Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C2C(=CC=CC=2)CCC1>CCOCC.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NCCc3cc(C)ccc32)cc1OC
Agent: [Pd]
Solvent: c1ccc2c(c1)CCCC2
Solvent: CCOCC
Product: COc1ccc(-c2nccc3cc(C)ccc23)cc1OC
Reaction time: 3.75 h
Yield: 107.4 %

Procedure:
A mixture of 1-(3,4-dimethoxyphenyl)-6-methyl-3,4-dihydroisoquinoline (C2) (5.0 g, 0.018 mol), 10% Pd/C (400 mg) and tetralin (50 ml) was boiled under nitrogen for 3.75 h. The cooled reaction mixture was diluted with ether and filtered The filtrate was treated with HCl gas to give 5.4 g (98%) of the title compound as the hydrochloride. A sample was recrystallized from i-PrOH to give pure 1-(3,4-dimethoxyphenyl)-6-methylisoquinoline hydrochloride, mp 225° dec.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][C:10]=1[Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:21]([O-])=O.[Na+]>O>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([N:15]=[N+:16]=[N-:21])=[O:14])=[CH:11][C:10]=1[Cl:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: NNC(=O)c1ccc(OCc2ccccc2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)c1ccc(OCc2ccccc2)c(Cl)c1
Temperature: 5 °C
Yield: 96.8 %

Procedure:
4-Benzyloxy-3-chlorobenzoic acid hydrazide (27.6 g., 0.1 mole) is suspended in 500 ml. 1N hydrochloric acid and the mixture cooled to about 0° C. A solution of sodium nitrite (7.0 g.) in 40 ml. water is added at such a rate as to keep the temperature below 5° C. The mixture is stirred at 5° C for 3/4 hr., filtered and the precipitate dried in vacuo to give 27.8 g., (96.8% yield) 4-benzyloxy- 3-chlorobenzoyl azide.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].C(N(CC)CC)C.Cl[C:20]1[N:25]=[C:24]([NH2:26])[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][CH:21]=1.O>CS(C)=O>[NH2:26][C:24]1[N:25]=[C:20]([N:7]2[CH2:8][CH2:9][CH2:10][C@@H:5]([C:3]([N:2]([CH3:11])[CH3:1])=[O:4])[CH2:6]2)[CH:21]=[CH:22][C:23]=1[N+:27]([O-:29])=[O:28]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)C(=O)[C@@H]1CCCNC1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Temperature: 110 °C
Yield: 83.7 %

Procedure:
To a solution of (R)—N,N-dimethylpiperidine-3-carboxamide (10 g, 64.04 mmol) in dimethylsulfoxide (100 mL) were added triethylamine (17.8 mL, 128.08 mmol) and 6-chloro-3-nitropyridin-2-amine (7.76 g, 44.82 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was heated at 110° C. for 16 h. The reaction mixture was added to cold water and extracted with ethyl acetate. The organic layer was washed with cold water 3 times, dried over sodium sulfate and evaporated under reduced pressure. The crude compound was purified via flash chromatography and then treated with 1:1 petroleum ether and diethyl ether to afford (R)-1-(6-amino-5-nitropyridin-2-yl)-N,N-dimethylpiperidine-3-carboxamide (11 g, 72%). MS (ES+APCI) (M+H) 294.1; LCMS retention time: 2.777 min (Method E1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[C:26]([CH:38]=O)[NH:25][C:24]=1[CH3:40])=[O:22])[CH3:19]>C(O)C.N1CCCCC1>[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[C:26]([CH:38]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:25][C:24]=1[CH3:40])=[O:22])[CH3:19]
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c1CCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.4 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (80.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester as a yellow solid (38.8 mg, 28%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([Br:11])[CH:5]=1)=[O:3].[BH4-].[Na+]>C1COCC1.CO>[Br:11][C:6]1[CH:5]=[C:4]([CH:2]([OH:3])[CH3:1])[CH:9]=[CH:8][C:7]=1[F:10]
Reactant: CC(=O)c1ccc(F)c(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)c1ccc(F)c(Br)c1
Temperature: 70 °C
Yield: 97.3 %

Procedure:
To a solution of 3-bromo-4-fluoroacetophenone (10 g, 46 mmol) in THF (100 mL) and methanol (1.0 mL) was added sodium borohydride (2.1 g, 55.5 mmol). The mixture was heated up to 70° C. for 1 h, then cooled down to rt. The reaction was quenched by 100 ml of 1N HCl solution and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography to give 9.8 g of 84A (97% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (d, J=6.15 Hz, 3H) 7.24-7.33 (m, 1H) 7.59 (dd, J=6.59, 2.20 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:17]([CH2:18][O:19][CH3:20])[CH:16]=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[C:22]1([CH2:28][C:29]([N:31]=[C:32]=[S:33])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:32]([NH:31][C:29](=[O:30])[CH2:28][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[S:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:17]([CH2:18][O:19][CH3:20])[CH:16]=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COCn1ccc2ncnc(Oc3ccc(N)cc3F)c21
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: COCn1ccc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c21
Reaction time: 3 h
Yield: 31.9 %

Procedure:
To a suspension of 245 (18 mg, 0.062 mmol) in THF (1 mL) was added 2-phenylacetyl isothiocyanate (12 mg, 0.069 mmol). The reaction mixture was stirred for 3 hours, concentrated under reduced pressure and the residue was purified by flash chromatography, eluent hexane/EtOAc (3:2) followed by recrystallization (MeCN/water), and preparative HPLC (Aquasil C-18, gradient: 60% MeOH to 95% MeOH in water), to afford title compound 246 (9.2 mg, 33% yield) as a white solid. 1HNMR: (CD3OD) δ (ppm): 8.35(s, 1H), 8.03 (d, J=12.4 Hz, 1H), 7.96(d, J=3.13 Hz, 1H), 7.44-7.26(m, 6H), 6.69 (d, J=3.13 Hz, 1H), 5.29 (quintuplet, J=6.65 Hz, 1H), 3.75(s, 2H), 3.60 (d, J=10.96 Hz, 3H), 1.63(d, J=6.65 Hz, 6H). MS (m/z): 464.16 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:11])=[N:4][C:5]([S:9][CH3:10])=[N:6][C:7]=1[Cl:8].ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Br:1][C:2]1[C:3]([NH2:11])=[N:4][C:5]([S:9]([CH3:10])=[O:20])=[N:6][C:7]=1[Cl:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(N)c(Br)c(Cl)n1
Solvent: ClCCl
Product: CS(=O)c1nc(N)c(Br)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a stirring solution of 5-bromo-6-chloro-2-(methylthio)pyrimidine-4-amine (intermediate 1) (52.2 mmol) in 450 ml of DCM, a solution of 12.9 g (57.4 mmol) of m-chloroperbenzoic acid (77%) (Sigma-Aldrich) in 100 ml of DCM was slowly added. The reaction mixture was stirred at room temperature for 1 hour. The formed white precipitate was filtered, washed several times with DCM and dried. 13.96 g of 5-bromo-6-chloro-2-(methylsulfinyl)pyrimidine-4-amine were obtained (98.9%).
Reaction SMILES: I[CH2:2][CH2:3][C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].[C-:17]#[N:18].[Na+].O.[CH3:21]S(C)=O>>[F:15][C:4]([F:16])([C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8])[CH2:3][CH2:2][CH2:21][C:17]#[N:18]
Reactant: [C-]#N
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Reactant: CS(C)=O
Agent: [Na+]
Solvent: O
Product: N#CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 66 %

Procedure:
1-Iodo-3,3,4,4,5,5,6,6,6-nonafluorohexane (10.0 g, 26.2 mmol) and sodium cyanide (3.85 g, 78.6 mmol) were stirred in dimethyl sulfoxide (50 ml) for 30 minutes at 60° C. Water was added to the reaction mixture, which was then extracted with ether. The resulting organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give 4,4,5,5,6,6,7,7,7-nonafluoroheptanecarbonitrile (4.7 g, Yield 66%) as a brown oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:19][C:20]1[CH:21]=[C:22]([C@@:27]2([CH2:33][CH2:34][OH:35])[O:32][CH2:31][CH2:30][NH:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26]>C(#N)C>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([N:29]2[CH2:30][CH2:31][O:32][C@:27]([CH2:33][CH2:34][OH:35])([C:22]3[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=3)[CH2:28]2)=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OCC[C@@]1(c2ccc(Cl)c(Cl)c2)CNCCO1
Solvent: CC#N
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCO[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)phenylacetic acid (10.0 g, 36.8 mmol) in acetonitrile (100 ml), N,N′-carbonyldiimidazole (9.5 g, 58.8 mmol) was added at room temperature, then (2R)-2-[2-(3,4-dichlorophenyl)morpholin-2-yl]ethanol (17.3 g, 62.5 mol) was further added, and the resulting mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was evaporated to dryness. To the obtained residue, methylene chloride (100 ml), water (100 ml) and concentrated hydrochloric acid (15 ml) were added, and the resulting mixture was partitioned. The separated organic layer was washed with water twice (100 ml each) and evaporated to dryness. The residue obtained was purified by chromatography on a silica gel column to afford the title compound [13.3 g, yield: 68.1%] as an oil.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([C:7]1[S:33][C:10]2[N:11]=[C:12]([NH2:32])[N:13]=[C:14]([C:15]3[CH:20]=[C:19]([O:21][CH2:22][CH:23](OCC)OCC)[C:18]([Cl:30])=[CH:17][C:16]=3[Cl:31])[C:9]=2[CH:8]=1)=[O:6])[CH3:3].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.ClCCl>[CH2:2]([NH:4][C:5]([C:7]1[S:33][C:10]2[N:11]=[C:12]([NH2:32])[N:13]=[C:14]([C:15]3[CH:20]=[C:19]([O:21][CH2:22][CH2:23][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:18]([Cl:30])=[CH:17][C:16]=3[Cl:31])[C:9]=2[CH:8]=1)=[O:6])[CH3:3]
Reactant: C1COCCN1
Reactant: CCNC(=O)c1cc2c(-c3cc(OCC(OCC)OCC)c(Cl)cc3Cl)nc(N)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)c1cc2c(-c3cc(OCCN4CCOCC4)c(Cl)cc3Cl)nc(N)nc2s1
Reaction time: 18 h

Procedure:
Hydrochloric acid was added to a solution of 2-Amino-4-(2,4-dichloro-5-(2,2-diethoxyethoxy)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl amide in THF and the solution stirred for ˜18 hrs. Morpholine was added and the solution stirred, sodium triacetoxyborohydride was added and the resulting suspension stirred for ˜18 hrs. Dichloromethane was added and the mixture washed with aqueous ammonia (0.880), water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a pale yellow solid. The crude product was purified by chromatography on silica eluting with mixtures of ethyl acetate and hexane.
Reaction SMILES: O=O.[S:3]([N:13]1[CH2:16][C:15]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:14]1)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(=O)(O)[O-:22].[Na+]>O.[Pt]>[S:3]([N:13]1[CH2:14][C:15]([CH2:19][OH:20])([C:17]([OH:22])=[O:18])[CH2:16]1)([C:6]1[CH:7]=[CH:8][C:9]([CH3:10])=[CH:11][CH:12]=1)(=[O:4])=[O:5]
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)N2CC(CO)(CO)C2)cc1
Agent: [Pt]
Agent: O=O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CC(CO)(C(=O)O)C2)cc1
Reaction time: 5 h

Procedure:
Oxygen was bubbled rapidly through a stirred mixture of N-tosyl-3,3-bishydroxymethyl azetidine (0.5 g, 0.0018 mol), sodium bicarbonate (0.155 g, 0.0018 mol) and 5% Pt/C (0.3 g) in distilled water (10 ml) at 60° C. for 15 h. Sodium bicarbonate (0.155 g, 0.0018 mol) was added to maintain pH7-8 and the reaction continued a further 5 h. After cooling, the catalyst was filtered off, washed with water and the filtrate acidified with 4N HCl. Extraction with ether (x3), drying and evaporating left a white solid. The catalyst was washed again with water and the above procedure repeated to yield further solid. The whole was recrystallised from ethanol/water to give the title product as white crystals m.p. 148°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([C:9]2[O:15][C:14](=[O:16])[C:11]3([CH2:13][CH2:12]3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].N1C=CC=CC=1.C(Cl)Cl>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([NH:10][C:11]1([C:14](=[O:16])[N:20]([O:21][CH3:22])[CH3:19])[CH2:13][CH2:12]1)=[O:15]
Reactant: CNOC
Reactant: COc1cccc(C2=NC3(CC3)C(=O)O2)c1C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)NC2(C(=O)N(C)OC)CC2)c1C
Temperature: 25 °C
Yield: 69.7 %

Procedure:
A mixture of 5-(3-methoxy-2-methyl-phenyl)-6-oxa-4-aza-spiro[2.4]hept-4-en-7-one (VII, R1=2-Me-3-MeO-Ph, R2═R3═—(CH2)2—, 1.90 g, 8.2 mmol), N,O-dimethylhydroxylamine hydrochloride (0.96 g, 9.9 mmol), pyridine (0.80 mL, 9.9 mmol) and methylene chloride (30 mL) was stirred at room temperature for 1 week. The mixture was diluted with ethyl acetate (150 mL), washed with 5% aqueous HCl (2×50 mL) and saturated aqueous NaHCO3 (2×50 mL), and dried. Removal of the solvent afforded a crude product (2.54 g) as a syrup. The crude product was purified by flash chromatography on a silica gel (75 g) column eluted sequentially with 0, 20, 40, 60, 80, 100% ether in hexanes (200 mL of each) and ethyl acetate (500 mL) to afford 3-methoxy-N-[1-(methoxy-methyl-carbamoyl)-cyclopropyl]-2-methyl-benzamide (1.67 g, 69%) as a white solid, mp 173-175° C. 1H NMR (CDCl3) δ (ppm): 1.15 (m, 2H), 1.53 (m, 2H), 2.23 (s, 3H), 3.22 (s, 3H), 3.69 (s, 3H), 3.82 (s, 3H), 6.67 (s, 1H), 6.86 (d, J=7.9 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 7.13 (t, J=7.9 Hz, 1H); 13C NMR (CDCl3) δ 12.3, 15.1, 33.6, 35.1, 55.6, 61.0, 111.4, 118.6, 124.9, 126.5, 137.4, 157.9, 170.3, 170.9. Calculated for C15H20N2O4: C, 61.63; H, 6.90; N, 9.58. Found: C, 61.24; H, 6.75; N, 9.30.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.CO.[Fe]>[O:14]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)=[CH:11][N:12]=[CH:13]1
Reactant: O=[N+]([O-])c1ccc(-c2cnco2)cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(-c2cnco2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A mixture of 5-(4-nitro-phenyl)-oxazole (2.0 g, 10.5 mmol), iron powder (2.4 g, 42.8 mmol) in acetic acid (5 ml) and methanol (30 ml) was stirred at 60° C. for 1 hour. After filtration through a pad of celite under suction, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (3:4 followed by 3:2) to give 4-oxazol-5-yl-phenyl-amine (1.4 g, 83% yield). 1H NMR (acetone-d6) δ 5.0 (br s, 2H, NH), 6.76 (d, 2H, J=8.7 Hz, Ar), 7.12 (s, 1H, Ar), 7.45 (d, 2H, J=8.6 Hz, Ar), 8.04 (s, 1H, Ar).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.C([N:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH2:16]1)#N.Cl.O1CCO[CH2:24][CH2:23]1>>[O:9]=[C:7]1[NH:15][C:20]([C:19]2[CH:18]=[N:17][CH:16]=[CH:23][CH:24]=2)=[N:1][C:2]2[S:3][C:4]([CH3:12])=[CH:5][C:6]1=2
Reactant: N#CN1C=CC=NC1
Reactant: CCOC(=O)c1cc(C)sc1N
Reactant: C1COCCO1
Agent: Cl
Product: Cc1cc2c(=O)[nH]c(-c3cccnc3)nc2s1

Procedure:
2-Amino-5-methyl-3-ethoxycarbonyl-thiophene (5 g) is solved with 3-cyanopyrimidine (2.7 g) in dioxane (40 ml). Then gaseous HCl is conducted through the solution for 5 hours. The usual workup yields 3,4-dihydro-4-oxo-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine (6 g).
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:27]=3[C:37]([F:40])([F:39])[F:38])[O:23][N:22]=2)=[CH:17][CH:16]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[O:4]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[OH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:27]=3[C:37]([F:38])([F:39])[F:40])[O:23][N:22]=2)=[CH:17][CH:16]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:4]
Reactant: CC(C)(C)OC(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 102.4 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 70 mg, 0.162 mmol) was dissolved in DMF (2 mL) prior to the addition of 4-methylmorpholine (0.107 mL, 0.974 mmol), tert-butyl 3-aminopropanoate-HCl (53.1 mg, 0.292 mmol), and HATU (111 mg, 0.292 mmol). This was stirred overnight before EtOAc and brine were added. The organic layer was washed with brine, 1N HCl, and saturated NaHCO3. The organic layer was then dried (MgSO4), filtered, and concentrated to give tert-butyl 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoate (85 mg, 0.152 mmol, 94% yield): LCMS=559.3 [M+H]+, which was taken to the next step. This material, tert-butyl 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoate (160 mg, 0.286 mmol), was dissolved in CH2Cl2 (1 mL) and TFA (2.0 mL). This was stirred for 1 h and was then concentrated to give single enantiomer 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (147 mg, 0.293 mmol): LCMS=503.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.35 Hz), 7.69 (4 H, d, J=7.91 Hz), 7.52-7.65 (3 H, m), 5.11 (1 H, s), 3.50 (2 H, t, J=6.59 Hz), 2.54 (2 H, t, J=6.81 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C@:8]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7].Br[CH2:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(#N)C>[CH3:54][O:53][C:51](=[O:52])[CH2:50][CH2:49][CH2:48][NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C@:8]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7]
Reactant: COC(=O)CCCBr
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCCN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCCNCCCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 78 °C

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-aminopropylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (30 mg, 0.048 mmol), methyl 4-bromobutanoate (25.9 mg, 0.143 mmol) and potassium carbonate (19.78 mg, 0.143 mmol) in dioxane (1 mL) and Acetonitrile (1 mL) was heated up at 78° C. for 3 hours. LCMS indicated the formation of desired product, the reaction mixture was filtered and the clear solution was purified by prep HPLC to give the title compound as a white solid (10 mg, 29%). LCMS: m/e 729.48 (M+H)+, 2.62 min (method 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)ccn1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccnc(Cl)c2)cc1
Temperature: 150 °C
Yield: 72.8 %

Procedure:
2-Chloro-4-iodopyridine (1.6 mmol), 4-cyanophenyl boronic acid (2.5 mmol), 2 M potassium carbonate (3.3 mmol), tetrakis(triphenyphosphine)palladium(0) (0.01 mmol) and dioxane (8 mL) were combined in a vial and heated by microwave for 10 min at 150° C. The crystallized product was filtered and subsequently dried in vacuo to yield 250 mg of 4-(2-chloropyridin-4-yl)-benzonitrile as yellow needles. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=5.1 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.2 Hz, 2H), 7.55 (m, 1H), 7.43 (dd, J=5.2, 1.4 Hz, 1H); EIMS 214 m/z (M+).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:13]=[C:12]([NH:14][C:15]3[S:16][C:17]([C:23]4[N:24]=[N:25][N:26]([CH2:28][Si](C)(C)C)[CH:27]=4)=[CH:18][C:19]=3[C:20]([NH2:22])=[O:21])[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[CH3:28][N:26]1[CH:27]=[C:23]([C:17]2[S:16][C:15]([NH:14][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:13]=3)=[C:19]([C:20]([NH2:22])=[O:21])[CH:18]=2)[N:24]=[N:25]1
Reactant: C[Si](C)(C)Cn1cc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCOCC4)n3)s2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCOCC4)n3)s2)nn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-{[6-(morpholin-4-ylmethyl)pyridin-2-yl]amino}-5-{1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}thiophene-3-carboxamide (65 mg, 0.14 mmol) in THF (2.0 mL) was added TBAF (1.0 M in THF, 0.276 ml, 0.276 mmol). The reaction was stirred at room temperature for 4 h. The solution was diluted with water and extracted with 5:1 CH2Cl2:MeOH (3×). The combined organic layers were dried (MgSO4), filtered, and evaporated. The crude solid was triturated with CH2Cl2 and filtered to isolate the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: OCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. ES-MS m/e (%): 294 (M+H+, 100).