Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][C:34]#[N:35])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-:37].[K+].[K+].OO>CS(C)=O>[OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][CH2:33][C:34](=[O:37])[NH2:35])=[CH:28][CH:29]=1)[CH2:20][CH:21]([CH3:22])[CH3:23])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(OCCCC#N)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(OCCCC(N)=O)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 90.1 %

Procedure:
The nitrile from Example 105 (0.32 g, 0.68 mmol) and potassium carbonate (0.23 g, 1.67 mmol) were slurried in DMSO (5 mL) and cooled to 0° C. in an ice bath. Aqueous hydrogen peroxide (1.5 mL) was added slowly, and the reaction stirred at room temperature for 48 hours. The reaction was quenched by pouring into water, and extracting the aqueous layer with ethyl acetate. The combined organic layers were dried (MgSO4), and concentrated in vacuo to a light tan oil. The material was purified by flash chromatography over silica gel eluting with EtOAc/hexanes/10% NH4OH in MeOH (5:4:1) to provide 0.30 g (89%) of a light tan oil. MS (FD+) 489.62. NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]([F:22])([F:21])[F:20].C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:17][CH2:18][C:19]([F:20])([F:21])[F:22])=[CH:4][C:5]([C:8]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[Br:30]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(c2ccc(N)c(OCC(F)(F)F)c2)CCC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C1(c2cc(Br)c(N)c(OCC(F)(F)F)c2)CCC1
Temperature: 25 °C
Yield: 48.5 %

Procedure:
To a stirred solution of ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (2.4 g, 8.3 mmol) in dry CHCl3 (50 mL), NBS (1.4 g, 7.8 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 hat room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents were dried over Na2SO4, filtered and concentrated under educed pressure. The crude reaction mixture was purified by column chromatography to give ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (1.5 g) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]=[C:18]([C:20]([O-])=[O:21])[S:19][C:12]=12.[Li+]>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:20]([C:18]2[S:19][C:12]3[C:13](=[N:14][CH:15]=[CH:16][C:11]=3[Cl:10])[CH:17]=2)=[O:21])=[CH:3][CH:2]=1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: NCCc1ccncc1
Agent: [Li+]
Product: O=C(NCCc1ccncc1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 2-pyridin-4-yl-ethyl amine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 318/320 (MH+); HPLC Rf: 4.08 min.; HPLC purity 99%.
Reaction SMILES: [NH:1]([C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[N:14]([CH3:23])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])=[O:4])[NH2:2].Cl[C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C)C(=O)C>[CH3:23][N:14]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:5]([C:3]([NH:1][NH:2][C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:4])=[CH:13]2
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CN(c1cccc2cc(C(=O)NN)[nH]c12)S(=O)(=O)c1cccs1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CC(=O)NNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of N-[2-(hydrazinocarbonyl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (0.88 g) in N,N-dimethylacetamide (16 mL) was added ethyl 3-chloro-3-oxopropanoate (0.35 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. Diethyl ether was added to the obtained oil, and the resulting crystals were filtrated, washed with diethyl ether, and dried to give the title compound (0.96 g, yield 84%) as colorless crystals. melting point 119-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[O:26][C:25]3[C:16](=[CH:17][C:18]4[CH2:19][C@@H:20]([C:36](O)=[O:37])[N:21]([C@H:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:28][CH3:29])[CH2:22][C:23]=4[CH:24]=3)[N:15]([CH3:39])[C:14]2=[O:40])=[CH:9][CH:8]=1.[CH3:45][O:46][C:47](=[O:65])[C@H:48]([NH2:64])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62]#[N:63])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1>>[CH3:45][O:46][C:47](=[O:65])[C@H:48]([NH:64][C:36]([C@@H:20]1[CH2:19][C:18]2[CH:17]=[C:16]3[C:25]([O:26][C@H:13]([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]5[CH:41]=[CH:42][C:43]([Cl:44])=[C:2]([Cl:1])[CH:3]=5)=[CH:12][CH:11]=4)[C:14](=[O:40])[N:15]3[CH3:39])=[CH:24][C:23]=2[CH2:22][N:21]1[C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][CH3:29])=[O:37])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62]#[N:63])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid was coupled to (R)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester following general procedure 0 to provide (R)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester. Title compound was prepared from (R)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (267 mg) following general procedure B. LC-MS (m/z): 880.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][OH:10].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[Si:20]([O:10][CH2:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH2:1])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(Cl)cc1CO
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cc(Cl)ccc1N
Reaction time: 24 h

Procedure:
To a stirred solution of 2-amino-5-chlorophenylmethanol (11.1 g, 70.4 mmol) in tetrahydrofuran (50 mL) was added imidazole (5.27 g, 77.5 mmol), followed by careful addition of tert-butyldimethylchlorosilane (10.62 g 70.4 mmol). The reaction mixture was stirred for 24 hours. Imidazole (528 mg, 7.75 mmol) and tert-butyldimethylchlorosilane (1.06 g, 7.03 mmol) were then added. After 1 hour the solid was filtered off and washed with diethyl ether (2×20 mL) and the filtrate was washed with water (10 mL), brine (10 mL), dried over magnesium sulfate and concentrated in vacuo to give the product as a brown oil, 18.83 g (98%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([NH2:25])[CH2:21][CH:22]([CH3:24])[CH3:23]>>[Cl:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: CC(C)CCN
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2Cl)cn1
Product: CC(C)CCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(Cl)c1
Yield: 65.7 %

Procedure:
Using a method similar to Example 405, a reaction of 5-(2-chloro-4-formylphenoxy)pyridine-2-carboxamide (0.0388 g, 0.140 mmol) and isoamylamine (0.012 g, 0.140 mmol) gives the title compound (0.0320 g, 65.6%): TOF MS ES+ 348.1 (M+H)+, HRMS calcd for C18H23N3O2Cl 348.1479 (M+H)+, found 348.1466, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.4 min, 100% purity.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14](=[O:21])[C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[NH2:16]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][C@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([O:13][CH3:12])=[O:21])=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: COC(=O)[C@H](N)CC(C)C
Reactant: Cc1cc(C(=O)O)ccc1F
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1ccc(F)c(C)c1

Procedure:
Prepared in a similar manner to example 4 using 4-fluoro-3-methylbenzoic acid and D-leucine methyl ester. MS (M+H, 282).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11]Cl)[S:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][NH:21][CH3:22].C(Cl)Cl>CN(C=O)C>[CH3:20][N:21]([CH2:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=1)[CH3:22]
Reactant: CCOC(=O)c1csc(CCl)n1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1csc(CN(C)C)n1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
2-Chloromethyl-thiazole-4-carboxylic acid ethyl ester (500 mg, 2.431 mmol) and potassium carbonate (504 mg, 3.65 mmol) were dissolved in dry DMF. Dimethylamine hydrochloride (218 mg, 2.67 mmol) in dry DMF was added slowly to the reaction mixture and stirred at RT over three nights. DCM was added and the mixture was washed with concentrated NaHCO3 and water. Organic phase was evaporated to dryness and the product was purified by Flash-chromatography. Yield 34.2%. 1H-NMR (400 MHz; CDCl3): δ 1.41 (t, 3H), 2.49 (s, 6H), 3.99 (s, 2H) 4.43 (q, 2H), 8.20 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=O)[CH:12]=[N:13][CH:14]=1.O>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[N:7][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH:12]=[N:13][CH:14]=1
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1cncc(Br)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)S(=O)N=Cc1cncc(Br)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 101.4 %

Procedure:
To a solution of 2-methyl-propane-2-sulfinamide (11 g, 91 mmol) and 5-bromo-3-pyridine-carboxaldehyde (14 g, 75 mmol) in dichloromethane (500 mL) is added titanium isopropoxide (43 g, 150 mmol). The reaction is then heated at reflux (bath temperature=60° C.) for 4 hours. The resultant mixture is cooled to room temperature and poured into a stirred mixture of diatomaceous earth (50 g) and water (150 mL). The slurry is stirred for 10 min and then filtered. The organic layer from the filtrate is washed with brine and dried over sodium sulfate. Filtration and concentration in vacuo affords 2-methyl-propane-2-sulfinic acid 1-(5-bromo-pyridin-3-yl)-methylideneamide as a yellow solid (22 g, 99%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.C(=O)([O-])O.[Na+].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(OCC)(=O)C>[CH3:26][S:27]([O:1][CH2:2][CH2:3][CH2:4][N:5]([C:6]([O:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[O:12])[CH3:13])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl N-(3-hydroxypropyl)-N-methylcarbamate (12.0 g) and triethylamine (11.5 ml) in ethyl acetate (300 ml), methanesulfonyl chloride (5.4 ml) was added under cooling with ice. After 2 hours' stirring, saturated aqueous sodium hydrogencarbonate solution was added to the reaction liquid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and condensed under reduced pressure to provide 3-[(tert-butoxycarbonyl)-(methyl)amino]propyl methanesulfonate (14.8 g) as an oily substance.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[Na+].Cl[C:16]1[N:24]=[C:23]2[C:19]([N:20]=[CH:21][N:22]2[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[C:18]([NH2:31])[N:17]=1>COCCOC.O>[CH:1]1([CH2:7][O:8][C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)=[C:18]([NH2:31])[N:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCC1
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1nc(OCC2CCCCC2)nc2c1ncn2C1CCCCO1
Temperature: 93 °C

Procedure:
Cyclohexylmethanol (4.5784 g) was diluted with 1,2-dimethoxyethane (99%+) (20 mL) before sodium tert-butoxide (3.853 g) was added gradually with stirring under nitrogen. An exotherm was observed on addition of sodium tert-butoxide. 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2.5428 g) was added and the resultant mixture was heated to reflux at 93° C. (internal). A further quantity of 1,2-dimethoxyethane (99%+) (20 mL) was added to help dissolution and refluxed overnight. The reaction mixture was dissolved in water (100 mL) and extracted with ethyl acetate (100 mL, twice). The combined organic extracts were washed with brine (100 mL) before the organic layer was separated and dried by passing through a hydrophobic frit. Evaporated volatiles under reduced pressure and then azeotroped with toluene (50 mL, twice) to give mobile amber oil. This material was purified by silica chromatography (ISCO) eluting with 0-100% ethyl acetate: cyclohexane). This gave the title compound after placing under vacuo as pale yellow foam (1.0364 g) (94% purity by LCMS, 6% 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine) and was used in next step without further purification.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].[H][H].[C:14]([OH:17])(=[O:16])[CH3:15]>[Pt]=O>[C:14]([OH:17])(=[O:16])[CH3:15].[CH3:5][C:2]([CH:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)([CH3:1])[CH2:3][OH:4]
Reactant: [H][H]
Reactant: CC(C)(CO)c1ccncc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)(CO)C1CCNCC1

Procedure:
4-(1,1-Dimethyl-2-hydroxyethyl)pyridine [which may be prepared as described by Fraenkel et al, J. Amer. Chem. Soc. (1971), 93, 7228; 3 g] was dissolved in acetic acid (30 ml) and hydrogenated in the presence of platinum oxide catalyst for 10 hours at a maximum temperature of 37° C. and a pressure of 50 pounds per square inch, until 100% of the theoretical uptake of hydrogen had occurred. The reaction mixture was then filtered and the filtrate was evaporated under reduced pressure (15 mmHg) to give a pale yellow oil, which was then distilled (b.p. 120° C./0.2 mmHg) to give a colourless oil, which was recrystallised from a mixture of ethanol and diethyl ether to give 4-(1,1-dimethyl-2-hydroxyethyl)piperidine acetate (1.8 g), m.p. 108°-110° C., in the form of colourless crystals.
Reaction SMILES: [OH:1][C@H:2]([C@H:12]([OH:21])[C@H:13]([OH:20])[C:14]#[C:15][C:16]#[C:17][C:18]#[CH:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:22](OCC)(=O)C>C(OCC)C>[OH:1][C@H:2]([C@H:12]([OH:21])[C@H:13]([OH:20])[C:14]#[C:15][C:16]#[C:17][C:18]#[CH:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:22])=[O:10]
Reactant: CCOC(C)=O
Reactant: C#CC#CC#C[C@@H](O)[C@@H](O)[C@@H](O)CCCCCCC(=O)O
Solvent: CCOCC
Product: C#CC#CC#C[C@@H](O)[C@@H](O)[C@@H](O)CCCCCCC(=O)OC
Reaction time: 0.17 h

Procedure:
A quantity of a 1 mg/ml solution in ethyl acetate of 8(S),9(S),10(R)-trihydroxy-11,13,15-hexadecatriynoic acid (10 ml, 34.2 μmols) was stirred at ambient temperature in a flask equipped with a vacuum adapter. A solution of CH2N2 in diethyl ether (1 ml) was added and the progress of the reaction followed by thin layer chromatography. After 10 minutes, vacuum was applied and the excess CH2N2 was removed. The mixture was partially concentrated to 0.2 ml and applied to a short silica gel column. The desired material was eluted with diethyl ether. After partial concentration, the solvent was replaced by repeated removal of CDCl3 under reduced pressure and the reaction quantized by nmr spectroscopy (using an internal standard) to establish recovery of the title compound (6.8 mg, 65%). Structure assignment was supported by the nmr spectrum.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:32])=[C:14]([C:16]2[NH:17][C:18]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH3:31])[N:25]=3)=[CH:19][C:20]=2[C:21]([NH2:23])=[O:22])[CH:15]=1.O>CN(C=O)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:32])=[C:14]([C:16]2[NH:17][C:18]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH3:31])[N:25]=3)=[C:19]([I:1])[C:20]=2[C:21]([NH2:23])=[O:22])[CH:15]=1
Reactant: CNc1nccc(-c2cc(C(N)=O)c(-c3cc(Cl)ccc3C)[nH]2)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: CNc1nccc(-c2[nH]c(-c3cc(Cl)ccc3C)c(C(N)=O)c2I)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.9 %

Procedure:
N-iodosuccinimide (301 mg, 1.34 mmol) was added to a solution of 2-(5-chloro-2-methylphenyl)-5-[2-(methylamino)pyrimidin-4-yl]-1H-pyrrole-3-carboxamide (433 mg, 1.27 mmol) in dry DMF (5 mL). The reaction mixture was stirred at room temperature for 5 h and poured into iced water (50 mL). The solid was then filtered with suction, washed thoroughly with water, dried in an oven under vacuum at 50° C. and purified by flash chromatography over silica gel (DCM/MeOH/7 N NH3 in MeOH 95/5/0.5) to afford the title compound (344 mg, 58%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:33]=[N:34][CH:35]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: OB(O)c1cncc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2cncc(F)c2)c1

Procedure:
(S)-5-Bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1, 60 mg, 0.13 mmol), (5-fluoropyridin-3-yl)boronic acid (60.8 mg, 0.261 mmol), Pd(PPh3)2Cl2 (9.15 mg, 0.013 mmol) and Na2CO3 (41.5 mg, 0.391 mmol) were added to a MW vial. The vial was sealed, evacuated/purged with argon, and DME (553 μL), water (158 μL) and EtOH (79 μL) were added. The RM was subjected to MW irradiation at 120° C. for 15 min. The RM was diluted with DME (2 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g, 103 mg, 0.130 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 12, 15% to 45% in 14 min) to yield the title compound as a yellow solid. UPLC-MS (condition 1) tR=1.90 min, m/z=487.0 [M+H]+, m/z=485.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.27 (t, J=7.58 Hz, 3H) 1.50-1.62 (m, 1H) 1.77-1.89 (m, 1H) 2.15-2.28 (m, 1H) 2.82 (q, J=7.58 Hz, 2H) 2.99 (dd, J=11.00, 6.60 Hz, 1H) 3.08-3.20 (m, 2H) 3.21-3.30 (m, 2H) 3.29-3.38 (m, 1H) 4.60 (br. s, 1H) 7.34 (d, J=8.80 Hz, 2H) 7.38 (d, J=8.07 Hz, 1H) 7.75 (dd, J=7.82, 1.96 Hz, 1H) 7.86 (d, J=9.05 Hz, 2H) 8.02 (d, J=2.20 Hz, 1H) 8.55 (d, J=1.96 Hz, 1H) 8.75 (d, J=2.20 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][CH:12]1[CH2:14][O:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:30])[CH2:27][CH2:28][SH:29].C(N(CC)CC)C>CO>[CH2:1]([O:8][C:9]1[C:18]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][CH:12]([OH:13])[CH2:14][S:29][CH2:28][CH2:27][C:26]([O:25][CH3:24])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCS
Reactant: c1ccc(COc2c(CC3CO3)cccc2C2CCCC2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CCSCC(O)Cc1cccc(C2CCCC2)c1OCc1ccccc1

Procedure:
20 g (59 mmol) of (2-benzyloxy-3-cyclopentylbenzyl)-oxirane, 24.5 g (0.204 mol) of methyl-3-mercaptopropionate and 26.1 g (0.257 mol) of triethylamine are stirred in 150 ml of dry methanol at room temperature and under protective gas (argon or nitrogen) overnight. The solvent is removed by distillation in vacuo, and the residue is chromatographed on a silica gel column (gradient dichloromethane→ethyl acetate). 19.0 g (65% of theory) or methyl 7-(2-benzyloxy-3-cyclopentylphenyl)-6-hydroxy-4-thiaheptanoate are obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=O)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C[Si]([N:57]=[N+:58]=[N-:59])(C)C>C1COCC1>[CH:1]1([N:4]2[C:5]([CH:7]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)=[N:59][N:58]=[N:57]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NC2CC2)CC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nnnn2C2CC2)CC1
Reaction time: 0.08 h
Yield: 24 %

Procedure:
The title compound from Step A above (200 mg, 0.745 mmol) and triphenylphosphine (391 mg, 1.49 mmol) were placed in a 50 ml round bottom flask and then THF (20 ml) was added followed by DIAD (0.29 mL, 1.49 mol) at RT. After 5 min of stirring, trimethylsilylazide (0.2 mL, 1.50 mmol) was added and the resulting mixture was stirred overnight at RT. The volatiles were removed under reduced pressure and the resulting residue was partitioned between ethyl acetate and brine, combined, dried over sodium sulfate, filtered and concentrated. The material was purified by Mass Directed HPLC to give the title compound (52 mg, 24%) as a clear oil/film. ESI-MS calculated for C14H23N5O2: Exact Mass: 293.38. Found 194.35 (M-Boc)+ and 316.36 (MNa)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>C1COCC1>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][C:26]([OH:29])([CH:7]([C:8]([OH:10])=[O:9])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(O)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C(C(=O)O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of phenylacetic acid (13.7 g, 0.100 mol) in THF (90 mL) at 0° C. was slowly added iPrMgCl (2M in Et2O, 100 mL, 0.200 mol). The mixture was stirred at rt for 1 h and then N-Boc-4-piperidone (20.0 g, 0.100 mol) was added as a solid. Stirring was continued for 1 h and then the mixture was quenched with sat. NH4Cl and acidified to pH 2 using concentrated HCl. The mixture was extracted with EtOAc (×3) and the combined organic layers were dried over Na2SO4, filtered and concentrated to give the title compound (33.3 g, 99%) as a colorless foam which was of sufficient purity to continue to the next step: