Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:32]=[CH:31][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([N:20]3[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH:59]2[CH2:61][O:60]2)=[CH:53][CH:52]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:29]([O:28][C:26]([CH:23]1[CH2:22][CH2:21][N:20]([C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:10]3[CH:31]=[CH:32][C:7]([CH2:6][CH2:5][NH:4][CH2:61][C@H:59]([OH:60])[CH2:58][O:57][C:54]4[CH:55]=[CH:56][C:51]([OH:50])=[CH:52][CH:53]=4)=[CH:8][CH:9]=3)[CH2:13][CH2:14]2)=[O:19])[CH2:25][CH2:24]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C1CCN(C(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CCOC(=O)C1CCN(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)CC1
Yield: 42.4 %

Procedure:
Ethyl 1-({4-[4-(2-aminoethyl)anilino]-1-piperidinyl}carbonyl)-4-piperidinecarboxylate formate (0.312 g, 0.696 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.20 g, 0.495 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.17 g, 0.21 mmol).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH:22]=O)[CH:18]=[CH:17]2.C([O:26][C:27](=O)[C:28](=[O:36])[CH2:29][C:30](=[O:35])[CH2:31][CH:32]([CH3:34])[CH3:33])C>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:22]([C:19]4[CH:18]=[CH:17][C:16]5[C:21](=[C:12]([OH:11])[CH:13]=[CH:14][CH:15]=5)[N:20]=4)[C:29]([C:30](=[O:35])[CH2:31][CH:32]([CH3:34])[CH3:33])=[C:28]([OH:36])[C:27]3=[O:26])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C(=O)CC(=O)CC(C)C
Reactant: O=Cc1ccc2cccc(O)c2n1
Reactant: Nc1ccc2[nH]cnc2c1
Solvent: CCO
Product: CC(C)CC(=O)C1=C(O)C(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc2cccc(O)c2n1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1H-Benzoimidazol-5-ylamine (1 mmol) and 8-Hydroxy-quinoline-2-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 6-Methyl-2,4-dioxo-heptanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]>C1COCC1>[CH3:5][CH:4]([CH3:6])[CH2:3][CH2:2][NH:1][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(C)CCN
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: C1CCOC1
Product: CC(C)CCNc1ccccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 59.8 %

Procedure:
A solution of amino 3-methylbutane (1.5 g) in THF (20 ml) was dropped into a solution of 2-fluoronitrobenzene (2.4 g) in THF (20 ml), at 23° under a nitrogen atmosphere. The mixture was stirred at 23° for 3 h, then heated at reflux for 1.5 h. The mixture was allowed to cool to 23°, then concentrated under vacuum to give a crude compound which was purified by flash chromatography on silica gel using CH-EA 9/1 as eluants to give the title compound as a yellow oil (2.12 g). T.l.c. CH-EA (8/2), Rf 0.79. IR:3383 (NH); 1620 (C=C) cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:16][OH:17]>C(O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:16][OH:17])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a stirred solution of 4-bromobenzaldehyde (3.0 g, 16.2 mmol) in ethanol (100 mL) and water (25 mL) was added sodium acetate (1.7 g, 21.0 mmol) and hydroxylamine hydrochloride (1.4 g, 19.5 mmol). The resulting mixture was heated to reflux for 2 hours. The solution was allowed to cool to room temperature, concentrated, and filtered to give 4-bromobenzaldehyde oxime (3.02 g, 93%). 4-Bromobenzaldehyde oxime (0.25 g, 1.25 mmol) was added to a stirred solution of 3-cyanophenyl boronic acid (0.28 g, 1.87 mmol) in glyme (13 mL). Sodium carbonate (0.39 g, 3.75 mmol) in water (2 mL) and tetrakis(triphenylphosphine) palladium (0) (0.07 g, 0.06 mmol) was added and the resulting solution was heated to reflux for 3 hours. The solution was cooled to room temperature and partitioned between a saturated ammonium chloride solution (100 mL) and ethyl acetate (150 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (20% ethyl acetate in hexane) and triturated with ether to give 4′-[(E)-(hydroxyimino)methyl]-1,1′-biphenyl-3-carbonitrile as a white solid (0.17 g, 61%). MS m/z 223; HRMS: calcd for C14H10N2O+H+, 223.08659; found (ESI, [M+H]+), 223.087; Anal. Calcd for C14H10N2O: C, 75.66; H, 4.54; N, 12.60. Found: C, 75.49; H, 4.98; N, 12.51.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:17])[S:5][C:6]=1[S:7]([N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)(=[O:9])=[O:8].C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1.[CH:30]1([NH:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.O>CN(C1C=CN=CC=1)C.ClC(Cl)C.C(Cl)Cl>[CH:37]1([N:36]([CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[C:23]([NH:17][C:4]2[S:5][C:6]([S:7]([N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)(=[O:9])=[O:8])=[C:2]([CH3:1])[N:3]=2)=[O:24])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: Cc1nc(N)sc1S(=O)(=O)N1CCN(C)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CC(Cl)Cl
Product: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1S(=O)(=O)N1CCN(C)CC1
Temperature: 120 °C
Yield: 123.2 %

Procedure:
Prepared in the microwave oven (EmrysOptimizer®). 4-Methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamine (0.04 g; 0.141 mmol), CDI (0.023 g; 0.141 mmol) and DMAP were mixed dichloroethane (1.5 ml) in a microwave vessel (2.5 ml). The reaction mixture was heated 600 sec at 120° C., dicyclohexylamine (0.025 g; 0.141 mmol) dissolved in dichloroethane (0.2 ml) was added through the septum and the reaction mixture was heated for additional 600 sec. at 120° C. To the reaction mixture was added water and DCM (25 ml). The water phase was extracted with DCM (3×25 ml), dried with MgSO4 filtered and evaporated in vacuo to afford the title compound, (84 mg) as a yellow oil. Purification by prep. HPLC gave 3 mg (Yield: 4%)
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][C:20]=1[O:27][CH3:28].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([O:39][CH3:40])=[O:38]>>[OH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:30]=2)[C:37]([O:39][CH3:40])=[O:38])=[C:20]([O:27][CH3:28])[CH:21]=1
Reactant: COc1cc(CO)ccc1O
Reactant: COC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: COC(=O)C(Oc1ccc(CO)cc1OC)c1ccccc1
Yield: 25.2 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 1.00 g (6.49 mmol) of 4-hydroxy-3-methoxybenzyl alcohol was alkylated with 1.64 g (7.14 mmol) of methyl 2-bromophenylacetate to afford 0.495 g (25%) of the title compound.
Reaction SMILES: [H-].[Na+].O1C[CH2:6][CH2:5][CH2:4]1.[C:8]1([CH2:16][OH:17])[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.C(Br)C#C>O.CN(C)C=O>[CH2:6]([O:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:16][OH:17])=[CH:9][CH:10]=1)[C:5]#[CH:4]
Reactant: OCc1ccc(CO)cc1
Reactant: C1CCOC1
Agent: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
To a mixture of sodium hydride (400 mg, 8.4 mmol, 50% in oil) and tetrahydrofuran (30 mL) was added 1,4-benzenedimethanol (2.3 g, 17 mmol) at 0° C., and then N,N-dimethylformamide (30 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes, after which propargyl bromide (1.0 g, 8.4 mmol) was added dropwise to the reaction mixture at 0° C. The reaction mixture was stirred at room temperature for 1 hour, after which water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed and saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue thus obtained was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:2) to obtain the title compound (860 mg, 58%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:18][C:19]1[CH:20]=[C:21]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[N:12]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: c1ccc(COc2cccc3[nH]ncc23)cc1
Reactant: COc1ccc(B(O)O)cc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-n2ncc3c(OCc4ccccc4)cccc32)cc1C
Yield: 73.2 %

Procedure:
The 4-[(phenylmethyl)oxy]-1H-indazole (D1) (500 mg, 2.23 mmol), the [3-methyl-4-(methyloxy)phenyl]boronic acid (740 mg, 4.46 mmol), copper (II) acetate (608 mg, 3.345 mmol), pyridine (0.36 mL, 4.46 mmol) and powdered molecular sieves (400 mg) in DCM (75 mL) were stirred at room temperature in the presence of air. After 41 hours the mixture was filtered through a pad of celite and washed with water. The aqueous was re-extracted with DCM and the combined organics were washed with brine and dried over MgSO4. The crude (1.17 g) was purified by flash chromatography (Biotage SP4) with a gradient of EtOAc 0 to 30% in hexane to afford 562 mg of title compound (D34) containing an impurity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].[CH:35]1([NH:38][CH2:39][C@@H:40]2[CH2:44][CH2:43][CH2:42][NH:41]2)[CH2:37][CH2:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:35]1([NH:38][CH2:39][C@@H:40]2[CH2:44][CH2:43][CH2:42][N:41]2[C:31](=[O:32])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:37][CH2:36]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: C1CN[C@H](CNC2CC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CCC[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.5 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (225 mg, 0.43 mmol), cyclopropyl-(S)-1-pyrrolidin-2-ylmethyl-amine (91 mg, 0.64 mmol), HOBt (91 mg, 0.67 mmol), EDAC (130 mg, 0.68 mmol) and TEA (0.15 mL, 1.1 mmol) in DMF was stirred at rt for 48 hours. The reaction was concentrated, diluted with sodium bicarbonate and extracted with DCM. The combined DCM was dried, concentrated and purified on a silica gel column to give 211 mg (76%) of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([C:32](Cl)=[O:33])[CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1.CCCCCC>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([C:32](=[O:33])[NH:15][C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:14]=[CH:13][N:12]=2)[CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: COc1ccccc1-c1cc(N)ncn1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccccc1-c1cc(NC(=O)C2CCCN(C(=O)OCc3ccccc3)C2)ncn1
Reaction time: 2 h

Procedure:
To a solution of 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (5 g) in 20 ml of dichloromethane was added 4-dimethylaminopyridine (1.2 eq) followed by dropwise addition of 3-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (XXV) (1.1 eq.) at room temperature. The reaction mixture was stirred for 2 hours and then washed with water. The organic layer was separated, dried over sodium sulfate and concentrated. The obtained crude residue was passed through a pad of silica gel eluting with 25% ethyl acetate in hexane to provide 3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XXVI) (5.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>O1CCCC1>[C:12]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2)(=[O:14])[CH3:13]
Reactant: Nc1ccc2c(c1)COC2=O
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)COC2=O

Procedure:
3 g of 5-amino-phthalide, 10 ml of acetic anhydride and 30 ml of tetrahydrofuran are refluxed for 1 hour. The crystals that are precipitated after cooling are suctioned off and washed with isopropylether. 3.3 g of the title compound is obtained, flash point >300° C.
Reaction SMILES: CCN(CC)CC.O[C@@H:9]([CH3:27])[C@@H:10]([NH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:16])[C:11]([OH:13])=[O:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:21]1([CH2:20][CH2:19][CH2:18][O:17][C:15](=[O:16])[NH:14][C@H:10]2[C:11](=[O:13])[O:12][C@H:9]2[CH3:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H](O)[C@@H](NC(=O)OCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OCCCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
In a four necked round bottom flask, Et3N (1.4 ml, 10.1 mmol) was added to a solution of (2R,3S)-3-hydroxy-2-{[(3-phenylpropoxy)carbonyl]amino}butanoic acid (0.95 g, 3.38 mmol) in dry CH2Cl2 (40 mL) under argon. After cooling at 0° C., HBTU (1.92 g, 5.07 mmol, 1.5 eq) was added and the mixture stirred 3 h at 0° C., then 16 h at rt. The obtained solid was filtered off and the solvent removed under vacuum. The crude was purified by typical silica gel column chromatography, eluting with Cy/AcOEt (from 95:5 to 60:40). The resulting white solid (0.280 g) was further triturated with cyclohexane to afford the pure title compound (0.240 g, 31%), as white solid. MS (ESI) m/z: 262.27 [M−H]−. Rf=0.29 (Cy/EtOAc 8:2; detection: phosphomolybdic acid). FTIR (cm−1): 3328, 3064, 3030, 2972, 2929, 2859, 1851, 1691, 1542, 1333, 1270, 1130, 1083, 1024, 843, 822, 697. 1H NMR (CDCl3): δ 1.46 (d, 3H); 1.93-2.00 (m, 2H); 2.67-2.71 (m, 2H); 4.09-4.18 (m, 2H); 4.84-4.90 (m, 1H); 5.38-5.48 (m, 2H); 7.11-7.31 (m, 5H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]#[N:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:42]=[N+:43]=[N-:44])(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3[NH:44][N:43]=[N:42][N:26]=3)=[CH:15][CH:16]=2)[C:8]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(C#N)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(c2ccccc2)c2nnn[nH]2)cc1

Procedure:
A mixture of 3-butyl-4-[[4-[1-cyano-1-phenyl-methoxy]phenyl]methyl]-5-(4-nitrobenzylthio)-4H-1,2,4-triazole (from Example 3, Step B), trimethyltin azide (3.5 equivalents), and toluene is stirred at reflux for about 2 days. The mixture is then cooled and concentrated in vacuo. The residue is partitioned between 0.5N HCl and ethyl acetate. The ethyl acetate phase is dried (MgSO4), filtered, and concentrated. The residue is taken up in methanol and stirred with silica gel (4-5 g per mmol of cyano starting material) for about 1 hour. The mixture is then evaporated in vacuo to give a dry powder, which is layered on top of a column of silica gel packed in CH2Cl2. Elution of the column with a gradient of methanol in CH2Cl2 affords the title compound.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C(Cl)Cl>[Cl:16][CH2:17][C:18]([NH:1][C@H:2]([CH2:7][OH:8])[C@H:3]([CH2:5][CH3:6])[CH3:4])=[O:19]
Reactant: CC[C@H](C)[C@H](N)CO
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](CO)NC(=O)CCl
Temperature: -20 °C

Procedure:
To a stirred solution of L-isoleucinol (20 g, 0.17 mol) and triethylamine (28.56 ml, 0.204 mol) in CH2Cl2 (500 ml) at -78° C. was added chloroacetyl chloride (16.3 ml, 0.204 mol) over 5 minutes. The cooling bath was removed and the solution allowed to warm to -20° C. The mixture was diluted with EtOAc and washed sequentially with 1M HCl, and brine and dried (Na2SO4). Evaporation in vacuo afforded the title compound Rf=0.3 CH2Cl2 :MeOH (95:5);
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CS(C)=O>[ClH:1].[ClH:21].[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:18][CH2:19][CH2:20][Cl:21])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cl
Product: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 74 %

Procedure:
Utilizing the procedure described in Example 1(a), 20.0 g of 1-(4-chlorobenzyl)piperazine, 100 ml of dimethyl sulfoxide, 15.0 g of potassium hydroxide and 15.0 of 1-bromo-3-chloropropane yielded 25.1 g (74% of theory) of 1-(4-chlorobenzyl)-4-(3-chloropropyl)piperazine dihydrochloride as a white crystalline solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([NH:17][CH3:18])=[O:16].NC1[CH:25]=[N:24][CH:23]=[C:22]([Cl:26])[N:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:26][C:22]1[N:21]=[C:18]([NH:17][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:16])[CH:25]=[N:24][CH:23]=1
Reactant: CNC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: Nc1cncc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O

Procedure:
This compound was prepared from 4-hydroxy-2-methyl-N-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, 2-amino-6-chloro-pyrazine and p-toluenesulfonic acid analogous to Example 14.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]3=[O:25])=[C:12]([F:26])[CH:11]=[C:10]([Cl:27])[C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[C:1]([C:5]1[O:6][C:7]2[C:13]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[N:16]([CH3:28])[C:15]3=[O:25])=[C:12]([F:26])[CH:11]=[C:10]([Cl:27])[C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2o1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(C(C)(C)C)oc23)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.1 %

Procedure:
A stirred solution of 0.85 gram (2.1 mmole) of 3-(2-t-butyl-4-chloro-6-fluorobenzoxazol-7-yl)-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione, 0.48 gram (3.5 mmole) of potassium carbonate, 0.91 gram (6.4 mmole) of iodomethane, and 35 mL of acetone was heated at 40° C. for 2 hours, then stirred at ambient temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was extracted with two 50 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a yellow oil, which was subjected to column chromatography on silica gel. Elution was accomplished with 8:1 hexane:ethyl acetate. The product-containing fractions were combined and concentrated under reduce pressure, yielding 0.60 gram of 3-(2-t-butyl-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione, m.p. 68°-70° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[N:15]2[C:10]([C:11](=O)[NH:12][C:13](=O)[NH:14]2)=[N:9][CH:8]=1.[ClH:18].C(N(CC)CC)C>>[Br:6][C:7]1[N:15]2[C:10]([C:11]([Cl:3])=[N:12][C:13]([Cl:18])=[N:14]2)=[N:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cl
Reactant: O=c1[nH]c(=O)c2ncc(Br)n2[nH]1
Solvent: CCN(CC)CC
Product: Clc1nc(Cl)c2ncc(Br)n2n1
Temperature: 110 °C
Yield: 218.8 %

Procedure:
(I9F): Phosphoryl trichloride (200 mL, 2178 mmol) was added to a mixture of 7-bromoimidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (20 g, 87 mmol) and triethylamine hydrochloride (24 g, 174 mmol) in 500 ml pressure tube. The reaction was heated to 110° C. for 24 hrs. The reaction mixture was cooled to room temperature and concentrated using high vacuum pump. The residue was suspended in toluene and azotroped with toluene (3×250 ml). The residue was taken in a cooled mixture of 1000 ml of ethyl acetate and 500 ml of saturated sodium bicarbonate solution. The organic layer was separated. Aqueous layer was extracted with ethyl acetate (3×300 ml). Combined organic layer was washed with aqueous sodium bicarbonate solution (2×150 ml) and 100 ml of brine solution. The organic layer was dried over sodium sulphate and concentrated to give 51 g of 7-bromo-2,4-dichloroimidazo[2,1-f][1,2,4]triazine.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:14](=[O:17])(O)[O-:15].[Na+]>C(Cl)Cl>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([C@H:11]([NH:13][C:14](=[O:17])[O:15][C:8]([CH3:11])([CH3:9])[CH3:7])[CH3:12])=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: O=C([O-])O
Reactant: C[C@@H](N)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(R)-1-(4-nitrophenyl)ethanamine hydrochloride salt (1.0 g, 4.9 mmol), tert-butoxycarbonyl (BOC) anhydride (1.18 g, 5.43 mmol), and 10.0 mL of 1M sodium bicarbonate solution were dissolved in DCM (15 mL) and allowed to stir at 25° C. for 24 h. The organic layer was collected, and the aqueous layer was washed with DCM. The combined organic layers were then washed with water and 0.1 N HCl, dried over MgSO4, filtered, and concentrated to provide C1 as a white solid. Yield: 1.2 g, 92%. GC-MS=266. 1H NMR (500 MHz, d6-DMSO) δ: 8.15 (d, 2H), 7.56 (d, 1H), 7.52 (d, 2H), 4.68 (m, 1H), 1.32 (s, 9H), 1.27 (d, 3H).