Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N+:8]([O-])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11]1([NH:17][C:18](=O)[CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:19][C:18]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]2[C:3]([N:8]=1)=[N:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=[N+]([O-])c1ncccc1Br
Reactant: CC(=O)Nc1ccccc1
Product: Cc1nc2ncccc2n1-c1ccccc1
Yield: 46.8 %

Procedure:
The title compound was prepared with the analogous procedure described in example 3 using 3-Bromo-2-nitropyridine (101 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as brown viscous oil (49 mg, 47% yield). 1H NMR (DMSO) δ 2.54 (s, 3 H), 7.35-7.68 (m, 6 H), 7.77 (d, J=8.8 Hz, 1 H), 8.58 (br s, 1 H); 13C NMR δ 14.0, 118.9, 120.1, 126.8, 128.5, 129.6, 130.1, 133.9, 143.0, 151.6, 156.7. HRMS (FAB): cal. for C13H12N3 [M-FH+]: 210.1031; found: 210.1026.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:12][C:13]3[C:14]([F:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1.[CH2:24]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH2:26].O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:26]([C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:12][C:13]3[C:14]([F:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1)[CH:25]=[CH2:24]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: NC(=O)c1c(F)ccc(OCc2nc3ccc(Br)nc3s2)c1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2n1
Temperature: 120 °C
Yield: 74.8 %

Procedure:
To a solution of 3-(5-bromo-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.15 g, 0.37 mmol) in 5 ml of anhydrous DMF was added allyl tributyltin (0.26 ml, 0.86 mmol) and degassed the reaction mixture for the 10 minutes. Tetrakis(triphenylphosphine) palladium (0) (0.007 g, 0.0056 mmol) was then added and the reaction mixture was heated at 120° C. for 1 h under the nitrogen atmosphere. Then reaction mixture was cooled to room temperature added water (25 mL) and extracted the compound with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (100-200 M) using ethyl acetate/Hexane (60:40) as the eluent to provide the title compound (0.10 g, 75%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[NH:7][C:6](=O)[C:5]=1[N+:14]([O-:16])=[O:15])[CH3:2].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:6]1[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([NH:3][CH2:1][CH3:2])[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[N:7]=1
Reactant: CCNc1cc(C(C)C)[nH]c(=O)c1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: CCNc1cc(C(C)C)nc(Cl)c1[N+](=O)[O-]

Procedure:
A mixture of 4-ethylamino-6-isopropyl-3-nitro-1H-pyridin-2-one (520 mg, 2.31 mmol) in POCl3 is stirred at reflux for 1.5 h. After cooling, the solution is concentrated in vacuo. The reaction flask is then placed in an ice bath and crushed ice is added to the residue. The mixture is swirled vigorously for a few minutes and then stirred at 0° C. for 1 h. The mixture is then extracted with EtOAc. The extract is washed with additional H2O (20 mL) and brine (20 mL). The extract is dried over Na2SO4 and concentrated to afford (2-chloro-6-isopropyl-3-nitro-pyridin-4-yl)-ethyl-amine as a yellow solid. The material is sufficiently pure to be used without further purification. 1H NMR (CDCl3, 400 MHz) δ 6.62 (br, 1H), 6.44 (s, 1H), 3.31 (m, 2H), 2.91 (sept, J=6.8 Hz, 1H), 1.33 (t, J=7.4 Hz, 3H), 1.26 (d, J=6.8 Hz, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([NH2:13])=[CH:11][C:10]([CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](=O)[CH2:21][C:22](=O)[C:23]([O:25][CH3:26])=[O:24]>CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[N:13]=[C:20]([C:16]4[O:15][CH:19]=[CH:18][CH:17]=4)[CH:21]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[C:11]=3[C:10]([CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)CC(=O)c1ccco1
Reactant: Cc1cc(N)n(-c2cccc(Cl)c2)n1
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccco2)nc2c1c(C)nn2-c1cccc(Cl)c1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
(see, e.g., Volochnyuk, D. M., et al., J Comb Chem 2010, 12, 510-7). A solution of 22 (306 mg, 1.47 mmol) and 20 (295 mg, 1.50 mmol) in glacial AcOH (10 mL) was heated to reflux for 3 h. When the reaction mixture was cooled down to room temperature, yellow precipitates formed which were filtered and washed with H2O. Filtercake was placed in a vacuum oven to give the title compound (470 mg, 87%) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.48 (s, 1H), 8.29 (d, J=9.1 Hz, 1H), 8.06 (s, 1H), 7.62 (s, 1H), 7.43 (t, J=8.1 Hz, 1H), 7.28-7.23 (m, 2H), 6.63-6.59 (m, 1H), 4.06 (s, 3H), 2.75 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 165.53, 152.95, 151.82, 148.42, 144.43, 143.32, 140.31, 134.59, 133.91, 129.93, 125.41, 120.77, 118.52, 113.87, 112.57, 112.24, 110.94, 52.73, 16.21.
Reaction SMILES: [CH3:1][C:2]([CH3:57])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:54])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:53])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42](=[O:52])[NH:43][C@@H:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=4)[CH3:45])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:56])[CH3:55])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].[C:58]([OH:64])([C:60]([F:63])([F:62])[F:61])=[O:59]>ClCCl>[CH:37]([C:33]1[C:34](=[O:36])[CH2:35][C@:23]2(/[CH:40]=[CH:41]/[C:42](=[O:52])[NH:43][C@@H:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[CH3:45])[CH2:22][CH2:21][C@:20]3([CH3:53])[C@H:25]([CH2:26][CH2:27][C@H:28]4[C@@:19]3([CH3:54])[CH2:18][CH2:17][C@@H:16]3[C@:29]4([CH3:32])[CH2:30][CH2:31][C@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:57])[C:3]([OH:5])=[O:4])[C:15]3([CH3:55])[CH3:56])[C:24]=12)([CH3:38])[CH3:39].[F:61][C:60]([F:63])([F:62])[C:58]([OH:64])=[O:59]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@H](C)c2ccccn2)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@H](C)c2ccccn2)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3a-((E)-3-oxo-3-(((R)-1-(pyridin-2-yl)ethyl)amino)prop-1-en-1-yl)-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (470 mg, 0.599 mmol) in dichloromethane (10 mL) stirred at rt was added TFA (5 mL). The reaction mixture was stirred at rt for 2 h. Then, it was evaporated in vacuo to get crude product. This material was purified by preparative-HPLC to provide the title compound trifluoroacetic acid salt (225 mg, 0.267 mmol, 44.6%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=9.23 (d, J=6.8 Hz, 1H), 8.75 (d, J=3.5 Hz, 1H), 8.32 (t, J=7.7 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.84-7.69 (m, 1H), 6.77 (d, J=15.8 Hz, 1H), 5.89 (d, J=15.8 Hz, 1H), 5.49-5.21 (m, 1H), 4.50 (dd, J=5.4, 10.7 Hz, 1H), 3.32-3.05 (m, 1H), 2.78-2.49 (m, 3H), 2.33-2.01 (m, 3H), 2.03-0.63 (m, 47H); LC/MS: m/z calculated 728.5. Found 729.4 (M+1)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1O.N1C=CC=CC=1.P(Br)(Br)[Br:18]>C(Cl)(Cl)Cl>[Br:18][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: BrP(Br)Br
Reactant: OC1Cc2ccccc2C1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: BrC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 80 gms of 2-indanol in 200 ml of chloroform was added 12 ml of pyridine. The solution was cooled to 0° C. with an ice bath, and 64 ml of phosphorous tribromide slowly added over 30 minutes. The ice bath was removed, and the solution was refluxed for 1 hour, and let stand overnight.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:3]=1.[CH2:21]([CH2:24][OH:25])[CH2:22][NH2:23].CCN(C(C)C)C(C)C>CCCCO>[O:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:23][CH2:22][CH2:21][CH2:24][OH:25])[CH:3]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: Clc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Reactant: NCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OCCCNc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Temperature: 200 °C
Yield: 40 %

Procedure:
165 mg of 6-chloro-N-(4-morpholinophenyl)pyrimidin-4-amine, 86 mg of propanolamine and 147 mg of DIPEA were dissolved in 2 mL of n-BuOH, The mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. n-BuOH was evaporated off and the evaporation residue was subjected to crystallization from n-BuOH-EtOH solvent mixture. 3-(6-(4-Morpholinophenylamino)pyrimidin-4-ylamino)propan-1-ol was obtained in the form of a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][O:24][C:25]1[CH:49]=[CH:48][C:28]([CH2:29][O:30][C:31]([NH:33][C:34]2[NH:35][C:36](=[O:47])[C:37]3[N:38]=[CH:39][N:40]([CH2:43][C:44](O)=[O:45])[C:41]=3[N:42]=2)=[O:32])=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:44](=[O:45])[CH2:43][N:40]1[CH:39]=[N:38][C:37]2[C:36](=[O:47])[NH:35][C:34]([NH:33][C:31]([O:30][CH2:29][C:28]3[CH:48]=[CH:49][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[O:32])=[N:42][C:41]1=2)[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: COc1ccc(COC(=O)Nc2nc3c(ncn3CC(=O)O)c(=O)[nH]2)cc1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccc(OC)cc3)nc21
Yield: 77.9 %

Procedure:
The title compound (2.72 g, 78%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [2-N-(4-methoxybenzyloxycarbonyl)-guanin-9-yl]-acetic acid (1.89 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 8.26 (dd, 1H), 8.15 (dd, 1H), 7.80 (s, 0.6H), 7.76 (s, 0.4H), 7.65 (m, 2H), 7.36 (d, 2H), 6.94 (d, 2H), 5.16 (s, 2H), 5.09 (s, 1.2H), 4.90 (s, 0.8H), 4.42 (s, 0.8H), 4.16 (q, 0.8H), 4.06 (s, 1.2H), 4.03 (q, 1.2H), 3.75 (s, 3H), 3.63(t, 1.2H), 3.43 (t, 1.2H), 3.39 (t, 0.8H), 3.20 (t, 0.8H), 1.21 (t, 1.2H), 1.12 (t, 1.8H).
Reaction SMILES: O[CH2:2][C:3]1[S:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Br-:9].[C:10]1([PH+:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[Br-:9].[CH3:8][C:5]1[S:4][C:3]([CH2:2][P+:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][CH:6]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(CO)s1
Agent: [Br-]
Solvent: CC#N
Product: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)s1
Temperature: 75 °C

Procedure:
2-Hydroxymethyl-5-methyl-thiophene (4.6 g.) was dissolved in 100 ml. of acetonitrile and 12.2 g. of triphenylphosphonium bromide were added. The reaction mixture was heated to 75° C. for 2.5 hours. After cooling the resulting precipitate was filtered off, washed with benzene and dried at 80° C. under high vacuum. The resulting (5-methyl-2-thenyl)triphenylphosphonium bromide has a m.p. 262°-266° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH3:20][C:21]([O:24][C:25](=[O:43])[NH:26][CH:27]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:28](=[O:35])[NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)([CH3:23])[CH3:22].C(N(CC)CC)C>C(#N)C>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:32]4[CH2:33][CH2:34][CH:30]([NH:29][C:28](=[O:35])[CH:27]([NH:26][C:25]([O:24][C:21]([CH3:22])([CH3:20])[CH3:23])=[O:43])[CH2:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[CH2:31]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)NC1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1

Procedure:
A suspension of 14.1 g (50 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 18.3 g (55 mmol) of [R-(R*,S*)]-[1-phenylmethyl-2-oxo-2-[(3-pyrrolidinyl)amino]ethyl]carbamic acid 1,1-dimethylethyl ester, 15.2 g (0.15 mol) of triethylamine and 200 ml of acetonitrile was heated at reflux for four hours. The solvent was removed in vacuo and the residue was dissolved in methylene chloride and washed with 100 ml of cold 1.0M hydrochloric acid and then water. After drying (MgSO4) and filtering, the solvent was removed in vacuo to give 26.2 g of the title compound.
Reaction SMILES: Br[CH:2]([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[Cl:13])=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][C:18]=1[N:26]([CH2:30][CH2:31][CH3:32])[C:27]([NH2:29])=[S:28]>>[Cl:13][C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[C:3]1[N:29]=[C:27]([N:26]([C:18]2[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=[CH:22][C:17]=2[O:16][CH3:15])[CH2:30][CH2:31][CH3:32])[S:28][C:2]=1[CH3:14]
Reactant: COc1ccc(C(=O)C(C)Br)c(Cl)c1
Reactant: CCCN(C(N)=S)c1cc(C(=O)O)ccc1OC
Product: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(C(=O)O)ccc1OC
Yield: 70 %

Procedure:
By following the procedure of EXAMPLE 2 and by using 2-bromo-1-(2-chloro-4-methoxyphenyl)propan-1-one (Compound 1-2) and N-(2-methoxy-5-carboxyphenyl)-N-propylthiourea (Compound 12-1), the expected product is obtained in the form of white crystals; yield=70%; m.p.=109° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[OH:24].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH2:2]([O:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCBr
Reactant: Cc1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1cc(C)ccc1C
Yield: 86.4 %

Procedure:
1-bromotetradecane (44.4 mL, 0.149 mol), 2,5-dimethylphenol (20.0 g, 0.164 mol) and K2CO3 (82.4 g, 0.596 mol) were combined in a round bottom flask in acetonitrile (200 mL). The flask was equipped with a stir-bar, and a water-cooled condenser and protected under a nitrogen atmosphere. The mixture was heated at reflux for overnight. Synthetic progress was monitored by the disappearance of the signal (triplet) from the C1 hydrogens on the alkyl bromide (˜3.5 ppm) in 1H NMR. Upon completion, the reaction was removed from heat and excess K2CO3 was removed by gravity filtration (rinsed with CH2Cl2). The crude product was concentrated in vacuo and the resulting material was dissolved in CH2Cl2, washed with 1 M NaOH (2×, to remove unreacted 2,5-dimethylphenol or p-cresol), dH2O (2×) and brine (1×), dried over Na2SO4, gravity filtered, and concentrated in vacuo to remove the solvent. The material was of sufficient purity (by 1H and 13C NMR) to be used in the subsequent reactions. Yielded 41.0 g (86%) of an off-white solid, mp=36.9-37.9° C. 1H NMR (CDCl3, 400 MHz) δ: 7.01 (d, 3J=7.4 Hz, 1H, Ar—H); 6.66 (d, 3J=7.6 Hz, 1H, Ar—H); 6.65 (s, 1H, Ar—H); 3.95 (t, 3J=6.5 Hz, 2H, OCH2); 2.33 (s, 3H); 2.20 (s, 3H); 1.80 (m, 2H, OCH2CH2); 1.49 (m, 2H, OCH2CH2CH2); 1.42-1.26 (m, 20H); 0.90 (t, 3J=6.8 Hz, 3H, CH2CH3). 13C NMR (CDCl3, 100 MHz) δ: 157.15, 136.40, 130.25, 123.65, 120.53, 112.01, 67.88, 31.93, 29.70, 29.68, 29,66, 29.62, 29.42, 29.40, 29.37, 26.16, 22.70, 21.40, 15.78, 14.11. HRMS (DART): [M+H]+=319.29460 (calcd for C22H39O 319.29954).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:38]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:38])=[O:26])=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccccc1F
Solvent: CO
Product: CC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1F

Procedure:
In a similar manner as described for example A5, 2.98 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[1-(2-fluorophenyl)ethoxy]thiophene-2-carboxylate and 115 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.Br[C:28]1[CH:33]=[C:32]([CH3:34])[N+:31]([O-:35])=[C:30]([CH3:36])[CH:29]=1>>[OH:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:33]=[C:32]([CH3:34])[N+:31]([O-:35])=[C:30]([CH3:36])[CH:29]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccccc4)OC3=O)cc2)cc(C)[n+]1[O-]

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2,6-dimethylpyridine-N-oxide in Step 4. LC-MS Method 2 tR=1.086, m/z=461.1; 1H NMR (CDCl3) 1.34 (m, 1H), 1.50 (d, 3H), 1.61-1.72 (m, 2H), 1.88-2.00 (m, 2H), 2.18 (m, 1H), 2.22-2.34 (m, 2H), 2.62 (s, 6H), 2.88 (m, 1H), 3.51 (t, 2H), 5.65 (m, 1H), 6.93 (d, 2H), 7.21 (m, 1H), 7.26 (m, 4H), 7.29-7.38 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[N:11][CH:10]=[C:9]([OH:21])[C:8]=2[C:7]1=[O:22].C(OO)(=[O:29])C.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:21])[CH:10]=[N+:11]([O-:29])[C:12]=2[C:16]([N:18]([CH3:19])[CH3:20])=[O:17])[C:7]1=[O:22]
Reactant: CC(=O)OO
Reactant: CN(C)C(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)C(=O)c1c2c(c(O)c[n+]1[O-])C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 50 °C

Procedure:
6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide (24 g, 63.5 mmol) was dissolved in 1000 mL glacial acetic acid and per-acetic acid (32% by weight in acetic acid, 151 mL, 635 mmol) and sodium acetate (2.6 g, 31.7 mmol) was added. The reaction was warmed to 50° C. and aged overnight at which time LCMS showed the reaction done. The solution reduced in volume to ⅓ on the rotoevaporator, cooled in an ice bath and quenched slowly with 10% Na2SO3 solution until no peroxide was detected by a starch paper test. The reaction was transferred to a separatory funnel and water (500 mL) and chloroform was added. The layers were separated and the water extracted with CHCl3 several times. The combined organic layers were washed with slightly acidic water, brine and dried over Na2SO4, filtered and evaporated to give the product as an oil. The initial NMR shows an excessive number of methyl group peaks, perhaps as a result of oxalyl chloride reacting with dimethylamine in the second step and this impurity being carried through. A small sample was purified by reverse phase chromatography eluting with 95:5-5:95 water/acetonitrile 0.1% TFA to give clean material for NMR.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([CH2:9][N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=[C:11]2[NH:19][CH:20]2[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][OH:29])[CH2:22][CH2:21]2)=[CH:6][CH:5]=1.Cl[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1.O>CN(C)C=O>[N:32]1[CH:33]=[CH:34][CH:35]=[N:36][C:31]=1[O:29][CH2:28][CH2:27][N:23]1[CH2:24][CH2:25][CH2:26][CH:20]([NH:19][C:11]2[N:10]([CH2:9][C:7]3[O:8][C:4]([CH3:3])=[CH:5][CH:6]=3)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=2)[CH2:21][CH2:22]1
Reactant: Clc1ncccn1
Reactant: Cc1ccc(Cn2c(NC3CCCN(CCO)CC3)nc3cccnc32)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2c(NC3CCCN(CCOc4ncccn4)CC3)nc3cccnc32)o1
Reaction time: 0.25 h
Yield: 34.8 %

Procedure:
To a stirred mixture of 1 part of a sodium hydride dispersion 50% and 94 parts of N,N-dimethylformamide is added dropwise a solution of 5.5 parts of hexahydro-4-[[3-[(5-methyl-2-furanyl)methyl]-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1H-azepine-1-ethanol in N,N-dimethylformamide. Upon complete addition, stirring is continued for 15 minutes at room temperature. 1.9 Parts of 2-chloropyrimidine are added portionwise and upon completion, stirring is continued for 2 hours at room temperature. The reaction mixture is decomposed with water and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent was evaporated. The residue is converted into the ethanedioate salt in ethanol. The salt is filtered off and dried, yielding 3.4 parts (34.8%) of N-[hexahydro-1-[2-(2-pyrimidinyloxy)ethyl]-1H-azepin-4-yl]-3-[(5-methyl-2-furanyl)methyl]-3H-imidazo[4,5-b]pyridin-2-amine (compound 169).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26].C(N(CC)CC)C>CO>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:27])(=[O:26])[N:28]([CH3:29])[CH3:30])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CN(C)S(=O)(=O)c1ccc(Cl)cc1CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
(Step 3) To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.50 g) in methanol (10 ml) was added a solution of 2-(aminomethyl)-4-chloro-N,N-dimethylbenzenesulfonamide hydrochloride obtained in Step 2 (0.85 g) and triethylamine (0.58 ml) in methanol (5 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (5 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, the residue was extracted with 1N hydrochloric acid, and the extract was washed with ethyl acetate. The aqueous layer was basified with 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (1 ml) was added. The mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.43 g).