Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:26][CH2:27][C:28](O)=O)[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([CH:17]=[C:16]([O:15][CH3:14])[C:21]=1[O:22][CH3:23])[CH2:26][CH2:27][C:28]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Product: COc1cc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)cc(OC)c1OC

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol) and 3-(3,4,5-trimethoxyphenyl)propionic acid (241 mg; 1 mmol) as described in method 2; yield: 0.016 g (4.2%); MS m/z: 381.4 [M+H]+; 1H-NMR (CD3OD, 400 MHz): δ 3.12-3.16 (m, 2H); 3.31-3.33 (m, 2H); 3.70 (s, 3H), 3.77 (s, 6H); 6.56 (s, 2H); 7.94 (d, 1H, 3J=8.7 Hz); 8.15 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.381-8.382 (m, 1H); 9.12 (s, 1H); HPLC (METHOD [A]): rt 10.41 min (89.6%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[S:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:16]=2[N:17]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([S:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[C:4]([Cl:11])[CH:5]=1
Reactant: N#Cc1ccc2nc(Sc3c(Cl)cc([N+](=O)[O-])cc3Cl)sc2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccc2nc(Sc3c(Cl)cc(N)cc3Cl)sc2c1
Yield: 98.2 %

Procedure:
The title compound was prepared using the method of example 270, starting with 2-(2,6-dichloro-4-nitro-phenylsulfanyl)-benzothiazole-6-carbonitrile (260) (1.9 g, 4.97 mmol), tin chloride dihydrate (Aldrich, 5.62 g, 24.9 mmol). Compound 272 (1.72 g, 98%) was obtained as a yellowish solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9]B(O)O)=[CH:5][CH:4]=1)=[O:2].C(N(CC)CC)C.[CH3:20][O:21][C:22](=[O:34])[C:23]1[CH:28]=[C:27](O)[CH:26]=[C:25]([O:30][CH:31]([CH3:33])[CH3:32])[CH:24]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:20][O:21][C:22](=[O:34])[C:23]1[CH:24]=[C:25]([O:30][CH:31]([CH3:32])[CH3:33])[CH:26]=[C:27]([O:9][C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)[CH:28]=1
Reactant: O=Cc1ccc(OB(O)O)cc1
Reactant: COC(=O)c1cc(O)cc(OC(C)C)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Oc2ccc(C=O)cc2)cc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
After adding 1.05 g of molecular sieves 4A, 1.00 g (6.70 mol) of p-formylphenylboric acid, 605 mg (3.30 mol) of copper (II) acetate and 2.32 ml (16.6 mol) of triethylamine to a solution of 700 mg (3.30 mmol) of the obtained phenol compound in methylene chloride (30 ml), the mixture was stirred at room temperature overnight under a oxygen atmosphere. The reaction mixture was filtered and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=5:1) to obtain 593 mg of 3-(4-formylphenoxy)-5-isopropoxybenzoic acid methyl ester (yield: 57%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]([C:34]#[C:35][CH2:36][NH:37][C:38]([NH:40][CH3:41])=[O:39])=[CH:27][C:26]=1[Cl:42].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:42][C:26]1[CH:27]=[C:28]([C:34]#[C:35][CH2:36][NH:37][C:38]([NH:40][CH3:41])=[O:39])[C:29]2[O:33][CH2:32][O:31][C:30]=2[C:25]=1[NH:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: CNC(=O)NCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)NCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Yield: 60.8 %

Procedure:
This was prepared by the method described in example 4 using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (200 mg, 0.59 mmol), N-[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]-N′-methylurea (170 mg, 0.60 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 1.24 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using 10% methanol in dichloromethane as eluent. There was thus obtained the title compound (209 mg, 61%) as a yellow solid; NMR Spectrum:(DMSOd6) 1.96 (quintet, 2H), 2.39 (m, 4H), 2.45 (t, 2H), 2.57 (d, 3H), 3.60 (m, 4H), 3.94 (s, 3H), 4.08 (d, 2H), 4.20 (t, 2H), 5.91 (q, 1H), 6.15 (s, 2H), 6.38 (t, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.81 (s, 1H), 8.32 (s, 1H), 9.51 (s, 1H); Mass Spectrum: M+H+ 583/585.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:18][CH3:19])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)#[N:21].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:18][CH3:19])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:29][NH:28][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:31][CH:30]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(C(=O)NN)cc1
Reactant: CCc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
(2R,3R)-2-(3-chloro-4-cyano-2-ethylphenylamino)-3-hydroxybutanoic acid (700 mg, 2.48 mmol), 4-cyanobenzohydrazide (439 mg, 2.73 mmol) and anhydrous THF (20 mL) were placed in a 50 mL round bottomed flask and the mixture was cooled to −15° C. 1-Hydroxybenzotriazole hydrate (335 mg, 2.48 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (589 mg, 3.07 mmol) at −15° C. followed by triethylamine (0.43 mL, 3.07 mmol). The reaction mixture was maintained at −15° C. and stirred for 1 h after which, stirring continued overnight while the mixture slowly warmed to room temperature. After 18 h, the mixture was filtered under vacuum and the residue washed with THF (30 mL). The THF solution was concentrated to ca. 10 mL, whereupon EtOAc (40 mL) was added followed by water (30 mL). The phases were partitioned and the organic phase washed with water (15 mL), brine (15 mL), dried (Na2SO4), filtered and concentrated to furnish a light brown solid. Purification by flash column chromatography [EtOAc-hexanes (4:1) as eluent] afforded the title compound as a white solid (890 mg, 62%). 1H NMR (500 MHz, acetone-d6, δ in ppm) δ 9.67 (br s, 2H), 8.11 (d, J=8.8 Hz, 2H), 7.96 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.8 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 5.66 (d, J=7.03 Hz, 1H), 4.62 (br s, 1H), 4.32-4.22 (m, 1H), 4.18 (dd, J=1.7 Hz, 7.4 Hz, 1H), 2.94-2.77 (m, 2H) 1.39 (d, J=6.2 Hz, 3H), 1.17 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(C(=O)C(C)C)cc1)C(=O)CC
Product: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(=O)C(C)C)cc1

Procedure:
The title compound was prepared by the method of Preparation 1c using (3-amino-4-chlorophenoxy)acetic acid methyl ester and 2-(4-isobutyrylbenzyl)-3-oxopentanoic acid ethyl ester.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[CH:15]=[C:16]([Cl:32])[C:17]([CH2:29][C:30]#[N:31])=[C:18]([C:27]#[N:28])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:32][C:16]1[C:17]([CH2:29][C:30]#[N:31])=[C:18]([C:27]#[N:28])[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:15]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1cc(Cl)c(CC#N)c(C#N)c1-c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c(CC#N)c(C#N)c1-c1cccc(F)c1
Temperature: 90 °C
Yield: 34.3 %

Procedure:
A mixture of 6-bromo-9H-purine (22 mg, 0.11 mmol), 6-(1-aminoethyl)-4-chloro-3-(cyanomethyl)-3′-fluorobiphenyl-2-carbonitrile (17 mg, 0.054 mmol), and N,N-diisopropylethylamine (0.032 mL, 0.18 mmol) in isopropyl alcohol (0.4 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (8 mg, 30%). LCMS calculated for C22H16ClFN7 (M+H)+: m/z=432.1. found: 432.1.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[C:6]([Br:24])[CH:7]=[C:8]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])[C:9]=2CO)[NH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:24][C:6]1[C:5]2[NH:4][N:3]=[CH:2][C:10]=2[C:9]2[CH2:18][O:17][C:15](=[O:16])[C@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:13][C:8]=2[CH:7]=1
Reactant: COC(=O)C[C@H](Cc1cc(Br)c2[nH]nc(Br)c2c1CO)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2COC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
(S)-Dimethyl 2-((3,7-dibromo-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (440 mg, 1.065 mmol) was dissolved in toluene (30 mL). p-Toluenesulfonic acid monohydrate (28 mg, 0.147 mmol) was added to the mixture. Reaction was warmed to reflux and held for 18 hours with stirring. Mixture was cooled to room temperature and then diluted with ethyl acetate. Material was washed with aqueous sodium bicarbonate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as amber oil in 42% yield. MS (M+H)+=367.2, 369.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].C[Si]([C:20]#[CH:21])(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[CH:8]=[C:9]([OH:10])[CH:21]=[CH:20]2
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Oc1ccc2cc(F)ccc2c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of 2-(4-fluorophenyl)acetyl chloride (5.0g; 29 mmol) in CH2Cl2 was added to AlCl3 (7.73g;58 mmol) in CH2Cl2 at −20° C. over 30 min. Trimethylsilyl acetylene (9.96g; 101.43 mmol) was added also over 30 min and stirred at −10° C. for 1h. The mixture was poured in ice and extracted with EtOAc. The organic phase was washed with water, NaHCO3 and brine. After purification by gel silica chromatography (10% EtOAc in hexane) 2.43 g (36%) of 3-(trimethylsilyl)-6-chloro-2-naphthol was collected. The desylilation was done with TFA in CH2Cl2 at rt overnight. Purification by gel silica chromatography (10% EtOAc in hexane) afforded the title compound in 69% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:15]=[CH:16][C:17]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH2:18][C:19]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])([CH3:21])[CH3:20])[N:6]=1)=[O:4].[BH4-].[Na+].CCCCCC.C(OCC)(=O)C>CO>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:15][CH2:16][C:17]([OH:35])([C:31]([F:32])([F:33])[F:34])[CH2:18][C:19]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])([CH3:21])[CH3:20])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 40, 420 mg (0.85 mmol) of 5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino] quinoline-2-carboxylic acid methyl ester is dissolved in 10 ml of methanol and mixed with 130 mg (3.41 mmol) of sodium borohydride. After chromatography on silica gel with hexane-ethyl acetate (0-100%), 75 mg (18% of theory) of the product is obtained.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][S:13]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=1)(=[O:15])=[O:14]>C(Cl)Cl.C(OCC)(=O)C>[CH3:12][S:13]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24]([CH3:25])=[O:6])[N:19]=1)(=[O:14])=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(COS(C)(=O)=O)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)c1nccc(COS(C)(=O)=O)n1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
m-Chloroperoxybenzoic acid (75%, 2.4 g, 10 mmol) was added to a solution of 4-methanesulfonyloxymethyl-2-methylthiopyrimidine (2.4 g, 10 mmol, Reference Compound No. 8-2) in anhydrous methylene chloride (30 mL) and the mixture was stirred for 15 minutes under ice-cooling. m-Chloroperoxybenzoic acid (0.29 g, 1.3 mmol) was added thereto and the whole was stirred for 10 minutes under ice-cooling. The reaction mixture was diluted with ethyl acetate (100 mL), washed twice with saturated aqueous sodium hydrogencarbonate solution (30 mL), and then washed with brine (30 mL). The aqueous layer was extracted twice with chloroform (100 mL), then the extract was mixed with the ethyl acetate layer, and the whole was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to give 2.2 g of the title Reference Compound as a colorless oil (Yield: 88%).
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([OH:41])[C:37](OC)=[O:38])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([OH:41])[C:37]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)=[O:38])([C:27]([CH3:30])([CH3:28])[CH3:29])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#Cc1ccc(N)nc1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(C#N)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
Trimethylaluminium (2M in toluene) (6.21 mL, 12.42 mmol) was added to 6-aminonicotinonitrile (1.480 g, 12.42 mmol) in toluene (80 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes. (S)-Methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (2.5 g, 6.21 mmol) in toluene (20 mL) was added. The reaction was heated to 110° C. for 2 hours and cooled to RT. The reaction mixture was concentrated. The residue was neutralised with citric acid (1M, aq) and then diluted with water and extracted with EtOAc. The combined organics were dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (1.780 g, 58.5%). 1H NMR (400 MHz, CDCl3) δ 1.04 (9H, s), 3.65-3.69 (3H, m), 3.81-3.91 (4H, m), 4.35 (1H, q), 7.35-7.45 (6H, m), 7.65-7.67 (4H, m), 7.92-7.95 (1H, m), 8.36-8.38 (1H, m), 8.55-8.56 (1H, m), 9.40 (1H, s); m/z (ES+) (M+H)+=490; HPLC tR=3.07 min.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.[CH3:11][N:12]([CH3:16])[C:13](Cl)=[O:14].C(N(CC)CC)C>ClCCl>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[O:10][C:13](=[O:14])[N:12]([CH3:16])[CH3:11])#[N:7]
Reactant: CN(C)C(=O)Cl
Reactant: N#Cc1ccc(F)cc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)Oc1cc(F)ccc1C#N
Yield: 67 %

Procedure:
Under N2, a stirred solution of 4-fluoro-2-hydroxybenzonitrile (685 mg, 5.00 mmol), dimethylcarbamoyl chloride, and triethylamine (606 mg, 6 mmol) in dichloromethane (10 mL) was heated at reflux for 20 hrs. The cooled mixture was diluted with dichloromethane (10 mL) washed with water, and brine. The organic layer was separated, dried (Na2SO4), concentrated, and the residue purified by column chromatography (SiO2, 5% ethyl acetate-CH2Cl2) to provide 700 mg (Yield 67%) of the title compound as a white crystalline solid: 1H NMR (CDCl3, 500 MHz) δ ppm: 3.03 (3H, s, NMe), 3.15 (3H, s, NMe), 6.99 (1H, dt, J=2.5 Hz, 8.5 Hz, Ar—H), 7.23 (1H, dd, J=2.5 Hz, 9.5 Hz, Ar—H), 7.61 (1H, dd, J=9 Hz, 6 Hz, Ar—H); 13C NMR (CDCl3, 125.77 Hz) δ ppm: 36.76, 37.06, 102.84, 102.86, 111.59, 111.79, 113.24, 113.42, 114.99, 134.36, 134.45, 152.54, 155.06, 155.16, 164.26, 166.31. HRMS (ESI) calcd for C10H10N2O2F (M+H) 209.0726, found 209.0722.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[OH:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52]Cl)=[CH:50][CH:49]=1>>[CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][Si:27]([C:40]([CH3:41])([CH3:43])[CH3:42])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[O:44][CH2:52][C:51]1[CH:54]=[CH:55][C:48]([Cl:47])=[CH:49][CH:50]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccc(Cl)cc1
Yield: 48.3 %

Procedure:
General procedure A using using methyl 3,4-di-O-benzyl-6-O-(tert-butyldiphenylsilyl)-β-D-glucopyranoside (0.124 g, 0.202 mmol), NaH (15 mg, 0.303 mmol, 60% in mineral oil) and 4-chlorobenzylchloride (34.2 mg, 0.212 mmol) and gave 72 mg (48%) of 23 as a colorless oil after purification by flash column chromatography on silica gel (10% EtOAc/Hexanes). [α]24D: +6.9° (c 1.16, CH2Cl2); IR (thin film) 2929, 1492, 1428, 1072 cm−1; 1H-NMR (CDCl3) δ 7.82 (dd, J=1.5, 7.9 Hz, 2H), 7.76 (dd, J=1.2, 7.9 Hz, 2H), 7.49-7.31 (m, 18H), 7.27-7.24 (m, 2H), 4.97-4.88 (m, 4H), 4.76 (d, J=10.7 Hz, 1H), 4.75 (d, J=11.3 Hz, 1H), 4.37 (d, J=7.6 Hz, 1H), 3.99 (s, 2H), 3.83 (dd, J=9.2, 9.5 Hz, 1H), 3.71 (dd, J=9.2, 9.2 Hz, 1H), 3.64 (s, 3H), 3.49 (dd, J=7.9, 8.8 Hz, 1H), 3.41-3.39 (m,1H), 1.12 (s, 9H); 13C-NMR (CDCl3) 6138.7, 138.4, 137.4, 136.1, 135.8, 135.0, 133.8, 133.5, 133.3, 129.8, 129.5, 128.7, 128.6, 128.1, 128.0, 127.9, 127.8, 104.6, 84.8, 82.7, 77.9, 76.1, 75.8, 75.4, 74.1, 62.8, 56.9, 27.0, 26.8, 19.5; FAB MS m/z (M)+: calcd 759.2885, obsd 759.2881.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([F:21])([F:20])[F:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.Cl>>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:10]2[C:11]3[C:16](=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)=[O:29])=[CH:26][CH:25]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(OC(F)(F)F)cc23)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Product: COc1ccc(C(=O)n2cc(C3=CCN(C)CC3)c3cc(OC(F)(F)F)ccc32)cc1

Procedure:
(22.2 mg, 67%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethoxy-1H-indole (Example 4h, 20 mg, 0.068 mmol) and 4-methoxybenzoyl chloride (18.3 mg, 0.107 mmol), HRMS-FAB+ for C23H21N2O3F3.HCl, calculated MH+ (--HCl): 431.15826; found: 431.15694.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[CH2:27](O)[CH3:28]>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:27][CH3:28])=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CCO
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Agent: Cl
Product: CCOC(=O)CCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (15.8 mg, 0.047 mmol) was added 1.25M hydrogen chloride in ethanol (1.124 mL, 1.405 mmol). The reaction was stirred at 60° C. for 2 h. The mixture was concentrated and triturated with acetonitrile to give the title compound. LCMS m/z=366.6 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.22 (t, J=7.1 Hz, 3H), 1.24 (d, J=6.9 Hz, 0.5H), 1.56 (d, J=6.5 Hz, 2.5H), 1.75-1.90 (m, 1H), 1.98-2.14 (m, 2H), 2.22-2.38 (m, 1H), 2.66 (t, J=7.4 Hz, 2H), 2.97 (t, J=7.6 Hz, 2H), 3.00-3.21 (m, 3H), 3.30-3.41 (m, 2H), 3.45-3.54 (m, 1H), 3.69-3.79 (m, 1H), 4.11 (q, J=7.1 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H), 7.58 (d, J=8.1 Hz, 2H), 7.62 (d, J=8.1 Hz, 2H).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH3:13][NH:14][CH2:15][C:16]1[S:24][C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:17]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29]([CH:32]=[CH:33][C:34]([OH:36])=O)=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.O>[NH2:25][C:26]1[N:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([N:14]([CH3:13])[CH2:15][C:16]2[S:24][C:23]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[CH:17]=2)=[O:36])=[CH:28][CH:27]=1
Reactant: Nc1ccc(C=CC(=O)O)cn1
Reactant: CNCc1cc2cnccc2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc2cnccc2s1)C(=O)/C=C/c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
EDC hydrochloride (118 mg, 0.62 mmol) was added to a solution of methyl-thieno[3,2-c]pyridine-2-ylmethyl-amine (100 mg, 0.56 mmol), (−3-(6-amino-pyridin-3-yl)acrylic acid (101 mg, 0.62 mmol), HOBt.H2O (83 mg, 0.62 mmol) and triethylamine (235 μL, 1.68 mmol) in anhydrous DMF (5 mL). The mixture was stirred at room temperature overnight then diluted with H2O (10 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic fractions were dried over MgSO4, filtered and evaporated to give a yellow residue which was subjected to flash chromatography on silica gel (10% MeOH: CH2Cl2) to yield the title compound (61.0%). 1H-NMR (300 MHz, CDCl3) δ 9.04 (s, 1H), 8.45 (d, J=5.3 Hz, 1H), 8.26 (s, 1H), 7.76-7.67 (m, 3H), 7.32 (d, J=15.0 Hz, 1H), 6.76 (d, J=15.2 Hz, 1H), 6.53 (d, J=8.3 Hz, 1H), 4.95 (s, 2H), 4.76 (br s, 2H), 3.22 (s, 3M); MS (ES) m/e 325.1 (M+H)+.