Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[CH:12]=[C:13](Br)[S:14][C:8]=2[C:7]=1[OH:16])=[O:5])[CH3:2].[Cu][C:18]#[N:19]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[CH:12]=[C:13]([C:18]#[N:19])[S:14][C:8]=2[C:7]=1[OH:16])=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1ncc2cc(Br)sc2c1O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc2cc(C#N)sc2c1O
Temperature: 140 °C
Yield: 19.3 %

Procedure:
A mixture of 2-bromo-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid ethyl ester (example 21.d, 150 mg, 0.5 mmol) and copper(I) cyanide (90 mg, 1.0 mmol) suspended in 2 mL DMF was heated at 140° C. for 30 minutes in a CEM microwave reactor. The resultant mixture was partitioned between ethyl acetate and water, and the organic fraction was washed with brine, dried over anhydrous sodium sulfate, and concentrated to a crude residue. The desired product was purified by column chromatography eluting from silica gel with a gradient of 20-70% ethyl acetate in hexanes to give 24 mg of a white solid; MS: (+) m/z 248.9 (M+1)
Reaction SMILES: [O-:1][C:2]#N.[K+].[I:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:8][CH:7]=1.Cl.[OH2:22]>C(O)(=O)C>[I:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:13]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:19](=[O:22])[NH:20][C:2]2=[O:1])=[CH:10][CH:11]=1
Reactant: N#CC1(Nc2ccc(I)cc2)CCCCC1
Reactant: N#C[O-]
Reactant: O
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Product: O=C1NC(=O)C2(CCCCC2)N1c1ccc(I)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.8 g (22.2 mmol, 2 eq.) of potassium cyanate are added at 30° C. to a solution of 3.7 g (11.3 mmol, 1 eq.) of 1-(4-iodophenylamino)cyclohexanecarbonitrile in 30 ml of glacial acetic acid. The reaction medium is stirred at 60° C. overnight. 5 ml of hydrochloric acid and then 3 ml of water are added. The medium is heated at 90° C. for 1 hour and then at room temperature for 3 hours. Water is then poured into the reaction medium, and the precipitate formed is filtered off and then chromatographed on silica gel (50/50 heptane/ethyl acetate). 180 mg of 1-(4-iodophenyl)-1,3-diaza-spiro[4.5]decane-2,4-dione are obtained in the form of an orange-coloured solid.
Reaction SMILES: [I-].[CH:2]([O:15][C:16]([C:18]1[N:23]2[C:24](=[O:33])[C:25](=[CH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:22]2[S:21][CH:20]([NH2:34])[C:19]=1[CH2:35][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.[C:57](=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O>[CH:26](=[C:25]1[C:24](=[O:33])[N:23]2[C:18]([C:16]([O:15][CH:2]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:17])=[C:19]([CH:35]=[CH2:57])[CH:20]([NH2:34])[S:21][C@H:22]12)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC1S[C@@H]2C(=Cc3ccccc3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(=Cc3ccccc3)[C@H]2SC1N
Temperature: 25 °C

Procedure:
To a solution of [4-benzhydryloxycarbonyl-7-benzylidene-amino-3-cephem-3-yl]methyl-triphenylphosphonium iodide (16.9 g) in methylene chloride (200 ml) and water (100 ml) was added 36% aqueous formaldehyde (48 ml), followed by adjusting to pH 9.0 with sodium carbonate. After the mixture was stirred at ambient temperature for an hour, the separated organic solution was washed with an aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave benzhydryl 7-benzylidene-amino-3-vinyl-3-cephem-4-carboxylate (8.6 g), mp 124°-132° C.
Reaction SMILES: C(Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.Cl.[C:11]1([CH3:19])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1.[C:11]1([CH3:19])[CH2:16][C:15]([OH:8])([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1
Reactant: Cc1cc(C)cc(C)c1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: CC1=CC(C)(O)CC(C)=C1
Product: c1ccncc1
Yield: 63 %

Procedure:
First, by effecting Friedel Krafts reaction between hydrochloride nicotinic acid chloride and mesitylene in accordance with Reynold C. Fuson and John J. Miller's method [cf. J.Am.Chem. Soc. 79.3477 (1957)], 3-mesitol pyridine (yield: 63%, b.p.:157.5°-158°C/4mmHg) is obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH:8]([CH3:10])[CH3:9].[N:11]1([C:17]2[C:22](=[O:23])[NH:21][CH:20]=[C:19]3[CH2:24][N:25]([CH2:28][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[C:26](=[O:27])[C:18]=23)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(#N)C>[CH:8]([N:21]1[C:22](=[O:23])[C:17]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[C:18]2[C:26](=[O:27])[N:25]([CH2:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH2:24][C:19]2=[CH:20]1)([CH3:10])[CH3:9]
Reactant: O=C1c2c(c[nH]c(=O)c2N2CCOCC2)CN1CCc1ccc2ccccc2n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)n1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Temperature: 105 °C
Reaction time: 24 h
Yield: 12.6 %

Procedure:
A solution of potassium carbonate (2.5 g, 18.09 mmol), 2-iodopropane (1.0 ml, 10.00 mmol) and 7-morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (0.5 g, 1.281 mmol, see Example 15) were dissolved in acetonitrile (30 ml). The suspension was stirred at about 105° C. for about 24 h. After cooling to r.t., LC-MS analysis indicated complete conversion. The crude product was purified by preparative HPLC to afford the title compound (70 mg, 0.162 mmol, 12.64% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:35])=[C:4]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]2=[O:34])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.F[C:37]1C=C(O)C(C2C3C(=CC=CC=3)N(CC3C=CC(OC)=CC=3)C2=O)=CC=1C#N>>[Cl:1][C:2]1[C:3]2[O:35][CH2:37][C:12]3([C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:13]3=[O:34])[C:4]=2[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: COc1ccc(CN2C(=O)C(c3cc(C#N)c(F)cc3O)c3ccccc32)cc1
Reactant: O=C1C(c2c(O)c(Cl)cc3c2OCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1c(Cl)cc3c(c12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2.40 and making non-critical variations using 3-(7-chloro-6-hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one to replace 2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile, 6-chloro-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one was obtained (65%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.42-7.26 (m, 10H), 7.20-7.15 (m, 1H), 7.11 (s, 1H), 7.03-6.95 (m, 2H), 6.78 (s, 1H), 6.50-6.45 (m, 1H), 5.02 (d, J=8.7 Hz, 1H), 4.76 (d, J=8.7 Hz, 1H), 4.12-3.84 (m, 4H); MS (ES+) m/z 496.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:25]([CH3:26])=[CH:24][S:23][C:14]=2[N:15]=[C:16]([C:18]2[O:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[O:22]1[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:25]([CH3:26])=[CH:24][S:23][C:14]=3[N:15]=2)=[CH:19][CH:20]=[N:21]1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1csc2nc(-c3ccno3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccno3)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-dichlorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3].BrC([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]2=[O:38])=[CH:28][C:27]=1[F:39])C(N)=O>C1COCC1>[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:10][N:9]([CH2:15][C:13](=[O:14])[NH:12][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]3=[O:38])=[CH:28][C:27]=2[F:39])[CH2:8]1)=[O:6])[CH3:3]
Reactant: NC(=O)C(Br)c1ccc(-n2ccccc2=O)cc1F
Reactant: CCOC(=O)[C@H]1CNC[C@@H]1NC(=O)c1ccc(Cl)s1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CN(CC(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
40.4 Using general procedure A with THF as solvent (3S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-3-carboxylic acid ethyl ester hydrochloride was reacted with 2-bromo-[2-fluoro-4-(2-oxopyridin-1-yl)-phenyl]-acetamide to give (3S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl-carbamoyl]-methyl}-pyrrolidine-3-carboxylic acid ethyl ester. Light brown solid. MS 547.2 [M+H+].
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.Cl.[CH2:21]1[C:29]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[CH2:23][NH:22]1>>[CH2:21]1[C:29]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[CH2:23][N:22]1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: c1cc2c(cn1)CNC2
Agent: Cl
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3Cc4ccncc4C3)n2)c1

Procedure:
B49 was prepared following the general procedure reported for B10 using A1 and 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine hydrochloride; yield: 139.0 mg (36%), brown amorphous solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 4.27 (s, 2H), 4.92 (s, 2H), 4.97 and 4.99 (2 s, 2H), 6.87 and 6.88 (2 s, 2H), 7.01 (d, J=7.5 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.59-7.72 (m, 2H), 7.98 (bs, 1H), 8.31 (d, J=1.4 Hz, 1H), 8.62 (t, J=6.0 Hz, 1H), 8.76 (d, J=5.7 Hz, 1H), 9.82 (s, 1H). MS (ES) C17H17N7O2S requires: 383. found: 384 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1.CC(N(C)C)=O.C(N(CC)CC)C.[C:26](Cl)(=[O:34])[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1>[O:27]([C:26]([NH:3][C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1)=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc2[nH]nnc2c1)Oc1ccccc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To 62.1 g of 5-aminobenzotriazole dihydrochloride was added 500 ml of dimethylacetamide, and 83,7 ml of triethylamine was added dropwise thereto while being cooled in an ice bath. To the mixture was further added dropwise 21.0 ml of pyridine, and 42.3 g of phenyl chlorocarbonate was then added dropwise thereto while maintaining the system at 5° C. or lower, followed by stirring at room temperature for 2 hours. After the reaction, the reaction mixture was poured into 2 (of ice-water for crystallization, followed by filtration to obtain 60.8 g of 5-phenoxycarbonylaminobenzotriazole.
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:17])=[O:5])C.[O-:18][C:19]#[N:20].[K+].C(O)(=O)C>O>[C:11]1([C:10]2[C:6]3[C:4](=[O:5])[NH:20][C:19](=[O:18])[NH:17][C:7]=3[S:8][CH:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#C[O-]
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2c(-c3ccccc3)csc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Amino-4-phenyl-thiophene-3-carboxylic acid ethyl ester (2.0 g, 8.1 mmol), and Potassium Cyanate (Aldrich, 2.0 g, 24.3 mmol) were added to glacial acetic acid (VWR, 20 ml) and stirred at ambient temperature for 18 h. The reaction was diluted with water (50 ml) and the resultant precipitate filtered, washed with water and dried to a damp cake. The solid was suspended in water (100 ml) and made alkaline to pH 12-14 by the addition of concentrated sodium hydroxide. The resultant suspension was heated at 100° C. for 2 h with stirring, then cooled to ambient temperature and acidified by the addition of glacial acetic acid. The resulting solid was collected by filtration, washed with water and dried in vacuo at 40° C. to give 5-Phenyl-1H-thieno[2,3-d]pyrimidine-2,4-dione as a white solid. Yield=(1.1 g, 56%).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])(=[O:4])=[O:3].[CH3:14][C:15]([CH3:20])=[CH:16][C:17]([OH:19])=[O:18].S(=O)(=O)(O)O>>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][C:10]([C:15]([CH3:20])([CH3:14])[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][C:6]=1[O:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CC(C)=CC(=O)O
Reactant: COc1ccccc1OS(C)(=O)=O
Agent: O=S(=O)(O)O
Product: COc1ccc(C(C)(C)CC(=O)O)cc1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 23.4 %

Procedure:
To a mixture of 2-methoxyphenyl methanesulfonate (Example 50b) (82 g, 406.4 mmol) and 3-methylbut-2-enoic acid (20.3 g, 203.2 mmol), was added concentrate sulfuric acid (11 mL, 96%, 206.3 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min, then heated to 70° C. and stirred under nitrogen overnight. Upon completion, the reaction was cooled to room temperature, quenched with ice water (500 mL) and extracted with ether (1×). The phases were separated, and the organic layer was washed with 2N NaOH (1×). The combined aqueous layers were acidified to pH 1 with 12N HCl at 0° C. and extracted with ether (1×). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a red-brown oil (14.4 g, contained<20% 3-methylbut-2-enoic acid)1H NMR (400 MHz, DMSO-d6) δ 1.33 (s, 6H), 2.53 (s, 2H), 3.31 (s, 3H), 3.79 (s, 3H), 7.08-7.31 (m, 3H), 11.87 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[OH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2.C(N(CC)CC)C>CC(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([O-:3])=[O:2]
Reactant: Oc1cccc2cccnc12
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Oc2cccc3cccnc23)c([N+](=O)[O-])c1

Procedure:
D. Reinheimer, et al, disclose (J. Org. Chem., 1957, vol. 22, p. 1743) that 2,4-dinitrofluorobenzene reacts with 8-hydroxyquinoline in acetone, in the presence of triethylamine, to form 8-(2,4-dinitrophenoxy)quinoline.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]1([NH:18][C:19](=[O:47])[C:20]2[CH:25]=[C:24]([N:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C@@H:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@@H:34]([CH3:37])[CH:35]=O)[C:27]3=[O:44])[C:23]([CH3:45])=[C:22]([F:46])[CH:21]=2)[CH2:17][CH2:16]1.[NH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:15]1([NH:18][C:19](=[O:47])[C:20]2[CH:25]=[C:24]([N:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C@@H:33]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C@@H:34]([CH3:37])[CH2:35][N:48]4[CH2:52][CH2:51][CH2:50][CH2:49]4)[C:27]3=[O:44])[C:23]([CH3:45])=[C:22]([F:46])[CH:21]=2)[CH2:17][CH2:16]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)[C@@H](C)C=O)c1=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)[C@@H](C)CN2CCCC2)c1=O
Temperature: 22 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (0.284 g) was added to N-cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2R)-2-methyl-3-oxo-1-phenylpropyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide (Example 328e, 0.3 g), pyrrolidine (0.221 mL) and Hunig's Base (0.467 mL) in DCM (15 mL). The resulting suspension was stirred at 22° C. for 2 h. The reaction mixture was basified with satd sodium bicarbonate solution before extracting with DCM. The combined organic phases were concentrated in vacuo and the residue purified by preparative HPLC (Phenominex column using a 75-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent). The fractions containing the desired compound were evaporated to dryness to afford the title compound as a solid (0.046 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH:37]1[CH2:40][CH2:39][CH2:38]1>CN(C=O)C.C(OCC)(=O)C>[CH:37]1([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([N:10]4[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH3:19])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:28]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: C[C@@H](COC1CCN(c2nc3cc(O)ccc3o2)CC1)NC(=O)OC(C)(C)C
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COC1CCN(c2nc3cc(OCC4CCC4)ccc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 83.2 %

Procedure:
To a solution of tert-butyl [(1S)-2-{[1-(5-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (389 mg) in DMF (5 mL) were added potassium carbonate (413 mg) and (bromomethyl)cyclobutane (297 mg), and the mixture was stirred with heating at 60° C. for 6 hr under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (380 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][N:13]=2)[CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:27]=1.C(N(CC)CC)C>CS(C)=O.O>[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([O:11][C:10]3[CH:9]=[C:8]([CH:25]=[CH:24][CH:23]=3)[CH:7]=[C:4]3[CH2:5][CH2:6][N:1]([C:33]([NH:32][C:28]4[N:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[O:34])[CH2:2][CH2:3]3)=[N:13][CH:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: C(=C1CCNCC1)c1cccc(Oc2ccc(N3CCCC3)cn2)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(N4CCCC4)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
To a solution of 2-(3-(piperidin-4-ylidenemethyl)phenoxy)-5-(pyrrolidin-1-yl)pyridine (0.118 g, 0.352 mmol) in DMSO (2 mL) was added phenyl pyridazin-3-ylcarbamate (0.076 g, 0.352 mmol) followed by triethylamine (0.048 mL, 0.352 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The residue was purified by silica gel column chromatography (28% acetone/hexane) to give the title compound (0.125 g, 78% yield). 1H NMR (500 MHz, CDCl3): δ 8.78 (s, 1H), 8.39 (s, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.45 (d, J=4.6 Hz, 1H), 7.27 (m, 2H), 6.95 (m, 1H), 6.92 (m, 2H), 6.84 (m, 2H), 6.38 (s, 1H), 3.69 (m, 2H), 3.58 (m, 2H), 3.27 (m, 4H), 2.59 (m, 2H), 2.45 (m, 2H), 2.03 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 156.56, 153.78, 147.15, 141.50, 138.54, 137.14, 130.50, 129.31, 128.31, 125.21, 123.64, 122.70, 119.41, 117.31, 113.03, 47.85, 45.70, 44.70, 35.76, 29.12, 25.39; m/z (457.1, MH+); HPLC: 97.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:12]=[CH:11]3)[CH:5]=[CH:6][CH:7]=1.[C:22](Cl)([C:24](Cl)=[O:25])=[O:23].C1C[O:31]CC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:12]=[C:11]3[C:24](=[O:25])[C:22]([OH:31])=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Clc1cccc(-c2ccc3c(ccn3C3CCCC3)c2)c1
Product: O=C(O)C(=O)c1cn(C2CCCC2)c2ccc(-c3cccc(Cl)c3)cc12

Procedure:
The product from Step 3 of Example 45 was dissolved in 0.5 ml anhydrous THF and 50 μL (COCl)2 was added. The solution was mixed at room temperature overnight with orbital shaking. An aliquot removed for LC analysis indicated that the reaction was complete. The solution was added to 1 mL aqueous NaHCO3 and the vial was capped and shaken. 0.1 mL 2N HCl was added and the vial was again capped and shaken. The reaction was concentrated to dryness under vacuum. The residue was purified by RP-HPLC (see Note 1 below) to give 6.4 mg of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.Cl.[CH3:13][NH:14][O:15][CH2:16][C:17]([OH:19])=[O:18].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([N:14]([CH3:13])[O:15][CH2:16][C:17]([OH:19])=[O:18])=[S:10])[CH:7]=1
Reactant: CNOCC(=O)O
Reactant: Cc1ccc(Cl)cc1N=C=S
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)cc1NC(=S)N(C)OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A mixture of 5-chloro-2-methylphenyl-isothiocyanate (36.7 g), N-methyl aminooxy acetic acid hydrochloride (28.3 g), triethylamine (50 g) and chloroform (300 mL) was heated at reflux for one hour, stirred at ambient temperature for one hour, then evaporated to dryness. The residue was dissolved in ethyl acetate (700 mL) and washed with 2N HCl (3×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness affording (48 g) of [[[[(5-Chloro-2-methylphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid as a semi solid. 1H-NMR (DMSO-d6; 300 Mhz) δ12.8 (br s, 1H), 10.15 (s, 1H), 7.35-7.20 (m, 3H), 4.62 (s, 2H), 3.56 (s, 3H), and 2.18 ppm (s, 3H). The acid (48 g) was dissolved in benzene (300 mL). Phosphorus pentachloride (42 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with sodium bicarbonate saturated solution (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (10% ethyl acetate in hexane). Crystallization from ethyl acetate/hexane afforded the title compound (18 g) as a solid, m.p. 100-102° C. Mass spectrum (El, M.+) m/z 270/272. 1H-NMR (CDCl3; 400 MHz) δ7.32 (d, 1H), 7.24 (d, 1H), 7.14 (s, 1H), 4.84 (ABq, 2H), 3.74 (s, 3H), and 2.13 ppm (s, 3H).
Reaction SMILES: [I-:1].[Na+].CN[C@@H]1CCCC[C@H]1NC.Br[C:14]1[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1.CCCCCCCCCCCC>C(OCC)(=O)C.[Cu]I>[I:1][C:14]1[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1
Reactant: [I-]
Reactant: Cc1cc(C)cc(Br)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCCCCCCCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(I)c1
Temperature: 110 °C
Reaction time: 23 h

Procedure:
A Sclenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), sodium iodide (fine powder, dried, 300 mg, 2.00 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.10 mmol, 10 mol %), 5-bromo-m-xylene (136 μL, 1.00 mmol), and solvent (1.0 μL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 23 h. The resulting suspension was allowed to reach room temperature. Ethyl acetate (2 mL) and dodecane (internal GC standard, 230 μL) were added to the reaction mixture. A 50 μL sample of the supernatant solution was diluted with ethyl acetate (1 mL) and analyzed by GC. The results are tabulated below.