Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)[C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared in accordance with Example 8(c) using 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester and 4-(trifluoromethyl)phenylboronic acid, followed by hydrolysis in accordance with the procedure described in Example 1(c).
Reaction SMILES: C(OC([NH:8][S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:24]=[C:23]([C:25]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[CH:28]=[C:27]([CH3:41])[N:26]=3)[CH:22]=[CH:21][N:20]=2)[CH:14]=1)(=[O:11])=[O:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:41][C:27]1[N:26]=[C:25]([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([C:15]3[CH:14]=[C:13]([NH:12][S:9]([NH2:8])(=[O:11])=[O:10])[CH:18]=[CH:17][CH:16]=3)[N:24]=2)[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:39])([F:38])[F:40])=[CH:33][CH:32]=2)[CH:28]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(NS(=O)(=O)NC(=O)OC(C)(C)C)c3)n2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(NS(N)(=O)=O)c3)n2)n1
Temperature: 23 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
To N-(tert-butoxycarbonyl)-N′-(3-{4-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidin-2-yl}-phenyl)-sulfamide (example 335) (0.100 g, 0.171 mmol) was added TFA (5 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was evaporated to dryness and partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.065 g, 78%). MS (ISP) 486.3 [(M+H)+].
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1[Cl:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[N:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(O)C>[Cl:12][C:11]1[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:14])[C:2]=1[N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19]1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCO
Product: CCOC(=O)N1CCN(C2=C(Cl)C(=O)c3ccccc3C2=O)CC1
Yield: 45.9 %

Procedure:
A mixture of 11.35 g of 2,3-dichloro-1,4-naphthoquinone, 15.8 g of 1-piperazinecarboxylic acid, ethyl ester and 400 ml of absolute ethanol was heated at reflux for 3 hours and then evaporated to dryness. The residue was taken up in 300 ml of dichloromethane and filtered through silica gel. The filtrate was evaporated and the residue triturated with ether, giving 8.0 g of the desired product as red crystals, mp 120-122°C.
Reaction SMILES: [F:1][C:2]([F:30])([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]2([CH3:29])[CH3:28])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10])=[O:4].O.[OH-].[K+]>CO>[F:1][C:2]([F:30])([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([CH3:26])([CH3:27])[CH2:21][CH2:20][C:19]2([CH3:29])[CH3:28])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10])=[O:4]
Reactant: COC(=O)c1cccc(NC(=O)C(F)(F)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C(F)(F)C(=O)Nc3cccc(C(=O)O)c3)ccc21
Temperature: 70 °C
Yield: 84 %

Procedure:
Methyl 3-(2,2-difluoro-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)acetamido)benzoate 19 (0.50 g, 1.20 mmol) was dissolved in methanol (33.5 mL). Water (3.35 mL) was added via syringe at RT and KOH (0.27 g, 4.81 mmol) was added. The reaction mixture was heated at 70° C. for 2 h. After cooling to RT the mixture was evaporated in vacuo. The crude product was dissolved in water (30 mL) and extracted with ether (2×50 mL). The aqueous layer was acidified by a solution of HCl 1M to about pH=1. The aqueous layer was extracted with ether (2×100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography using as eluent cyclohexane: EtOAc=98:02. 3-(2,2-Difluoro-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)acetamido)benzoic acid 20 was obtained (0.41 g, 84% yield) as an orange solid.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(=O)C.[NH4+]>CN(C=O)C>[CH:1]([O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:13](=[O:14])[C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:25]/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][CH:7]=1)([CH3:3])[CH3:2]
Reactant: BrCC=Cc1ccccc1
Reactant: CC(C)OC(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1ccc(C(C/C=C/c2ccccc2)C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
To a solution of isopropyl-4-[2-(4-fluorophenyl)-2-oxoethyl]benzoate(0.970 g, 3.23 mmol) in DMF (10 ml) at 0° C. was added NaH (0.100 g, 4.16 mmol). After a period of 0.5 h to the reaction mixture was added a solution of cinnamyl bromide (0.630 g, 3.21 mmol) in DMF (10 ml), and the reaction was stirred at room temperature for 1 hour. Saturated ammonium acetate solution (20 ml) was added and the mixture was extracted with ethyl acetate (20 ml). The organic phase was washed with brine and dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography using a gradient from hexane/ethyl acetate 2% to hexanel ethyl acetate 10% giving 0.39 g of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][C:3](=[CH:7][CH2:8][CH2:9][OH:10])[CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:2]1
Reactant: OCCC=C1CCCOC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: OCCCC1CCCOC1
Yield: 91 %

Procedure:
To the solution of compound 3-(dihydro-2H-pyran-3(4H)-ylidene)propan-1-ol (11.2 g, 0.0789 mol) in methanol (200 mL) was added Pd(OH)2/C (1.12 g). The reaction flask was degassed and filled into H2. Stirring was continued until the starting material disappeared. When the reaction was over, the mixture was filtered through celite, and the filter cake was washed with MeOH (2×10 mL). The combined organic layers were dried over Na2SO4, and concentrated in vacuo to give 3-(tetrahydro-2H-pyran-3-yl)propan-1-ol (10.35 g, yield 91%), which was used for the next step without purification. 1H NMR (CD3OD) δ 3.9-3.8 (m, 1H), 3.7-3.6 (m, 2H), 3.5-3.4 (m, 1H), 3.3 (m, 1H), 3.1-2.9 (t, 1H), 2.6-2.4 (m, 1H), 2.3-1.8 (m, 3H), 1.6-1.4 (m, 4H), 1.3-1.0 (m, 2H).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].N1C=CC=CC=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>C(Cl)Cl>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)(=[O:24])=[O:23]
Reactant: OCCNCCO
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
Diethanolamine (8.40 g, 80 mmol, 1.50 equiv) was dissolved in CH2Cl2 (30 mL) and pyridine (5.1 mL, 63.6 mmol, 1.2 equiv). A solution of 4-methoxybenzenesulfonyl chloride (10.9 g, 53 mmol, 1.0 equiv) n CH2Cl2 (30 mL) was added quickly and the resulting mixture was stirred at rt overnight, then poured into H2O and extracted with EtOAc. The organic layers were washed with 1M HCl and brine, dried (MgSO4), filtered, and the filtrate was concentrated to give an oil which was purified by column chromatography (95/5 CH2Cl2/MeOH) to give 12 g (83%) of the sulfonamide as an oil which crystallized on standing: 1H NMR (500 MHz) 7.75 (d, J=8.8, 2H, HAr); 6.99 (d, J=8.8, 2H, HAr); 3.87 (a, 3H, H3CO); 3.86 (t, J=4.9, 4 H, H2C(1′); 3.42 (br s, 2H, OH); 3.26 (t, J=4.9, 4H, H2C(2′)). 13C NMR (100 MHz) 163.05; 129.85; 129.37; 114.37; 62.25; 55.61; 52.90.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.Cl[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:21]1([CH:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:19]/[CH:18]=[CH:17]\[CH2:16][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClC/C=C\CC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(C/C=C\CC(c2ccccc2)c2ccccc2)CC1
Temperature: 60 °C
Yield: 82.3 %

Procedure:
A stirred suspension of 1.16 g (5.78 mmol) of 4-piperidinylcarbamic acid, 1,1-dimethylethyl ester (Example 1 Part B), 1.35 g (5.26 mmol) of (Z)-1-chloro-5,5-diphenyl-2-pentene, and 799 mg (5.78 mmol) of potassium carbonate in 15 mL of N,N-dimethylformamide was heated to 60° C. for eighteen hours, cooled, filtered and concentrated to a dark oil which was chromatographed on silica gel (150 g) eluted with 95:5 methylene chloride/methanol to provide 1.82 g (82%) of title compound, as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]1)=[O:5].Br[CH2:25][CH2:26][O:27][C:28]1[CH:47]=[CH:46][C:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)=[CH:30][CH:29]=1>>[C:37]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:38]=[CH:39][C:34]([CH2:33][O:32][C:31]2[CH:46]=[CH:47][C:28]([O:27][CH2:26][CH2:25][O:1][C:2]3[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][C:3]=3[C:4]([N:6]3[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]3)=[O:5])=[CH:29][CH:30]=2)=[CH:35][CH:36]=1
Reactant: COC(=O)c1ccc(O)c(C(=O)N2CCC(C(=O)OC)CC2)c1
Reactant: BrCCOc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Product: COC(=O)c1ccc(OCCOc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)N2CCC(C(=O)OC)CC2)c1

Procedure:
Preparation takes place in analogy to Example 22 from methyl 1-[2-hydroxy-5-(methoxycarbonyl)benzoyl]piperidine-4-carboxylate and 4-{[4-(2-bromoethoxy)-phenoxy]methyl}biphenyl.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH:21]([OH:23])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[CH3:33][S:34]([O:23][CH:21]([CH3:22])[CH2:20][O:19][C@H:16]1[CH2:17][CH2:18][C@H:13]([C:11]2[O:12][C:8]3[CH:7]=[C:6]([O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH:25]=[CH:24][C:9]=3[N:10]=2)[CH2:14][CH2:15]1)(=[O:36])=[O:35]
Reactant: CC(O)CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-({trans-4-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]cyclohexyl}oxy)propan-2-ol (271 mg) and triethylamine (0.22 mL) in THF (5 mL) was added methanesulfonyl chloride (0.1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (283 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[CH2:8](O)[CH2:9][OH:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:7]1[CH2:8][CH2:9][O:10][CH:6]1[C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: OCCO
Reactant: O=Cc1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: c1cc(C2OCCO2)cs1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a solution of thiophene-3-carboxaldehyde (5.0 g, 44.58 mmole) in benzene (200 mL) was added ethylene glycol (25 mL, 445.8 mmole) and p-toluenesulfonic acid hydrate (848 mg, 4.458 mmole). The mixture was heated to reflux under a Dean-Stark trap. After 18 hr the mixture was cooled to RT, washed with saturated NaHCO3 then with H2O, dried (MgSO4), and concentrated under reduced pressure to give the title compound (6.32 g, 91%) as a light amber oil: 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.32 (m, 1H), 7.16 (m, 1H), 5.91 (s, 1H), 4.12-3.99 (m, 4H).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH2:28][CH2:29][N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH:32]([NH:40][C:41]([C:43]2[NH:44][C:45]3[C:50]([CH:51]=2)=[CH:49][C:48]([Cl:52])=[CH:47][CH:46]=3)=[O:42])[C:31]1=[O:53])(C(C)(C)C)(C)C>C1COCC1>[Cl:52][C:48]1[CH:49]=[C:50]2[C:45](=[CH:46][CH:47]=1)[NH:44][C:43]([C:41]([NH:40][CH:32]1[CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:30]([CH2:29][CH2:28][CH2:27][OH:26])[C:31]1=[O:53])=[O:42])=[CH:51]2
Reactant: CC(C)(C)[Si](C)(C)OCCCN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NC1Cc2ccccc2N(CCCO)C1=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.4 %

Procedure:
A 1 M solution of TBAF in THF (1 mL) was added dropwise to a solution of N-[1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-5-chloro-1H-indole-2-carboxamide (Method 13, 400 mg, 0.78 mmol) in THF (5 mL). The reaction was stirred at ambient temperature for 24 h, partitioned between EtOAc (25 mL) and saturated aqueous NH4Cl solution (20 mL), the layers separated and the organic phase dried (MgSO4). The volatiles were removed under reduced pressure to give an off-white solid which was washed with water, isohexane, diethyl ether and dried under vacuum to give the title compound (234 mg, 75%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]2[N:18]=[C:17]3[S:19][C:20]([NH:22]C(=O)C4C=CC=CC=4)=[N:21][C:16]3=[CH:15][CH:14]=2)=[CH:11][N:10]([CH3:31])[N:9]=1.O.[OH-].[Na+]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]2[N:18]=[C:17]3[S:19][C:20]([NH2:22])=[N:21][C:16]3=[CH:15][CH:14]=2)=[CH:11][N:10]([CH3:31])[N:9]=1
Reactant: Cn1cc(-c2ccc3nc(NC(=O)c4ccccc4)sc3n2)c(-c2ccccc2F)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(-c2ccc3nc(N)sc3n2)c(-c2ccccc2F)n1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
A solution of N-(5-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridine-2-yl)benzamide (0.36 g, 0.838 mmol, 1.0 eq.) in 70% aqueous H2SO4 (4.2 mL) was heated at 105° C. for 2 h. After cooling to room temperature, the reaction mixture was added to water. At 0° C., 30% aqueous NaOH followed by solid NaOH were added until pH ˜13 by litmus paper. The precipitate was washed with water and dried to give 5-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridine-2-amine as a tan solid (0.1493 g, 55% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[S:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29](Cl)=[O:30]>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:29]([C:25]5[S:24][CH:28]=[CH:27][N:26]=5)=[O:30])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(Cl)c1nccs1
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1nccs1
Yield: 64.7 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (155 mg, 0.50 mmol), N-methylpyrrolidone (3 mL) and 1,3-thiazole-2-carbonyl chloride (89 mg, 0.60 mmol), and in the same manner as in Example 162, the title compound (136 mg, yield 65%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([CH3:18])=[N:14][O:15][C:16]=3[CH3:17])[N:7]([CH2:19][CH2:20][CH2:21][CH2:22]O)[C:6]=2[C:5]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[C:13]([CH3:18])=[N:14][O:15][C:16]=4[CH3:17])[CH2:22][CH2:21][CH2:20][CH2:19][N:7]3[C:6]=2[C:5]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)noc3C)n(CCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1c(C)noc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
To a solution of 4-{4-chloro-2-[(3,5-dimethylisoxazol-4-yl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl}butan-1-ol (173 mg, 0.428 mmol) in pyridine (2 mL) was added methanesulfonyl chloride (0.10 mL, 1.28 mmol) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 3 hr. Aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude mesylate was dissolved in 1-methyl-2-pyrrolidinone (2 mL) and potassium carbonate (160 mg, 1.16 mmol) was added. The mixture was stirred at 80° C. for 3 hr. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-40% ethyl acetate/n-hexane gradient mixture followed by recrystallization from ethyl acetate/n-hexane to give the title compound (93 mg, 0.24 mmol, 56%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:34][CH3:35])[C:13]([O:32][CH3:33])=[C:14]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([P:24](=[O:31])([O:28]CC)[O:25][CH2:26][CH3:27])=[CH:20][CH:19]=3)[CH:15]=2)=[CH:4][N:3]=1.[OH-].[Na+:37]>C(O)C>[Na+:37].[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:34][CH3:35])[C:13]([O:32][CH3:33])=[C:14]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]([P:24](=[O:28])([O-:31])[O:25][CH2:26][CH3:27])=[CH:22][CH:23]=3)[CH:15]=2)=[CH:4][N:3]=1
Reactant: CCOP(=O)(OCC)c1ccc(C#Cc2cc(Cc3cnc(N)nc3N)cc(OC)c2OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)([O-])c1ccc(C#Cc2cc(Cc3cnc(N)nc3N)cc(OC)c2OC)cc1
Yield: 50 %

Procedure:
150 mg of diethyl [4-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenylethynyl]-phenyl]-phosphonate (Example 12bo)) are dissolved in 7 ml of ethanol and treated with 2 ml of a 2N sodium hydroxide solution. The solution is held under reflux for 45 min., then cooled and chromatographed on MCl-gel with water/acetonitrile. 74 mg of monoethyl [4-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenylethynyl]-phenyl]-phosphonate sodium salt are isolated. Yield: 50%. Mass spectrum: peaks inter alia at m/e: 491 (M++Na, 10%), 469.2 (M++H, 100%), 419.4 (15%), 413.3 (20%), 391.3 (45%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9](/[CH:13]=[CH:14]/[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:16])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[N:25]1[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27][CH:26]=1>>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([CH2:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[O:16])[C:31]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)=[O:32])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CON=C1CCc2cc(/C=C/C(=O)c3ccc(OC)cc3)ccc21
Reactant: O=Cc1ccncc1
Product: CON=C1CCc2cc(C(CC(=O)c3ccc(OC)cc3)C(=O)c3ccncc3)ccc21
Yield: 86 %

Procedure:
The title compound (8.82 g, 86%) was prepared from the product of Step 1 and pyridine-4-carboxaldehyde fusing the method of Example 1 Step 4; MS(ES+) m/e 429 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[O:6])[CH2:3][CH2:2]1.[C:19]([O:23][C:24](=[O:40])[NH:25]/[C:26](/N1C=CC=N1)=[N:27]/[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl>[C:30]([O:29][C:28]([NH:27]/[C:26](/[NH:18][C:15]1[CH:14]=[CH:13][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@@H:7]2[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:6])=[CH:17][CH:16]=1)=[N:25]/[C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:40])=[O:34])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)n1cccn1
Reactant: Nc1ccc(N2CCC[C@@H]2C(=O)NC2CC2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)Nc1ccc(N2CCC[C@@H]2C(=O)NC2CC2)cc1
Reaction time: 8 h

Procedure:
(R)-1-(4-Amino-phenyl)-pyrrolidine-2-carboxylic acid cyclopropylamide (Method 61; 1.2 g, 4.9 mmol) in DCM (60 ml) was added di-tert-butyl[(Z)-1H-pyrazol-1-ylmethylylidene]biscarbamate (1.9 g, 6.1 mmol) in one portion. The reaction was stirred overnight before removal of the solvent in vacuo. The residue was purified via column chromatography eluting with 20% ethylactetate/isohexane, 50% EtOAc/isohexane and finally 100% EtOAc. The title compound was obtained as a white foam (2.0 g, 81%). NMR (299.954 MHz, CDCl3) 11.63 (s, 1H), 10.09 (s, 1H), 7.60 (s, 1H), 7.40 (d, 2H), 6.45 (m, 3H), 3.92 (t, 1H), 3.59 (t, 1H), 3.19 (q, 1H), 2.69 (m, 1H), 2.29-2.22 (m, 2H), 2.03-1.84 (m, 2H), 1.53 (s, 9H), 1.49 (s, 9H), 0.80-0.68 (m, 2H), 0.44-0.32 (m, 2H); m/z 488.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]O)=[CH:15][CH:14]=1.[Cl:21]C1C=C2C(C=CC(COC3C=CC(CO)=CC=3)=N2)=CC=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][Cl:21])=[CH:15][CH:14]=1
Reactant: OCc1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Reactant: OCc1ccc(OCc2ccc3ccccc3n2)cc1
Product: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 47 %

Procedure:
The procedure from Example 6, part B was used except 4-(quinolin-2-ylmethoxy)benzyl alcohol was substituted for 4-(7-chloroquinolin-2-ylmethoxy)benzyl alcohol. The intermediate was obtained in 47% yield.