Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C=O)C>[C:21]([Si:24]([CH3:26])([CH3:25])[O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:19])([CH3:23])([CH3:22])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCOCCOCCOCCOCCOCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOCCOCCOCCOCCOCCO

Procedure:
Compound 28c was prepared according to the procedure described hereinabove for Compound 6a, using hexaethylene glycol (5 grams, 17.7 mmol), TBDMSCl (1.65 grams, 11 mmol), and imidazole (0.748 grams, 11 mmol) in DMF (26 ml), yielding 1 gram of the product (14% yield).
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[C:6]([CH:10]3[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([C:21]([F:24])([F:23])[F:22])[NH:13][C:12]([CH:25]=[O:26])=[C:11]3[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:7][CH:8]=[CH:9][C:2]=12.[BH4-].[Na+].Cl>C(O)C>[N:1]1[O:5][N:4]=[C:3]2[C:6]([CH:10]3[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([C:21]([F:24])([F:23])[F:22])[NH:13][C:12]([CH2:25][OH:26])=[C:11]3[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: CCOC(=O)C1=C(C=O)NC(C(F)(F)F)=C(C(=O)OCC)C1c1cccc2nonc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(CO)NC(C(F)(F)F)=C(C(=O)OCC)C1c1cccc2nonc12
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
A solution of diethyl 4-(4-benzofurazanyl)-2-formyl-1,4-dihydro-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (1.1 g; 2.5 mmoles) in dry ethanol (90 ml) was cooled to 0° and sodium borohydride (0.14 g; 3.7 mmoles) was added portionwise over 3 minutes. After 10 minutes, 10% aqueous hydrochloric acid was added dropwise to pH3, and the mixture concentrated in vacuo at room temperature. The resulting yellow oil was dissolved in ether (50 ml) and saturated aqueous sodium bicarbonate was added to pH9. The organic solution was separated, washed with saturated aqueous sodium bicarbonate solution, water, brine and dried (MgSO4). Evaporation of the solvent left a yellow oil which was crystallised from 2-propanol to give the title compound (0.5 g) mp 110°-11°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:20]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[F:38])[S:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:4][C:5]([NH:8]CC2C=CC(OC)=C(OC)C=2)=[N:6][CH:7]=1.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([CH:20]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[F:38])[S:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: COc1ccc(CNc2cc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(F)cc3)c(Cl)cn2)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)c(Cl)cn1
Temperature: 65 °C
Reaction time: 17 h
Yield: 98.6 %

Procedure:
[5-Chloro-4-[(2,5-difluorophenyl)-(4-fluorophenylsulfonyl)methyl]pyridin-2-yl](3,4-dimethoxybenzyl)amine (157 mg, 0.28 mmol) was dissolved in trifluoroacetic acid (5.0 ml). The resulting solution was stirred at 65° C. for 17 hours. After cooling, the reaction mixture was concentrated under reduced pressure. To the residue thus obtained was added a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give the title compound (114 mg, 99%) as a white solid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:16]3[N:15](COCC[Si](C)(C)C)[C:14]4[CH2:27][CH:28]5[NH:32][CH:31]([C:13]=4[C:12]=3[C:11]=2[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29]5)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:16]3[NH:15][C:14]4[CH2:27][CH:28]5[NH:32][CH:31]([C:13]=4[C:12]=3[C:11]=2[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29]5)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)c1c(S(=O)(=O)c2ccccc2)ccc2c1c1c(n2COCC[Si](C)(C)C)CC2CCC1N2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(S(=O)(=O)c2ccccc2)ccc2[nH]c3c(c12)C1CCC(C3)N1
Yield: 92.2 %

Procedure:
To a solution of the product of step B (1.28 g, 2.25 mmol) in THF (30 mL) was added a 1M solution of TBAF in THF (12 mL, 12.0 mmol) and the resulting solution heated to reflux overnight. The reaction was concentrated in vacuo to a reduced volume and diluted with a saturated aqueous solution of ammonium chloride followed by water. The mixture was extracted with dichloromethane and the organic phase dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 4:1 to 1:1 hexane/ethyl acetate) to give tert-butyl 2-phenylsulfonyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-carboxylate (0.91 g, 93%) as a white foam: 1H NMR (CD3OD, 300 MHz) δ 8.12 (s, 1H), 7.91-7.96 (m, 2H), 7.48-7.62 (m, 4H), 7.41 (d, J=8.7 Hz, 1H), 5.19-5.28 (m, 1H), 4.52-4.61 (m, 1H), 3.35-3.48 (m, 1H), 2.58 (d, J=16.2 Hz, 1H), 2.15-2.41 (m, 2H), 1.90-1.99 (m, 1H), 1.64-1.75 (m, 1H), 1.27-1.49 (m, 9H).
Reaction SMILES: [CH2:1](OC1C=CC=CC=1)[C:2]1C=CC=[CH:4][CH:3]=1.[CH2:15]([N:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:29]1([N:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:15][C:16]2[C:17]3[C:18](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:19]=[CH:20][CH:21]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Reactant: c1ccc(COc2ccccc2)cc1
Product: c1ccc(N(Cc2cccc3ccccc23)c2ccccc2)cc1
Yield: 74 %

Procedure:
N-phenylnaphthaldimine (2.20 g, 0.010 mol) and benzylphenyl ether (1.84 g, 0.010 mol) were reacted as above for the preparation of benzyldiphenylamine. Aqueous work-up afforded a precipitate which was isolated by filtration and recrystallized from 95% ethanol to yield 2.3 g (74%) of needles, mp 170°-172° C. Anal. calcd. for C23H19N: C 89.28, H 6.19, N 4.53%; found: C 89.11, H 6.26, N 4.44%. 1H NMR (200 MHz, CDCl3) δ (assignment): 5.52 (s, 2H, CH2), 7.00-8.10 (m, 17H, aromatic). MS [m/e (70 ev, % of base peak)] (C10H7)CH2N(C6H5)2 309 (M+., 4.8), 308 (M+-H., 29.0), 168 (M+-((C10H7)CH2)., 18.0), 141 (((C10H7)CH2)+., 100 ). FTIR (CDCl3): 3063, 3040, 1606, 1602, 1594, 1584, 1574, 1559, 1512, 1501, 1497, 1488, 1485, 1474, 1465, 1460, 1451 cm-1.
Reaction SMILES: C(OC([C:8]1[C:9]([NH:22][CH3:23])=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:23][NH:22][C:9]1[CH:8]=[CH:21][CH:20]=[CH:19][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: CNc1c(OCCCC(=O)OC)cccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccccc1OCCCC(=O)OC
Reaction time: 1 h
Yield: 101.4 %

Procedure:
A solution of methyl 4-(3-t-butoxycarbonyl-[-methyl]aminophenoxy)butyrate(0.2 g) in a mixture of dichloromethane(1 mL) and trifluoroacetic acid(1 mL) was kept at ambient temperature for 1 h and evaporated to dryness. The residue was treated with water and ethyl acetate and the mixture was stirred while making basic with potassium carbonate. The organic phase was separated, dried and evaporated to dryness to give the product (0.14 g), [m/e224, MH+].
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:10](=[O:12])[CH3:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>C1COCC1>[S:22]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:10](=[O:12])[CH3:11])[C:4]=2[CH:3]=[CH:2]1)([C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: CC(=O)c1nccc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1nccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a mixture of 1-(1H-pyrrolo[3,2-c]pyridin-4-yl)ethanone (680 mg, 4.25 mmol) in anhydrous THF (40 mL) at 0° C. was added NaH (60% in mineral oil, 204 mg, 5.1 mmol). After the mixture was stirred at 0° C. for 30 min, 4-methylbenzene-1-sulfonyl chloride (850 mg, 4.46 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into water (150 mL), extracted with EtOAc (3×50 mL) and concentrated under reduced pressure to afford 1.32 g (98.9%) of 1-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)ethanone as yellow solid: MS (ESI) m/z: 315.2 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[N:22]=[CH:23][N:24]=[C:25]4[C:32]=3[C:31]3[C@@H:30]([CH2:33][C:34]#[N:35])[CH2:29][CH2:28][C:27]=3[S:26]4)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:36][Li].O.OO>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[N:22]=[CH:23][N:24]=[C:25]4[C:32]=3[C:31]3[C@@H:30]([CH2:33][C:34]([NH2:35])=[O:36])[CH2:29][CH2:28][C:27]=3[S:26]4)[CH2:16][CH2:15]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCN(Cc6ccccc6)CC5)CC4)c3c21
Reactant: [Li]O
Agent: OO
Solvent: O
Solvent: CO
Product: NC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCN(Cc6ccccc6)CC5)CC4)c3c21
Temperature: 0 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
To a solution of 2-[(3R)-12-[[4-(4-benzylpiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetonitrile (270 mg, 0.55 mmol, 1.00 equiv) in methanol (25 mL) were added LiOH.H2O (70 mg) and H2O2 (30%) (1.2 mL). The resulting solution was stirred for 4 h at 0° C. in a water/ice bath. The reaction was then quenched by the addition of 100 mL of Na2SO3 (sat.). The resulting solution was extracted with 6×50 mL of dichloromethane and the organic layers combined. After evaporation, the residue was purified by silica gel column with dichloromethane/methanol (4:1). This resulted in 90 mg (32%) of Compound I-122 as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[CH:29]=[CH:28][C:13]3[N:14]=[C:15]([N:17]4[C@@H:21]5[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]5[O:19][C:18]4([CH3:27])[CH3:26])[S:16][C:12]=3[CH:11]=2)[C:3]=1[N+:30]([O-])=O.CCOC(C)=O>CO.[Pd]>[CH3:26][C:18]1([CH3:27])[N:17]([C:15]2[S:16][C:12]3[CH:11]=[C:10]([CH2:9][NH:8][C:4]4[C:3]([NH2:30])=[CH:2][N:7]=[CH:6][N:5]=4)[CH:29]=[CH:28][C:13]=3[N:14]=2)[C@@H:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]2[O:19]1
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(CNc3ncnc(Cl)c3[N+](=O)[O-])cc2s1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(CNc3ncncc3N)cc2s1
Reaction time: 15 h
Yield: 125.9 %

Procedure:
To a stirred mixture of 6-chloro-N-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-5-nitropyrimidin-4-amine (153 mg, 0.3 mmol) from Step 5 of this Example in MeOH (5 mL) and EtOAc (5 mL) was added Pd 10% wt. on carbon (20 mg, 0.02 mmol). Hydrogen gas was bubbled through the stirred mixture for 2 min, then stirring was continued for 15 h under 1 atm of H2. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford N4-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)pyrimidine-4,5-diamine as an oil (155 mg). The material was used in the next step without further purification. LCMS (ESI) m/z 411 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:17][C:16](=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[Cl:21][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:17]=1
Reactant: Cc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1nc(Cl)c2ccccc2n1

Procedure:
A mixture of 7.6 g of 2-(2-methylphenyl)quinazolin-4(3H)-one and 55 ml of thionyl chloride was treated with 2.35 g of dimethylformamide as described in Example I. The isolated solid was recrystallized from cyclohexane to give 5.1 g of 4-chloro-2-(2-methylphenyl)quinazoline, m.p. 103°-104°; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: C1C(=O)N(OC(CCCCCN[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]2[S:27][CH2:26][C@@H:25]3[NH:28][C:29]([NH:31][C@H:24]23)=[O:30])=[O:18])=O)C(=O)C1.P([O-])([O-])([O-])=[O:33]>>[OH:33][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[C@@H:24]2[C@@H:25]([NH:28][C:29]([NH:31]2)=[O:30])[CH2:26][S:27]1)=[O:18]
Reactant: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: O=P([O-])([O-])[O-]
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
OA (manufactured by Sigma Co., 30 mg) was dissolved in 0.1M phosphate buffer (pH 7.0 , 1 ml), thereto was added an NHS-LC-biotin solution (manufactured by Pierce Chemical Co., 12.6 mg/ml 0.1M phosphate buffer, pH 7.0; 100 μl) and the mixture was reacted at 30° C. for 1 hour. Thereafter, the procedure in Example 5 (a) was repeated to give a biotin-OA fraction.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:30]=[C:29]([CH2:31][N:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)[CH:28]=[CH:27][CH:26]=2)[N:4]=1)[CH3:2].[ClH:45]>C(OCC)(=O)C>[ClH:45].[ClH:45].[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([CH2:31][N:32]3[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]3)[N:30]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCc1nn(Cc2cccc(CN3CCNCC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl 4-((6-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)pyridin-2-yl)methyl)piperazine-1-carboxylate in ethyl acetate was added hydrogen chloride (1 mL; 4M in dioxane) and the mixture was stirred for 45 minutes. The solvent was removed under reduced pressure and the material was dried under high vacuum to give N-(3-ethyl-1-((6-(piperazin-1-ylmethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (12 mg). MS (APCI), positive scan, m/z=495.3 (M+H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[CH:11]=2)=O.S(O)(O)(=O)=O.[CH3:33][N:34]([CH3:38])[C:35]([NH2:37])=[NH:36].[O-]CC.[Na+].C(OCC)(=O)C>C(O)C>[CH3:33][N:34]([CH3:38])[C:35]1[N:37]=[C:5]([C:7]2[CH:8]=[C:9]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[CH:11]=3)[CH:4]=[CH:3][N:36]=1
Reactant: COc1ccc2cc(C(=O)C=CN(C)C)cc(NC(=O)OC(C)(C)C)c2c1
Reactant: CN(C)C(=N)N
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2cc(-c3ccnc(N(C)C)n3)cc(NC(=O)OC(C)(C)C)c2c1
Temperature: 80 °C
Yield: 98.8 %

Procedure:
To a solution of tert-butyl (3-(3-(dimethylamino)acryloyl)-7-methoxynaphthalen-1-yl)carbamate (31) (250 mg, 0.67 mmol), and N,N-dimethylguanidine sulfate (220 mg, 0.8 mmol) in ethanol (10 ml) was added 21% wt sodium ethoxide in ethanol (218 μl, 0.67 mmol). The mixture was heated to 80° C. for 24 hours followed by addition of N,N-dimethylguanidine sulfate (110 mg, 0.4 mmol) and 21% wt sodium ethoxide in ethanol (100 μl). After a further 2 days at 80° C. the mixture was poured into ethyl acetate (150 ml) washed with water (100 ml), brine (100 ml) and dried over anhydrous magnesium sulfate. Evaporation to dryness yielded tert-butyl (3-(2-(dimethylamino)pyrimidin-4-yl)-7-methoxynaphthalen-1-yl)carbamate (140) as a pale brown foam (261 mg). 1H NMR (CDCl3) 400 MHz δ 8.41-8.36 (m, 3H), 7.88-7.87 (d, J=8.8 Hz, 1H), 7.52 (m, 2H), 7.19 (dd, J=2.4 and 9.2 Hz 1H), 7.13 (m, 1H), 7.02 (d, J=5.6 Hz, 1H) 6.65 (s, 1H), 3.97 (s, 1H), 3.31 (s, 6H), 1.57 (s, 9H), LCMS m/e 395 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[OH-].[K+].F[B-](F)(F)F.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]#[N:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(O)(=O)C>O>[Cl:1][C:2]1[C:7]([N:26]=[N:25][C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=2)=[N:6][CH:5]=[C:4]([OH:8])[CH:3]=1
Reactant: Oc1cncc(Cl)c1
Reactant: N#[N+]c1ccc([N+](=O)[O-])cc1
Agent: F[B-](F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(N=Nc2ncc(O)cc2Cl)cc1
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of 5-chloro-3-pyridinol (20.0 g, 0.154 mol, Aldrich) and KOH (13.0 g, 0.232 mol) in 300 mL of water at 0° C. was added p-nitrobenzenediazonium tetrafluoroborate (36.6 g, 0.154 mol, Aldrich). After 1 hour, 50 mL of glacial acetic acid was added, and the bright red precipitate was filtered and air-dried. Chromatography (silica gel; CH2Cl2 /MeOH, 95:5-90:10) afforded the title compound as a bright red solid (28.8 g, 67%): 1H NMR (DMSO-d6, 300 MHz) δ 7.14 (d, J=2.4 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 8.00 (m, 2H), 8.39 (m, 2H); MS (CI/NH3) m/z: 279, 281 (M+H)+.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>COCCOCCOC>[F:10][C:11]([F:19])([F:20])[C:12]1[CH:13]=[C:14]([NH:15][C:3]2[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CSc1nccc(=O)[nH]1
Solvent: COCCOCCOC
Product: O=c1ccnc(Nc2cccc(C(F)(F)F)c2)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
To 2-(methyl-thio)pyrimidine-4(3H)-one, 1, (5 g, 35.21 mmol) in diglyme (25 mL) is added 3-trifluoromethylaniline (5.26 mL, 42.25 mmol). The resulting mixture is heated to reflux and stirred for 18 hours. A solid forms upon cooling the mixture to room temperature. The solid is washed with hexanes to afford 1.9 g (21% yield) of the desired compound. MS (ESI, pos. ion) m/z: 256 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2([CH:18]=[CH2:19])[CH2:13][C:12](OC)([O:14]C)[CH2:11]2)=[C:4]([I:20])[CH:3]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2([CH:18]=[CH2:19])[CH2:13][C:12](=[O:14])[CH2:11]2)=[C:4]([I:20])[CH:3]=1
Reactant: C=CC1(COc2ccc(Br)cc2I)CC(OC)(OC)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC1(COc2ccc(Br)cc2I)CC(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
The mixture of 4-bromo-1-[(3,3-dimethoxy-1-vinylcyclobutyl)methoxy]-2-iodobenzene (3.16 g, 6.98 mmol) and 1M aqueous HCl (14 mL) in THF (31 mL) was stirred for ambient temperature for 1 hour. Then the mixture was stirred for 4 hours at 50° C. The mixture was cooled to room temperature and added saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure to give 3-[(4-bromo-2-iodophenoxy)methyl]-3-vinylcyclobutanone (2.91 g).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)=[N:12][NH:11][C:10]2=[O:20])=[C:5]([F:21])[CH:4]=1.C(N(CC)C(C)C)(C)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>ClCCl>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:31](=[O:34])[CH2:32][CH3:33])[CH2:16]3)=[N:12][NH:11][C:10]2=[O:20])=[C:5]([F:21])[CH:4]=1
Reactant: CCC(=O)Cl
Reactant: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(Br)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
Into a 4 mL screwcap vial was placed 4-(4-bromo-2-fluorophenyl)-5-[(3S)-3-pyrrolidinylmethyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (0.318 mmol). Added to the vial in succession was dichloromethane (3 mL), N,N-diisopropylethylamine (0.916 mmol), and propanoyl chloride (0.319 mmol). The vial was capped and stirred at room temperature overnight. The solution was concentrated in vacuo and the residue was purified by reverse phase HPLC (10-40% acetonitrile w/0.1% TFA/water w/0.1% TFA). The combined product fractions were concentrated in vacuo for 1 h to remove the acetonitrile. The aqueous solution was neutralized with the addition of saturated aqueous sodium bicarbonate, and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (100 mg, 79% yield). MS(ES)+ m/e 397.0, 399.1 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=O.[NH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[C:11]([O:10][C:8](=[O:9])[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:17]=[CH:16][CH:15]=1)[CH2:1][NH:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)COc1cccc(C=O)c1
Reactant: CC(C)(C)OC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)CNCc1cccc(OCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
To a solution of tert-butyl (3-formylphenoxy)acetate (1.50 g) in dichloroethane (20.0 mL) were added tert-butyl glycinate (874 mg) and acetic acid (1.09 mL), and then sodium triacetoxyborohydride (2.69 g) was added thereto under ice-cooling. The reaction suspension was stirred at room temperature for 16 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain tert-butyl N-[3-(2-tert-butoxy-2-oxoethoxy)benzyl]glycinate (1.18 g).
Reaction SMILES: [F:1][C@H:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1CC1C=CC(OC)=CC=1)[CH3:3]>C(O)(C(F)(F)F)=O>[F:1][C@H:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)[CH3:3]
Reactant: COc1ccc(CN2C(=O)OC[C@@H]2[C@H](C)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](F)[C@H]1COC(=O)N1
Yield: 87.6 %

Procedure:
A solution of (R)-4-((S)-1-fluoroethyl)-3-(4-methoxybenzyl)oxazolidin-2-one (1.98 g 7.8 mmol) in 40 mL TFA was heated at 65° C. for 16 h. The reaction mixture was concentrated to remove TFA. Flash column chromatography (EtOAc/CH2Cl2, 0 to 100%) gave 0.91 g (R)-4-((S)-1-fluoroethyl)-oxazolidin-2-one as a pale brown solid. TLC (1:2 heptane:EtOAc) Rf=0.25. 1H NMR (400 MHz, CDCl3) δ 5.60 (br s, 1H), 4.72-4.54 (m, 1H), 4.51 (td, J=8.9, 0.9 Hz, 1H), 4.32 (dd, J=9.2, 4.8 Hz, 1H), 4.02-3.88 (m, 1H), 1.38 (dd, J=24.0, 6.3 Hz, 3H).