Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.Br[C:20]1[S:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][N:24]=1>CN(C)C=O.C(OCC)(=O)C>[CH:3]1([N:7]2[CH2:8][CH2:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][C:20]4[S:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][N:24]=4)=[CH:14][C:11]=3[CH2:12][CH2:13]2)[CH2:6][CH2:5][CH2:4]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: O=[N+]([O-])c1cnc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% disp. in mineral oil, 150 mg, 3.66 mmol) was added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (530 mg, 2.43 mmol) in dimethylformamide (10 ml) at 5° C. After 0.5 hours a solution of 2-bromo-5-nitro-1,3-thiazole (1.0 g, 4.78 mmol) in dimethylformamide (5 ml) was added and the reaction mixture was allowed to warm to room temperature and stir for 2 hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with water, brine, dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.25:2.25:97.5) afforded the title compound (E210a); MS (ES+) m/e 346 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])[S:5][N:4]=1)[CH3:2].[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])[S:5][N:4]=1)[CH3:2]
Reactant: CCc1nsc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nsc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
A solution of tert-butyl 4-{1-[(3-ethyl-1,2,4-thiadiazol-5-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (321 mg; compound B22) in DCM (10 ml) is reacted with trifluoroacetic acid (2 ml) according to the procedure described in example B43 to afford the title compound as a solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]2[CH2:7][S:8][CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:4]2[NH:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[CH:50]1[C:62]2[CH:61]([CH2:63][O:64][C:65](=[O:82])[NH:66][C:67]3[CH:72]=[CH:71][C:70]([NH2:73])=[C:69]([O:74][CH2:75][C:76]4[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=4)[CH:68]=3)[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1>CC(N(C)C)=O>[CH:50]1[C:62]2[CH:61]([CH2:63][O:64][C:65](=[O:82])[NH:66][C:67]3[CH:72]=[CH:71][C:70]([NH:73][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]4[CH:4]5[CH:5]([NH:6][C:2](=[O:1])[NH:3]5)[CH2:7][S:8]4)=[C:69]([O:74][CH2:75][C:76]4[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=4)[CH:68]=3)[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1
Reactant: Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1OCc1ccccc1
Reactant: O=C(O)CCCCC1SCC2NC(=O)NC21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(CCCCC1SCC2NC(=O)NC21)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoic acid (388) (0.293 g, 1.2 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (HBTU) (0.455 g, 1.2 mmol) were combined and dissolved in DMA (24 mL). iPr2EtN (0.313 mL, 1.8 mmol) was added and the mixture was shaken for 30 minutes at room temperature. The (4-amino-3-benzyloxy-phenyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (65) (0.25 g, 0.573 mmol) was added and the mixture was shaken in a 40 mL I-Chem vial for 16 h. LC-MS indicated complete coupling at this point. The mixture was poured into ice-water and a very pale/purple powder precipitated. Collection by filtration under reduced pressure followed by drying under high vacuum for 16 h gave the desired product (389) as a white/purple solid (0.28 g, 0.422 mmol, 73.7% yield). LC-MS (ESI): (exact mass: 662.26) m/e 663.2 [M+1]+ (100%).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:30]>CN(C)C=O>[CH2:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH2:18][O:19][CH3:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cccc(N(Cc2ccccc2)Cc2ccccc2)c1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1c(N(Cc2ccccc2)Cc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The product from Example 46B (0.12 g, 0.33 mmoles) in anhydrous N,N-dimethylformamide (1 mL) was treated with 60% sodium hydride (0.016 g, 0.40 mmoles). After stirring for 10 minutes at room temperature, the mixture was treated with iodomethane (0.031 mL, 0.50 mmoles) and allowed to stir overnight at room temperature. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (3×). The ethyl acetate phases were combined, dried with sodium sulfate, filtered and the filtrate concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 363 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11](Cl)=[O:12])[S:10][C:3]=12.[CH3:14][N:15]([CH3:17])[NH2:16]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH:16][N:15]([CH3:17])[CH3:14])=[O:12])[S:10][C:3]=12
Reactant: CN(C)N
Reactant: O=C(Cl)c1cc2nccc(Cl)c2s1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)NC(=O)c1cc2nccc(Cl)c2s1
Reaction time: 5 h
Yield: 72.3 %

Procedure:
To a suspension of 7-chlorothieno[3,2-b]pyridine-2-carbonyl chloride 20 (1 g, 4.33 mmol) (scheme 6) in DCM (22 mL), 1,1-dimethylhydrazine (0.33 mL, 4.33 mmol) was added in one portion and the mixture was stirred for 5 h. More 1,1-dimethylhydrazine (0.33 mL, 4.33 mmol) was added and the mixture was stirred overnight at room temperature. The crude was diluted with EtOAc, extracted with 1N HCl, the aqueous solution basified to pH˜11 by addition of 1N NaOH, extracted with EtOAc, the organic phase dried over anhydrous Na2SO4 and concentrated under reduced pressure affording 237 (798 mg, 3.13 mmol, 72%) as a crude mixture that was used in the next step without further purification. MS (m/z): (M+1) 255.9 (100%), 257.9 (39%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]([CH3:15])[CH3:14])[C@@:11](O)([C:16]([F:19])([F:18])[F:17])[O:10]C1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:12]([CH:13]([CH3:14])[CH3:15])[C@H:11]([OH:10])[C:16]([F:19])([F:18])[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1N(C(=O)OC(C)(C)C)CO[C@]1(O)C(F)(F)F
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
(4S,5S)-5-Hydroxy-4-isopropyl-5-trifluoromethyl-1,3-oxazolidine-3-carboxylic acid t-butyl ester (4.51 g, 0.015 mol) obtained in Example 6 was dissolved in methanol (50 ml), and thereto was slowly added sodium borohydride (500 mg, 0.013 mol) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction solution was added saturated brine, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=5:1) and recrystallized from n-hexane/ethyl acetate to give the desired compound (2.1 g, yield: 51%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12](C)[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1>CN(C=O)C.C([O-])([O-])=O.[K+].[K+].CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[NH:12][C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3ncc4[nH]c(=O)n(-c5cn(C)nc5C)c4c3c2)cn1
Temperature: 105 °C
Reaction time: 1.5 h

Procedure:
A mixture of 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage A.1, 49 mg, 0.137 mmol), 2-methoxypyridine-5-boronic acid (Sigma-Aldrich, Buchs, Switzerland, 26 mg, 0.170 mmol), and PdCl2(PPh3)2 (6 mg, 0.0085 mmol) in DMF (1.2 ml) and 1 M aqueous K2CO3 (0.343 ml) was stirred under argon at 105° C. for 1.5 h. The RM was cooled toll. The mixture was diluted with MeOH+3 drops TFA and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 60:40). The fractions containing products were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: tR 2.46 min (Method A); M+H=387 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 11.66 (s, br, 1H), 8.72 (s, 1H), 8.33-8.26 (m, 1H), 8.16-8.10 (m, 1H), 8.09-8.01 (m, 1H), 7.91-7.84 (m, 1H), 7.81-7.74 (m, 1H), 7.51-7.43 (m, 1H), 6.98-6.91 (m, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:24]=2[N:23]([CH2:25][CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)[CH:22]=[CH:21]3)=[O:15])[CH3:12])=[CH:7][CH:6]=1)=[O:4].C(OC(=O)C)C.[ClH:45]>C1COCC1>[ClH:45].[NH:29]1[CH2:28][CH2:27][CH:26]([CH2:25][N:23]2[C:24]3[C:20](=[CH:19][CH:18]=[CH:17][C:16]=3[C:14]([NH:13][C@H:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=3)[CH3:12])=[O:15])[CH:21]=[CH:22]2)[CH2:31][CH2:30]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3ccn(CC4CCN(C(=O)OC(C)(C)C)CC4)c23)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3ccn(CC4CCNCC4)c23)cc1
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 4-{[7-({(1S)-1-[4-(methoxycarbonyl)phenyl]ethyl}carbamoyl)-1H-indol-1-yl]methyl}piperidine-1-carboxylate (1.67 g), and THF (20 mL) was added a 4 M hydrogen chloride ethyl acetate solution (2.0 mL) at room temperature, followed by stirring for 1 hour. The reaction mixture was stirred at 60° C. for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was washed with ethyl acetate and diethyl ether, collected by filtration, and dried under reduced pressure to obtain methyl 4-[(1S)-1-({[1-(piperidin-4-ylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoate hydrochloride (1.46 g).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.O.[CH3:23]O>C1COCC1>[CH3:23][O:20][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=2)=[CH:14][CH:15]=1)=[O:21]
Reactant: CO
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 86 %

Procedure:
Concentrated sulfuric acid (approximately 4 ml) was carefully added to a solution of 4'-hydroxy-4-biphenylcarboxylic acid (Aldrich) (8.20 g, 38.3 mmol) in 1 liter of methanol. The reaction mixture was refluxed for three days and the solvent was evaporated. The resulting solid was filtered, washed with water, and recrystallized as follows. The crude solid was dissolved in a minimum amount of hot THF, and approximately three equivalents of methanol was added to the solution. The solution was brought to a boil, and water was added with vigorous stirring until the solution remained cloudy. After cooling, the tan precipitate was filtered, washed with cold ethanol, and air dried to yield 7.57 g (86%) of a tan solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.[I:27]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.CCCCCC>[I:27][C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Ic1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
3.33 g (10 mmol) of 9-bromo-10-phenylanthracene was dissolved in 80 mL of tetrahydrofuran (abbreviation: THF), and cooled to −78° C. Then, in a reaction solution thereof, 7.5 mL (12.0 mmol) of n-buthyllithium (abbreviation: n-BuLi) (1.6 mol/L hexane solution) was dropped by a dropping funnel and then stirred for one hour. A solution in which 5 g (20.0 mmol) of iodine dissolved in 20 mL of THF was dropped therein, and the further stirred for 2 hours at −78° C. After reaction, a sodium thiosulfate aqueous solution was added therein and stirred. An organic layer was washed with a sodium thiosulfate aqueous solution and saturated saline, and then dried with magnesium sulfate. The mixture was filtrated naturally, then the filtrate was concentrated, and then recrystallized with ethanol, 3.1 g of 9-iodo-10-phenylanthracene that was a target substance was obtained as a light yellow solid at a yield of 83% (Synthesis scheme (b-3)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O.[C:13]([CH2:15]C(O)=O)#[N:14].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=[CH:15][C:13]#[N:14]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: N#CCC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(OC)c(C=CC#N)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
A mixture of 166 g of 2,5-dimethoxybenzaldehyde, 76 g of cyanoacetic acid, 5 ml of piperidine and 400 ml of pyridine was heated at 80° C understirring for 2 hours and then refluxed with heating at 140° C for 5 hours. After the reaction, the mixture was cooled to room temperature and poured into 2 liters of ice water. The precipitated crystals were filteredout and recrystallized from ethanol to give 117 g of the end product havinga melting point of 70 ~ 71° C (yield 62%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15](B(O)O)=[CH:14][C:13]=1[CH3:21].C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([C:2]2[C:3]([CH3:9])=[CH:4][CH:5]=[C:6]([NH2:8])[N:7]=2)=[CH:14][C:13]=1[CH3:21]
Reactant: COc1ncc(B(O)O)cc1C
Reactant: Cc1ccc(N)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ncc(-c2nc(N)ccc2C)cc1C
Temperature: 80 °C
Reaction time: 12 h
Yield: 29.7 %

Procedure:
6-Chloro-5-methylpyridin-2-amine (1.426 g, 10 mmol), 6-methoxy-5-methylpyridin-3-ylboronic acid (2.0 g, 12 mmol) and Pd(PPh3)4 (577.8 mg, 0.5 mmol) were combined in a flask. DME (100 mL) was added followed by aqueous Na2CO3 (10.00 mL of 2 M, 20.0 mmol). The flask was fitted with a condenser and heated at 80° C. for 12 hours under N2 atmosphere. More Pd(PPh3)4 (577.8 mg, 0.5 mmol) was added, the condenser was removed and the flask was fitted with a rubber stopper. N2 (g) was flushed through the flask and the reaction was stirred at 80° C. for an additional 12 hours under N2(g) balloon. The reaction mixture was filtered through a bed of Celite, the Celite was washed with ethyl acetate and the combined filtrates were concentrated. The residue was purified by column chromatography (30-100% ethyl acetate-Hexanes) to yield 680 mg of the product as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.66 (s, 1H), 7.29 (d, J=8.3 Hz, 1H), 6.37 (d, J=8.3 Hz, 1H), 5.75 (s, 2H), 3.91 (s, 3H), 2.18 (s, 3H), 2.14 (s, 3H). ESI-MS m/z calc. 229.1. found 230.5 (M+1)+. Retention time 0.91 minutes.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-])=O.Br[CH2:10][CH2:11][OH:12]>CN(C=O)C>[NH2:1][C:4]1[N:5]=[CH:6][N:7]([CH2:10][CH2:11][OH:12])[CH:8]=1
Reactant: OCCBr
Reactant: O=[N+]([O-])c1c[nH]cn1
Solvent: CN(C)C=O
Product: Nc1cn(CCO)cn1

Procedure:
2-(4-amino-1H-imidazol-1-yl)ethanol was prepared by Procedure A using 4-nitro-1H-imidazole and 2-bromoethanol in DMF instead of ACN.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:33])(=O)=O.[N-:44]=[N+:45]=[N-:46].[Na+]>CN(C)C=O.O>[CH3:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][O:34][C:32]([N:8]2[CH2:9][C@@H:10]([S:12][C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:11][C@H:7]2[CH2:6][N:44]=[N+:45]=[N-:46])=[O:33])=[CH:41][CH:40]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2COS(C)(=O)=O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN=[N+]=[N-])cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a solution of (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-tritylthiopyrrolidine-2-methanol methanesulfonate (27.81 g ) in dimethylformamide (120 ml), a solution (12 ml) of sodium azide (3.50 g: 53.8 mmole) in water is added. The mixture is stirred at 80° C. for 8 hours. The reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is successively washed with water and brine and concentrated. The residue is purified by silica gel column chromatography to give (2S, 4S)-1-p-methoxybenzyloxycarbonyl-2-azidomethyl-4-tritylthiopyrrolidine (17.27 g: 30.64 mmole). Total yield of Steps 4 and 5:74%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:42])[CH:5]=[C:6]([Cl:41])[C:7]=1[CH2:8][C@@H:9]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[C:28]([O:36][CH2:37][CH:38]2[CH2:40][CH2:39]2)[CH:27]=1)[O:10][C:11](=[O:25])[CH2:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15](=[O:23])[C:14]1=[O:24].Cl[CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:42])[CH:5]=[C:6]([Cl:41])[C:7]=1[CH2:8][C@@H:9]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[C:28]([O:36][CH2:37][CH:38]2[CH2:39][CH2:40]2)[CH:27]=1)[O:10][C:11](=[O:25])[CH2:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[C:15](=[O:23])[C:14]1=[O:24]
Reactant: O=C(Cn1c(=O)c(=O)[nH]c2ccccc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1c(=O)c(=O)n(CCN2CCOCC2)c2ccccc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reaction time: 5 h
Yield: 26.7 %

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)acetoxy)-ethyl)pyridine 1-oxide (70 mg, 0.112 mmol) dissolved in DMF (1 mL), 4-(2-chloroethyl)morpholine (34 mg, 0.225 mmol) and potassium carbonate (23 mg, 0.169 mmol) were added. The mixture was stirred at 40 degrees for 5 hours. The mixture was then diluted with H2O (10 mL) and the aqueous phase extracted with AcOEt (2×3 mL). The organic phase was washed with brine (10 ml), dried over Na2SO4 and the solvent was evaporated, to yield 22 mg of the title compound (yield 37%). MS/ESI+ 735.4 [MH]+; 1H NMR (400 MHz, acetone) δ ppm 8.01 (s, 2H), 7.53-7.62 (m, 1H), 7.28-7.39 (m, 1H), 7.09-7.24 (m, 3H), 6.99-7.07 (m, 2H), 6.93 (t, J=75.00 Hz, 1H), 5.97-6.21 (m, 1H), 5.10-5.21 (m, 1H), 4.76-4.84 (m, 1H), 4.36-4.56 (m, 2H), 3.89-4.12 (m, 2H), 3.61 (m, 4H), 3.35-3.51 (m, 1H), 3.15-3.27 (m, 1H), 2.76-2.80 (m, 2H), 2.52-2.65 (m, 4H), 1.25-1.39 (m, 1H), 0.55-0.68 (m, 2H), 0.37-0.52 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=[CH:10][N+:11]([O-])=O)=[CH:7][C:6]([CH2:14][CH3:15])=[C:5]([CH3:16])[N:4]=1>CO.Cl.[Pd]>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][C:6]([CH2:14][CH3:15])=[C:5]([CH3:16])[N:4]=1
Reactant: CCc1cc(C=C[N+](=O)[O-])c(OC)nc1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCc1cc(CCN)c(OC)nc1C
Reaction time: 15 h

Procedure:
A suspension of 2-methoxy-3-(2-nitroethenyl)-5-ethyl-6-methylpyridine (445 mg, 2.0 mmol) in methanol (10 mL) and 4.7M methanolic hydrogen chloride (2 mL) containing 5% palladium/carbon (110 mg) was hydrogenated at atmospheric pressure over 10-20 hours. The catalyst was filtered off and the solvent evaporated. The residue was made basic with sodium hydroxide solution and the product extracted into methylene chloride, dried, filtered and the solvent evaporated to yield 332 mg of crude oily product. No further purification was performed.
Reaction SMILES: Cl[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[NH3:17]>>[CH2:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH2:17])=[CH:8][CH:9]=1)[CH2:14][CH2:15][CH3:16]
Reactant: N
Reactant: CCCCc1ccc(CC(Cl)C(=O)O)cc1
Product: CCCCc1ccc(C[C@H](N)C(=O)O)cc1
Temperature: 40 °C
Reaction time: 96 h
Yield: 46 %

Procedure:
α-Chloro-β-p-butylphenylpropionic acid 3 (128 g, 0.534 moles) was suspended in 800 mL 30% aqueous ammonia. The reaction was stirred for 4 days at 40° C. in a tightly stoppered flask. After cooling to room temperature, the precipitate was removed by filtration through a coarse glass frit. The solid was washed thoroughly with ethanol followed by diethyl ether. The solid was dried under vacuum yielding 54.3 g (0.245 moles, 46% yield) of p-butylphenylalanine as a white solid. The solid was recrystallized from 2N HCl to give a white solid, mp 218°-223° C.
Reaction SMILES: [OH:1][CH:2]([C:6]1[C:7]([CH:12]([CH3:14])[CH3:13])=[N:8][CH:9]=[N:10][CH:11]=1)[CH:3]([CH3:5])[CH3:4].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[CH3:15][S:16]([O:1][CH:2]([C:6]1[C:7]([CH:12]([CH3:14])[CH3:13])=[N:8][CH:9]=[N:10][CH:11]=1)[CH:3]([CH3:5])[CH3:4])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1ncncc1C(O)C(C)C
Solvent: c1ccncc1
Product: CC(C)c1ncncc1C(OS(C)(=O)=O)C(C)C
Temperature: 0 °C
Yield: 90.5 %

Procedure:
8.3 g (43 mmol) of 5-(1-hydroxy-2-methylpropyl)-4-isopropylpyrimidine was dissolved in 10 ml of pyridine, and under cooling with ice, 9.8 g (86 mmol) of methylsulfonyl chloride was dropwise added. The reaction mixture was reacted at room temperature for 2 hours, and then, 100 ml of ice water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with an aqueous citric acid solution and water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure to obtain 10.6 g (yield: 90%) of 5-(1-methylsulfonyloxy-2-methylpropyl)-4-isopropylpyrimidine.