Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)[CH:14]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>CN(C=O)C>[ClH:2].[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:39][CH2:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[O:9])=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)[CH:14]=1
Reactant: NCCCN1CCOCC1
Reactant: Cc1csc(Nc2cc(Oc3cc(C(=O)O)ccc3Cl)ccn2)n1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1csc(Nc2cc(Oc3cc(C(=O)NCCCN4CCOCC4)ccc3Cl)ccn2)n1
Yield: 45.6 %

Procedure:
Following procedure of Example 83, 4-chloro-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid hydrochloride (0.100 g, 0.2511 mmol), triethylamine (0.1016 g, 1.004 mmol), (DMF (3 mL), ethyl carbonochloridate (0.02641 mL, 0.2762 mmol) and 4-(3-aminopropyl)morpholine (0.07242 g, 0.5022 mmol) were reacted to afford 4-chloro-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)-N-(3-morpholinopropyl)benzamide hydrochloride (0.030 g, 20.50% yield) as off white solid. 1H NMR (DMSO) δ 11.20 (bs, 1H), 10.37 (bs, 1H), 8.83 (t, 1H), 8.23 (d, 1H), 7.87 (dd, 1H), 7.84 (d, 1H), 7.82 (d, 1H), 6.58 (m, 2H), 6.55 (d, 1H), 3.94 (d, 2H), 3.72 (t, 2H), 3.40 (d, 2H), 3.32 (q, 2H), 3.12 (m, 2H), 3.03 (m, 2H), 2.21 (d, 3H), 1.93 (m, 2H); Mass spectrum (esi) m/z=488 (100) (M+H—HCl).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[H][H]>N.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: NCc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
900 mg (2.7 mmol) of (Z)-3-[1-(4-cyanophenylamino)-1-phenyl-methylidene]-2-indolinone are hydrogenated in 200 ml of methanolic ammonia for 7 hours over 1.4 g of Raney nickel at a hydrogen pressure of 3 bar. The catalyst is filtered off, the solution is concentrated by evaporation and the residue is divided between water/dichloromethane. The organic phase is dried, concentrated by evaporation, triturated with ether, suction filtered and dried.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([C:23](O)=[O:24])=[N:21][CH:22]=1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([N:13]2[CH2:12][CH2:11][N:10]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[C:5]([CH3:9])[N:4]=3)[CH2:15][CH2:14]2)=[O:24])=[N:21][CH:22]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cn3)CC2)nc1C
Yield: 63.3 %

Procedure:
Using 1-(3,5,6-trimethylpyridin-2-yl)piperazine (1.5 g) described in Preparation Example 92 and 5-bromo-2-picolinic acid (1.5 g) and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (1.8 g) was obtained
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6]B(O)[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]1=2.Br[C:14]1[CH:34]=[CH:33][C:17]2[NH:18][C:19]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:20][C:16]=2[CH:15]=1.C(Cl)Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:19]2[NH:18][C:17]3[CH:33]=[CH:34][C:14]([C:4]4[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=4[C:2]([OH:6])([CH3:12])[CH3:1])=[CH:15][C:16]=3[N:20]=2)=[CH:24][CH:25]=1
Reactant: CC1(C)OB(O)c2ccccc21
Reactant: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 90 °C
Yield: 30.7 %

Procedure:
A mixture of 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol (66.5 mg, 0.411 mmol), 5-bromo-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzimidazole (76.2 mg, 0.205 mmol), PdCl2(dppf)2.CH2Cl2 (34 mg, 0.041 mmol), and tetrabutylammonium bromide (66 mg 0.205 mmol) in 8 mL of DME and 1.64 mL of Na2CO3 solution (1.0 M) was degassed and purged with argon twice. The mixture was then heated to 90° C. for 12 h. The mixture was then cooled to room temperature, and filtered though a pad of Celite 545. The filtrate was concentrated under reduced pressure to yield a dark brown oil. The residue was purified by chromatography (silica, ethyl acetate:hexanes, 1:1) to afford the title compound as an off-white solid (26.8 mg, 30%). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.81 (dd, 1H, J=8.1 Hz, J=1.1 Hz), 7.63 (m, 2H), 7.56 (m, 1H), 7.45 (m, 1H), 7.34 (td, 1H, J=7.8 Hz, J=1.5 Hz), 7.16-7.26 (m, 4H), 7.05 (dd, 1H, J=7.4 Hz, J=1.7 Hz), 5.44 (s, 2H), 1.32 (s, 6H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C24H21F3N2O2: 427.43 (M+H), Found 427.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:24])=O.CN(C=O)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:24])=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CC(=O)O)ccc1OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-benzyloxy-3-methoxyphenylacetic acid (5.0 g, 18 mmol), from Step 2, in THF (40 mL) was added oxalyl chloride (2.54 g, 20 mmol, 1.1 equivalent) followed by a catalytic amount of DMF (~0.2 mL). The resulting mixture was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure to give the title compound which was used without purification.
Reaction SMILES: Cl.[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:15]1[CH:37]=[CH:36][C:18]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1)C(C(OC)=O)=O)([CH3:4])[CH3:3].[Cl-].COC(=O)C(O)=O>>[CH:2]([O:5][CH2:6][CH2:7][NH:8][C:15]1[CH:37]=[CH:36][C:18]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH2:25][CH2:26]2)=[O:20])=[CH:17][CH:16]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)C(=O)N(CCOC(C)C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: COC(=O)C(=O)O
Agent: Cl
Agent: [Cl-]
Product: CC(C)OCCNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
In a manner analogous to that described in Example 23, 1-{4-[N-(2-isopropyloxyethyl)-N-methoxycarbonylcarbonylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine hydrochloride having a melting point of 152°-154° is obtained from 3 g of 1-{4-[N-(2-isopropyloxyethyl)amino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine by reaction with oxalic acid monomethyl ester chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:6]([O:5][CH3:1])=[O:7])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
In methanol (50 ml), 2-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydroisoquinoline (1.34 g) was dissolved, followed by the addition of triethylamine (0.73 ml), palladium (II) acetate (40 mg) and 1,3-(diphenylphosphino)propane (145 mg). The resulting mixture was stirred overnight at 70° C. under a carbon monoxide gas stream. After the reaction mixture was concentrated under reduced pressure, the residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=15:1), whereby the title compound (665 mg, 65%) was obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[NH:49]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>>[N:49]1([C:30]([C:29]2[CH:33]=[CH:34][C:26]([Br:25])=[CH:27][C:28]=2[NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])=[O:31])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: C1CCCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12)N1CCCCCC1

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-bromo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 1, Step G) and azepane and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C21H21BrN4O3S, 488.0; m/z found, 487/489 [M−H]−. HPLC (reverse phase): RT=9.34 min. 1H NMR (500 MHz, CDCl3, rotameric broadening): 9.08 (d, J=1.8 Hz, 1H), 9.00 (d, J=1.8 Hz, 1H), 8.87 (br s, 1H), 8.50 (d, J=7.3 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 7.87 (dd, J=8.4, 7.4 Hz, 1H), 7.80 (d, J=1.8 Hz, 1H), 7.16 (dd, J=8.1, 1.8 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 3.33-3.28 (br m, 2H), 2.93-2.91 (m, 2H), 1.68-1.65 (m, 2H), 1.58-1.52 (m, 2H), 1.50-1.42 (br m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:16]([OH:18])=O)=[N:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:8]=1)[CH3:2].S(Cl)([Cl:21])=O>>[CH2:1]([O:3][C:4]1[C:5]([C:16]([Cl:21])=[O:18])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:8]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOc1cn(-c2ccc(F)cc2)nc1C(=O)O
Product: CCOc1cn(-c2ccc(F)cc2)nc1C(=O)Cl

Procedure:
D3 (43 mg, 0.17 mmol, 1.0 eq.) was heated in thionyl chloride (1 mL) for 4 h at 67° C. Solvent was removed in vacuo and the crude material was resolved in dry toluene and evaporated under reduced pressure again to yield D4. The crude material was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:21]2[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=2)([C:13]2[CH:18]=[C:17]([Cl:19])[N:16]=[C:15]([Cl:20])[CH:14]=2)[N:5]=1.[Cl:28][C:29]1[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[C:30]=1[S:36](Cl)(=[O:38])=[O:37]>O1CCCC1>[Cl:28][C:29]1[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[C:30]=1[S:36]([O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:6]2([C:13]3[CH:14]=[C:15]([Cl:20])[N:16]=[C:17]([Cl:19])[CH:18]=3)[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([NH2:3])=[N:5]2)[CH:22]=1)(=[O:37])=[O:38]
Reactant: NC1=NC(c2cccc(O)c2)(c2cc(Cl)nc(Cl)c2)c2ccccc21
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Oc1cccc(C2(c3cc(Cl)nc(Cl)c3)N=C(N)c3ccccc32)c1
Yield: 27.1 %

Procedure:
Aqueous sodium hydroxide (2.0 M, 0.559 ml, 1.12 mmol) was added to a solution of 3-(3-amino-1-(2,6-dichloropyridin-4-yl)-1H-isoindol-1-yl)phenol (Scheme #19, D, 0.069 g, 0.19 mmol) in tetrahydrofuran (1 mL) at 0° C. 5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (0.051 g, 0.22 mmol) was then added to the reaction mixture. After 30 minutes the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. Purification by flash chromatography using ethyl acetate followed by purification using preparative HPLC afforded 0.029 g (28% yield) of the title compound. 1H NMR (DMSO-d6) δ 7.87-7.77 (m, 2 H), 7.56-7.48 (m, 2 H), 7.41-7.34 (m, 2 H), 7.29 (s, 2 H), 7.12-7.01 (m, 3 H), 6.91 (d, J=1.77 Hz, 1 H), 3.74 (s, 3 H), 1.89 (s, 3 H); MS (AP) m/z 562 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.C([Li])CCC.Cl[C:15]([O:17][CH3:18])=[O:16]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]([O:17][CH3:18])=[O:16])=[C:4]([F:8])[N:3]=1
Reactant: COC(=O)Cl
Reactant: Fc1cccc(Cl)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)nc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-6-fluoropyridine (298 mg, 2.3 mmol) was taken up in tetrahydrofuran (11.4 mL) and cooled to −78° C. n-Butyllithium (1.42 mL of 1.6 M in hexanes, 2.3 mmol) was added dropwise over 5 min. The solution was stirred for 30 minutes and methyl chloroformate (0.3 mL, 3.9 mmol) was added dropwise over 15 minutes. The resulting mixture was stirred at −78° C. for 2 hrs and then warmed to 0° C. and stirred for 3 hours. The reaction was then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (silica, 0-17% ethyl acetate/hexanes) to afford the title compound as a white solid.
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.C[C:11]1[NH:12][C:13]([CH3:34])=[C:14]([C:30]([O:32][CH3:33])=[O:31])[CH:15]([C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:16]=1[C:17]([O:19][CH3:20])=[O:18].N1C=CC=CC=1>C(O)C>[CH3:34][C:13]1[NH:12][C:11]2[CH2:20][O:19][C:17](=[O:18])[C:16]=2[CH:15]([C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:14]=1[C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccc2c(c1)OCO2
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: CCO
Product: COC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a similar manner, 2.78 grams (6.95 millimoles) of pyridinium bromide perbromide was added in one portion to a cooled to 0° C. mixture of 2 grams of dimethyl 2,6-dimethyl-4-(3,4-methylenedioxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.81 milliliter of pyridine in 40 milliliters of ethanol-free chloroform, the resulting mixture stirred at 0° C. for 30 minutes then heated at reflux temperature for 90 minutes to obtain a methyl 2-methyl-4-(3,4-methylenedioxyphenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate product in the reaction mixture. The product was recovered in a manner similar to that previously described and purified over silica with 70/30 ethyl acetate/hexane to obtain 740 milligrams (39 percent yield) of white crystals. An analytical sample having a melting point of 226°-228° C. was obtained by recrystallizing from ethyl acetate/hexane and drying at 80° C./0.005 millimeters Hg pressure for 48 hours. Elemental analyses were as follow:
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[N+:13]([C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1)([O-])=O.C(=O)([O-])O.[K+]>CCCCC(=O)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:25]1[CH2:24][CH2:23][N:22]([C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=2)[NH2:13])[CH2:27][CH2:26]1
Reactant: ClCC1COc2ccccc2O1
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCCCC(C)=O
Product: Nc1cccc(N2CCN(CC3COc4ccccc4O3)CC2)c1

Procedure:
A solution of 54.2 mmol (10 g) of 2-chloromethyl-2,3-dihydro-1,4-benzodioxin, 54.2 mmol (9.2 g) of 3-nitrophenylpiperazine and 6 g of potassium hydrogen carbonate in 100 ml of methyl-4-pentanone is heated at reflux for 72 hours. After cooling, the reaction mixture is concentrated. The residue is taken up in 200 ml of water and extracted with 200 ml of dichloromethane. The organic phase is dried over magnesium sulphate, concentrated and purified by chromatography on silica gel, using as eluant a 99/1/0.1 dichloromethane/methanol/ammonium hydroxide mixture, to yield the expected product.
Reaction SMILES: C([CH:3]1[CH2:8][CH:7]([C:9]([F:12])([F:11])[F:10])[CH2:6][CH2:5][C:4]1=O)C.[NH:14]1[CH2:17][CH:16]([NH:18][C:19](=[O:36])[CH2:20][NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:10][C:9]([F:12])([F:11])[CH:7]1[CH2:8][CH2:3][CH:4]([N:14]2[CH2:15][CH:16]([NH:18][C:19](=[O:36])[CH2:20][NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:34])([F:33])[F:35])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH2:17]2)[CH2:5][CH2:6]1
Reactant: CCC1CC(C(F)(F)F)CCC1=O
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(C(F)(F)F)CC2)C1

Procedure:
Reaction of ethyl 4-(trifluoromethyl)cyclohexanone with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product. 1H NMR (CHLOROFORM-d) δ: 8.60 (s, 1 H), 8.21 (t, J=5.4 Hz, 1 H), 8.12 (s, 1 H), 7.71-7.81 (m, 2 H), 6.92 (d, J=7.8 Hz, 1 H), 4.49-4.66 (m, 1 H), 4.28 (d, J=5.6 Hz, 2 H), 3.57 (t, J=7.5 Hz, 2 H), 2.85-3.00 (m, 2 H), 2.31 (t, J=3.2 Hz, 1 H), 1.89-2.14 (m, 2 H), 1.53-1.78 (m, 5 H), 1.28-1.42 (m, 2 H); ESI-MS (m/z): Calcd. For C21H23F6N5O: 475.18. found: 476 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:20][S:21]([C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[O:31][CH3:32])(=[O:23])=[O:22].Cl[C:34]1C=CC(OC)=C(S(Cl)(=O)=O)[CH:39]=1>>[CH2:34]([O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([NH:20][S:21]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[O:31][CH3:32])(=[O:23])=[O:22])[CH:4]=2)=[CH:10][CH:11]=1)[CH3:39]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Nc1cc(C(=O)Nc2ccc(C(=O)O)cc2)ccc1Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cc(Cl)ccc3OC)c2)cc1

Procedure:
4-[4-Chloro-3-(5-chloro-2-methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=493.1 (M−H), was prepared in analogy to example 21, steps A to D. Step C was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride and yielded 4-[4-chloro-3-(5-chloro-2-methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([CH2:9][C:10]([O:12]CC)=[O:11])[CH2:3]1.CO.[OH-].[K+]>O>[CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([CH2:9][C:10]([OH:12])=[O:11])[CH2:3]1
Reactant: CCOC(=O)CC1CC(C)CC(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CC(C)CC(CC(=O)O)C1
Yield: 92.8 %

Procedure:
44.7 g of ethyl 3,5-dimethyl-cyclohexylacetate are treated with 300 ml of methanol and 15 g of potassium hydroxide, dissolved in 140 ml of water, and saponified by heating to reflux temperature for 3 hours. The working-up yields 35.6 g of a solid crude product which is used directly. A sample is distilled for the purpose of analysis.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@:34]4([CH3:39])[CH2:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH3:40][CH:41]([CH3:44])[CH:42]=O>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@:34]4([CH3:39])[CH2:38][CH2:37][CH2:36][N:35]4[CH2:40][CH:41]([CH3:44])[CH3:42])=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@]4(C)CCCN4)ncn3)cccc2s1
Reactant: CC(C)C=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@]4(C)CCCN4CC(C)C)ncn3)cccc2s1

Procedure:
(2S)-N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)-2-methylpyrrolidine-2-carboxamide, Example 57, (56 mg, 0.1 mmol) was reacted with 2-methyl-propionaldehyde (0.011 mL, 0.12 mmol, Aldrich) under the conditions of Example 3(d) to give the title compound as a white solid. MS (ESI, pos. ion.) m/z: 613 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br.[Br:21][C:22]1[CH:23]=[C:24]([CH2:29]Br)[C:25]([NH2:28])=[N:26][CH:27]=1.O>CN(C=O)C>[NH2:28][C:25]1[C:24]([CH2:29][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:23][C:22]([Br:21])=[CH:27][N:26]=1
Reactant: Nc1ncc(Br)cc1CBr
Reactant: CCOC(=O)CNc1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(Cc1cc(Br)cnc1N)c1ccccc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 33.9 %

Procedure:
To a solution of phenyl glycine ethyl ester (4.94 g, 27.6 mmol) and K2CO3 (11.42 g, 82.7 mmol) in anhydrous DMF (300 mL) under argon was added 5-bromo-3-(bromomethyl)pyridin-2-amine hydrobromide (9.52 g, 27.6 mmol). The mixture was stirred for 12 h at 40° C. Water (500 mL) was added and the mixture was extracted with ethyl acetate (3×500 mL). Combined organic layers were washed with water (2×400 mL) and brine (400 mL), dried over MgSO4, filtered and concentrated to a brown oil. Purification by column chromatography (silica gel, gradient elution of 30% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) gave ethyl 2-(((2-amino-5-bromopyridin-3-yl)methyl)(phenyl)amino)acetate (3.41 g, 34%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 7.89-7.88 (m, 1H), 7.36-7.35 (m, 1H), 7.17-7.11 (m, 2H), 6.68-6.64 (m, 1H), 6.47-6.44 (m, 2H), 6.09 (s, 2H), 4.30-4.29 (m, 4H), 4.12 (q, J=6.9 Hz, 2H), 1.19 (t, J=6.9 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[C:17]3[C:12](=[C:13]([F:18])[CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:19])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[C:11]([NH2:19])=[N:10][C:9]2([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:32]2[CH:33]=[N:28][CH:29]=[N:30][CH:31]=2)[CH:3]=1)[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH3:27])[CH:21]=1
Reactant: COc1cc(C2(c3ccc(F)c(Br)c3)N=C(N)c3c(F)cccc32)ccn1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(C2(c3ccc(F)c(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)ccn1
Yield: 39.4 %

Procedure:
1-(3-Bromo-4-fluorophenyl)-4-fluoro-1-(2-methoxypyridin-4-yl)-1H-isoindol-3-amine (98.9 mg, 0.23 mmol), 5-pyrimidinylboronic acid (31.3 mg, 0.25 mmol), 1,1′-bis (diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9.39 mg, 0.01 mmol), 2 M aqueous potassium carbonate (0.345 mL, 0.69 mmol) and DMF (2.0 mL) were put in a microwave vial and irradiated in a microwave oven at 110° C. for 20 min. Additional 5-pyrimidinylboronic acid (18.51 mg, 0.15 mmol) and [1,1′-bis (diphenylphosphino)ferrocene]palladium(II) chloride (9.39 mg, 0.01 mmol) were added and the resulting mixture was irradiated at 110° C. for 40 min. The resulting product mixture was filtered and purified by preparative-HPLC to give the title compound (38.9 mg, 39.4% yield).