Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:12][C:13](=[O:33])[C:14]2[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[C:16]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[BH4-].[Na+].C(N(S(F)(F)[F:42])CC)C>CO>[F:42][CH:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:5]2([C:3]([OH:2])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:33])=[CH:15][C:16]=1[O:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)[CH3:21]
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)C1(NC(=O)c2ccc(C(C)=O)c(OCCc3cccc(C)c3)c2)CCCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)CCCCCC3)ccc2C(C)F)c1
Reaction time: 1 h

Procedure:
The compound of step 2 of example 60 (110 mg, 0.244 mmol) was dissolved in methanol (1.1 ml) and cooled in an ice bath. Sodium borohydride (9.2 mg, 0.244 mmol) was added and stirring continued for 1 h. This mixture was partitioned between EA and saturated sodium hydrogencarbonate solution, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue (100 mg) was dissolved in DCM (2 ml) and diethylaminosulfur trifluoride (36 mg, 0.22 mmol) was added. The mixture was stirred for 3 h, partitioned between EA and saturated sodium hydrogencarbonate solution, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The obtained ester was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:13]1[O:15][CH2:14]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:20]([OH:25])[CH2:21][CH:22]([CH3:24])[CH3:23]>>[CH2:20]([O:25][CH2:14][CH:13]([OH:15])[C@@H:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CCO
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CO1
Product: CC(C)CCOCC(O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 100 mg of (3S)-3-carbobenzoxyamino-5-methyl-1,2-epoxyhexane, 2 g of dry neutral alumina, and 2 ml of isoamyl alcohol was stirred for 16 hours at 100° C., and then stirred for 90 minutes at 140° C. After filtration of the alumina, the filtrate was evaporated under reduced pressure to obtain 97 mg of (2RS, 3S)-3-carbobenzoxyamino-2-hydroxy-5-methylhexyl isoamyl ether as a colorless oil.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])([O-:4])=[O:3].[C:13](OCC)(=[O:19])[C:14]([O:16]CC)=[O:15].[OH-].[Na+]>O.C(O)C>[CH3:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=1[CH2:12][C:13](=[O:19])[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc([N+](=O)[O-])c1CC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
Sodium (3.802 g, 165.38 mmol, 2.5 eq) was added portionwise into ethanol (66 mL, 1M) at 0° C. Next, 3-nitro-ortho-xylene (10.00 g, 66.15 mmol, 1 eq) and diethyl oxalate (19.33 g, 132.23 mmol, 2 eq) were added. The mixture was stirred at room temperature for 18 hours and then refluxed for 10 minutes. 1N sodium hydroxide and water were added and the reaction was stirred for one hour. The ethanol was removed under vacuum. Water was added and the aqueous solution was acidified with concentrated hydrochloric acid to ph~2. The mixture was extracted with methylene chloride. The extracts were dried (magnesium sulfate) and concentrated to give the title compound (9.0 g, 61%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Cl:19])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[CH3:27][NH:28][NH2:29].O1CCCC1>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:10]=2[C:11]([N:28]([CH3:27])[NH2:29])=[O:13])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: CNN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)N(C)N)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1.0 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one, 0.35 ml of methylhydrazine and 20 ml of tetrahydrofuran was stirred at room temperature for 24 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate three times. The combined organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.85 g of 3-bromo-N-[4-chloro-2-(N-methylhydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[Li]CCCC.[CH3:15][N:16]([CH3:24])[CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1>C(OCC)C>[Br:9][C:4]1[CH:3]=[C:2]([C:20]2([OH:23])[CH2:21][CH2:22][CH:17]([N:16]([CH3:24])[CH3:15])[CH2:18][CH2:19]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: CN(C)C1CCC(=O)CC1
Reactant: Fc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN(C)C1CCC(O)(c2cc(F)cc(Br)c2)CC1
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
Dissolve 1,3-dibromo-5-fluoro-benzene (19.8 g, 77.90 mmol) in dry diethyl ether (300 mL) and cool to −60° C. Add 1.6M n-BuLi in hexanes (50.9 mL, 81.44 mmol) dropwise over 15 min. and stir an additional 15 min. Add a pre-cooled (−60° C.) solution of 4-dimethylamino-cyclohexanone (10.0 g, 70.8 mmol) in diethyl ether (200 mL) dropwise over 30 min. Stir at −60° C. to −20° C. for 2 hr., then warm to ambient temperature and stir for 1 hr. Quench the reaction with water (200 mL) and extract with ethyl acetate (3×200 mL). Dry over sodium sulfate, filter and concentrate. Purify the residue by flash chromatography (15% 2M NH3/MeOH in DCM) to obtain 1-(3-Bromo-5-fluoro-phenyl)-4-dimethylamino-cyclohexanol as a white foam (14.5 g, 64.8%). MS (ES) m/z=316 (M−H)−, 318 (M+H)+; 1H NMR (CDCl3): δ 7.41 (d, 1H, J=2 Hz), 7.15 (m, 2H), 2.3 (m, 8H), 1.78 (m, 8H).
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH2:6]I)#[N:2].C(=O)([O-])[O-].[K+].[K+].[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:27][SH:28].O>CN(C)C=O>[C:1]([C:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH2:6][S:28][CH2:27][C:26]([O:30][CH2:31][CH3:32])=[O:29])#[N:2]
Reactant: CCOC(=O)CS
Reactant: N#CC(CCCI)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CSCCCC(C#N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.6 %

Procedure:
To a solution of 4-cyano-4,4-diphenyl iodobutane (0.4 g, 1.1 mmol.) in N,N-dimethylformamide (3 ml) were added potassium carbonate (0.31 g, 2,2 mmol.) and ethyl thioglycolate (0.14 g, 1.2 mmol.). The mixture was stirred for 15 hours at room temperature. To the reaction mixture was added water, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography, eluting with hexane - ethyl acetate (4:1) to afford the title compound (0.22 g).
Reaction SMILES: OC(C)C[NH:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1.O[CH:18](C)CN(CC(O)C)C1C=CC(C(OCC)=O)=CC=1>>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH:12]([CH3:13])[CH3:18])=[O:10])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccc(N(CC(C)O)CC(C)O)cc1
Reactant: CCOC(=O)c1ccc(NCC(C)O)cc1
Product: CC(C)OC(=O)c1ccc(N)cc1

Procedure:
ethyl N-(2-hydroxypropyl)-p-aminobenzoate and ethyl N,N-bis(2-hydroxypropyl)-p-aminobenzoate, which are sold under the trade name Amerscreen P
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C@H:11]([CH2:14][OH:15])[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CN=C1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:16])[NH:10][C@H:11]([CH2:14][O:15][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
Subsequently, to a solution of [(1S)-1-(hydroxymethyl)propyl]carbamic acid benzyl ester (4.27 g, 19.1 mmol) in dimethylformamide (128 ml) were added t-butyldiphenylsilyl chloride (5.97 ml, 22.9 mmol) and imidazole (1.56 g, 22.9 mmol) in an ice bath. The mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (6:1→4:1) as the eluant to afford [(1S)-1-(t-butyldiphenylsilyloxymethyl)propyl]carbamic acid benzyl ester (9.48 g, yield 100%) as a white solid.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:12][N+:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)=[CH:15][CH:14]=2)=[O:11])=[CH:6][CH:5]=1.[BH4-].[Na+].ClCCl>CO>[OH:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)[CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:19]2[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][CH2:14]1
Reactant: COc1ccc(C(=O)C[n+]2ccc(C3=NNC(=O)CC3)cc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C(O)CN2CC=C(C3=NNC(=O)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
1-[(4-Methoxyphenyl)carbonylmethyl]-4-(4,5-dihydropyridazin-3 (2H)-one-6-yl)pyridinium bromide (300 mg, 0.74 mmol) was dissolved in methanol (5 ml), gradually added with sodium borohydride (280 mg, 7.4 mmol) under ice cooling and then stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue obtained was added with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed to obtain the titled compound (145 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:16]3[CH2:21][N:20]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC3)cc1
Reactant: CC(C)(C)C(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(=O)C(C)(C)C)C3)cc1

Procedure:
Method as example 18 using 1-ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 14) and pivaloyl chloride as starting materials.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:20][C:14]1[CH:19]=[CH:18][C:17]([C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:12])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)c2ccccc2)cc1
Temperature: 30 °C
Reaction time: 12 h
Yield: 73.5 %

Procedure:
To the mixture of anhydrous AlCl3 (85 g, 0.64 mole) with dried toluene (90 mL) was added benzoyl chloride (50 mL, 0.43 mole) dropwise at 10±2° C. The mixture was warmed to 30±2° C. and stirred for 12 hours, and then heated to 100±5° C. and stirred for another 2 hr before it was cooled and added into ice water (200 mL) to terminate the reaction. The organic layer was separated and washed successively with water, 5% sodium carbonate and then water again till neutralized. The organic layer was dried over anhydrous magnesium sulfate and evaporated for solvent removal. The residue was recrystallized from n-hexane to obtain 62.1 g 4-methylbenzophenone in a yield 73.5%. mp: 55-57° C.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:24])[N:9]2[CH2:18][C:19](OCC)=[O:20])[CH:2]=[CH2:3].O.[NH3:26]>CO>[C:19]([CH2:18][N:9]1[C:10]2[C:5](=[C:4]([CH2:1][CH:2]=[CH2:3])[C:13]([OH:14])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:24])(=[O:20])[NH2:26]
Reactant: N
Reactant: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CC(=O)OCC
Solvent: CO
Solvent: O
Product: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CC(N)=O
Yield: 80 %

Procedure:
1.65 Grams of 5,7-diallyl-1-(ethoxy-carbonylmethyl)-3,4-dihydro-6-hydroxy-2(1H)-quinolinone obtained in Example 57 was dissolved in 50 ml of methanol, then 20 ml of 25% ammonia water thereto, the reaction mixture was stirred for 24 hours. Then the reaction mixture was concentrated under reduced pressure. The concentrate was extracted with chloroform, washed with water, dried, then concentrated again under reduced pressure. Thus obtained crude crystals were subjected to purification by passing it through a silica gel column and by using methylene chloridemethanol (50:1) as the eluent, there was obtained 1.2 g (80%) of 1-(carbamoylmethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1=[O:42])[CH3:35]>>[CH2:34]([N:36]1[CH2:41][CH2:40][N:39]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:38][C:37]1=[O:42])[CH3:35]
Reactant: CCN1CCNCC1=O
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCN1CCN(c2cc(C(=O)Nc3nc4c(OC)ccc(N5CCOCC5)c4s3)ccn2)CC1=O

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 1-ethyl-piperazin-2-one. ES-MS m/e (%):519 (M+Na+, 28), 497 (M+H30 , 100).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2cccc(C(F)(F)F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cccc(C(F)(F)F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (679 mg, 1.69 mmol) was dissolved in MeOH (8 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.498 mL, 1.69 mmol) dissolved in water (0.800 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.104 mL, 1.69 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (8.71 mL, 52.27 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a white solid. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (311 mg, 50%) was isolated. MS m/z 371 (M+H)+
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1ccc(N)cc1
Agent: O=S(=O)(O)O
Product: CC(C)c1ccc(N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
25 g (185 mmol) 4-isopropyl-aniline were dissolved in to 260 ml conc. sulfuric acid and treated at −5° C. with 17.9 g nitric acid (65%). After stirring the mixture at 0° C. for 0.5 h, the reaction mixture was poured on ice water and the precipitating product collected via filtration and dried. The resulting 23.8 g product were essentially pure and were used for the subsequent step without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8]2)(=O)[CH3:2].IC1C=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>O.[Cu].C(O)CC(C)C>[CH2:10]1[C:11]2[C:7](=[CH:6][C:5]([NH:4][C:1]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:2]=3)=[CH:13][CH:12]=2)[CH2:8][CH2:9]1
Reactant: Cc1ccc(I)cc1
Reactant: CC(=O)Nc1ccc2c(c1)CCC2
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)CCO
Product: Cc1ccc(Nc2ccc3c(c2)CCC3)cc1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
26.28 g (0.15 mol) of 5-(N-acetylamino)indane, 43.61 g (0.20 mol) of p-Iodotoluene, 25.88 g (0.188 mol) of anhydrous potassium carbonate and 2.38 g (0.038 mol) of a copper powder were mixed and while introducing a nitrogen gas, the resulting mixture was heated to 20° C. and stirred for 6 hours. After completion of the reaction, 22.3 g of potassium hydroxide dissolved in 20 ml of water and 50 ml of isoamyl alcohol were added to conduct hydrolysis at 130° C. for 2 hours. After completion of the hydrolysis, 250 ml of water was added, and Isoamyl alcohol was removed by azeotropic distillation. 200 ml of toluene was added to dissolve the reaction product. After filtration, the reaction product was dehydrated with magnesium sulfate. After filtering out the magnesium sulfate, the filtrate was concentrated, and purified with column chromatography (carrier: silica gel, elute: toluene:hexane=1:4) to obtain 32.3 of indan-5-yl-p-tolylamine.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[NH:12][CH:11]=2)=[CH:5][N:4]=1.[H-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[C:21]1([S:27]([N:12]2[C:13]3[N:14]=[CH:15][N:16]=[CH:17][C:18]=3[C:10]([CH2:9][C:6]3[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:8][CH:7]=3)=[CH:11]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CSc1ncc(Cc2c[nH]c3ncncc23)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncncc23)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54 %

Procedure:
To 5-(2-methylsulfanyl-pyrimidin-5-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (56, 1.20 g, 4.66 mmol) in 55.0 mL of N,N-dimethylformamide, sodium hydride (0.280 g, 7.00 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes, followed by addition of benzenesulfonyl chloride (40, 0.714 mL, 5.60 mmol). The reaction was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (57, 1.00 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH2:10]([O:12][P:13]([C:18]1[C:19](=[O:29])[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([Cl:28])[CH:22]=2)(=[O:17])[O:14][CH2:15][CH3:16])[CH3:11]>>[CH2:10]([O:12][P:13]([C:18]1[C:19](=[O:29])[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([N+:1]([O-:4])=[O:2])=[C:23]([Cl:28])[CH:22]=2)(=[O:17])[O:14][CH2:15][CH3:16])[CH3:11]
Reactant: CCOP(=O)(OCC)c1cc2ccc(Cl)cc2[nH]c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOP(=O)(OCC)c1cc2cc([N+](=O)[O-])c(Cl)cc2[nH]c1=O
Reaction time: 0.25 h

Procedure:
55 ml of nitric acid are added dropwise to a solution of 55 ml of 96% sulphuric acid cooled in an ice bath, and then (7-chloro-2-oxo-1,2-dihydro-3-quinolyl)-phosphonic acid diethyl ester (14.7 g, 46.6 mmol) is added in portions whilst maintaining the temperature at less than or equal to 5° C. When the addition is complete, stirring is continued for 15 minutes and then the ice bath is withdrawn and the reaction mixture is brought to room temperature over a period of about 1 hour 30 minutes. The solution is poured into ice and the precipitate is stirred to obtain a filterable solid. Filtration is carried out, followed by washing with water to neutrality and drying in vacuo. The solid is suspended in 210 ml of ethanol at reflux; the batch is left to cool and filtered to obtain the title product after drying.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[F:23])=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1O>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:30]3[C:29]([F:32])=[CH:28][C:27]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:26][C:25]=3[F:24])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[C:17]([F:23])[CH:18]=1
Reactant: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2F)nsc1C(F)(F)F
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: O=C(O)CCc1cc(F)c(OCc2c(-c3ccc(Cl)cc3F)nsc2C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(2-fluoro-4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.30-7.44 (m, 3H), 6.73-6.81 (m, 2H), 5.16 (s, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.58 (t, J=7.5 Hz, 2H) Mass spectrum (ESI, m/z): Calcd. for C20H12ClF6NO3S, 496.0 (M+H). found 496.0.