Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].S([O-])([O-])(=O)=O.[Mg+2].[OH:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23]2[N:28]=[N:27][C:26]([O:29][CH3:30])=[C:25]([C:31](=O)[CH2:32][CH3:33])[CH:24]=2)=[CH:18][C:17]=1[CH3:35].C(O)(=O)C>CC(N(C)C)=O>[CH3:30][O:29][C:26]1[N:27]=[N:28][C:23]([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([OH:15])=[C:17]([CH3:35])[CH:18]=2)=[CH:24][C:25]=1[C:31]1[NH:4][C:3]2[C:2]([C:32]=1[CH3:33])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCC(=O)c1cc(-c2cc(C)c(O)c(C)c2)nnc1OC
Reactant: Nc1ccccc1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1[nH]c2ccccc2c1C
Temperature: 140 °C

Procedure:
73.4 μl of 2-chloroaniline and 21 mg of anhydrous magnesium sulfate are suspended in 3 ml dimethylacetamide. 100 mg of 1-[6-(4-hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-propan-1-one and 31.4 mg acetic acid are added and the reaction is degassed with argon. 96 mg of tripotassium phosphate and 35.7 mg of bis(tri-tert-butylphosphine) palladium (0) are added and the reaction is degassed with argon. The reaction is heated to 140° C. for 16 h. The solution is filtered. The product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 35 mg.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[N:57]=[CH:56][C:55]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:54][N:53]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[N:53]=[CH:54][C:55]([C:58]2[CH:59]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:61]=[CH:62][CH:63]=2)=[CH:56][N:57]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: COc1ncc(-c2cccc(N)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cn1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-methoxy-pyrimidin-5-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.012 g of product in 48% yield: LCMS (ESI) m/z 404 (MH+).
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[N:16]([CH2:31][C@H:32]4[CH2:37][CH2:36][C@H:35]([CH3:38])[CH2:34][CH2:33]4)[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][C@H:20]4[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:18][C:14]=3[CH:13]=[C:12]([C:39]([O:41]C)=O)[N:11]=2)[CH:7]=[N:8][CH:9]=1>CO.ClCCl>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[N:16]([CH2:31][C@H:32]4[CH2:33][CH2:34][C@H:35]([CH3:38])[CH2:36][CH2:37]4)[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][C@H:20]4[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[N:18][C:14]=3[CH:13]=[C:12]([C:39]([NH:1][NH2:2])=[O:41])[N:11]=2)[CH:7]=[N:8][CH:9]=1
Reactant: NN
Reactant: COC(=O)c1cc2nc(N3CCOC[C@H]3c3ccccc3)n(C[C@H]3CC[C@H](C)CC3)c2c(-c2cncc(Cl)c2)n1
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C(=O)NN)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hydrazine (9.2 mL, 293 mmol) was added to methyl 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxylate (4.11 g, 7.33 mmol) dissolved in methanol (36.6 mL), and the solution was stirred at room temperature for 30 minutes. The mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbohydrazide. MS ESI calc'd. for C30H34ClN7O2 [M+H]+ 560. found 560.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]4[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=4)[N:15]=[C:5]3[C:4]=2[CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>>[CH:21]([N:20]1[C:16]([C:14]2[N:15]=[C:5]3[C:4]4[CH:3]=[C:2]([N:27]5[CH2:28][CH2:29][NH:24][C:25](=[O:30])[CH2:26]5)[N:12]=[CH:11][C:10]=4[O:9][CH2:8][CH2:7][N:6]3[CH:13]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: O=C1CNCCN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(N3CCNC(=O)C3)ncc1OCC2

Procedure:
A solution of 10-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (80.0 mg, 0.242 mmol), piperazin-2-one (48.4 mg, 0.484 mmol), XPhos (23.0 mg, 0.0484 mmol), and Sodium-tert-butoxide (46.5 mg, 0.484 mmol) in was heated in microwave at 125 C for 30 min. The reaction was filtered thru celite then rinsed with EtOAc. The filtrate was washed water, brine. The organic layer was dried Na2SO4, concentrated to give 307, analyzed by rHPLC. MS: (ESI+)=395.2. 1H NMR (500 MHz, DMSO) δ 8.06 (s, 1H), 8.03 (d, J=5.7 Hz, 2H), 7.93 (s, 1H), 7.59 (s, 1H), 5.72 (dt, J=13.1, 6.6 Hz, 1H), 4.62-4.52 (m, 2H), 4.51-4.39 (m, 2H), 3.94 (s, 2H), 3.73-3.62 (m, 2H), 3.37-3.30 (m, 2H), 1.51 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1O[C:4](=[O:15])[C:5]2[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24]>>[CH3:1][C:2]1[N:16]([CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]2=[O:24])[C:4](=[O:15])[C:5]2[C:6](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[N:7]=1
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1
Reactant: NC1CCC(=O)NC1=O
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1C1CCC(=O)NC1=O

Procedure:
In yet another embodiment, provided herein is a method for preparing 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; comprising the steps of (a) reacting 2-amino-6-nitrobenzoic acid with activated acetic acid in a solvent to form 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one; (b) reacting 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one with 3-aminopiperidine-2,6-dione or a salt thereof in a solvent in the presence of a coupling reagent to form 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione; and (c) reducing 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione via transfer hydrogenation in a solvent to form 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof. In one aspect of the embodiment, the molar ratio of the activated acetic acid versus 2-amino-6-nitrobenzoic acid is ranging from about 1 to about 10, from about 1 to about 5, from about 1.5 to about 5, or from about 1.5 to about 2.5; and wherein steps (a), (b), and (c) are each as described herein elsewhere.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[C:13]2[S:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:12]=2[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25]C(=O)C)=[CH:21][CH:20]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[CH:9]2.CO>C1COCC1>[Br:3][C:4]1[C:13]2[S:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:12]=2[C:11]([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[CH:9]2
Reactant: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)cc3)c2c1C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
Aqueous potassium hydroxide (6.0 mL, 6.0 mmol) was added to a stirred, room temperature solution of acetic acid 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (0.48 g, 1.14 mmol) in THF (15 mL)/methanol (10 mL). After 1 h, the organic solvents were removed, water was added, the reaction mixture was acidified with 10% HCl and the resulting solid was washed with water and triturated with pet. ether and then dried in vacuo to provide the title compound as a white solid (0.32 g, 73%): mp: 165-168° C.; NMR (DMSO-d6); δ 9.68 (s, 1H), 8.17 (d, J=8 Hz, 1H), 7.62 (ddd, J=8, 6, 1 Hz, 1H), 7.50 (d, J=8 Hz, 1H), 7.44 (ddd, J=8, 7, 1 Hz, 1H), 7.13 (d, J=9 Hz, 2H), 6.91 (d, J=9 Hz, 2H), 2.42 (d, J=1 Hz, 3H), 1.59 (d, J=1 Hz, 3H); MS (EI): 1 bromine isotope pattern 382 (95%0, MI), 384 (100%); Anal. Calc. for C20H15BrOS: C, 62.67, H, 3.95, N, 0.00. Found: C, 62.40, H, 3.91, N, 0.09.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:13][OH:14]>CO.O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:13][OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(C=NO)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
52.9 g (0.35 mol) of p-nitrobenzaldehyde was dissolved in 100 ml of methanol and a solution of 27.8 g (0.38 mol) of hydroxylamine hydrochloride in 35 ml of water was added dropwise over 30 minutes while maintaining the temperature at 30° C. and then, stirred at the same temperature for two hours followed by dilution with 300 ml of water. White crystals deposited were filtered and dried to obtain 55 g of p-nitrobenzaldoxime. Yield 94.7%; M.P. 128°-131° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]2[C:12]([I:13])=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[Cl:3][C:4]1[N:5]=[C:6]2[C:12]([I:13])=[CH:11][N:10]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[C:7]2=[N:8][CH:9]=1
Reactant: Clc1cnc2[nH]cc(I)c2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(I)c2nc(Cl)cnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
Sodium hydride (60% in mineral oil, 404 mg, 10.09 mmol) was added to an ice-cold solution of EXAMPLE 33A (2.35 g, 8.41 mmol) in anhydrous DMF (20 mL) under nitrogen. The reaction mixture was stirred at 0° C. for 30 minutes and benzenesulfonyl chloride (1.19 mL, 9.25 mmol) was then added. The ice-bath was removed and the mixture was stirred at room temperature overnight. This reaction was quenched with the addition of 50 mL of water. An off white solid material was collected by filtration, washed with water and hexane, and dried to give 3.38 g of the title product. Yield: 96%. MS (DCI+) m/z 280 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9][CH2:8]2)[CH:2]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([CH3:41])[C:38]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH:46]2[CH2:51][CH2:52][CH2:53][S:54](Cl)(=[O:56])=[O:55])(=[O:44])=[O:43])=[C:37]([CH3:58])[CH:36]=1>C(Cl)Cl>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH3:58])[C:38]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH:46]2[CH2:51][CH2:52][CH2:53][S:54]([N:13]2[CH2:12][CH2:11][C:10]3([CH2:9][CH2:8][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)([O:18][CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)[CH2:15][CH2:14]2)(=[O:55])=[O:56])(=[O:44])=[O:43])=[C:39]([CH3:41])[CH:40]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)Cl)c(C)c1
Reactant: c1cncc(C2(OCCN3CCCC3)CCC3(CCNCC3)CC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)N2CCC3(CC2)CCC(OCCN2CCCC2)(c2cccnc2)CC3)c(C)c1
Reaction time: 1 h
Yield: 47 %

Procedure:
9-(Pyridin-3-yl)-9-(2-(pyrrolidin-1-yl)ethoxy)-3-azaspiro[5.5]undecane (0.26 mmol, 1 eq) was dissolved in methylene chloride (3 ml) at 0° C., triethylamine (1.04 mmol, 4 eq) was added, and 3-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)propane-1-sulfonyl chloride (0.26 mmol, 1 eq), dissolved in methylene chloride (2 ml) was added to the mixture. After 1 h at room temperature, the mixture was diluted with methylene chloride (20 ml). The organic phase was washed with water (10 ml) and saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (1-5% methanol in methylene chloride). Yield: 47%. MS, Rt=3.6 min, m/z=731.5 [MH]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])[CH:4]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]([CH2:30][C@H:31]([OH:36])[C:32]([F:35])([F:34])[F:33])[C:26](=[O:29])[NH:27][N:28]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]([CH2:30][C@H:31]([OH:36])[C:32]([F:34])([F:35])[F:33])[C:26](=[O:29])[N:27]([CH2:2][C:3]3[CH:8]=[CH:7][N:6]=[C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=4[Cl:16])[CH:4]=3)[N:28]=2)=[CH:20][CH:19]=1
Reactant: Clc1cccc(-c2cc(CBr)ccn2)c1Cl
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=c1n(Cc2ccnc(-c3cccc(Cl)c3Cl)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 65 °C
Reaction time: 16 h

Procedure:
81 mg (0.26 mmol) of the compound from Example 66A were dissolved in 3 ml of acetonitrile and 79 mg (0.26 mmol) of the compound from Example 5A and 125 mg (0.38 mmol) of cesium carbonate were added. The mixture was stirred at 65° C. for 2 h and at RT for a further 16 h. The solid was then filtered off and rinsed with a little acetonitrile. The filtrate was concentrated under reduced pressure and directly purified chromatographically [Method 19]. This gave 79 mg (56% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)OC)[CH:5]=[CH:4][C:3]=1[Cl:13].[OH-].[K+]>CO.O>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[Cl:13]
Reactant: COC(=O)Nc1ccc(Cl)c(Br)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(Cl)c(Br)n1
Yield: 82.3 %

Procedure:
To a solution of methyl 6-bromo-5-chloropyridin-2-ylcarbamate (1.1 g, 4.1 mmol) in methanol (50 mL) was added KOH (700 mg, 13 mmol) at room temperature. The mixture was heated at reflux for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by column chromatography on silica gel (5% to 10% EtOAc in petroleum ether) to give 6-bromo-5-chloropyridin-2-amine (700 mg, 81%). 1H NMR (400 MHz, CDCl3) 7.54 (d, J=8.0 Hz, 1H), 6.41 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:17].C(OCC)(=O)C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N+:9]([O-:17])[CH:10]=1)[CH3:1]
Reactant: Cc1ccc(OC(C)C)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(OC(C)C)c[n+]1[O-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 217.2 %

Procedure:
5-(1-methylethoxy)-2-methylpyridine (227 mg, 0.661 mmol) was dissolved in dichloromethane (7.5 mL), added 3-chloroperoxybenzoic acid (408 mg, 0.733 mmol) under ice-cold conditions, and the mixture was stirred at 0° C. for 45 minutes. The reaction solution was added ethyl acetate, saturated aqueous solution of sodium metabisulfite, and an aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (ethyl acetate), and 5-(1-methylethoxy)-2-methylpyridine 1-oxide (240 mg (yield 6%)) was obtained as a colorless oil.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][N:24]([S:27]([NH:30][C@H:31]([CH:36]([CH3:38])[CH3:37])[C:32]([O:34][CH3:35])=[O:33])(=[O:29])=[O:28])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45]O)[CH:40]=1>C1C=CC=CC=1>[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:30]([S:27]([N:24]2[CH2:25][CH2:26][CH:21]([C:18]3[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=3)[CH2:22][CH2:23]2)(=[O:28])=[O:29])[C@H:31]([CH:36]([CH3:38])[CH3:37])[C:32]([O:34][CH3:35])=[O:33])[CH:40]=1
Reactant: COC(=O)[C@H](NS(=O)(=O)N1CCC(c2ccc(Br)cc2)CC1)C(C)C
Reactant: OCc1cccnc1
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: COC(=O)[C@@H](C(C)C)N(Cc1cccnc1)S(=O)(=O)N1CCC(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41 %

Procedure:
Tri-n-butylphosphine (0.37 ml, 1.5 mmol) was added to a solution of methyl 2-(R)-{[4-(4-bromophenyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate (560 mg, 1.25 mmol), 3-pyridylcarbinol (0.15 ml, 1.5 mmol), and 1,1'-(azodicarbonyl)piperidine (377 mg, 1.5 mmol) in benzene (30 ml). After stirring at RT for 48 h, the reaction mixture was concentrated and the residue was triturated with ether (60 ml). After filtering off the solids, the ether layer was concentrated in vacuo and the residue was chromatographed (SiO2, 40% ethyl acetate/hexane) to give methyl 2-(R)-{(pyridin-3-ylmethyl)-[4-(4-bromophenyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate as a colorless oil (41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2O.P(Cl)(Cl)([Cl:18])=O>C(#N)C>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2nccc(O)c2cc1OC
Solvent: CC#N
Product: COc1cc2nccc(Cl)c2cc1OC
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 69.5 %

Procedure:
A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60° C. and phosphorus oxychloride (POCl3, 130.6 kg) was added. After the addition of POCl3, the temperature of the reaction mixture was raised to approximately 77° C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2 to 7° C. and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26% NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25° C., and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to −20 to −25° C. and held for 2.5 hours resulting in solid precipitate, which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25° C. under nitrogen to afford the title compound (35.6 kg).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:9][C:10]([O-:12])=[O:11].[Na+]>C1COCC1.CS(C)=O>[CH:1]1([O:7][CH2:9][C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])CCl
Reactant: OC1CCCCC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(O)COC1CCCCC1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A solution of cyclohexanol (1.75 g, 17.5 mmol) in THF was added, and the mixture was warmed to 25° C. for 1 hour. The THF was removed by distillation under vacuum, and a solution of sodium chloroacetate (2.5 g, 22 mmol) in DMSO (50 ml) was added. The reaction mixture was treated as in Example 3 and 2.3 g of product (83% yield) was obtained as a colorless oil.
Reaction SMILES: CC(C)([O-])C.[K+].CS(C)=O.[F:11][C:12]([F:18])([CH:15]([F:17])[F:16])[CH2:13][OH:14].[Br:19][C:20]1[CH:25]=[C:24](F)[CH:23]=[C:22]([F:27])[CH:21]=1>O>[Br:19][C:20]1[CH:25]=[C:24]([O:14][CH2:13][C:12]([F:18])([F:11])[CH:15]([F:17])[F:16])[CH:23]=[C:22]([F:27])[CH:21]=1
Reactant: OCC(F)(F)C(F)F
Reactant: Fc1cc(F)cc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1cc(Br)cc(OCC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.2 %

Procedure:
To a 50 mL flask flushed with nitrogen, equipped with a stir bar was added potassium tertbutoxide (1.1 g, 10 mmol, 95%). DMSO was added (10 mL) followed by addition of a solution of 2,2,3,3-tetrafluoropropan-1-ol (0.95 mL, 11 mmol) via syringe. After 5 min, 1-bromo-3,5-difluorobenzene (1.1 mL, 9.5 mmol) was added and the reaction mixture stirred at room temperature for 18 h. Water was added (100 mL), and the aqueous phase extracted with ether (2×100 mL). The organic portion was then washed successively with water (2×100 mL) and saturated NaCl solution (2×100 mL), dried over Na2SO4, decanted and concentrated under reduced pressure yielding a crude yellow liquid which was purified by distillation under reduced pressure at 140° C. yielding the 1-Bromo-3-fluoro-5-(2,2,3,3-tetrafluoropropoxy)benzene as a colorless oil (1.6 g, 54% yield).
Reaction SMILES: [SH2:1].CC(C)([O-])C.[K+].[CH2:8]([C:10]1O[C:12]2[CH2:19][CH2:18][C:17]3[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:16]=3[C:15](=[O:25])[C:13]=2[N:14]=1)[CH3:9]>CN(C)C=O>[CH2:8]([C:10]1[S:1][C:12]2[CH2:19][CH2:18][C:17]3[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:16]=3[C:15](=[O:25])[C:13]=2[N:14]=1)[CH3:9]
Reactant: CCc1nc2c(o1)CCc1cc(C)ccc1C2=O
Reactant: S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc2c(s1)CCc1cc(C)ccc1C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrogen sulphide was passed through a suspension of potassium tert-butoxide (9.31 g) in N,N-dimethylformamide (80 ml) at 5° C. until the mixture was saturated. The product from example 1 step (v) (5.0 g) was added and the reaction mixture stirred at room temperature for 2 h. The mixture was poured onto ice, acidified to pH3 and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 40-50% ethyl acetate in isohexane.