Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.C(N(CC)CC)C.Cl.Cl.[F:17][C:18]1[CH:19]=[C:20]([C:34]([N:36]2[CH2:45][C:44]3[CH:43]=[N:42][N:41]([CH3:46])[C:40]=3[NH:39][C:38]3[CH:47]=[CH:48][CH:49]=[CH:50][C:37]2=3)=[O:35])[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][O:24][C:23]2[CH:22]=[CH:21][C:20]([C:34]([N:36]3[CH2:45][C:44]4[CH:43]=[N:42][N:41]([CH3:46])[C:40]=4[NH:39][C:38]4[CH:47]=[CH:48][CH:49]=[CH:50][C:37]3=4)=[O:35])=[CH:19][C:18]=2[F:17])[CH2:29][CH2:30]1
Reactant: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(OCCCN3CCNCC3)c(F)c1)C2
Reactant: CC(C)(C)CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC(=O)O
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(OCCCN3CCN(CCC(C)(C)C)CC3)c(F)c1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,3-Dimethylbutyraldehyde (120 mg, 1.20 mmol) and triethylamine (to pH9) were added to a solution of [3-fluoro-4-(3-piperazin-1-yl-propoxy)-phenyl]-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone dihydrochloride from Example E49 (585 mg, 1.09 mmol) in methanol/acetic acid (99:1, v/v, 20 ml) and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (103 mg, 1.30 mmol) was added and the mixture was stirred at room temperature for 18 h then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to yield (4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-fluoro-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone, which was lyophilised from aqueous trifluoroacetic acid to give a white solid identified as the title compound (700 mg, 83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].CCN(CC)CC.NCCS(O)(=O)=[O:43].Cl>CN1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([OH:43])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NCCS(=O)(=O)O
Agent: CN1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 26.6 %

Procedure:
To a solution of 8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (223 mg, 0.5 mmol) in N-methylpyrollidine (5 mL) was added Et3N (0.1 mL) followed by 2-aminoethanesulfonic acid (200 mg, 1.5 mmol, 3 eq) and the reaction mixture was heated to 50° for 12 h. 1 M aq HCl was then added dropwise till pH 3. The reaction mixture was then extracted with EtOAc (2×20 mL). Organic layers were combined, washed with satd aq NaCl, dried (MgSO4), filtered and solvent was evaporated. The yellow residue was then purified by flash chromatography to give an oily product, which was then recrystalized from methanol:H2O (3:1) to afford 51 mg of pure 8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-hydroxy-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3): δ 2.24 (s, 3H), 6.31 (d, 1H, J=9.8 Hz), 7.02 (m, 5H), 7.23 (m, 1H), 7.352 (m, 1H), LC MS (m/e)=384.2 (MH+). Rt=1.65 min
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[Br:14]Br>CCOCC>[Br:14][CH:9]1[CH2:8][CH2:7][O:6][C:5]2[CH:12]=[CH:13][C:2]([Br:1])=[CH:3][C:4]=2[C:10]1=[O:11]
Reactant: O=C1CCCOc2ccc(Br)cc21
Reactant: BrBr
Solvent: CCOCC
Product: O=C1c2cc(Br)ccc2OCCC1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To 7-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (3 g, 12 mmol) in ether (110 mL) was added bromine (0.7 mL, 14 mmol) and allowed to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified via ISCO chromatography (hexane to 20% hexane in EtOAc over 45 minutes). Collected fractions and concentrated to give 4,7-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (3.53 g, 89%). 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J=2.5, 1H), 7.52 (dt, J=28.5, 14.2, 1H), 6.97 (d, J=8.7, 1H), 4.95 (dd, J=7.6, 6.8, 1H), 4.53-4.36 (m, 1H), 4.17 (ddd, J=12.8, 9.9, 4.4, 1H), 3.04-2.84 (m, 1H), 2.52 (ddt, J=14.7, 7.8, 4.5, 1H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:34][CH3:35])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36].C1C=C(Cl)C=C(C(OO)=[O:45])C=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:34]([CH3:35])=[O:45])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36]
Reactant: CSc1nc(-c2cc(C(=O)Nc3nccs3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
A solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide (1.65 g, 3.16 mmol) in DCM (53 mL) was mixed with mCPBA (0.736 g, 4.75 mmol). The mixture was stirred at room temperature for about 10 minutes before directly loaded onto a column. Flash chromatography (mobile phase EtOAc/Hexane) then provided the title compound as a white solid 1.38 g (81%). MS (ES) m/z 538 (M+H)+; 1H-NMR (MeOD) δ 2.35 (s, 3 H), 2.81 (s, 3 H), 6.98 (d, J=10.0 Hz, 1 H), 7.30 (d, J=3.6 Hz, 1 H), 7.46 (t, J=8.6 Hz, 2 H), 7.57 (d, J=3.6 Hz, 1 H), 7.66 (d, J=8.0 Hz, 1 H), 7.72 (m, 1 H), 7.85 (d, J=10.0 Hz, 1 H), 8.25 (d, J=8.0 Hz, 2 H).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([NH2:13])(=[O:12])=[O:11])[C:4]=2[CH2:3][O:2]1.C(N=[C:19]=[O:20])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([N:13]=[C:19]=[O:20])(=[O:11])=[O:12])[C:4]=2[CH2:3][O:2]1
Reactant: CCCCN=C=O
Reactant: NS(=O)(=O)c1cccc2c1COC2
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)c1cccc2c1COC2

Procedure:
A mixture of 7.0 g of 1,3-dihydrobenzo[c]furan-4-sulfonamide, 4.0 ml of butyl isocyanate, 0.1 g of DABCO® and 150 ml xylene was heated to reflux. Phosgene (3.1 ml) was added in small portions to the reaction mixture while maintaining the reaction temperature >130°. When addition of phosgene was complete, the reaction mixture was heated to reflux (128°) for 1 hour, then cooled under nitrogen. The reaction mixture was filtered under nitrogen, and the filtrate was concentrated in vacuo to give 1,3-dihydrobenzo[c]furan-4-sulfonyl isocyanate as an amber oil. The crude sulfonyl isocyanate was dissolved in methylene chloride (total volume=28 ml) for reaction with amino heterocycles.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=CC2C=CC=CC=2)=[CH:5][N:4]=[C:3]1[N+:15]([O-:17])=[O:16].C[OH:19]>O=[Os](=O)(=O)=O.O>[CH3:1][N:2]1[C:6]([CH:7]=[O:19])=[CH:5][N:4]=[C:3]1[N+:15]([O-:17])=[O:16]
Reactant: Cn1c(C=Cc2ccccc2)cnc1[N+](=O)[O-]
Reactant: CO
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: Cn1c(C=O)cnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h
Yield: 60 %

Procedure:
To a solution of 0.8 g. of 1-methyl-2-nitro-5-styrylimidazole in 300 ml. of methanol, a solution of 1.6 g. of NaIO4 in 40 ml. of water, and 0.02 g. of OsO4 are added. The mixture is stirred at room temperature for 10 hours, then an additional 0.01 g. of OsO4 is added and stirring is carried on for 8 hours. The reaction mixture is filtered and evaporated to dryness under vacuum at room temperature. The residue is extracted with ethyl acetate. After concentration of the resulting solution, 0.325 g. of the product are obtained. Yield 60%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.[C:18]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:23]=CC=C[CH:19]=1.C(O)(C)C.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[CH3:19][CH:18]([O:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1)[CH3:23]
Reactant: CCCC(=O)NC[C@@H]1C[C@H]1c1cccc(O)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)O
Product: CCCC(=O)NC[C@@H]1C[C@H]1c1cccc(OC(C)C)c1
Reaction time: 2 h
Yield: 30.8 %

Procedure:
To a rapidly stirred solution of (trans)-N-[[2-(3-hydroxyphenyl)cyclopropyl]methyl]butanamide (390 mg, 1.7 mmol), triphenylphosphine (498 mg, 1.9 mmol) and isopropanol (150 mg, 2.5 mmol) in THF (10 mL) at 0° C. was added diethyl azodicarboxylate (331 mg, 1.9 mmol) in one portion. After stirring for 2 h, the suspension was diluted with Et2O (100 mL), washed with H2O, 2N NaOH, and brine, dried (K2CO3) and concentrated to a give a crude wax. The resulting material was purified by chromatography (silica gel, 35% EtOAc/hexane) to afford 144 mg (31%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 0.85-0.94 (m, 5H), 1.22-1.24 (m, 1H), 1.29 (d, J=6.7 Hz, 6H), 1.58-1.68 (m, 2H), 1.70-1.77 (m, 1H), 2.14 (t, J=6.0 Hz, 2H), 3.14-3.36 (m, 2H), 4.44-4.54 (m, 1H), 5.81 (br s, 1H), 6.53-6.67 (m, 3H), 7.13 (t, J=7.2 Hz, 1H); IR (NaCl Film) 3294, 2974, 1644, 1610, 1550, 1492 cm-1 ; MS m/e 275; Analysis calc'd for C17H25NO2 : C, 74.14; H, 9.15; N, 5.09; found: C, 73.77; H, 8.99; N, 4.82.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].Cl.[CH3:16][N:17]1[C:26]2[NH:25][C:24]3[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:23]=3[N:22]([C:32]([CH:34]3[CH2:39][CH2:38][CH:37]([CH2:40][NH:41][C:42](=[O:50])[CH2:43][CH:44]4[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]4)[CH2:36][CH2:35]3)=[O:33])[CH2:21][C:20]=2[CH:19]=[N:18]1>ClCCl.C(N(CC)CC)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2]([N:47]2[CH2:48][CH2:49][CH:44]([CH2:43][C:42](=[O:50])[NH:41][CH2:40][CH:37]3[CH2:36][CH2:35][CH:34]([C:32]([N:22]4[CH2:21][C:20]5[CH:19]=[N:18][N:17]([CH3:16])[C:26]=5[NH:25][C:24]5[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:23]4=5)=[O:33])[CH2:39][CH2:38]3)[CH2:45][CH2:46]2)=[O:3])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)CC2CCNCC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)CC2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-nitrobenzyl chloroformate (1.08 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-2-piperidin-4-yl-acetamide hydrochloride from Example E17 (2.58 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=658.5
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:14])=[N:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C:2]1[N:3]=[CH:4][C:5]([NH2:14])=[N:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1(C)OB(c2ccncc2Cl)OC1(C)C
Reactant: Nc1cnc(Br)c(-c2cccnc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cnc(-c2ccncc2Cl)c(-c2cccnc2)n1
Reaction time: 16 h
Yield: 48.2 %

Procedure:
An oven dried resealable Schlenk tube was charged with 5-bromo-6-pyridin-3-ylpyrazin-2-amine (Preparation 6, 0.3 g, 1.17 mmol), 3-cloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.56 g, 2.35 mmol), cesium carbonate (1.15 g, 3.525 mmol) in dioxane (10 mL) and water (2.8 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (58 mg, 0.071 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in a 90° C. oil bath. After 16 h, the mixture was cooled, partitioned between water and ethyl acetate, the aqueous phase extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4) and evaporated. Flash chromatography (95:5 dichloromethane/methanol) gave the title compound (0.16 g, 48%) as a solid.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:14][C:15]1[N:20]=[C:19]([OH:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[C:17]([CH3:32])[N:16]=1.CN(C=O)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C:18]2[C:19]([O:21][S:9]([C:2]3[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=3[CH3:13])(=[O:11])=[O:10])=[N:20][C:15]([NH2:14])=[N:16][C:17]=2[CH3:32])=[C:24]([O:30][CH3:31])[CH:25]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COc1cc(O)ccc1Cc1c(C)nc(N)nc1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(OS(=O)(=O)c2c(C)cc(C)cc2C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Mesitylenesulfonyl chloride (5.25 g) was added to a mixture of the product from step (iii) (5 g), TEA (7 ml) and DMAP (120 mg) in DCM (100 ml) and stirred at rt for 24 h. DMF (10 ml) was added and the mixture heated under reflux for 12 h. Another portion of 2-mesitylenesulfonyl chloride (2 g) was added and heated under reflux for a further 24 h. The mixture was partitioned between DCM/water, the organics separated, washed with aq NaHCO3 soln, brine, dried and evaporated under reduced pressure. The residue was triturated with ether/isohexane and filtered to afford the subtitle compound, 9.515 g.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CN(C)C=O>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][N:17]1[C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]2[C:13]1=[O:23]
Reactant: BrCc1ccc2ccccc2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2ccccc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
To a solution of 2-(bromomethyl)naphthalene (0.500 g) in N,N-dimethylformamide (11 mL) was added potassium phthalimide (0.461 g), and the resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (15 mL). The organic layer was washed successively with water (15 mL×2) and brine (15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.380 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[CH2:14]([Mg]Br)[CH3:15].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]([OH:9])[CH2:14][CH3:15])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A cooled (0° C.) solution of 4-(trifluoromethoxy)benzaldehyde (5.000 g; 26.29 mmol) in anh. THF (50 ml) was treated dropwise with a solution of ethylmagnesium bromide (3 M in Et2O; 10.50 ml; 31.50 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 17 h. The resulting reaction mixture was cooled to 0° C., and aq. sat. NH4Cl (30 ml) was added dropwise. The separated aq. layer was further extracted with AcOEt (3×20 ml), and the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=60/1) afforded 1-(4-(trifluoromethoxy)phenyl)propan-1-ol as a colorless oil. LC-MS (conditions A): tR=0.79 min.; no ionisation.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=4)[N:15]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:14]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Br[C:39]1[S:40][C:41]([S:44][CH3:45])=[N:42][N:43]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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>[CH3:45][S:44][C:41]1[S:40][C:39]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:14]=[C:13]3[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[N:12]=2)=[N:43][N:42]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CSc1nnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CSc1nnc(-c2ccc3c(c2)c(-c2cccc(N4CCOCC4)n2)cn3C(=O)OC(C)(C)C)s1
Temperature: 100 °C
Yield: 47.1 %

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 3-(6-morpholinopyridin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (1.20 g, 2.374 mmol) and 2-bromo-5-(methylthio)-1,3,4-thiadiazole (1.002 g, 4.75 mmol) in p-dioxane/H2O (4:1, 15 mL) followed by potassium carbonate (0.984 g, 7.12 mmol, Aldrich) and Pd(PPh3)4 (0.137 g, 0.119 mmol, Strem). The reaction was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 2 h. The mixture was diluted with DCM (150 mL) and washed with H2O. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 0-18% EtOAc in DCM) to give tert-butyl 5-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-3-(6-morpholinopyridin-2-yl)-1H-indole-1-carboxylate (570 mg, 1.118 mmol, 47.1%) as a yellow solid. MS (ESI, pos. ion) m/z: 510 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 8.91 (1H, s), 8.17-8.32 (2H, m), 7.98 (1H, dd, J=8.7, 1.7 Hz), 7.65 (1H, t, J=8.0 Hz), 7.18 (1H, d, J=7.4 Hz), 6.70 (1H, d, J=8.4 Hz), 3.92-4.01 (4H, m), 3.68-3.77 (4H, m), 2.84 (3H, s), 1.72 (9H, s).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38].O>C(#N)C>[OH:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][OH:41])[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4]
Reactant: OCCNCCO
Reactant: O=C(CCl)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(CN(CCO)CCO)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]acetamide (177 mg) in acetonitrile was added potassium carbonate (118 mg) and diethanolamine (65 μl). The mixture was stirred at room temperature. Water was added to the reaction mixture. Solution was extracted with ethyl acetate. Organic extract was dried and evaporated. 2-[Bis(2-hydroxyethyl)amino]-N-[6-(2-phenyl-chroman-6-yloxy)pyridin-3-yl]acetamide was purified by column chromatography using 10% methanol in methylenechloride as eluant. 1H-NMR (400 MHz; d6-DMSO) δ: 10.1 (s, 1H), 8.31 (d, 1H, J 2.7 Hz), 8.07 (dd, 1H, J 2.7, 8.8 Hz), 7.46-7.31 (m, 5H), 6.95 (d, 1H, J 8.8 Hz), 6.86-6.84 (m, 3H), 5.11 (dd, 1H, J 2.1, 10.0 Hz), 4.71 (t, 2H, J 5.4 Hz), 3.50 (q, 4H, J 5.4 Hz), 2.97-2.92 (m, 1H), 2.74-2.70 (m, 1H), 2.67 (t, 4H, J 5.4 Hz), 2.18-2.14 (m, 1H), 2.02-1.97 (m, 1H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38]([C:31]5[C:32]6[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=6)[N:28]=[CH:29][CH:30]=5)=[O:39])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)c1ccnc2ccccc12
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccnc2ccccc12

Procedure:
The title compound, white solid (80 mg, 66%), MS (ISP) m/z=486.6 [(M+H)+], mp 222° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and quinoline-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2=O.[OH-:14].[Na+].Cl.[NH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=O>O.C(O)C.O.O1CCCC1>[NH2:17][C:18]1[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[N:7][C:8]2[C:4]([C:5]=1[C:6]([OH:12])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=2[Cl:11]
Reactant: NCC(=O)c1ccc(-c2ccccc2)cc1
Reactant: [OH-]
Reactant: O=C1Nc2c(Cl)cc(Cl)cc2C1=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(-c2ccc(-c3ccccc3)cc2)nc2c(Cl)cc(Cl)cc2c1C(=O)O
Temperature: 90 °C

Procedure:
A 3.02 g portion of 5,7-dichloroisatin was suspended in 25 ml of water in a 500 ml three-necked flask. A solution of 3.96 g of sodium hydroxide in 15 ml of water was added and the mixture heated to 90° C. A 6.0 g portion of 2-amino-4'-phenylacetophenone hydrochloride was dissolved in a mixture of 80 ml of absolute ethanol:water (1:1) and 20 ml of tetrahydrofuran. This solution was kept warm and with stirring, added dropwise to the 5,7-dichloroisatin solution over 1.5 hours. The resulting solution was refluxed 1.5 hours, then the solvent was distilled off at 85° C. The red solids were collected and washed with 50 ml of water. These solids were then stirred in 1800 ml of water, filtered and the filtrate acidified to pH 5 with glacial acetic acid. The resulting orange solids were collected and dried, giving 3.25 g of the desired product, mp 244°-245° C.