Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1C(C)(C)C.O.[C:19]([OH:23])(=O)[CH:20]=[O:21].O>ClCCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:6]([CH3:11])([CH3:7])[CH3:5])[C:9]2[O:12][C:20](=[O:21])[CH:19]([OH:23])[C:10]=2[CH:11]=1
Reactant: COC(=O)CCc1ccc(O)cc1C(C)(C)C
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCCl
Product: COC(=O)CCc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Yield: 200 %

Procedure:
23.6 g of 3-(2-tert-butyl-4-hydroxy-phenyl)-propionic acid methyl ester (U.S. Pat. No. 43070-A2), 10.1 g of glyoxylic acid monohydrate and 0.08 g of p-toluenesulfonic acid are boiled in 80 ml of 1,2-dichloroethane for 7 hours using a water separator. The reaction solution is then cooled, washed three times with 50 ml of water each time and freed of solvent using a rotary evaporator. 29.2 g of 3-(7-tert-butyl-3-hydroxy-2-oxo-2,3-dihydro-benzofuran-5-yl)-propionic acid methyl ester are obtained in the form of a yellowish oil. That yellowish oil is placed in 50 ml of toluene with 15 ml of thionyl chloride and 3 drops of DMF and the reaction mixture is then slowly heated to 100° C. at such a rate that the evolution of HCl and SO2 remains vigorous yet controllable. The reaction mixture is then stirred at that temperature for a further hour. Approximately 50 ml of liquid are then distilled off in order to remove the excess thionyl chloride. The residue is diluted with 160 ml of toluene and, at room temperature, 14 ml of triethylamine are added dropwise thereto. The thick, red reaction mixture is then heated under reflux for 30 min. After cooling to room temperature, the triethylamine hydrochloride which has precipitated is filtered off and the filtrate is concentrated to an oily consistency using a rotary evaporator. The isoxindigo is crystallised out by adding 100 ml of acetonitrile, is filtered off, washed with acetonitrile and dried. 7.4 g (27% of the theoretical yield) of 3-[7,7′-di-tert-butyl-2,2′-dioxo-[3,3′]bibenzofuranyliden-5-yl]-5,5′-propionic acid methyl ester (LVIa) are obtained.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].[CH3:18]O>C(OCC)(=O)C>[OH:2][CH:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=1)[CH3:18]
Reactant: CO
Reactant: CC(C)(C)C(=O)Nc1cccc(C=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(O)c1cccc(NC(=O)C(C)(C)C)n1
Reaction time: 3 h
Yield: 80 %

Procedure:
To solution of N-(6-formylpyridin-2-yl)-2,2-dimethylpropanamide (3.0 g, 14.9 mmol) in methanol (10 mL) was added sodium borohydride (1.37 g, 37.1 mmol) and stirred for 3 hours. The mixture diluted with ethyl acetate (50 mL). The mixture was washed with aqueous hydrochloric acid (2×30 mL, 0.1 N) and saturated sodium bicarbonate (2×50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford the above-titled intermediate as a white solid (2.49 g, 80%). 1H NMR (400 MHz, CDCl3), δ: 8.16 (d, J=8.3 Hz, 1H), 8.00 (br s, 1H), 7.71 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.5 Hz, 1H), 4.05-3.96 (m, 2H), 1.35 (s, 9H); LRMS (ESI): m/z: 209.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([CH3:27])[CH:21]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:24][C:23]1[CH:25]=[CH:26][C:20]([O:19][CH3:18])=[CH:21][C:22]=1[CH3:27]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: COc1ccc(N)c(C)c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)c(C)c1

Procedure:
A reaction mixture of 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 164.6 mg (1.2 mmol) of 4-methoxy-2-methyl-aniline and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed under N2 for 3 hr. After removal of the solvent, the residue was diluted with water and neutralized to pH 7-8 with diluted sodium carbonate solution. The precipitate was filtered and washed with water and ether. After drying in vacuo. this yielded 250.2 mg (71.7%) of the product as a off red solid, m.p.>131° C. (dec.), mass (electrospray, m/e): M+H 349.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:16]=2)[C:9]1=[O:13]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3ccccc32)cc1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(N3CCN(c4cnccc4C)C3=O)c3ccccc32)cc1
Yield: 29.3 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.00084 mol) was reacted with 3-bromo-1-(toluene-4-sulfonyl)-1H-indole (292 mg, 0.00084 mol), 1,4-dioxane (20 mL), copper iodide (0.015 g, 0.000084 mol), trans-1,2-diamino cyclohexane (0.028 g, 0.00025 mol) and potassium phosphate (356 mg, 0.00168 mol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3), followed by preparative HPLC afforded 110 mg of 1-(4-Methyl-pyridin-3-yl)-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-imidazolidin-2-one (33.66% yield).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.C[O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:4]([C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:30][C:26]2[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=2)[C:23]([OH:31])=[O:22])=[CH:11][CH:12]=1)([OH:3])=[O:20]
Reactant: COC(=O)c1cccc(O)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc(C(=O)O)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 3-hydroxy-benzoic acid methyl ester via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:56]1[CH2:61][CH2:60][CH:59]([O:62][CH2:63][C:64]([N:66]2[CH2:70][CH2:69][CH2:68][CH2:67]2)=[O:65])[CH2:58][CH2:57]1>CC(N(C)C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:56]1[CH2:61][CH2:60][CH:59]([O:62][CH2:63][C:64](=[O:65])[N:66]2[CH2:67][CH2:68][CH2:69][CH2:70]2)[CH2:58][CH2:57]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: O=C(COC1CCNCC1)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)N1CCCC1
Reaction time: 2 h

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.20 g, 0.67 mmol) and HBTU (0.381 g, 1.01 mmol) were added to DMA (4 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and then 2-(piperidin-4-yloxy)-1-(pyrrolidin-1-yl)ethanone (106) (0.142 g, 0.67 mmol). The reaction was stirred for 2 hours before being evaporated to dryness and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH+) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to the desired compound as a white solid (0.168 g, 50.9%); 1H NMR (400.132 MHz, CDCl3) δ 1.90-1.56 (m, 6H), 2.01-1.93 (m, 2H), 3.16-3.07 (m, 1H), 3.57-3.42 (m, 6H), 3.72 (septet, J=3.6 Hz, 1H), 4.06-4.00 (m, 1H), 4.12 (q, J=11.9 Hz, 2H), 4.26 (s, 2H), 7.02 (t, J=8.8 Hz, 1H), 7.32-7.25 (m, 2H), 7.79-7.70 (m, 3H), 8.47-8.44 (m, 1H), 10.01-9.97 (m, 1H); m/z (LC-MS, ESI+), RT=1.66 (M+H 493).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(NCC)C.[CH3:37][CH:38]([OH:42])[CH2:39][C:40]#[CH:41]>[Cu]I.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.CN(C)C=O>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:41]#[C:40][CH2:39][CH:38]([OH:42])[CH3:37])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#CCC(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC(O)CC#Cc1cc(CN2CCOCC2)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reaction time: 96 h

Procedure:
A flame-dried flask under an atmosphere of nitrogen gas containing N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Preparation # 15) (0.55 g) is treated with copper (I) iodide (0.02 g) and dichlorobis(triphenylphosphine)palladium (II) (0.07 g). The solids are treated with dimethylformamide (DMF) (6 mL) and diethylamine (6 mL). The resulting suspension is treated with 4-pentyn-2-ol (0.2 mL) and stirred for 4 days. The reaction is concentrated under reduced pressure and the residue is partitioned between ethyl acetate and phosphate buffer (pH=7). The aqueous phase is extracted with dichloromethane:ethyl acetate. The combined organic layers are washed with phosphate buffer (pH=7), brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue is flash column chromatographed on silica eluting with 5% to 11% methanol in ethyl acetate. The product-containing fractions are combined and concentrated under reduced pressure. The resulting material is crystallized from acetonitrile:methanol and then re-crystallized from toluene to afford the title compound (0.33 g) as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH2:18][C:19](O)=[O:20].[CH2:22]([N:24]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=1[C:35]([F:38])([F:37])[F:36])[CH2:25][CH3:26])[CH3:23]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH2:18][C:19]([NH:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:24]([CH2:22][CH3:23])[CH2:25][CH3:26])=[C:29]([C:35]([F:36])([F:37])[F:38])[CH:30]=1)=[O:20]
Reactant: CCN(CC)Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C(O)Cc1c(Cl)cc(-n2cnc3cccnc32)cc1Cl
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)Cc1ccc(NC(=O)Cc2c(Cl)cc(-n3cnc4cccnc43)cc2Cl)cc1C(F)(F)F

Procedure:
The title compound is prepared as described in Example 7 but using (2,6-dichloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 56.1) and 4-diethylaminomethyl-3-trifluoromethyl-phenylamine (disclosed in WO2005/051366). Title compound: ES-MS: 549.9/551.9 [M+H]+; tR=3.93 min (System 1); Rf=0.28 (CH2Cl2/MeOH, 95:5+0.1% NH3aq).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[N:14][C:15]([N:18]=C(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:16][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]2[CH:13]=[N:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(N=C(c3ccccc3)c3ccccc3)nc2)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(c2ccc(N)nc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of 3-[6-(benzhydrylideneamino)-pyridin-3-yl]-azetidine-1-carboxylic acid tert-butyl ester (400 mg, 0.97 mmol) in THF (20 mL) was added citric acid (10 mL, 10% aqueous) and the reaction mixture was stirred at room temperature overnight. The resultant mixture was quenched by adding sodium hydrogen carbonate solution and was then extracted with ethyl acetate (×2). The combined organic washings were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (70-100% ethyl acetate in cyclohexane) to afford the title compound as a white solid (183 mg, 76%). LCMS (Method C): RT=1.85 min, m/z: 250 [M+H+].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:24]=[CH:23][C:11]2[C:12]3[C:13]([CH3:22])([CH3:21])[CH2:14][C:15](=O)[NH:16][C:17]=3[CH2:18][CH2:19][C:10]=2[CH:9]=1.[OH-].[Na+]>O1CCCC1>[Cl:7][C:8]1[CH:24]=[CH:23][C:11]2[C:12]3[C:13]([CH3:21])([CH3:22])[CH2:14][CH2:15][NH:16][C:17]=3[CH2:18][CH2:19][C:10]=2[CH:9]=1
Reactant: CC1(C)CC(=O)NC2=C1c1ccc(Cl)cc1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCNC2=C1c1ccc(Cl)cc1CC2

Procedure:
3.36 g (0.089 mol) of lithium aluminum hydride are suspended in 100 ml of tetrahydrofuran under argon. 11.6 g (0.044 mol) of 8-chloro-1,1 -dimethyl-1,2,5,6-tetrahydrobenzo[f}quinolin-3-one are slowly added thereto and the mixture is boiled under reflux for 2.5 hours. The mixture is then cooled to 0°, 12 ml of 18 percent sodium hydroxide solution are added dropwise thereto and the mixture is filtered. On evaporation of the filtrate, there is obtained 8-chloro-1,1-dimethyl-1,2,3,4,5,6-hexahydrobenzo[f]quinoline as a yellow oil which is processed directly.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.[Br:19][CH2:20][C:21](Br)=[O:22]>C(Cl)Cl>[Br:19][CH2:20][C:21]([N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)=[O:22]
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)CBr)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 99 %

Procedure:
A mixture of 2.00 g (13.2 mmol) of N-methyl-4-nitroaniline and 1.46 g (14.5 mmol) of Et3N in 20 mL of CH2Cl2 at O° C. under N2 is treated with a solution of 5.33 g (26.4 mmol) of bromoacetyl bromide in 4 mL of CH2Cl2. After 3.5 h, the reaction is poured into ice water and extracted with CH2Cl2. The extract is treated with Darco, dried (MgSO4) and evaporated. The residue is filtered through Magnesol (CHCl3), evaporated and dried in vacuo to give 3.57 g (100%) of yellow solid. 1H NMR (DMSO-d6) δ 8.27 (d, 2H, J=7.47 Hz), 7.66 (d, 2H, J=7.47 Hz), 4.06 (s, 2H), 3.28 (s, 3H); MS (ESI) m/z 273.0 (M+1).
Reaction SMILES: C(OC(C)(C)C)(=O)C=C.[CH3:10][N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH:20]=O)=[CH:12]1.[CH3:22][N:23]1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:10][N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH2:20][NH:23][CH3:22])=[CH:12]1
Reactant: Cn1cc(C=O)c2cccnc21
Reactant: Cc1c(C=O)n(C)c2ccccc12
Agent: C=CC(=O)OC(C)(C)C
Product: CNCc1cn(C)c2ncccc12
Yield: 45 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.4 g, 2.5 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.2 g, 45%) was prepared as a yellow oil: MS (ES) m/e 176 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=C([N+]([O-])=O)C=C[C:3]=1N.C(NC1C=CC=CC=1)=O.[NH2:21][C:22]1([C:28]([OH:30])=O)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.NC1(C(OC)=O)CCOCC1.NC1(CO)CCOCC1.OCCN.C(=O)C(C)C>>[CH:2]([CH:8]1[O:30][CH2:28][C:22]2([CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[NH:21]1)([CH3:3])[CH3:1]
Reactant: NC1(C(=O)O)CCOCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Agent: CC(C)C=O
Agent: COC(=O)C1(N)CCOCC1
Agent: NC1(CO)CCOCC1
Solvent: NCCO
Product: CC(C)C1NC2(CCOCC2)CO1

Procedure:
2-Methyl-4-nitroaniline was converted to the 2-methyl-4-nitroformanilide according to Method A3a, Step 1. The formanilide was converted to 2-methyl-4-nitrophenyl isocyanide dichloride according to Method A3a, Step 2. 4-Aminotetrahydro-2H-pyran4-carboxylic acid was converted to the methyl ester according to Method B1b, Step 1. Methyl 4-aminotetrahydro-2H-pyran-4-carboxylate was reduced to 4-amino-4-(hydroxymethyl)tetrahydro-2H-pyran according to Method B1b, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford 2-isopropyl-1-aza-3,8-dioxaspiro[4.5]decane. The oxazolidine was reduced to 4-isobutylamino-4-(hydroxymethyl)tetrahydro-2H-pyran. The substituted 2-hydroxyethylamine was converted to 4-isobutylamino-4-(acetylthiomethyl)tetrahydro-2H-pyran according to Method C6c, Step 1. The thioacetate was saponified according to Method C6c, Step 2 to give 4-isobutylamino-4-(thiomethyl)tetrahydro-2H-pyran. The 2-thioethylamine was reacted with 2-methyl-4-nitrophenyl isocyanide dichloride to afford 2-(2-methyl-4-nitrophenylimino-1-isobutyl-1-aza-8-oxa-3-thiaspiro[4.5]decane.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[C:19]1([C:25]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:33]3[C@H:29]([CH2:30][NH:31][CH2:32]3)[C:28](=[O:34])[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:35]1([C:25]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@H:33]3[C@H:29]([CH2:30][N:31]([C:8](=[O:9])[CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:32]3)[C:28](=[O:34])[CH2:27][CH2:26]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CN(C(=O)Cc3ccccc3)C[C@H]12
Reaction time: 2 h

Procedure:
A solution of phenylacetyl chloride (4 cc) and triethylamine (8.6 cc) in dichloromethane (10 cc) is added dropwise to a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (10 g) in dry dichloromethane (80 cc) cooled to +5° C. The reaction mixture is stirred for 2 hours at +5° C. and then for 20 hours at 20° C. The reaction mixture is treated with a saturated aqueous solution (30 cc) of sodium bicarbonate; the organic phase is washed with distilled water (2 * 50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile (15 cc). The crystals are drained, washed with acetonitrile (10 cc) and with isopropyl ether (10 cc) and dried. (3aR,7aR)-7,7-diphenyl-2-(phenylacetyl)-4-perhydroisoindolone (5.7 g) melting at 173° C. is obtained; [a]D20 =-282° (c=1, methanol).
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([C:8]1([C@H:11]2[CH2:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[CH2:12]2)[CH2:10][CH2:9]1)=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[OH:5][CH2:6][C:8]1([C@H:11]2[CH2:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:18])[CH2:12]2)[CH2:9][CH2:10]1
Reactant: CCOC(=O)C1([C@H]2CC(=O)N([C@@H](C)c3ccccc3)C2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N1C[C@@H](C2(CO)CC2)CC1=O
Temperature: 70 °C
Reaction time: 30 h
Yield: 74 %

Procedure:
Lithium borohydride (1.174 g, 53.90 mmol) was added to a solution of 1-[(3R)-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidin-3-yl]cyclopropanecarboxylic acid ethyl ester [see Journal of Medicinal Chemistry, Vol. 46, No. 6, p. 1005 (2003)] (2.03 g, 6.74 mmol) in tetrahydrofuran (20 mL). The mixture was heated with stirring on an oil bath at 70° C. for 30 hours. After cooling to room temperature, the reaction solution was poured into an ice-cooled 10% citric acid solution (80 mL), followed by extraction with ethyl acetate (200 mL). The organic layer was washed with water (80 mL) and brine (80 mL), dried over anhydrous sodium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2→1:1→2:1→1:0→chloroform:methanol=9:1) to give 1.30 g (74%) of the title compound as a colorless transparent gummy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][CH:36]=[CH:37][N:38]=2)=[C:30]([F:39])[C:29]=1[F:40].O1C=NC(C2C=CC(CN([C@@H]3CCCC[C@H]3CO)S(C3C=CC(Cl)=CC=3)(=O)=O)=CC=2)=N1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[O:35][CH:36]=[CH:37][N:38]=3)=[C:30]([F:39])[C:29]=2[F:40])[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Fc1c(CBr)ccc(-c2ncco2)c1F
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCCC[C@H]1CO
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)c(F)c1F)[C@@H]1CCCC[C@H]1CO
Yield: 39.6 %

Procedure:
The title compound was synthesized from 4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (200 mg, 0.66 mmol), cesium carbonate (257 mg, 0.79 mmol), and 2-(4-(bromomethyl)-2,3-difluorophenyl)oxazole (217 mg, 0.79 mmol)) according to the procedure described for N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 11) to give 4-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (130 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.35 (s, 1H), 7.83 (d, J=8.50 Hz, 2H), 7.80 (d, J=7.50 Hz, 1H), 7.64 (d, J=8.00 Hz, 2H), 7.45 (t, J=7.05 Hz, 1H), 4.52 (s, 2H), 3.41-3.52 (m, 1H), 3.29-3.40 (m, 1H), 3.25 (dd, J=10.45, 2.64 Hz, 1H), 2.80 (t, J=9.32 Hz, 1H), 1.95 (br. s., 1H), 1.52-1.60 (m, 2H), 1.38 (br. s., 3H), 1.18 (br. s., 1H), 0.86-1.04 (m, 2H). Analytical HPLC R.T.=23.46 min. MS [M+H]+=497; [M+Na]+=519. HRMS [M+H]+ calc'd 497.1113, found 497.1093.