Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([S:13]([NH:16][CH2:17][CH2:18][O:19][CH3:20])(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:31]1([O:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>C1COCC1>[C:31]1([O:37][C:38](=[O:39])[NH:1][C:2]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([S:13](=[O:14])(=[O:15])[NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH:8]=3)[N:5]=[C:4]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COCCNS(=O)(=O)c1cccc(-n2nc(C(C)(C)C)cc2N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCNS(=O)(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.3 %

Procedure:
To a mixture of 3-(5-amino-3-tert-butyl-pyrazol-1-yl)-N-(2-methoxyethyl)benzene sulfonamide (940 mg, 2.67 mmol) and solid sodium carbonate (493 mg, 5.87 mmol, 2.2 eq) in anhydrous THF was slowly added phenylchloroformate (0.40 mL, 3.20 mmol, 1.2 eq), and the reaction mixture was stirred at room temperature under nitrogen for 6 h. The reaction mixture was poured into ethyl acetate, and then the organic phase was separated and washed with water and brine, dried over Na2SO4, filtered, and concentrated at reduced pressure. Purification by MPLC (35% EtOAc/hexane) afforded the title compound (887 mg, 70%) as a white solid. 1H-NMR (CD3OD) δ 10.17 (broad s, 1H), 7.94 (t, J=1.5 Hz, 1H), 7.89 (t, J=6.0 Hz, 1H), 7.81 to 7.69 (m, 3H), 7.34 to 7.29 (m, 2H), 7.19 (t, J=7.2 Hz, 1H), 7.09 (broad s, 2H), 6.38 (s, 1H), 3.25 (t, J=6.0 Hz, 2H), 3.09 (s, 3H), 2.90 (broad s, 2H), 1.26 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([OH:21])[CH:20]=1>>[Cl:13][C:10]1[CH:11]=[CH:12][C:3]([CH2:2][O:21][C:19]2[CH:18]=[N:17][CH:16]=[C:15]([Cl:14])[CH:20]=2)=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Reactant: Oc1cncc(Cl)c1
Product: COC(=O)c1cc(Cl)ccc1COc1cncc(Cl)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromomethyl)-5-chlorobenzoate and 3-chloro-5-hydroxypyridine:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:28]([F:31])([F:30])[F:29])=[N:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:19]=[N:20][C:21](Cl)=[C:22]([CH3:25])[C:23]=3[CH3:24])[CH2:14][C@H:13]2[CH3:27])=[N:10][CH:11]=1)=[O:5])[CH3:2].[Br-].[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36][Zn+]>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.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:28]([F:31])([F:30])[F:29])=[N:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:19]=[N:20][C:21]([CH2:36][C:35]4[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:34]=4[F:33])=[C:22]([CH3:25])[C:23]=3[CH3:24])[CH2:14][C@H:13]2[CH3:27])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc(C[Zn+])c(F)c1
Reactant: CCOC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)C[C@H]2C)nc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(N2CCN(c3nnc(Cc4ccc(F)cc4F)c(C)c3C)C[C@H]2C)nc1C(F)(F)F
Temperature: 60 °C
Yield: 81.7 %

Procedure:
To a solution of 2-[(R)-4-(6-chloro-4,5-dimethyl-pyridazin-3-yl)-2-methyl-piperazin-1-yl]-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl ester (229 mg, 0.50 mmol, 1 eq) and THF (1.4 mL) in a microwave vial is added 2,4-difluorobenzylzinc bromide (2.0 mL 0.5 M solution in THF, 2.0 mmol, 4 eq) and tetrakis(triphenylphosphine)palladium (25 mg, 0.03 mmol, 0.05 eq). The vial is sealed and heated in the microwave at 60° C. (high absorption setting) for 25 min. An additional aliquot of 2,4-diflorobenzylzinc bromide (1.0 mL 0.5 M solution in THF, 1.0 mmol, 2 eq) is added and the reaction mixture is heated in the microwave at 100° C. (high absorption setting) for 5 min. The reaction mixture is quenched with water (10 mL) and then extracted with EtOAc (2×25 mL). The combined organic fractions are dried over magnesium sulfate, concentrated and purified by silica gel chromatography (25-75% EtOAc/Heptane) to yield the desired compound (225 mg, 81%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[N:16]=[C:17]([C:21](=[O:38])[NH:22][C:23]2[C:24]([C:28](=[O:37])[NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[N:25][NH:26][CH:27]=2)[N:18]([CH3:20])[CH:19]=1)(C)(C)C>ClCCl>[F:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:28]([C:24]2[C:23]([NH:22][C:21]([C:17]3[N:18]([CH3:20])[CH:19]=[C:15]([NH2:14])[N:16]=3)=[O:38])=[CH:27][NH:26][N:25]=2)=[O:37])=[CH:31][CH:32]=1
Reactant: Cn1cc(NC(=O)OC(C)(C)C)nc1C(=O)Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(N)nc1C(=O)Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
Trifluoroacetic acid (200 μl) was added to a stirred suspension of {2-[3-(4-fluoro-phenylcarbamoyl)-1H-pyrazol-4-ylcarbamoyl]-1-methyl-1H-imidazol-4-yl}-carbamic acid tert-butyl ester (30 mg) in dichloromethane (5 ml), then stirred at room temperature for 2 hours. The solvent was evaporated then re-evaporated with toluene (2×10 ml). The residue was triturated with diethyl ether and the resultant solid collected by filtration. The solid was washed with diethyl ether then dried under vacuum to give 15 mg of 4-[(4-amino-1-methyl-1H-imidazole-2-carbonyl)-amino]-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide as an off-white solid. (LC/MS: [M+H]+343.72).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].[CH:11]1(I)[CH2:15][CH2:14][CH2:13][CH2:12]1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][N:3]=1
Reactant: IC1CCCC1
Reactant: Oc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OC2CCCC2)cn1
Temperature: 120 °C
Reaction time: 72 h
Yield: 45 %

Procedure:
2-Bromo-5-hydroxypyridine (3 mmol) is dissolved in DMF (10 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30 min cyclopentyl iodide (2.2 eq.) is added and the reaction solution is stirred 3 days at 120° C. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are dried over MgSO4 and the solvent is removed in vacuo. 2-Bromo-5-cyclopentyloxy-pyridine is obtained after column chromatography (heptane/ethylacetate) as yellow oil in a yield of 45%; HPLC (method C): 2.08 min; LC-MS (method A): 2.05 min, 241.95 (M+H+).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+]>>[CH2:17]([N:11]1[CH:10]=[CH:9][C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:4])=[C:14]([OH:15])[C:13]=2[C:12]1=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ncc2ccn(Cc3ccccc3)c(=O)c2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1ncc2ccn(Cc3ccccc3)c(=O)c2c1O
Yield: 69.9 %

Procedure:
A mixture of 6-benzyl-4-hydroxy-5-oxo-5,6-dihydro-[2,6]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.081 mmol), glycine (805 mg, 10.7 mmol) and NaOMe solution (16 mL, 8.06 mmol, 0.5 M in MeOH) was refluxed for 16 h. Solvent was evaporated in vacuo, and the residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 2 with 4 M HCl, and then extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 20 mg of the title compound as a yellow solid. MS: (+)
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:4]
Reactant: C1COCCN1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCOCC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
To an ice cold solution of chloroacetyl chloride (1.29 g, 11 mmol) in 10 mL of methylene chloride was added morpholine (1 g, 11 mmol) in 10 mL of methylene chloride containing triethylamine (2.32 g, 23 mmol). The reaction mixture was stirred at 5° C. for 30 minutes then warmed to room temperature and stirred for 18 hours. After quenching with water (20 mL) at 5° C., additional methylene chloride (100 mL) was added. The organic layer was separated, washed with 1N HCl (1×50 mL), saturated aqueous NaHCO3 (1×50 mL), brine (1×50 mL), dried over MgSO4, filtered and concentrated at reduced pressure. The concentrated residue was dried in vacuo to give 0.52 g (28.8%) of 4-(2-chloroacetyl)morpholine as a brown oil. 1H NMR (300 MHz / CDCl3): δ 3.51-3.54 (m, 2H), 3.61-3.64 (m, 2H), 3.68-3.74 (m, 4H), 4.06 (s, 2H). HRMS: calcd for C6H10N1O2 Cl1 164.0478, found 164.0498.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)[N:22]=[C:21]([C:32]3[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=3)[N:20]=2)=[CH:15][CH:14]=1.Br[C:40]1[N:45]=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[CH:43]=[CH:42][CH:41]=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.O1CCCC1>[C:27]1([CH3:31])[CH:28]=[CH:29][CH:30]=[C:25]([C:23]2[N:22]=[C:21]([C:32]3[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=3)[N:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:40]4[N:45]=[C:44]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=5)[CH:43]=[CH:42][CH:41]=4)=[CH:18][CH:17]=3)[N:24]=2)[CH:26]=1
Reactant: Cc1cccc(-c2nc(-c3ccc(Br)cc3)nc(-c3cccc(C)c3)n2)c1
Reactant: Brc1cccc(-c2ccccn2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccc(-c2nc(-c3ccc(-c4cccc(-c5ccccn5)n4)cc3)nc(-c3cccc(C)c3)n2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
Under a stream of argon, 2.1 ml of a hexane solution containing 3.3 mmol of butyl lithium was slowly added to 60 ml of tetrahydrofuran cooled to −78° C. in which 1.25 g of 2-(4-bromophenyl)-4,6-di-m-tolyl-1,3,5-triazine obtained in Reference Example 2 had been dissolved. After stirring at −78° C. for 15 minutes, 0.91 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 20 ml portion of tetrahydrofuran prepared by dissolving 0.85 g of 6-bromo-2,2′-bipyridyl and 0.14 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 14 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (developing solvent hexane:chloroform=1:1 to 1:2) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 6-[4-(4,6-di-m-tolyl-1,3,5-triazin-2-yl)phenyl]-2,2′-bipyridyl (0.89 g, yield 61%). Its melting point is shown in Table 4. In this case, a distinct point of glass transition was not observed.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1>>[OH:17][C:13]1[C:5]2[C:6](=[O:12])[NH:7][C:8]3[C:3]([C:4]=2[CH:16]=[CH:15][CH:14]=1)=[C:2]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[CH:11]=[CH:10][N:9]=3
Reactant: O=c1[nH]c2nccc(Cl)c2c2cccc(O)c12
Reactant: Nc1ccc(NC(=O)c2ccccc2)cc1
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4c(O)cccc4c23)cc1)c1ccccc1

Procedure:
The intermediate ethyl ester was synthesized according to the procedure described for the preparation of Example 378, method 2 using 1-chloro-7-hydroxy-5H-benzo[c][1,8]naphthyridin-6-one and N-(4-amino-phenyl)-benzamide to provide 446. LC-MS (M+H=423, obsd.=423). 1H NMR (400 MHz, DMSO-d6): δ, 6.95 (d, 2H), 7.21 (d, 2H), 7.55 (m, 2H), 7.76 (d, 2H), 7.95 (d, 2H), 8.09 (d, 1H), 8.21 (d, 1H), 8.88 (s, 1H), 10.23 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[Br:10].[CH3:11][O:12][CH:13]([O:16]C)[CH:14]=[CH2:15].C(N(CC)CC)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Br:10][C:3]1[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[CH2:15][CH2:14][C:13]([O:12][CH3:11])=[O:16]
Reactant: C=CC(OC)OC
Reactant: Fc1cc(F)c(Br)c(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCc1cc(F)cc(F)c1Br
Temperature: 90 °C

Procedure:
A mixture of 1,2-dibromo-3,5-difluorobenzene (4.5 g), 3,3-dimethoxyprop-1-ene (5.1 mL), tetrabutylammonium chloride (4.6 g) and triethylamine (3.5 mL) in N,N-dimethylformamide (50 mL) is purged with nitrogen for 20 minutes. Palladium-(II)-acetate (111 mg) is added and the mixture heated for 16 hours at 90° C. After cooling the mixture is partitioned between aqueous HCl (1 M) and diethyl ether, the organic layer dried (Na2SO4), volatiles evaporated under reduced pressure and the residue purified by column chromatography (silica gel; hexane:ethyl acetate 98:2→80:20) to give the title compound (Yield 3.6 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](O)=[O:27]>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:26]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)=[O:27])=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1cccs1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Product: O=C(CNC(=O)c1cccs1)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and thiophene-2-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=3)[CH2:10]2)=[CH:6][CH:5]=1)[CH3:2].Br[C:25]1[CH2:29][O:28][C:27](=[O:30])[CH:26]=1>C1COCC1>[CH2:1]([O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:10][N:11]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][C:25]4[CH2:29][O:28][C:27](=[O:30])[CH:26]=4)[CH3:20])=[CH:15][CH:14]=3)[CH2:12]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(OC2CN(c3ccc([C@H](C)N)cc3)C2)cc1
Reactant: O=C1C=C(Br)CO1
Solvent: C1CCOC1
Product: CCOc1ccc(OC2CN(c3ccc([C@H](C)NC4=CC(=O)OC4)cc3)C2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To 0.040 g (0.13 mmol) (S)-1-{4-[3-(4-ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethylamine (X.1) in 1.5 mL THF are added 54 μL (0.38 mmol) TEA and 0.021 g (0.13 mmol) 4-bromo-2(5H)-furanone. The mixture is stirred for 12 h at 80° C. After concentration in vacuo the residue is purified by HPLC (SunfireC18, MeOH/water (+0.3% formic acid)) to yield the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)[CH:16]=[C:4]2[N:3]=1.O.[NH2:24][NH2:25]>O1CCOCC1>[N:8]1([C:6]2[N:5]3[N:14]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[N:21][CH:22]=4)[CH:16]=[C:4]3[N:3]=[C:2]([NH:24][NH2:25])[CH:7]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: NN
Reactant: Clc1cc(N2CCOCC2)n2nc(-c3cncnc3)cc2n1
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc(N2CCOCC2)n2nc(-c3cncnc3)cc2n1
Reaction time: 6 h
Yield: 96 %

Procedure:
There was suspended, in 1,4-dioxane (1.0 mL), 5-chloro-7-morpholin-4-yl-2-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidine (20 mg, 2.4 mM) prepared in the preceding step 1, then hydrazine monohydrate (29 μL, 0.6 mM) was added to the suspension and the mixture was stirred for 6 hours while refluxing the same with heating. After the stirring operation, the reaction liquid was concentrated, the concentrate was diluted with water and then the mixture was extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate and the solvent was distilled off to thus give a crude product of the title compound (18 mg, yield: 96%).
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=[C:6]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:9]2=[O:15])[CH:7]=1.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B(O)O>>[O:15]=[C:9]1[NH:10][C:11](=[O:14])[CH:12]=[CH:13][N:8]1[C:6]1[CH:7]=[C:2]([C:34]2[S:33][CH:37]=[CH:36][CH:35]=2)[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=1
Reactant: COc1c(Br)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CNS(C)(=O)=O
Reactant: OB(O)c1cccs1
Product: COc1c(-c2ccc3c(c2)CC=C3CNS(C)(=O)=O)cc(-n2ccc(=O)[nH]c2=O)cc1-c1cccs1
Yield: 32 %

Procedure:
The product from Example 93, Part A (26.5 mg, 0.051 mmol) was reacted with thiophen-2-yl boronic acid (8.3 mg, 0.065 mmol) as described in Example 93, Part B to give the title compound as an off-white solid (8.6 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1H) 7.86 (d, J=7.72 Hz, 2H) 7.55-7.78 (m, 5H) 7.50 (t, J=6.25 Hz, 1H) 7.38 (d, J=2.57 Hz, 1H) 7.16-7.21 (m, 1H) 6.58 (s, 1H) 5.69 (d, J=7.72 Hz, 1H) 4.19 (d, J=4.78 Hz, 2H) 3.48 (s, 2H) 3.30 (s, 3H) 2.96 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25].Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:22][N:23]([CH3:28])[S:24](=[O:26])(=[O:25])[O:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=2[CH:3]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)Oc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 0 °C

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (2.3 g, 0.01 mole), triethylamine (1.4 ml) and 4-dimethylaminopyridine (200 mg) in dimethylformamide (20 ml) was added dimethylsulfamoyl chloride (1.1 ml). The reaction mixture was heated on a steam bath for 18 hours, poured into ice water and excess hydrochloric acid, extracted into ethyl acetate, washed with water and dried over magnesium sulfate. The ethyl acetate was evaporated and the (2-sulfamoyl-6-benzothiazolyl) N,N-dimethylsulfamate purified by chromatography on a 2 mm preparative silica gel TLC plate developed with chloroform/methanol 9:1 (v/v) m.p.=162°-164° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:13])[CH:9]=2)[CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CN(C)C=O>[CH3:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([CH2:2][N:29]1[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[CH2:27][CH2:28]1)[CH:12]=[CH:11]2
Reactant: Cc1ccc2cc(CCl)ccc2c1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2cc(CN3CCN(c4ccccn4)CC3)ccc2c1

Procedure:
A mixture of 11.0 g. of 2-chloromethyl-6-methylnaphthalene, 7.0 g. of sodium carbonate and 10.0 g. of 2-pyridylpiperazine in 75 ml. of dimethylformamide is stirred for six hours. The reaction mixture is cooled, filtered and the filtrate is concentrated. The precipitate is then washed with water and crystallized from ethanol to yield 1-(6-methyl-β-naphthylmethyl)-4-(2-pyridyl)piperazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccc(F)cc4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccc(F)cc4)nc3)cc2)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,1-dimethylethyl (2S)-4-({4-[({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D16) (32.39 g, 0.0606 mol) in DCM (150 mL) was cooled in an ice/water bath and TFA (80 mL) was added drop-wise over 10 minutes. The reaction mixture was stirred at room temperature overnight then concentrated to a yellow gum. The gum was dissolved in MeOH (100 mL) and loaded onto SCX resin (150 g, pre-washed with MeOH). Elution with MeOH (750 mL) gave unchanged TFA salt of the title compound, and elution with 2M NH3 in MeOH (750 mL) gave title compound free base. The recovered TFA salt was treated in a similar manner to that described above using further SCX resin (100 g) to give a further batch of title compound free base. The two batches of the free base were combined in DCM and concentrated to give the title compound as a pale yellow gum (26.78 g). δH (CDCl3, 400 MHz) 8.07 (1H, d), 7.65 (1H, dd), 7.22 (2H, d), 7.04 (6H, m), 6.70 (1H, d), 3.48 (3H, s), 3.42 (2H, s), 2.89 (3H, m), 2.68 (2H, d), 1.97 (1H, m), 1.64 (1H, t), 1.49 (1H bs), 1.00 (3H, d). MS (ES): MH+ 435.1.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][S:7]([C:10]1[CH:34]=[CH:33][C:13]2[N:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)O)[CH2:19][CH2:18]3)[CH:15]=[N:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].C(N(CC)CC)C>ClCCl>[Cl:5][CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][CH:17]([N:14]2[C:13]3[CH:33]=[CH:34][C:10]([S:7]([CH3:6])(=[O:9])=[O:8])=[CH:11][C:12]=3[N:16]=[CH:15]2)[CH2:18][CH2:19]1
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1ccc2c(c1)ncn2C1CCN(CCC(O)c2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc2c(c1)ncn2C1CCN(CCC(Cl)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulphonyl chloride (0.46 ml) was added to a solution of 3-{4-[5-(methylsulfonyl)-1H-benzimidazol-1-yl]piperidin-1-yl}-1-phenylpropan-1-ol (2.1 g) and triethylamine (0.9 ml) in dichloromethane (30 ml) at 0° C. The mixture was allowed to warm to room temperature and stirring was continued for 16 hours. The reaction mixture was washed with water (15 ml) and brine (15 ml) and dried. Removal of the solvent gave the title compound as an orange foam, yield 1.85 g, M+H 432.
Reaction SMILES: [Na].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1.[CH2:10](O)[CH3:11]>>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:10][CH3:11])=[N:4][CH:5]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCO
Agent: [Na]
Product: CCc1ccc(Br)cn1

Procedure:
Sodium metal (4.87 g, 0.212 mol) was added to ethanol (200 mL) and stirred until completely dissolved. To this solution was added 2,5-dibromopyridine 9-1 (10 g, 0.0424 mol) and the resulting mixture was stirred at reflux for 16 hr. The solvent was removed in vacuo and the residue partitioned between water and EtOAc. After extraction with EtOAc (2×), the organic layer was washed with brine, dried (MgSO4) and concentrated to give 9-2 as a red-brown solid which was used as such in the next step.