Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:24])[CH2:22][CH3:23]
Reactant: CCC(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a solution of 700 mg (2.90 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 1.62 ml (11.6 mmol) of triethylamine in 30 ml of methylene chloride was added 0.30 ml (3.48 mmol) of propionyl chloride and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain the powder which was washed with ether and dried to obtain 483 mg of the desired compound (74.2% , yellow prisms), mp: 50.0°-51.0° C.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.Br.Br[C:8]1[S:9][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:11][N:12]=1.C(N(CC)CC)C>C(O)C>[CH:1]1([CH2:4][NH:5][C:8]2[S:9][C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[N:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: NCC1CC1
Reactant: Brc1nnc(-c2cccnc2)s1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1cncc(-c2nnc(NCC3CC3)s2)c1
Temperature: 125 °C
Yield: 26.4 %

Procedure:
A suspension of cyclopropylmethanamine (0.528 g, 0.743 mmol), 2-bromo-5-(3-pyridyl)-1,3,4-thiadiazole hydrobromide (0.2 g, 0.619 mmol) and triethylamine (0.3 ml, 2.16 mmol) in ethanol (20 mL) was heated to 125° C. for 42 minutes in a microwave reaction vessel, cooled to room temperature, concentrated under reduced pressure and resuspended in 2:1 saturated aqueous sodium bicarbonate:ethyl acetate (100 mL). The suspension was shaken vigorously and the organic extract collected and washed with water (50 mL) and brine (30 mL) before drying over magnesium sulfate. The solution was concentrated under reduced pressure and purified by silica column chromatography, eluting with a gradient of methanol in ethyl acetate. The slower eluting fraction was concentrated under reduced pressure to afford the title compound as a yellow solid (38 mg, 26%): mp 162-165° C.; IR (ATR) 1573 (s), 1549 (s), 1464 (m), 1063 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J=1.6 Hz, 1H), 8.63 (dd, J=4.8, 1.6 Hz, 1H), 8.18 (ddd, J=8.0, 2.2, 1.7 Hz, 1H), 7.38 (ddd, J=8.0, 4.8, 0.7 Hz, 1H), 5.68 (s, 1H), 3.29 (d, J=7.1 Hz, 2H), 1.26-1.09 (m, 1H), 0.72-0.53 (m, 2H), 0.42-0.25 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 170.01, 154.19, 150.61, 147.94, 133.64, 127.47, 123.76, 52.20, 10.76, 3.73; ESIMS m/z 231.8 ([M−H]−).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12](O)(=[O:32])/[CH:13]=[CH:14]\[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl.O>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][C:12](=[O:32])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:2]=[O:1]
Reactant: CCCCCCCCCC=CC=CC=CC=C/C=C\C(=O)O
Reactant: COc1cc(C=O)ccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCC=CC=CC=CC=CC=CC(=O)Oc1ccc(C=O)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
To a solution of vanillin (330 mg, 2.2 mmol), cis-eicosapentaenoic acid (800 mg, 2.65 mmol) and catalytic amount of 4-(dimethylamino)pyridine in dichloromethane (DCM, 15 mL) was added a solution of N,N′-dicyclohexylcarbodiimide (720 mg, 3.53 mmol) in DCM (5 mL) for 5 min at ice cold temperature. The mixture was stirred at rt for 16 h and diluted with water. DCM layer was separated and the aqueous layer was extracted with DCM (3×100 mL). The combined DCM layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and the residue was chromatographed over silica gel column using hexane-ethyl acetate (95:5) as an eluent to give the product as an oil (710 mg, 75%). IR (neat) νmax 3012, 2961, 2931, 2855, 1767, 1701, 1600, 1271, 1149, 1119, 1032 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.94 (1H, s, —CHO), 7.49 (1H, d, J=1.6 Hz, H-2), 7.47 (1H, dd, J=8.0, 1.6 Hz, H-6), 7.20 (1H, d, J=8.0 Hz, H-5), 5.30-5.48 (10H, m, H-5′, 6′, 8′, 9′, 11′, 12′, 14′, 15′, 17′, 18′), 3.89 (3H, s, —OCH3), 2.80-2.88 (8H, m, H-7′, 10′, 13′, 16′), 2.58-2.67 (2H, m, H-2′), 2.22-2.25 (2H, m, H-19′), 2.05-2.11 (2H, m, H-4′), 1.81-189 (2H, m, H-3′), 0.97 (3H, t, J=7.4 Hz, H-20′).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[C:13]([F:18])[CH:12]=2)[N:8]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[C:6]=1[Cl:23])(=O)C.C(Cl)(=O)C>CO>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[C:13]([F:18])[CH:12]=2)[N:8]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[C:6]=1[Cl:23]
Reactant: COC(=O)c1nc(-c2ccc(Br)c(F)c2)cc(NC(C)=O)c1Cl
Solvent: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(Br)c(F)c2)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
To a 100-mL round bottom flask, equipped with a stir bar, was added methyl 4-acetamido-6-(4-bromo-3-fluorophenyl)-3-chloropicolinate (0.411 g, 1.023 mmol), methanol (5.12 mL) and acetyl chloride (1.45 mL, 20.5 mmol). The reaction was allowed to stir at room temperature for 18 hours. The solvent was removed with a rotary evaporator. The resulting solid was dissolved in 1 N NaHCO3 and extracted with ethyl acetate (3×75 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to afford the title compound as a white solid (0.324 g, 88%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[Si](C)(C)C.[C:38]1([C@@H:44]([CH3:48])[CH2:45][CH:46]=O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[NH2:49][OH:50]>C1COCC1>[OH:50][NH:49][CH:46]([CH2:45][C@@H:44]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:48])[CH2:1][S:2]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][Si:19]([CH3:21])([CH3:20])[CH3:22])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: C[C@@H](CC=O)c1ccccc1
Reactant: C[Si](C)(C)C#Cc1ccc(N2CCN(S(C)(=O)=O)CC2)cc1
Reactant: NO
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](CC(CS(=O)(=O)N1CCN(c2ccc(C#C[Si](C)(C)C)cc2)CC1)NO)c1ccccc1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a stirred suspension of 1-(methylsulfonyl)-4-[4-(trimethylsilylethynyl)phenyl]piperazine (673 mg, 2 mmol) in THF (13 mL) at −40° C., was added dropwise a solution of LiHMDS in THF (4.5 mL, 11.0M solution, 4.5 mmol). The resulting suspension was stirred at −40° C. for 10 minutes before being treated with chlorotrimethylsilane (254 μL, 2 mmol). The solution was then maintained at −40° C. for 10 minutes before being treated with a solution of (3S)-3-phenylbutanal (385 mg, 2.6 mmol, CAS number 53531-194) in THF (8 mL). The solution was allowed to warm to −15° C. over 1 hour before being quenched with a solution of hydroxylamine (1.23 mL, 50% aqueous solution in water, 20 mmol). The reaction was stirred for 3 hours at RT. The reaction was partitioned between ethyl acetate (30 mL) and water (30 mL). The combined organic extracts were then dried, (sat. brine and MgSO4), filtered and concentrated in vacuo. The residue was then purified by flash chromatography (silica, 30–40% ethyl acetate in iHexane) to give 1-{[(4S)-2-(hydroxyamino)-4-phenylpentyl]sulfonyl}-4-[4-(trimethylsilylethynyl)phenyl]piperazine (720 mg, 1.44 mmol, 68% @ 94 wt %).
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[C:10]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[CH:30]=2)=[CH:11][C:12]2[CH:17]=[N:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[N:14][C:13]=2[N:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39](Cl)(=[O:42])[CH:40]=[CH2:41].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([NH:5][C:6](=[O:7])[NH:8][C:9]1[C:10]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[CH:30]=2)=[CH:11][C:12]2[CH:17]=[N:16][C:15]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])[C:39](=[O:42])[CH:40]=[CH2:41])=[N:14][C:13]=2[N:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)Cl
Reactant: CCN(CC)CCCCNc1ncc2cc(-c3cc(OC)cc(OC)c3)c(NC(=O)NC(C)(C)C)nc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N(CCCCN(CC)CC)c1ncc2cc(-c3cc(OC)cc(OC)c3)c(NC(=O)NC(C)(C)C)nc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material 1-(tert-butyl)-3-(2-((4-(diethylamino)butyl)amino)-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl)urea (PD173074) can be purchased from, e.g., SelleckChem.com. In a dried vessel, acryloyl chloride (2 equiv.) and diisopropylethylamine (4.3 equiv.) are added to a solution of 1-(tert-butyl)-3-(2-((4-(diethylamino)butyl)amino)-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl)urea (1 equiv.) in anhydrous dichloromethane at 0° C. After stirring at room temperature for 2 hours, the reaction mixture is concentrated, diluted with DMSO and purified by reverse phase HPLC (5-95% water/acetonitrile). After concentrating the fractions, the product N-(7-(3-(tert-butyl)ureido)-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-2-yl)-N-(4-(diethylamino)butyl)acrylamide is obtained as a pale yellow foam. LCMS (M+1)=578.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]2[N:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:21][O:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:29]Br.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:29][C:28]2[CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:33]=[C:26]([C:25]([F:24])([F:38])[F:39])[CH:27]=2)[C:14]2[N:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:21][O:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: COC[C@@H]1C[C@H](Nc2ncc(Br)cn2)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of ((2S,4S)-4-(5-bromo-pyrimidin-2-ylamino)-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.84 mmol; 1.1 g), 3,5-bis(trifluoromethyl)benzyl bromide (4.3 mmol; 0.78 mL) and sodium hydride (60% dispersion in mineral oil, 4.3 mmol; 0.17 g) in DMF (9 mL) is stirred for 1 hour at room temperature under nitrogen. The reaction mixture is quenched with water then saturated ammonium chloride solution. The product is extracted twice with EtOAc. The combined organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is passed though silica pad (eluent: n-hexane/EtOAc) to give (2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester. To a mixture of (2S,4S)-4-[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester, 1-methylpyrazol-3-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (7.1 mmol, 1.48 g), tetrakis(triphenylphosphine)palladium(0) (0.43 mmol, 490 mg) and 2M aqueous sodium hydrogen carbonate (3.6 mL) in 1,2-dimethoxy-ethane (4 mL) is allowed to warm to 95° C. and stirred for 3 hours. The mixture is cooled to room temperature and then added water. The mixture is extracted with CH2Cl2, and the combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (2S,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.3 g, 74% overall yield for 2 steps); ESI-MS m/z: 615 [M+1]+, Retention time 2.12 min (condition A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10][C:11]([NH:13][C:14]([CH3:22])([CH:19]([CH3:21])[CH3:20])[C:15]([O:17]C)=O)=[O:12].CC([O-])(C)C.[K+].O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[C:15](=[O:17])[C:14]([CH:19]([CH3:21])[CH3:20])([CH3:22])[NH:13][C:11]1=[O:12]
Reactant: COC(=O)C(C)(NC(=O)Cc1c(Cl)cccc1OC)C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(Cl)c1C1C(=O)NC(C)(C(C)C)C1=O
Temperature: 25 °C
Yield: 93.6 %

Procedure:
23.8 g (0.073 mol) of methyl N-(2-chloro-6-methoxyphenylacetyl)-2-amino-2,3-dimethyl-butyrate, dissolved in 150 ml of absolute toluene, are added dropwise to a suspension of 18.06 g (0.16 mol) of potassium tert-butylate in 50 ml of absolute tetrahydrofuran at the boil, and the mixture was heated at reflux temperature for 1.5 hours. After the reaction mixture has cooled to room temperature, 230 ml of water are added, the aqueous phase is separated off, the toluene phase is reextracted using 110 ml of water, and the combined aqueous phases are acidified at 15-20° C. using approximately 25 ml of concentrated hydrochloric acid. The product is filtered off with suction and dried. 20.2 g (93% of theory) of 3-(2-chloro-6-methoxyphenyl)-5-isopropyl-5-methyl-pyrrolidine-2,4-dione of m.p. 172-174° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]2C(=O)C3=CC=CC=C3C2=O)[CH2:10][C@H:9]1[CH2:24][O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NN.O>CCO>[NH2:13][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([CH2:24][O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N2C(=O)c3ccccc3C2=O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
To a stirred solution of N-[cis-1tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy) methyl-4-pyrrolidinyl]phthalimide (1.60 g, 2.74 mmol) in EtOH (8 ml) was added NH2NH2.H2O(206 mg, 4.11 mmol) at room temperature. The reaction mixture was stirred at 70 for 1 hr. The mixture was concentrated in vacuo. The resulting solid was filtered off, and washed with CHCl3. The filtrate was concentrated in vacuo. The resulting solid was filtered off, and washed with CHCl3. The filtrate was concentrated in vacuo to give cis-4-amino-1-tert-butoxycarbonyl-(2S)-(tert-butyl diphenylsilyloxy) methylpyrrolidine (1.3 g, quant) as a pale yellow oil. The crude product was used to the subsequent reaction without further purification. 1H-NMR (CDCl3) δ 1.06 (s, 9H), 1.30 and 1.45 (each s, total 91), 1.59 (m, 1H), 1.85 (m, 1H), 2.94 (m, 1H), 3.44 (m, 1H), 3.78–4.07 (m, 4H), 7.36–7.41 (m, 6H), 7.51–7.65 (m, 4H).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([B:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]2)=[CH:11][CH:10]=1)(=O)=O.[NH2:24][C@@H:25]([CH3:35])[C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[OH:27].C(OCC)(=O)C>CN(C)C=O>[CH3:21][C:18]1([CH3:20])[C:17]([CH3:22])([CH3:23])[O:16][B:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][NH:24][C@@H:25]([CH3:35])[C@@H:26]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[OH:27])=[CH:14][CH:13]=2)[O:19]1
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Reactant: CC1(C)OB(c2ccc(OCCOS(C)(=O)=O)cc2)OC1(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](NCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)[C@H](O)c1ccc(O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 16.6 %

Procedure:
A mixture of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)phenoxy]ethyl methanesulfonate (1.20 g) and 4-((1R,2S)-2-amino-1-hydroxypropyl)phenol (1.76 g) in N,N-dimethylformamide (20 mL) was stirred at 80° C. for 5 hrs. Ethyl acetate was added to the reaction mixture. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1, methylene chloride/methanol=9/1) to afford the title compound (0.24 g).
Reaction SMILES: [C:1](OC=O)(=[O:3])C.C(O)=O.C(OC(=O)C)(=O)C.[NH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]1[NH:23][C:24]([CH3:45])=[C:25]([C:41]([O:43][CH3:44])=[O:42])[CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[Cl:40])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1>[Cl:40][C:34]1[C:35]([Cl:39])=[CH:36][CH:37]=[CH:38][C:33]=1[CH:26]1[C:25]([C:41]([O:43][CH3:44])=[O:42])=[C:24]([CH3:45])[NH:23][C:22]([CH2:21][O:20][CH2:19][CH2:18][NH:17][CH:1]=[O:3])=[C:27]1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: CC(=O)OC=O
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(COCCNC=O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Formic acetic anhydride (15 ml; prepared by heating a mixture of formic acid (5 ml) and acetic anhydride (10 ml) at 50°-60° C. for 1 hour) was added over 10 minutes to a stirred, ice-cooled solution of 2-(2-aminoethoxymethyl)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (4.4 g) in tetrahydrofuran (30 ml). The mixture was stirred at room temperature for 1.5 hours and then evaporated. The residue was dissolved in dichloromethane and the solution washed with 10% aqueous sodium carbonate solution, dried (Na2SO4), and evaporated. The residual solid was collected, washed with diethyl ether and dried to give the title compound as a hemihydrate (4.0 g), m.p. 178°-181° C. Found: C, 52.69; H, 5.05; N, 6.06. C21H24Cl2N2O6.0.5H2O requires C, 52.51; H, 5.25; N, 5.83%.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:17])[C:10]3[CH:16]=[CH:15][S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].C(Cl)(Cl)Cl.C1C(=O)N([Br:29])C(=O)C1>CC(O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:17])[C:10]3[CH:16]=[C:15]([Br:29])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2c3sccc3C(C)C2C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)N1CC2c3sc(Br)cc3C(C)C2C1

Procedure:
A solution of the product from step i) (204 mg, 0.81 mmol) in AcOH (2 ml) and CHCl3 (2 ml) was treated with NBS (152 mg, 0.85 mmol) at 22° C. for 30 minutes. Next, the reaction was carefully quenched with sat. NaHCO3 (10 ml), extracted with EtOAc (2×75 ml) and the combined organic layers were dried (MgSO4). The crude product was filtered through a plug of silica gel using hexanes:EtOAc (50:50) to give the subtitle compound. MS calculated for C13H16BrNO2S+H 330, observed 332.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[N:32]=[C:31]([C:33]([NH:35][CH2:36][C:37]5[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=5)=[O:34])[C:30]([OH:44])=[CH:29][CH:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[C:45]([O-])([O-])=O.[Cs+].[Cs+].ClCI>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[CH:28]=[CH:29][C:30]5[O:44][CH2:45][N:35]([CH2:36][C:37]6[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=6)[C:33](=[O:34])[C:31]=5[N:32]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(C(=O)NCc4ccc(F)cn4)n3)cc12
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)C(=O)N(Cc3ccc(F)cn3)CO4)cc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 63.1 %

Procedure:
To a solution of 6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-N-((5-fluoropyridin-2-yl)methyl)-3-hydroxypicolinamide (30 mg, 0.05 mmol) and Cs2CO3 (47 mg, 0.14 mmol) in DMF (3 mL) at 100° C. was added chloroiodomethane (13 mg, 0.07 mmol) under N2 protection dropwise. The mixture was stirred at 100° C. for 3 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic phase was dried over Na2SO4 After concentration, the residue was purified by prep-HPLC to give the product of 2-(4-fluorophenyl)-5-(3-((5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydro-2H-pyrido[2,3-e][1,3]oxazin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 60%). 1H-NMR (CDCl3, 400 MHz) δ 8.33 (s, 1H), 7.90˜7.94 (m, 3H), 7.69 (d, J=8.8 Hz, 1H), 7.56 (s, 1H), 7.40˜7.44 (m, 2H), 7.31˜7.36 (m, 1H), 7.13 (t, J=8.8 Hz, 2H), 6.19 (br s, 1H), 5.43 (s, 2H), 4.82 (s, 2H), 3.15 (s, 3H), 2.92 (d, J=4.8 Hz, 3H), 2.85 (s, 3H). MS (M+H)+: 634.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH:23]1([N:19]2[CH2:18][CH2:17][N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:4]3[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]3)[CH2:21][CH2:20]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCC1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2ccccc2N2CCN(C3CCCC3)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (25 mg, 0.0832 mmol) produced in Example (8b), cyclopentanone (9.1 mg, 0.108 mmol), sodium triacetoxyborohydride (33.5 mg, 0.158 mmol) and acetic acid (0.009 mL, 0.158 mmol) was stirred for 1 hour and 40 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed three times with ethyl acetate. The organic layer was concentrated to produce a residue, which was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 1-cyclopentyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a colorless oil.
Reaction SMILES: Br[C@H:2]1[C:28](=[O:29])[C@@:27]2([CH3:30])[C@@H:13]([CH2:14][C@@H:15]3[O:20][C@@:19]4([O:26][CH2:25][C@H:23]([CH3:24])[CH2:22][CH2:21]4)[C@@H:17]([CH3:18])[C@@H:16]32)[C@H:12]2[C@H:3]1[C@:4]1([CH3:32])[C@@H:9]([CH2:10][CH2:11]2)[CH2:8][C@@H:7]([OH:31])[CH2:6][CH2:5]1.C([OH:37])(C)(C)C.[OH-].[Na+]>O>[CH3:18][C@@H:17]1[C@:19]2([O:26][CH2:25][C@H:23]([CH3:24])[CH2:22][CH2:21]2)[O:20][C@H:15]2[CH2:14][C@@H:13]3[C@@:27]([CH3:30])([C@@H:16]12)[C@H:28]([OH:29])[C:2](=[O:37])[C@H:3]1[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@:4]1([CH3:32])[CH2:5][CH2:6][C@H:7]([OH:31])[CH2:8]2
Reactant: CC(C)(C)O
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@@H](Br)C(=O)[C@]3(C)[C@H]1[C@@H]2C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Temperature: 83 °C

Procedure:
A glass lined reactor was charged with 12.4 Kg of (3β,5α,11β,25R)-11-bromospirostan-3-ol-12-one (24.34 mole), 33 gallons of t-butanol, 33 gallons of water and 7.5 Kg (189 mole, 7.75 eq) of sodium hydroxide pellets. The reaction was heated to reflux over 1.5 hours, maintained at reflux for 4.5 hours (pot temperature was 83° C.), then cooled to room temperature. TLC at this point indicated complete reaction.