Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[O:8])[CH:3]1[C:14]([OH:16])=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:17][C:2]1([CH3:1])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH:13]2[CH2:12][CH2:11]2)=[O:8])[CH:3]1[C:14]([OH:16])=[O:15]
Reactant: CC1(C)C(C=CC(=O)OC2CCC2)C1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)C(C=CC(=O)OCC2CC2)C1C(=O)O

Procedure:
A mixture of 12.32 g of the product of Step A, 0.6 g of p-toluene sulfonic acid and 120 ml of toluene was refluxed for 45 minutes and was cooled and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 7-3 n-hexane-ethyl acetate mixture containing 1% o acetic acid to obtain 8.94 g of (1R, cis, ΔZ) 2,2-dimethyl-3-(3-cyclopropylmethoxy-3-oxo-1-propenyl) cyclopropane-carboxylic acid melting at 106° C.
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]2[NH:6][C:7]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:17])[CH:10]=3)=[N:8][C:4]=2[CH:3]=1.Br[CH2:22][CH2:23][O:24][CH3:25].[H-].[Na+]>CN(C)C=O>[F:17][C:11]1[CH:10]=[C:9]([C:7]2[N:6]([CH2:22][CH2:23][O:24][CH3:25])[C:5]3[CH:18]=[C:19]([CH3:20])[C:2]([CH3:1])=[CH:3][C:4]=3[N:8]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: COCCBr
Reactant: Cc1cc2nc(-c3ccc(C#N)c(F)c3)[nH]c2cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1c(-c2ccc(C#N)c(F)c2)nc2cc(C)c(C)cc21
Temperature: 100 °C

Procedure:
4-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-2-fluorobenzonitrile 3 (110 mg, 0.4 mmol) was combined with 1-bromo-2-methoxyethane (76 mg, 0.55 mmol), NaH (13 mg, 0.55 mmol), and N,N-dimethyl formamide (5 ml). The reaction was heated at 100° C. for 1.5 hours. The product solution (confirmed by LCMS: 324.22) was carried on to the next step without purification.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][OH:9])[O:4]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[S:16]([O:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][O:9][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[O:4]1)([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: OC[C@@H]1CC[C@H](CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@@H](COS(=O)(=O)c3ccc(C)cc3)O2)cc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a three-neck flask equipped with a thermometer, reflux condenser, mechanical stirrer, and dropping funnel a solution of 924 grams (7 moles) of cis-2,5-bis-(hydroxymethyl) tetrahydrofuran, represented by formula (I), in 900 ml of pyridine was placed and cooled at 5° C. A solution of 2669 grams (14 moles) of p-toluenesulfonyl chloride in 4 liters of pyridine was added slowly through the dropping funnel. The temperature during the addition was kept below 10°-15° C. After the addition of p-toluenesulfonyl chloride, the reaction mixture was stirred for 2 hours and then let stand at room temperature overnight. The reaction mixture was poured over ice-water and the product precipitated. The ditosylate, represented by formula (II), was filtered off and washed several times with water and dried. The product obtained had a melting point of 125°-126.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH2:14][NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:32][CH:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>C(Cl)Cl>[CH3:20][CH:19]([S:16]([NH:15][CH2:14][CH:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:35]([CH:33]([CH3:34])[CH3:32])(=[O:37])=[O:36])[CH:3]=2)=[CH:24][CH:23]=1)[CH3:22])(=[O:18])=[O:17])[CH3:21]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(N)c2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(NS(=O)(=O)C(C)C)c2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 264.3 %

Procedure:
To a solution of {2-[4-(3-aminophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine (125 mg, 0.3587 mmol, prepared in example 3) dissolved in methylene chloride (2.5 mL, anhydrous) was added triethylamine (0.125 mL, 0.8968 mmol) under a nitrogen system. The mixture was cooled to 0° C. and 2-propanesulfonyl chloride (0.06 mL, 0.5381 mmol) was added by syringe. The mixture was allowed to warm to room temperature, and stirred overnight, under a nitrogen system. The reaction was quenched with excess water, and the organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, yielding 431 mg viscous oil. Purification was conducted using a Chromatotron®, on a 4000 μm rotor and eluting with a 1:1 hexane:ethyl acetate solvent system, yielding 400 mg of two inseparable coeluting spots. This mixture was purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate, yielding the title compound (16.7 mg, 1%) as a slow crystallizing foam.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([C:16]([CH2:18][NH:19][C@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]4[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=4)[C:29]([O:31]C)=[O:30])[CH2:21]3)=[O:17])=[C:13]([CH3:15])[N:14]=2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([C:16]([CH2:18][NH:19][C@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]4[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=4)[C:29]([OH:31])=[O:30])[CH2:21]3)=[O:17])=[C:13]([CH3:15])[N:14]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1cccc(N2CCC[C@H](NCC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)CN[C@H]1CCCN(c2cccc(C(=O)O)c2)C1
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A 1 mol/L aqueous potassium hydroxide solution (1 mL) was added to methyl(S)-3-[3-[[2-(4-chlorophenyl)-4-methylthiazole-5-carbonyl]methylamino]piperidin-1-yl]benzoate (59.4 mg, 0.123 mmol) in methanol (5 mL). The mixture was stirred for 1 hour while being refluxed. The solvent was then evaporated and the residue was dissolved in water. The mixture was made acidic by the addition of 2 mol/L hydrochloric acid. The crystallized powdery product was collected by filtration. Washing this product with water gave 56.4 mg (98%) of the desired product as a colorless amorphous product.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(#N)C>[CH:12]1([NH:18][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)cc1NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
2,4-Difluoronitrobenzene (2.00 g, 12.57 mmol) was dissolved in acetonitrile (20 mL) and cyclohexylamine (1.25 g, 12.57 mmol) and DIPEA (2.2 mL, 12.57 mmol) added. The reaction mixture was stirred at RT overnight. The resultant mixture was concentrated in vacuo to afford a bright yellow gum. This was purified by column chromatography (silica gel, gradient 0-10% EtOAc in cyclohexane) to afford the title compound as a bright yellow oil (2.4 g, 92%). 1H NMR (CDCl3, 400 MHz): δ 8.20 (1H, dd, J=9.50, 6.22 Hz), 6.49 (1H, dd, J=11.75, 2.62 Hz), 6.31 (1H, ddd, J=9.51, 7.26, 2.61 Hz), 3.47-3.33 (1H, m), 2.11-1.98 (2H, m), 1.85-1.77 (2H, m), 1.72-1.60 (1H, m), 1.48-1.26 (5H, m)
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH3:20])[CH2:16][CH:17]=1.Cl>[Pd].CO>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]1
Reactant: CCCN1CC=C(c2cccc(C(F)(F)F)c2F)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCN1CCC(c2cccc(C(F)(F)F)c2F)CC1
Reaction time: 15 h
Yield: 51.1 %

Procedure:
A mixture of 4-[2-fluoro-3-(trifluoromethyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridine (5.0 g, 17.4 mmol), palladium on carbon (0.4 g) and hydrochloric acid (0.5 ml, conc) in methanol (30 ml) was hydrogenated at 50 psi for 15 h under hydrogen. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated and evaporated to dryness to give 4.7 g of crude product. Purification by flash column chromatography (Isooctane/ethylacetate, 1:1) gave the title compound (2.57 g, 51%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 258-260° C. MS m/z (relative intensity, 70 eV) 289 (M+, 4), 261 (16), 260 (bp), 177 (6) 70 (15).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[CH3:7][CH2:8][CH2:9][CH2:10][SnH:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15]>C1C=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>[C:2]1([Sn:11]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9][CH2:8][CH3:7])[CH2:1][CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: C1=CCCC=C1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)C1=CCCCC1
Reaction time: 0.25 h
Yield: 235 %

Procedure:
To a solution of 1,3-cyclohexadiene (0.96 g, 12 mmol, d=0.84, 1143 uL) and Pd(PPh3)4 (462.2 mg, 0.4 mmol) in benzene (10 mL) under nitrogen atmosphere, was added Bu3SnH (1.16 g, 4 mmol, d=1.098, 1.06 mL) dropwise at room temperature and stirred for 15 minutes. After the solvent was removed on rotavap, the product was purified on silica flash chromatography (column 1.5 cm ID×20 cm) using a solvent gradient of 10:0 (100 mL) to 19:1 (100 mL) to 9:1 (100 mL) of hexanes/EtOAc to afford cyclohexenyltributyltin (3.5 g, 9.4 mmol, 78.6% yield) as a clear liquid. Cyclohexenyltributyltin was characterized by 1H-NMR (CDCl3, 500 MHz). See FIG. 51.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16](OC)=[O:17])=[CH:15][C:8]=23)=[CH:4][CH:3]=1.[CH3:22][NH2:23].[H-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]([NH:23][CH3:22])=[O:17])=[CH:15][C:8]=23)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Reactant: CN
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 61A (100 mg, 0.3135 mmol) and methylamine (2M solution in THF, 0.467 mL, 0.941 mmol) in THF (2 mL) at 0° C. was treated with NaH (12 mg, 0.47 mmol), stirred at room temperature for 1 hour, treated with water (0.1 mL), and concentrated. The residue was purified by flash chromatography on silica gel with 20% acetone/hexane to provide the title compound.
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:41]=[C:40]([C:42]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([O:52][Si](C(C)(C)C)(C)C)[CH:47]=2)=[O:43])[CH:39]=[C:38]([CH3:60])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([OH:37])=[O:36])[CH2:26][NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])=[O:23]>O1CCCC1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:41]=[C:40]([C:42]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([OH:52])[CH:47]=2)=[O:43])[CH:39]=[C:38]([CH3:60])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([O:37][CH3:2])=[O:36])[CH2:26][NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])=[O:23]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(Cl)c1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
Tetra-n-butylammonium fluoride (1 M in tetrahydrofuran; 3.4 mL, 3.4 mmol) was added to a solution of N-[2-chloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]-6-methylbenzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine (2.0 g, 3.1 mmol) in tetrahydrofuran (10 mL). The solution was stirred at room temperature for 20 min, then diluted with ethyl acetate and washed with water and then brine. The solution was dried (MgSO4), filtered, evaporated, concentrated, evaporated, dried overnight under high vacuum and then crystallized from methanol to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine, methyl ester (1.06 g) as a solid. The mother liquors were concentrated and chromatographed (70% ethyl acetate/hexanes then methanol/ethyl acetate/hexanes 10:133:57) to give a further portion of the product (0.16 g). The overall yield was 1.22 g (74%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+].COCCOC>O>[N:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[CH:4][C:5]3[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=3[CH:12]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1COc2ccc(Br)cc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C1COc2ccc(-c3ccncc3)cc2N1
Yield: 42.7 %

Procedure:
A mixture of 6-bromo-4H-benzo[1,4]oxazin-3-one [N. Mazharuddin et al., Indian J. Chem. 1969, 7, 658] (1.37 g. 6 mmol), pyridine-4-boronic acid (0.72 g, 6 mmol), sodium bicarbonate (1.51 g, 18 mmol), (tetrakis-triphenylphosphine)palladium (0) (348 mg, 0.3 mmol) in water (18 mL), and 1,2-dimethoxyethane (30 mL), was stirred at reflux under an argon atmosphere for 72 h. Reaction mixture was cooled and partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and dried (Na2SO4) and evaporated in vacuo to give a brown solid which was purified by chromatography on silica gel (30 g) eluting with 0-5% MeOH in EtOAc to give the title compound (0.58 g, 43%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[C:8]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:9]=3[N:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[Cl:33].Cl.Cl[CH2:36][CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:33][C:3]1[CH:4]=[C:5]([O:6][C:7]2[C:8]3[CH:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:22][CH2:36][CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:20][CH:21]=4)[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:9]=3[N:10]=[CH:11][N:12]=2)[CH:31]=[CH:32][C:2]=1[NH2:1]
Reactant: CCN(CC)CCCCl
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(O)cc2)cc2c(Oc3ccc(N)c(Cl)c3)ncnc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCOc1ccc(-c2cc3c(Oc4ccc(N)c(Cl)c4)ncnc3n2COCC[Si](C)(C)C)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 84.5 %

Procedure:
After dissolving 47 mg of the 4-[4-(4-amino-3-chlorophenoxy)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol synthesized in Production Example 160-1 in 0.5 ml of dimethylformamide, there were added 56 mg (3.1 equivalents) of (3-chloropropyl)diethylamine hydrochloride and 94 mg (7 equivalents) of potassium carbonate, and the mixture was stirred at 80° C. for 24 hours. It was then returned to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 49 mg of the title compound.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.O1CCOCC1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCCCBr
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: C1COCCO1
Product: N#CCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A suspension of 4,4-diphenylpiperidine (4.15 g, 17.5 mmol, 1.00 equiv), 4-bromobutyronitrile (2.10 mL, 21.0 mmol, 1.20 equiv, Aldrich), potassium carbonate (4.85 g, 35.0 mol, 2.00 equiv), and potassium iodide (581 mg, 3.50 mmol, 0.20 equiv) in n-butanol (20 mL) and 1,4-dioxane (20 mL) was stirred at reflux under argon for 48 hours. The mixture was cooled to room temperature and concentrated. Water (50 mL) was added and the mixture was extracted with CH2Cl2 (4×150 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc) to afford 4.65 g (87%) of white solid, which was characterized spectroscopically.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[NH2:38])[CH2:22][CH2:21]1.Cl.O1CCOCC1>CO>[N:23]1([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:28][C:27]=2[NH:38][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:3]=2[CH3:19])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2cccc(F)c2)nc2ccccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2cccc(F)c2)nc2ccccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-2-(3-fluorophenyl)-3-methylquinoline (127 mg, 467 μmol), 2,5-dimorpholinobenzenamine (123 mg, 467 μmol) and 4N hydrochloric acid solution in dioxane (0.12 mL, 467 μmol) in MeOH (3.00 mL) to afford product as a colorless solid after purification by chromatography on silica gel, eluting with MeOH gradient in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 8.16 (1H, d, J=8.2 Hz), 7.90 (1H, dd, J=8.0, 1.0 Hz), 7.66-7.75 (1H, m), 7.43-7.56 (2H, m), 7.32-7.43 (2H, m), 7.25 (1H, s), 7.07-7.22 (2H, m), 6.45 (1H, dd, J=8.6, 2.7 Hz), 6.03 (1H, d, J=2.7 Hz), 3.88-3.99 (4H, m), 3.67-3.80 (4H, m), 3.01-3.14 (4H, m), 2.88-2.99 (4H, m), 2.32 (3H, s). Mass Spectrum (ESI) m/e=499.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:16][C:11]1([CH3:17])[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:15]=3)[C:7]=2[C:8](=[O:25])[C:9]2[CH:21]=[CH:20][C:19]([C:22]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:24])=[CH:18][C:10]1=2
Reactant: C1COCCN1
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)c2cc(C(=O)N3CCOCC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To the tetrahydrofuran (1 ml) solution of 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic acid (Compound B2-28, 15 mg, 0.045 mmol), morpholine (6 μl, 1.5 eq.), hexafluorophosphoric acid uronium 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylmethane aminium (HATU) (26 mg, 1.5 eq.), and N,N-diisopropylethylamine (24 μl, 3.0 eq.) were added and the mixture was stirred at room temperature for 3 hr. The reaction solution was filtered to remove insoluble matters and the residues obtained after concentration under reduced pressure were purified by high performance liquid chromatography to obtain the title compound (11 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[O:18][N:17]=[C:16]([C:19](O)=[O:20])[CH:15]=1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:19]([C:16]3[CH:15]=[C:14]([CH3:13])[O:18][N:17]=3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cc1cc(C(=O)O)no1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 5-methylisoxazole-3-carboxylic acid (221 mg, 1.74 mmol) and triethylamine (606 μL, 4.35 mmol) in CH2Cl2 (10 mL) at room temperature was treated with BOP-Cl (162 mg, 1.74 mmol). The mixture was stirred at room temperature overnight and additional BOP-Cl (81 mg, 0.87 mmol) and 5-methylisoxazole-3-carboxylic acid (110 mg, 0.87 mmol) were added. The mixture was stirred for an additional 48 hours at room temperature. Next, 2M LiOH (3 mL) was added to the mixture and stirred for 1 hour. The organic solvent was removed in vacuo, and water:CH2Cl2 (11 mL; 10:1) were added to the aqueous residue. The solid formed was filtered, washed with additional water and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylisoxazole-3-carboxamide (210 mg, 71% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.12 (s, 1H), 10.22 (s, 1H), 8.33 9d, 1H), 7.58 (s, 1H), 2.45 (s, 3H); LCMS (APCI+) m/z 338.9, 340.9 (M+H)+, Retention time=3.16 minutes (Method 2).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[C:15]1([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:22]4[N:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH:5]=3)=[C:10]([C:11]([F:14])([F:12])[F:13])[O:9][N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1ncccn1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: FC(F)(F)c1onc(-c2ccccc2)c1-c1cn(-c2ncccn2)cn1
Yield: 35 %

Procedure:
As described for Example 4, 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (67.4 mg, 0.48 mmol) was converted, using 2-chloropyrimidine instead of 4-fluorobenzotrifluoride, to the title compound (40 mg, 35%) which was obtained as a white solid. MS: m/e=358.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[C:20]([Cl:21])=[C:19]([CH3:22])[S:18][C:16]=2[N:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[C:20]([Cl:21])=[C:19]([CH3:22])[S:18][C:16]=2[N:17]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1Cl
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 2,4,5-trichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2,5-dichloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.