Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[CH3:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][NH:18][NH2:19])=[CH:15][CH:14]=1.N1C=CC=CC=1>C(O)C.O>[NH2:10][C:6]1[NH:19][N:18]([CH2:17][C:16]2[CH:20]=[CH:21][C:13]([CH3:12])=[CH:14][CH:15]=2)[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: Cc1ccc(CNN)cc1
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1ccc(Cn2[nH]c(N)cc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 13.6 g of 4-methylbenzylhydrazine are introduced into 75 ml of pyridine. The mixture is stirred for 8 hours at room temperature and the pyridine is driven off under reduced pressure. The reisidue is treated with a solution of 4.6 g of Na in 100 ml of ethanol and the mixture is warmed to 60° for 1 hour. The alcohol is driven off and the residue is taken up in 100 ml of water. The aqueous phase is extracted with ether, clarified with charcoal and acidified. A yellow-colored precipitate is obtained, which melts at 149° after recrystallisation from alcohol. The yield is 7.3 g of the compound identified above, corresponding to 36% of theory.
Reaction SMILES: [C:1]([O:4][CH:5]([CH:20]([CH3:22])[CH3:21])[C:6]([CH3:19])([CH3:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[C:16]#[N:17])(=[O:3])[CH3:2].[S:23](Cl)(=[O:26])(=[O:25])[NH2:24]>>[C:1]([O:4][CH:5]([CH:20]([CH3:22])[CH3:21])[C:6]([CH3:19])([CH3:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:23](=[O:26])(=[O:25])[NH2:24])[C:10]=1[C:16]#[N:17])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C(C)C)C(C)(C)COc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Product: CC(=O)OC(C(C)C)C(C)(C)COc1cccc(NS(N)(=O)=O)c1C#N
Yield: 90 %

Procedure:
Prepared as in Example 215a from 1-(3-amino-2-cyanophenoxy)-2,2,4-trimethylpentan-3-yl acetate (Example 243b) and sulfamoyl chloride in 90% yield. MS 384 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]=[C:11]=[S:12])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[C:29]=1[CH3:36].C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[S:12])=[C:30]([CH3:35])[C:29]=1[CH3:36]
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (60 mg, yield 78%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Mg]Br)=[CH:18][CH:17]=1.C1COCC1>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.Cl>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[CH:3]=2)[CH:8]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a mixture of 2-bromo-6-methoxynaphthalene (23.79 g, 100.3 mmol) and tetrakis(triphenylphosphine)palladium (5.8 g, 5 mmol) was added a solution of 4-methoxyphenylmagnesium bromide in THF (400 mL of 0.5 N solution, 200 mmol). The stirred solution was heated to reflux for 3 hr, cooled to RT, and stirred into 200 mL of 1N HCl. The mixture was extracted with dichloromethane and filtered through a short silica plug with dichloromethane. The solvent was removed to yield a crude yellow solid which was further purified by silica chromatography (20–50% ethyl acetate-hexanes) to yield 25.68 g (97%) of the title compound as a white solid: mp 190° C.; 1H NMR (CDCl3): δ 3.86 (3H, s), 3.93 (3H, s), 7.01 (2H, d, J=8.57 Hz), 7.14–7.18 (2H, m), 7.63 (2H, d, J=8.50 Hz), 7.67 (1H, dd, J=1.68 Hz, J=8.73 Hz), 7.76–7.80 (2H, m), 7.91 (1H, d, J=0.94 Hz); MS (ESI) m/z 265 (M+H)+.
Reaction SMILES: FC1C=CC(C2C=CC3C(=CC=C(OC)C=3)C=2)=C(N)C=1.BrC1C=CC(OCCN2CCCCC2)=C(F)C=1.[F:38][C:39]1[CH:40]=[CH:41][C:42]([C:62]2[CH:71]=[CH:70][C:69]3[C:64](=[CH:65][CH:66]=[C:67]([O:72]C)[CH:68]=3)[CH:63]=2)=[C:43]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][N:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)=[C:48]([F:61])[CH:47]=2)[CH:44]=1>>[F:38][C:39]1[CH:40]=[CH:41][C:42]([C:62]2[CH:63]=[C:64]3[C:69](=[CH:70][CH:71]=2)[CH:68]=[C:67]([OH:72])[CH:66]=[CH:65]3)=[C:43]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][N:55]3[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]3)=[C:48]([F:61])[CH:47]=2)[CH:44]=1
Reactant: COc1ccc2cc(-c3ccc(F)cc3Nc3ccc(OCCN4CCCCC4)c(F)c3)ccc2c1
Agent: COc1ccc2cc(-c3ccc(F)cc3N)ccc2c1
Agent: Fc1cc(Br)ccc1OCCN1CCCCC1
Product: Oc1ccc2cc(-c3ccc(F)cc3Nc3ccc(OCCN4CCCCC4)c(F)c3)ccc2c1
Yield: 96.6 %

Procedure:
Synthesized from 5-fluoro-2-(6-methoxynaphthalen-2-yl)phenylamine and 1-[2-(4-bromo-2-fluorophenoxy)ethyl]piperidine according to an analogous synthetic method to Example 116, [5-fluoro-2-(6-methoxynaphthalen-2-yl)phenyl][3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl]amine (406 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (381 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:20][S:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[C:3]([CH2:20][S:21][C:22]2[NH:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: Cc1c(SCCCNCc2ccccc2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CCCSc1ccnc(CSc2nc3ccccc3[nH]2)c1C)Cc1ccccc1
Reaction time: 1 h

Procedure:
2-((3-Methyl-4-(3-benzylaminopropylthio)-2-pyridyl)methylthio)-1H-benzimidazole (2.0 g) was dissolved in dimethylformamide (25 ml) and thereto were added ethyl bromoacetate (0.834 g) and potassium carbonate (0.984 g). The mixture was stirred at 40°-50° C. for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure. The residue was subjected to column chromatography and eluted with chloroform-methanol to give 2-((3-methyl-4-(3-(N-benzyl-N-ethoxycarbonylmethylamino)propylthio)-2-pyridyl)methylthio)-1H-benzimidazole.
Reaction SMILES: C([O:4][C:5]1[N:6]=[C:7]([C:27]([O:29]CC)=[O:28])[C:8]2[CH2:9][CH2:10][N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[C:12](=[O:17])[C:13]=2[C:14]=1[O:15][CH3:16])(=O)C.O.[OH-].[Li+].O.Cl>C(O)C>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[F:25])[CH2:18][N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[C:14]([O:15][CH3:16])[C:5](=[O:4])[NH:6][C:7]=2[C:27]([OH:29])=[O:28])[C:12]1=[O:17]
Reactant: CCOC(=O)c1nc(OC(C)=O)c(OC)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1c2c(c(C(=O)O)[nH]c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O

Procedure:
A mixture of ethyl 3-(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (217 g, 0.48 mol), lithium hydroxide monohydrate (70.7 g, 1.67 mol), and water (320 mL) in ethanol (1.8 L) was sonicated for 20 minutes. The reaction mixture was cooled in an ice-water bath and treated with hydrochloric acid (425 mL, 3 M). The resultant light yellow solid was filtered, washed successively with water (1 L), a 3:2 v/v mixture of water and ethanol (500 mL), MTBE (750 mL), and air dried. The yellow solid was dissolved in anhydrous DMF (700 mL) and concentrated under vacuum. The procedure was repeated twice to remove residual water. The yellow solid was triturated with MTBE, filtered, and stored under vacuum overnight to afford the title acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:8][CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: NCCCN
Reactant: Brc1ccccn1
Product: NCCCNc1ccccn1
Yield: 44.9 %

Procedure:
2-Bromopyridine (100 g; 0.633 mol) and 1,3-diaminopropane (234.5 g; 3.16 mol) were refluxed for 7 h. After the reaction was complete, the mixture was evaporated, and distillation of the remaining residue under oil pump vacuum afforded 43 g of the required product; ESI-MS [M+H+]=152.15.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[N:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.C(Cl)Cl.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:20]=[N:21][CH:22]=[C:17]([F:16])[CH:18]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: OB(O)c1cncc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1c(-c2cncc(F)c2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Prepared according to procedure F by stirring 2,4-dichloro-5,7-difluoro-3-methylquinoline (1 g, 4.03 mmol), 5-fluoropyridine-3-boronic acid (0.568 g, 4.03 mmol), PdCl2(PPh3)2 (0.283 g, 0.403 mmol), sodium carbonate (0.505 mL, 12.09 mmol), 1,4-dioxane (5 mL), and water (1.25 mL) at 95° C. for 3 h. Trituration of the crude product with DCM afforded 4-chloro-5,7-difluoro-2-(5-fluoropyridin-3-yl)-3-methylquinoline. Mass Spectrum (ESI) m/e=309.0 (M+1).
Reaction SMILES: [2H][C:2]1[C:7]([2H])=[C:6]([NH2:9])[C:5]([NH2:10])=[C:4]([2H])[C:3]=1[2H].C(O)(=O)C(O)=O.[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O>C(O)C.O>[Br:19][C:20]1[CH:21]=[C:22]([C:23]2[NH:10][C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=3[N:9]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: [2H]c1c([2H])c([2H])c(N)c(N)c1[2H]
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CCO
Product: Brc1cccc(-c2nc3ccccc3[nH]2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
Method 1—Step a O-phenylenediamine (81.8 g, 756.6 mmol) and oxalic acid (3.40 g, 37.8 mmol) were completely dissolved in EtOH—H2O/1:1 (2 L) previously warmed at 80° C. 3-Bromobenzaldehyde (44.10 mL, 378.30 mmol) was then added dropwise to the solution. The reaction mixture was stirred overnight at 70° C. to the open air. The day after solid was filtered off and triturated with MeOH (150 mL) to give the product as a pale yellow solid (27.50 g). 3.8 g were recovered from the mother liquors. Total yield 31.30 g (30%).
Reaction SMILES: [CH3:1][N:2]([CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:6]=2[N:7]=1>C(O)(=O)C.[Fe]>[NH3:2].[CH3:1][N:2]([CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCCC(N(C)c2nc3cc([N+](=O)[O-])ccc3o2)C1
Agent: [Fe]
Solvent: CC(=O)O
Product: CN1CCCC(N(C)c2nc3cc(N)ccc3o2)C1
Product: N
Temperature: 25 °C
Yield: 195.9 %
Yield: 10 %

Procedure:
Place methyl-(1-methyl-piperidin-3-yl)-(5-nitro-benzooxazol-2-yl)-amine (440 mg, 1.51 mmol) and iron powder (423 mg, 7.58 mmol) in acetic acid (10 mL). Heat the reaction to 40° C. for 2 h. Cool to rt and then load onto a Varian™ SCX column. Wash the column with methanol and DCM. Flush the compound off the column by eluting with 2M NH3 in methanol. Collect filtrate and concentrate in vacuo. Chromatograph (silica gel, eluting with 0-10% 2M NH3 in MeOH:DCM, then 10% 2M NH3 in MeOH:DCM) to yield 385 mg (98%) of the title compound: mass spectrum (ion-spray): (m/z)=261.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH3:11])[C:5]([N+:8]([O-])=O)=[CH:6][CH:7]=1.C1CCCCC=1>[Pd].C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Cc1c([N+](=O)[O-])ccc(Cl)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Cc1c(N)ccc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 3-chloro-2,6-dinitrotoluene (2.46 g, 9.5 mmol), cyclohexene (10 mL) and 10% palladium on charcoal (0.6 g) in ethanol (50 mL) was heated at reflux under an atmosphere of nitrogen for 2 h. After this time the reaction mixture was cooled to room temperature, filtered through celite and then evaporated under reduced pressure. The residue was dissolved in diethyl ether and filtered through a short silica column. Evaporation of the ether afforded the product as an orange solid. 1H NMR (400 MHz) (CDCl3) δ 7.15 (d, J=8.7 Hz, 1H); 6.72 (d, J=8.7 Hz, 1H); 3.80 (bs, 2H); 2.11 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][CH2:2][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(CN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.3 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aminomethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (15 mg, 0.025 mmol) in DCM (4 mL) was added TFA (0.4 ml, 5.19 mmol) and the mixture was stirred at room temperature. The color of the solution turned pinkish. After 6 h, the solvent was removed in vacuo and the crude was purified by reverse phase prep. HPLC to afford the title compound as a white foam (12 mg, 80%). LCMS: m/e 544.49 (MH+), 2.60 min (method 3). 1H NMR (500 MHz, MeOD) δ ppm 7.94 (2H, d, J=8.5 Hz), 7.24 (2H, d, J=8.5 Hz), 5.32 (1H, dd, J=6.3, 1.7 Hz), 4.77 (1H, d, J=1.8 Hz), 4.66 (1H, s), 3.10-3.24 (1H, m), 2.73-2.84 (1H, m), 2.50 (1H, td, J=10.6, 5.6 Hz), 2.17 (1H, dd, J=17.1, 6.4 Hz), 1.98-2.11 (1H, m), 1.67-1.89 (8H, m), 1.54-1.66 (3H, m), 1.44-1.56 (5H, m), 1.33-1.45 (2H, m), 1.27-1.34 (3H, m), 1.23-1.28 (1H, m), 1.15-1.24 (4H, m), 1.11 (3H, s), 1.06 (3H, s), 0.92-1.02 (6H, m).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[C:13]([O:24][CH3:25])=[CH:14][C:15]([O:22][CH3:23])=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18]>O1CCCC1>[CH3:23][O:22][C:15]1[CH:14]=[C:13]([O:24][CH3:25])[C:12]([NH:11][CH:1]=[O:3])=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc(N)c(OC)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC=O)c(OC)cc1OC
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A 1.96 g portion of acetic anhydride was mixed with 0.89 ml of formic acid, followed by stirring at 50° C. for 2 hours. The resulting solution was mixed with 1.5 g of methyl 5-amino-2,4-dimethoxybenzoate dissolved in advance in 3 ml of tetrahydrofuran, followed by 6 hours stirring. After completion of the reaction, the thus precipitated product of interest was collected by filtration, washed with diethyl ether and then dried under a reduced pressure to give 1.62 g of methyl 2,4-dimethoxy-5-formylaminobenzoate.
Reaction SMILES: [O:1]([CH2:9][C@H:10]([OH:12])[CH3:11])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][C:34](=[O:50])[C:35]1[CH:40]=[C:39](O)[CH:38]=[C:37]([S:42][C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[CH:36]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OC(=O)C)C.O>[CH3:32][O:33][C:34](=[O:50])[C:35]1[CH:40]=[C:39]([O:12][C@@H:10]([CH3:11])[CH2:9][O:1][Si:2]([C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:4])[CH3:3])[CH:38]=[C:37]([S:42][C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[CH:36]=1
Reactant: COC(=O)c1cc(O)cc(Sc2ccc(C)cc2)c1
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(Sc2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
After adding 1.40 g (7.40 mmol) of (2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and 2.00 g (7.40 mmol) of triphenylphosphine to a solution of 1.20 g (4.13 mmol) of the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl ester obtained in Production Example 1 in tetrahydrofuran (10 ml), 3.20 ml (7.40 mmol) of diethyl azodicarboxylate was added while cooling on ice, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, extraction was performed with acetic acid ethyl ester, and then the organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=95:5) to obtain 1.63 g of 5-((1S)-2-(t-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(4-methylthiophenoxy)-benzoic acid methyl ester (yield: 95%) as a colorless oil. After adding 2.06 g (12.0 mmol) of m-chloroperbenzoic acid to a solution of 1.84 g (3.97 mmol) of the obtained ester compound in chloroform (40 ml) while cooling on ice, the reaction mixture was stirred for 0.5 hour while cooling on ice. Aqueous sodium thiosulfate was added to the reaction mixture, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine, dried, and concentrated under reduced pressure to obtain a crude sulfone compound.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:6]=[C:7]([N:11]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:12]([C:14]2[O:15][C:16]3[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]=2O)=[NH:13])[CH:8]=[CH:9][CH:10]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[C:7]([N:11]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:12]([C:14]2[O:15][C:16]3[C:23]([NH:24][C:32](=[O:34])[CH3:33])=[CH:22][CH:21]=[CH:20][C:17]=3[CH:18]=2)=[NH:13])[CH:8]=[CH:9][CH:10]=1
Reactant: N=C(c1oc2c(N)cccc2c1O)N(OC1CCCCO1)c1cccc(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cccc2cc(C(=N)N(OC3CCCCO3)c3cccc(Cl)c3)oc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a dichloromethane solution of 42 mg of N-(3-chloro-phenyl)-hydroxy-7-amino-N-(tetrahydro-pyran-2-yloxy)-benzofuran-2-carboxamidine was 200 μl of pyridine and 200 μl of acetic anhydride. The resulted solution was stirred at room temperature for 20 min. The reaction mixture was concentrated under vacuum. The crude product was purified by flash chromatography on silica gel eluted with 5–10% methanol/dichloromethane to give 43 mg of N-{2-[N-(3-chloro-phenyl)-N-(tetrahydro-pyran-2-yloxy)-carbamimidoyl]-benzofuran-7-yl}-acetamide in 99% yield.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:61][CH3:62])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([F:60])=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][C@@H:50]7[CH2:52][C@H:47]6[CH2:48][N:49]7C(OC(C)(C)C)=O)[CH:40]=5)[CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl.CCOC(C)=O>[C@H:47]12[CH2:52][C@H:50]([NH:49][CH2:48]1)[CH2:51][N:46]2[CH2:45][C:41]1[CH:40]=[C:39]([C:37]2[C:36]([F:60])=[CH:35][CH:34]=[C:33]([CH2:32][NH:31][C:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:21]([NH:20][CH2:19][C:10]4[C:11]([NH:12][CH:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)=[C:6]5[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]5=[N:8][C:9]=4[CH2:61][CH3:62])=[O:22])[CH:24]=3)=[O:30])[CH:38]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4C[C@@H]5C[C@H]4CN5C(=O)OC(C)(C)C)c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4C[C@@H]5C[C@H]4CN5)c3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl (1S,4S)-5-[(5′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}-carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.0488 g, 0.058 mmol) was dissolved in CH2Cl2 (9 mL) and treated with trifluoroacetic acid (1 mL) at 0° C. and then allowed to warm to room temperature. This mixture was stirred for a total of 2 h. The solvents were pumped off, and the material was passed though 2 quaternary ammonium hydroxide cartridges, but 19F NMR still indicated residual TFA. The product was taken up in EtOAc and washed 3× with 0.5 N NaOH, 1× with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound as a tan solid. LC-MS m/z 746 (M+H)+, 1.30 min (ret time); mp 129-133° C. Analytical HPLC shows 96.8% purity, (ret time 9.820 min).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.CCOC(C)=O>[C:21]([C:18]1[N:19]=[CH:20][C:15]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:16][CH:17]=1)#[N:22]
Reactant: N#Cc1ccc(Br)cn1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(C#N)nc2)cc1
Temperature: 80 °C
Yield: 76.8 %

Procedure:
4-Methoxycarbonylphenyl boronic acid (0.5 g) and 5-bromo-2-pyridinecarbonitrile (0.5 g) in a mixture of THF (5 ml) and water (5 ml) were treated with tetrakis(triphenyl phosphine)palladium(0) (0.32 g) and potassium carbonate (1 g). A further amount of THF (5 ml) was added and the reaction was heated at 80° C. for 1 h. After cooling the reaction mixture was diluted with EtOAc (30 ml) and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried (magnesium sulfate) and concentrated to give a crude residue that was purified by column chromatography (silica-gel, gradient 0-100% EtOAc in hexane) to give the title compound (D8) as a white solid (0.5 g). LCMS electrospray (+ve) 239 (MH+).