Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1I.[N+:21]([C:24]1[N:25]=[C:26]2[N:31]([CH:32]=1)[CH2:30][C@H:29]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][N:36]=1)[CH2:28][O:27]2)([O-:23])=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[C:38]1[CH:37]=[N:36][C:35]([CH2:34][O:33][C@H:29]2[CH2:28][O:27][C:26]3=[N:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][N:31]3[CH2:30]2)=[CH:40][CH:39]=1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)c(F)c1
Reactant: CC1(C)OB(c2ccc(CO[C@@H]3COc4nc([N+](=O)[O-])cn4C3)nc2)OC1(C)C
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1O[C@H](Cn2ccnn2)CN1c1ccc(-c2ccc(CO[C@H]3COc4nc([N+](=O)[O-])cn4C3)nc2)c(F)c1
Temperature: 60 °C
Yield: 48.2 %

Procedure:
3-(3-Fluoro-4-iodo-phenyl)-5(R)-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one (90 mg, 0.232 mmol), 2-Nitro-6(S)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylmethoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (108 mg, 0.278 mmol), K2CO3 (244 mg, 0.464 mmol) and Pd(PPh3)4 (27 mg, 0.023 mmol) were combined and suspended in DMF (2 ml) and water (0.2 ml). The mixture was heated to 60° C. for 1½ hours then quenched with sat. aqueous NH4Cl (2 mL) at rt. The mixture was diluted with EtOAc (10 mL) and washed with water (5 mL×5). The organic phases were dried (MgSO4) and concentrated. Column chromatography (2% MeOH/CH2Cl2) provided 60 mg (50%) of the title product as yellow solid. LCMS (ESI) m/z 523 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1)[CH3:2].C([O-])(O)=O.[Na+].[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O.[NH4+].[Cl-]>CC(O)(C)C.CN(C1C=CN=CC=1)C>[C:18]([O:17][C:15](=[O:14])[NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:1][CH3:2])[N:4]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CCc1csc(N)n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CC(C)(C)O
Product: CCc1csc(NC(=O)OC(C)(C)C)n1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
The above prepared 4-ethyl-thiazol-2-ylamine (1.50 g, 11.7 mmol) was dissolved in 23 mL of tBuOH and treated successively with DMAP (0.143 g, 0.1 eq.), NaHCO3 (2.46 g, 2.5 eq.) and BOC2O (2.81 g, 1.1 eq.). After stirring for 0.5 h at 40° C., the reaction mixture was poured onto icewater/NH4Cl, twofold extracted with ethyl acetate, washed with water, dried over sodium sulfate, and evaporated to dryness. Ensuing flash chromatography (SiO2, heptane/ethyl acetate=85/15), yielded finally 2.04 g of the title compound as yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.CO.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[C:18]1([C:2]2[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1
Temperature: 70 °C
Yield: 68.4 %

Procedure:
To a solution of 3A (8.3 g, 30.3 mmol) in THF (50 mL)-MeOH (50 mL) at RT was added phenylboronic acid (7.44 g, 61 mmol), PXPd (489 mg, 0.91 mmol), followed by K2CO3 (16.75 g, 121 mmol). The reaction mixture was stirred at 70° C. in a preheated oil bath for lh. After this time, the reaction mixture was cooled to RT. The reaction mixture was poured into water (100 mL), and the resultant mixture was extracted with EtOAc (3×100 mL). The combined organics were washed with saturated NaCl, dried (Na2SO4), filtered and concentrated. The resulting residue was triturated with 30% EtOAc in hexane. The solid was collected by filtration to give the title compound as an off-white solid (5.6 g, 68%). LC/MS (method A): retention time=2.83 min, (M+H)+=271.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[O:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][CH2:6]1.[Br:16]Br>C(Cl)Cl>[Br:16][C:12]1[CH:13]=[C:14]2[C:9]([C:8](=[O:15])[CH2:7][CH2:6][O:5]2)=[CH:10][CH:11]=1
Reactant: O=C1CCOc2ccccc21
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCOc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.12 h
Yield: 75.9 %

Procedure:
Into a round bottom flask kept at 0° C., AlCl3 (0.533 g, 3.99 mmol) and, 5 mL of CH2Cl2 was added. The reaction system was put under nitrogen and stirred for about 7 minutes before adding 10 mL of a CH2Cl2 solution of 4-chromanone (0.296 g, 1.99 mmol). After the reaction mixture was stirred for 10 minutes, 10 mL of Br2 (0.352 g, 2.20 mmol) was added and, the reaction mixture was stirred at room temperature for an hour. At the end of this period of time, the reaction mixture was poured into 30 mL of ice-water and, the product was extracted 3 times from the aqueous phase with EtOAc. The resultant organic phase was washed once with brine and dried under Na2SO4. After the solvent was evaporated, the solid formed was filtered and dried to obtain 0.361 g (1.51 mmol) of the product (93% pure) in a 74% yield.
Reaction SMILES: N1C2OCC(N)C=2C=CN=1.CO[N:13]=[C:14]1[C:22]2[C:17](=[CH:18][N:19]=[CH:20][C:21]=2[CH:23]2[CH2:25][CH2:24]2)[O:16][CH2:15]1>>[CH:23]1([C:21]2[CH:20]=[N:19][CH:18]=[C:17]3[O:16][CH2:15][CH:14]([NH2:13])[C:22]=23)[CH2:25][CH2:24]1
Reactant: CON=C1COc2cncc(C3CC3)c21
Agent: NC1COc2nnccc21
Product: NC1COc2cncc(C3CC3)c21

Procedure:
This compound was prepared using a method analogous to that of 5,6-dihydrofuro[2,3-c]pyridazin-5-amine (A.2.3.4), 4-cyclopropylfuro[2,3-c]pyridin-3(2H)-one O-methyl oxime replacing furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime;
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH:7]=[O:8].I[CH2:10][CH3:11].O>C1COCC1>[CH2:10]([N:5]1[C:6]([CH:7]=[O:8])=[C:2]([CH3:1])[N:3]=[CH:4]1)[CH3:11]
Reactant: Cc1nc[nH]c1C=O
Reactant: CCI
Solvent: O
Solvent: C1CCOC1
Product: CCn1cnc(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
To 4-methyl-1H-imidazole-5-carbaldehyde (5.0 g, 45.4 mmol) in anhydrous THF (50 mL) was added diaza(1,3)bicyclo[5.4.0]undecane (DBU, 6.8 mL, 45.4 mmol), and iodoethane (3.4 mL, 45.4 mmol). The mixture was stirred at room temperature overnight. Water (50 mL) was added before the THF was evaporated. The mixture was extracted with EtOAc (1×50 mL) and 2-butanol (2×50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-1% MeOH/DCM), affording 1-ethyl-4-methyl-1H-imidazole-5-carbaldehyde (806 mg, 13% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH:11]([OH:15])[CH2:12][CH2:13][Cl:14].[OH-].[Na+]>O>[Cl:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: OC(CCl)CCCl
Reactant: Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC(CCCl)COc1ccc(Cl)cc1

Procedure:
4-Chloro-1-(4-chlorophenoxy)-2-butanol was prepared using the procedure of Preparation 7 from 45 g. (0.5 mole) of p-chlorophenol, 72 g. (0.5 mole) of 1,4-dichloro-2-butanol, 40 g. (1.0 mole) of sodium hydroxide and 400 ml. of water to give 85 g. (36.1%) of product which melted at 62°-64° C. after recrystallization from isopropanol.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[F:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:13](=[O:15])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(F)cc2c(=O)o1
Yield: 230.8 %

Procedure:
In a separate preparation, 2-amino-5-fluorobenzoic acid (15 g, 97 mmol) was dissolved in tetrahydrofuran (250 mL) and triphosgene (10.04 g, 33.8 mmol) was added portion-wise. A thick white precipitate formed with a small exotherm. The slurry gradually became easier to stir and was left stirring at room temperature for 16 h. The mixture was filtered to provide a white solid which was rinsed with diethyl ether then dried at 50° C. in a vacuum over to give 6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (14.1 g, 78 mmol). The 6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione may be converted to a 7-fluoro-1-(4-methoxybenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione using the procedures described in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:11](=[O:29])[C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)C#N)[CH2:16][CH2:15]1)=[O:13])=[CH:5][NH:6]2.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C.O=[Mn]=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:11](=[O:29])[C:12]([N:14]1[CH2:15][CH2:16][N:17]([C:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:18][CH2:19]1)=[O:13])=[CH:5][NH:6]2
Reactant: Nc1ccccc1
Reactant: N#CC(c1ccccc1)N1CCN(C(=O)C(=O)c2c[nH]c3cccc(F)c23)CC1
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Product: O=C(C(=O)N1CCN(C(=Nc2ccccc2)c2ccccc2)CC1)c1c[nH]c2cccc(F)c12
Reaction time: 48 h

Procedure:
An excess amount of MnO2 (500 mg) was added into a solution of 2-(4-(2-(4-fluoro-1H-indol-3-yl)-2-oxoacetyl)piperazin-1-yl)-2-phenylacetonitrile (100 mg) and aniline (0.5 ml) in DMF (10 ml), and the reaction was kept stirring for 2 days. The solids were removed by filtration. The filtrate was concentrated under vaccum to give a residure which was purified by using Shimadzu automated preparative HPLC System to afford 1-(4-fluoro-1H-indol-3-yl)-2-(4-(phenyl(phenylimino)methyl)piperazin-1-yl)ethane-1,2-dione.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][OH:21])[O:16][C@@H:11]([O:12][CH2:13][CH:14]=[CH2:15])[C@@H:10]1[NH:22][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:46](Cl)(=[O:62])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61].CO>C(Cl)(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C:46](=[O:62])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[O:16][C@@H:11]([O:12][CH2:13][CH:14]=[CH2:15])[C@@H:10]1[NH:22][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=CCO[C@@H]1O[C@H](COC(=O)CCCCCCCCCCCCCCC)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Reaction time: 4 h

Procedure:
To 0.38 g. of allyl 3-O-benzyl-2-deoxy-2-palmitamido-β-D-glucopyranoside (Compound 5) in 7 ml. dry pyridine at about 15° C., was added 0.3 ml. of palmitoyl chloride. After warming and holding at room temperature for 4 hours, thin layer chromatography (5% methanol in chloroform) showed the reaction to be complete. Methanol was then added and the solvent evaporated and coevaporated with toluene. Column chromatography of the residue (5% acetone in CHCl3) yielded Compound 6.
Reaction SMILES: C(Cl)(=O)O[CH2:3][CH3:4].[CH3:7][NH:8][CH2:9][CH2:10][N:11]1C[CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O>[CH3:7][NH:8][CH2:9][CH2:10][N:11]1[CH2:4][CH2:3][N:14]([CH3:15])[CH2:13][CH2:12]1
Reactant: CNCCN1CCNCC1
Reactant: CCOC(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CNCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
Ethyl carbonochloridate (8.14 mL, 85.14 mmol) was added dropwise to N-methyl-2-piperazin-1-ylethanamine (5.0 g, 38.7 mmol) and triethylamine (12.95 mL, 92.88 mmol) in THF (40 mL) at 0° C. over a period of 10 minutes under N2. The resulting mixture was allowed to warm to r.t. and stirred for 2 h. The resulting white suspension was filtered, and washed through with THF (2×20 mL). The filtrate was concentrated in vacuo and the resulting residue was dissolved in EtOAc (75 mL). This solution was washed with sat. Na2CO3 (50 mL). The aqueous wash solution was then extracted with EtOAc (50 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo to give crude intermediate (10.55 g). This was dissolved in THF (60 mL) and cooled to 0° C. LiAlH4 (101 mL, 100.6 mmol, 1M in THF) was added dropwise under N2. The resulting mixture was stirred at reflux overnight, then cooled to 0° C. and treated successively (dropwise) with water (3.8 mL), 15% aq. NaOH (3.8 mL) and water (11.4 mL) with rapid stirring. Diatomaceous earth (Celite™) and MgSO4 were added and the mixture was filtered, washed with EtOAc and the filtrate was concentrated in vacuo to give a colourless oil (3.35 g). The filtercake was washed with EtOAc (100 mL), heated to 70° C. and then filtered. The filtrate was concentrated in vacuo to give a further batch (1.023 g) of the title compound. Total: 4.37 g, 72%; 1H NMR: (CDCl3) 2.28 (3H, s), 2.33-2.6 (13H, m), 2.67 (2H, t).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8](OC)=[O:9])[N:6]=1.CC(C[AlH]CC(C)C)C.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([CH2:7][CH2:8][OH:9])[N:6]=1
Reactant: COC(=O)Cc1nc(Br)sc1C
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1sc(Br)nc1CCO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
To a solution of ester prepared in Example 24 (3.80 g, 15.2 mmol) in CH2Cl2 (100 mL) was added DIBAL-H (33.4 mL, 33.4 mmol of a 1.0 M solution in toluene) at −78° C. After 15 minutes, the solution was warmed to 0° C. and stirred for an additional 90 minutes. An aqueous solution of 2N HCl (50 mL) was then added dropwise to quench the excess DIBAL-H. The solvent layers were separated and the aqueous layer extracted with CH2Cl2 (2×200 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (5:2 hexanes/EtOAc) to yield the title compound (2.5 g, 74%) as a yellowish oil that solidified upon standing. (C6H8BrNOS): LC-MS, RT 1.38 min, M+H 221.0; 1H NMR (CDCl3): δ 2.31 (s, 3H), 2.82 (t, 2H), 2.90-3.00 (broad s, 1H), 3.89 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C@@H:11]([CH3:29])[CH2:10]2)=[C:4]([F:30])[CH:3]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:42])[CH3:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:28])[C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C@@H:11]([CH3:29])[CH2:10]2)[C:40](=[O:42])[CH3:41])=[C:4]([F:30])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](Nc3ccc(Cl)cc3F)C[C@@H]2C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3F)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To a solution of (2S,4R)-N-(4-chloro-2-fluorophenyl)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine (60 mg, 0.14 mmol, 1 equ.) in acetyl chloride (0.5 mL) was added diisopropylethylamine (25 uL, 0.14 mmol, 1 equ.). The mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride/methanol 99.5/0.5) to afford pure N-(4-chloro-2-fluorophenyl)-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (140 mg, 92%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[S:35](Cl)(=[O:37])=[O:36]>C1COCC1.CS(C)=O>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH2:3][C@H:2]([NH:1][S:35]([C:31]2[O:30][CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])[CH2:10]3)[CH:16]=1
Reactant: N[C@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Reactant: O=S(=O)(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=S(=O)(N[C@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
(S)-(1-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.08 mmol, 25 mg) was dissolved in THF (1 mL) and triethylamine (0.25 mmol, 35 μL, 25 mg) followed by furan-2-sulfonyl chloride (0.084 mmol, 14.05 mg) and the solution stirred at room temperature overnight. The reaction was concentrated before partitioning between dichlormethane (3 mL) and 1N HCl (3 mL). The organic layer was collected and dried using a hydrophobic frit and concentrated under a stream of nitrogen to give a brown residue which was dissolved in DMSO (1 mL) and purified on preparative basic HPLC to give (S)—N-(5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)furan-2-sulfonamide (14.3 mg, 0.032 mmol, 40.5%) MS (ESI): m/z [M+H]+ 442.2
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1.[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.[CH3:34][S:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.C1COCC1>[CH3:34][S:35][C:36]1[CH:41]=[CH:40][C:39]([O:20][CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]2)=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CSc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56 %

Procedure:
A solution of diethyl azodicarboxylate in toluene (6.76 ml, 14.9 mmol) was added dropwise to a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (2 g, 9.94 mmol), 4-(Methylsulfanyl)phenol (2,8 g, 20 mmol), triphenylphosphine (3.9 g, 15 mmol) and THF (20 ml) over the period of 0.5 h at 0° C. The resulting solution was stirred at room temperature for 3 d. The mixture was diluted in ethyl acetate (20 ml) and the whole was washed with 1N aqueous sodium hydroxide (20 ml), 0.5N hydrochloric acid (20 ml) and saturated sodium chloride solution (20 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 25 g, ethyl acetate/hexane=1/20 to 1/10) to give the title compound (1.8 g, 52%) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[Br:1][C:2]1[C:3]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[N:4][N:5]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2n[nH]cc2Br)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)Cn1cc(Br)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 3 with 4-bromo-3-(4-nitrophenyl)-1H-pyrazole and dimethylethyl bromoacetate furnished the title compound. ESMS [M+H]+: 382.0
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([OH:9])[C:5]([Cl:8])=[CH:6][CH:7]=1.[C:11](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:11])[C:3]=1[F:10]
Reactant: Oc1c(Cl)ccc(Br)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1c(Cl)ccc(Br)c1F
Temperature: 85 °C

Procedure:
To a stirred solution of 3-bromo-6-chloro-2-fluorophenol (4.2 g, 18.63 mmol) in acetonitrile (35 mL) was added potassium carbonate (5.15 g, 37.3 mmol) followed by the addition of methyl iodide (2.330 mL, 37.3 mmol) dropwise at rt. The reaction mixture was heated to 85° C. for 3 h. The volatiles were evaporated; water (50 mL) was added and the solution extracted with ethyl acetate (2×80 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulphate, and concentrated under reduced pressure. The crude material was taken to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.20 (m, 1H), 7.05 (m, 1H), 3.98 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:7]2[O:8][CH2:9][CH:10]([OH:11])[CH:6]2[O:5][CH2:4]1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[CH:15][N:14]=1.CCN(CC)CC>CCO>[Cl:12][C:13]1[N:18]=[C:17]([NH:2][CH:3]2[CH:7]3[O:8][CH2:9][CH:10]([OH:11])[CH:6]3[O:5][CH2:4]2)[CH:16]=[CH:15][N:14]=1
Reactant: NC1COC2C(O)COC12
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC1COC2C(Nc3ccnc(Cl)n3)COC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a suspension of 6-aminohexahydrofuro[3,2-b]furan-3-ol hydrochloride (363 mg, 2.0 mmol) in EtOH (10 mL) were added 2,4-dichloropyrimidine (298 mg, 2.0 mmol) and Et3N (1.01 g, 10.0 mmol) and the mixture was stirred at rt under nitrogen atmosphere overnight. The reaction mixture was filtered and washed with DCM (30 mL) and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to give the title compound as a white solid (165 mg, 32%).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH:6]([C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[CH:7]([CH3:9])[CH3:8].O>ClCCl>[Cl:3][CH:6]([C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)C(O)c1ccc2c(c1)CCO2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)C(Cl)c1ccc2c(c1)CCO2

Procedure:
Thionyl chloride (2.02 cm3, 0.265 mol) was added dropwise to a stirred solution of 2,3-dihydro-5-(1-hydroxy-2-methyl-1-propyl)benzofuran (5.10 g, 0.0265 mol) pyridine (2.16 cm3, 0.0265 mol) in dichloromethane (45 cm3) at 0°-5° C., and the mixture was heated to reflux for 3 hr. The mixture was poured into water and separated. The organic layer was washed with hydrochloric acid (2 N, 20 cm3), water, dried (Na2SO4), filtered and the solvent was removed. The residue was subjected to column chromatography on silica using toluene as the eluant. The appropriate fractions were combined and the solvent was removed to give 5-(1-chloro-2-methyl-1-propyl)-2,3-dihydrobenzofuran. (5.43 g, 0.028 mol, 97.2%) RF 0.68.