Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][CH:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10](B1OC(C)(C)C(C)(C)O1)[CH:11]=2.Cl[C:38]1[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][CH:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([C:38]1[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=1)[CH:11]=2
Reactant: Cc1ccc(Cl)nn1
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(B4OC(C)(C)C(C)(C)O4)ccc3n2Cc2cccc(F)c2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc3c(c2)c2c(n3Cc3cccc(F)c3)CCC(NC(=O)C(C)C)C2)nn1
Temperature: 140 °C
Yield: 24.7 %

Procedure:
Dissolve N-[9-(3-flourobenzyl)-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]isobutyramide (Preparation 23) (150 mg, 0.31 mmol) and 3-chloro-6-methylpyridazine (39 mg, 0.31 mmol) in dioxane (2.5 mL) and 2M Na2CO3 (388 μL). Sparge the solution with nitrogen for 5 min, add dichlorobis(triphenylphosphine)palladium (II) (11 mg, 0.016 mmol) and seal the reaction vessel. Heat to 140° C. in a microwave reactor for 30 min, then dilute with water (20 mL). Extract into EtOAc (3×25 mL), dry organics (MgSO4), filter, and concentrate in-vacuo to give the crude product (179 mg) as a brown solid. Purify the crude product on silica gel (12 g), eluting with 25-70% (4% (2M NH3/MeOH)/CH2Cl2)/hexanes to afford 35 mg (25%) of the title compound as a white solid. MS (ES): m/z 457 (M+1), 455 (M−1); HPLC (Method B) Rt=3.37 min (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][NH:33][CH2:34][CH:35]([OH:38])[CH2:36][OH:37]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]([CH2:34][CH:35]([OH:38])[CH2:36][OH:37])[CH3:32])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: CNCC(O)CO
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(CC(O)CO)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(2,3-dihydroxy-propyl)-methyl-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and 3-Methylamino-propane-1,2-diol following General Procedure C.
Reaction SMILES: C[O:2][C:3]1[C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:6]2[O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[CH:4]=1.Br.BrC>C(O)(=O)C>[OH:2][C:3]1[C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:6]2[O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1C(=O)O)oc1ccccc12
Agent: Br
Agent: CBr
Solvent: CC(=O)O
Product: O=C(O)c1cc2oc3ccccc3c2cc1O
Temperature: 30 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A mixture of 2-methoxydibenzofuran-3-carboxylic acid 21.62 g, (prepared by the method disclosed in Cl. Routier, Ng. Ph. Buu-Hoi, and R. Royer, J. Chem. Soc., 4276 [1956] which is incorporated herein by reference), 48% hydrobromic acid (250 ml) and acetic acid (175 ml) was boiled under reflux, allowing bromomethane to escape, for 2 hrs, removed from the heat source, diluted with 400 ml of water with stirring, and cooled in ice to 30° C. The crystalline product was filtered, washed with water, and dried, to give 19.9 g (98%) of 2-hydroxy-dibenzofuran-3-carboxylic acid, m.p. 301°-2° dec. An analytical sample was prepared by twice recrystallizing a portion from 2-ethoxyethanol, m.p. 301°-303° dec.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].CS(O[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])(=O)=O>CCO>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccccc1CCOS(C)(=O)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1C)C(=O)OCC
Reaction time: 0.5 h

Procedure:
33.9 mL (0.223 mol) of diethyl malonate were added, under a nitrogen atmosphere and at room temperature, to a solution of sodium ethoxide (prepared in situ by dissolving 2.6 g (0.0151 mol) of Na in 80 mL of absolute EtOH). After 30 min, 14.5 g (0.0677 mol) of 2-methylphenethyl alcohol methanesulphonate dissolved in 40 mL of abs. EtOH were added dropwise and the resulting solution was heated to reflux for 3 h. EtOH was removed in vacuo, the residue was taken up in water and extracted with Et2O. The organic phase was washed successively with 10% HCl and brine, dried and the solvent was removed in vacuo. The excess diethyl malonate was removed by distillation under reduced pressure. The resulting oil (15.6 g) was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9]/[CH:10]=[C:11]2\[C:12](=[O:23])[NH:13][C:14](=[O:22])[C:15]3[C:20]\2=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]=1[NH:24][C:25](=[O:30])/[C:26](/C)=[CH:27]/C.NC1C=CC(CN/C=C2\C(=O)NC(=O)C3C\2=CC(I)=CC=3)=CC=1O[Si](C(C)C)(C(C)C)C(C)C.[Cl:65]/C=C\C(O)=O>>[Cl:65]/[CH:27]=[CH:26]\[C:25]([NH:24][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][NH:9]/[CH:10]=[C:11]2\[C:12](=[O:23])[NH:13][C:14](=[O:22])[C:15]3[C:20]\2=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)=[CH:7][C:2]=1[OH:1])=[O:30]
Reactant: C/C=C(\C)C(=O)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Reactant: O=C(O)/C=C\Cl
Agent: CC(C)[Si](Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)ccc1N)(C(C)C)C(C)C
Product: O=C(/C=C\Cl)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O

Procedure:
Following the acetylation and desilylation procedure employed for the preparation of (2E)-N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]-2-methylbut-2-enamide, (4Z)-4-[({4-amino-3-[(triisopropylsilyl)oxy]benzyl}amino)methylene]-6-iodoisoquinoline-1,3(2H,4H)-dione (65 mg, 0.11 mmol) is reacted with acid chloride derived from cis-3-chloroacrylic acid (0.12 g, 1.1 mmol). Following desilylation and precipitation, (2Z)-3-chloro-N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]acrylamide is obtained as a solid (10 mg, 17
Reaction SMILES: [CH3:1][C@@:2]12[C@H:11]3[CH2:12][C@@H:13]([OH:27])[C@:14]4([CH3:26])[C@@H:18]([C:19]5[CH2:24][O:23][C:21](=[O:22])[CH:20]=5)[CH2:17][CH2:16][C@:15]4([OH:25])[C@@H:10]3[CH2:9][CH2:8][C@@H:7]1[CH2:6][C@@H:5]([OH:28])[CH2:4][CH2:3]2.O=O>O.CC(C)=O.[Pt]>[CH3:1][C@@:2]12[CH:11]3[CH2:12][C@@H:13]([OH:27])[C@:14]4([CH3:26])[C@@H:18]([C:19]5[CH2:24][O:23][C:21](=[O:22])[CH:20]=5)[CH2:17][CH2:16][C@:15]4([OH:25])[CH:10]3[CH2:9][CH2:8][C@@H:7]1[CH2:6][C:5](=[O:28])[CH2:4][CH2:3]2
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2C[C@@H](O)[C@]2(C)[C@@H](C3=CC(=O)OC3)CC[C@]12O
Agent: [Pt]
Agent: O=O
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12[C@H](O)CC3C(CC[C@@H]4CC(=O)CC[C@]34C)[C@@]1(O)CC[C@@H]2C1=CC(=O)OC1
Yield: 101.5 %

Procedure:
Platinum IV oxide (0.5 g) was added to 1.0 g of Digoxigenin and dissolved in 100 mls of water and 150 mls of acetone. The mixture was pressurized to 2 atmospheres of oxygen and shaken for catalyst was filtered off, and the solvent stripped off leaving 1.01 g of white solid. This was dissolved in 100 mls of methylene chloride and extracted with 70 mls of water. The water was back-washed with two volumes of 50 mls of methylene chloride. The organic fractions were collected, dried with anhydrous sodium sulfate and the solvent was stripped off leaving 0.75 g of white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][C:17]2[C:18]([N:23]=1)=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:7].[H-].[Na+].I[CH3:34]>CN(C=O)C>[CH3:30][O:29][C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:26]=1[O:27][CH3:28])[C:6]([N:8]([CH3:34])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][C:17]2[C:18]([N:23]=1)=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:7]
Reactant: COc1cc(C(=O)Nc2ccccc2-c2nc3ncccc3o2)cc(OC)c1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C)c2ccccc2-c2nc3ncccc3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3,4,5-trimethoxy-N-(2-oxazolo[4,5-b]pyridin-2-yl-phenyl)-benzamide (0.03 g, 0.1 mmol) in 3 mL of DMF was added sodium hydride (60% dispersion in mineral oil, 0.006 g, 0.2 mmol). The mixture was stirred at RT for 30 minutes, becoming homogeneous. To this was then added iodomethane, drop wise (0.040 g, 0.3 mmol, 0.02 mL). After an additional hour at RT, the reaction was quenched with water and then partitioned between saturated NH4Cl and EtOAc. The organic layer was washed with brine and dried over MgSO4. The crude product was purified by silica chromatography, 0-5% methanol/dichloromethane. The desired product was isolated as a yellow solid. (Calc'd for C23H21N3O5: 419.44, [M+H]+ found: 420.1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12](OC)=[O:13])=[CH:7][CH:6]=2.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][OH:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2ncc(Cl)cc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2ncc(Cl)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Methyl 3-chloroquinoline-6-carboxylate (145 mg, 0.654 mmol) in THF (6 ml) Lithiumaluminium hydride 1M in THF (0.654 ml, 0.654 mmol) was added slowly at rt. The reaction was stirred for 2 h at rt. Sodium sulfate decahydrate was added to the reaction mixture to destroy the excess of Lithiumaluminium hydride. After 1 h, methanol was added and the fine suspension was filtered off. The filtrate was concentrated under vacuum, to afford crude (3-chloroquinolin-6-yl)methanol. MS (Method V) [M+H]+=194.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:13][C:12]2[CH:11]=[C:10]3[N:5]([CH2:6][CH2:7][NH:8][C:9]3=[O:14])[C:4]=2[CH2:3]1.[Br:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21](Cl)[C:18]=1[CH:19]=[O:20].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])(=O)C.[K+]>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].O1CCOCC1>[Br:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([N:8]2[CH2:7][CH2:6][N:5]3[C:10](=[CH:11][C:12]4[CH2:13][C:2]([CH3:15])([CH3:1])[CH2:3][C:4]=43)[C:9]2=[O:14])[C:18]=1[CH:19]=[O:20]
Reactant: CC1(C)Cc2cc3n(c2C1)CCNC3=O
Reactant: O=Cc1c(Cl)cc(F)cc1Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC1(C)Cc2cc3n(c2C1)CCN(c1cc(F)cc(Br)c1C=O)C3=O
Temperature: 80 °C
Yield: 50 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 4,4-dimethyl-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-9-one 103e (1.0 g, 4.90 mmol, 1.0 eq.), 2-bromo-6-chloro-4-fluorobenzaldehyde (2.76 g, 9.8 mmol, 2.0 eq.), Pd2(dba)3 (224 mg, 0.24 mmol, 0.050 eq.), Xantphos (283 mg, 0.49 mmol, 0.10 eq.), potassium acetate (1.44 g, 14.7 mmol, 3.0 eq.), and 1,4-dioxane (50 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 80° C. for 5 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified on silica-gel column eluting with 80:1 dichloromethane/methanol to afford 128a as a yellow solid (992 mg, 50%). MS: [M+H]+ 405.1
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[Na+]>O>[CH2:9]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Cc1ccc(N)cc1
Reactant: CCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCNc1ccc(C)cc1

Procedure:
A stirred mixture of p-toluidine (1100 parts) and nonyl bromide (478 parts) was heated on a steam bath for 20 hours, cooled and diluted with water (200 parts). The mixture was then made alkaline with caustic soda and after separation of the aqueous phase the residual oil was distilled under reduced pressure to obtain N-nonyl-p-toluidine (452 parts) as a pale yellow oil boiling at 136°-140° C. at 0.8 mm.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH2:19]([O:21][C:22](=[O:27])[NH:23][CH2:24][CH2:25]Cl)[CH3:20]>>[CH2:19]([O:21][C:22](=[O:27])[NH:23][CH2:24][CH2:25][O:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:8]2[CH:17]=[CH:18][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:6][CH:7]=2)=[CH:15][CH:14]=1)[CH3:20]
Reactant: CCOC(=O)NCCCl
Reactant: CC(C)(C)c1ccc(Oc2ccc(O)cc2)cc1
Product: CCOC(=O)NCCOc1ccc(Oc2ccc(C(C)(C)C)cc2)cc1

Procedure:
2-[p-(p-tert.butylphenoxy)phenoxy]ethylcarbamic acid ethyl ester as a yellow oil (nD20 =1.5436) is prepared from 4-[4-(1,1-dimethylethyl)phenoxy]phenol and (2-chloroethyl)carbamic acid ethyl ester.
Reaction SMILES: [H-].[Na+].[C:3]([N:22]1[CH:26]=[C:25]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[N:24]=[N:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:39][C:40]1[N:41]=[C:42]([CH:45]=[CH:46][C:47]2[CH:52]=[CH:51][C:50]([S:53]([C:55]([F:58])([F:57])[F:56])=[O:54])=[CH:49][CH:48]=2)[O:43][CH:44]=1.O>CN(C)C=O>[F:58][C:55]([F:56])([F:57])[S:53]([C:50]1[CH:51]=[CH:52][C:47](/[CH:46]=[CH:45]/[C:42]2[O:43][CH:44]=[C:40]([CH2:39][O:37][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][CH2:28][CH2:27][C:25]4[N:24]=[N:23][N:22]([C:3]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=5)([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=5)[CH:26]=4)=[CH:36][CH:35]=3)[N:41]=2)=[CH:48][CH:49]=1)=[O:54]
Reactant: Oc1ccc(CCCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nn2)cc1
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(CCCCc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nn4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h

Procedure:
8.1 mg (0.20 mmol) 95% sodium hydride were given at 0° C. to a solution of 90 mg (0.20 mmol) 4-[4-(1-trityl-1H-[1,2,3]triazol-4-yl)-butyl]-phenol in 3.0 ml N,N-dimethylformamide and stirred for 15 min. 66 mg (0.20 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at 25° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over sodium sulphate and the solvents distilled off in vacuo. Yield 146 mg.
Reaction SMILES: [C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](N1C2C(=CC(C)=CC=2)C(=O)C1=O)[CH2:24][CH:25](C)C>>[C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH2:21][CH:24]([CH3:25])[CH3:23])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCC(C)C
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Product: Cc1ccc2c(c1)C(OC(=O)c1ccccc1)C(=O)N2CCC(C)C

Procedure:
Was made in an analogous fashion to 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate using 1-isopentyl-5-methylindoline-2,3-dione. 1H NMR δ 8.12 (d, 2H), 7.58 (t, 1H), 7.45 (t, 2H), 7.25 (s, 1H), 7.16 (d, 1H), 6.77 (d, 1H), 6.15 (s, 1H), 3.75 (m, 2H), 2.30 (s, 3H), 1.70 (m, 1H), 1.59 (m, 2H), 1.00 (d, 6H).
Reaction SMILES: [BrH:1].CN(C)[CH:4]=[CH:5][C:6]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=1)=[CH:7][C:8]#[N:9]>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:8]1[CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[CH:5]=[CH:4][N:9]=1
Reactant: Br
Reactant: COc1cc(C(C=CN(C)C)=CC#N)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(-c2ccnc(Br)c2)cc(OC)c1OC
Yield: 62 %

Procedure:
Gaseous HBr was bubbled into a solution of 18 (3.6 g, 16.1 mmol) in chloroform for 15 minutes. The reaction was diluted with dichloromethane, washed with water, washed with brine, dried (MgSO4), and evaporated in vacuo to afford 3.2 g (62%) of 19 as an off-white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[C:8](C)[N:9]=1)(=[O:3])[CH3:2].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O>C(Cl)Cl>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([S:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][CH:8]=2)(=[O:13])=[O:12])[CH2:18][CH2:17]1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: CN1CCNCC1
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ncc(S(=O)(=O)N2CCN(C)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-acetamido-4-methyl-5-thiazolesulfonyl chloride (3 g, 11.8 mmol) in DCM (50 mL) and TEA (3.2 mL, 23.6 mmol) was slowly added N-methylpiperazine (1.2 g, 12.4 mmol). The reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, and the organic phase was isolated. The water phase was extracted with DCM (3×75 mL). The combined organic phase was dried with anhydrous magnesium sulphate, filtered, and evaporated in vacuo to give 2.6 g of yellow, impure crystals. Purification on a silica gel column (Eluent: DCM:MeOH (9:1)) gave N-[5-(4-methylpiperazine-1-sulfonyl)-thiazol-2-yl]-acetamide as light yellow crystals of N-[5-(4-methylpiperazine-1-sulfonyl)-thiazol-2-yl]-acetamide. Yield: 1.52 g (41%). 1H-NMR (CDCl3): δ3.20 (m, 4H); 2.55 (m, 7H); 2.32 (s, 3H); 2.29 (s, 3H).
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([OH:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)[C:8]2[NH:18][C:11]3=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([OH:28])([CH3:26])[CH3:27])=[CH:21][CH:20]=2)[C:8]2[NH:18][C:11]3=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]3[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(C(C)(C)O)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: COc1cnc2[nH]c(C(CC3CCCC3)c3ccc(C(C)(C)O)cc3)cc2c1
Temperature: 50 °C
Yield: 23.8 %

Procedure:
A mixture of 2-{4-[2-cyclopentyl-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-propan-2-ol (100 mg, 0.266 mmol) and 10% palladium on activated carbon (50 mg) in methanol (200 mL) was heated at 50° C. under hydrogen (50 psi) for 6 h. The mixture was cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-{4-[2-cyclopentyl-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-phenyl}-propan-2-ol (24 mg, 24%) as a white solid: LC/MS m/e calcd for C24H30N2O2 [M+H]+ 379.52, observed 379.2; 1H NMR (400 MHz, CD3OD) δ ppm 1.21 (m, 2H), 1.48 (m, 2H), 1.50 (s, 6H), 1.57-1.91 (m, 5H, H), 2.08 (m, 1H), 2.17 (m, 1H), 3.86 (s, 3H), 4.12 (t, J=7.8 Hz, 1H), 6.30 (s, 1H), 7.27 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.58 (d, J=2.5 Hz, 1H), 7.82 (br, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][N:18]=[C:17](Br)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][N:18]=[C:17]([CH:28]=[CH2:29])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2cc(Br)ncc2cc1NC(=O)OCc1ccccc1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
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: C1COCCO1
Solvent: O
Product: C=Cc1cc2nc(C(=O)OCC)c(NC(=O)OCc3ccccc3)cc2cn1
Temperature: 95 °C
Yield: 52 %

Procedure:
A mixture of ethyl 3-{[(benzyloxy)carbonyl]amino}-7-bromo-1,6-naphthyridine-2-carboxylate (22 mg, 0.051 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (43 μL, 0.26 mmol), tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.004 mmol), and potassium carbonate (21 mg, 0.15 mmol) in 1,4-dioxane (500 μL) and water (50 μL) in a vial was deoxygenated and purged with nitrogen several times. The vial was sealed under nitrogen and then heated at 95° C. for 3 h. The crude reaction mixture was filtered through a pad of diatomaceous earth and the inorganics were washed thoroughly with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (24 g silica gel column, eluting with 0-50% EtOAc/hexanes) to afford the sub-title compound (10 mg, 50%). LCMS (ESI) calc. for C21H20N3O4 [M+H]+: m/z=378.1. found: 378.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:17][NH2:18].[ClH:19]>>[ClH:19].[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][NH:18][CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=CC1(c2ccc(F)c(F)c2)CCCCC1
Reactant: CN
Agent: Cl
Product: CNCC1(c2ccc(F)c(F)c2)CCCCC1

Procedure:
The title compound was synthesized from 1-(3,4-difluorophenyl)-cyclohexanecarbaldehyde (131 mg, 0.58 mmol) and methyl amine (320 μL, 0.64 mmol, 2.0 M in THF) according to General Procedure H, followed by HCl salt formation. The HCl salt was recrystallized from CH3CN to give pure (1-(3,4-difluorophenyl)cyclohexyl)-N-methylmethanamine hydrochloride as colorless crystals. HPLC Rt=8.15 min; 1H NMR (400 mHz, MeOH-d4) 7.36-7.21 (m, 3H), 3.11 (s, 2H), 2.55 (d, J=3.67 Hz, 3H), 2.15-2.12 (m, 2H), 1.67-1.31 (m, 8H); LC-MS 7.04 min, (M+1)+ 240 @ 7.19 min.