Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Cl[C:30]1[N:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:39][O:38][C:36](=[O:37])[C:33]1[CH:32]=[CH:31][C:30]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:35][CH:34]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)nc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 9.1 %

Procedure:
To a solution of 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (200 mg, 0.48 mmol, Example 56, step 4) in N′N-dimethylformamide (2.0 ml) were added methyl 6-chloropyridine-3-carboxylate (93 mg, 0.53 mmol) and potassium carbonate (199 mg, 1.44 mmol). The mixture was stirred for 4 h at 110° C. After cooling to r.t. water was added and the mixture was extracted twice with AcOEt. The organic phases were washed with water and brine, dried (MgSO4) and concentrated. The product was purified by column chromatography (silica gel, heptane/AcOEt 4:1) to give the title compound (24 mg) as light yellow solid. MS (m/e)=551.2 [M+H+].
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:21]1[CH:22]=[CH:23][S:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccc2c(cc(-c3ccsc3)n2Cc2ccccc2)n1
Temperature: 25 °C

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.10 g, 0.31 mmol, from Example 62, Step 2) and 3-thienylboronic acid (0.044 g, 0.34 mmol, Aldrich) and Na2CO3 (0.16 g, 1.6 mmol) in 1,2-dimethoxyethane (3 mL) and water (0.6 mL) was degassed by a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.031 mmol) was added and the reaction was stirred at reflux for 15 minutes. Upon cooling to room temperature, the reaction was diluted with water. The product was extracted with EtOAc, and the combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. Flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes afforded product as a light yellow solid (47 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 7.43-7.37 (m, 2H), 7.36-7.27 (m, 4H), 7.20 (dd, J=5.0, 1.3 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 7.02-6.96 (m, 2H), 6.80 (d, J=0.8 Hz, 1H), 5.43 (s, 2H). LCMS (M+H)+: 324.9.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][C@@H:10]([CH3:25])[C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:26]Br.O>CO>[OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][C@@H:10]([CH3:25])[C@@H:11]2[C:12](=[O:14])[CH2:13][Br:26])[CH2:3]1
Reactant: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@@]21C
Reactant: BrBr
Solvent: O
Solvent: CO
Product: C[C@@H]1C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]2(C)[C@H]1C(=O)CBr

Procedure:
3α-Hydroxy-16α-methyl-5α-pregnane-11,20-dione (5 g.) was dissolved in dry methanol (350 ml.) and treated at 0° with a solution of bromine (1 ml.) in dry methanol (24 ml.) at such a rate that the yellow colour disappeared before further addition. After completion of the addition the mixture was poured into water. The precipitated product was dried and dissolved in chloroform (20 ml.) and put onto a column of silica gel MFC (700 g.). Elution with benzene:ethyl acetate (21/2:1) gave the title compound (3.6 g.) as a foam, [α]D + 112.4°.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].CN(C=O)C.[H-].[Na+].O([CH:18]=[CH:19][C:20](=[N:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C1C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([S:3][CH:18]=[CH:19][C:20](=[N:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:2]
Reactant: CCS
Reactant: C(=CC(=Nc1ccccc1)Oc1ccccc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSC=CC(=Nc1ccccc1)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Ethanethiol (0.11 ml) was dissolved to DMF (3 ml), and sodium hydride (60% in oil: 60 mg) was added under ice-cooling, and stirred for 30 minutes at the same temperature. Phenyl 3-phenoxy-N-phenylacrylimidate (0.30 g) was dissolved to DMF (2 ml), and the obtained solution was added to the above mentioned thiolate solution under ice-cooling, and stirred for two hours at the same temperature and for two hours at room temperature. Ethyl acetate (100 ml) was added to the reaction solution, and it was successively washed with 1N aqueous sodium hydroxide solution, water and aqueous saturated sodium chloride solution, dried over magnesium sulfate (anhydrous), concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain phenyl 3-ethylthio-N-phenylacrylimidate (0.14 g) as yellow oil.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5]CC)=O.[Br:10][C:11]1[CH:12]=[C:13]([CH2:18]Br)[C:14]([NH2:17])=[N:15][CH:16]=1>C1COCC1.C(OCC)(=O)C.[Zn]>[Br:10][C:11]1[CH:12]=[C:13]2[C:14](=[N:15][CH:16]=1)[NH:17][C:3](=[O:5])[C:2]([CH3:8])([CH3:9])[CH2:18]2
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1ncc(Br)cc1CBr
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)Cc2cc(Br)cnc2NC1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of activated Zn (1.0 g, 15 mmol) and ethyl 2-bromo-2-methylpropanoate (1.24 mL, 6.4 mmol) in THF (8 mL) were added together at 0° C. and stirred for 6 h while warming to room temperature. To this mixture a dropwise solution of 5-bromo-3-(bromomethyl)pyridin-2-amine in THF (5 mL) was added via canula and the reaction mixture was stirred for a further 19 h at rt. The mixture was diluted with ethyl acetate (25 mL) and washed with saturated aqueous NH4Cl (50 mL) and brine (50 mL), dried over magnesium sulphate, and concentrated in vacuo. The crude yellow solid product was triturated with diethyl ether and filtered to obtain the white solid product. Yield 158 mg (49%); 1H NMR (300 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.23 (s, 1H), 7.87 (s, 1H), 2.81 (s, 2H), 1.04 (s, 6H); ESI MS m/z 255, 257 [C10H11N2OBr+H]+.
Reaction SMILES: [N:1]([CH2:4][C:5](=O)[C:6]([OH:8])=[O:7])=[N+:2]=[N-:3].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[N:19]=[C:20]([NH:23][NH2:24])[S:21][CH:22]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]>C(O)(=O)C.C(O)C>[N:1]([CH2:4]/[C:5](=[N:24]\[NH:23][C:20]1[S:21][CH:22]=[C:18]([C:13]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=2)[N:19]=1)/[C:6]([OH:8])=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC(=O)C(=O)O
Reactant: NNc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Solvent: CC(=O)O
Solvent: CCO
Product: [N-]=[N+]=NC/C(=N\Nc1nc(-c2ccc(Cl)c(Cl)c2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
KY-757 3-azido-2-oxopropanoic acid, KY-740 (100 mg, 0.77 mmol) in 5% acetic acid 162 ul was added in to solution of [4-(3,4-Dichloro-phenyl)-thiazol-2-yl]-hydrazine (0.2 gr, 0.77 mmol) in ethanol 2 ml. the reaction mixture was stirred at room temperature for 5 h. and then cooled to room temperature. The yellow solid was precipitated out, filtered and washed by water. Yield 0.1 gr (35%). MS+(ESI) m/z 371.91, calcd mass 371.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7]([C:9]1O[CH:11]=[C:12]([Br:24])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C(O)C.[CH3:31][O:32][CH:33]([O:36][CH3:37])[CH2:34][NH2:35]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7]([C:9]1[N:35]([CH2:34][CH:33]([O:36][CH3:37])[O:32][CH3:31])[CH:11]=[C:12]([Br:24])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:8]
Reactant: COC(CN)OC
Reactant: O=C(NCc1cccc(Cl)c1)c1occ(Br)c(=O)c1OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: COC(Cn1cc(Br)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (1.50 g) in tetrahydrofuran (10 ml)-ethanol (10 ml) was added aminoacetaldehyde dimethyl acetal (0.73 ml) and the mixture was stirred at 60° C. for 1 hr. The solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3–1:2) to give 3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (1.35 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CS(Cl)(=O)=O.[CH:36]([N:39](CC)C(C)C)(C)C.CN.C1COCC1>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([CH2:29][NH:39][CH3:36])=[CH:25][CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CO)cc1
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNCc1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4′-(hydroxymethyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide (610 mg, 1.52 mmol), methanesulfonyl chloride (0.13 mL, 1.7 mmol), and N,N-diisopropylethylamine (0.79 mL, 4.6 mmol) were dissolved in dichloromethane (10 mL) at 25° C. The reaction was stirred for 10 minutes before a 2.0 M solution of MeNH2 in THF (15 mL, 30 mmol) was added. The mixture was stirred for 30 minutes at ambient temperature before it was extracted with 1N HCl (20 mL×2) and saturated NaHCO3 (20 mL×2). The organic extracts were dried over Na2SO4 and evaporated. The crude product was purified by chromatography on silica gel (eluting with 0-20% methanol in dichloromethane) to afford 1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((methylamino)methyl)biphenyl-3-yl)cyclopropanecarboxamide (379 mg, 60%). ESI-MS m/z calc. 414.5, found 415.5 (M+1)+; retention time 2.44 minutes.
Reaction SMILES: [C:1]([S:5]([NH:8][S:9](F)(=[O:11])=[O:10])(=[O:7])=[O:6])([F:4])([F:3])[F:2].FC(F)(F)S(N)(=O)=O.S(Cl)([Cl:23])=O.ClS(O)(=O)=O>>[C:1]([S:5]([NH:8][S:9]([Cl:23])(=[O:11])=[O:10])(=[O:7])=[O:6])([F:4])([F:3])[F:2]
Reactant: O=S(=O)(F)NS(=O)(=O)C(F)(F)F
Reactant: O=S(Cl)Cl
Agent: NS(=O)(=O)C(F)(F)F
Agent: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)NS(=O)(=O)C(F)(F)F

Procedure:
This example illustrates synthesis of CF3SO2NHSO2F by the reaction of trifluoromethane sulfonamide (CF3SO2NH2), thionyl chloride (SOCl2), chlorosulfonic acid (ClSO3H) to produce CF3SO2NHSO2Cl intermediate, which is then fluorinated with anhydrous hydrogen fluoride (HF) to produce CF3SO2NHSO2F.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[NH:15][C:14]4=[O:24])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1)#[CH:26].CN(C=O)C>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.[Cu]I.CCN(CC)CC>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:24])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:26]#[C:25][C:27]3[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Reactant: C#Cc1ccc(C=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(C#Cc4ccc(C=O)cc4)n[nH]c3c1)C(=O)N2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 12.2 %

Procedure:
To a mixture of (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxyspiro [cyclopropane-1,3′-indolin]-2′-one (862 mg, 2 mmol), 4-ethynylbenzaldehyde (286 mg, 2.2 mmol), Pd(PPh3)2Cl2 (28 mg, 0.04 mmol, 2 mmol %) and CuI (15.3 mg, 0.08 mmol, 4 mmol %) in a 50 mL of flask was added DMF (6 mL) and Et3N (10 mL). The resulting mixture was stirred at 100° C. (oil temp.) for 90 min. After removal of Et3N, H2O (20 mL) was added and the precipates were collected by suction filtration. Crystals formed in the mother liquor were collected and dried to give the title compound (106 mg) as a yellow solid. The remaining residue was combined and purified by flash chromatography (gradient: EtOAc.hex 0 to 50% to 100%), followed by trituration with H2O to give the title compound (440 mg) as a yellow solid. Total 546 mg (yield 63%). 1H NMR (400 MHz, DMSO-d6) δ 13.63 (s, 1H), 10.44 (s, 1H), 10.05 (s, 1H), 7.98 (d, J=7.6 Hz, 2H), 7.87 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.58 (d, J=8.0 Hz, 1H), 5.63 (s, 1H), 3.29 (s, 3H), 3.22 (t, J=8.4 Hz, 1H), 2.40-2.33 (m, 1H), 1.99 (dd, J=8.8 Hz, 4.8 Hz, 1H); MS ESI 434.2 [M+H]+, calcd for [C27H19N3O3+H]+ 434.1.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[NH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1.N1C=CC=CC=1>C(OCC)(=O)C>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: Nc1nccs1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1nccs1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 4-nitrophenyl chloroformate, 5.04 g (25 mMole), in 25 ml of dry ethyl acetate was added dropwise to an ice cooled, stirred solution of 2-aminothiazole, 5.01 g (50 mMole) in dry ethyl acetate, 25 ml, and dry pyridine, 50 ml. The ice bath was removed as the reaction mixture became viscous. Stirring was continued at 22° C. for three hours. Ethyl acetate was added. The insolubles were filtered, rinsed with ethyl acetate, with water, with acetone, dried and recrystallized from acetone furnishing 3.55 g of 2-(4-nitrophenoxycarbonyl)aminothiazole, m.p 211°-212° C. dec, which was characterized by nuclear magnetic resonance, mass spectra, infrared spectra and elemental analyses.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][CH:16]=[CH:17][C:18]2[CH:70]=[C:21]3[N:22]=[C:23]([CH3:69])[C:24]([C@H:58]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])[C:59]([O:61][CH2:62][CH3:63])=[O:60])=[C:25]([N:26]4[CH2:31][CH2:30][C:29]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][C@H:38]([O:40][Si](C(C)(C)C)(C5C=CC=CC=5)C5C=CC=CC=5)[CH3:39])([CH3:32])[CH2:28][CH2:27]4)[N:20]3[N:19]=2)=[C:13]([F:71])[C:12]([F:72])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(O)C.C1COCC1.[Pd]>[C:65]([O:64][C@@H:58]([C:24]1[C:23]([CH3:69])=[N:22][C:21]2[N:20]([N:19]=[C:18]([CH2:17][CH2:16][CH2:15][C:14]3[C:9]([OH:8])=[CH:10][CH:11]=[C:12]([F:72])[C:13]=3[F:71])[CH:70]=2)[C:25]=1[N:26]1[CH2:31][CH2:30][C:29]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][C@H:38]([OH:40])[CH3:39])([CH3:32])[CH2:28][CH2:27]1)[C:59]([O:61][CH2:62][CH3:63])=[O:60])([CH3:66])([CH3:67])[CH3:68]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3c(OCc4ccccc4)ccc(F)c3F)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(CCCc3c(O)ccc(F)c3F)nn2c1N1CCC(C)(OCCCC[C@@H](C)O)CC1
Yield: 45.6 %

Procedure:
To a solution of (S)-ethyl 2-(2-(3-(6-(benzyloxy)-2,3-difluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (114 mg, 0.114 mmol) in Ethanol (4 mL) was added 10% Pd—C (24 mg, 0.022 mmol) and the resulting mixture was stirred under balloon hydrogen atmosphere for 16 h. At this point LCMS indicates completion of reaction. Mixture was then filtered through a pad of celite, concentrated and dried under high vac. The residue was then treated with 1M TBAF (0.849 mL, 0.849 mmol) in THF (4 mL) for 16 h. Mixture was then concentrated and purified by Biotage (5-70% EtOAc/hexane) to afford (S)-ethyl 2-(tert-butoxy)-2-(2-(3-(2,3-difluoro-6-hydroxyphenyl)propyl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (35 mg, 0.052 mmol, 30% yield) as thick paste. 1H NMR (400 MHz, CDCl3) δ 6.90 (q, J=9.0 Hz, 1H), 6.59 (d, J=10.0 Hz, 1H), 6.36 (s, 1H), 5.91 (br. s., 1H), 4.32-4.15 (m, 2H), 3.85 (d, J=6.3 Hz, 2H), 3.44 (br. s., 3H), 2.94 (br. s., 1H), 2.89-2.71 (m, 4H), 2.63 (s, 3H), 2.15-2.04 (m, 2H), 2.04-1.94 (m, 2H), 1.90 (d, J=6.8 Hz, 2H), 1.75 (d, J=7.3 Hz, 1H), 1.57-1.44 (m, 6H), 1.38-1.27 (m, 12H), 0.94-0.87 (m, 6H). LCMS (M+H)=675.4.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Cl:27])[CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[Cl:27][C:24]1[CH:25]=[C:26]2[C:21]([CH:20]=[CH:19][CH:18]=[C:17]2[CH2:16][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])=[CH:22][CH:23]=1
Reactant: Clc1ccc2cccc(CBr)c2c1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: O=C(O)c1cc2ccccc2n1Cc1cccc2ccc(Cl)cc12

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-7-chloro-naphthalene and the product obtained was hydrolyzed to give 1-(7-chloro-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid as a white solid. MS: 334.0 ([M−H]).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][NH:14][C:15]2[C:16](=[O:32])[N:17]([C:28]([CH3:31])([CH3:30])[CH3:29])[S:18](=[O:27])(=[O:26])[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=O)=O)=CC=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](O)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:28]([N:17]1[C:16](=[O:32])[C:15]([NH:14][CH2:13][CH2:12][O:11][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:18]1(=[O:27])=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: Oc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)OCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCOc2cccnc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 36.6 %

Procedure:
2-[(2-tert-Butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]ethyl 4-methylbenzenesulfonate (150 mg, 0.313 mmol) was dissolved in dry MeCN (3 mL) under nitrogen atmosphere. Pyridin-3-ol (33 mg, 0.345 mmol) was added followed by potassium carbonate (217 mg, 1.567 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 15 mins. Potassium carbonate was filtered off and the reaction mixture was evaporated to dryness in a vacuum centrifuge. The crude product was purified by preparative HPLC affording the title compound (46 mg, 35.7%). 1H NMR (CDCl3, 500 MHz): δ 1.74 (s, 9H), 3.30 (q, 2H), 3.92 (t, 2H), 5.64 (t, 1H), 7.12-7.14 (m, 1H), 7.22-7.24 (m, 1H), 7.46-7.48 (m, 3H), 7.53-7.55 (m, 2H), 8.26-8.28 (m, 2H); 13C NMR (CDCl3, 125 MHz): δ 27.84, 43.32, 61.90, 66.37, 108.51, 121.55, 124.15, 125.03, 129.09, 130.10, 131.69, 135.11, 137.90, 143.23, 154.51, 159.64; Mass Spectrum: M+H+ 402.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C1C(=O)N([Cl:21])C(=O)C1>C1COCC1>[Cl:21][C:7]1[CH:6]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cc1ccc(O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 116.5 %

Procedure:
To a 0° C. solution of ethyl 2-(4-hydroxyphenyl)acetate (5.0 g, 0.02 mol) in THF (100 mL) was added NCS (4.45 g, 0.03 mol). The reaction mixture was then stirred at RT for 16 h and then extracted with EtOAc (2×200 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to afford ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (5 g, 84%) as a solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:28])[CH2:26][OH:27])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12].[F:29][C:30]1[CH:31]=[C:32]([CH:39]=[CH:40][C:41]=1F)[C:33]([N:35]1[CH2:38][CH2:37][CH2:36]1)=[O:34]>C(#N)C>[N:35]1([C:33]([C:32]2[CH:39]=[CH:40][C:41]([O:7][C:8]3[CH:9]=[C:10]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:28])[CH2:26][OH:27])[CH:23]=3)[C:11]([NH:13][C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)=[O:12])=[C:30]([F:29])[CH:31]=2)=[O:34])[CH2:38][CH2:37][CH2:36]1
Reactant: O=C(c1ccc(F)c(F)c1)N1CCC1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)CO)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3F)cc(O[C@@H](C)CO)c2)cn1
Temperature: 160 °C
Yield: 10.7 %

Procedure:
Potassium carbonate (182 mg, 1.32 mmol) was added to a mixture of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (200 mg, 0.66 mmol) and 1-(3,4-difluorobenzoyl)azetidine (137 mg, 0.69 mmol) in acetonitrile (5.0 mL) and the stirred mixture heated at 160° C. in a ‘Smith Creator Microwave’ for 4 hours. The mixture was allowed to reach ambient temperature and pressure and reduced in vacuo. The residual oil was partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate layer was separated, washed with brine, dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (34 mg).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([F:11])([F:10])[C:7]([F:13])([F:12])[C:6]=2[CH:14]=1.N([O-])=O.[Na+].[BrH:19]>O>[Br:19][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([F:11])([F:10])[C:7]([F:13])([F:12])[C:6]=2[CH:14]=1
Reactant: Nc1ccc2c(c1)C(F)(F)C(F)(F)O2
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: FC1(F)Oc2ccc(Br)cc2C1(F)F
Temperature: 3 °C

Procedure:
A stirred mixture of 5-amino-2,2,3,3-tetrafluorobenzofuran (5.0 g, 0.024 mole) and hydrobromic acid (7.3 ml of a 48% aqueous solution) and water (10 ml) was cooled to 3° C. in an ice bath. While maintaining a temperature of less than 5° C., a solution of sodium nitrite (1.7 g, 0.024 mole) in water was added. After complete addition this mixture was stirred for a brief period, then was added slowly to a stirred, refluxing mixture of cuprous bromid (6.9 g, 0.024 mole) in hydrobromic acid (10 ml of a 48% aqueous solution). After complete addition the mixture was stirred at reflux for 20 minutes, then allowed to cool to room temperature. The reaction mixture was poured into a separatory funnel and diluted with ice water. This mixture was extracted several times with diethyl ether. The extracts were combined and washed first with 100 ml of an aqueous saturated sodium chloride solution, then with two 100 ml portions of a 2 N aqueous sodium hydroxide solution. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated at atmospheric pressure, yielding 5.9 g of 5-bromo-2,2,3,3-tetrafluorobenzofuran as an oil.