Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:2][CH2:3][CH2:4][NH:5][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([F:6])=[CH:8][CH:9]=1
Reactant: NCCBr
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCBr)c1ccc(F)cc1
Temperature: 5 °C

Procedure:
To a suspension containing 0.23 mol of-bromoethylamine hydrobromide in 200 ml of chloroform, stirred at 5° C., is added dropwise a solution containing 0.21 mol of 4-fluorobenzoyl chloride in 50 ml of chloroform, followed by a solution containing 0.46 mol of triethylamine in 100 ml of chloroform. The mixture is then stirred at room temperature for 1 hour and then at reflux for 4 hours. After cooling and evaporation of the solvent, the residue is taken up in 200 ml of ether. After filtration of the salts and concentration of the solvent, the expected product is obtained by purification of the residue by chromatography on a column of silica, using a dichloromethane/acetone (98/2) mixture as eluent.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8]([C:22](=[O:38])[C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.I[C:40]1[CH:41]=[N:42][N:43]([CH3:47])[C:44]=1[C:45]#[N:46].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:45]([C:44]1[N:43]([CH3:47])[N:42]=[CH:41][C:40]=1[C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[O:38])=[CH:28][CH:27]=1)#[N:46]
Reactant: Cc1cccnc1N(C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Cn1ncc(I)c1C#N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccnc1N(C(=O)c1ccc(-c2cnn(C)c2C#N)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
Preparation 24, tert-butyl (3R)-3-{(3-methylpyridin-2-yl)[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]amino}piperidine-1-carboxylate (2.67 g, 5.12 mmol), Preparation 21, 4-iodo-1-methyl-1H-pyrazole-5-carbonitrile (1.19 g, 5.12 mmol), Pd2(dba)3 (234 mg, 0.256 mmol), and XPhos (257 mg, 0.512 mmol) were dissolved in dioxane (27 mL) under nitrogen atmosphere. A solution of Na2CO3 (1.63 g, 15.4 mmol) in H2O (3 mL) was added. The reaction was heated at 80° C. for 6 h, then stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (150 mL), washed by 50% brine solution (100 mL). The separated organic phase was dried over MgSO4, concentrated. The residue was purified by silica gel column chromatography eluting with a gradient of 15-100% EtOAc/heptane to afford tert-butyl (3R)-3-{[4-(5-cyano-1-methyl-1H-pyrazol-4-yl)benzoyl](3-methylpyridin-2-yl)amino}piperidine-1-carboxylate as a colorless solid (1.87 g, 73% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)[C:5]2[N:6]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>O>[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH:30][C:2]2[CH:3]=[C:4]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=3)[C:5]3[N:6]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=3)[N:7]=2)[CH2:26][CH2:25]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CCOc1ccc(Nc2cc(Cl)nn3c(C)c(C)nc23)cc1
Solvent: O
Product: CCOc1ccc(Nc2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C)c(C)nc23)cc1
Reaction time: 96 h

Procedure:
In a 2 dram reaction vial was added crude 6-chloro-N-(4-ethoxyphenyl)-2,3-dimethylimidazo[1,2-b]pyridazin-8-amine (0.013 g, 0.04 mmol) from 1b and trans-1,4-diaminocyclohexane (1.0 g, 8.0 mmol). The mixture was allowed to melt at 160° C. for 4 days. The melt was then cooled, diluted with water and extracted with dichloromethane. The organic layer was concentrated and then diluted with MeOH and then purified by preparative HPLC. This gave 0.005 g of the titled compound as a TFA salt. 1H NMR (500 MHz, MeOD) δ ppm 7.24 (2H, d, J=8.25 Hz), 7.00 (2H, d, J=8.80 Hz), 6.17 (1H, s), 4.05 (2H, q, J=6.96 Hz), 3.62-3.83 (1H, m), 3.02-3.21 (1H, m), 2.47 (3H, s), 2.42 (3H, s), 2.18-2.29 (2H, m, J=11.55 Hz), 2.03-2.14 (2H, m, J=12.65 Hz), 1.45-1.62 (2H, m), 1.39 (3H, t, J=6.87 Hz), 1.26-1.36 (2H, m). LC/MS, m/e 395 (M+1). HPLC Rt, 2.49 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][NH2:27])=[CH:22][CH:21]=1)([O-:19])=[O:18]>C(O)(=O)C>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][N:27]=[C:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[O:16])=[CH:24][CH:25]=1)([O-:19])=[O:18]
Reactant: CCCCC(=O)CC(=O)c1ccc(O)cc1
Reactant: NOc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: CCCCC(CC(=O)c1ccc(O)cc1)=NOc1ccc([N+](=O)[O-])cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
1-(4-Hydroxyphenyl)-1,3-heptandione, 1121 g, is dissolved in 4070 g acetic acid. O-(4-Nitrophenyl)hydroxylamine, 784 g, is added in portions keeping the temperature at ca 20° C. The formed slurry is stirred for 3 h, cooled to 15° C., filtered and washed with 1590 g acetic acid. 1944 g wet cake corresponding to 1596 g dry 1-(4-hydroxyphenyl)heptane-1,3-dione-3-[O-(4-nitrophenyl)oxime] is obtained. Yield 88%.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:4][CH:3]=1.[CH:14]1([NH:17][C:18](=[O:35])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:20]=2)[CH2:16][CH2:15]1.[F-].[Cs+].O1CCOCC1>CCOC(C)=O.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.O>[C:10]([NH:9][C:7]([C:5]1[S:6][C:2]([C:21]2[CH:20]=[C:19]([C:18](=[O:35])[NH:17][CH:14]3[CH2:16][CH2:15]3)[CH:24]=[CH:23][C:22]=2[CH3:25])=[CH:3][CH:4]=1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)NC(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NC(C)(C)C)s1
Temperature: 150 °C
Yield: 59.1 %

Procedure:
A 15 ml glass microwave reaction vessel was charged with 5-Bromo-N-tert-butylthiophene-2-carboxamide (1.5 g, 5.7 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.7 g, 5.7 mmol), cesium fluoride (0.63 g, 17 mmol), tetrakis(triphenylphosphine)palladium(0) (0.46 g, 0.40 mmol), 1,4-dioxane (4 ml, 57 mmol) and water (4 ml). The reaction mixture was heated in a Smith Synthesizer microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 150° C. for 20 min. The reaction mixture was diluted with EtOAc and filtered through Celite and the Celite was washed with DCM. The combined organic solutions were evaporated under reduced pressure. The crude residue was suspended in DCM and washed with saturated sodium bicarbonate followed by brine, water and dried over MgSO4. The organic solutions were evaporated under reduced pressure and the crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 5% to 95% MeOH in DCM to provide N-tert-butyl-5-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-2-carboxamide (1.2 g). MS (ES+): 357 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=2)=[C:4]([CH2:21][CH2:22][CH3:23])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[S:30][CH:31]=[CH:32][N:33]=1)CCC>C1(C)C=CC=CC=1.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>[F:20][C:16]1[N:15]=[C:14]([C:10]2[N:9]([CH2:8][C:5]3[N:6]=[N:7][C:2]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[CH:3][C:4]=3[CH2:21][CH2:22][CH3:23])[CH:13]=[CH:12][N:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CCCc1cc(Cl)nnc1Cn1ccnc1-c1cccc(F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCc1cc(-c2nccs2)nnc1Cn1ccnc1-c1cccc(F)n1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 6-chloro-3-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-4-propyl-pyridazine (268 mg, 0.81 mmol), 2-tributylstannanyl-thiazole (453 mg, 1.21 mmol), and Pd(PPh3)4 (0.08 mmol, 93 mg) in toluene (10 mL) is degassed. The mixture is then heated at 100° C. overnight. Saturated KF aqueous solution (8 mL) is added and the mixture is stirred for 15 minutes. The layers are separated and the aqueous layer is extracted with EtOAc (10 mL). The combined extracts are washed with brine (15 mL), dried (Na2SO4), and evaporated. Preparative TLC (5% methanol in DCM) purification of the residue provides the title product. 1H NMR (CDCl3) 8.14–8.18 (m, 2H), 7.97 (d, 1H0, 7.83 (q, 1H), 7.50 (d, 1H), 7.20 (d, 1H), 7.18 (d, 1H), 6.80 (dd, 1H), 6.28 (s, 2H), 2.80 (t, 2H), 1.62–1.73 (m, 2H), 0.97 (t, 3H).
Reaction SMILES: Br[CH:2]1[C:14]2([CH2:15][CH2:16][CH3:17])[C:9](=[CH:10][C:11](=[O:18])[CH2:12][CH2:13]2)[C:8]2[C:3]1=[CH:4][C:5]([O:21][CH3:22])=[C:6]([Cl:20])[C:7]=2[Cl:19].C[O:24]CCO>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:19][C:7]1[C:6]([Cl:20])=[C:5]([O:21][CH3:22])[CH:4]=[C:3]2[C:8]=1[C:9]1[C:14]([CH2:15][CH2:16][CH3:17])([CH:2]2[OH:24])[CH2:13][CH2:12][C:11](=[O:18])[CH:10]=1
Reactant: COCCO
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)C2Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CCCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)C2O

Procedure:
A mixture of 9-bromo-5,6-dichloro-7-methoxy-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (6.29 g, 0.0157 mole) and silver nitrate (7.89 g, 0.047 mol) in 2-methoxyethanol (200 ml) and H2O (100 ml) was heated at reflux for 2 hours, filtered and evaporated to dryness. Chromatography of the residue on silica gel eluted with ethyl acetate-hexane (1:1) gave 1.2 g of 5,6-dichloro-9-hydroxy-7-methoxy-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one which melted at 173°-5° C. and was used in Step C without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]#[N:20])[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:22].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]([NH2:20])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2c(-c3ccc(F)cc3)cc(C#N)nc2c1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc2c(-c3ccc(F)cc3)cc(C(N)=O)nc2c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4-(4-Fluorophenyl)-7-methylquinoline-2-carbonitrile (1-6, 25 mg, 0.095 mmol, 1.0 equiv.) was dissolved in acetone (2.3 mL)/water (1.5 mL) and sodium percarbonate (79.0 mg, 0.477 mmol, 5.0 equiv) was added. The resulting mixture was stirred at 50° C. for 1 hour. The mixture was cooled and concentrated. The crude residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier). Fractions containing product were pooled and treated with Na2CO3. The resulting mixture was extracted with CHCl3. The combined organic layers were dried (MgSO4), filtered, and concentrated to afford 4-(4-fluorophenyl)-7-methylquinoline-2-carboxamide (1-7). LRMS m/z (M+H)+ 280.9 found, 281.3 required.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([NH:23][C:24]3[S:28][N:27]=[C:26]([CH:29]4[CH2:35][CH:34]5[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:31]([CH2:32][CH2:33]5)[CH2:30]4)[N:25]=3)=[N:12][CH:13]=[C:14]([S:16]CCC(OC)=O)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].CC([O-])(C)C.[K+].Br[CH2:51][CH2:52][O:53][CH3:54]>C1COCC1>[CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([NH:23][C:24]3[S:28][N:27]=[C:26]([CH:29]4[CH2:30][CH:31]5[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:34]([CH2:33][CH2:32]5)[CH2:35]4)[N:25]=3)=[N:12][CH:13]=[C:14]([S:16][CH2:51][CH2:52][O:53][CH3:54])[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ncccc1Oc1cc(SCCC(=O)OC)cnc1Nc1nc(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)ns1
Reactant: COCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1ncccc1Oc1cc(SCCOC)cnc1Nc1nc(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)ns1
Temperature: 25 °C
Reaction time: 0.01 h
Yield: 92.3 %

Procedure:
tert-Butyl 3-(5-(3-(2-ethylpyridin-3-yloxy)-5-(3-methoxy-3-oxopropylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (115 mg, 0.183 mmol) was dissolved in THF (4 mL) and nitrogen was bubbled through the solution for 3 minutes. Potassium 2-methylpropan-2-olate (51.5 mg, 0.459 mmol) was added and the reaction was stirred at ambient temperature for 30 seconds. 1-Bromo-2-methoxyethane (19.0 μL, 0.202 mmol) was added and the reaction was stirred at ambient temperature for 30 minutes. The reaction was partitioned between EtOAc and aqueous NH4Cl. The organic layer was dried over sodium sulfate, filtered, concentrated and purified on silica gel (80% EtOAc in hexanes) to afford tert-butyl 3-(5-(3-(2-ethylpyridin-3-yloxy)-5-(2-methoxyethylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (101 mg, 0.169 mmol, 91.9% yield).
Reaction SMILES: [N:1]1[C:6]2[CH:7]3[CH2:12][NH:11][CH2:10][CH2:9][N:8]3[C:13](=[O:14])[C:5]=2[CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][C:26]=1[S:35]([N:11]1[CH2:10][CH2:9][N:8]2[C:13](=[O:14])[C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]=3[CH:7]2[CH2:12]1)(=[O:37])=[O:36]
Reactant: O=C1c2cccnc2C2CNCCN12
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2cccnc2C2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Br)CCN12
Temperature: 0 °C

Procedure:
To a solution of 8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-a]pyrazin-5(7H)-one (may be prepared as in Intermediate 7, 130 mg) in DCM (5 mL) was added DIPEA (0.360 mL, 2.061 mmol). The mixture was cooled to 0° C. and 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (233 mg) was added.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH:4]=O.[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:24]=[CH:23][C:22]4[N:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][C:14]=2[O:36][CH3:37])[CH2:9]1.C(O)(=O)C.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+].Cl.CCOCC>CO.C(Cl)(Cl)Cl>[ClH:34].[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[S:27][C:21]3[C:20](=[O:35])[N:19]([C:16]4[CH:17]=[CH:18][C:13]([O:12][CH:10]5[CH2:9][N:8]([CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])[CH2:11]5)=[C:14]([O:36][CH3:37])[CH:15]=4)[CH:24]=[CH:23][C:22]=3[N:25]=2)=[CH:29][CH:30]=1
Reactant: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CNC1
Reactant: O=CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CN(CCC(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.5 %

Procedure:
Add 3,3,3-trifluoropropanal (120 mg, 1.06 mmol) to a suspension of 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (390 mg, 0.89 mmol) in MeOH (2.96 mL). Add acetic acid (0.254 mL, 4.43 mmol) and stir vigorously. Add sodium cyanoborohydride (146.6 mg, 2.22 mmol). Stir overnight at room temperature. Add saturated NaHCO3 (10 mL) and stir for 30 min. Extract the mixture with CH2Cl2 (2×10 mL). Combine the organic layer and wash with water (5 mL). Dry, filter, and concentrate the organic solution. Purify the crude material by flash chromatography, using 0-40% THF (1% NH3/MeOH) in heptane as eluent, to give a white solid. Redissolve in CHCl3 and add HCl/Et2O (0.32 mL). Filter the HCl salt to provide 37 mg (7%) of the title compound. ES/MS m/z 536.0 (35Cl) [M+1]+.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]([O:41][C:42]([NH:44][C@@H:45]([CH2:50][C:51]#[CH:52])[C:46]([O:48][CH3:49])=[O:47])=[O:43])([CH3:40])[CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(C)C)(C)C>C(N(CC)CC)C.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.[Cu]I>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([CH3:17])[C:18]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])=[CH:22][C:21]([C:52]#[C:51][CH2:50][C@H:45]([NH:44][C:42]([O:41][C:38]([CH3:40])([CH3:39])[CH3:37])=[O:43])[C:46]([O:48][CH3:49])=[O:47])=[N:20][CH:19]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)NC(C)C
Product: COC(=O)[C@H](CC#Cc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1)NC(=O)OC(C)(C)C
Yield: 55.2 %

Procedure:
A solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO2005/002577 intermediate 4 D, 1 g, 1.877 mmol), methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (Intermediate 1, 1.279 g, 5.63 mmol), Pd(PPh3)2Cl2 (0.066 g, 0.094 mmol), copper(I) iodide (0.018 g, 0.094 mmol), triphenylphosphine (0.049 g, 0.188 mmol) in triethylamine (2 ml)/diisopropylamine (8 ml) was heated at 100° C. under microwave irradiation for 30 mins. The solvents were evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a column 40+M and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluent to afford the title compound (750 mg, 1.036 mmol, 55.2% yield) as a white solid. UPLC: Rt 1.02 min, m/z 724 [M+H]+.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1([CH3:14])[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[OH-:15].[Ba+2].[OH-]>O>[C:10]([NH:11][C@:7]([CH3:14])([C:8]([OH:15])=[O:13])[CH2:6][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:12])[NH2:9]
Reactant: [OH-]
Reactant: CC(C)(C)SCC1(C)NC(=O)NC1=O
Agent: [Ba+2]
Solvent: O
Product: CC(C)(C)SC[C@](C)(NC(N)=O)C(=O)O
Temperature: 95 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
First, 5-tert-butylthiomethyl-5-methylhydantoin (5 g, 23 mmol) was mixed with barium hydroxide (11.7), and water (10 g), and the mixture was heated to 95° C. and stirred for 2 hours. The HPLC analysis of the reaction solution showed the production of the title compound in a reaction yield of 39%.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:18][CH3:19])[CH3:8].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[O:7]1[CH:5]([CH2:4][CH:3]=[C:2]([CH3:20])[CH3:1])[C:6]1([CH:9]1[CH:10]([O:18][CH3:19])[CH:11]([OH:17])[CH2:12][CH2:13][C:14]1([CH2:15][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[OH:16])[CH3:8]
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Reactant: C1CCNC1
Product: COC1C(O)CCC(O)(CN2CCCC2)C1C1(C)OC1CC=C(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Fumagillol (500 mg) was dissolved in pyrrolidine (1 ml), and the solution was stirred at 50° C. overnight. Excess volume of pyrrolidine was distilled off under reduced pressure to leave 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(pyrrolidin-1-yl)methyl-1,4-cyclohexanediol as a crude product. This crude product was dissolved in dichloromethane (5 ml), to which was added methyl iodide (1.1 ml), and the mixture was stirred overnight. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: chloroform-methanol-ammoniacal water=0:1:0.1), followed by pulverizing with ether to obtain 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(N-methylpyrrolidin-1-ylio)methyl-1,4-cyclohexanediol iodide (446 mg: yield 50%) as colorless powder.
Reaction SMILES: C([NH:11][C@H:12]1[C@H:23]2[C:24]3[C:15](=[CH:16][C:17]([O:33][CH3:34])=[C:18]([O:31][CH3:32])[C:19]=3[CH2:20][C@@H:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:22]2)[CH2:14][CH2:13]1)(OCC1C=CC=CC=1)=O.[H][H]>CO.[Pd]>[NH2:11][C@H:12]1[C@H:23]2[C:24]3[C:15](=[CH:16][C:17]([O:33][CH3:34])=[C:18]([O:31][CH3:32])[C:19]=3[CH2:20][C@@H:21]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:22]2)[CH2:14][CH2:13]1
Reactant: COc1cc2c3c(c1OC)C[C@@H](c1ccccc1)C[C@H]3[C@H](NC(=O)OCc1ccccc1)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc2c3c(c1OC)C[C@@H](c1ccccc1)C[C@H]3[C@H](N)CC2
Yield: 88.3 %

Procedure:
A suspension of 0.65 g (1.4 mmol) of [1R,8S,9aR]-1-carbobenzyloxyamino-5,6-dimethoxy-2,3,7,8,9,9a-hexahydro-8-phenyl-phenalene, from Step 6, in 50 mL of methanol and 0.1 g of 10% palladium on carbon was stirred under 1 atmosphere of hydrogen for 1 hour. The solid dissolved as the reaction proceeded. The palladium catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give 0.4 g (87% yield) of crude product which was carried on to the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[NH:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:20]1.Cl>CC(C)=O>[C:9]1([CH2:8][N:19]2[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:20]2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1c[nH]cc1C(=O)OCC
Reactant: ClCc1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cn(Cc2cccc3ccccc23)cc1C(=O)OCC
Temperature: 25 °C
Reaction time: 96 h
Yield: 91.6 %

Procedure:
Potassium carbonate (5 g) followed by 1-(chloromethyl)naphthalene (4.60 g) were added to a solution of diethyl 3,4-pyrroledicarboxylate (5.00 g) in acetone (50 ml). The mixture was stirred at room temperature for 4 days, dilute hydrochloric acid (100 ml) was added and the mixture was extracted with ether (2×100 ml). The organic extracts were dried, filtered and evaporated to give the sub-title compound as a solid (7.62 g).