Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[N:8]=1)(=O)=O.CC1(C)COB([C:36]2[C:37]([CH3:44])([CH3:43])[O:38][C:39]([CH3:42])([CH3:41])[CH:40]=2)OC1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[N:8]=[C:7]([C:36]3[C:37]([CH3:44])([CH3:43])[O:38][C:39]([CH3:42])([CH3:41])[CH:40]=3)[CH:11]=2)=[CH:13][CH:14]=1
Reactant: COc1ccccc1-n1nc(OS(=O)(=O)C(F)(F)F)cc1-c1ccc(Cl)cc1
Reactant: CC1(C)COB(C2=CC(C)(C)OC2(C)C)OC1
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: CN(C)C=O
Product: COc1ccccc1-n1nc(C2=CC(C)(C)OC2(C)C)cc1-c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 78.1 %

Procedure:
To a solution of 5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl trifluoromethanesulfonate (Example 65, (c)) (337 mg, 0.78 mmol, 1 eq) in DMF (5 mL) was added 5,5-dimethyl-2-(2,2,5,5-tetramethyl-2,5-dihydro-furan-3-yl)-[1,3,2]dioxaborinane (223 mg, 0.93 mmol, 1.2 eq), sodium carbonate (198 mg, 1.87 mmol, 2.4 eq), and Pd(Ph3P)4 (90 mg, 0.078 mmol, 0.1 eq). Ar was bubbled through and the solution was heated to 100° C. for 5 hrs. Added water, extracted with EtOAc, dried over MgSO4 and conc. Purification by column chromatography (24 g) eluting with 5 to 10% EA/hexanes gave the title compound (249 mg, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:37]=[CH:36][C:28]2[N:29]=[C:30](S(C)(=O)=O)[O:31][C:27]=2[CH:26]=1.[OH-].[Na+].Cl>ClC(Cl)C.CO>[CH3:21][C:16]([CH3:22])([CH2:15][C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:30]3[O:31][C:27]4[CH:26]=[C:25]([CH3:24])[CH:37]=[CH:36][C:28]=4[N:29]=3)=[CH:7][CH:6]=2)=[CH:13][CH:12]=1)=[O:23])[C:17]([OH:19])=[O:18]
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Cc1ccc2nc(S(C)(=O)=O)oc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CO
Product: Cc1ccc2nc(Nc3ccc(-c4ccc(C(=O)CC(C)(C)C(=O)O)cc4)cc3)oc2c1
Temperature: 85 °C
Yield: 31.7 %

Procedure:
To a solution of methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (74 mg, 0.24 mmol) in dichloroethane (3 mL), 6-methyl-2-(methylsulfonyl)-1,3-benzoxazole (50 mg, 0.24 mmol) was added, and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation, and the residue was redissolved in DMF (5 mL). A solution of 1 N aqueous NaOH (0.72 mL, 0.72 mmol) was added, and the mixture was heated at 65° C. overnight. A solution of 1 N aqueous HCl (0.24 mL, 0.24 mmol) and methanol (5 mL) were added to the reaction mixture and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 2,2-dimethyl-4-{4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}-4-oxobutanoic acid as a white solid (32.6 mg, 32.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.00-7.50 (m, 8H), 7.30 (d, 2H), 7.05 (d, 1H), 3.30 (s, 2H), 2.50 (s, 3H), 1.10 (s, 6H); LC-MS ret. time 3.53 min (method 2), m/z 429.17 (MH+).
Reaction SMILES: C(=O)([O-])O.[Na+].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21]O)[C:15](=[O:23])[C@@H:14]1[CH3:24])=[O:12])([CH3:9])([CH3:8])[CH3:7].[Br-].[K+].Cl[O-].[Na+].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CC1(C)N([O])C(C)(C)CCC1>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:15](=[O:23])[C@@H:14]1[CH3:24])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: C[C@H]1C(=O)N(CCCO)CCN1C(=O)OC(C)(C)C
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@H]1C(=O)N(CCCN2CCCCC2)CCN1C(=O)OC(C)(C)C
Yield: 90.3 %

Procedure:
Saturated aq. sodium hydrogencarbonate solution (1.25 ml) was added to a solution of (S)-4-(3-hydroxy-propyl)-2-methyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (1.00 g, 3.67 mmol), potassium bromide (44 mg, 0.37 mmol), and 2,2,6,6-tetramethylpiperidin-1-oxyl (6 mg, 0.04 mmol) in dichloromethane (50 ml). Sodium hypochlorite solution (10% in water, 2.2 ml, 3.7 mmol) was added portionwise at 0° C., and the course of the oxidation was monitored by thin layer chromatography. After all starting material had reacted, the reaction mixture was washed with sat. aq. sodium hydrogencarbonate solution, and the aqueous layer was extracted twice with dichloromethane. The organic phases were pooled, dried (MgSO4), filtered, and evaporated, thus affoding (S)-4-(3-oxo-propyl)-2-methyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (950 mg). This was dissolved in dichloromethane (20 ml) and added over 20 min to a suspension of piperidine (297 mg, 3.49 mmol) triethylamine (353 mg, 3.49 mmol), acetic acid (419 mg, 6.98 mmol) and sodium triacetoxyborohydride (90% purity; 908 mg, 3.85 mmol) in dichloromethane (20 ml). After 16 h the reaction mixture was washed with 2 M aq. sodium carbonate solution, the organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (1.07 g, 86%). Light yellow oil, MS (ISP)=340.2 (M+H)+.
Reaction SMILES: N1C=CC=C(CN)C=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][NH2:16].FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[CH3:41][C:42]1[N:43]=[C:44]([N:50]2[CH2:54][C@@H:53]([CH3:55])[N:52]([CH2:56][C:57]3[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][CH:58]=3)[C:51]2=[O:67])[S:45][C:46]=1[C:47](O)=[O:48]>>[CH3:41][C:42]1[N:43]=[C:44]([N:50]2[CH2:54][C@@H:53]([CH3:55])[N:52]([CH2:56][C:57]3[CH:62]=[CH:61][C:60]([C:63]([F:64])([F:66])[F:65])=[CH:59][CH:58]=3)[C:51]2=[O:67])[S:45][C:46]=1[C:47]([NH:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=1)=[O:48]
Reactant: Cc1nc(N2C[C@@H](C)N(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1ccccn1
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C[C@@H](C)N(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1ccccn1

Procedure:
Following the procedure as described in EXAMPLE 2, making variations as required to replace pyridin-3-ylmethanamine with pyridin-2-ylmethanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-4-methyl-2-(4-methyl-2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a solid (61%): mp 136-137° C. (ethyl acetate/hexane); 1H NMR (300 MHz, DMSO-d6) δ 8.55-8.49 (m, 2H), 7.79-7.71 (m, 3H), 7.56 (d, J=8.1 Hz, 2H), 7.31-7.24 (m, 2H), 4.67 (d, J=16.1 Hz, 1H), 4.49-4.43 (m, 3H), 4.22 (dd, J=10.1, 9.1 Hz, 1H), 3.84-3.77 (m, 1H), 3.56 (dd, J=10.1, 6.8 Hz, 1H), 2.49 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 489.9 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:12]([NH2:15])(=[S:14])[CH3:13]>O1CCOCC1>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:15]=[C:12]([CH3:13])[S:14][CH:2]=2)=[CH:6][CH:7]=1
Reactant: CC(N)=S
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc(F)cc2)cs1
Yield: 73.1 %

Procedure:
Reflux a solution of 2-bromo-4′-fluoroacetophenone (10 g, 46 mmol) and thioacetamide (6.9 g, 92 mmol) in 1,4-dioxane (60 mL) for 3 h. Filter the precipitate and wash with EtOAc to give the title compound (6.5 g, 73%).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:5]=1[C:6]([OH:8])=[O:7].[C:15](Cl)(Cl)=[O:16]>O.C1(C)C=CC=CC=1>[CH3:14][O:13][C:9]1[C:5]2[C:6](=[O:8])[O:7][C:15](=[O:16])[NH:3][C:4]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)Cl
Reactant: COc1cccc(N)c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2[nH]c(=O)oc(=O)c12
Temperature: 0 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A solution of NaOH (6.6 g, 165 mmol) in water (300 mL) was treated with 2-amino-6-methoxylbenzoic acid (10 g, 59.9 mmol); cooled to 0° C., treated dropwise with a 20% wt solution of phosgene in toluene (75 mL), stirred overnight at room temperature and filtered. The filter cake provided 10.5 g of the desired product (yield: 91.0%). 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 6.65 (d, 1H), 6.80 (d, 1H), 7.65 (t, 1H), 11.58 (br s, 1H); MS (ESI(−) m/e 192 (M−H)−.
Reaction SMILES: O1[C:3]23[C@:16]([CH3:21])([CH:17]=[CH:18][C:19](=[O:20])[CH:2]12)[C@@H:15]1[C@H:6]([C@H:7]2[C@@:11]([CH2:13][CH2:14]1)([CH3:12])[C:10](=[O:22])[CH2:9][CH2:8]2)[CH2:5][C:4]3=[CH2:23].B(F)(F)[F:25].CCOCC>C(OCC)C>[F:25][C:2]1[C:19](=[O:20])[CH:18]=[CH:17][C@@:16]2([CH3:21])[C:3]=1[C:4](=[CH2:23])[CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22]
Reactant: C=C1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)C=CC(=O)C3OC132
Reactant: FB(F)F
Solvent: CCOCC
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C(F)=C12

Procedure:
A solution of 4,5-epoxy-6-methylenandrost-1-ene-3,17-dione (1.0 g) in diethyl ether (100 ether (100 ml) was treated with boron trifluoride etherate (1.4 ml) for 3 hours at room temperature. Then the solution was washed with 5% sodium carbonate solution, water, dried (Na2SO4) and evaporated in vacuo. The residue was dissolved in pyridine (20 ml) and 0.4 ml of thionyl chloride were added at 0° C. After 5 minutes water was added and the product isolated with ether. The ether extracts were washed with 2N hydrochloric acid, water, dried (Na2SO4) and evaporated. The resulting raw product was chromatographed on silica gel using hexane/ethyl acetate as eluant to yield 0.6 g of pure 4-fluoro-6-methylenandrosta-1,4-diene-3,17-dione. Found: C 76.30; H 7.35; F 5.91; C20H23FO2 requires: C 76.40; H 7.37; F 6.04.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([O:19]C)[CH:13]=1>>[C:1]1([C:15]2[CH:16]=[CH:17][C:12]([OH:11])=[CH:13][C:14]=2[OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(Br)c(OC)c1
Reactant: OB(O)c1ccccc1
Product: Oc1ccc(-c2ccccc2)c(O)c1

Procedure:
This compound was prepared using essentially the same procedure as that used in Example 3 with the difference that phenylboronic acid 17 (Aldrich Chemical) was used in place of 2-napthylboronic acid 13, and 1,3-dimethoxy-4-bromobenzene 15 was used in place of 1,3-dimethoxy-4-bromo-2-fluorobenzene 12.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([C:35]#[N:36])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:37][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[CH2:1]([O:3][P:4]([C:9]([C:35]#[N:36])([CH3:37])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:32])[CH3:33])=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOP(=O)(OCC)C(C#N)CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C)(C#N)CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Reaction time: 0.33 h
Yield: 14.2 %

Procedure:
To a solution of {(1-cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonic acid diethyl ester (45 mg, 0.084 mmol) in THF (0.5 mL) was added sodium bis(trimethysilyl)amide (1.0 M, 1.13 mL, 1.15 mmol). After stirring for 20 minutes, iodomethane (52 μL, 0.84 mmol) was added dropwise and the resulting mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to dryness. The residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to afford 6.6 mg (23%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 1.16 (dd, J=7, 8 Hz, 2H), 1.31 (t, 6H), 1.38 (d, 3H), 1.92 (s,3H), 2.17 (s, 3H), 2.23 (m, 1H), 2.65 (m, 1H), 3.30-3.42 (m, 2H), 3.73 (s, 3H), 4.14-4.27 (m, 6H), 5.08 (s, 2H), 5.28 (t, J=7.2 Hz, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 22.26 ppm; MS (m/z) 574 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:18][OH:19])[CH:5]=[C:6]([O:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:7]=1.C(OCC)C>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([O:8][CH2:9][CH2:10][NH:11][C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH:7]=1)[CH:18]=[O:19]
Reactant: Cc1cc(CO)cc(OCCNc2ccncc2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cc(C=O)cc(OCCNc2ccncc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of {3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-phenyl}-methanol (0.132 g) and manganese dioxide (0.370 g) in 1,4-dioxan (5 ml) was heated to reflux with stirring under an atmosphere of dry nitrogen for 5 h. After cooling to room temperature the mixture was filtered through Harborlite® and the pad washed with 1,4-dioxan and then methanol. The combined filtrates were evaporated to dryness under reduced pressure to give an off-white solid. Trituration with diethyl ether gave, after drying, the title compound as a white powder (0.074 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:31]([OH:33])=O)[C:11]3[C:16](/[CH:17]=[CH:18]/[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][N:14]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.C(N1CCNCC1)(OC(C)(C)C)=O.[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][NH:57][C@@H:56]([CH2:60][OH:61])[CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48]>>[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([C:31]([C:10]2[C:11]3[C:16](/[CH:17]=[CH:18]/[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][N:14]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:12]=3[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[CH:9]=2)=[O:33])[C@@H:56]([CH2:60][OH:61])[CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Reactant: O=C(O)c1cc(-c2ccc(O)cc2)nc2c1c(/C=C/c1ccccc1)nn2C1CCCCO1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(/C=C/c2ccccc2)nn3C2CCCCO2)[C@@H](CO)C1
Yield: 28 %

Procedure:
Utilizing the procedure described in example 1.6 except substituting 6-chloro-3-[(E)-2-(4-chloro-phenyl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid with 6-(4-hydroxy-phenyl)-3-((E)-styryl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid and 1-boc-piperazine with (R)-3-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester, (R)-3-hydroxymethyl-4-[6-(4-hydroxy-phenyl)-3-((E)-styryl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.16 g, 28%) was obtained as a yellow solid.
Reaction SMILES: [C:1]([N:4]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:29])[CH2:6]1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1.O>[C:1]([N:4]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:29])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCC(=O)O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.7 %

Procedure:
Methyl 3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)propanoate (200 mg, 0.4 mmol, 1 equ.) was dissolved in methanol/tetrahydrofuran (2/1) (1.5 ml). A solution of sodium hydroxide (32 mg, 0.8 mmol, 2 eq.) in water (0.5 ml) was added and reaction mixture stirred at room temperature for 20 h. The mixture was concentrated and the residue was acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)propanoic acid (190 mg, 97%).
Reaction SMILES: [F-].[K+].[NH2:3][CH2:4][C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][S:20]([N:23]([CH3:31])C(=O)OC(C)(C)C)(=[O:22])=[O:21])=[CH:15][CH:14]=2)[CH:6]=1.Cl[C:33]1[N:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=1>CS(C)=O>[Cl:39][C:36]1[CH:35]=[N:34][C:33]([NH:3][CH2:4][C:5]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:19][S:20]([NH:23][CH3:31])(=[O:21])=[O:22])=[CH:17][CH:18]=3)[CH:6]=2)=[N:38][CH:37]=1
Reactant: Cc1nc(CN)cc(Oc2ccc(CS(=O)(=O)N(C)C(=O)OC(C)(C)C)cc2)n1
Reactant: Clc1cnc(Cl)nc1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNS(=O)(=O)Cc1ccc(Oc2cc(CNc3ncc(Cl)cn3)nc(C)n2)cc1
Temperature: 120 °C
Reaction time: 17 h
Yield: 45 %

Procedure:
Add potassium fluoride (53.9 mg, 0.93 mmol) to a solution of tert-butyl N-[[4-[6-(aminomethyl)-2-methyl-pyrimidin-4-yl]oxyphenyl]methylsulfonyl]-N-methyl-carbamate (280 mg, 0.46 mmol) and 2,5-dichloropyrimidine (69.1 mg, 0.46 mmol) in DMSO (10 mL). Heat the mixture to 120° C. and stir it at that temperature for 17 hours. Cool the mixture to ambient temperature and quench the reaction with water. Extract the resulting mixture with EtOAc; combine the extract(s); dry the extracts with magnesium sulfate; filter; and concentrate the filtrate under reduce pressure to provide a residue. Purify the title compound using silica gel chromatography eluting with a gradient of EtOAc in hexanes (0-100%). Further purify the title compound using a second silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM. Concentrate the appropriate fractions under reduced pressure to provide the title compound as a glassy yellow solid (90 mg, 44.6%). MS (m/z): 435 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][C:10]([N:12]([C:15]1[C:16]([Cl:26])=[N:17][N:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:19]=1)[CH2:13][CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:30]I>>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:8][CH2:9][C:10]([N:12]([C:15]1[C:16]([Cl:26])=[N:17][N:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:19]=1)[CH2:13][CH3:14])=[O:11])[CH3:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CCN(C(=O)CCNC(=O)OC(C)(C)C)c1cn(-c2cccnc2)nc1Cl
Agent: [H-]
Agent: [Na+]
Product: CCN(C(=O)CCN(C)C(=O)OC(C)(C)C)c1cn(-c2cccnc2)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a clean vial with a stir bar tert-butyl(3-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-3-oxopropyl)carbamate (1.5 g, 3.8 mmol) was added and sealed with a septum cap. The headspace was purged with N2, dry DMF (5.4 mL) was added via a syringe, and the reaction was cooled to a temperature of about 0° C. in an ice bath under N2. NaH (60% dispersion in oil, 0.21 g, 5.3 mmol) was carefully added and stirred at a temperature of 0° C. for 30 minutes. Methyl iodide (0.29 mL, 4.6 mmol) was then added and stirred for 30 minutes at a temperature of 0° C. With the addition of methyl iodide, reaction became light yellow slurry. The reaction was warmed up to room temperature and stirred for 2 hours. As reaction warmed up, it turned to bright orange color. The reaction was quenched by the slow addition of water (100 mL). The suspension was vigorously stirred at room temperature for 2 hours. The water was filtered off, and remaining slurry was washed with hexanes. The slurry was then dissolved in methanol and passed through the filter. The resulting solution was concentrated, dried under high vacuum to afford brown, viscous oil (1.6 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:24][OH:25])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(CO)c23)c(C)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a solution of [9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (4.00 g, 11.15 mmol) in dimethylsulfoxide (70.0 mL) was added Dess-Martin reagent (5.20 g, 12.26 mmol). The mixture was stirred at room temperature for 3 hrs. The mixture was quenched with aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium thiosulfate and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was washed with ethyl acetate/diisopropyl ether to give the title compound as a pale yellow solid (3.69 g, 10.34 mmol, 93%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N+:9]([O-])=[CH:10]2)=[CH:5][CH:4]=1.BrC1C=C2C(=CC=1)C([Cl:25])=NC=C2>>[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[C:10]2[Cl:25])=[CH:5][CH:4]=1
Reactant: [O-][n+]1ccc2ccc(Br)cc2c1
Reactant: Clc1nccc2cc(Br)ccc12
Agent: Cl
Product: Clc1nccc2ccc(Br)cc12

Procedure:
Compound 37b was prepared from 37a using the procedure described for 1b. 1H-NMR 200 MHz (CDCl3)δ: 7.57-7.88 (3H, m), 8.32 (1H, d, J=6 Hz), 8.51-8.54 (1H, m)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([CH:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH:21]=2)[OH:19])=[C:13]([O:30][CH3:31])[CH:12]=1)[CH3:2].[H-].[Na+].I[CH2:35][CH3:36]>CN(C=O)C>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([CH:18]([O:19][CH2:35][CH3:36])[CH:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH2:21]2)=[C:13]([O:30][CH3:31])[CH:12]=1)[CH3:10]
Reactant: CCI
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(O)C2=CCCc3ccccc32)c(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(c1c(OC)cc(-c2c(CC)cccc2CC)nc1C)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of [6-(2,6-diethyl-phenyl)-4-methoxy-2-methyl-pyridin-3-yl]-(3,4-dihydro-naphthalen-1-yl)-methanol (75 mg, 0.18 mmol) in DMF (1 mL) is added to a suspension of NaH (22 mg, 0.90 mmol) in DMF (5 mL). The mixture is stirred for 1 hour at room temperature. Iodoethane 10.14 mL, 1.8 mmol) is added and the resulting mixture is stirred for 18 hours at room temperature, quenched with water, and extracted with ether. The combined extracts are washed with saturated brine, dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel to give 6-(2,6-diethyl-phenyl)-3-[ethoxy-(1,2,3,4-tetrahydro-naphthalen-1-yl)-methyl]-4-methoxy-2-methyl-pyridine as a colorless oil. 1H NMR (CDCl3) 7.71-7.68 (m, 1H), 7.32-7.26 (m, 1H), 7.21-7.10 (m, 5H), 6.67 (s, 1H), 5.04 (d, 1H), 3.80 (s, 3H), 3.51-3.46 (m, 1H), 3.36-3.19 (m, 2H), 2.89-2.2.72 (m, 2H), 2.75 (s, 3H), 2.47-2.38 (m, 4H), 1.90-1.81 (m, 1H), 1.69-1.59 (m, 2H), 1.41-1.1.32 (m, 1H), 1.17-1.08 (m, 9H).