), ethyl 2-butynoate (0.84 mL), tributylphosphine (0.9 mL), tetrahydrofuran (20 mL) and toluene (30 mL) was stirred at 50° C. for 13 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate/hexane=0/20/80 to 5/95/0, volume ratio), followed by basic silica gel column chromatography (ethyl acetate/hexane=20/80 to 90/10, volume ratio) to give the title compound (1.14 g, 55%) as a brownish amorphous solid. MS 578 (MH+).
Reaction SMILES: [BH4-].[Li+].C1COCC1.[CH3:8][O:9][C:10]1[CH:24]=[CH:23][C:13]([CH2:14][O:15][C:16]([CH3:22])([CH3:21])[C:17](OC)=[O:18])=[CH:12][CH:11]=1>O>[CH3:8][O:9][C:10]1[CH:24]=[CH:23][C:13]([CH2:14][O:15][C:16]([CH3:22])([CH3:21])[CH2:17][OH:18])=[CH:12][CH:11]=1
Reactant: COC(=O)C(C)(C)OCc1ccc(OC)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COC(C)(C)CO)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a mixture of lithium borohydride (2.29 g) and THF (200 mL) was added dropwise methyl 2-[(4-methoxybenzyl)oxy]-2-methylpropanoate (12.5 g) under ice-cooling, followed by stirring at 60° C. for 2 hours. To the reaction mixture was added water under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80) to obtain 2-[(4-methoxybenzyl)oxy]-2-methylpropan-1-ol (6.72 g) as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH2:10])[CH3:9].[NH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16]1.CC([O-])(C)C.[K+]>O1CCOCC1>[NH2:10][C@H:8]([C:7]1[N:6]=[C:5]2[CH:11]=[CH:12][N:13]([CH3:14])[C:4]2=[CH:3][C:2]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16]1)[CH3:9]
Reactant: OC1CCCNC1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](N)c1nc2ccn(C)c2cc1N1CCCC(O)C1
Temperature: 150 °C
Yield: 273.4 %

Procedure:
A mixture of (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethan-1-amine (508 mg, 2.00 mmol), piperidin-3-ol (1.01 g, 10.0 mmol) and potassium 2-methylpropan-2-olate (1.56 g, 14.0 mmol) in dioxane (15 mL) was heated to 150° C. for 2 hours in a microwave reactor. The solvent was evaporated in vacuo to give the crude product (1.5 g) as a yellow oil which was used in the next step without further purification. ESI-MS m/z [M+H]+ calc'd for C15H22N4O, 275. found 275.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([C:37]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:38])[CH2:29]2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)c3cnc4c(C(=O)O)cnn4c3NCc3ccccc3)CC2)c2ccccc21
Reactant: CS(N)(=O)=O
Product: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)c3cnc4c(C(=O)NS(C)(=O)=O)cnn4c3NCc3ccccc3)CC2)c2ccccc21
Yield: 36.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(1-(tert-butoxycarbonyl)spiro[indoline-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.150 g, 0.258 mmol) obtained in step 2 and methanesulfonamide (0.122 g, 1.29 mmol), the title compound (0.062 g, 25%) was obtained.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH:31]=O)=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH2:31][N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=Cc1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3nnc(CN4CCOCC4)s3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.8 %

Procedure:
To a solution of 5-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3,4-thiadiazole-2-carbaldehyde (300 mg) in tetrahydrofuran (20 mL) were added morpholine (83 mg), sodium triacetoxyborohydride (270 mg) and triethylamine (177 μL) and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (141 mg, yield 41%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate. MS: 543 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][NH:14][CH3:15]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([CH3:15])[CH3:13])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1Br
Reactant: CNC
Product: COc1cc(C(=O)N(C)C)ccc1Br

Procedure:
Starting with 4-bromo-3-methoxybenzoic acid and dimethyl amine, Int02.06 was prepared analogously to the procedure for the preparation of Int02.05.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:20]1
Reactant: CC(C)CCBr
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCCN(CCC(C)C)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[4-(3-piperidinyl)butyl]-9H-purin-6-amine and 1-bromo-3-methylbutane.
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[O:17][N:16]=[C:15]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:9][CH2:8]1)(=O)=O.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:36]=[CH:35][C:34](O)=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:20][CH:18]([C:15]1[N:14]=[C:13]([N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][O:5][C:34]3[CH:33]=[CH:32][C:31]([C:28]4[CH:29]=[CH:30][C:25]([S:22]([CH3:21])(=[O:23])=[O:24])=[CH:26][CH:27]=4)=[N:36][CH:35]=3)[CH2:12][CH2:11]2)[O:17][N:16]=1)[CH3:19]
Reactant: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A mixture of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (82.3 g, 271 mmol), 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (71.0 g, 285 mmol), powdered potassium carbonate (118 g, 855 mmol) and N,N-dimethylformamide (750 mL) was mechanically stirred and heated at 80° C. under nitrogen for 20 h. The reaction was cooled to ambient temperature, poured onto ice water (3 L) and allowed to stand for 1 h. The resulting solid was filtered, rinsed with water (2×500 mL) and air-dried. The solid was taken up in dichloromethane (300 mL) and methanol (500 mL). The dichloromethane was slowly removed via rotovap at 55° C. The methanol solution was allowed to stand at ambient temperature for 16 h. The resulting crystalline solid was filtered, rinsed with cold methanol and dried under vacuum at 60° C. for 18 h to afford the desired product (105.7 g, 84%) as a light tan solid. 1H NMR (400 MHz, CDCl3): δ 8.41 (d, 1H, J=2.8 Hz), 8.13 (d, 2H, J=8.6 Hz), 8.01 (d, 2H, J=8.6 Hz), 7.74 (d, 1H, J=8.7 Hz), 7.29 (dd, 1H, Ja=8.7 Hz, Jb=3.0 Hz), 4.24 (d, 2H, J=13.1 Hz), 3.95 (d, 2H, J=6.2 Hz), 3.17-3.04 (m, 5H), 2.94-2.84 (m, 1H), 2.11 (bs, 1H), 1.97 (d, 2H, J=12.6 Hz), 1.54-1.42 (m, 2H), 1.29 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 457 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Yield: 92.3 %

Procedure:
A solution of 1-(tert-butyloxycarbonyl)-4-piperidinol (5.2 g, 25.9 mmol), tert-butyldimethylsilyl chloride (4.07 g, 1.05 equiv.) and imidazole (2.7 g, 1.5 equiv.) in DMF (20 mL) was stirred for 16 h. After dilution with Et2O, the solution was washed successively with H2O (2×), 10% aqueous citric acid, a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried (MgSO4) and concentrated to dryness. The residue was purified by HPLC using a WATERS® LC-500 preparative chromatography apparatus [2 SiO2 columns: hexane-EtOAc (19:1), Millipore Corporation, Milford, Mass., USA] to give 1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsiloxy)piperidine (7.54 g, 92%). 1H NMR (CDCl3) δ3.87 (m, 1H), 3.61 (ddd, J=3.5, 7.5, 13.0 Hz, 2H), 3.24 (ddd, J=3.7, 8.0, 13.0 Hz, 2H), 1.48 (s, 9H), 0.88 (s, 9H), 0.07 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][C@H:19]1[CH2:21][O:20]1>CN(C=O)C>[OH:20][C@@H:19]([CH3:21])[CH2:18][N:3]1[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=[C:2]1[CH3:1]
Reactant: C[C@H]1CO1
Reactant: CCOC(=O)c1c[nH]c(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C[C@H](C)O)c(C)n1
Temperature: 60 °C
Reaction time: 5.5 h
Yield: 40.4 %

Procedure:
Ethyl 2-methyl-1H-imidazole-4-carboxylate (1.622 mmol, 250 mg) and potassium carbonate (16.22 mmol, 2241 mg) were dissolved in dry DMF (5 ml) under nitrogen atmosphere. (S)-2-methyloxirane (24.32 mmol, 1.723 ml) was added and the resulting mixture was heated to 60° C. and stirred for 5.5 h. More (S)-2-methyloxirane (1 ml) was added and the stirring continued at 60° C. for one additional hour. The solvent was evaporated. The crude product was purified by flash chromatography. 139 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.06 (d, 3H), 1.24 (t, 3H), 2.30 (s, 3H), 3.71-3.89 (m, 4H), 4.18 (q, 2H), 7.73 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]2[C:13]3[NH:14][C:15]4[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=4[C:21]=3[O:22][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:31][C:32]1[CH:45]=[CH:44][C:35]([O:36][CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:34][CH:33]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]2[C:13]3[N:14]([CH2:31][C:32]4[CH:45]=[CH:44][C:35]([O:36][CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:34][CH:33]=4)[C:15]4[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=4[C:21]=3[O:22][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CCOc1ccc(CCl)cc1
Reactant: COc1ccc2[nH]c3c4ccc(OCc5ccccc5)cc4oc3c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(Cn2c3ccc(OC)cc3c3oc4cc(OCc5ccccc5)ccc4c32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 7-benzyloxy-3-methoxy-10H-benzo[4,5]furo[3,2-b]indole (102 mg, 0.297 mmol) in DMF (5 mL) was added NaH (37 mg, 60% in mineral oil, 3.0 eq.) followed by [2-(4-chloromethyl-phenoxy)-ethyl]-diethyl-amine hydrochloride salt (99 mg, 0.356 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes, warmed to 25° C., and quenched by NH4Cl (solid). EtOAc and water were then added to the mixture. The reaction mixture was then partitioned between EtOAc and water. The aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield crude material. The crude material was purified by silica gel (EtOAc to CH2Cl2: MeOH 5:1) to yield the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15](F)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C-:22]#[N:23].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([C:22]#[N:23])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1F
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 20 h

Procedure:
5.0 g of 3-chloro-2-(4-fluoro-3-nitrophenyl)-5-trifluoromethylpyridine and 1.5 g of potassium cyanide in 50 ml of dimethylformamide were heated at 50° C. for 4 hours and then stirred at 23° C. for 20 hours. The mixture was then poured into 200 ml of water. The aqueous phase was extracted three times with 100 ml of tertbutyl methyl ether each time. The combined organic phases were washed twice with 50 ml of water each time, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate=9:1). Yield: 2.7 g (53%) of a yellow oil which slowly crystallized.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[F:13][C:14]1[CH:15]=[C:16]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]3)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: Oc1ccc2cc(Br)ccc2c1
Product: COc1ccc(-c2ccc3cc(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 6-bromo-2-naphthol (3.2 g, 18.8 mmol) with 3-fluoro-4-methoxyphenylboronic acid (3.5 g, 15.7 mmol) according to method A to yield 3.3 g (78%) of white solid: mp 174-176° C.; 1H NMR (DMDO-d6): δ 3.89 (3H, s), 7.11 (1H, dd, J=8.79 Hz, J=1.95 Hz), 7.13 (1H, s), 7.26 (1H, J=8.79 Hz), 7.57 (1H, d, J=8.79 Hz), 7.66 (1H, dd, J=13.18 Hz, J=1.95 Hz), 7.71 (1H, dd, J=8.79 Hz, J=1.46 Hz), 7.75 (1H, d, J=8.79 Hz), 7.82 (1H, d, J=8.79 Hz), 8.07 (1H, s), 9.81 (1H, s); MS (ESI) m/z267 (M−H)−.
Reaction SMILES: [CH3:1][NH2:2].Br.[CH3:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11])=[C:8]([NH:16][C:17]([O:19]C2C=CC=CC=2)=O)[S:7][N:6]=1>C(O)C>[CH3:1][NH:2][C:17](=[O:19])[NH:16][C:8]1[S:7][N:6]=[C:5]([CH3:4])[C:9]=1[C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11]
Reactant: CN
Reactant: CCCOC(=O)c1c(C)nsc1NC(=O)Oc1ccccc1
Agent: Br
Solvent: CCO
Product: CCCOC(=O)c1c(C)nsc1NC(=O)NC

Procedure:
A solution of methylamine in ethanol (33% w/v; 50 ml.) was added, cautiously with swirling, to 3-methyl-5-phenoxycarbonylamino-4-n-propoxycarbonylisothiazole hydrobromide (16 g.). When the initial exothermic reaction had subsided, the mixture was heated to reflux for 15 minutes, cooled and filtered. The solid was washed with water, and dried to give 3-methyl-1-(3-methyl-4-n-propoxycarbonylisothiazol-5-yl)urea (7.3 g.), m.p. 191° C.
Reaction SMILES: F[B-](F)(F)F.[H+].[F:7][C:8]1[C:9]([CH3:15])=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11].[N:16]([O-])=O.[Na+]>O>[F:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:10]2[C:9]=1[CH:15]=[N:16][NH:11]2
Reactant: O=N[O-]
Reactant: Cc1c(N)cccc1F
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Fc1cccc2[nH]ncc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To tetrafluoroboric acid (8.2 ml, 48 wt % in water) was added 3-fluoro-2-methylaniline (2.27 ml). The mixture was cooled to 0° C. when a precipitate formed which was redissolved by the addition of water (8 ml). A solution of sodium nitrite (1.38 g) in water (2.7 ml) was then added dropwise and the mixture was then allowed to warm to ambient temperature and then stirred for a further 1 hour. The precipitated solid was filtered, then washed with diethyl ether, and then dried under suction for 30 minutes. The resulting tetrafluoroborate salt was added to a suspension of potassium acetate (3.92 g) and 18-crown-6 (0.264 g) in chloroform (45 ml). After stirring for 3 hours at ambient temperature the bright orange mixture was filtered and the insoluble material was washed with dichloromethane, then subjected to flash column chromatography on silica eluting with a mixture of 40/60 petrol and ethyl acetate (3:1 v/v) to give 4-fluoro-1H-indazole (0.675 g) as an off-white solid. LC-MS (METHOD B): RT=2.70 minutes; 137 (M+H)+. (c) 4-Chloro-1H-indazole
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:25]=[CH:24][CH:23]=4)=[N:14]3)=[C:9]([F:33])[CH:8]=2)[CH2:3][CH2:2]1.C1COCC1>[Pd].CO>[F:33][C:9]1[CH:8]=[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:12]=[CH:11][C:10]=1[N:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]2[N:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:25]=[CH:24][CH:23]=2)=[N:14]1
Reactant: COc1cn(-c2ccc(C3=CCOCC3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cn(-c2ccc(C3CCOCC3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A mixture of 1-[4-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (300 mg, 0.675 mmol), 10% Pd—C (50% wet, 300 mg), THF (30 mL), and MeOH (30 mL) was hydrogenated for 2 h at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from MeOH/H2O to give the title compound (255 mg, 85% yield) as a white solid: mp 187-189° C.; NMR (300 MHz, CDCl3): δ ppm 1.57-1.83 (4H, m), 2.72-2.82 (1H, m), 3.45-3.58 (2H, m), 3.90 (3H, s), 4.09 (2H, td, J=3.0, 11.3 Hz), 6.35 (1H, t, J=8.3 Hz), 6.86 (1H, dd, J=1.5, 8.3 Hz), 7.03 (1H, dd, J=1.9, 12.8 Hz), 7.28 (1H, d, J=1.9 Hz), 7.35-7.46 (5H, m), 7.78 (1H, d, J=1.9 Hz), 7.79 (1H, d, J=2.6 Hz). LC-MS (ESI) m/z 447 [M+H]+. Anal. Calcd for C25H23FN4O3: C, 67.25; H, 5.19; N, 12.55. Found: C, 67.13 H, 5.13; N, 12.57.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Br:24][CH2:25][C:26](Cl)=[O:27].C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:26](=[O:27])[CH2:25][Br:24])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: O=C(Cl)CBr
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1c2ccc(NC(=O)CBr)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (130 mg) with bromoacetyl chloride (69 l) and N,N-diisopropylethylamine (121 l) in dichloromethane (10 ml) was performed according to the method described in example 6.