Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[N:33]1[CH:38]=[C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[CH:36]=[N:35][CH:34]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:42][C:39]5([C:37]6[CH:38]=[N:33][CH:34]=[N:35][CH:36]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: NC1(c2cncnc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cncnc5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(pyrimidin-5-yl)cyclopropanamine (0.074 g, 0.55 mmol, 1.2 eq), EDCI.HCl (0.076 g, 0.4 mmol, 1.2 eq), HOBT (0.054 g, 0.4 mmol, 2 eq) and TEA (0.14 ml, 1.02 mmol, 3 eq) were dissolved in dichloromethane and the above mixture was stirred at room temperature for 18 h. The mixture was then added with water. The Organic layer was separated, washed with water, concentrated and the crude product was purified by Prep. TLC (20 mm thickness) using 5% methanol/DCM as an eluent. Yield: 50 mg (20%) 1H NMR (400 MHz, DMSO-d6): δ 1.33-1.36 (m, 2H), δ 1.42-1.45 (m, 2H), 2.29 (s, 3H), 2.81-2.82 (d, J=4.4 Hz, 3H), 3.96 (s, 3H), 7.14 (s, 1H), 7.33 (dd, J=1.6, 8.4 Hz, 1H), 7.40 (t, J=8.8, 2H), 7.50 (d, J=1.2 Hz, 1H), 7.52 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.97-8.01 (m, 2H), 8.47 (q, J=4.4 Hz, 1H), 8.67 (s, 2H), 8.91 (s, 1H), 9.00 (s, 1H) LCMS: (ES+) m/z=551.2 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][O:12][CH2:11][C@H:10]2[CH3:15])[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[NH:27][CH:26]=1>C(#N)C.CCOC(C)=O>[N:25]1([C:2]2[N:7]=[C:6]([NH:8][C@H:9]3[CH2:14][CH2:13][O:12][CH2:11][C@H:10]3[CH3:15])[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][N:3]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[CH:26]1
Reactant: C[C@@H]1COCC[C@@H]1Nc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H]1COCC[C@@H]1Nc1nc(-n2cnc3ccccc32)ncc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 66.2 %

Procedure:
To a solution of 2-chloro-N-(cis-3-methyl-tetrahydro-2H-pyran-4-yl)-5-nitropyrimidin-4-amine (115 mg) in acetonitrile (5 mL) was added potassium carbonate (300 mg) and benzimidazole (150 mg). The mixture was stirred at 70° C. for 2.5 hours. After diluting with 70 mL EtOAc, the mixture was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Column chromatography (50→100% EtOAc/hexanes) provided 99 mg of the title compound.
Reaction SMILES: [C:1](=[O:6])=[N:2][C:3](Cl)=[O:4].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][NH:36][OH:37])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.O1CCCC1.Cl>O>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[C:3](=[O:4])[NH:2][C:1](=[O:6])[O:37]3)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2ccc(CNO)cc2)cc1
Reactant: O=C=NC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2ccc(Cn3oc(=O)[nH]c3=O)cc2)cc1
Reaction time: 0.5 h
Yield: 53 %

Procedure:
N-(Chlorocarbonyl)isocyanate (0.2 mL, 2.6 mmol) was added dropwise into a cold (−5° C.) mixture of N-{4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ylmethyl}-hydroxylamine (1.1, 2.6 mmol), and tetrahydrofuran (20.0 mL). The reaction mixture was stirred for 30 minutes, poured into water, acidified with HCl (2 N), and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acidic silica gel (hexanes/EtOAc 2:1) gave a white solid (0.68 g, 53% yield): mp 196-198; MS m/e 493 (M+);
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:32][C:33]1[CH:38]=[C:37]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[O:12])=[CH:21][CH:20]=3)[CH:16]=[C:17]2[C:22]([N:24]2[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH:36]=[CH:35][CH:34]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(Cl)c1)N1CCN(C2CCC2)CC1
Yield: 72 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (72%).
Reaction SMILES: [CH2:1](N(CC([O-])=O)CC([O-])=O)[CH2:2][N:3]([CH2:8][C:9]([O-:11])=O)[CH2:4][C:5]([O-])=[O:6].[Na+].[Na+].[Na+].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:30]>>[N:3]([CH2:2][CH2:1][OH:30])([CH2:8][CH2:9][OH:11])[CH2:4][CH2:5][OH:6]
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CC(=O)[O-]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Na+]
Product: OCCN(CCO)CCO

Procedure:
SEQUESTRENE® Na2 (disodium EDTA): 0.05 pbw
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:9]2=[C:10](Cl)[N:11]=1)=[O:5])[CH3:2].[CH3:30][Sn](C)(C)C>CN(C=O)C.CCOC(C)=O.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>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:9]2=[C:10]([CH3:30])[N:11]=1)=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1nc(Cl)c2c(c(-c3ccccc3)cn2-c2ccc(F)cc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C)c2c(c(-c3ccccc3)cn2-c2ccc(F)cc2)c1O
Temperature: 135 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
A mixture of 7-chloro-1-(4-fluoro-phenyl)-4-hydroxy-3-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (60 mg, 0.146 mmol), tetramethyltin (104 mg, 0.584 mmol) and Pd(PPh3)2Cl2 in DMF (1 mL) was stirred at 135° C. for 2 h; then the reaction was cooled, diluted with EtOAc, washed with water and saturated sodium chloride aqueous solution respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, the residue was purified on column to give the desired title product (30 mg); ESI MS (m/z): 391 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:19][CH2:18][O:17][CH2:16]3)[CH:11]=[C:10]([C:20]([O:22]C)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].OS(O)(=O)=O>O1CCOCC1.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:19][CH2:18][O:17][CH2:16]3)[CH:11]=[C:10]([C:20]([OH:22])=[O:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OC2CCOC2)cc(-c2ccc(C)cc2)c1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc(OC3CCOC3)cc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 4′-methyl-5-(tetrahydrofuran-3-yloxy)biphenyl-3-carboxylate (150 mg, 0.46 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added lithium hydroxide (55 mg, 2.3 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then acidified with 2N aq. H2SO4 to pH 4-5 and concentrated in vacuo. The residue was treated with water and extracted with CH2Cl2 (10 mL×3). The combined organic layers were dried (MgSO4), and concentrated to afford the title compound. 1H NMR (CD3OD, 400 MHz): 7.85 (t, J=1.6 Hz, 1H), 7.52 (d, 2H, J=8.4 Hz), 7.48 (dd, 1H=2.4, 1.2 Hz), 7.34 (dd, 1H, J=2.4, 1.6 Hz), 7.28 (d, 2H, J=8.4 Hz), 5.15 (m, 1H), 4.05-3.87 (m, 4H), 2.38 (s, 3H), 2.36-2.27 (m, 1H), 2.20-2.11 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:12]1([O:11][C:4]2[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([O:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ncc(Oc2ccccc2)cc1OC1CCCC1
Temperature: 100 °C
Yield: 60 %

Procedure:
5-Chloro-3-cyclopentyloxy-2-nitro-pyridine (0.8 mmol) is dissolved in DMF (8 ml), phenol (3 eq.) and K2CO3 (4 eq.) is added. The reaction mixture is heated to 100° C. in the microwave for 60 min. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-Cyclopentyloxy-2-nitro-5-phenoxy-pyridine is obtained after column chromatography (heptane/ethyl acetate) as yellow oil in a yield of 60%; HPLC (method C): 2.23 min; LC-MS (method A): 2.31 min, 301.15 (M+H+).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:49])[N:32]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:33]1[S:34][C:35]([CH:39]=[O:40])=[C:36]([Cl:38])[N:37]=1)([CH3:29])([CH3:28])[CH3:27].O>O1CCCC1>[C:26]([O:30][C:31](=[O:49])[N:32]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:33]1[S:34][C:35]([CH:39]([OH:40])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)=[C:36]([Cl:38])[N:37]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1nc(Cl)c(C=O)s1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2sc(N(Cc3ccc(Cl)cc3)C(=O)OC(C)(C)C)nc2Cl)c2cccnc21
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 57.4 %

Procedure:
To a solution of 3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 99 mg, 0.25 mmol) in tetrahydrofuran (5 ml) at −20° C. under nitrogen was added 2.0 M solution isopropylmagnesium chloride in tetrahydrofuran (0.2 ml, 0.31 mmol). The reaction mixture was stirred for 1.5 hours, then allowed to warm to 5° C. After the reaction mixture was cooled down to −20° C., a solution of (4-Chloro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (95, 80 mg, 0.2 mmol) in tetrahydrofuran (5 mL) was slowly added. The reaction mixture was stirred for 2.5 hrs, then allowed to warm to 5° C. The reaction mixture was poured into iced water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as an off-white solid (97, 76 mg, 50%). MS (ESI) [M+H+]=661.32, 663.32.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[C:10]([C:14]1[CH:15]=[C:16]([NH2:36])[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH:20]=2)[N:18]=1)([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](=[O:6])[NH:36][C:16]1[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([CH:27]([CH3:29])[CH3:28])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:31])[CH3:32])[CH:20]=2)[N:18]=[C:14]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:15]=1
Reactant: CC(C)[Si](Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1)(C(C)C)C(C)C
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
2,2,2-Trichloroethylchloroformate (1.09 mL, 7.92 mmol) was added to a solution of Intermediate 22a (1.53 g, 3.96 mmol) and DIPEA (2.75 mL, 15.8 mmol) in THF (40 mL) at 0° C. The reaction was stirred at RT for 3 h then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, to give the title compound (2.22 g, 99%). LCMS (Method 4): Rt 5.55 min, m/z 560, 562 [MH+].
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][O:5][CH2:6]Cl.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([O:26][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:9])([CH3:8])[CH3:1])([C:18]([F:19])([F:20])[F:21])[C:22]([F:24])([F:25])[F:23])=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)CCOCOC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
A solution of 2-(trimethylsilyl)ethoxymethyl chloride (25.9 g, 0.155 mol) in CH2Cl2 (50 mL) was added dropwise to a solution of 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol from Step 1 (38.6 g, 0.120 mol) in the same solvent (500 mL) at 0° C. After completion of the addition, the mixture was allowed to warm to room temperature, and stirred for 3 h before it was diluted with CHCl3 (500 mL). The resulting solution was washed successively with 1N HCl (2×), saturated aqueous NaHCO3, water and brine, dried (Na2SO4) and concentrated. The residue was distilled under reduced pressure (bp 128° C./0.9 mmHg) to afford the title compound as a colorless liquid (50.0 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[N:11][N:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]=1[NH2:21].N1C=CC=CC=1.[Cl:28][CH:29]([CH:33]1[CH2:36][CH2:35][CH2:34]1)[C:30](Cl)=[O:31]>CN(C)C=O>[Cl:28][CH:29]([CH:33]1[CH2:36][CH2:35][CH2:34]1)[C:30]([NH:21][C:9]1[N:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[N:12][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:31]
Reactant: O=C(Cl)C(Cl)C1CCC1
Reactant: Nc1c(-c2ccccc2F)nnn1CSc1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Nc1c(-c2ccccc2F)nnn1CSc1ccccc1)C(Cl)C1CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31359.2 %

Procedure:
To a cooled (0° C.), stirred solution of 5-(2-fluorophenyl)-3-phenylsulfenylmethyl-3H-1,2,3-triazol-4-ylamine (1 g, 3.33 mmol) in dimethylformamide (15 ml) was added pyridine (460μl, 4.33 mmol) followed by 2-chloro-2-cyclobutylacetyl chloride (810 mg, 3.83 mmol) and the reaction stirred at 0° C. for 1 hour. The reaction was quenched by partitioning between ethyl acetate (100 ml) and water (100 ml). The layers were separated and the aqueous layer extracted with ethyl acetate (100 ml). The combined organic extracts were washed with citric acid (50 ml, 10% aqueous), sodium bicarbonate (50 ml, sat. aqueous), brine (50 ml). dried (Na2SO4) and the solvent removed in vacuo. The crude product was purified by flash chromatography (40% EtOAc/hexanes) to afford 2-chloro-2-cyclobutyl-N-[5-(2-fluorophenyl)-3-phenylsulfenylmethyl-3H-1,2,3-triazol-4-yl]acetamide (450 g, 31%; 52% based on recovered starting material) as a crystalline solid, m.p. 103-104° C.; δH (400 MHz, CDCl3) 1.79-2.18 (6H, m, CH(CH2)3), 2.83-2.93 (1H, m, CH(CH2)3), 4.28 (1H, d, J=8 Hz, CHCl), 5.58 (1H, d, J=14.3 Hz, PhSCH2A), 5.64 (1H, d, J=14.3 Hz, PhSCH2B), 7.10-7.16 (1H, m, ArH), 7.23-7.41 (7H, m, ArH), 7.79-7.85 (1H, m, ArH), 8.00-8.10 (1H, br m, NH); m/z (ES+) 431 (100%) (35ClM+H+), 433 (40%) (37 ClM+H+).
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[S:21][C:12]2[NH:13][C:14](=[O:20])[C:15]([C:18]#[N:19])=[C:16]([OH:17])[C:11]=2[C:10]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1.C(O[C:40]1(O[Si](C)(C)C)[CH2:42][CH2:41]1)C.[BH3-]C#N.[Na+]>CO>[Cl:8][C:9]1[S:21][C:12]2[NH:13][C:14](=[O:20])[C:15]([C:18]#[N:19])=[C:16]([OH:17])[C:11]=2[C:10]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][N:33]([CH:40]3[CH2:42][CH2:41]3)[CH2:32][CH2:31]2)=[CH:26][CH:27]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: N#Cc1c(O)c2c(-c3ccc(OCC4(O)CCNCC4)cc3)c(Cl)sc2[nH]c1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N#Cc1c(O)c2c(-c3ccc(OCC4(O)CCN(C5CC5)CC4)cc3)c(Cl)sc2[nH]c1=O

Procedure:
A mixture of 2-chloro-4-hydroxy-3-{4-[(4-hydroxy-piperidin-4-yl)methoxy]phenyl}-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile TFA salt (70 mg, 0.128 mmol),[(1-ethoxycyclopropyl)oxy]trimethylsilane (0.103 mL, 0.513 mmol), 3A molecular sieves (30 mg), and NaCNBH3 (32 mg, 0.513 mmol) in MeOH (1 mL) was heated to reflux for 12 h. The reaction was then quenched by the addition of H2O (1 mL) and EtOAc (1 mL). The layers were separated, and the aqueous was extracted with additional EtOAc (2×1 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by RP-HPLC to give the title compound. MS (ESI) m/e 472 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.84 (m, 2H), 0.94 (m, 2H), 1.80 (d, J=12.0 Hz, 2H), 1.94 (m, 2H), 2.97, (m, 1H), 3.40 (m, 4H), 3.86 (s, 2H), 5.22 (s, 1H), 6.92 (d, J=8.82 Hz, 2H), 7.22 (d, J=8.82 Hz, 2H), 8.81 (s, 1H), 10.77 (s, 1H).
Reaction SMILES: [C:1]1([N:7]([CH2:9][CH2:10][OH:11])N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:14]([CH2:28][CH3:29])[C:15]([CH:17]1[CH2:26][C:25](=O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[S:18]1)=[O:16])[CH3:13].S(=O)(=O)(O)O>C(O)C>[CH2:28]([N:14]([CH2:12][CH3:13])[C:15]([CH:17]1[C:26]2[C:6]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[N:7]([CH2:9][CH2:10][OH:11])[C:25]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:18]1)=[O:16])[CH3:29]
Reactant: NN(CCO)c1ccccc1
Reactant: CCN(CC)C(=O)C1CC(=O)c2ccccc2S1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCN(CC)C(=O)C1Sc2ccccc2-c2c1c1ccccc1n2CCO
Temperature: 25 °C
Yield: 85.8 %

Procedure:
To a solution of 2-(N-phenyl-hydrazino)-ethanol (ii) (0.59 g, 1.9 mmol) and 4-oxo-thiochroman-2-carboxylic acid diethylamide (iii) (0.5 g, 1.9 mmol) in ethanol 10 ml was added conc. sulfuric acid 0.5 ml. The reaction mixture was stirred and refluxed for 20 hours. It was then cooled to room temperature and poured onto water 50 ml. The resulting precipitate was collected by filtration and washed with water (3×30 ml). It was then dried in desiccators under vacuum with P2O5 as the drying agent to give the product 11-(2-Hydroxy-ethyl)-6,11-dihydro-5-thia-11-aza-benzo[α]fluorene-6-carboxylic acid diethylamide (iv) as a yellow solid 0.62 g, which was used to next step without further purification. Yield: 86%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[CH:4][CH:3]=1.CN(C(O[N:33]1N=N[C:35]2C=CC=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.NC1CCOCC1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:33][CH:34]([CH3:39])[CH3:35])=[O:22])=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Agent: F[B-](F)(F)F
Agent: NC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)nnn2C)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (94 mg, 0.29 mmol) and TBTU (101 mg, 0.32 mmol) in DMF (1.5 mL) was added DIPEA (245 μL, 1.43 mmol). Then 4-aminotetrahydropyran (56 mg, 0.55 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (82 mg, 70%) as a white solid after recrystallisation from methanol/water. MS: m/e=412.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]([OH:12])=O.Cl.[CH2:14]([O:16][C:17](=[O:21])[CH2:18][NH:19][CH3:20])[CH3:15].CN1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]([N:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:21])[CH3:20])=[O:12]
Reactant: CCOC(=O)CNC
Reactant: O=C(O)C#Cc1ccccc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)CN(C)C(=O)C#Cc1ccccc1F
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a 0° C. slurry of 3-(2-fluorophenyl)prop-2-ynoic acid (151 g, 0.92 mol) in CH2Cl2 (3L) was added DMAP (118 g, 0.96 mol, 1.05 equiv), followed by sarcosine ethyl ester hydrochloride (148 g, 0.96 mol, 1.05 equiv), and NMM (233 g, 2.3 mol, 2.5 equiv). The resulting clear solution was allowed to warm to room temperature and was maintained for 17 h. The reaction mixture was washed with a 2N HCl solution (4×500 mL). The aqueous layers were combined and the mixture was adjusted to pH 2 using conc. H2SO4, then back-extracted with CH2Cl2 (2×500 mL). The organic layers were combined, washed with a 10% H2SO4 solution (2×500 mL), dried (Na2SO4) and concentrated under reduced pressure to give ethyl 2-[3-(2-fluorophenyl)-N-methylprop-2-ynoylamino]acetate (174 g, 72%) as a brown oil: TLC (40% EtOAc/hex) Rf 0.61; 1H NMR (CDCl3; of rotomeric mixture) δ 1.27 (t, J=7.2 Hz, 3H), 3.07 (s, 1.4H, N—CH3), 3.36 (s, 1.6H, N—CH3), 4.17-4.27 (m, 3.2H), 4.41 (s, 0.8H, N—CH2), 7.06-7.17 (m, 2H), 7.37-7.58 (m, 2H); 13C NMR (CDCl3; of rotomeric mixture) δ 14.00, 14.03, 33.5, 37.2, 48.0, 52.5, 61.3, 61.5, 83.6, 84.3, 85.7 (d, JC−F=9.9 Hz, 1C), 108.9 (d, JC−F=15.5 Hz, 1C), 109.1, (d, JC−F=15.5 Hz, 1C), 115. (d, JC−F=10.4 Hz, 1C), 115.6 (d, JC−F=10.4 Hz, 1C), 124.2, 132.0 (d, JC−F=7.8 Hz, 1C), 132.1 (d, JC−F=7.8 Hz, 1C), 134.10, 134.15, 154.6, 163.3 (d, JC−F=254.4 Hz, 1C), 168.1, 168.5; HPLC ES-MS m/z (rel abundance) 264 (MH+, 75%).