Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12].Cl.[CH3:17][NH:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N:18]([CH3:19])[CH3:17])[CH:7]=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12]
Reactant: COC(=O)c1cc(F)ccc1C(F)(F)F
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(N(C)C)ccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a stirred solution of 4.48 g (22.5 mmol) 5-Fluoro-2-trifluoromethyl-benzoic acid methyl ester (Rarechem) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 8 h at 60° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 15a was obtained in 72% yield (4.00 g, 16.2 mmol).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Br:24][C:25]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:26]=1[CH2:27]Br>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:27][C:26]3[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:25]=3[Br:24])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Fc1ccc(Br)c(CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (2.0 g, 6.39 mmol) in THF (40 mL) at 0° C. was added NaH (285 mg, 60 w/w % in mineral oil, 7.13 mmol, 1.1 eq.) in one portion. The resulting foaming mixture was stirred in an ice bath. Additional THF (50 mL) was added into the reaction. The mixture was stirred at 0° C. for 30 min. A solution of 2-bromo-5-fluorobenzyl bromide (1.712 g, 6.39 mmol) in THF (20 mL) was added. The resulting mixture was stirred cold for 30 min and then allowed to warm to room temperature. The reaction was completed in 3 hours. The reaction was quenched with NH4Cl (aq., sat.,80 mL). Volatiles were removed in vacuo. The crude mixture was extracted with EtOAc and dried over Na2SO4. The residue was purified by flash chromatography on SiO2 (Biotage 40+M cartridge, EtOAc/hexane, gradient). (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one was obtained as a clear oil. LC-MS: 500.09 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 1H), 7.79 (s, 2H), 7.55 (dd, J=8.8, 5.2 Hz, 1H), 7.17 (dd, J=8.7, 4.5 Hz, 1H), 6.95 (m, 1H), 5.74 (d, J=8.0 Hz, 1H), 4.83 (d, J=15.8, 1H), 4.54 (d, J=16.0 Hz, 1H), 4.11 (m, 1H), 0.80 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)[C:12]=1[C:10]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]1[CH2:2][NH:1][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1)=[O:11]
Reactant: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-c2ncccn2)[C@@H]1CN
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-c2ncccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 474 [M+1]+. 1H NMR (500 MHz, DMSO-d6) δ 8.90-6.50 (m, 10H), 4.95-2.70 (m, 5H), 2.00-0.65 (m, 8H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([O:7][CH:8]([CH3:10])[CH3:9])[NH:3]1.[Li+].CCC[CH2-].[CH:16]([S:24](Cl)(=[O:26])=[O:25])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.CCCCCC>[CH:16]([S:24]([N:3]1[CH:4]([O:7][CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][C:2]1=[O:1])(=[O:26])=[O:25])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: CC(C)OC1CCC(=O)N1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)OC1CCC(=O)N1S(=O)(=O)C=Cc1ccccc1
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
To a solution of 3.53 g of 2-oxo-5-isopropyloxy pyrrolidine in 85 cm3 of anhydrous tetrahydrofuran, cooled to -10° C., 15.42 g of a 1.6M solution of N-butyllithium in hexane is added, operating at -10° to -5° C. This is agitated for 30 minutes, while cooling to -45° C., then a solution of 5 g of styrenesulphonyl chloride (CA 47, 3262c, 1953) in 35 cm3 of anhydrous tetrahydrofuran is added slowly, while operating at -45° to -40° C. After allowing a return to ambient temperature, the solvent is evaporated off under reduced pressure and the residue is chromatographed on silica, eluting with a mixture of ethyl ethyl acetate and hexane (1--1). The product obtained is crystallized from ethanol, and 3.1 g of the expected product is obtained. m.p. 92°-94° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21](=[NH:24])OC)[CH:16]=2)[NH:11][N:10]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(CC)CC)C>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([C:21](=[NH:24])[N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:25]=[CH:26][CH:27]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: COC(=N)c1cccc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)c1
Reactant: C1COCCN1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=N)N4CCOCC4)c3)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 10 %

Procedure:
A solution of methyl 3-(3-(2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzimidate from Step in MeOH (1.0 mL) was added morpholine (15.3 mg, 0.176 mmol) and triethylamine (90 mg, 0.88 mmol), the mixture was stirred at room temperature for 3 days. The solvent was then removed and the crude product purified by reverse phase HPLC to afford C-{3-[3-(2-Methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-C-morpholin-4-yl-methyleneamine (3.7 mg, 10% yield two steps) as a white solid. 1H-NMR (500 MHz, CD3OD) δ 8.86 (d, 2 Hz, 1H), 8.45 (d, 2 Hz, 1H), 8.37 (br s, 1H), 8.02 (m, 1H), 7.96 (t, 1.8 Hz, 1H), 7.76 (t, 7.8 Hz, 1H), 7.66 (dd, 1.8 Hz, 7.8 Hz, 1H), 7.63 (m, 1H), 7.49 (m, 1H), 7.21 (d, 8 Hz, 1H), 7.12 (dt, 1 Hz, 7.8 Hz, 1H), 3.95 (m, 2H), 3.88 (s, 3H), 3.82 (m, 2H) 3.78 (m, 2H), 3.59 (m, 2H). MS: m/z 414.1 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[N:19]1[CH2:23][C:22](=[O:24])[NH:21][S:20]1(=[O:26])=[O:25])[CH:15]=[C:14]([C:27]1[CH:28]=[C:29]([CH2:33][C:34]([OH:36])=[O:35])[CH:30]=[CH:31][CH:32]=1)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37](O)([C:39](F)(F)F)=O>CCO>[CH2:37]([O:35][C:34](=[O:36])[CH2:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:14]2[CH:13]=[CH:12][C:11]3[C:16](=[CH:17][C:18]([N:19]4[CH2:23][C:22](=[O:24])[NH:21][S:20]4(=[O:26])=[O:25])=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH:15]=2)[CH:28]=1)[CH3:39]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)Cc1cccc(-c2ccc3cc(OCc4ccccc4)c(N4CC(=O)NS4(=O)=O)cc3c2)c1
Solvent: CCO
Product: CCOC(=O)Cc1cccc(-c2ccc3cc(OCc4ccccc4)c(N4CC(=O)NS4(=O)=O)cc3c2)c1
Temperature: 40 °C

Procedure:
To a solution of {3-[6-benzyloxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-naphthalen-2-yl]-phenyl}-acetic acid (600 mg, 1.2 mmol) in EtOH (50 mL) is added TFA (25 mL) and the mixture is heated at 40° C. for 2 h. EtOH and TFA are removed via vacuum and the residue is purified by HPLC to give the title compound.
Reaction SMILES: Br[C:2]1[N:3]([CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[C:8]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[CH3:20])[CH:7]=[CH:6][CH:5]=2.[CH3:28]B(O)O.C(=O)([O-])[O-].[K+].[K+].O>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>[CH3:20][C:14]1[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=1[C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10](=[O:12])[C:11]([CH3:28])=[CH:2][N:3]2[CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24]
Reactant: CB(O)O
Reactant: CCCC(CCC)n1c(Br)cc(=O)c2c(-c3ccc(C)cc3C)cccc21
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: O
Solvent: C1COCCO1
Product: CCCC(CCC)n1cc(C)c(=O)c2c(-c3ccc(C)cc3C)cccc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
3 Bromo-5-(2,4-dimethylphenyl)-1-(1-propylbutyl)quinolin-4(1H)-one was then charged with methylboronic acid (0.19 g, 3.2 mmol), potassium carbonate (0.22 g, 1.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.16 mmol) and diluted with dioxane (8 mL) under nitrogen gas. Water (29 μL, 1.6 mmol) was added last. The reaction was stirred at 90° C. overnight. The solution was cooled and concentrated. Flash chromatography (40% ethyl acetate/hexanes) gave 0.049 g (43% yield) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1([CH2:18][CH2:19][OH:20])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[O:9][C:8]2[C:3]1=[CH:4][C:5]([I:17])=[CH:6][CH:7]=2.[N+:21]([C:24]1[CH:34]=[CH:33][C:27]([C:28]([N:30]=[C:31]=[S:32])=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C1COCC1>[Br:16][C:13]1[CH:14]=[C:15]2[C:2]([NH:1][C:31]([NH:30][C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:34][CH:33]=3)=[S:32])([CH2:18][CH2:19][OH:20])[C:3]3[C:8](=[CH:7][CH:6]=[C:5]([I:17])[CH:4]=3)[O:9][C:10]2=[N:11][CH:12]=1
Reactant: NC1(CCO)c2cc(I)ccc2Oc2ncc(Br)cc21
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(NC(=S)NC1(CCO)c2cc(I)ccc2Oc2ncc(Br)cc21)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-(5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)ethanol (0.930 g, 2.080 mmol) in THF (20.80 ml) was added cooled to 0° C. and solid 4-nitrobenzoyl isothiocyanate (0.442 g, 2.122 mmol) was added. The reaction mixture was stirred at 0° C. for 20 min. The reaction mixture was concentrated under reduced pressure to yield N-((3-bromo-5-(2-hydroxyethyl)-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)carbamothioyl)-4-nitrobenzamide as a yellow solid.
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])=[O:21])[CH3:19])(CC1C=CC=CC=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:37][C@H:38]([C:46]([OH:48])=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:45])[NH2:44].[H][H]>CO.O.[C].[Pd]>[NH2:37][C@H:38]([C:46]([OH:48])=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45].[NH2:37][C@H:38]([C:46]([OH:48])=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45].[CH2:1]([P:8](=[N:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])=[O:21])[CH3:19])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: O
Solvent: CO
Product: C[C@H](N=[P+]([O-])Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Yield: 103.6 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-prolyl-L-proline (1 g, 1.84 mmole) and L-arginine (0.64 g, 3.67 mmol) were dissolved in a mixture (20 ml) of methanol and water (1:1, v/v) and 5% palladium carbon (0.1 g) was added thereto. Hydrogen gas (41.2 ml, 1.84 mmol) was adsorbed by the solution while stirring. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. Water was added thereto and the water solution was freeze-dried to obtain monobenzylphosphoryl-L-alanyl-L-prolyl-L-proline di-L-arginine salt (1.46 g, quantitative yield).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:4].[C:27](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:15]([S:16]([CH3:19])(=[O:18])=[O:17])[CH3:27])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(I)cc12
Temperature: 60 °C
Yield: 100 %

Procedure:
To 2-(4-Fluoro-phenyl)-5-iodo-6-methanesulfonylamino-furo[2,3-b]pyridine-3-carboxylic acid methylamide (9 mg, 0.018 mmol) and potassium carbonate (25.4 mg, 0.184 mmol) in acetone (0.1 ml) is added iodomethane (0.115 ml, 1.840 mmol). After heating at 60° C. for 1 day, the reaction mixture is filtered and concentrated to dryness to afford 2-(4-Fluoro-phenyl)-5-iodo-6-(methanesulfonyl-methyl-amino)-furo[2,3-b]pyridine-3-carboxylic acid methylamide (9.3 mg, 0.018 mmol, 100% yield). MS (ESI) m/z 503.9 (M+1). 1H NMR (400 MHz, CD3CN) δ ppm 8.60 (s, 1H), 7.95 (m, 2H), 7.23-7.18 (m, 2H), 6.79 (br s, 1H), 3.14 (s, 3H), 2.80-2.79 (d, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=[O:15])=[C:6]1[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:32]=[N:33][N:34](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:35]=2)=[CH:21][CH:20]=1)O)[CH2:2][CH2:3][CH3:4]>[Pd].C(O)(=O)C.C1COCC1>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=[O:15])=[C:6]1[CH2:17][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:32]=[N:33][NH:34][N:35]=2)=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(C(O)c2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C(=O)O)c2ccccc21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCn1c(Cc2ccc(-c3ccccc3-c3nn[nH]n3)cc2)c(C(=O)O)c2ccccc21
Yield: 75.6 %

Procedure:
A mixture of 1-butyl-2-{2'-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-biphenyl-4-yl(hydroxy)methyl}-1H-indole-3-carboxylic acid (2.5 g, 3.52 mmol) and 10% palladium on carbon (1.2 g) in 20 mL of acetic acid and 80 mL of THF under a hydrogen atmosphere (200 psi) at 48° C. for approximately 48 hours. The mixture was then cooled, filtered and diluted with 500 mL of water. The mixture was extracted with 100 mL of ethyl acetate and the ethyl acetate layer was washed three times with water. The ethyl acetate layer was concentrated to give 1-butyl-2-[2'-(2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-indole-3-carboxylic acid (1.2 g, 2.66 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[F:11][CH:12]([F:25])[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][CH3:24])[C:15]=2[N:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][CH3:24])[C:15]=3[N:14]=[C:13]2[CH:12]([F:11])[F:25])[CH:7]=1
Reactant: CCOc1cccc2[nH]c(C(F)F)nc12
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cccc2c1nc(C(F)F)n2-c1cc(Cl)nc(SC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A mixture of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (700 mg), 2-(difluoromethyl)-4-ethoxy-1H-benzimidazole (761 mg), potassium carbonate (744 mg), and N,N-dimethylformamide (7 mL) was stirred at room temperature overnight. To the mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0-80:20) to obtain 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-4-ethoxy-1H-benzimidazole (464 mg) (Preparation Example 86-1) and 1,1′-[2-(methylsulfanyl)pyrimidine-4,6-diyl]bis[2-(difluoromethyl)-4-ethoxy-1H-benzimidazole]. 1,1′-[2-(Methylsulfanyl)pyrimidine-4,6-diyl]bis[2-(difluoromethyl)-4-ethoxy-1H-benzimidazole] was suspended in ethyl acetate and warmed. After leaving to be cooled, the insoluble matter was collected by filtration to obtain 1,1′-[2-(methylsulfanyl)pyrimidine-4,6-diyl]bis[2-(difluoromethyl)-4-ethoxy-1H-benzimidazole] (275 mg) (Preparation Example 86-2).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:37]
Reactant: O=C(N[C@@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A142) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:15]([O-:17])=[O:16])[C:6]1=[O:18])[CH3:4].[C:19](OC(=O)C)(=[O:21])[CH3:20].C(N(CC)CC)C.C(Cl)Cl>CNC1(NC)C=CN=CC1>[C:19]([O:1][CH2:2][C@H:3]([N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:15]([O-:17])=[O:16])[C:6]1=[O:18])[CH3:4])(=[O:21])[CH3:20]
Reactant: C[C@H](CO)n1ccc2c([N+](=O)[O-])cccc2c1=O
Reactant: CC(=O)OC(C)=O
Agent: CNC1(NC)C=CN=CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])cccc2c1=O
Yield: 99.1 %

Procedure:
(R)-2-(1-hydroxypropan-2-yl)-5-nitroisoquinolin-1(2H)-one (19 g, 0.073 mol), acetic anhydride (10 g, 0.1 mol), triethylamine (30 g, 0.3 mol), 4,4-dimethylaminopyridine (200 mg, 0.002 mol) and methylene chloride (500 mL, 8 mol) were stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue was purified flash chromatography to afford the title compound as a yellow oil (21 g, 100% yield).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[C:2]=[S:3].[NH2:10][C:11]1[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=1)[O:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].CCN(CC)CC>CN(C1C=CN=CC=1)C.C1COCC1>[CH:4]1([NH:1][C:2](=[S:3])[NH:10][C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[O:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: S=C=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(N)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCOc1cccc(NC(=S)NC2CCCCC2)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A mixture of isothiocyanatocyclohexane (27) (0.16 mL, 1.17 mmol), tert-butyl 2-(3-aminophenoxy)ethylcarbamate (3) (0.282 g, 1.12 mmol), DMAP (0.024 g, 0.196 mmol) and Et3N (0.3 mL, 2.15 mmol) in anhydrous THF was stirred under argon at 50° C. for 24 h. The mixture was concentrated under reduced pressure. Purification by flash chromatography (30% to 60% EtOAc—hexanes gradient) gave tert-butyl 2-(3-(3-cyclohexylthioureido)phenoxy)ethylcarbamate (28) as a white solid. Yield (0.1917 g, 44%); 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 7.59 (br.d, J=7.6 Hz, 1H), 7.15 (t, J=8.2 Hz, 1H), 6.97 (br.t, J=5.5 Hz, 1H), 6.85-6.89 (m, 1H), 6.58-6.63 (m, 1H), 4.06 (br.s, 1H), 3.88 (t, J=5.9 Hz, 2H), 3.25 (q, J=5.7 Hz, 2H), 1.82-1.90 (m, 2H), 1.60-1.70 (m, 2H), 1.47-1.57 (m, 1H), 1.36 (s, 9H), 1.07-1.34 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C:17]#[CH:18])[C:12]([Br:19])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>C(#N)C>[Br:19][C:12]1[C:13]([NH:15][CH2:16][C:17]#[CH:18])=[N:14][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:23]([NH:22][CH2:20][CH3:21])=[O:24])=[CH:3][CH:4]=2)=[N:10][CH:11]=1
Reactant: C#CCNc1nc(Nc2ccc(N)cc2)ncc1Br
Reactant: CCN=C=O
Solvent: CC#N
Product: C#CCNc1nc(Nc2ccc(NC(=O)NCC)cc2)ncc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N2-(4-Amino-phenyl)-5-bromo-N4-prop-2-ynyl-pyrimidine-2,4-diamine (100 mg, 0.3 mmole, prepared in analogy to procedure 21) was dissolved in acetonitrile (10 ml) and ethyl isocyanate (0.5 ml) was added at room temperature. The reaction mixture was heated under reflux for 5 hours and then cooled to room temperature and stirred overnight. The solid was filtered off and dried under high vacuum to provide 47 mg of 1-[4-(5-Bromo-4-prop-2-ynylamino-pyrimidin-2-ylamino)-phenyl]-3-ethyl-urea. ESI-MS: 390.
Reaction SMILES: C(OC(=O)[NH:5][C:6](=S)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:23])[CH:16]=2)=[CH:10][N:9]=1)C.[Cl-].O[NH3+].C([N:39](CC)C(C)C)(C)C.C(O)C>CO>[NH2:39][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22]([C:24]4[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=4)=[O:23])[CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[N:5]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3ncccc3C)c2)cn1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Solvent: CO
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
A mixture of ethyl{[5-(3-{[(3-methylpyridin-2-yl)carbonyl]amino}phenoxy)pyridin-2-yl]carbamothioyl}carbamate (2.00 g, 4.43 mmol), hydroxylammonium chloride (3.13 g, 45.0 mmol), N,N-diisopropylethylamine (4.70 mL, 26.9 mmol), ethanol (50 mL) and methanol (50 mL) was stirred at 80° C. for 5 hr. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (1.35 g, 84%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:32]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([N:41]3[CH2:42][CH2:43][CH:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:39][CH2:40]3)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NS(=O)(=O)c1ccc(F)cc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Product: O=C(O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (S)-3-(4-benzyloxy-phenyl)-2-(4-fluoro-benzenesulfonylamino)-propionic acid was condensed with 4-phenyl-piperidine hydrochloride to give the title compound, mp=75-78° C.