Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:26])[N:15]([C:18]4[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([CH3:27])=[N:10]2)=[CH:5][CH:4]=1.[CH3:28][NH:29][CH3:30]>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]3[C:14](=[O:26])[N:15]([C:18]4[CH:19]=[CH:20][C:21]([C:22]([N:29]([CH3:30])[CH3:28])=[NH:23])=[CH:24][CH:25]=4)[CH2:16][CH2:17][C:12]=3[C:11]([CH3:27])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2nc(C)c3c2C(=O)N(c2ccc(C#N)cc2)CC3)cc1
Reactant: CNC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(-n2nc(C)c3c2C(=O)N(c2ccc(C(=N)N(C)C)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
Part A. 4-[1-(4-Methoxy-phenyl)-3-methyl-7-oxo-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-benzonitrile (0.250 g, 0.98 mmol) was dissolved in 1:1 MeOH/CHCl3 (30 mL). Hydrogen chloride gas was bubbled through the solution for 15 min, and it was then tightly capped and sealed. The reaction was stirred overnight at rt and then concentrated to dryness. The crude intermediate was dissolved in methanol (30 mL) and 2M dimethylamine (5.23 mL, 10.5 mmol) was added. The reaction was tightly capped and sealed and stirred overnight at rt. The reaction was concentrated and purified by reverse phase HPLC and freeze-dried to yield 4-[1-(4-methoxy-phenyl)-3-methyl-7-oxo-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-N,N-dimethyl-benzamidine (0.255 g, 71%): 1H NMR (CHCl3) δ 9.66 (s, 0.5H), 8.73 (s, 0.5H), 7.51–7.38 (m, 6H), 6.91 (d, j=8.8 Hz, 2H), 4.13(t, j=6.6 Hz, 2H), 3.80 (s, 3H), 3.33 (s, 3H), 3.06 (s, 3H), 2.96 (t,j=6.4 Hz, 2H), 2.35 (s, 3H) ppm; Mass Spec 404.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([NH2:35])[CH:30]1[O:34][CH2:33][CH2:32][CH2:31]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>>[O:34]1[CH2:33][CH2:32][CH2:31][CH:30]1[CH2:29][NH:35][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: NCC1CCCO1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=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)NCC3CCCO3)ccc21
Yield: 60.7 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide (73 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), tetrahydrofurfurylamine (27 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 492.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.37 (bs, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.77 (d, 1H), 7.72 (d, 1H), 7.47 (d, 1H), 7.34 (d, 1H), 4.03-3.94 (m, 1H), 3.78 (q, 1H), 3.74-3.57 (m, 5H), 3.38-3.31 (m, 1H), 2.00-1.73 (m, 3H), 1.68-1.53 (m, 1H).
Reaction SMILES: B.C1C[O:5]CC1.[Br:7][C:8]1[CH:21]=[CH:20][C:19]2[O:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Br:22])[CH:16]=3)[C:11](=[CH2:23])[C:10]=2[CH:9]=1.OO.[OH-].[Na+]>C1COCC1.O>[Br:7][C:8]1[CH:21]=[CH:20][C:19]2[O:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Br:22])[CH:16]=3)[CH:11]([CH2:23][OH:5])[C:10]=2[CH:9]=1
Reactant: C=C1c2ccc(Br)cc2Oc2ccc(Br)cc21
Reactant: C1CCOC1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Product: OCC1c2ccc(Br)cc2Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
Borane-THF complex (36.5 mL, 1M THF, 36.5 mmol) was added to a stirred solution of 2,6-dibromo-9-methylene-9H-xanthene (9-1) (6.43 g, 18.27 mmol) in THF (75 mL) at 0° C. The mixture was allowed to warm up to rt and stirred for 1 h. The reaction mixture was cooled to 0° C. and a mixture of hydrogen peroxide (35 wt % in water) (5.76 mL, 65.8 mmol) and NaOH (25.6 mL, 2 M aq, 51.1 mmol) was added cautiously. The mixture was allowed to warm up to rt over 30 min. The reaction mixture was then poured into water (200 mL) and extracted with DCM (3×150 mL). The combined organics were washed with water (2×200 mL), brine (200 mL), dried over MgSO4, filtered and volatiles removed in vacuo to give a yellow solid. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc/isohexanes) to afford (2,6-dibromo-9H-xanthen-9-yl)methanol (10-1) (2.5 g, 37.0% yield) as a yellow solid. 1H NMR (CDCl3) δ 7.42-7.39 (1H, m), 7.37-7.35 (1H, m), 7.28-7.27 (1H, m), 7.25-7.21 (1H, m), 7.16-7.12 (1H, m), 7.00-6.97 (1H, m), 4.00 (1H, t, J=5.9 Hz), 1.46 (2H, d, J=5.9 Hz) ppm.
Reaction SMILES: [C:1]1(=[O:24])[N:5]([C@H:6]2[C@@H:9](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:8][C:7]2=[O:18])[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.C(N(CC)CC)C.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C)C=O.C(OCC)(=O)C.O>[C:4]1(=[O:19])[N:5]([C@H:6]2[C@@H:9](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C:7]2=[O:18])[C:1](=[O:24])[C:2]2=[CH:23][CH:22]=[CH:21][CH:20]=[C:3]12
Reactant: O=C1N[C@H](/C=C/c2ccccc2)[C@@H]1N1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](N2C(=O)c3ccccc3C2=O)[C@H]1/C=C/c1ccccc1

Procedure:
In 6 ml of N,N-dimethylformamide is dissolved 546 mg of cis-3-phthalimido-4-(E)-styryl-2-oxoazetidine and under ice-cooling and stirring, 0.36 ml of triethylamine and 323 mg of tert-butyldimethylsilyl chloride are added. The mixture is stirred for 30 minutes and further stirred at room temperature for 4 hours and, then, the reaction mixture is shaken with ethyl acetate and water. The ethyl acetate layer is taken, washed twice with water and once with saturated aqueous sodium chloride in this order and dried over anhyrous sodium sulfate. It is concentrated under reduced pressure and the residue is purified by silica gel column chromatography (eluent:chloroform) and crystallized from ether to give cis-3-phthalimido-4-(E)-styryl-1-(tertbutyldimethylsilyl)-2oxoazetidine, melting at 167°-168° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:10]([C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[N:9]=1)=[O:7])C>CO>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:10]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccc(OC)nc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-n2nc(C(=O)O)cc2-c2ccc(F)cc2)cn1
Yield: 87.7 %

Procedure:
Aqueous 1N sodium hydroxide (1.2 L) was added to 5-(4-fluorophenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid ethyl ester (164 g) in methanol (1.6 L), and the resultant mixture was stirred at room temperature for 5 hours. The reaction solvent was removed under reduced pressure, and the residue was partitioned between water and diethyl ether. The aqueous layer was adjusted at pH 2 through addition of aqueous 1N hydrochloric acid (1.5 L), and the precipitated crystals were dissolved in chloroform. The resultant solution was partitioned by use of saturated brine, and the organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, and the precipitated crystals from diethyl ether were recovered by filtration, to thereby give the title compound (132.0 g, 88%).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[Cl:7][CH:8]([Cl:12])[C:9](Cl)=[O:10].C(N(CC)CC)C>C(OCC)C>[Cl:7][C:8]1([Cl:12])[CH:1]2[CH:2]([CH2:3][CH2:4][CH:5]=[CH:6]2)[C:9]1=[O:10]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C1=CCCC=C1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1C2CCC=CC2C1(Cl)Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.5 %

Procedure:
A mixture of 34.0 g of cyclohexadiene and 35.0 g of dichloroacetyl chloride in 300 ml of diethyl ether under nitrogen was refluxed while adding 31.5 g of triethylamine dropwise over a period of 3 hours. The mixture was then stirred at room temperature for 20 hours and filtered. The filtrate was washed with brine, 1N hydrochloric acid, saturated sodium bicarbonate and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue distilled to give 32 g of 8,8-dichlorobicyclo[4.2.0]oct-2-en-7-one.
Reaction SMILES: [O:1]([C:8]([N:10]=[C:11]=[O:12])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([O:22][CH3:23])[C:17]([O:20][CH3:21])=[CH:18][CH:19]=1>O1CCOCC1>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:9])=[O:12])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: O=C=NC(=O)Oc1ccccc1
Reactant: COc1ccc(N)cc1OC
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)NC(=O)Oc2ccccc2)cc1OC

Procedure:
To a solution of phenoxycarbonylisocyanate (7.0 g., 0.043 mole) in 50 ml. of dioxane is added 4-aminoveratrole (6.57 g., 0.043 mole) under a nitrogen atmosphere while maintaining a temperature of 20°-25°. Following the addition of the 4-aminoveratrole, a second 50 ml. portion of dioxane is added and the solution refluxed for a period of one hour. Concentration of the reaction mixture under reduced pressure provides an oily solid residue. Titration of this residual material with about 40 ml. of cold carbon tetrachloride followed by crystallization from acetonitrile provides analytically pure 1-(3,4-dimethoxyphenyl)-3-phenoxycarbonylurea, m.p. 139.5°-142°.
Reaction SMILES: C([O-])C.[Na+].C(OC(=O)[N:9]=[S:10]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[O:34][CH3:35])[C:24]([F:36])=[CH:23][N:22]=2)[CH:15]=1)([CH3:12])=[O:11])C>CCO.[Cl-].[Na+]>[F:36][C:24]1[C:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[O:34][CH3:35])=[N:26][C:21]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][S:10]([CH3:12])(=[NH:9])=[O:11])[CH:15]=2)=[N:22][CH:23]=1
Reactant: CCOC(=O)N=S(C)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OC)n2)c1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(F)ccc1-c1nc(Nc2cccc(CS(C)(=N)=O)c2)ncc1F
Temperature: 60 °C
Reaction time: 5 h
Yield: 72.7 %

Procedure:
A freshly prepared 1.5M solution of sodium ethanolate in EtOH (0.37 mL; 0.56 mmol) was added under argon to a solution of (rac)-ethyl[(3-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]-amino}benzyl)(methyl)oxido-λ6-sulfanylidene]carbamate (53 mg; 0.11 mmol) in EtOH (1.0 mL). The batch was stirred at 60° C. for 5 hours. After cooling the batch was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (3×). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by chromatography (DCM/EtOH 95:5) to give the desired product (33 mg; 0.08 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[S:17])[C:14]3=[C:18]([CH3:22])[N:19]=[C:20]([CH3:21])[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+].Br.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=1.ClCCl>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([S:17][CH2:35][C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)[C:14]3=[C:18]([CH3:22])[N:19]=[C:20]([CH3:21])[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nn3c(C)nc(C)c3c(=S)[nH]2)cc1OC
Reactant: BrCc1cccnc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(-c2nc(SCc3cccnc3)c3c(C)nc(C)n3n2)cc1OC
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of Example 27A (50 mg, 0.16 mmol) in 5 ml of DMSO is added to 5 ml of a saturated sodium hydrogencarbonate solution. 80 mg (0.32 mmol) of 3-picolyl bromide hydrobromide are then added and the reaction mixture is stirred at 60° C. overnight. After cooling, the batch is poured onto 50 ml of dichloromethane and washed with water (3×50 ml). The organic phase is dried (sodium sulphate) and the solvent is removed in vacuo. The crude material obtained is purified by flash chromatography (eluent dichloromethane/methanol 20:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.N1C=CC(B(O)O)=CC=1.Br[C:21]1[CH:48]=[CH:47][C:24]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]3([CH2:38][O:37][C:36]4[CH:39]=[C:40]5[C:44](=[CH:45][C:35]3=4)[CH2:43][CH2:42][O:41]5)[C:27]2=[O:46])=[CH:23][CH:22]=1.BrC1OC(CN2C3C(=CC=CC=3)C3(COC4C=C5C(=CC3=4)CCO5)C2=O)=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:21]1[CH:48]=[CH:47][C:24]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]3([CH2:38][O:37][C:36]4[CH:39]=[C:40]5[C:44](=[CH:45][C:35]3=4)[CH2:43][CH2:42][O:41]5)[C:27]2=[O:46])=[CH:23][CH:22]=1
Reactant: O=C1N(Cc2ccc(Br)cc2)c2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: OB(O)c1ccccc1F
Agent: O=C1N(Cc2ccc(Br)o2)c2ccccc2C12COc1cc3c(cc12)CCO3
Agent: OB(O)c1ccncc1
Product: O=C1N(Cc2ccc(-c3ccccc3F)cc2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 11.15 and making non-critical variations using 2-fluorophenylboronic acid to replace pyridin-4-ylboronic acid, and 1′-(4-bromobenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 1′-[(5-bromofuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-[(2′-fluorobiphenyl-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (34%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.72-7.91 (m, 12H), 7.61 (s, 1H), 7.54 (s, 1H), 6.11 (ABq, 2H), 5.97 (ABq, 2H), 5.64 (t, J=8.6 Hz, 2H), 4.20-4.01 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.9, 161.8, 161.3, 158.0, 142.1, 135.3 (2C), 135.2, 132.8, 130.6 (2C), 129.5, 129.4, 129.2, 129.1, 128.7, 128.4, 128.3, 127.5, 124.4 (2C), 123.9, 123.4, 120.2, 119.9, 118.9, 116.3, 116.0, 109.3, 93.2, 80.6, 72.4, 57.7, 43.9, 29.0.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]=1[CH3:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>ClCCl>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:16][CH2:17][CH2:18][CH:19]=[O:20])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]=1[CH3:7]
Reactant: Cc1c(I)cnn1CC1(OCCCO)CCCCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c(I)cnn1CC1(OCCC=O)CCCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of EXAMPLE 155B (393 mg) in dichloromethane (20 mL) was added Dess-Martin Periodinane (425 mg). After the reaction mixture was stirred for 4 hours at room temperature, 2N NaOH aqueous solution (10 mL) was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated NaCl solution. After the organic layer was dried over Na2SO4 and filtered, the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([F:34])=[C:8]2[C:12]([C:13](=[O:33])[C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:25]=[N:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:11][NH:10][C:9]=12)(=O)[CH3:2].Cl.[O:36]([NH2:38])[CH3:37]>CCO>[F:34][C:7]1[CH:6]=[N:5][C:4](/[C:1](=[N:38]/[O:36][CH3:37])/[CH3:2])=[C:9]2[NH:10][CH:11]=[C:12]([C:13](=[O:33])[C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:26]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:25]=[N:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])[C:8]=12
Reactant: CON
Reactant: CC(=O)c1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Agent: Cl
Solvent: CCO
Product: CO/N=C(\C)c1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 25 °C

Procedure:
To a suspension of 1-(7-acetyl-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (0.05 g, 0.11 mmol) in EtOH (10 mL) was added methoxylamine hydrochloride (0.05 g, 0.60 mmol). The mixture was heated to reflux for 1 h, and was then cooled to rt, and concentrated in vacuo. The residue was diluted with MeOH, and the solids that formed were collected and washed with water. The title compound was isolated as a light-yellow solid (0.025g). LCMS: m/e 492.4 (M+H)+, ret time 2.068 min (method 2). 1H NMR (500 MHz, DMSO-D6) δ ppm 12.02 (s, 1 H) 8.36 (d, J=2.14 Hz, 1 H) 8.27 (d, J=3.36 Hz, 1 H) 7.56-7.71 (m, 5 H) 4.13-4.16 (m, 3 H) 3.68-3.73 (m, 2 H) 3.43-3.48 (m, 2 H) 3.29-3.36 (m, 2 H) 3.13-3.18 (m, 2 H) 2.36 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:24])[C:9]2[N:14]=[C:13]3[S:15][C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])=[N:17][C:12]3=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[N:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)=[C:26]=[O:27].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:26](=[O:27])[NH:25][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][CH:29]=2)[CH:3]=1)[C:9]1[N:14]=[C:13]2[S:15][C:16]([NH:18][C:19]([CH:21]3[CH2:22][CH2:23]3)=[O:20])=[N:17][C:12]2=[CH:11][CH:10]=1
Reactant: CN(c1cccc(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1cccc(NC(=O)Nc2ccc(C(F)(F)F)cc2)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a solution of N-{5-[(3-aminophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (100 mg, 0.295 mmol) produced in Example 8(x) in N,N-dimethylformamide (1.0 mL) was added 1-isocyanato-4-(trifluoromethyl)benzene (50.5 μL, 0.354 mmol), and the mixture was stirred at room temperature for 1 hr. Aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitate was collected by filtration and recrystallized from hexane/tetrahydrofuran to give the title compound (98 mg, 63%) as a colorless powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[F:26])[C:9](=[O:27])[C:8]=2[C:7](O)=[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=12)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S([O:44][CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.O>CN(C=O)C>[CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[F:26])[C:9](=[O:27])[C:8]=2[C:7]([O:44][CH2:45][C:46]([F:47])([F:48])[F:49])=[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=12)[CH3:2]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3O)C2=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.2 %

Procedure:
To a solution ethyl {4-[4-(ethyloxy)-9-hydroxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-fluorophenyl}acetate (0.2 g, 0.458 mmol) in DMF (3 ml), was added sodium carbonate (0.097 g, 0.915 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.159 g, 0.687 mmol). This was stirred at room temperature for 24 hours. Water was added to the reaction mixture with rapid stirring. The resulting yellow coloured solid was collected by filtration, washed with water and dried in the vacuum oven to give the title compound (0.119 g, 0.23 mmol). LC/MS: Rt=3.82, [MH]+ 520.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([N:14]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[O:13])[S:9][CH:10]=1)C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(S(C)(=O)=O)=CC=2)CCCC1.C(OC(=O)CC1N=C(N)SC=1)C>>[CH:26]1([CH2:25][N:14]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:17][CH:16]=2)[C:12](=[O:13])[NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:31])=[O:3])[N:7]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCOC(=O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n1
Agent: CCOC(=O)Cc1csc(N)n1
Agent: CS(=O)(=O)c1ccc(NCC2CCCC2)cc1
Agent: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Product: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)ureido]-thiazol-4-yl}-acetic acid ethyl ester employing the coupling and hydrolysis protocol used for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and (2-amino-thiazol-4-yl)-acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C(B(CC)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Br)c1
Reactant: CCB(CC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2cccnc2)c1
Temperature: 25 °C
Yield: 103 %

Procedure:
3-bromo anisole (17.4 g, 93.03 mmol) was dissolved in 650 mL tetrahydrofuran and 210 mL water in a 2 L round bottom flask equipped with a magnetic stirrer. Diethyl-(3-pyridyl)borane (15.73 g, 106.99 mmol), sodium carbonate (44.4 g, 418.64 mmol) and dichlorobis(triphenylphosphine)palladium (II) (9.8 g, 13.95 mmol) were added and the mixture heated at reflux for 4 h then cooled to ambient temperature. The mixture was diluted with 300 mL water and extracted with diethyl ether (2×300 mL). The extracts were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was purified by flash chromatography (1:1 ethyl acetate/hexanes). Product fractions were concentrated under reduced pressure to yield 17.75 g (99%) of the desired compound as a pale yellow oil.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:7]=[CH:8][S:9][CH:10]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[O:13]=[C:14]1[N:18]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:17][CH2:16][N:15]1[C:23](Cl)=[O:24]>O>[O:13]=[C:14]1[N:18]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:17][CH2:16][N:15]1[C:23]([NH:1][CH:2]([C:6]1[N:7]=[CH:8][S:9][CH:10]=1)[C:3]([OH:5])=[O:4])=[O:24]
Reactant: NC(C(=O)O)c1cscn1
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)N1CCN(C(=O)NC(C(=O)O)c2cscn2)C1=O
Reaction time: 1 h
Yield: 53 %

Procedure:
DL-2-Amino-2-(thiazol-4-yl)acetic acid (214 mg) [prepared by the method described in J. Med. Chem. 16, 978 (1973)] was taken up in water (10 ml) and the pH was adjusted to 6.5 by the addition of 2N sodium hydroxide solution. 2-Oxo-3-methylsulphonylimidazolidin-1-ylcarbonyl chloride (310 mg) was added to the stirred solution at room temperature in portions; the pH being maintained between 6.0 and 7.0 by the addition of 2N sodium hydroxide solution. When the addition was complete, the mixture was stirred for one hour, filtered, and the filtrate was washed with ethyl acetate (2×20 ml), acidified to pH 1.0, and extracted with ethyl acetate (2×20 ml). The combined extracts were washed with saturated sodium chloride solution (20 ml), dried (MgSO4), filtered and evaporated to dryness in vacuo. The residue was triturated with methylene chloride and the solid product was separated by filtration to give the title compound as a white solid, (250 mg).