Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[F:31][C:32]([F:43])([F:42])[O:33]C1C=C(C=CC=1)C=O>>[F:31][C:32]([F:43])([F:42])[O:33][C:30]1[CH:29]=[C:6]([CH:5]=[CH:4][CH:3]=1)[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Product: O=C(NCCNCc1cccc(OC(F)(F)F)c1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 3-(trifluoromethoxy)benzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 476 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.29 (1H, s) 8.04 (1H, t, J=5.56 Hz) 8.01 (1H, d, J=5.42 Hz) 7.77 (1H, dd, J=5.42, 0.15 Hz) 7.47 (1H, d, J=5.37 Hz) 7.39 (1H, d, J=7.76 Hz) 7.26-7.35 (3H, m) 7.18 (1H, d, J=7.96 Hz) 6.80 (1H, d, J=5.42 Hz) 6.42 (1H, dd, J=3.47, 1.90 Hz) 3.74 (2H, s) 3.35 (2H, q, J=6.35 Hz) 2.63 (2H, t, J=6.49 Hz)
Reaction SMILES: [CH3:1][NH:2]/[C:3](=[N:30]\[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)/[N:4]1[CH2:9][CH2:8][C:7]2[N:10]=[C:11]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22]C(=O)OC(C)(C)C)=[O:14])[S:12][C:6]=2[CH2:5]1.Cl>>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:13]([C:11]1[S:12][C:6]2[CH2:5][N:4]([C:3]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:2][CH3:1])[CH2:9][CH2:8][C:7]=2[N:10]=1)=[O:14]
Reactant: CN/C(=N\c1ccccc1)N1CCc2nc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)sc2C1
Agent: Cl
Product: CN=C(Nc1ccccc1)N1CCc2nc(C(=O)Nc3ccccc3N)sc2C1

Procedure:
tert-butyl {2-[({5-[(E)-(methylamino)(phenylimino)methyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}carbonyl)amino]phenyl}carbamate obtained in step II above was treated with ethereal HCl at room temperature for 5-15 h. Solvent was evaporated and the residue was purified by either column chromatography or preparative HPLC to give N-(2-aminophenyl)-5-[anilino(methylimino)methyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide, which was then converted into its dihydrochloride salt.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH2:6][C@H:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:14])[CH3:13])[CH:3]=[O:4].C(O)(=O)C1C=CC=CC=1>>[CH3:1][C:2](=[CH:5][CH2:6][C@H:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:14])[CH3:13])[CH2:3][OH:4]
Reactant: CC(C=O)=CC[C@H]1CC=C(C)C1(C)C
Agent: O=C(O)c1ccccc1
Product: CC(=CC[C@H]1CC=C(C)C1(C)C)CO
Temperature: 100 °C

Procedure:
(R)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-enal (as a 98/2 E/Z isomers mixture) (384 g, 2 mol.), benzoic acid (2.44 g, 0.02 mol., 1 mol.%) and (ethylenediamine)[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]ruthenium(bispivalate) (37.6 mg, 0.04 mmol, 0.002 mol.%) were loaded altogether in a 1 L autoclave equipped with a mechanical stirring device. Sealed autoclave was then purged under stirring with nitrogen (3 times 5 bars) and hydrogen (3 times 5 bars) before being pressurized to 50 bars hydrogen. It was then heated to 100° C. and hydrogen pressure was maintained to 50 bars during all the reaction to afford desired product with 97.5% selectivity as a 98/2 E/Z isomers mixture and no loss of optical purity. Upon complete reaction conversion (checked by both hydrogen consumption and GC), autoclave was cooled down to 25° C. It was then depressurized and purged with nitrogen (3 times 5 bars). After flash distillation, (R)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol was obtained in 96.5% yield.
Reaction SMILES: N1C(C[OH:8])=CC=CC=1CO.[C:11]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12]>>[C:11]([C:19]1[CH:24]=[C:23]([OH:8])[C:22](=[CH:21][CH:20]=1)[OH:25])([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:12])[CH3:13]
Reactant: OCc1cccc(CO)n1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(O)c1
Yield: 54 %

Procedure:
The procedure of Example 9 was repeated, except 0.2% by weight of pyridine-2,6-dimethanol was used as a catalyst and the reaction was carried out at 50°C. Consequently, the conversion of para-tert.-octyl phenol was 6.2%, 4-tert.-octyl pyrocatechol was formed in a yield of 54% based on the converted octyl phenol and the conversion of perpropionic acid was 97.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Cl)[C:3]=1[C:4]#[N:5].C[S:12](C)=O>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([SH:12])[C:3]=1[C:4]#[N:5]
Reactant: CS(C)=O
Reactant: N#Cc1c(Cl)cccc1Cl
Product: N#Cc1c(S)cccc1Cl

Procedure:
The solution of 2,6-dichloro-benzonitrile (20 mmol) in DMSO (dimethyl sulfoxide, 30 mL) was heated to 70° C., followed by addition of Na2S.9H2O portionwise under stirring. The mixture was stirred for 1 hour. TLC monitored the reaction. After the reaction completed, the mixture was cooled and extracted between water and ethyl acetate. The aqueous layer was acidified by hydrochloric acid to pH=3˜4 under stirring. The formed solids were collected by filtration and dried to give 2.3 g of 2-chloro-6-mercapto-benzonitrile (2A). MS (ESI): M++1=170.6.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.N1C=CC=CC=1>O1CCOCC1>[Br:12][C:5]1[CH:6]=[C:7]([S:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Reactant: C1COCCN1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Nc1ncc(Br)cc1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 2-amino-5-bromo-3-pyridinesulfonyl chloride (0.50 g, 1.84 mmol) in anhydrous dioxane (2 mL) cooled to 5° C. was added (0.16 mL, 1.84 mmol) of morpholine followed by (0.174 mL, 2.15 mmol) of pyridine. The reaction mixture was stirred at room temperature for 2 hrs and then heated at 50° C. for 1 hour. After cooling to room temperature, a white precipitate formed which was collected by suction filtration, washing with water and petroleum ether to give the title compound as an off-white solid. (0.539 g, 91% yield). MS (ES)+ m/e 323.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.[H-].[Na+].I[CH2:24][CH:25]([CH3:27])[CH3:26]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[N:12]=1
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)c(OC)c1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(CC(C)C)c3c(F)cccc23)c(OC)c1
Yield: 51.8 %

Procedure:
Prepared according to Method D step B from 3-(2,4-dimethoxyphenyl)-7-fluoro-1H-indazole (0.300 g, 1.10 mmol), sodium hydride (60% in oil, 0.058 g, 1.50 mmol) and 1-iodo-2-methylpropane (0.23 mL, 2.00 mmol) to give the title compound (0.187 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12].Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CC(=O)CC>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)(=[O:13])=[O:12]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(C)cc1
Solvent: CCC(C)=O
Product: CCOC(=O)CCCN(c1ccccc1C(=O)OC)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Yield: 64.9 %

Procedure:
A mixture of 2-(Toluene-4-sulfonylamino)-benzoic acid methyl ester (1000 g, 3.27 mol), ethyl 4-bromobutyrate (639 g, 3.45 mol) in 2-butanone (5.6 L) was heated at reflux for 24 hours. After the reaction was completed, the mixture was poured into ice-water, and the resultant precipitates were collected by filtration. The filtrates were washed with ethyl acetate to give 2-[(3-Ethoxycarbonyl-propyl)-(toluene-4-sulfonyl)-amino]-benzoic acid methyl ester (890 g, 65%).
Reaction SMILES: C([N:8]([CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])C1C=CC=CC=1>C(O)C.C(O)(=O)C.[Pd]>[CH2:22]([O:21][P:16]([CH2:15][NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:18][CH2:19][CH3:20])=[O:17])[CH3:23]
Reactant: CCOC(=O)CN(Cc1ccccc1)CP(=O)(OCC)OCC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CNCP(=O)(OCC)OCC
Temperature: 50 °C
Reaction time: 32 h

Procedure:
A 250-mL pressure tank reactor was purged, flushed and maintained with a hydrogen atmosphere, then, was added a solution of ethyl 2-(benzyl((diethoxyphosphoryl)methyl)amino)acetate (8.0 g, 23.32 mmol, 1.00 equiv) in ethanol (180 mL), acetic acid (10 mL), Pd/C (0.9 g). The resulting solution was stirred at 20 atm for 32 h at 50° C. The solids were filtered out, and the resulting mixture was concentrated under vacuum. This resulted in 6.0 g (82%) of the acetic acid salt of ethyl 2-((diethoxyphosphoryl)methylamino)acetate as a brown oil.
Reaction SMILES: C[C@H]1[C@@]23C(O[C@H](C2)C[C@@H]1C1C=CC2OCOC=2C=1)=CC(=O)C(OC)=C3.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[O:34]=[CH:35][C:36]1[CH:44]=[CH:43][C:40]([O:41][CH3:42])=[C:38]([OH:39])[CH:37]=1>>[CH2:26]([O:39][C:38]1[CH:37]=[C:36]([CH:44]=[CH:43][C:40]=1[O:41][CH3:42])[CH:35]=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C=O)cc1O
Agent: COC1=C[C@]23C[C@H](C[C@H](c4ccc5c(c4)OCO5)[C@H]2C)OC3=CC1=O
Product: COc1ccc(C=O)cc1OCc1ccccc1

Procedure:
FIGS. 17 and 18 disclose a procedure for synthesizing futoenone and futoenone derivative compounds. Benzyl bromide (BnBr) is used to protect isovanillin (201) by reaction using phase transfer conditions to yield 3-benzyloxy-4-methoxybenzaldehyde (202). Oxidation of 3-benzyloxy-4-methoxybenzaldehyde (202) with m-chloroperbenzoic acid followed by hydrolysis in refluxing methanol yields 3-benzyloxy-4-methoxyphenol (203). The phenol is placed in toluene and the suspension is treated with n-butyl-lithium to form a precipitate. 1,4-dibromobutene is then added to the reaction and the contents are heated to reflux overnight to form vinylbenzofuran (206). An ester (207) is formed using a Horner-Emmons modified Wittig reaction and is subsequently reduced to the allylic alcohol (208) using diisobutylaluminum hydride. The allylic alcohol can then be epoxidized in a Sharpless epoxidation to form 2-(2,3'-epoxybutanol)-7-benzyloxy-6-methoxydihydrobenzofuran (209).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH:8]2[CH2:14][NH:13][CH:12]([CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:18].[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[C:24]([CH:28]=1)[C:25](O)=[O:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH:8]2[CH2:14][N:13]([C:25](=[O:26])[C:24]3[CH:28]=[C:20]([CH3:19])[CH:21]=[CH:22][C:23]=3[N:29]3[N:33]=[CH:32][CH:31]=[N:30]3)[CH:12]([CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc(OCC2CCCC(C)NC2)ccc1F
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC(COc3ccc(F)c(C)c3)CCCC2C)c1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
A solution of 6-[(4-fluoro-3-methylphenoxy)methyl]-2-methylazepane (2-7, 50 mg, 0.20 mmol, 1.0 equiv) in DMF (3 mL) was treated with 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (45 mg, 0.22 mmol, 1.1 equiv), EDC (46 mg, 0.24 mmol, 1.2 equiv), HOBT (37 mg, 0.24 mmol, 1.2 equiv) and triethylamine (83 ul, 60 mg, 0.60 mmol, 3.0 equiv) and the resulting mixture was stirred at 23° C. for 16 hours. The mixture was filtered and purified by reverse phase liquid chromatography (Sunfire C18 OBD 5 um, 20×150 mm column; 0-100% CH3CN/H2O gradient w/0.10% TFA present) to yield 6-[(4-fluoro-3-methylphenoxy)methyl]-2-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]azepane (2-8). δ 7.95-6.14 (m, 8H), 4.97-0.65 (m, 21H). LRMS m/z (M+H) 437.4 found, 437.2 required.
Reaction SMILES: N(C(C)=O)(CNC(C)=O)CNC(C)=O.C=O.O.[C:18]([OH:21])(=[O:20])[CH3:19].N(CC(O)=O)CC(O)=O.[C:31]([NH:34][CH2:35][C:36]([OH:38])=[O:37])(=[O:33])[CH3:32]>COCCOC>[C:31]([N:34]([CH2:35][C:36]([OH:38])=[O:37])[CH2:19][C:18]([OH:21])=[O:20])(=[O:33])[CH3:32]
Reactant: CC(=O)NCC(=O)O
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)NCN(CNC(C)=O)C(C)=O
Agent: O=C(O)CNCC(=O)O
Solvent: COCCOC
Solvent: O
Product: CC(=O)N(CC(=O)O)CC(=O)O
Temperature: 125 °C
Yield: 93 %

Procedure:
A 300 mL autoclave was charged with acetamide (VII)(11.8 g, 0.2 mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (6.5 g, 0.36 mole), acetic acid (16.8 g, 0.28 mol, 0.19 g/mL of DME), DME (90 mL) and Co2(CO)8 (4.1 g, 0.012 mole) and pressurized to 1500 psi (10,345 kPa) CO:H2 (95:5) at 25° C. This mixture was heated to 125° C. for 30 min. HPLC analysis of this stream gave a 93% yield of (XVI), 1% (XIV), and 4% (XVIII).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[C:6]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39].[H-].[Na+].Cl[C:43]1[N:48]=[CH:47][CH:46]=[CH:45][N:44]=1.CN(C=O)C>C1COCC1>[N:44]1[CH:45]=[CH:46][CH:47]=[N:48][C:43]=1[O:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=2)[C:6]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39]
Reactant: Clc1ncccn1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCOc1ncccn1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
4-i-Propyl-phenyl sulfamic acid-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (60 mg, Example 3) was dissolved in THF (8 ml) and sodium hydride (14 mg, 60% dispersion in mineral oil) was added and stirring continued for 10 min. 2-Chloro-pyrimidine (22 mg) was added and the mixture was heated to 60° C. for 90 min. DMF (0.5 ml) was added and the solution was stirred at r.t. for 48 h. The solvents were evaporated, water (12 ml) and a 10/solution of citric acid was added until the pH was 3. The precipitate was filtered off and washed with water and purified by recrystallization from diethyl ether to give 4-i-propyl-phenyl sulfamic acid-[6-[2-(pyrimidin-2-yloxy)-ethoxy]-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (50 mg). tR=4.80 min, (LC); [M+H]+=630.91 (ES+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]4[C:38]5[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=5)[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([N:23]3[CH2:24][CH2:25][CH:26]([C:29]4[C:38]5[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=5)[N:32]=[CH:31][N:30]=4)[CH2:27][CH2:28]3)=[O:22])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4)CC3)c2cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(C5=CCNCC5)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
4-(4-{[4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl]-amino}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (10 mg, 0.017 mmol), as prepared in Example 61, was dissolved in 50% TFA/DCM (5 mL). The solution was stirred at room temperature for 4 h. It was evaporated and the residue was quenched with 2N ammonium in MeOH (6 mL). The solvent was removed and the residue was washed with water, dried in vacuo to afford the title compound as a white solid (8 mg, 100%). 1H NMR (300 MHz, CD3OD) δ 8.94 (s, 1H), 7.58 (s, 1H), 7.42 (s, 4H), 7.32 (s, 1H), 6.12 (m, 1H), 4.37 (m, 2H), 4.06 (s, 3H), 4.04 (s, 3H), 3.93 (m, 1H), 3.82 (m, 2H), 3.44 (t, J=6.29 Hz, 2H), 3.22 (m, 2H), 2.78 (m, 2H), 1.93-2.10 (m, 4H). LC-MS (ESI) calcd mass 473.2, found 474.5 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10](OCC)=[O:11])=[CH:6][CH:5]=[C:4]([O:15][CH3:16])[N:3]=1.CC(C)([O-])C.[K+].[NH4+].[Cl-]>O1CCCC1>[CH3:16][O:15][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][CH2:9][C:10](=[O:11])[NH:1][C:2]=2[N:3]=1
Reactant: CCOC(=O)CNc1ccc(OC)nc1N
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc2c(n1)NC(=O)CN2
Yield: 63.3 %

Procedure:
Ethyl N-[2-amino-6-(methyloxy)-3-pyridinyl]glycinate (40.6 g, 135 mmol) was dissolved in tetrahydrofuran (THF) (1 L) at room temperature under argon and treated with potassium tert-butoxide (15.17 g, 135 mmol). After 2 h at room temperature saturated NH4Cl (500 ml) was added and the THF evaporated. Water (500 ml) was added followed by 20% MeOH/DCM (1 L); the insoluble material was filtered off, washed with diethyl ether and dried in the vacuum oven at 40° C. overnight to afford the desired product as a yellow solid (15.3 g): LCMS and NMR consistent with product (9% of oxidized material present by NMR).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]1[N:16]([CH2:17][CH2:18][CH2:19][C:20](OCC)=O)[C:15]2[C:25]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:26][CH:27]=[CH:28][C:14]=2[N:13]=1.[BH4-].[Li+].CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.N1C=CC=CC=1.O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:11]1[C:12]2=[N:13][C:14]3[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:15]=3[N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)CCCn1c(Nc2ccc(OC)cc2OC)nc2cccc(C(CC)CC)c21
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: CCC(CC)c1cccc2nc3n(c12)CCCCN3c1ccc(OC)cc1OC
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 29.1 %

Procedure:
To a solution of ethyl 4-[2-[(2,4-dimethoxyphenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 56; 569.3 mg, 1.26 mmol) in tetrahydrofuran (5.0 mL) was added lithium borohydride (82.0 mg, 3.77 mmol) at 0° C. The reaction mixture was stirred at 60° C. for 1.5 hr. After cooling, the reaction mixture was quenched with water at 0° C. and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting crude butanol (MS Calcd.: 411; Found: 412 (M+H)) was subjected for the next step without further purification. To a solution of the crude material in pyridine (1.0 mL) was added methanesulfonyl chloride (490 μL, 6.28 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude mesylate was subjected for the next step without further purification. To the crude material (MS Calcd.: 489; Found: 490 (M+H)) in NAN-dimethylformamide (1.0 mL) was added potassium carbonate (346.9 mg, 2.51 mmol). The reaction mixture was stirred at 60° C. for 19 hr. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was washed with n-hexane to give the title compound as a colorless powder (144.5 mg, 0.367 mmol, 29%).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][CH:9]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:6]1=[O:31])(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:4][C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][CH:9]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:6]1=[O:31]
Reactant: COc1ccc([C@H]2SC=C(c3ccccc3)N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc([C@H]2SC=C(c3ccccc3)N(CCN(C)C)C(=O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A mixture of 1.2 g (0.003 mol) of (-)-cis--6-(acetyloxy)-6,7-dihydro-7-(4-methoxyphenyl)-4[2-(dimethylamino)ethyl)-3-phenyl-1,4-thiazepin-5(4H)-one and 30 mL 0.5M potassium carbonate in 45 mL ethanol was stirred at room temperature for one hour. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The ethyl acetate solution was washed with brine and dried (MgSO4). Removal of the solvent gave the crude base, which after recrystallization from ether afforded 1.1 g (100%) of (-)-cis-6,7-dihydro-6-hydroxy-7-(4-methoxyphenyl)-4-[2(dimethylamino)ethyl]-3-phenyl-1,4-thiazepin-5(4H)-one, mp 110°-112°, [α]25-115.36° (C 0.99, MeOH).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:14]2[CH:13]=[C:12](B(O)O)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Br:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][C:24](Br)=[CH:25][CH:26]=2)[CH:21]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(COC)OC>[Br:19][C:20]1[CH:21]=[C:22]2[C:27]([CH:26]=[CH:25][C:24]([C:12]3[CH:11]=[CH:10][C:9]4[C:8]5[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:2]([CH3:1])([CH3:18])[C:14]=4[CH:13]=3)=[CH:23]2)=[CH:28][CH:29]=1
Reactant: CC1(C)c2ccccc2-c2ccc(B(O)O)cc21
Reactant: Brc1ccc2ccc(Br)cc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Solvent: O
Product: CC1(C)c2ccccc2-c2ccc(-c3ccc4ccc(Br)cc4c3)cc21
Temperature: 85 °C
Reaction time: 9 h
Yield: 48 %

Procedure:
In argon atmosphere, a mixture of 16.65 g (69.9 mmol) of 9,9-dimethyl-9H-fluorene-2-ylboronic acid, 20.00 g (69.9 mmol) of 2,7-dibromonaphthalene, 4.04 g (3.50 mmol) of tetrakis(triphenylphosphine)palladium (0), 200 ml of toluene, 200 ml of dimethoxyethane, and 106 g of a 2 M sodium carbonate aqueous solution was stirred at 85° C. for 9 h and left standing overnight. The reaction mixture was added with water and stirred at room temperature for one hour. After filtration, the filtrate was extracted with toluene. The organic phase was washed with water and then with a saturated saline solution and dried over sodium sulfate, and then the toluene was removed by distillation under reduced pressure. The obtained brown oily substance was purified by silica gel chromatography to obtain 13.4 g (yield: 48%) of 2-(7-bromonaphthalene-2-yl)-9,9-dimethyl-9H-fluorene.