Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1.[CH2:23]1C[O:26][CH2:25][CH2:24]1.C(N(CC)CC)C.C(Cl)(=O)C=C>CN(C=O)C>[Cl:22][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:25](=[O:26])[CH:24]=[CH2:23])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: C1CCOC1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Agent: C=CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved 1.00 g (3.20 mmol) 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-3-quinolinecarbonitrile in 2 ml hot DMF, added 12 ml THF and chilled to 0° C. under N2. Added 490 μl (3.52 mmol) triethyl amine and 295 μl (3.52 mmol) acryloyl chloride. Removed ice bath at 15 minutes, and at 1.5 hours stripped solvent. Slurried residue with a dilute sodium bicarbonate, collected solids, and washed with water. Recrystallized from ethyl acetate, giving 215 mg of yellow solid: mass spectrum (electrospray m/e): M+H=367.1, 369.1.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1(C)[CH:14]=[CH:13][C:12](S(O)(=O)=O)=[CH:11][CH:10]=1.C1(=O)CCCCC1>C(O)C>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[NH:6][C:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]2=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O=C1CCCCC1
Solvent: CCO
Product: Fc1ccc2[nH]c3c(c2c1)CCCC3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.6 g of p-fluoroaniline was dissolved in 100 ml of ethanol and a catalytic amount of p-toluenesulfonic acid was added thereto. 9.8 g of cyclohexanone was then added dropwise to the mixture at room temperature. After completion of the addition, the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. Dilute sulfuric acid prepared from 190 ml of water and 20 ml of concentrated sulfuric acid was added to the residue and the mixture was heated at 110° C. for 15 minutes on an oil bath to precipitate light orange crystals. The crystals thus formed were filtered, washed 3 times with water and dried to obtain 17.4 g of 6-fluoro-1,2,3,4-tetrahydrocarbazole which was identified by NMR spectrum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)=[O:10])[CH:3]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:4]([C:9]([C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:15]=2)=[O:10])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(c1cnn(-c2ccccc2)c1)c1cc(F)ccc1O
Product: CCOC(=O)COc1ccc(F)cc1C(=O)c1cnn(-c2ccccc2)c1
Yield: 91 %

Procedure:
Prepared from 4-fluoro-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenol (282 mg) and ethyl bromoacetate according to GP2 to give 335 mg (91%) yellow solid: LC/MS (an10n8): Rt 3.16, m/z 339.0 [M−H]−; 1H NMR (CDCl3): δ 1.26 (t, J=7.0 Hz, 3H), 4.23 (t, J=7.1 Hz, 2H), 4.63 (s, 2H), 6.81 (dd, J=9.0, 4.0 Hz, 1H), 7.13 (ddd, J=8.9, 4.5, 3.0 Hz, 1H), 7.21 (dd, J=8.1, 3.2 Hz, 1H), 7.31-7.37 (m, 1H), 7.24-7.50 (m, 2H), 7.72-7.78 (m, 2H), 8.18 (s, 1H), 8.58 (s, 1H); 13C NMR (CDCl3): δ14.3, 61.8, 66.1, 114.0 (d, JCF=7.6 Hz), 116.8 (d, JCF=24.5 Hz), 118.3 (d, JCF=23.5 Hz), 119.7, 125.2, 127.7, 129.7, 131.8, 139.6, 142.8, 151.1 (d, JCF=2.2 Hz), 157.6 (d, JCF=241.1 Hz), 168.7, 187.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([F:13])[CH:6]=1.[CH3:15][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3](=[O:14])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([F:13])[CH:6]=1)[CH3:15]
Reactant: COC(=O)Cc1ccc(C#N)c(F)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(C#N)c(F)c1
Temperature: 25 °C

Procedure:
(4-Cyano-3-fluoro-phenyl)-acetic acid methyl ester (3.06 g, 15.84 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) and cooled in a dry ice-acetone bath. Lithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 17.42 mL) was added under a nitrogen atmosphere. The solution was stirred for 1 h, at which point methyliodide (4.91 mL) was added dropwise. The reaction was allowed to warm to ambient temperature while stirring. Upon reaction completion satd. aq. ammonium chloride (100 mL) was added and the bulk of the tetrahydrofuran evaporated under a nitrogen stream. The aqueous layer was then extracted with ethyl acetate (3×300 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography with ethyl acetate:hexanes (3:17) to give the title compound (1.73 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:21]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:13](=[O:21])[CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCCN1C(=O)OC(C)(C)C
Reactant: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
To a vigorously stirred solution of RuCl3.H2O (2.39 g, 11.5 mmol) and NaIO4 (24.6 g, 115.0 mmol) in water (250 mL) was added (S)-piperidine-1,2-dicarboxylic acid di-tert-butyl ester (8.22 g, 28.8 mmol) in ethyl acetate (250 mL) at room temperature. After stirring for 4 h, the reaction mixture was partitioned and the aqueous layer washed with ethyl acetate. To the combined organic layers was added iPrOH (2.5 mL) and stirring was continued for 2 hours in order to destroy excess RuO4. The precipitate was removed by filtration through a pad of celite and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate in hexane) to afford the title compound as a pale yellow oil, which crystallized upon standing (6.69 g, 78%): 1H NMR (400 MHz, CDCl3) δ 1.49 (9H, s), 1.52 (9H, s), 1.75-1.82 (2H, m), 1.97-2.06 (1H, m), 2.15-2.21 (1H, m), 2.41-2.61 (2H, m), 4.59 (1H, dd, J=3.5 Hz)
Reaction SMILES: [NH2:1][C:2]([C:4]([NH2:6])=[S:5])=[S:3].[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O>>[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[S:3][C:2]2[N:1]=[C:12]([C:8]3[O:7][CH:11]=[CH:10][CH:9]=3)[S:5][C:4]=2[N:6]=1
Reactant: O=Cc1ccco1
Reactant: NC(=S)C(N)=S
Product: c1coc(-c2nc3sc(-c4ccco4)nc3s2)c1

Procedure:
2,5-bis(furyl)thiazolo[5,4-d]thiazole was prepared from dithiooxamide and 2-furaldehyde. 2-furaldehyde (furfural) was purchased from Aldrich Chemical Company, Milwaukee, Wis.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[NH:8].CS([C:19]1[N:24]=[C:23](/[CH:25]=[C:26]2/[C:27](=[O:32])[NH:28][C:29](=[O:31])[S:30]/2)[CH:22]=[CH:21][N:20]=1)(=O)=O.C(N(C(C)C)C(C)C)C>CS(C)=O>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[NH:8])[N:9]1[CH2:10][CH2:11][N:12]([C:19]2[N:24]=[C:23](/[CH:25]=[C:26]3/[C:27](=[O:32])[NH:28][C:29](=[O:31])[S:30]/3)[CH:22]=[CH:21][N:20]=2)[CH2:13][CH2:14]1
Reactant: CS(=O)(=O)c1nccc(/C=C2\SC(=O)NC2=O)n1
Reactant: N=C(c1ccco1)N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N=C(c1ccco1)N1CCN(c2nccc(/C=C3\SC(=O)NC3=O)n2)CC1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
The crude material from Step 2, furan-2-yl(piperazin-1-yl)methanimine hydrochloride (16.3 mg, 0.076 mmol) was diluted in DMSO (Volume: 0.75 mL) and added to (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (19.4 mg, 0.068 mmol) in a 2-dram vial. The reaction solution was then treated with N-ethyl-N-isopropylpropan-2-amine (50 mg, 0.387 mmol) and then shaken at 100° C. for 16 h. The reaction was then purified by RP-HPLC using TFA as the modifier to provide (Z)-5-((2-(4-(furan-2-yl(imino)methyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([C:11]([Cl:14])([Cl:13])[Cl:12])[N:7]=1)=[O:4].[C:15]([N:23]=[C:24]=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.NC(N)=O>C1C=CC=CC=1>[C:15]([NH:23][C:24]([N:2]([CH3:1])[C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([C:11]([Cl:12])([Cl:14])[Cl:13])[N:7]=1)=[O:4])=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CNC(=O)Nc1nc(C(Cl)(Cl)Cl)ns1
Agent: NC(N)=O
Solvent: c1ccccc1
Product: CN(C(=O)NC(=O)c1ccccc1)C(=O)Nc1nc(C(Cl)(Cl)Cl)ns1
Temperature: 145 °C
Yield: 35.5 %

Procedure:
A glass pressure vessel was charged with 5.5 grams (0.02 mole) 1-methyl-3-(3-trichloromethyl-1,2,4-thiadiazol-5-yl)urea, 3.2 grams (0.02 mole) benzoyl isocyanate and 50 milliliters benzene. A magnetic stirring bar was added and the vessel sealed. The stirred reaction mixture was heated at 145° C. for 1.5 hours and then allowed to cool to room temperature where 4.5 grams of starting urea precipitates. The urea was removed by filtration and the filtrate concentrated in vacuo to leave 3.0 grams of residue. Extraction of the residue with hot cyclohexane, followed by cooling the extract yielded 0.2 grams (11% selectivity) of pure product; m.p. 70° C.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:17]=[C:18]([CH:20]=[C:21]([CH2:23][OH:24])[CH:22]=2)[NH2:19])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH:25](=O)[CH3:26]>ClCCl.N1C=CC=CC=1>[CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[C:18]([N:19]=[CH:25][CH3:26])[CH:17]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: CC=O
Reactant: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC=Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reaction time: 5 h
Yield: 80.1 %

Procedure:
3-(9-acridinylamino)-5-(hydroxymethyl)aniline was dissolved in dichloromethane/pyridine(1/1, v/v, 40 ml), and thereto acetaldehyde (2.09 g, 47.56 mmol) was added. The resulting mixture was stirred for 5 hours, and the solvent used was removed under the reduced pressure. Then, the resulting product was purified by column chromatography to give the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].C[O-].[Mg+2].C[O-].O1CCCC1.[CH2:20]([O:38][C:39]1[S:43][C:42](C(N2C=CN=C2)=O)=[CH:41][CH:40]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH2:30][CH:31]=[CH:32][CH2:33][CH:34]=[CH:35][CH2:36][CH3:37]>CO>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([C:42]1[S:43][C:39]([O:38][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH2:30][CH:31]=[CH:32][CH2:33][CH:34]=[CH:35][CH2:36][CH3:37])=[CH:40][CH:41]=1)=[O:8])[CH3:2]
Reactant: CCC=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)n2ccnc2)s1
Reactant: CCOC(=O)CC(=O)O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: C1CCOC1
Product: CCC=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)CC(=O)OCC)s1

Procedure:
A mixture of 14.5 g (0.110 mole) of malonic acid mono ethyl ester, 19.0 g (0.220 mole) of magnesium methoxide and anhydrous tetrahydrofuran is heated with stirring under nitrogen allowing the methanol produced to distill off. To this mixture is added 45.0 g (0.105 mole) of N-[5-(9,12,15-octadecatrien-1-yloxy)-2-thenoyl]imidazole with stirring and cooling on an ice bath for four hours. The solvent is removed and the residue diluted with ice-concentrated HCl (1:1) solution to give 5-(9,12,15-octadecatrien-1-yloxy)then-2-oylacetic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:39]([O:41][CH2:42][CH3:43])=[CH2:40])CCC.CCOC(C)=O>O1CCOCC1.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>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[OH:20])[CH:8]=3)[N:3]=[C:2]([C:39]([O:41][CH2:42][CH3:43])=[CH2:40])[CH:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)cc(-c3cccc(Cl)c3)c2c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc2n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 117.4 %

Procedure:
A mixture of (±)-2-chloro-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol (0.0061 mol), described in International Patent Specification WO 00/39082, tributyl (1-ethoxyethenyl)-stannane (0.0091 mol) and Pd(PPh3)4 (0.0007 mol) in dioxane(30 ml) was stirred at 80° C. for 24 hours, cooled and poured out into ice water. EtOAc was added and the mixture was filtered over celite. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 3.8 g of (±)-4-(3-chlorophenyl)-α-(4-chlorophenyl)-2-(1-ethoxyethenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.Cl[C:25]1[CH:26]=[CH:27][C:28]2[N:29]([C:31]([CH2:34][C:35]3[CH:36]=[C:37]4[C:42](=[CH:43][C:44]=3[F:45])[N:41]=[CH:40][CH:39]=[CH:38]4)=[CH:32][N:33]=2)[N:30]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.CCOC(C)=O.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>[F:45][C:44]1[CH:43]=[C:42]2[C:37]([CH:38]=[CH:39][CH:40]=[N:41]2)=[CH:36][C:35]=1[CH2:34][C:31]1[N:29]2[N:30]=[C:25]([C:13]3[CH:12]=[N:11][N:10]([CH2:9][CH2:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH:14]=3)[CH:26]=[CH:27][C:28]2=[N:33][CH:32]=1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12

Procedure:
A solution of [2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 171.4, 77 mg, 0.240 mmol), 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Stage 173.1, 55 mg, 0.160 mmol), PdCl2(PPh3)2 (5.6 mg) and 2 M K2CO3 (0.216 mL) in DME (0.5 mL was stirred at 90° C. for 2 h under argon atmosphere. The RM was then diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, evaporated to dryness and the residue was purified (CombiFlash® Companion System®, with RediSep® silica gel column, DCM/DCM/MeOH 9:1=100:0->0:100) to afford the title compound (tR 3.97 min (conditions 3), MH+=473.1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[O:5][CH2:4][CH2:3]1.[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1.C(N(CC)CC)C>O1CCCC1>[Cl:13][C:14]1[N:15]=[N:16][C:17]([N:10]2[CH2:11][CH2:12][C:6]3([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:7]3)[CH2:8][CH2:9]2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CN1CCOC2(CCNCC2)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCOC2(CCN(c3ccc(Cl)nn3)CC2)C1
Yield: 44.8 %

Procedure:
To a solution of compound 405 (406.0 mg, 2.39 mmol) in tetrahydrofuran (17 mL) was added 3,6-dichloropyridazine (361.7 mg, 2.43 mmol), followed by triethylamine (0.680 mL, 4.89 mmol). The resulting solution was stirred at reflux for 38 hours. The reaction mixture was then concentrated and the residue was purified by reverse phase HPLC (acetonitrile/H2O containing 0.1% TFA each, 25 min from 10 to 40%) to give compound 406 as a sticky yellow solid (303 mg, 45%). LCMS-ESI (POS), M/Z, M+1: Found 283.1, Calculated 283.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH2:9][OH:10])[CH:3]=1.[O-:11][Mn](=O)(=O)=O.[K+:16]>CC(C)=O>[K+:16].[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1cc(Br)cc(CO)n1
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(Br)cc(C(=O)[O-])n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 116 %

Procedure:
To a solution of (4-bromo-6-methyl-pyridin-2-yl)-methanol (1.31 g, 6.48 mmol) in acetone (150 mL), KMnO4 (2.61 g, 16.5 mmol) is added. The mixture is stirred at 40° C. for 2 h before it is filtered over a sintered glass funnel. The filtrate is evaporated to dryness, the remaining solid is washed with water and dried under HV to give 4-bromo-6-methyl-pyridine-2-carboxylic acid potassium salt (1.91 g) as a white solid; LC-MS: tR=0.45 min, [M+1]+=217.89.
Reaction SMILES: Br[C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[OH-].[NH4+:18]>O.S([O-])([O-])(=O)=O.[Cu+2]>[NH2:18][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: O=C(O)c1nc(-c2ccccc2)ncc1Br
Reactant: [NH4+]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [OH-]
Solvent: O
Product: Nc1cnc(-c2ccccc2)nc1C(=O)O
Temperature: 80 °C

Procedure:
To a suspension of 8.75 g (0.0314 mole) of 5-bromo-2-phenyl-pyrimidine-4-carboxylic acid in 69 mL of concentrated ammonium hydroxide was added 0.39 g of copper (II) sulfate in 1.6 mL water. The mixture was sealed and heated to 80° C. for 6 days. After cooling to room temperature, and filtration, the solid was taken in 100 ml boiling water, filtered, cooled and acidified with acetic acid. Filtration and drying yielded 4.40 g of 5-amino-2-phenyl-pyrimidine-4-carboxylic acid as a tan solid, mp. 199-202° C.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]=O)=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10](/[CH:15]=[N:21]/[OH:22])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C=O)ccc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(/C=N/O)ccc12
Temperature: 85 °C
Reaction time: 17.5 h
Yield: 52.5 %

Procedure:
Step 1 A mixture of 4-bromo-7-formyl-9H-carbazole-1-carboxamide (prepared according to Step 1 of Example 41-1, 200 mg, 0.631 mmol) and hydroxylamine hydrochloric acid salt (65.7 mg, 0.946 mmol) in ethanol (3 mL) was treated with 2 M aqueous sodium carbonate (0.236 mL, 0.473 mmol) and heated at 80-90° C. After 17.5 h, the mixture was cooled to rt and partitioned between EtOAc and water. The organic phase was dried and concentrated, and the residue was triturated with methanol, and the precipitate was collected by filtration, rinsed with methanol and dried to provide (E)-4-bromo-7-((hydroxyimino)methyl)-9H-carbazole-1-carboxamide as a gray-tan solid (110 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ 11.87 (1H, s), 11.33 (1H, s), 8.65 (1H, d, J=8.4 Hz), 8.32 (1H, s), 8.28 (1H, br. s.), 8.09 (1H, s), 7.92 (1H, d, J=8.1 Hz), 7.64 (1H, br. s.), 7.58 (1H, d, J=8.6 Hz), 7.51 (1H, d, J=8.1 Hz). Mass spectrum m/z 332, 334 (M+H)+.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[C:14]3[S:21][CH:20]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:23]=4[F:32])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:8][CH2:7]1.C([O-])([O-])=O.[K+].[K+].I[CH:40]([CH3:42])[CH3:41]>CNC=O.CC(C)=O>[F:32][C:23]1[CH:24]=[C:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:26]=[CH:27][C:22]=1[C:19]1[C:15]2[N:16]=[CH:17][N:18]=[C:13]([O:12][CH:9]3[CH2:10][CH2:11][N:6]([C:5]4[N:1]=[N:2][N:3]([CH:40]([CH3:42])[CH3:41])[N:4]=4)[CH2:7][CH2:8]3)[C:14]=2[S:21][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(-c2csc3c(OC4CCN(c5nn[nH]n5)CC4)ncnc23)c(F)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CNC=O
Product: CC(C)n1nnc(N2CCC(Oc3ncnc4c(-c5ccc(S(C)(=O)=O)cc5F)csc34)CC2)n1
Temperature: 25 °C

Procedure:
700 mg of 4-(1-(2H-tetrazol-5-yl)piperidin-4-yloxy)-7-(2-fluoro-4-methanesulfonyl-phenyl)thieno[3,2-d]pyrimidine obtained in step 94-1 and 41 mf of K2CO3 were added in a mixture of methylformamide and acetone, and 44 μl of 2-iodopropane was dropwise added with stirring. The resulting mixture was stirred at 50° C. for 12 hr, cooled to room temperature and extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under a reduced pressure to obtain 51 mg of the title compound.
Reaction SMILES: C(O)C.[O:4]=[C:5]([N:25]1[CH2:29][C:28]2=[CH:30][S:31][CH:32]=[C:27]2[CH2:26]1)[CH2:6][CH:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]([O:10]CC1C=CC=CC=1)=[O:9].[OH-].[Na+]>O1CCCC1>[O:4]=[C:5]([N:25]1[CH2:26][C:27]2=[CH:32][S:31][CH:30]=[C:28]2[CH2:29]1)[CH2:6][CH:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(OCc1ccccc1)C(CC(=O)N1Cc2cscc2C1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C(CC(=O)N1Cc2cscc2C1)Cc1ccccc1
Reaction time: 1 h
Yield: 75 %

Procedure:
15 ml of ethanol are added to a solution of 1.22 g (3 mmol) of phenylmethyl γ-oxo-α-(phenylmethyl)-5,6-dihydro-4H-thieno[3,4-c]pyrrole-5-butanoate in 15 ml of tetrahydrofuran, followed, at 0° C., by a solution of 0.36 g (9 mmol) of sodium hydroxide. After 1 h at room temperature, the medium is concentrated to about 15 ml, 15 ml of water are added and then the mixture is acidfied with 2N hydrochloric acid to pH 2 and extracted with three times 25 ml of ethyl acetate. The organic phases are pooled, washed with a saturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The residue is triturated with diethyl ether to give 0.71 g of a white solid.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[C:9](OC(C)(C)C)=O)#[N:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1.[Cl-].[NH4+]>C(OCC)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:9]2[NH:2][C:1]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)=[C:3]3[C:4]=2[CH2:5][CH2:6][CH2:7][CH2:8]3)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCC[C@@H]1C#N
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: Fc1ccc(-c2[nH]c(-c3ccc(F)cc3)c3c2CCCC3)cc1
Reaction time: 2 h

Procedure:
A solution of 14.75 g of the compound of Step A diluted with 30 ml of ethyl ether is added dropwise, at 35° C., to 80 ml of a 2M solution of 4-fluorophenylmagnesium bromide in ethyl ether. After 2 hours, the reaction mixture is cooled and hydrolysed with 20 ml of a saturated ammonium chloride solution. After filtration and washing with ethyl ether, the organic phases are combined and dried over calcium sulphate and then concentrated. The product is isolated by chromatography on silica gel (eluant: cyclohexane/ethyl acetate:97.5/2.5). Crystallisation yields 2 g of the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15](Cl)=[O:16])=[CH:9][CH:8]=1.[CH3:21][NH2:22]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([NH:22][CH3:21])=[O:16])=[CH:9][CH:8]=1
Reactant: O=C(Cl)C=Cc1ccc(OCc2cccc(F)c2)cc1
Reactant: CN
Solvent: ClCCl
Solvent: O
Product: CNC(=O)C=Cc1ccc(OCc2cccc(F)c2)cc1
Yield: 30 %

Procedure:
500 mg (1.72 mmol) of the crude 3-[4-(3-fluoro-benzyloxy)-phenyl]-acryloyl chloride is dissolved in 2 ml dichloromethane and 0.4 ml of a 41% solution of methylamine in water is added. The reaction mixture is heated under reflux for about 3 hours, cooled, filtered and washed with cold dichloromethane to yield 149 mg (30%) of a colorless solid. MS: m/e=286.2 (M+).