Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](=[O:14])[CH2:12][Cl:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@@H](C2C=CC=CC=2)[C@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[C:1]([NH:9][C@@H:10]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C@H:11]([OH:14])[CH2:12][Cl:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)c1ccccc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
(3S)-3-Benzoylamino-1-chloro-4-phenyl-2-butanone (301.8 mg, 1.0 mmol) and a formic acid/triethylamine azeotropic mixture (0.2 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.67 mg, 0.001 mmol, s/c=1000) in ethyl acetate (0.5 ml), followed by stirring at room temperature for 2 hours. Quantitative analysis by HPLC revealed production of a desired compound, (2S, 3S)-3-benzoylamino-1-chloro-2-hydroxy-4-phenylbutane (295.6 mg; yield: 97.3%). The production ratio of the desired (2S,3S)-form to the isomeric (2R,3S)-form, (2S,3S):(2R,3S), was 22.6:1. The results of elementary analysis were as follows.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:39])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:37])(=[O:36])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:38])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[F:38][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:39])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:36])(=[O:37])[NH:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)NCc3ccc(OC)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(CNS(=O)(=O)c2ccc(-c3c(C)c(CC(=O)O)cc4ccc(F)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.4 %

Procedure:
Lithium hydroxide monohydrate (0.017 g, 0.43 mmol) was added to a solution {6-fluoro-4-[4-(4-methoxy-benzylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.054 g, 0.10 mmol) in a 3:1 mixture of THF—H2O mixture (6 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove the THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane gave {6-fluoro-4-[4-(4-methoxy-benzylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.052 g, 99%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (br. s, 1 H), 8.22 (t, J=6.40 Hz, 1 H), 8.01 (dd, J=8.80, 6.80 Hz, 1 H), 7.92 (d, J=8.20 Hz, 2 H), 7.89-7.90 (m, 1 H), 7.36-7.44 (m, 3 H), 7.12-7.17 (m, 2 H), 6.80-6.84 (m, 2 H), 6.69 (dd, J=11.20, 2.40 Hz, 1 H), 4.09 (d, J=6.60 Hz, 2 H), 3.82-3.88 (m, 2 H), 3.68 (s, 3 H), 2.06 (s, 3 H). MS calcd. for C27H23FNO5S [(M−H)−] 492, obsd. 492.3.
Reaction SMILES: [CH:1]1[NH:2][C:3]2[N:9]=[C:8]([NH2:10])[N:7]=[C:6](Cl)[C:4]=2[N:5]=1.C(N(CC)CC)C.C[O-:20].[Na+].O>C(O)C>[NH:7]1[C:6](=[O:20])[C:4]2[NH:5][CH:1]=[N:2][C:3]=2[N:9]=[C:8]1[NH2:10]
Reactant: C[O-]
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1nc2nc[nH]c2c(=O)[nH]1

Procedure:
6-Chloroguanine derivative prepared in Preparation 6 (100 mg) was dissolved in 10 ml of ethanol, 32 ml of triethylamine and 53 mg of sodium methoxide were added, and the resulting mixture was refluxed for 4 hours. The reaction was stopped by adding 10 ml of water. The reaction solution was extracted with dichloromethane and distilled under reduced pressure. The residue was purified by silica gel column to give a compound wherein 6-position of guanine was substituted by ethoxy group.
Reaction SMILES: ClN1C(=O)CCC1=O.N1C=CC=CC=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=[N:22][OH:23].[CH2:24]([O:26][C:27](=[O:36])/[CH:28]=[C:29](/N1CCCC1)\[CH3:30])[CH3:25].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:24]([O:26][C:27]([C:28]1[C:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)=[N:22][O:23][C:29]=1[CH3:30])=[O:36])[CH3:25]
Reactant: ON=Cc1ccccn1
Reactant: CCOC(=O)/C=C(\C)N1CCCC1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(-c2ccccn2)noc1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 10.7 %

Procedure:
To a solution of N-chlorosuccinimide (46.58 g, 349 mmol) in chloroform (211 mL) and pyridine (2.8 mL, 35 mmol) was added at room temperature within 15 min a solution of pyridine-2-carbaldehyde oxime (42.6 g, 349 mmol) in chloroform (1090 mL). The reaction mixture was stirred at 50° C. for 3 h and then cooled to room temperature. Within 15 min a solution of (E)-3-pyrrolidin-1-yl-but-2-enoic acid ethyl ester (63.9 g, 349 mmol) in chloroform (42 mL) was added to the reaction mixture, which then was heated again to 50° C. and a solution of triethylamine (48.6 mL, 349 mmol) in chloroform (42 mL) was added dropwise within 1 h. After stirring at 50° C. for 1 h the reaction mixture was cooled to room temperature and then poured on ice water (2 L). Extractive workup followed by drying over sodium sulfate, filtering and evaporation of the organic solvent furnished a dark brown oil. Chromatographic purification (silica, heptane:AcOEt=80:20 to 50:50) afforded the title compound (8.7 g, 11%) as a yellow oil MS: m/e=233.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][NH2:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.[C:33]([C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39])#[N:34].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:33]([C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH:20][O:19][CH:16]1[CH2:17][CH2:18][N:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[CH2:14][CH2:15]1)=[O:39])#[N:34]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(C(=O)NOC2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 35.9 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (160 mg, 0.84 mmol) was added to a solution of O-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yl)hydroxylamine (238 mg, 0.70 mmol), 1-hydroxybenzotriazole (114 mg, 0.84 mmol), 3-cyanobenzoic acid (103 mg, 0.70 mmol) and N,N-diisopropylethylamine (271 mg, 2.10 mmol) in N,N-dimethylformamide (6 ml). The reaction mixture was stirred at room temperature for 17 hours and quenched with H2O (10 ml) and aqueous 1 N HCl solution (pH=3). The aqueous phase was extracted with CH2Cl2 (20 ml×3) and the combined organic phase was washed with aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane: 33/67) to give 3-cyano-N-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxy)benzamide (118 mg, 36%) as a white solid: LCMS: 470 [M+1]+. 1H NMR (DMSO-d6) δ: 1.77 (s, 2H), 1.92 (s, 2H), 3.02 (s, 2H), 3.12 (s, 2H), 4.03 (s, 1H), 7.67 (m, 3H), 8.01 (m, 5H), 11.7 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][CH:22]=2)[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=2)[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:17])[F:15])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(N(CCOc2ccc(C=O)cc2)CC2CC2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(N(CCOc2ccc(CO)cc2)CC2CC2)cc1C(F)(F)F
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
To a solution of 4-((cyclopropylmethyl){2-[(4-formylphenyl)oxy]ethyl}amino)-2-(trifluoromethyl)benzonitrile (0.0701 g, 0.181 mmol) in MeOH (1 mL) at 0° C. was added NaBH4 (0.0034 g, 0.090 mmol) in one portion. The mixture was stirred 15 min, quenched by dropwise addition of NH4Cl (sat'd) and poured into water. The whole was extracted with CH2Cl2 (×3), combined organic portions were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.0556 g of the title compound as a colorless film: 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J=8.9 Hz, 1H), 7.28 (app. d, J=8.4 Hz, 2H), 7.12 (d, J=2.4 Hz, 1H), 6.91 (dd, J=8.9, 2.5 Hz, 1H), 6.83 (app. d, J=8.5 Hz, 2H), 4.61 (s, 2H), 4.16 (t, J=5.6 Hz, 2H), 3.91 (t, J=5.6 Hz, 2H), 3.40 (d, J=6.3 Hz, 2H), 1.69 (bs, 1H), 1.14-0.99 (m, 1H), 0.69-0.59 (m, 2H), 0.36-0.28 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:18])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][O:1][C:2]2[C:11]3[C:6](=[C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:8]=[CH:9][CH:10]=3)[O:5][C:4](=[O:18])[C:3]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:29][CH2:30]1
Reactant: ClCCN1CCOCC1
Reactant: O=c1oc2c(-c3ccccc3)cccc2c(O)c1-c1ccccc1
Product: O=c1oc2c(-c3ccccc3)cccc2c(OCCN2CCOCC2)c1-c1ccccc1
Yield: 75 %

Procedure:
15.7 g. (0.05 mol) of 4-hydroxy-3,8-diphenyl-coumarin are treated, as in Example 8, with 9.7 g. (0.065 mol) of 1-chloro-2-morpholinoethane. After recrystallisation from isopropanol, 16 g. are obtained. M.P. 106°-108° C. Yield 75% (theoretical yield 21.3 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH2:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:18])=[O:17])[C:4]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33].C[OH:35]>>[OH:35][CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][CH2:19][S:16]([NH:15][C:5]1[C:4]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[C:3]([O:2][CH3:1])[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=1)(=[O:17])=[O:18]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)CCC(C)(C)C)nc(-c2ncccn2)nc1OC
Reactant: CO
Product: COc1ccccc1Oc1c(NS(=O)(=O)CCC(C)(C)CO)nc(-c2ncccn2)nc1OC
Reaction time: 48 h

Procedure:
Streptomyces rimosus subsp. rimosus ATCC10970 maintained on a quarter strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flask containing 50 ml of AS-7H inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron™ Shaker with 1″ throw. 2 mls of this inoculum medium was then transferred to twenty six 300 ml Erlenmeyer flask containing 50 ml of AP-5H production medium and incubated under the same conditions for a further 24 hours. At this point 4.5 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-3,3-dimethyl-1-butanesulfonamide (Preparation 1) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 20 hours. The flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid, 430 mg .
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][NH:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][N:33]([C@H:34]1[CH2:35][CH2:36][C@H:37]([CH3:40])[CH2:38][CH2:39]1)[C:6](=[O:8])[CH:5]=[CH:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1]
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: O=C(O)C=Cc1ccccc1Cl
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCN(C(=O)C=Cc1ccccc1Cl)[C@H]1CC[C@H](C)CC1

Procedure:
Using 1.1 g of 2-chlorocinnamic acid, 1.4 ml of diethyl chlorophosphate, 1.4 ml of triethylamine, 60 ml of methylene chloride, 1.4 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexyl amine (Example 78), and 0.25 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 1.94 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-2-chlorocinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [N:1]1([CH2:7][C:8]2([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:21]([N:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)([CH3:23])[CH3:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[CH:21]([N:24]1[CH2:29][CH2:28][CH:27]([O:20][C:17]2[CH:16]=[CH:15][C:14]([C:8]3([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:19][CH:18]=2)[CH2:26][CH2:25]1)([CH3:23])[CH3:22]
Reactant: CC(C)N1CCC(O)CC1
Reactant: Oc1ccc(C2(CN3CCOCC3)CCOCC2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)N1CCC(Oc2ccc(C3(CN4CCOCC4)CCOCC3)cc2)CC1
Yield: 12 %

Procedure:
The title compound (52 mg, 12%) was prepared using 4-[4-(morpholin-4-ylmethyl)tetrahydro-2H-pyran-4-yl]phenol, 1-isopropyl-4-hydroxypiperidine (step 1 of intermediate 21), PPh3 and DIAD similarly to the procedure used for intermediate 55. 1H NMR (400 MHz, CD3OD) δ 1.09 (d, 6H), 1.74-1.80 (m, 2H), 1.83-1.90 (m, 2H), 1.98-2.04 (m, 2H), 2.12-2.18 (m, 6H), 2.40 (s, 2H), 2.47 (t, 2H), 2.75 (m, 1H), 2.80-2.85 (m, 2H), 3.47-3.54 (m, 6H), 3.71-3.77 (m, 2H), 4.36 (m, 1H), 6.90 (d, 2H), 7.28 (d, 2H). HRMS ESI+ m/z 403.2951 [MH]+.
Reaction SMILES: [K].[C:2]([C:4](=[CH:9][CH:10]([CH3:12])[CH3:11])[CH2:5][C:6]([OH:8])=[O:7])#[N:3]>CO>[C:2]([C@@H:4]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][C:6]([OH:8])=[O:7])#[N:3]
Reactant: CC(C)C=C(C#N)CC(=O)O
Agent: [K]
Solvent: CO
Product: CC(C)C[C@H](C#N)CC(=O)O
Temperature: 45 °C
Reaction time: 0.17 h

Procedure:
A glass liner is charged with the potassium salt of 3-cyano-5-methylhex-3-enoic acid (from Example 1B) and methanol and placed in a 600 mL PARR hydrogenation vessel. The vessel is purged with nitrogen and then with hydrogen via charging to 60 psi and stirring for 10 minutes to ensure thorough equilibration of gases and releasing of the pressure on five cycles. The vessel is heated to 45° C., and a solution of [(R,R)-MeDuPHOS]Rh(COD)BF4− in deoxygenated methanol (11 mg in 10 mL) is added via syringe. The vessel is again purged with hydrogen and then pressurized to 60 psi with stirring. Periodically, hydrogen is added to maintain the pressure between 50 to 65 psi. Hydrogen uptake ceases after 120 minutes. After 2 hours, the mixture is cooled to room temperature, the pressure is released, and the solvent is removed to give the crude product. A small sample is removed and acidified with 1 N HCl to give (S)-3-cyano-5-methylhexanoic acid. GC analysis shows >99% conversion with 96.7% e.e S isomer.
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([NH:24][C@H:25]([C:29]([O:31]CCCC)=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:23])=[C:18]([O:36][CH3:37])[CH:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.CO.O.[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:39]=[CH:38][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([NH:24][C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:23])=[C:18]([O:36][CH3:37])[CH:17]=4)=[CH:14][CH:15]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CCCCOC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1OC)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)ccc1C(=O)N[C@H](C(=O)O)C(C)C
Temperature: 50 °C
Yield: 128.3 %

Procedure:
Butyl N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-L-valinate (0.02 g, 0.03 mmol) was suspended in THF (1 mL), MeOH (1 mL) and water (0.5 mL), and then LiOH (0.01 g, 0.35 mmol) was added. The reaction mixture was heated at 50° C. for 3 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure and acidified with 2N HCl. The resulting solid was collected by filtration and purified by HPLC (15-80% CH3CN in H2O/0.1% TFA gradient), yielding 19 mg (91%) of the title compound. LC/MS m/z 494.1 (MH+), retention time 3.47 min. 1H NMR (400 MHz, CD3OD) δ 1.06 (d, 6H), 2.32-2.39 (m, 1H), 4.10 (s, 3H), 4.60 (d, 1H), 7.05 (t, 1H), 7.35-7.58 (m, 4H), 7.60 (d, 2H), 7.80 (d, 2H), 8.05 (d, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C@@H:10]1[CH2:14][O:13][C@@H:12]2[C@H:15]([O:18][C:19]3[N:20](COCC[Si](C)(C)C)[C:21]4[C:22]([N:40]=3)=[N:23][C:24]([C:28]3[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:30][CH:29]=3)=[C:25]([Cl:27])[CH:26]=4)[CH2:16][O:17][C@H:11]12>C(Cl)Cl>[CH3:8][O:9][C@@H:10]1[CH2:14][O:13][C@@H:12]2[C@H:15]([O:18][C:19]3[NH:20][C:21]4[C:22]([N:40]=3)=[N:23][C:24]([C:28]3[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:30][CH:29]=3)=[C:25]([Cl:27])[CH:26]=4)[CH2:16][O:17][C@H:11]12
Reactant: CO[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
TFA (0.7 ml, 9.09 mmol) was added to a stirred solution of 2-[[2-[[(3R,3aR,6R,6aR)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-5-(4-phenylphenyl)-imidazo[4,5-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane in DCM (0.7 ml). The reaction mixture was stirred at room temperature. After 1.5 hours, the reaction mixture was evaporated under reduced pressure to give a colorless residue. This material was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile+0.05% TFA flush. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C25H22ClN3O4 463.13 observed m/e: 464.16 (M+H)+ (Rt 1.21/2 min); 1H NMR δ (ppm) (CD3OD): 8.10 (s, 1H), 7.78 (ab qt, J=8.2 Hz, J=11.5 Hz, 4H), 7.72 (d, J=8.0 Hz, 2H), 7.50 (t, J=7.8 Hz, 2H), 7.40 (t, J=7.5 Hz, 1H), 5.62 (qt, J=5.0 Hz, 1H), 5.02 (t, J=5.3 Hz, 1H), 4.65 (t, J=4.8 Hz, 1H), 4.18 (dd, J=4.4 Hz, J=10.6 Hz, 1H), 4.14 (dd, J=5.4 Hz, 10.6 Hz, 1H), 3.99-4.03 (m, 1H), 3.98 (t, J=7.2 Hz, 1H), 3.64 (t, J=8.3 Hz, 1H), 3.49 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[CH2:25]([C:27]1[N:32]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:31](=[O:40])[C:30]([C:41](O)=[O:42])=[CH:29][CH:28]=1)[CH3:26].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:41]([C:30]5[C:31](=[O:40])[N:32]([C:33]6[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=6)[C:27]([CH2:25][CH3:26])=[CH:28][CH:29]=5)=[O:42])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: CCc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Yield: 36.8 %

Procedure:
Using N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.306 mmol), 6-ethyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (95.9 mg, 0.367 mmol), N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (105 μL, 0.612 mmol) and HATU (151 mg, 0.40 mmol) and in the same manner as in Example 68, the title compound (64.1 mg, 37%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:18][OH:19])[CH2:16][OH:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1C=CC(S(O)(=O)=O)=C[CH:26]=1>C1(C)C=CC=CC=1.CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:18][O:19][C:21]([CH3:26])([CH3:20])[O:17][CH2:16]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC(CO)c1ccc(OCc2ccccc2)cc1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)OCC(c2ccc(OCc3ccccc3)cc2)CO1
Temperature: 30 °C
Reaction time: 18 h
Yield: 79.5 %

Procedure:
To a suspension of 2-(4-(benzyloxy)phenyl)propane-1,3-diol (2.0 gm, 0.00775 moles) in dry toluene (500 ml), dry acetone (20 ml) and PTSA (1.2 gm, 0.0062 mole) were added and the reaction mixture was stirred for 18 hours at 30° C. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The organic extract was washed successively with water & brine, dried over sodium sulfate and evaporated under reduced pressure to yield 1.47 gm product as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([OH:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(F)c(OCC(=O)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(F)c(OC[C@@H](O)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c1
Reaction time: 0.25 h

Procedure:
400 mL dry THF, 93 mL of 1M (S)-CBS reagent in toluene, and 30.3 g borane-diethylaniline complex were stirred together 10 min at rt. 3-{2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-ethoxy}-4-fluoro-benzonitrile (40 g) in 1.2 L dry THF was then added through an addition funnel at rt over 10 min. The mixture stirred for 15 min, then was quenched by slow addition of 100 mL MeOH. After gas evolution ceased the mixture was evaporated to a yellow oil. The oil was dissolved in 200 mL diethyl ether, precipitated with 1.2 L of hexanes and stored 18 h at −20° C. The desired product was collected by filtration and dried under vacuum to give 28.9 g. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.38 (m, 2H), 7.3-7.15 (m, 4H), 6.97 (m, 2H), 5.13 (m, 1H), 5.03 (s, 2H), 4.10 (m, 2H), 2.63 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17](O)=[O:18])=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.Cl>C1COCC1>[OH:18][CH2:17][C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)=[CH:12][C:11]=2[CH:13]=1
Reactant: O=C(O)c1ccc2oc(-c3ccc(O)cc3)cc2c1
Agent: Cl
Solvent: C1CCOC1
Product: OCc1ccc2oc(-c3ccc(O)cc3)cc2c1
Reaction time: 2 h
Yield: 35.1 %

Procedure:
Compound 143 (0.21 g, 0.83 mmol) in THF (10 ml) was treated with BH3 THF (4.0 ml of 1.0M) and the reaction was heated to reflux. After 2 hr, the reaction was cooled and then poured into 2N HCl and extracted with EtOAc. The organic layer was dried, concentrated and the product was purified by cloumn chromatography (60% EtOAc/Hexane) to give 144 as a solid (0.07 g, 37%); Mp=248-250°; 1H NMR (DMSO-d6) δ 9.86 (br s, 1 H), 7.72 (d, 2 H, J=8.3 Hz), 7.52-7.49 (m, 2 H), 7.19 (dd, 1 H, J=8.3 Hz, 1.6 Hz), 7.15 (s, 1 H), 6.87 (d, 2 H, J=8.8 Hz), 5.19 (t, 1 H, J=5.2 Hz), 4.56 (d, 2 H, J=4.1 Hz); MS 239 (M−H)−