Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.[H-].[Na+].[C:9]([CH2:11]P(=O)(OCC)OCC)#[N:10].[O:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=O)[CH2:21]1>C1COCC1.O>[O:20]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]([CH2:11][C:9]#[N:10])=[CH:21]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1COc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: N#CCc1coc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
To a stirred mixture of hexane washed sodium hydride (2.21 g, 0.046 mol, 50%/mineral oil) in THF (125 mL), was added diethyl cyanomethylphosphonate (8.15 g, 0.046 mol) dropwise. The reaction was stirred at room temperature for 1/2 hour, 3-coumaranone (sublimed) (5.6 g, 0.042 mol) in THF (100 mL) was added dropwise at 0° C., and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (300 mL), and extracted with ether (800 mL). The extracts were washed with brine (2×100 mL), dried (MgSO4), and concentrated to yield 6.67 g (100%) of the product as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][C:38]1[C:39]([N:47]2[CH2:53][CH2:52][CH2:51][N:50]([CH2:54][CH2:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH3:37])[C:39]([N:47]4[CH2:53][CH2:52][CH2:51][N:50]([CH2:54][CH2:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:49][CH2:48]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: COc1cc(N2CCCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: OCC(F)(F)F
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(C)c(N4CCCN(CCS(C)(=O)=O)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 100 °C
Yield: 60 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.2 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]hexahydro-1H-1,4-diazepin-1-yl}aniline (67 mg, 0.2 mmol), and p-toluenesulfonicacid (90 mg, 0.47 mmol) were weighed into a 20 mL vial. 1 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 24 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (94 mg, 0.12 mmol, 59%). 1H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.36 (s, 1H), 8.44 (s, 1H), 8.22 (d, J=5.13 Hz, 1H), 8.04 (d, J=2.20 Hz, 1H), 7.74 (dd, J=8.62, 2.02 Hz, 1H), 7.69 (d, J=8.80 Hz, 1H), 7.41-7.48 (m, 2H), 7.32-7.41 (m, 1H), 7.26 (d, J=8.80 Hz, 1H), 7.18 (t, J=8.07 Hz, 2H), 6.94 (t, J=6.78 Hz, 1H), 6.79 (s, 1H), 6.55 (d, J=5.13 Hz, 1H), 4.26 (q, J=6.97 Hz, 2H), 3.78 (s, 3H), 3.28 (t, J=7.15 Hz, 2H), 3.06-3.14 (m, 4H), 3.04 (s, 3H), 2.92 (t, J=6.78 Hz, 2H), 2.80 (t, J=5.68 Hz, 4H), 2.15 (s, 3H), 1.85 (qd, J=5.74, 5.50 Hz, 2H), 1.42 (t, J=6.78 Hz, 3H); MS (ESI): 811 [M+H]+.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=1[F:17]>CC(O)=O.C1(C)C=CC=CC=1>[Br:9][C:10]1[C:11]([F:17])=[CH:12][C:13]([NH2:14])=[C:15]([I:1])[CH:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc(Br)c(F)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Nc1cc(F)c(Br)cc1I
Temperature: 25 °C
Yield: 87 %

Procedure:
N-iodosuccinimide (2.90 ml, 28.9 mmol) was added to a solution of 4-bromo-3-fluoroaniline (5.00 g, 26.3 mmol) in AcOH (52.6 ml). The reaction was maintained at ambient temperature for 1.5 h, then diluted with 20 mL toluene and concentrated. The residue was dissolved in EtOAc and washed with 2 N aqueous NaOH. The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Ultra SNAP column, 25-g silica gel loading column, 2-10% EtOAc/Heptane) to give 4-bromo-5-fluoro-2-iodoaniline (7.23 g, 22.89 mmol, 87% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.74-7.78 (m, 1H), 6.53-6.57 (m, 1H). m/z (ESI) 315.9 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][CH:11]=[C:10]([C:15]#[C:16][CH2:17][O:18][CH3:19])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1)#[CH:21].C(N(CC)CC)C.N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:21]#[C:20][C:22]2([OH:30])[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[CH:12][CH:11]=[C:10]([C:15]#[C:16][CH2:17][O:18][CH3:19])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC#Cc1ccc(Br)c(Cc2ccccc2)n1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC#Cc1ccc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)n1
Reaction time: 2 h
Yield: 57.7 %

Procedure:
Next, a mixture of 170 mg of 2-benzyl-3-bromo-6-(3-methoxy-1-propinyl)pyridine, 90 mg of 3-ethynyl-3-quinuclidinol, 30 mg of tetrakis(triphenylphosphine)palladium(0), 1 mg of cuprous iodide, 0.22 ml of triethylamine and 1 ml of N,N-dimethylformamide was stirred for 2 hours in an oil bath kept at 85° C. in a nitrogen atmosphere. Ethyl acetate and aqueous dilute ammonia were added to the reaction solution to separate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography using NH-silica gel to elute with 20-100% ethyl acetate/hexane and then with 2.5% methanol/ethyl acetate, to give 120 mg of the target compound.
Reaction SMILES: [P:1](=[O:90])([S:84][CH2:85][S:86][C:87](=[O:89])[CH3:88])([O:43][CH:44]([OH:83])[C@H:45]1[O:49][C@@H:48]([N:50]2[CH:58]=[C:56]([CH3:57])[C:54](=[O:55])[NH:53][C:51]2=[O:52])[CH2:47][C@@H:46]1[O:59]C(C1C=CC=CC=1)(C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1)[O:2][C@@:3]1([OH:42])[C@@H:7]([CH2:8][O:9]C(C2C=CC=CC=2)(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)[O:6][C@@H:5]([N:33]2[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]2=[O:35])[CH2:4]1>C(O)(=O)C.O.CO>[P:1](=[O:90])([S:84][CH2:85][S:86][C:87](=[O:89])[CH3:88])([O:43][CH:44]([OH:83])[C@H:45]1[O:49][C@@H:48]([N:50]2[CH:58]=[C:56]([CH3:57])[C:54](=[O:55])[NH:53][C:51]2=[O:52])[CH2:47][C@@H:46]1[OH:59])[O:2][C@@:3]1([OH:42])[C@@H:7]([CH2:8][OH:9])[O:6][C@@H:5]([N:33]2[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]2=[O:35])[CH2:4]1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)OP(=O)(OC(O)[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2OC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)SCSC(C)=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)SCSP(=O)(OC(O)[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O)O[C@]1(O)C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 25 °C

Procedure:
The totally protected phosphorothioate dinucleoside (3c) is dissolved in an acetic acid/water/methanol mixture (8:1:1, v:v:v) (5 ml) and left with stirring at ambient temperature all night. The following day, the reaction mixture is evaporated and coevaporated several times with water and with toluene. The residue is then chromatographed on a column of silica gel using a gradient of methanol (0 to 10%) as eluent. The fractions containing the detritylated phosphorothioate triester dinucleoside (4c) are collected and concentrated under reduced pressure. The residue is coevaporated with dioxane and then lyophilized in dioxane. (4c) is obtained in the form of a white powder (20 mg, 85%).
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH3:4].Cl.N1C=CC=CC=1.[NH2:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:28]=1[NH:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])=[CH:26][CH:25]=[CH:24][CH:23]=2>C(#N)C>[CH2:2]([C:1]1[N:29]([CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:18]=1)[CH2:3][CH3:4]
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Reactant: CCCC(OC)(OC)OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Temperature: 25 °C

Procedure:
Trimethyl orthobutyrate (1.90 g, 12.7 mmol) and pyridine hydrochloride (0.13 g, 1.2 mmol) were added to a suspension of 1-[(3-aminoquinolin-4-yl)amino]-2-methylpropan-2-ol (prepared as described in Part A of Example 8, approximately 2.7 g, 11.5 mmol) in acetonitrile (60 mL). The reaction mixture was heated at reflux for 45 minutes with a Dean Stark trap, then was allowed to cool to room temperature and was concentrated under reduced pressure. The crude product was subjected to flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to yield a mixture of compounds that were combined and resubjected to the reaction conditions. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure to afford 1-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a white solid that was used in the next step without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH:22][C:14](=[O:16])[CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:12][CH:11]=1
Reactant: O=C(O)Cc1ccc(-c2ccccn2)cc1
Reactant: NCc1cccc(F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(-c2ccccn2)cc1)NCc1cccc(F)c1
Reaction time: 8 h

Procedure:
(4-Pyridin-2-yl-phenyl)-acetic acid (0.2 gm, 0.9 mmole), 3-fluorobenzylamine (0.14 ml, 1.lmmole), PyBOP (0.57 gm, 1.1 mmole), and DIEA (0.36 ml, 2.2 mmole) was dissolved in DMF stirred overnight, the reaction mixture was then poured into water, solid was collected by filtration, re-crystallized using water-methanol. (0.13 gm, 45%); H1-NMR INOVA-500 (DMSO d6) δ 3.563 (s, 2H), 4.305 (d, J=6.0 Hz, 2H), 7.032-7.095 (m, 3H), 7.332-7.360 (m, 2H), 7.404 (d, J=8.0 Hz, 2H), 7.874 (t, J=7.0 Hz, 1H), 7.948 (d, J=8.0 Hz, 1H), 8.034 (d, J=8.0 Hz, 2H), 8.659 (d, J=4. Hz, 2H). MS (m/z) 321.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH:61]([C@@H:63]1[CH2:67][CH2:66][CH2:65][N:64]1[C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])/[CH:29]=[CH:61]/[C@@H:63]4[CH2:67][CH2:66][CH2:65][N:64]4[C:68]([O:70][C:71]([CH3:72])([CH3:74])[CH3:73])=[O:69])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.2 %

Procedure:
N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (156 mg, 0.25 mmol) was dissolved in 3 mL of tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (375 μL, 0.38 mmol). After the reaction mixture was stirred for 45 minutes, a solution of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate 2c (100 mg, 0.50 mmol) in 2 mL of tetrahydrofuran was added. The reaction mixture was stirred for another 1 hour, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound tert-butyl (2S)-2-[(E)-3-[[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]amino]-3-oxo-prop-1-enyl]pyrrolidine-1-carboxylate 2d (161 mg, yield 96.2%) as a light yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:67]=[CH:66][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:67]=[CH:66][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:63])[F:64])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 101 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine in 1 ml DMF were added. After 2.5 h stirring at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The yellow solid foam was purified by column chromatography (8 g silica gel; heptane/EtOAc 9:1) to give 124 mg (84%) of a colorless gum. MS (ISP) 479.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[N:35]1C=CC(CO)=CC=1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][CH2:20][C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][N:35]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCc1ccncc1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccn1
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed 4-pyridylmethanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give 2-pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (11 mg, 0.023 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.0N HCl in ether (0.1 mL) was added slowly. The precipatate was collected through filtration under nitrogen to give 4-pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate hydrochloride (12 mg, 0.023 mmol). 1H NMR (DMSO-d6) δ 1.91(m, 2H), 2.16(m, 2H), 3.55(m, 2H), 3.90(s, 3H), 4.03 (m, 2H), 4.92(m, 1H), 5.34(s, 2H), 7.06(d, J=8.2 Hz, 1H), 7.16(s, 1H), 7.73(m, 1H), 7.81(m, 1H), 7.87(s, 1H), 8.46(s, 1H), 8.76(d, J=5.6 Hz, 1H), 9.05(s, 1H). LC/MS: MH30 =475.
Reaction SMILES: O.[O:2]([CH2:9][C:10]([NH:12][CH:13]1[C:35](=[O:36])[N:15]2[CH:16]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[C:17]([CH3:21])([CH3:20])[S:18](=[O:19])[C@H:14]12)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:37]N1C(=O)C2=CC=CC=C2C1=O>C1(C)C=CC=CC=1>[CH3:20][C:17](=[CH2:21])[CH:16]([N:15]1[C:35](=[O:36])[CH:13]([NH:12][C:10](=[O:11])[CH2:9][O:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:14]1[S:18]([Cl:37])=[O:19])[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:23]
Reactant: O=C1c2ccccc2C(=O)N1Cl
Reactant: CC1(C)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S1=O
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1S(=O)Cl

Procedure:
Toluene (425 ml.) was heated in equipment containing a Dean-Stark water trap to azeotropically remove any moisture which may be present, and 25 ml. of toluene were removed thereby. To the remaining toluene were added 10.0 g. (20 mmol.) of p-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide, the toluene being maintained at a temperature slightly below reflux. Toluene (200 ml.) was separately distilled, and 4.0 g. (22 mmol.) of N-chlorophthalimide were added. The resulting solution (warm) was added dropwise to the solution of the penicillin sulfoxide ester over a period of 30 minutes. The mixture remained a light yellow solution throughout addition. The mixture then was refluxed for 55 minutes after which time a sample was removed, and nmr (CDCl3) analysis of the sample indicated virtually entire conversion of the penicillin sulfoxide ester to the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([C:25]([OH:27])=O)[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:35][OH:36].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.C1COCC1.O>[OH:36][NH:35][C:25]([C:12]1([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:27]
Reactant: NO
Reactant: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-(4-Methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid (2.0 g, 5.1 mmol) and DMF (2 drops) in CH2Cl2 (100 ml) at 0° C., oxalyl chloride (1.0 gm, 8 mmol) was added in a drop-wise manner. After the addition, the reaction mixture was stirred at room temperature for 1 hour. Simultaneously, in a separate flask a mixture of hydroxylamine hydrochloride (2.0 gm, 29 mmol) and triethylamine (5 ml, excess) was stirred in THF:water (5:1, 30 ml) at 0° C. for 1 hour. At the end of 1 hour, the oxalyl chloride reaction mixture was concentrated and the pale yellow residue was dissolved in 10 ml of CH2Cl2 and added slowly to the hydroxylamine at 0° C. The reaction mixture was stirred at room temperature for 24 hours and concentrated. The residue obtained was extracted with chloroform and washed well with water. The product obtained was purified by silica gel column chromatography and eluted with chloroform the product 4-(4-Methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid hydroxyamide was isolated as a colorless solid. mp 90-95° C.; Yield, 1.2 g, 48%; MS: 405 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ2.29 (m, 3H), 2.76-2.79 (m, 2H), 3.43 (m, 4H),4.30 (s, 2H), 7.14-7.17 (d,2H), 7.50-7.73 (m, 5H), 9.37 (s,1H), 10.53 (s, 1H), 11.18 (s, 1H).
Reaction SMILES: C1(N2C(C(F)(F)F)=C(C3ON=C4C5C(CCC=34)=CC(C=C)=CC=5)C=N2)C=CC=CC=1.[I:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)/[C:38](=[N:42]/[OH:43])/[CH2:37][CH2:36][CH2:35]2.[C:44]1([C:50]2[O:54][N:53]=[C:52]([C:55](OC)=O)[C:51]=2[C:59]([F:62])([F:61])[F:60])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[I:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[C:38]1=[N:42][O:43][C:55]([C:52]3[C:51]([C:59]([F:60])([F:61])[F:62])=[C:50]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[O:54][N:53]=3)=[C:37]1[CH2:36][CH2:35]2
Reactant: COC(=O)c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: O/N=C1\CCCc2cc(I)ccc21
Agent: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Product: FC(F)(F)c1c(-c2onc3c2CCc2cc(I)ccc2-3)noc1-c1ccccc1

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 89A employing (E)-6-iodo-3,4-dihydronaphthalen-1(2H)-one oxime (121A) and methyl 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylate (Intermediate I-5) as starting materials. The compound had an HPLC retention time=4.42 min. (condition C); LC/MS M+1=509.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.CN1CCOCC1.ClC(OCC)=O.C(=[N:31][CH2:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)C1C=CC=CC=1>ClCCl>[NH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][N:36]([C:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:10])[CH2:35][CH2:34]1
Reactant: O=C(O)c1cccnc1Cl
Reactant: C(=NCC1CCNCC1)c1ccccc1
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: NCC1CCN(C(=O)c2cccnc2Cl)CC1
Reaction time: 2 h
Yield: 76.7 %

Procedure:
A solution of 2-chloropyridine-3-carboxylic acid (4.09 g) and 1-methylmorpholine (2.7 ml) in dichloromethane (100 ml) was stirred at -5° C. under nitrogen and ethyl chloroformate (2.4 ml) was added dropwise. After 10 minutes a solution of N-benzylidene-1-(4-piperidyl)methylamine (5.0 g) in dichloromethane (25 ml) was added and stirring continued at -5° C. for 2 hours then at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue stirred with potassium hydrogen sulphate solution (1 M; 250 ml) for 5 hours. The mixture was filtered and the filtrate washed with dichloromethane (2×150 ml), basified with aqueous sodium hydroxide solution (5 M) and extracted with dichloromethane (3×150 ml). The combined extracts were dried over magnesium sulphate and the solvent was evaporated to give 4-(aminomethyl)-1-(2-chloro-3-pyridylcarbonyl)-piperidine (4.81 g) contaminated with some 1-methylmorpholine. This material was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[C:19](O)(=O)C.C=O.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1
Reactant: CC(=O)O
Reactant: Cc1nnc2c(NC3CCNCC3)cc(Cl)nn12
Agent: C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnc2c(NC3CCN(C)CC3)cc(Cl)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(6-Chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)-piperidin-4-yl-amine (0.26 g; 0.97 mmol) was dissolved in 5.0 ml THF. Acetic acid (0.11 ml; 1.94 mmol), formaldehyde 37% in water (0.29 ml; 3.89 mmol) and STAB (0.27 g; 1.27 mmol) were added and stirred at ambient temperature for 1 hour. The crude material was purified by using reversed phase chromatography under basic conditions.