Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[CH:24]=[C:23]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:11][C:10]=1[F:33])[C:2]1[CH:7]=[CH:6]C=CC=1.[F:34]C1(CO)CC1>>[F:33][C:10]1[CH:11]=[C:12]([C:16]2[O:17][C:18]3[CH:24]=[C:23]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])[CH:22]=[CH:21][C:19]=3[N:20]=2)[CH:13]=[C:14]([F:15])[C:9]=1[O:8][CH2:1][C:2]1([F:34])[CH2:7][CH2:6]1
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(OCc4ccccc4)c(F)c3)oc2c1
Reactant: OCC1(F)CC1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(OCC4(F)CC4)c(F)c3)oc2c1

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-3,5-difluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide and (1-fluorocyclopropyl)methanol, and in the same manner as in Step A and Step B of Example 4, the title compound was obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[S:4]([C:7]1[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5])[CH3:2].C(N=[C:24]=[O:25])CCC.C(Cl)(Cl)=O>>[CH2:17]([N:3]([CH2:1][CH3:2])[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:24]=[O:25])(=[O:14])=[O:15])(=[O:6])=[O:5])[CH3:18]
Reactant: CCN(CC)S(=O)(=O)c1ccccc1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: O=C(Cl)Cl
Product: CCN(CC)S(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Reaction time: 0.5 h

Procedure:
A solution of 13.2 g of N,N-diethyl-1,2-benzenedisulfonamide, 4.5 g of n-butylisocyanate, and 0.2 g of 1,4-diaza[2,2,2]bicyclooctane (DABCO) in 90 ml of mixed xylenes was heated to 135°. To this solution was added 3.3 ml of liquid phosgene at such a rate that the temperature was maintained between 125° and 135° (about 2 hours). The temperature was kept at 130° for 1/2 hour after the addition. The solution was cooled and filtered to remove a small amount of insoluble solid then concentrated at 60°-70° in-vacuo. The residue of o-N,N-diethylsulfamoylbenzenesulfonyl isocyanate was an oil weighing 16.8 g and was sufficiently pure for further reaction.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14](=[N:20][OH:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[Br:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([Br:33])[C:31]=1[OH:32])[C:26](O)=O>N1C=CC=CC=1>[Br:22][C:23]1[CH:24]=[C:25]([C:26]2[O:21][N:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=2)[CH:29]=[C:30]([Br:33])[C:31]=1[OH:32]
Reactant: O=C(O)c1cc(Br)c(O)c(Br)c1
Reactant: CCOC(=O)C(N)=NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1noc(-c2cc(Br)c(O)c(Br)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.2 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.32 g, 10 mmol) was added in one portion to a stirred solution of ethyl 2-amino-2-(hydroxyimino)acetate (1.32 g, 10 mmol) plus 3,5-dibromo-4-hydroxybenzoic acid (2.95 g, 10 mmol) in pyridine (20 mL), the resulting solution was stirred at room temperature for 2 h and then at 90° C. for 5 h. After standing at room temperature overnight the pyridine was evaporated in vacuo and the residue was purified by flash chromatography (silica gel, 10% ethyl acetate/dichloromethane) to give the title compound (0.48 g, 12%) as a colourless solid. 1H NMR δ (ppm) (DMSO-d6): 1.48 (3 H, t), 4.47 (2 H, d), 8.13 (2 H, s), 11.54 (1 H, s, br).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1.[Cl:13][CH:14]([Cl:18])[C:15](Cl)=[O:16]>CCCCCC>[Cl:13][C:14]1([Cl:18])[CH:8]2[CH:9]([CH2:10][CH:11]=[CH:12]2)[C:15]1=[O:16]
Reactant: C1=CCC=C1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: O=C1C2CC=CC2C1(Cl)Cl
Reaction time: 15 h

Procedure:
Over a period of 1.5 hr 21.7 g of dry triethylamine in 200 ml of hexane was added to a vigorously stirred solution mixture of 27.2 g of freshly distilled cyclopentadiene (I), 30.5 g of dichloroacetyl chloride, and 200 ml of hexane (dried over molecular sieves). After stirring for 15 hours under an atmosphere of nitrogen, the reaction mixture was filtered and the filter cake was washed with hexane. The solvent was removed under vacuum, yielding a 35.2 g of liquid, which, when redistilled under vacuum, afforded 30 g of 7,7-dichlorobicyclo(3.2.0)hept-2-en-6-one (II).
Reaction SMILES: [F:1]N(C(C)(C)C)S(C1C=CC(C)=CC=1)(=O)=O.[C:17]1([O-:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.[K+]>O1CCCC1.CCOCC>[F:1][C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]=1[OH:27]
Reactant: [O-]c1cccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)N(F)C(C)(C)C)cc1
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Oc1c(F)ccc2ccccc12
Yield: 60 %

Procedure:
Potassium hydride (93.6 mg as a 35% oil dispersion, 0.82 mmol) was suspended in anhydrous tetrahydrofuran (2.5 mL) under nitrogen. 1-Naphthol (72 mg, 0.5 mmole) was added and the mixture was stirred until hydrogen evolution ceased (about 5 minutes) to produce potassium naphtholate. N-Fluoro-N-t-butyl-p-toluenesulfonamide (122 mg, 0.5 mmole) was dissolved in anhydrous tetrahydrofuran (2.5 mL) and the solution was added dropwise to the potassium naphtholate. After 20 minutes the reaction mixture was diluted with ether (100 mL), washed with aqueous 1N oxalic acid solution (30 mL), water (30 mL), and saturated aqueous sodium chloride solution (30 mL), and then dried over anhydrous magnesium sulfate. Filtration, removal of solvent under reduced pressure, and purification by flash column chromatography (silica, 25% methylene chloride in hexane) yielded 2-fluoro-1-naphthol (49 mg, 60% yield) as a white crystalline solid. This material, and an additional sample prepared by this procedure, were analyzed and provided the following results: 1H NMR (90 MHz, CDCl3) δ5.58 (b, 1H, OH), 7.00-8.30 (m, 6H, aromatic); 19F NMR (94.1 MHz, CDCl3) -146.78(m); HRMS calcd. for C10H7OF: 162.0480; found: 162.0439.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:15]=[C:14]([C:16]3[N:20]([CH:21]4[CH2:23][CH2:22]4)[CH:19]=[N:18][N:17]=3)[S:13][CH:12]=2)=[O:9])[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:21]1([N:20]2[CH:19]=[N:18][N:17]=[C:16]2[C:14]2[S:13][CH:12]=[C:11]([NH:10][C:8]([C:4]3[CH:3]=[C:2]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH:7]=[CH:6][N:5]=3)=[O:9])[CH:15]=2)[CH2:23][CH2:22]1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1csc(-c2nncn2C2CC2)c1)c1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(Nc1csc(-c2nncn2C2CC2)c1)c1cc(-c2cccnc2)ccn1
Temperature: 90 °C
Yield: 20.2 %

Procedure:
A suspension of 4-bromo-N-(5-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiophen-3-yl)picolinamide (55 mg, 0.14 mmol), 3-pyridine boronic acid (17 mg, 0.14 mmol), dppf(Pd)C12 (5.2 mg, 0.0071 mmol), potassium carbonate (49 mg, 0.35 mmol) in degassed toluene (0.70 mL), degassed water (0.35 mL) and degassed ethanol (0.35 mL) was heated at 90° C. for 3 hours. The aqueous layer was separated, the organic layer was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC to give N-(5-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiophen-3-yl)-3,4′-bipyridine-2′-carboxamide as a white powder (11 mg, 20% yield). N-(5-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiophen-3-yl)-3,4′-bipyridine-2′-carboxamide; C20H16N6OS. 389.2 (M+1). 1H NMR (DMSO) δ 11.45 (s, 1H), 9.11 (d, J=2 Hz, 1H), 8.85 (d, J=5 Hz, 1H), 8.70-8.74 (m, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 8.31-8.36 (m, 2H), 8.10 (dd, J=2, 5 Hz, 1H), 8.06 (s, 1H), 7.60 (dd, J=5, 8 Hz, 1H), 3.56-3.59 (m, 1H), 1.11-1.27 (m, 4H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:21]3[CH2:20][N:19]([C:22]4[N:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][N:23]=4)[CH2:18][CH2:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:61][O:62][CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][O:64]1>C(Cl)Cl>[O:64]1[CH2:65][CH2:66][CH2:67][CH2:68][CH:63]1[O:62][NH:61][C:28]([C:25]1[CH:24]=[N:23][C:22]([N:19]2[CH2:18][CH2:17][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:21]=3[CH2:20]2)=[N:27][CH:26]=1)=[O:29]
Reactant: O=C(O)c1cnc(N2CCc3c(n(CCN4CCCCC4)c4ccccc34)C2)nc1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NOC1CCCCO1)c1cnc(N2CCc3c(n(CCN4CCCCC4)c4ccccc34)C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
To a solution of the acid 2-[9-(2-piperidin-1-ylethyl)-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxylic acid (200 mg, 0.49 mmol) in DCM (20 mL) was added EDCI (140 mg, 0.73 mmol), HOBT (99 mg, 0.73 mmol), DIEA (183 mg, 1.46 mmol) and NH2OTHP (57 mg, 0.48 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography using EtOAc in hexanes (50%) to obtain N-(tetrahydro-2H-pyran-2-yloxy)-2-[9-(2-piperidin-1-ylethyl)-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxamide (80 mg). 1H NMR (200 MHz, CDCl3) ppm: 8.75 (s, 2H), 7.50 (d, 1H, J=7.0 Hz), 7.30 (m, 1H), 7.16 (m, 2H), 5.13 (s, 2H), 5.04 (s, 1H), 4.24 (m, 4H), 4.00 (m, 1H), 2.91 (m, 2H), 2.70 (m, 2H), 2.49 (m, 4H), 1.85-1.45 (m, 11H); m/e=504 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][C@H:28]([OH:31])[CH2:29][OH:30]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][CH2:27][C@H:28]([OH:31])[CH2:29][OH:30])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NC[C@H](O)CO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC[C@H](O)CO)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (2S)-3-aminopropane-1,2-diol. MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J=7.83, 1.26 Hz, 1 H), 7.89 (d, J=7.33 Hz, 1 H), 7.63 (td, J=7.45, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.50-7.35 (m, 2 H), 7.29 (dd, J=8.59, 1.77 Hz, 1 H), 6.13 (s, 1 H), 5.14 (s, 2 H), 4.55 (brs, 2 H), 4.04-3.89 (m, 1 H), 3.69 (d, J=5.56 Hz, 2 H), 3.64-3.49 (m, 4 H), 2.41 (s, 3 H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[CH2:29]([O:31][CH2:32][CH2:33][NH2:34])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:29]([O:31][CH2:32][CH2:33][NH:34][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:14])[CH3:30]
Reactant: CCOCCN
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2CC
Yield: 37.4 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (66.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (150.0 mg), 2-ethoxy-ethylamine (45.0 mg), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 479.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[C:4]([O:15][CH3:16])[C:3]=1[C:17](=[O:34])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH2:29][O:30][CH3:31])=[C:22]([O:32][CH3:33])[CH:21]=1.[H-].[Na+].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CN(C)C=O>[CH3:14][O:13][C:6]1[CH:5]=[C:4]([O:15][CH3:16])[C:3]([C:17](=[O:34])[CH2:18][CH2:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH2:29][O:30][CH3:31])=[C:22]([O:32][CH3:33])[CH:21]=2)=[C:2]([O:1][CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:7]=1[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)CBr
Reactant: COCOc1c(OC)cc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1c(OC)cc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2OCC(=O)OC)cc1OC
Reaction time: 0.75 h

Procedure:
Then, 10 ml of dimethylformamide was dropped into a mixture of 2.3 g of 1-(2-hydroxy-4,6-dimethoxy-3-isopentylphenyl)-3-(3,5-dimethoxy-4-methoxymethoxyphenyl)-1-propanone and 0.2 g of sodium hydride at 0° C., and the mixture was stirred for 45 minutes. Then, 0.5 ml of methyl α-bromoacetate was added to the mixture at 0° C., and the mixture was stirred for 20 minutes. After the reaction, the solvent was removed from the reaction liquid mixture by distillation and the residue was dried under a reduced pressure to obtain substantially quantitatively 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(3,5-dimethoxy-4-methoxymethoxyphenyl)-1-propanone in the form of a colorless transparent oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[Cl:17][S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19]>CCOCC>[Cl:17][S:18]([NH:21][C:22](=[O:23])[O:16][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=1[C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:20])=[O:19]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOCC
Product: Cc1cc(C(C)(C)C)c(OC(=O)NS(=O)(=O)Cl)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 74.1 %

Procedure:
A solution of 2,6-di-t-butyl-4-methylphenol (22.04 g, 0.1 moles) in 100 mL Et2O was added dropwise to a solution of chlorosulfonyl isocyanate (8.7 mL, 0.1 moles) in 100 mL Et2O at -15° C. under an atmosphere of N2. This was stirred for 2 hours, concentrated and trituration of the resulting gel with hexanes gave 26.82 g (74%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][C:21]([C:24]([OH:26])=O)([CH3:23])[CH3:22])[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCCCCC.C(OCC)(=O)C>C(OC(=O)C)C>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][C:21]([C:24](=[O:26])[N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])([CH3:22])[CH3:23])[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNCC
Reactant: Cc1[nH]c2ccc(OC(C)(C)C(=O)O)cc2c1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)C(C)(C)Oc1ccc2[nH]c(C)c(C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.3 %

Procedure:
5-(1-Carboxy-1-methyl-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (1.0 g, 2.76 mmol, 1.0 eq) was dissolved in ethylacetate (100 mL), and treated with diethylamine (0.241 g, 3.3 mmol, 1.2 eq) followed by HBTU (0.446 g, 3.3 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 24 hours and was followed by TLC (hexane/ethyl acetate 1/1). The reaction was quenched with aqueous sodium bicarbonate, extracted with ethyl acetate, and the organic layers dried over sodium sulfate, evaporated, and loaded on silica gel, followed by flash chromatography (hexane/ethyl acetate 1/1). 0.109 g of the product was obtained, 12% yield. LC/MS (ESI+) 422.52 (M+1) (C25H30N2O4).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([S:12]([N:15]([CH3:29])[C@@H:16]2[CH2:24][CH2:23][CH2:22][C:21]3[N:20]([CH2:25][C:26]([OH:28])=[O:27])[N:19]=[CH:18][C:17]2=3)(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(O)(=O)C>CS(C)=O>[CH3:29][N:15]([S:12]([C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=[C:2]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:3]=1)(=[O:13])=[O:14])[C@@H:16]1[CH2:24][CH2:23][CH2:22][C:21]2[N:20]([CH2:25][C:26]([OH:28])=[O:27])[N:19]=[CH:18][C:17]1=2
Reactant: C1CCNC1
Reactant: CN([C@@H]1CCCc2c1cnn2CC(=O)O)S(=O)(=O)c1cc(F)cc(C(F)(F)F)c1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CN([C@@H]1CCCc2c1cnn2CC(=O)O)S(=O)(=O)c1cc(N2CCCC2)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 46.7 %

Procedure:
{(R)-4-[(3-Fluoro-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid (25 mg, 0.066 mmol) and pyrrolidine (47 mg, 0.66 mmol) were dissolved in dimethyl sulfoxide (1.5 mL). The mixture was heated in a microwave oven at 180° C. for 50 minutes. The resulting mixture was acidified with acetic acid to pH 4, and then filtered and purified by preparative HPLC to afford {(R)-4-[methyl-(3-pyrrolidin-1-yl-5-trifluoromethyl-benzenesulfonyl)-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid (15 mg, 48.5%) as a white powder. 1H NMR (400 MHz, CD3OD) δ ppm 7.24 (s, 1 H), 7.14 (s, 1 H), 6.98 (s, 1 H), 6.41 (s, 1 H), 5.05 (t, 1 H), 4.75 (s, 2 H), 3.35 (t, 4 H), 2.61 (s, 3 H), 2.45 (m, 2 H), 2.08-1.61 (m, 8 H). MS calcd. for C21H25F3N4O4S 486, obsd. (ESI+) [(M+H)+] 487.
Reaction SMILES: [OH:1][CH:2]([PH:5](=[O:7])[OH:6])[CH2:3][Cl:4].[CH2:8](O)[CH2:9][CH2:10][CH3:11].O>C1C=CC=CC=1>[OH:1][CH:2]([PH:5](=[O:6])[O:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][Cl:4]
Reactant: CCCCO
Reactant: O=[PH](O)C(O)CCl
Solvent: O
Solvent: c1ccccc1
Product: CCCCO[PH](=O)C(O)CCl
Yield: 64.6 %

Procedure:
A solution of α-hydroxy-β-chloroethylphosphinic acid (2.9 g) and 1-butanol (10.0 g) in benzene (30 ml) was heated for 3 hours with removal of water through a Dean-Stark apparatus. The same work-up as in Example 6 gave 2.60 g (64.8%) of n-butyl α-hydroxy-β-chloroethylphosphinate (Compound No. 82).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH:32]C(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH2:32])[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc(NC(c3ccc(OC)cc3)c3ccc(OC)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A cooled (0° C.) solution of 1-[6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.1 g, 0.149 mmol) in dry dichloromethane (4 ml) is treated dropwise with TFA (2 ml). The mixture is stirred at room temperature for 12 h and then concentrated in vacuo. The residue is co-evaporated with chloroform three times to remove excess trifluoro acetic acid and purification of the residue by preparative HPLC affords the title compound.
Reaction SMILES: [C:1]([C:3]1([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[OH-].[Na+]>C(O)C.C(O)C.O>[NH2:2][CH2:1][C:3]1([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(CC2CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CN)(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of the tert-butyl 4-cyano-4-cyclopropylmethylpiperidine-1-carboxylate (I-2) (1.00 g, 3.78 mmol) in ethanol (5 mL) was added to 1M sodium hydroxide in 95% ethanol-water (75 mL) and the solution degassed with nitrogen. Raney Nickel (50% slurry in water) (2.6 g) was added and the black suspension shaken under hydrogen pressure (40 psi) at room temperature for 12 h. The catalyst was filtered off and washed with 95% ethanol-water. The filtrate was evaporated in vacuo then partitioned between water and DCM. The organic phase was separated and the aqueous phase re-extracted with DCM twice. The combined organic phase was dried (MgSO4) and the solvent removed in vacuo to leave tert-butyl 4-aminomethyl-4-cyclopropylmethylpiperidine-1-carboxylate (I-3) that was used in the next step without further purification. 1H NMR (500 MHz, CDCl3): δ 3.44 (m, 2H), 3.32 (m, 2H), 2.71 (s, 2H), 1.41 (s, 9H), 1.46-1.38 (m, 4H), 1.28 (d, J=6.7, 2H), 1.46 (s, 9H), 0.60 (m, 1H), 0.46 (m, 2H), 0.05 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[CH:6][C:5]=1[OH:12].C(Cl)Cl.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:17](=[O:20])[CH:18]=[CH2:19])=[CH:6][C:5]=1[OH:12]
Reactant: C=CC(=O)Cl
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(O)c(C(=O)OC)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester, was added DCM and triethylamine. This mixture was cooled to 0° C. and acryloyl chloride was added dropwise with stirring. After approximately 2 hours, the reaction was quenched by adding MeOH at 0° C. and the resulting mixture was stirred at room temperature for about 15 min and then concentrated in vacuo. DCM and water were added to the residue and this mixture was mixed thoroughly. The layers were separated and the aqueous layer was extracted with DCM. The organic layers were combined, dried (Na2SO4), filtered and the solvent was removed in vacuo to give 4-acryloylamino-5-chloro-2-hydroxybenzoic acid methyl ester. This ester was then combined with Preparation 1, followed by the addition of a THF-MeOH solvent. The mixture was heated and stirred for about 16 hours to provide biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-3-hydroxyphenylcarbamoyl)ethyl]piperidin-4-yl ester was made. Using this ester, and following the procedure described in Example 2 and substituting the appropriate amine, the title compound was prepared. MS m/z [M+H+] calcd for C35H38N4O5, 595.7; found, 595.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1
Reactant: COc1cc(OC)c2c3c(c(=O)oc2c1)CNCC3
Reactant: ClCCN1CCCCC1
Product: COc1cc(OC)c2c3c(c(=O)oc2c1)CN(CCN1CCCCC1)CC3

Procedure:
In the same way as described in Example 5, 0.02 m of 1,2,3,4-tetrahydro-8,10-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one was alkylated with N-(2-chloroethyl)-piperidine to give, after crystallization from MeOH, 3.0 g of product; mp 190°-224° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH2:15][C:16](N)=[O:17]>>[C:16](=[O:17])([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:13][CH:12]=1)[NH2:15]
Reactant: NC(N)=O
Reactant: CCCCCCCc1ccc(O)cc1
Product: CCCCCCCc1ccc(OC(N)=O)cc1
Yield: 78 %

Procedure:
The same method as step (6-1) of Example 6 was carried out with the exception of using 14629 g of p-heptyl phenol instead of 4-phenyl phenol, using 959 g of urea and carrying out the reaction for 17 hours. When a portion of the reaction liquid was removed and analyzed by liquid chromatography, the formation of (p-heptylphenyl) carbamate was confirmed. The yield was about 78% based on the charged amount of urea.