Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1.[ClH:44]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:44][C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1
Reactant: Cl
Reactant: COC(=O)COc1nc(Cl)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)COc1nc(Cl)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
First, isoamyl nitrite is added dropwise to a mixture of methyl [3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-chloro-2-pyridyloxy]acetate, copper (I) chloride, copper (II) chloride, and acetonitrile at room temperature, and the mixture is stirred for 1 hour. The reaction mixture is poured into 2% hydrochloric acid, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue is subjected to silica gel column chromatography to give methyl [3-{2 -chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-chloro-2-pyridyloxy]acetate (compound a-108).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]([F:48])([F:47])[F:46])=[CH:35][CH:34]=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]([F:46])([F:47])[F:48])=[CH:37][CH:38]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(CC(=O)NC1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Product: CC(C)(CC(=O)NC1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)C1=O)NC(=O)OCc1ccccc1

Procedure:
Prepared from 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl ]-butanamide (Example 51, Step A) and 4'-bromomethyl-2-trifluoromethyl-1,1'-biphenyl by the procedure described in Example 1, Step K. 1H NMR (300 MHz,CDCl3): 1.37 (s,3H), 1.39 (s,3H), 1.73 (m,1H), 2.2-2.6 (m,5H), 4.50 (m,1H), 4.82 (d,15Hz,1H), 5.06 (s,2H), 5.29 (d,15Hz,1H), 5.65 (s,1H), 6.70 (d,7Hz,1H), 7.1-7.4 (m,14H), 7.44 (t,8Hz,1H), 7.52 (t,8Hz,1H), 7.71 (d,8Hz,1H). FAB-MS: calculated for C37H36F3N3O4 643; found 644 (M+H,55%).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[C:45]3[O:44][C:43]([NH2:46])=[N:42][C:41]=3[C:40]([O:47][CH3:48])=[CH:39][CH:38]=2)=[CH:33][CH:32]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[C:45]3[O:44][C:43]([NH:46][C:1](=[O:5])[CH2:2][CH3:3])=[N:42][C:41]=3[C:40]([O:47][CH3:48])=[CH:39][CH:38]=2)=[CH:35][CH:36]=1
Reactant: CCC(=O)O
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCC(=O)Nc1nc2c(OC)ccc(-c3ccc(F)cc3)c2o1

Procedure:
From propionic acid, HATU and N-diethylisopropylamine in THF, then treatment with 7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-ylamine in dioxane and DMF. ES-MS m/e (%): 315 (M+H+, 100).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.C(O)(C(F)(F)F)=O.[K+].[Br-]>C(#N)C.O>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([C:19]2[CH:18]=[C:17]([CH2:16][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)[O:21][N:20]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)COc1ccc(SCc2cc(-c3ccc(C(F)(F)F)cc3)no2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(O)COc1ccc(SCc2cc(-c3ccc(C(F)(F)F)cc3)no2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 89A. mp 166-168° C.; HPLC: area %=96.95, r.t.=3.140 min, γ=214 nm, mobile phase=acetonitrile/water w/0.10% TFA. IR (KBr) cm−1: 3140, 3085, 1742, 1322, 1255, 1109; 400 MHz 1H NMR (DMSO-d6): δ 12.96 (br(s), 1H), 7.99 (d, 2H, J=8.3 Hz), 7.81 (d, 2H, J=8.3 Hz), 7.14 (d, 1H, J=8.4 Hz), 6.81 (s, 1H), 6.61 (d, 1H, J=8.4 Hz), 4.63 (s, 2H), 4.23 (s, 2H), 2.76 (t, 4H, J=7.5 Hz), 1.91 (pentet, 2H); MS m/z 450 (M+1). Anal. Calc'd for C22H18F3NO4S: C, 58.79; H, 4.04; N, 3.12. found: C, 58.38; H, 3.92; N, 2.95.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K].Cl.CC#N>CN(C=O)C.[Cl-].[Na+].O>[O:4]=[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][N:15]1[C:11](=[O:21])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14]1=[O:16]
Reactant: O=C(CBr)c1cccnc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: Cl
Agent: [Cl-]
Agent: [K]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1cccnc1

Procedure:
A solution of bromomethylpyridin-3-yl ketone (4.55 g, 16.2 mmol) and potassium phthalimide (6.0 g, 32.4 mmol) in DMF (50 mL) was stirred for 3 days at rt before the added to diluted brine (500 ml, 1:1). The solution was made acidic (pH 2) with diluted hydrochloric acid (1M) before washed with ethyl acetate (2×100 ml). The aqueous layer was then made alkaline (pH 12) again with sodium hydroxide solution (2 M) and extracted with DCM (4×200 ml). The extracts were combined and dried (MgSO4) before concentrated in vacuo. Recrystallisation from methanol (2×) allows to remove crystalline phthalimide and to enrich the title compound in the mother liquer. The crude product was used in Preparation 98 without further purification. δH (d6 DMSO): 5.33 (2H, s), 7.64 (1H, dd), 7.92, 7.97 (4H, 2m), 8.43 (1H, m), 8.88 (1H, m), 9.28 (1H, s); m/z (ES+)=308.13 [M+MeCN+H]+; RT=2.39 min.
Reaction SMILES: F[C:2](F)(F)C(O)=O.C([Zn]CC)C.ICI.[I:16][C:17](=[CH2:37])[CH2:18][C@H:19]([CH2:28][O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:20][Si:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>ClCCCl>[I:16][C:17]1([CH2:18][C@H:19]([CH2:28][O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:20][Si:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:2][CH2:37]1
Reactant: C=C(I)C[C@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)C(F)(F)F
Agent: CC[Zn]CC
Solvent: ICI
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H](CC1(I)CC1)O[Si](C)(C)C(C)(C)C
Reaction time: 0.58 h
Yield: 76.7 %

Procedure:
Trifluoroacetic acid (TFA; 281 mg, 2.47 mmol) was added to a solution of diethyl zinc (ZnEt2, 2.5 mL, 2.5M in hexane) in DCE (1 mL) at 0° C. and stirred for 35 mins. Diiodomethane (CH2I2, 66 mg, 2.5 mmol) was then added at 0° C., and the mixture stirred for an additional 20 min. A solution of (R)-5-(2-iodoallyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (step D; 188 mg, 0.41 mmol) in DCE (2 ml) was added and the reaction stirred at room temperature overnight. The reaction was then quenched by addition of a mixture of methanol (5 mL) and brine (0.5 mL). After stirring for an additional hour, the mixture was concentrated under reduced pressure. The crude material was extracted with aq.NH4Cl/CHCl3 and the organic layer washed with brine, dried (MgSO4) and concentrated under reduced pressure. The crude material was triturated in hexane and the solution filtered and evaporated to afford (R)-5-((1-iodocyclopropyl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (148 mg, 77%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([CH3:11])[CH2:6]1.Cl.[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:14].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][CH2:4][CH:5]2[O:9][C:8](=[O:10])[N:7]([CH3:11])[CH2:6]2)[CH2:26][CH2:27]1)[CH3:14]
Reactant: CN1CC(CCCCl)OC1=O
Reactant: CCOc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: CCOc1ccccc1N1CCN(CCCC2CN(C)C(=O)O2)CC1
Yield: 45.9 %

Procedure:
Following the procedure of Example 5, a mixture of 5-(3-chloropropyl)-3-methyl-2-oxazolidinone (5.0 g, 0.0282 mol), 1-(2-ethoxyphenyl)piperazine monohydrochloride (6.86 g, 0.0282 mol), potassium carbonate (15.62 g, 0.113 mol), and potassium iodide (1.0 g) in n-butanol (100 mL) gave an oil (4.5 g, 46% yield). The oil was triturated in warm isopropyl ether and the resulting suspension was stirred at room temperature. The solid was collected by filtration, rinsed with light pet ether and dried under high vacuum to give 2.58 g, mp 79°-81° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1COCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:12])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)C#N)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(C(C)CN)c1
Reaction time: 8 h
Yield: 55758.3 %

Procedure:
To a solution of 2-(3-methoxyphenyl)propanenitrile (1.33 g, 8.26 mmol) in THF (10 mL) at room temperature was added lithium aluminum hydride (9.1 mL, 1M in THF, 9.1 mmol). The reaction was stirred overnight. More lithium aluminum hydride (0.5 mL) was added and the reaction was refluxed for 4 h. 1 N HCl was added carefully to quench the reaction. It was diluted with ether, washed with H2O. Aqueous layer was treated with NaOH and extracted with CH2Cl2. CH2Cl2 layer was washed with saturated NaCl, dried and concentrated to give 2-(3-methoxyphenyl)-propan-1-amine (761 g, 56% yield) as a pale yellow oil. HPLC retention time (Method C)=1.59 min. LC/MS (ESI) (M+H)+=166.07. 1H NMR (CDCl3, 400 MHz) δ ppm 1.24 (d, J=6.85 Hz, 3H), 2.65-2.77 (m, 1H), 2.85 (d, J=8 Hz, 2H), 3.80 (s, 3H), 6.71-6.84 (m, 3H), 7.20-7.26 (m, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]([CH3:22])[NH:11][C:12](=O)[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:24]>ClCCCl>[C:1]1([S:7]([N:10]([CH3:22])[N:11]=[C:12]([Cl:24])[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CN(NC(=O)c1c(Cl)cccc1Cl)S(=O)(=O)c1ccccc1
Solvent: ClCCCl
Product: CN(N=C(Cl)c1c(Cl)cccc1Cl)S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
Into a 1 L three necked round bottom flask equipped with a magnetic stirrer and condenser under an atmosphere of nitrogen was added N-benzenesulfonyl-N-methyl-2,6-dichlorobenzoyl hydrazine (35.9 g, 0.10 mol), 1,2-dichloroethane (500 mL), and phosphorus pentachloride (31.2 g, 0.15 mol). The temperature of the mixture was raised to the point of reflux and was allowed to stir for 30 min. The solvent was removed in vacuo and the residue dissolved in methylene chloride and carefully diluted with water. The organic phase was washed with water, brine, dried (Na2SO4) and the solvent removed in vacuo to give an oil which solidified when triturated with ethyl acetate/hexanes mixture to give 36.1 g (95.7% yield) N-benzenesulfonyl-N-methyl-2,6-dichlorobenzhydrazonoyl chloride as a white crystalline solid: mp 103-104° C.; 1H NMR (CDCl3) δ 7.9 (m, 2H), 7.4-7.7 (m, 3H), 7.2-7.4 (m, 3H), 3.1 (s, 3H)
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][C:33]1[S:34][C:35]([S:39](Cl)(=[O:41])=[O:40])=[C:36]([CH3:38])[N:37]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:39]([C:35]1[S:34][C:33]([CH3:32])=[N:37][C:36]=1[CH3:38])(=[O:41])=[O:40]
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(C)c(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 2,4-dimethylthiazole-5-sulfonyl chloride (12 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 25 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-2,4-dimethylthiazole-5-sulfonamide (percentage yield: 87%), was obtained.
Reaction SMILES: C(Cl)CCl.[CH3:5][C:6]1[O:7][C:8]([CH3:14])=[C:9]([C:11]([OH:13])=O)[N:10]=1.C[O:16][C:17](=[O:67])[C@@H:18]([NH:34][C:35]([C@@H:37]1[CH2:46][C:45]2[CH:44]=[C:43]3[O:47][CH2:48][C@H:49]([C:51]4[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]5[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=5)=[CH:53][CH:52]=4)[O:50][C:42]3=[CH:41][C:40]=2[CH2:39][NH:38]1)=[O:36])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>C(Cl)Cl>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C@H:18]([NH:34][C:35]([C@@H:37]3[CH2:46][C:45]4[CH:44]=[C:43]5[O:47][CH2:48][C@H:49]([C:51]6[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]7[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=7)=[CH:53][CH:52]=6)[O:50][C:42]5=[CH:41][C:40]=4[CH2:39][N:38]3[C:11]([C:9]3[N:10]=[C:6]([CH3:5])[O:7][C:8]=3[CH3:14])=[O:13])=[O:36])[C:17]([OH:67])=[O:16])=[CH:25][CH:24]=2)=[CH:27][CH:28]=1)#[N:33]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: Cc1nc(C(=O)O)c(C)o1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)c(C)o1
Reaction time: 0.67 h

Procedure:
EDC (3 eq.) and 2,5-dimethyl-oxazole-4-carboxylic acid (6 eq.) were dissolved in DCM and stirred 40 minutes. To this solution was added (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino [2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (20 mg) and stirred for 12 hours. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (22 mg). LCMS (m/z): 860.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[ClH:22].[N:23]1([C:28](N)=[NH:29])C=CC=N1.C(N(CC(C)C)CC)C(C)C>CN(C=O)C>[ClH:22].[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:28]([NH2:29])=[NH:23])[CH2:15][CH2:16]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: NCCCCN1CCC(c2c[nH]c3cc(F)ccc23)CC1
Reactant: N=C(N)n1cccn1
Agent: CCN(CC(C)C)CC(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(N)NCCCCN1CCC(c2c[nH]c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of 6-fluoro-3-(1-(3-cyanopropyl)-4-piperidyl)indole (453 mg, 1.6 mmol) in ethanol (30 mL) was added platinum oxide (110 mg) and a concentrated hydrochloric acid (0.8 mL), and the resulting mixture was stirred under hydrogen atmosphere at room temperature overnight. After filtrating the reaction mixture through Celite, the filtrate was concentrated, and a saturated aqueous sodium hydrogencarbonate was added to pH of 10, and the resulting mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the chloroform layer was concentrated to afford 6-fluoro-3-(1-(4-aminobutyl)-4-piperidyl)indole (470 mg, yield: 100%) as a pale yellow solid. To a solution of this amine (68 mg, 0.23 mmol) in DMF (0.22 mL) was added lH-pyrazole-1-carboxamidine hydrochloride (35 mg, 0.23 mmol) and diisobutylethylamine (31 mg, 0.23 mmol), and the mixture was stirred at room temperature overnight. After washing with diethyl ether, the reaction mixture was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; chloroform:methanol=4:1) to afford a free form (61 mg, yield: 77%) of the title compound as a yellow viscous oil. After adding hydrochloric acid/methanol to a solution of the free form (61 mg) in methanol was concentrated and was then freeze-dried to afford the title compound (53 mg) as a white amorphous solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:14])[CH2:4][CH2:3]1.[C:15]([O:19][C:20]([NH:22][C@@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O)(=O)C.[Na]>CO>[C:15]([O:19][C:20]([NH:22][CH:23]1[CH2:27][CH2:26][N:25]([C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:14])[CH2:4][CH2:3]2)[CH2:24]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C1CCC(c2cccc[n+]2[O-])CC1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN([C@H]2CC[C@H](c3cccc[n+]3[O-])CC2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 17.8 mL of methanol containing 2-(4-oxocyclohexyl)pyridine N-oxide (1.8 g, 9.41 mmol) and 1.75 g (9.41 mmol) of (3R)-(+)-3-(tert-butoxycarbonylamino)-pyrrolidine was added 3.23 mL (56.4 mmol) of glacial acetic acid under an inert atmosphere. The resulting solution was stirred at ambient temperature for 20 minutes, cooled to 0° C., and treated with four equal portions of solid sodium cyanoborohyride (total: 296 mg, 4.71 mmol). The reaction mixture was stirred at 0° C. for 20 minutes more. All volatiles were removed under reduced pressure and the residue was taken up in 200 mL of ethyl acetate. The organic layer was washed with 10% sodium carbonate solution and brine, then dried (sodium sulfate) and concentrated to yield 2.86 g of the crude product as an oil. The desired trans-2-[4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-cyclohexyl]-pyridine N-oxide was obtained via preparative centrifugal chromatography on silica gel (chloroform-methanol gradient elution). A portion of this material (544 mg, 1.505 mmol) was dissolved in 300 mL ethyl acetate at 0° C., and HCl gas was bubbled through the solution for 10 min. The reaction mixture was allowed to come to room temperature over a 1 hour period. All volatiles were rotoevaporated under reduced pressure to give a white solid. This material was resuspended in 200 mL of ethyl acetate and treated with 10 ml of 10% sodium carbonate solution. After 10 minutes the phases were separated and the organic layer was dried (sodium sulfate). The aqueous layer was concentrated to dryness and the residue was stirred with a chloroform-methanol mixture (4:1, v/v). The suspension was filtered and the filtrate was combined with the ethyl acetate extracts. The combined organic extracts were then concentrated and azeotropically dried with toluene to give 400 mg of the title compound as a tan powder.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[F:22].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.[C:72](=[NH:85])([C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1.CC(C)([O-])C.[Na+]>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[C:79]1([C:72]([C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)=[N:85][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][N:8]3[CH3:11])=[CH:4][C:3]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[F:22])[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=1
Reactant: Cn1ncc2cc(Oc3ccc([N+](=O)[O-])cc3F)c(Br)cc21
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1ncc2cc(Oc3ccc([N+](=O)[O-])cc3F)c(N=C(c3ccccc3)c3ccccc3)cc21
Temperature: 150 °C
Yield: 89.8 %

Procedure:
To a 10 mL microwave vial is added 6-bromo-5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazole (500 mg, 1.37 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (73 mg, 123 μmol) and Pd2(dba)3 (38 mg, 41 μmol). The mixture is suspended in toluene (5 mL, 47 mmol) and benzophenone imine (272 mg, 1.5 mmol) and sodium tert-butoxide (203 mg, 2.05 mmol) are added. The mixture is heated at 150° C. for 20 min in a microwave reactor. After cooling, the reaction solution is concentrated to give a brown oil which is dissolved in DCM (150 mL) and washed with saturated aqueous sodium chloride (2×50 mL). The aqueous layers are combined and extracted with DCM (1×50 mL), dried with Na2SO4, filtered and concentrated to give a brown residue. The residue is purified on a silica gel column eluting with hexanes (A) and EtOAc (B), gradient from 85%(A): 15%(B) to 50%(A):50%(B) over 50 min to give a yellow solid material as the title compound (574 mg, 90.1% yield). MS (m/z): 467.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:16]=[O:17].O>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[N:12]([CH2:16][OH:17])[C:11](=[O:15])[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]c(=O)n(-c2ccc(Cl)c(Cl)c2)o1
Reactant: C=O
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=c1on(-c2ccc(Cl)c(Cl)c2)c(=O)n1CO
Reaction time: 2 h

Procedure:
2-(3,4-Dichlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.05 mole) dissolved in methanol (100 ml) and aqueous formaldehyde (37% conc.; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux, with stirring for a period of about 2 hours. After this time the reaction mixture is stripped of methanol and water, leaving a residue. This residue is dissolved in methylene chloride, and the resulting solution is washed with water. The washed solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(3,4-dichlorophenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione.