Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[CH:38]=[O:39].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:34]2[CH:35]=[CH:36][C:37]([CH:38]=[O:39])=[C:32]([F:31])[CH:33]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: O=Cc1ccc(B(O)O)cc1F
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(C=O)c(F)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 88 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (300 mg, 0.63 mmol) and (3-fluoro-4-formylphenyl)boronic acid (160 mg, 0.94 mmol) in dioxane (6 mL), aqueous 2M Na2CO3 solution (1.15 mL, 2.3 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (72 mg, 0.06 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (288 mg, 88%).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](O)=[O:8])=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([Cl:19])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(-c2ccccc2)cc1
Yield: 46 %

Procedure:
To a solution of biphenyl-4-carboxylic acid (2.1 mmol) in dry CH2Cl2 (5.3 mL) and dry DMF (1 mL), kept at 0° C. under N2, was added oxalyl chloride (0.3 mL, 3.13 mmol). The mixture was reacted 20 min at 0° C. and 2 h at room temperature, then concentrated to give crude biphenyl-4-carbonyl chloride as a light-yellow solid. An amount of his sample (2 mmol) were dissolved in dry THF (20 mL) and the resulting solution added dropwise, at 0° C., to a suspension obtained by mixing 3 (1.3 mmol), Et3N (1.143 mL, 8.2 mmol) and dry THF (3 mL) at 0° C. under N2. The ensuing mixture was reacted at 0° C. for 30 min and at room temperature for 3 h, then evaporated. Purification by flash-chromatography (cyclohexane/EtOAc 1:1) and recrystallization gave pure URB894 as an ivory coloured solid. Yield 46%. Mp 218-220° C. (acetone/petroleum ether; sealed capillary tube; decomposition of the sample with changing of colour and shrinking of the mass was noted starting from 146° C.); [α]D20=−20° (c 0.55, CH3CN). MS (EI): m/z 267 (M+), 222, 181, 167 (100). IR (Nujol) 3270, 1827, 1641, 1540 cm−1; 1H NMR (d6-acetone) δ 4.53-4.65 (m, 2H), 4.50-4.59 (m, 1H), 7.38-7.55 (m, 3H), 7.70-7.84 (m, 4H), 8.00-8.07 (m, 2H), 8.68 (br d, 1H, J=7 Hz) ppm. 13C NMR (d6-acetone): δ 58.8, 65.1, 126.9, 127.0, 128.0, 128.1, 129.0, 131.9, 139.7, 144.4, 166.4, 169.2 ppm.
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[Cl:22])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:39][NH:40]2)C1C=CC=CC=1)C>>[Cl:22][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([C:6]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)=[CH:5][C:4]([NH:40][CH3:39])=[O:23])[CH:14]=2)[NH:18][N:17]=1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: CCOC(=O)C=C(c1cccnc1)c1ccc2[nH]nc(Cl)c2c1
Product: CNC(=O)C=C(c1cccnc1)c1ccc2[nH]nc(Cl)c2c1

Procedure:
3-(3-Chloro-1H-indazol-5-yl)-N-methyl 3-pyridin-3-yl-acrylamide CCXXIV was prepared from 3-(3-chloro-1H-indazol-5-yl)-3-pyridin-3-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9]C=O)=[C:4]([Cl:12])[N:3]=1.O.P(=O)(O)(O)O>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCO
Product: Nc1nc(Cl)c(N)c(Cl)n1

Procedure:
A mixture of 2-amino-4,6-dichloro-5-[(dimethylamino)methylene]amino}pyrimidine (Example 2, 500 mg, 2.14 mmol), pH 3.2 aqueous potassium phosphate buffer (1.5 M, 6 mL, prepared as described in Example 3), water (1 mL), and ethanol (5 mL) was refluxed gently for 28 hours. During the reflux period, pH was maintained at ca. 3 by addition of 85% phosphoric acid. Volatiles were evaporated in vacuo and the residual solids partitioned between water (30 mL, adjusted to ph 8 with dilute ammonium hydroxide) and chloroform (75 mL). The chloroform layer was dried (sodium sulfate) and the chloroform evaporated to leave off-white solid (0.30 g). Crystallization of this solid from ethanol:water/4:1 gave the tile compound (IV) as light pink needles (332 mg, 61%); darkens and shrinks to black solid above 185° C., does not become fluid below 300° C.; 1H-NMR (DMSO-d6) and mass spectra identical to those descaled in Example 4.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][N:8]=[CH:7][C:6]=2[CH:5]=[CH:4][C:3]=1I.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[Br:1][C:2]1[C:10]2[S:9][N:8]=[CH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([F:12])[CH:18]=1
Reactant: Brc1c(I)ccc2cnsc12
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1cccc(-c2ccc3cnsc3c2Br)c1
Yield: 60.4 %

Procedure:
A suspension of 7-bromo-6-iodo-1,2-benzothiazole (29.6 mg, 0.0871 mmol), 3-fluorobenzeneboronic acid (12.8 mg, 0.0915 mmol), potassium carbonate (39.2 mg, 0.284 mmol), and Pd(PPh3)4 (12.2 mg, 0.0106 mmol) in 4:1 1,4-dioxane:water (1 mL) was heated to 80° C. for 15 h. The reaction mixture was concentrated in vacuo. Purification of the residue by ISCO chromatography (0 to 100% dichloromethane:heptane) to afford 16.2 mg (59%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 9.08 (s, 1H), 7.73 (d, J=7.58 Hz, 1H), 7.52 (dt, J=5.81, 7.96 Hz, 1H), 7.37 (qd, J=0.88, 7.71 Hz, 1H), 7.33 (d, J=7.58 Hz, 1H), 7.28-7.31 (m, 1H), 7.20 (ddt, J=1.01, 2.59, 8.43 Hz, 1H); MS (ESI): 307.87, 309.86 [M+H]+; HPLC tR=4.33 min (ZQ3: nonpolar—5 min).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([F:37])[C:35]=1[F:36])[CH2:31][NH2:32]>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:32][CH2:31][C:30]1[CH:33]=[C:34]([F:37])[C:35]([F:36])=[C:28]([F:27])[CH:29]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Reactant: NCc1cc(F)c(F)c(F)c1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCc2cc(F)c(F)c(F)c2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 67.2 %

Procedure:
A mixture of intermediate 59 (0.5 g, 1.36 mmol), 3,4,5-trifluorobenzylamine (0.66 g, 4.0 mmol) and MeOH (0.2 mL) is heated at 100° C. for 2 days. The reaction mixture is cooled to RT, and the mixture is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (70:30-50:50) gives 0.44 g of the product 83. 1H NMR (CDCl3) δ 7.59 (s, 1 H), 7.20-7.05 (m, 2 H), 7.05-6.90 (m, 8 H), 6.80-6.70 (m, 2 H), 5.45-5.30 (m, 2 H), 4.70-4.50 (m, 2 H), 1.16 (s, 9 H); MS: m/z 482 (M++1).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Cl:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@H](COC)n1cc(Cl)nc(Cl)c1=O
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Product: CC[C@H](COC)n1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 143-146° C.; 1H NMR (300 MHz, CDCl3): δ 7.15 (d, J=1.8 Hz, 1 H), 7.09 (d, J=1.8 Hz, 1 H), 7.03 (s, 1H), 4.94-4.90 (m, 1 H), 4.32 (t, J=8.1 Hz, 2 H), 3.65 (dd, J=10.6, 5.5 Hz, 1 H), 3.54 (dd, J=10.7, 3.3 Hz, 1H), 3.33 (s, 3 H), 3.10 (t, J=8.1 Hz, 2 H), 1.88-1.70 (m, 2 H), 0.91 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C17H19N3O2Cl3 (M+H)+: 402.0543; found m/z 402.0568.
Reaction SMILES: [CH3:1][S:2](O)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[S:14]([NH2:17])(=[O:16])=[O:15].N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][C:8]=1[S:14]([NH2:17])(=[O:15])=[O:16]
Reactant: Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CS(=O)(=O)O
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 23 °C
Reaction time: 20 h
Yield: 86.3 %

Procedure:
2,5-Diamino-benzenesulfonamide methanesulfonate (1.80 kg, 6.35 mol) was suspended in acetonitrile (24 L). Pyridine (1.55 L, 19.1 mol) was added, followed by the careful slow addition of methanesulfonyl chloride (517 mL, 6.68 mol). After stirring at 23° C. for 20 h, the mixture was partially concentrated in vacuo at 55° C. Water (18 L) was added to the concentrate, and the resulting suspension was stirred at 23° C. for 2 h. The solid was filtered and was then washed with water (4 L) and air dried on the filter. The solid was suspended in absolute ethanol (9 L), stirred at 23° C. for 9 h, and was then filtered. The solid was washed with absolute ethanol (2×2 L), and was then further dried in vacuo at 50° C. to afford the desired product, 2-amino-5-methanesulfonylamino-benzenesulfonamide (1.45 kg, 5.48 mol, 86%), as a purple solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:24]2[CH2:23][CH2:22][N:21]([C:18]3[CH:19]=[CH:20][C:15]([C:7]4[NH:6][C:5](=[O:27])[C:4]5[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=5[O:2][CH3:1])[N:8]=4)=[CH:16][CH:17]=3)[CH2:26][CH2:25]2)=[CH:31][CH:30]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(Cc5ccc(F)cc5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.200 g, 0.55 mmol) in DMF (5 mL) was added 4-fluorobenzyl bromide (0.07 mL, 0.55 mmol) and K2CO3 (0.15 g, 1.10 mmol). The reaction was stirred at room temperature for 2 hours then diluted with H2O and the solids filtered off to afford the title compound (0.17 g, 65%) as a light brown solid. 1H NMR (300 MHz, DMSO-d6): δ 11.76 (br s, 1H), 8.09 (d, J=8.1 Hz, 2H), 7.26-7.52 (m, 2H), 7.08-7.25 (m, 2H), 7.00 (d, J=8.0 Hz, 2H), 6.68 (s, 1H), 6.46 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.51 (s, 2H), 3.08-3.41 (m, 4H), 2.23-2.68 (m, 4H). APCI MS m/z 475 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.[CH2:28]([O:30][C:31](=[O:56])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([NH:43][C:44](OCC(Cl)(Cl)Cl)=[O:45])=[CH:41][C:40]([C:52]([CH3:55])([CH3:54])[CH3:53])=[N:39]2)[CH:33]=1)[CH3:29].CCN(C(C)C)C(C)C>O1CCOCC1>[CH2:28]([O:30][C:31](=[O:56])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([NH:43][C:44]([NH:27][C@@H:20]3[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C@H:17]([O:16][C:13]4[CH:14]=[CH:15][C:10]5[N:11]([C:7]([C@@H:3]6[CH2:4][CH2:5][CH2:6][N:2]6[CH3:1])=[N:8][N:9]=5)[CH:12]=4)[CH2:18][CH2:19]3)=[O:45])=[CH:41][C:40]([C:52]([CH3:55])([CH3:54])[CH3:53])=[N:39]2)[CH:33]=1)[CH3:29]
Reactant: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCN5C)n4c3)c3ccccc32)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A mixture of Intermediate 5c (163 mg, 0.45 mmol), Intermediate 30a (208 mg, 0.45 mmol) in 1,4-dioxane (3 mL) and DIPEA (119 μL, 0.68 mmol) was stirred at 90° C. for 3 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-12% MeOH in DCM, to give the product (291 mg, 96%). A 64 mg portion of this was further purified by HPLC (C18 X-select column, 30-98% MeCN in H2O, 0.1% HCO2H) to give the title compound as a white powder after freeze-drying powder (38 mg). LCMS (Method 5): Rt 3.85 min, m/z 677.3 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26-1.33 (12H, m), 1.80-2.27 (11H, m), 2.30-2.39 (1H, m), 3.09-3.16 (1H, m), 3.99 (1H, br t, J 8.2), 4.32 (2H, q, J 7.1), 4.74-4.83 (1H, m), 5.36-5.41 (1H, m), 6.33 (1H, s), 7.11 (1H, d, J 8.6), 7.19-7.37 (5H, m), 7.66 (1H, t, J 7.9), 7.75 (1H, d, J 9.9), 7.80-7.84 (1H, m), 7.93-7.98 (1H, m), 8.07-8.09 (1H, m), 8.22-8.28 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]2[S:15][CH:16]=[C:17]([OH:19])[N:18]=2)=[C:12]([C:20]2[CH:21]=[N:22][N:23]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[C:24]=2[C:25]([F:28])([F:27])[F:26])[O:11][N:10]=1.[CH3:36]I.[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]2[S:15][CH:16]=[C:17]([O:19][CH3:36])[N:18]=2)=[C:12]([C:20]2[CH:21]=[N:22][N:23]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[C:24]=2[C:25]([F:28])([F:26])[F:27])[O:11][N:10]=1
Reactant: CI
Reactant: Oc1csc(-c2c(-c3c(F)cccc3Cl)noc2-c2cnn(-c3cccc(F)c3)c2C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1csc(-c2c(-c3c(F)cccc3Cl)noc2-c2cnn(-c3cccc(F)c3)c2C(F)(F)F)n1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 52 mg (0.1 mmol) hydroxyl thiazole (example 9) in 5 ml dioxane were added alternately in small portions 0.140 g (1.0 mmol) of CH3I and a solution of 40 mg (1.0 mmol) NaOH in 1 mL water. The pH has to be kept at 8-9 and the temperature at 40-50° C. Then the reaction mixture was stirred for 1 hour at 40-50° C., diluted with 15 mL water, neutralized with HCl to pH 6-7. Thick oil was extracted with CCl4, dried with MgSO4 and purified by column chromatography on silica gel, using CCl4, then CHCl3/CCl4 (1:1, v/v) as eluents. Yield of glassy substance of example 10 is 20 mg (37%). Result of LC/MS MH+: 539.03; 1H NMR (DMSO-d6; CCl4): 3.73 (3H, s, CH3), 6.59 (1H, s, CH-thiazole), 7.52-7.78 (7H, m, CH-arom.), 8.62 (1H, s, CH-pyraz.)
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](=[O:9])[NH:7][CH:8]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:5]1[C:6](=[O:9])[NH:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]cc(C(F)(F)F)cc1Br
Yield: 75.8 %

Procedure:
0.4 g of 5-trifluoromethyl-2-pyridone was dissolved in 10 ml of acetic acid, and 0.4 g of bromine was added to the solution which was subsequently reacted for 4 hours while stirring. After completion of the reaction, the acetic acid was distilled off, and recrystallization was carried out from a mixed solvent of methylene chloride and n-hexane to obtain 0.45 g of the titled compound having a melting point of 162° to 165° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:33][CH:34]1[CH2:39][CH2:38][N:37]([C:15](=[O:16])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:31])([F:30])[F:32])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:36][CH2:35]1
Reactant: OC1CCNCC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N3CCC(O)CC3)ccc21
Yield: 73.5 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]amide (65 mg) was prepared by following General Procedure F starting from {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (75 mg), 4-hydroxypiperidine (18 mg), HBTU (73 mg), and DIEA (42 uL), with a modification of General Procedure F where DIEA was slowly added to the reaction mixture as the last reagent. LC/MS: m/z 549.7. 1H NMR (DMSO-d6, 400 MHz): δ 8.41 (t, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.80 (d, 1H), 7.65 (bs, 1H), 7.51 (d, 1H), 7.37 (d, 1H), 4.15 (d, 2H), 3.98-3.89 (m, 2H), 3.78-3.69 (m, 2H), 3.68 (s, 3H), 3.20 (t, 1H), 3.04 (t, 1H), 1.84-1.67 (m, 2H), 1.45-1.20 (m, 2H), —NH proton signal was not observed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[C:14]1[CH:15]=C(C=C(OC(C)C)[CH:23]=1)C(OC)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:14]([CH3:15])[CH3:23])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(OC(C)C)c1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Product: COC(=O)c1ccc(OC(C)C)c(Cl)c1

Procedure:
Prepared from methyl 3-chloro-4-hydroxybenzoate according to the procedure for methyl 3-bromo-5-isopropoxybenzoate. LCMS-ESI (m/z) calculated for C11H13ClO3: 228.7. found 229.1 [M+H]+, tR=3.90 min. 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=2.1 Hz, 1H), 7.89 (dd, J=8.7, 2.2 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 4.67 (dt, J=12.2, 6.1 Hz, 1H), 3.89 (s, 3H), 1.37 (dd, J=34.4, 30.1 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-])=O)(=[O:13])=[O:12].Cl.C(O)(=O)C>O>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[Cl:1])[C:6]([OH:8])=[O:7])(=[O:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccccc1S(=O)(=O)c1cc(C(=O)O)ccc1Cl

Procedure:
A mixture of 4-chloro-3-(o-nitrophenylsulphonyl)benzoic acid (1.71g), stannous chloride (3.12g), concentrated hydrochloric acid (6.6 ml) and acetic acid (25 ml) was heated on the steamm bath for 30 min., cooled, and diluted with water. 3-(o-Aminophenylsulhonyl)-4-chlorobenzoic acid was filtered off, washed with water and dried, m.p. 235°-238° C, providing on recrystallisation from acetic acid, m.p. 246°-248° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>CN(C1C=CN=CC=1)C.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([N:19]([CH2:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:36](=[O:39])[CH:37]=[CH2:38])[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)Cl
Reactant: Brc1cccc(Nc2ncnc3cnc(NCCCN4CCOCC4)cc23)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)N(CCCN1CCOCC1)c1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Reaction time: 1 h

Procedure:
To a stirred solution of 4-[(3-bromophenyl)amino]-6-[(3-morpholinopropyl)amino]pyrido[3,4-d]pyrimidine (400 mg, 0.90 mmol), (prepared from 4-[(3-bromophenyl)amino]-6-fluoropyrido[3,4-d]pyrimidine and 3-morpholinoprop-1-ylamine) DMAP (40 mg) and Et3N (excess, 2.0 mL) at 0° C. under N2 was added acryloyl chloride (1.2 mol eq., 1.08 mmol, 89 μL). After 1 hour stirring, a further two portions of acid chloride (89 μL each) were added over the next 2 hours, and the reaction was then stirred at 20° C. for 1 hour, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure before being chromatographed on silica gel eluting with MeOH/EtOAc (1:9) to MeOH/EtOAc (1:5) to give N-[4-[(3-bromophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]-N-[3-morpholinopropyl]acrylamide](142 mg, 32%) as a cream powder, mp (CH2Cl2/hexane) 178-180° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH3:8])=[C:4]([CH2:9][CH2:10][CH3:11])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[N+:6]([O-:20])[C:5]([CH3:8])=[C:4]([CH2:9][CH2:10][CH3:11])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1cc(Cl)nnc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCc1cc(Cl)n[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-3-methyl-4-propyl-pyridazine (8.03 g, 47.06 mmol) in CH2Cl2 (200 ml) is added mCPBA (11.6 g, 77%, 51.77 mmol). The mixture is stirred at room temperature overnight. Saturated K2CO3 aqueous solution (50 ml) is added and the layers are separated. The organic layer is then washed with brine (100 ml) and dried (Na2SO4) and evaporated, which provides the title product as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:15]=[N:16][N:17]([CH2:19][C:20]([O:22]CC)=O)[CH:18]=1.[CH3:25][NH2:26]>CO>[CH3:25][NH:26][C:20](=[O:22])[CH2:19][N:17]1[CH:18]=[C:14]([C:3]2[N:4]=[C:5]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[S:6][C:2]=2[CH3:1])[CH:15]=[N:16]1
Reactant: CN
Reactant: CCOC(=O)Cn1cc(-c2nc(Nc3ccccn3)sc2C)cn1
Solvent: CO
Product: CNC(=O)Cn1cc(-c2nc(Nc3ccccn3)sc2C)cn1
Yield: 46 %

Procedure:
According to Scheme 18 Step 2: A solution of ethyl 2-(4-(5-methyl-2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazol-1-yl)acetate (87 μmol, 30 mg) and methylamine (0.26 mmol, 8.1 mg) in MeOH (4 mL) was heated at 60° C. for 4 hours. After evaporation, the crude product was purified by flash chromatography over silica gel using DCM/MeOH (100:0 to 90:10) as eluent to afford N-methyl-2-(4-(5-methyl-2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazol-1-yl)acetamide (40 μmol, 13 mg, 45%) as a white powder.