Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[S:24][CH:25]=[N:26][N:27]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[C:35]([F:37])[CH:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CO.C(Cl)Cl>[S:24]1[CH:25]=[N:26][N:27]=[C:23]1[NH:22][S:19]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[C:9]([C:5]1[C:4]([O:28][CH3:29])=[CH:3][C:2]([C:33]3[CH:32]=[C:31]([F:30])[CH:36]=[C:35]([F:37])[CH:34]=3)=[C:7]([F:8])[CH:6]=1)=[N:10][CH:11]=[CH:12]2)(=[O:20])=[O:21]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COc1cc(Cl)c(F)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(-c2cc(F)cc(F)c2)c(F)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Temperature: 120 °C
Yield: 30.5 %

Procedure:
A vial was charged with 1-(4-chloro-5-fluoro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE HHHHH; 88.75 mg, 0.197 mmol). (3,5-difluorophenyl)boronic acid (62.2 mg, 0.394 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (2.020 mg, 4.92 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (7.46 mg, 9.84 μmol), and potassium phosphate (125 mg, 0.590 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (895 μl) and water (89 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 1 h at 120° C. The mixture was extracted with EtOAc (4×). The combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-4% MeOH/DCM, then with 4-10% MeOH/DCM) to give N-(1,3,4-thiadiazol-2-yl)-1-(2,3′,5′-trifluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonamide (31.54 mg, 0.060 mmol, 30.3% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=14.50 (br. s., 1H), 8.78 (s, 1H), 8.71 (d, J=5.7 Hz, 1H), 8.57 (d, J=1.6 Hz, 1H), 8.14 (d, J=5.5 Hz, 1H), 7.90 (dd, J=1.8, 8.9 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.49 (d, J=7.6 Hz, 2H), 7.43-7.34 (m, 3H), 3.73 (s, 3H). m/z (ESI) 528.9 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:18]=[C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])[CH:16]=2)[CH:10]=1)(=O)=O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.[CH:42]([OH:44])=[O:43].ClC1C=C(N2C(C3C=CC=C(OCCCN(C)C)C=3)=CC(C(N3CC(=O)NC3)=O)=N2)C=CC=1>O1CCCC1>[CH:42]([OH:44])=[O:43].[CH:42]([OH:44])=[O:43].[Cl:26][C:22]1[CH:21]=[C:20]([N:19]2[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:6][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)[CH:10]=3)=[CH:16][C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])=[N:18]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Reactant: CN1CCNCC1
Agent: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: O=CO
Solvent: C1CCOC1
Product: CN1CCN(CCOc2cccc(-c3cc(C(=O)N4CNC(=O)C4)nn3-c3cccc(Cl)c3)c2)CC1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 121A and 1-methylpiperazine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 46 mg (38% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:22]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([F:22])=[O:13])=[CH:5]2
Reactant: Fc1nc(F)nc(F)n1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(F)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h

Procedure:
A solution of 5-chloro-1H-indole-2-carboxylic acid (10.0 g, 51.1 mmol) and pyridine (33.1 mmol) in acetonitrile was added to a solution of cyanuric fluoride (2.76 g, 20.4 mmol) in acetonitrile (total 340 mL) at 25° C. The reaction was followed by TLC on aliquots quenched with butylamine and appeared nearly complete at 1 hour. The mixture was poured onto ice, extracted with ether, dried (Na2SO4), and concentrated giving a solid which was used without purification (10.0 g, 99%). TLC of a butylamine-quenched aliquot showed some 5-chloroindole-2-carboxylic acid and the less polar N-butylamide. A sample was purified by chromatography on silica gel eluting with ethyl acetate-hexanes (50-100%) for characterization (16368-130-1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[S:31](Cl)([CH3:34])(=[O:33])=[O:32]>ClCCl>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.628 mmol) and triethylamine (106 μL, 0.754 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of mesyl chloride (58 μL, 0.754 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with a saturated aqueous solution of NaHCO3 and water then dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound (140 mg, 56%). 1H NMR (400 MHz, CDCl3) δ7.19 (d, 2H), 6.94 (d, 2H), 4.04 (t, 2H), 3.79 (m, 2H), 3.57 (m, 2H), 3.24 (d, 2H), 2.75 (s, 3H), 2.63 (t, 2H), 2.54 (m, 4H), 2.12 (m, 2H), 2.01 (m, 2H), 1.88 (m, 2H), 1.80 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH2:10]([NH:17][C:18]([C:20]1[S:21][C:22]([N:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]2=[O:33])=[CH:23][C:24]=1[CH3:25])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:18]([C:20]1[S:21][C:22]([N:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=3)=[CH:28][C:27]2=[O:33])=[CH:23][C:24]=1[CH3:25])=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1cc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Product: Cc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 43 %

Procedure:
Following the procedure as described in Example 9, making variations only as required to use 1-(bromomethyl)-4-fluorobenzene in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-benzyl-5-(4-hydroxy-2-oxopyridin-1(2H)-yl)-3-methylthiophene-2-carboxamide, the title compound was obtained as a pale yellow solid in 43% yield: mp 195-197° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.56 (t, J=6.0 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.55-7.49 (m, 2H), 7.37-7.20 (m, 8H), 6.28 (dd, J=7.9, 2.7 Hz, 1H), 6.15 (d, J=2.7 Hz, 1H), 5.14 (s, 2H), 4.41 (d, J=6.0 Hz, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.2, 162.4, 160.9, 139.6, 138.8, 137.2, 135.2, 135.1, 131.7 (d, JC-F=3.0 Hz), 130.4 (d, JC-F=8.4 Hz), 128.2, 127.3, 127.1, 126.6, 120.6, 115.3 (d, JC-F=21.5 Hz), 102.5, 97.3, 69.3, 42.5, 15.5; MS (ES+) m/z 449.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([CH3:9])=[N:6][C:5]2=[C:10]([C:12]([OH:14])=O)[CH:11]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[Cl:46][C:47]1[C:48]([CH3:54])=[C:49]([CH:51]=[CH:52][CH:53]=1)[NH2:50]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([CH3:9])=[N:6][C:5]2=[C:10]([C:12]([NH:50][C:49]2[CH:51]=[CH:52][CH:53]=[C:47]([Cl:46])[C:48]=2[CH3:54])=[O:14])[CH:11]=1
Reactant: Cc1nc2c(C(=O)O)cc(Br)cc2o1
Reactant: Cc1c(N)cccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc2c(C(=O)Nc3cccc(Cl)c3C)cc(Br)cc2o1
Temperature: 25 °C

Procedure:
To a solution of 6-bromo-2-methyl-1,3-benzoxazole-4-carboxylic acid (136 mg) in DMF (2 mL), were added HBTU (242 mg) and triethylamine (110 μL). To the mixture was added 3-chloro-2-methylaniline (76 μL) and it was stirred at room temperature over night. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on silica gel column chromatography to obtain the titled compound (53 mg) as white powder.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1CCC[CH2:18]1.C[Li].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)C>[Si:1]([O:8][CH:9]1[CH2:13][C:12]([CH3:18])([OH:14])[C:11]([CH2:15][CH3:16])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Reactant: C1CCOC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C
Solvent: CCOCC
Product: CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1(C)O
Reaction time: 2 h
Yield: 98 %

Procedure:
To a liquid mixture of 2 g of (RS)-3-ethyl-4-oxo-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether and 20 ml of tetrahydrofuran was added under nitrogen stream 10 ml of 1.07 M diethyl ether solution of methyllithium at -78° C. and the resulting mixture was stirred at the same temperature for 2 hours. Then the reaction liquid was poured into ice-cooled 5% aqueous solution of citric acid and extracted two times with diethyl ether. The combined ether layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography to obtain 2.1 g of (1RS,4RS)-3-ethyl-4-methyl-4-hydroxy-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 98%
Reaction SMILES: C[N:2]([C:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:17]=[CH:18][C:11]=2[S:10][CH:9]=1)[C:3]([C:5](N)=[O:6])=[O:4].[OH-:23].[Na+]>C(O)C.O>[CH2:19]([C:16]1[CH:17]=[CH:18][C:11]2[S:10][CH:9]=[C:8]([NH:2][C:3](=[O:4])[C:5]([OH:6])=[O:23])[C:13](=[O:14])[C:12]=2[CH:15]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1ccc2scc(N(C)C(=O)C(N)=O)c(=O)c2c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCc1ccc2scc(NC(=O)C(=O)O)c(=O)c2c1

Procedure:
6.15 g (0.0193 mol) of N-[6-(n-butyl)-4H-1-benzothiopyran-4-on-3-yl]-oxamide methyl ester are stirred with a solution of 22.6 ml of 1N sodium hydroxide solution in 147 ml of ethanol and 970 ml of water for 2 hours at 70°. A small degree of cloudiness is then removed by filtration and the filtrate is acidified with hydrochloric acid, a crystalline product being precipitated. After cooling, the crystals are filtered with suction and washed first with water, then with ethanol and subsequently with ether. After drying there is obtained N-[6-(n-butyl)-4H-1-benzothiopyran-4-on-3-yl)-oxalic acid monoamide having a melting point of 208° (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH3:26])=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:46]1([CH:52](O)[CH2:53][CH3:54])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:54][CH2:53][CH2:52][N:46]4[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH3:26])=[O:24]
Reactant: CCC(O)N1CCCCC1
Reactant: CNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCN4CCCCC4)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinaz-olinyl)oxy]phenyl}-N′-methylurea (2.0 g) was dissolved in N,N-dimethylformamide (50 ml), and triphenylphosphine (2.8 g), piperidinopropanol (0.9 g), and diethyl azodicarboxylate (1.9 g) were added to the solution. The mixture was stirred at room temperature for 2 hr. Triphenylphosphine (2.8 g), piperidinopropanol (0.6 g), and diethyl azodicarboxylate (1.9 g) were then again added to the reaction solution, followed by stirring at room temperature for additional 10 hr. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol (20/1) to give 650 mg (yield 25%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:27][NH2:28])=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2.CCN(C(C)C)C(C)C>CC(O)C>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:28][CH2:27][C:21]4[CH:20]=[CH:19][C:18]([F:17])=[C:26]5[C:22]=4[CH:23]=[CH:24][NH:25]5)[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: NCc1ccc(F)c2[nH]ccc12
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1ccc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)c2cc[nH]c12
Temperature: 120 °C

Procedure:
A tube was charged with 53 (63 mg, 0.27 mmol), 114 (44 mg, 0.27 mmol), DIPEA (2 mL) in IPA (5 mL), degassed, sealed and heated at 120° C. overnight. The solvent was evaporated in vacuo and the residue was purified by preparative HPLC to afford 56 mg (57%) of I-47 as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][C:32]([F:48])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH2:41].C(=O)(O)[O-].[Na+].[I-].[Na+]>CS(C)=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21][NH:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]([F:31])([F:48])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCCCCOCC(F)(F)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCOCC(F)(F)c1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 140 °C

Procedure:
To a solution of (8-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)quinolin-2(1H)-one (4.80 g, 9.83 mmol) and Intermediate 9 (3.04 g, 11.8 mmol) in dimethylsulfoxide (13.5 mL) was added sodium bicarbonate (2.49 g, 29.4 mmol) and sodium iodide (2.22 g, 14.8 mmol). The mixture was heated at 140° C. for 2 hours. After cooling, the reaction was diluted with water (40 mL) and extracted with diethyl ether (2×20 mL). The combined organic extracts were washed with water (2×10 mL) and brine (20 mL), dried (Na2SO4), and the solvent removed under reduced pressure. The title compound was obtained (6.40 g, 98%) as oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][N:18]4[N:21]=[CH:22][C:23]([CH:24]=O)=[C:17]4[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[NH:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[O:28].N1CCCCC1>CCO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][N:18]4[N:21]=[CH:22][C:23]([CH:24]=[C:32]5[NH:26][C:27](=[O:28])[NH:29][C:30]5=[O:31])=[C:17]4[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cccc(Nc3ccn4ncc(C=O)c4n3)c2)CC1
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN1CCN(c2cccc(Nc3ccn4ncc(C=C5NC(=O)NC5=O)c4n3)c2)CC1
Temperature: 70 °C

Procedure:
To 5-(3-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (74 mg, 0.221 mmol) in EtOH was added hydantoin (22 mg, 0.221 mmol) and piperidine (22 μL, 0.221 mmol). The mixture was heated at 70° C. The solid formed was filtered off and the filtrate was prepared by HPLC to yield 5-((5-(3-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=419)
Reaction SMILES: O[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]#[N:14])[N:4]=1.P(Br)(Br)[Br:16].C([O-])(O)=O.[Na+]>C1COCC1>[Br:16][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]#[N:14])[N:4]=1
Reactant: N#Cc1cc2ccccc2c(CO)n1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cc2ccccc2c(CBr)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 1-(hydroxymethyl)isoquinoline-3-carbonitrile (0.150 g, 0.814 mmol) in THF (0.8 mL) and treated with PBr3 (0.814 mL, 0.814 mmol). The reaction mixture was stirred at RT for 2 hours, then poured over ice and neutralized with saturated aqueous NaHCO3. The mixture was warmed to RT and extracted with EtOAc (20 mL). The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a yellow solid. The crude product was dried under high vacuum and used without further purification (0.15 g, 75%). ESI-MS m/z [M+H]+ 247.5.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[S:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=3)[CH:14]=2)[C:9](=[O:24])[N:8]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:7]=1[CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:2][CH2:3][CH3:4].Cl.C([N:41]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[NH2:41][C:21]([C:19]1[N:20]=[C:16]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:24])[N:8]([CH2:25][CH:26]([CH3:27])[CH3:28])[C:7]([CH2:29][NH:30][C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:6]3[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[S:17][CH:18]=1)=[O:22]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C(=O)O)cs3)cc12
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C(N)=O)cs3)cc12
Yield: 93.3 %

Procedure:
A solution of 2-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylic acid (0.79 g, 1.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.58 g, 3 mmol) and 1-hydroxybenzotriazole ammonium salt (0.46 g, 3 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give tert-butyl [6-[4-(aminocarbonyl)-1,3-thiazol-2-yl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.74 g, 93.7%) as crystals.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:15][C:16]([NH-:23])([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].[Li+].CC(N)(C)CC(C)(C)C.C([Li])CCC>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[NH:23][C:16]([CH3:22])([CH3:15])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)CC(C)(C)[NH-]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Agent: CC(C)(C)CC(C)(C)N
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(C)(C)CC(C)(C)N[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 81 %

Procedure:
In an argon atmosphere, a solution obtained by dissolving 5.14 g (22.1 mmol) of Si(tBuNCHCHNtBu)(H)Cl in 10 mL of hexane was added to a lithium(1,1,3,3-tetramethylbutylamide) solution prepared by adding 10 mL of hexane and 2.94 g (22.8 mmol) of 1,1,3,3-tetramethylbutylamine to 13.8 mL (22.8 mmol) of a hexane solution (concentration: 1.65 mol/L) of butyllithium and stirring the mixture at room temperature for 14 hours, and the resulting mixture was stirred at room temperature for 24 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was sublimated (heating temperature: 180° C./64 Pa) to obtain 1,3-di-tert-butyl-2-(1,1,3,3-tetramethylbutyl)amino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHtOct) as a white solid (yielded amount: 5.85 g, yield: 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cc(C(F)(F)F)ccc1Cl

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-chloro-5-trifluoromethylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=1[C:21](O)=O.S(Cl)([Cl:26])=O.[BH4-].[Na+]>CO>[Cl:26][CH2:21][C:10]1[N:11]([CH3:20])[C:12](=[O:19])[C:13]2[C:18]([C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: Cc1ccc(-c2c(C(=O)O)n(C)c(=O)c3ccccc23)c(C)c1
Reactant: O=S(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-c2c(CCl)n(C)c(=O)c3ccccc23)c(C)c1
Temperature: 70 °C
Yield: 5.3 %

Procedure:
A suspension of 4-(2,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid (21.6 g) in thionyl chloride (218 mL, 2987 mmol) was heated at 70° C. for 2 hours. The mixture was concentrated, dissolved in tetrahydrofuran (THF) (15 mL), and treated with sodium borohydride (0.929 g, 24.56 mmol). The resulting mixture was heated to 70° C. for 2 hours until LCMS indicated complete reaction. The mixture was cooled to 0° C. and methanol was added until gas evolution ceased. The mixture was concentrated, diluted with water and then extracted three times with dichloromethane. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was treated with thionyl chloride (20 mL) and heated at 70° C. for 2 hours. The mixture was concentrated and then purified on silica gel (0-70% EA/Hexane) to afford the title compound (1.17 g, 76%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.46-8.59 (m, 1 H) 7.47-7.57 (m, 2 H) 7.05-7.24 (m, 3 H) 6.87-6.99 (m, 1 H) 4.43-4.55 (m, 1 H) 4.31-4.41 (m, 1 H) 3.86 (s, 3 H) 2.43 (s, 3 H) 2.01 (s, 3 H). LC/MS (m/z) ES+=312 (M+1).