Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[C:26]=1[F:27])(=O)=O.O1CCOCC1.B([C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[O:48][CH3:49])[C:42]([OH:44])=[O:43])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>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.O>[F:27][C:26]1[C:11]2[C:12]([C:22](=[O:25])[NH:23][CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[O:14][C:10]=2[CH:9]=[CH:8][C:7]=1[C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[O:48][CH3:49])[C:42]([OH:44])=[O:43]
Reactant: COc1ccc(C(=O)O)cc1B(O)O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)c(F)c12
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3OC)c(F)c12
Temperature: 85 °C
Yield: 35.4 %

Procedure:
To a small sealed tube was added 4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (64.5 mg, 0.111 mmol), dioxane (6 mL), water (1.200 mL), 3-borono-4-methoxybenzoic acid (26.1 mg, 0.133 mmol), cesium carbonate (54.2 mg, 0.167 mmol) and finally Tetrakis(triphenylphosphine)palladium(0) (2.6 mg, 2.2 μmol). The tube was sealed and the reaction mixture heated at 85° C. for twenty hours. The reaction mixture was cooled to room temperature, pushed through a plug of celite and evaporated to a dark oil under a stream of nitrogen. The residue was triturated with 15 mL of ice water then air dried overnight giving 17.2 mgs (35.4% yield) of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methoxy benzoic acid as a white solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. LCMS rt=2.770 min., m/z 438.3 (M+H), 93% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>O1CCOCC1>[O:14]=[C:13]1[C:12]2[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10](=[O:15])[N:1]1[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: N#Cc1cccc(N)c1
Solvent: C1COCCO1
Product: N#Cc1cccc(N2C(=O)c3ccccc3C2=O)c1
Temperature: 0 °C
Yield: 50.8 %

Procedure:
Dissolved 3-aminobenzonitrile (1.5 g, 12.7 mmol) in anhydrous dioxane (42 mL) under N2. Added phthalic anhydride (2.54 g, 17.1 mmol). Affixed Dean-Stark trap and refluxed for 16 h. Cooled to 0° C. and filtered off solid (2-((3-cyanophenyl)carbamoyl)benzoic acid). Concentrated filtrate to afford 3-(1,3-dioxoisoindolin-2-yl)benzonitrile (1.6 g) as a white solid. MS, calc'd=248.06. Obsv'd m/z: 248.91 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[CH:11][CH:12]=[C:13]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1-c1ccc(Cl)cc1Cl
Reactant: N#Cc1ccc(NCCN)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NCCNc2ccc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)c2)nc1
Temperature: 85 °C
Yield: 58.4 %

Procedure:
To 2-(2,4-dichlorophenyl)-4-fluoro-1-nitrobenzene(32 mgs, 0.1 mmol) in acetonitrile was added 2-(2-aminoethylamino)-5-cyanopyridine (19.2 mgs, 0.1 mmol) and N,N diisopropylethylamine (18 μl, 0.1 mmol), and the mixture was heated to 85° C. over-night. The mixture was partitioned between ethyl acetate and water and the organic layer was dried (MgSO4) and concentrated. Purification on silica gel with 5% methanol in dichloromethane as the eluent yielded 25 mgs of 6-({2-[(2′,4′-dichloro-6-nitro-1,1′-biphenyl-3-yl)amino]ethyl}amino)nicotinonitrile.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([N:15]([CH2:23][CH:24]=[CH2:25])[CH:16]([C:18](OCC)=[O:19])[CH3:17])=[O:14])=[CH:8][CH:7]=1)[CH2:4][CH3:5].O(C)[Na]>CO>[CH2:23]([N:15]1[CH:16]([CH3:17])[C:18](=[O:19])[N:12]([C:9]2[CH:10]=[CH:11][C:6]([C:3](=[N:2][OH:1])[CH2:4][CH3:5])=[CH:7][CH:8]=2)[C:13]1=[O:14])[CH:24]=[CH2:25]
Reactant: C=CCN(C(=O)Nc1ccc(C(CC)=NO)cc1)C(C)C(=O)OCC
Agent: CO[Na]
Solvent: CO
Product: C=CCN1C(=O)N(c2ccc(C(CC)=NO)cc2)C(=O)C1C

Procedure:
0.01 mol of this urea is dissolved in 150 mL of CH3OH. the pH is adjusted to approximately 10.0 using 25% NaOCH3 solution in CH3OH. The solution is heated to reflux for 2.5 hours, after which time the solvent is removed in vacuo. The residue is washed with cold water and dried in vacuo to yield crude 1-allyl-3-[4-(1-hydroxyiminopropyl)phenyl]-5-methylhydantoin. The hydantoin is purified by recrystallization from CH3OH: H2O.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@@:12]1([CH3:19])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:14][CH2:13][C@:12]1([CH3:19])[CH2:16][CH2:17][CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: C[C@@]1(C(=O)O)CCCN1C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@]1(CO)CCCN1C(=O)OCc1ccccc1
Yield: 62.6 %

Procedure:
To a solution obtained by dissolving 840 mg of the compound [63-1] in 16 mL of tetrahydrofuran, 4.31 mL of a borane-methyl sulfide complex (a 2 M tetrahydrofuran solution) was added at room temperature, and the mixture was heated under reflux for 4 hours. To the reaction solution, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0 to 60/40) to obtain 498 mg of benzyl (2S)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate [63-2] (hereinafter, referred to as the compound [63-2]).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Li+].[Li+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
4-Hydroxyphenylacetic acid (2.0 kg) is dissolved in DMF (8 L) and lithium carbonate (1.07 kg) is added in one portion followed by benzyl bromide (1.88 L). The mixture is heated to 100° C. over 1 hour, aged for 3 hours. The mixture is cooled to 85° C. and transferred into a 50 L vessel and quenched with 2N HCl (10 L).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15])=[N+:2]=[N-:3].[OH-].[K+].Br[C@H:19]([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:27])[C:5]1=[O:15])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Reactant: C[C@@H](Br)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C(=O)OC(C)(C)C)N1C(=O)C(N=[N+]=[N-])CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-Azido-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (as prepared in example 1,5 g) was added in one portion to a stirred suspension of potassium hydroxide (1.8 g) and tetrabutylammonium bromide (0.8 g) in tetrahydrofuran (50 ml) maintained at 0° under a nitrogen atmosphere. Stirring was continued for 5 minutes, then (R)-t-butyl 2-bromopropionate [J. P. Greenstein et al., J. Am. Chem. Soc. 76, 6054 (1954), H. Niedrich and G. Koller, J. Prakt. Chem. 316, 729 (1974)] (5.2 g) in tetrahydrofuran (15 ml) was added during 5 minutes. The reaction mixture was allowed to warm to room temperature while stirring for an additional 2 hours. The reaction mixture was filtered and the tetrahydrofuran removed at reduced pressure. The residue was partitioned between water (50 ml) and ether (100 ml). The organic phase was washed with 2N hydrochloric acid (10 ml), dried over magnesium sulfate, and the solvent evaporated under reduced pressure to give 3-azido-1-(1-t-butyloxycarbonylethyl)-2,3,4,5-tetrahydro-1H[1]-benzazepin-2-one as an oil that was used without further purification.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:26]([O-])(=[O:28])C.[Na+]>CN(C)C=O>[CH3:6][N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([CH:26]=[O:28])=[CH:10][CH:9]=1
Reactant: CCCCOC(=O)CCCCCN(C)c1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCOC(=O)CCCCCN(C)c1ccc(C=O)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
Phosphorus oxychloride (18.4 g, 0.12 mol) was added dropwise with stirring, at 5° C., under nitrogen, to N,N-dimethylformamide (DMF, 50 mL). The resulting orange solution was stirred for 2 hours, then 27.6 g (0.81 mol) of butyl 6-(N-methyl-N-phenylamino)hexanoate was dropwise. The reaction mixture was stirred at 5° C. for 1 hour and then was heated in a water bath to 90° C., for 4 hours. After cooling the hot solution was poured over 200 g of crushed ice and naturalized to pH 6 by a slow addition of solid sodium acetate with vigorous stirring. The mixture was extracted with three portions of 200 mL dichloromethane. The combined organic extracts were washed three times with water, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was distilled in vacuo yielding 23.4 g (76.8%) of pale yellow oil bp 151°-153° C. (3×10-4 mm).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])[CH2:4][CH2:3]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].CCN(C(C)C)C(C)C.ClCCl>O>[CH3:15][S:16]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])[CH2:6][CH2:7]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCOC(=O)N1CCC(N)CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)N1CCC(NS(C)(=O)=O)CC1
Reaction time: 2 h
Yield: 95.9 %

Procedure:
In a dried reaction flask, butyl 4-aminopiperidine-1-carboxylate (2.0 g, 10.0 mmol), methanesulfonyl chloride (0.77 mL, 10 mmol), and DIEA (2.6 mL, 15 mmol) were added to dichloromethane (40 mL). The mixture was stirred under an ice-water bath for 2 hr. LC-MS showed that the product was formed and the reactants vanished. The solution was concentrated under reduced pressure to produce a yellow oil. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and was purified with silica-gel column chromatography (ethyl acetate:petroleum ether=1:2) to obtain a white solid (2.67 g) in 96.0% yield.
Reaction SMILES: BrC1C(F)=CC(F)=C([C@]23CO[C@@H](COC)C[C@H]2CSC(NC(=O)C2C=CC=CC=2)=N3)C=1.[CH2:32]([O:39][CH2:40][C@@H:41]1[O:59][CH2:58][C:44]2([C:60]3[CH:65]=[C:64]([C:66]#[N:67])[C:63]([F:68])=[CH:62][C:61]=3[F:69])[N:45]=[C:46]([NH:49][C:50](=[O:57])[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[S:47][CH2:48][CH:43]2[CH2:42]1)C1C=CC=CC=1>>[C:66]([C:64]1[C:63]([F:68])=[CH:62][C:61]([F:69])=[C:60]([C@:44]23[CH2:58][O:59][C@@H:41]([CH2:40][O:39][CH3:32])[CH2:42][C@H:43]2[CH2:48][S:47][C:46]([NH:49][C:50](=[O:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[N:45]3)[CH:65]=1)#[N:67]
Reactant: N#Cc1cc(C23CO[C@@H](COCc4ccccc4)CC2CSC(NC(=O)c2ccccc2)=N3)c(F)cc1F
Agent: COC[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(Br)c(F)cc2F)CO1
Product: COC[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(C#N)c(F)cc2F)CO1

Procedure:
N-[(4aR,6R,8aS)-8a-(5-Bromo-2,4-difluorophenyl)-6-(methoxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C15) was converted to the product using the method described for the synthesis of N-[(6R)-6-[(benzyloxy)methyl]-8a-(5-cyano-2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C10) in Example 1. Yield: 92.0 mg, 0.209 mmol, 110%. LCMS m/z 458.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[C:8](Cl)=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:5].C(#N)C.ClCCl.C(OCC)(=O)C>S1(CCCC1)(=O)=O>[CH2:18]([C:15]1[CH:16]=[CH:17][C:2]2[NH:1][C:8]3[N:9]=[CH:10][CH:11]=[CH:12][C:7]=3[NH:6][C:4](=[O:5])[C:3]=2[CH:14]=1)[CH3:19]
Reactant: CCc1ccc(N)c(C(=O)Nc2cccnc2Cl)c1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1ccc2c(c1)C(=O)Nc1cccnc1N2
Temperature: 170 °C
Reaction time: 0.33 h

Procedure:
160.0 g (0.58 mol) of the 2-amino-5-ethyl-N-(2-chloropyridin-3-yl)benzamide obtained were dissolved in 256 ml of sulpholane and heated to 170° C. with stirring for 20 minutes. The mixture was left to cool, stirred with 1 liter of acetonitrile, the resulting crystal slurry was suction filtered and washed successively with 50 ml acetonitrile and 100 ml conc. ammonia. It was recrystallised from hot 70% acetic acid and after drying in a circulating air dryer 114.0 g (48% of theory) of pale yellow crystals were obtained, m.p. 232°-234° C., RF 0.78 (Macherey-Nagel, PolygramRSIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/ethyl acetate 1/1 v/v).
Reaction SMILES: [OH:1][C:2]1C(O)=CC2C(=CC=CC=2)C=1.[OH:13][C:14]1[C:23]2[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=2[OH:24])[C:17]([OH:26])=[CH:16][CH:15]=1>>[OH:13][C:14]1([CH:2]=[O:1])[C:23]2[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=2[OH:24])[C:17]([OH:26])=[CH:16][CH2:15]1
Reactant: Oc1cc2ccccc2cc1O
Reactant: Oc1ccc(O)c2c(O)ccc(O)c12
Product: O=CC1(O)CC=C(O)c2c(O)ccc(O)c21

Procedure:
The procedure of Production Example 5 was repeated, except that the 2,3-dihydroxynaphthalene was replaced with 1,4,5,8-tetrahydroxynaphthalene, to give a 1,4,5,8-tetrahydroxynaphthalene-formaldehyde condensate.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:43])[CH2:39][CH2:40][CH2:41][CH3:42]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:38](=[O:43])[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:27][CH:28]=2)[N:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(=O)Cl
Reactant: Nc1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
80 mg (0.19 mmol)) of Compound 5050 was dissolved in 5 mL of dry methylene chloride. To this solution at 0° C. was added triethylamine (0.19 mmol, 25 μL) followed by pentanoyl chloride (0.19 mmol, 22 μL). Reaction mixture was stirred at 0° C. for 15 minutes. Reaction mixture was quenched using water and evaporated. It was redissolved in 5 mL of DMF and purified using reverse phase HPLC. MS: 507.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9](N(OC)C)=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Mg]Br)=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[C:3]([C:9]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1nc(Cl)ccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1nc(Cl)ccc1Br
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of 3-bromo-6-chloro-N-methoxy-N-methylpicolinamide (5.34 g, 19.1 mmol) in anhydrous THF (38 mL) at 0° C. was slowly added a solution of (4-chlorophenyl)magnesium bromide (1M in Et2O) (76 mL, 76 mmol). After 3 h at 0° C., a saturated aqueous solution of ammonium chloride was added and the product was extracted with MTBE (repeated 4 times). The organic layers were combined, dried over Na2SO4 and concentrated to dryness. The residue was purified by flash chromatography (hexane/EtOAc 10:0 to 8:2) to give the title compound as a white solid (5.98 g). LC/MS m/z 332 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:19][O:18][C:17](=[O:20])[C:16]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH2:19][O:18][C:17](=[O:20])[C:16]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccccc4)cc3)COC2=O)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C2=C(c3ccc(O)cc3)COC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a 0° C. solution of 4-(4-(benzyloxy)phenyl)-3-(4-methoxyphenyl)furan-2(5H)-one (1.5 g, 0.004 mol) in MeOH (50 mL) was added Pd(OH)2 (150 mg, 1.068 mol) under an inert atmosphere. The reaction mixture was then stirred under a hydrogen atmosphere for 2 h at RT, filtered through a pad of Celite® and the filtrate was concentrated in vacuo to afford 4-(4-hydroxyphenyl)-3-(4-methoxyphenyl)furan-2(5H)-one (900 mg, 81%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:15]([O:17][CH2:18][CH2:19][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[N:29]1[CH2:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][C:38]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:42][CH2:41][NH:40][CH2:39]2)[CH2:31][CH2:30]1)[CH3:16]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:4]=1[C:5]([N:40]1[CH2:41][CH2:42][C:38]([CH2:37][CH2:36][N:32]2[CH2:33][CH2:34][CH2:35][N:29]([C:21]3[N:20]([CH2:19][CH2:18][O:17][CH2:15][CH3:16])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=3)[CH2:30][CH2:31]2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:39]1)=[O:7]
Reactant: COc1ccc(C#N)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(C#N)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-cyanobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:11](O)=[O:12].C1(N=C=NC2CCCCC2)CCCCC1>C(O)C>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:10]1[C:11](=[O:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:9]1
Reactant: COc1ccccc1C(CSc1ccccc1N)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCO
Product: COc1ccccc1C1CSc2ccccc2NC1=O
Yield: 87.2 %

Procedure:
11.7 g of the acid of Step D, 7.95 g of dicyclohexylcarbodiimide and 350 ml of ethanol were stirred for 6 hours at ambient temperature and after evaporation to dryness, the residue was taken up in 1500 ml of methylene chloride. The insoluble part was filtered off and the filtrate was concentrated to dryness. The residue was taken up in 1500 ml of ethanol and separation was effected to obtain 9.6 g of the desired product melting at 219° C. which was used as is for the following step. An analytical sample was prepared by crystallizing 350 mg of product from 40 ml of ethanol to obtain 240 mg of the desired structure melting at 223° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:10](=O)[CH2:11][O:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si](N=[N+]=[N-])(C)C.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:8]=2)[N:7]=1
Reactant: COc1ccc2c(OCC(=O)NNc3ccc(Cl)nn3)ccnc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: C[Si](C)(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(OCc3nnc4ccc(Cl)nn34)ccnc2c1
Temperature: 50 °C

Procedure:
N′-(6-chloropyridazin-3-yl)-2-(7-methoxyquinolin-4-yloxy)acetohydrazide (2.53 g, 7.0 mmol) was suspended in tetrahydrofuran (50 mL) then added triphenylphosphine (2.8 g, 11 mmol) and trimethylsilyl azide (1.4 ml, 11 mmol). To this suspension, was added diethylazodicarboxylate (2.0 ml, 13 mmol) in rapid drops with a syringe. The mixture became clear and hot to the touch. The reaction mixture was heated at 50° C. for 30 minutes. The reaction mixture was concentrated in vacuo. The remaining oil was triturated with diethyl ether. A gel-like solid formed which was collected on a glass frit, washing with diethyl ether. The solid was then triturated with ethyl acetate, and finally acetonitrile. An amorphous solid formed which was collected on a glass frit, washing with acetonitrile. The solid was further dried under high vacuum. In addition, the ethyl acetate filtrate was concentrated in vacuo. The remaining oil was then triturated with acetonitrile. An amorphous solid formed and was collected on a glass frit, washing with acetonitrile. The solid was further dried under high vacuum affording 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline as a tan solid. MS (ESI, pos. ion) m/z: 342.1 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH2:19]([O:18][C:16]([NH:15][CH:9]1[C:8]2[C:13](=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[S:12][CH2:11][CH2:10]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc2c(c1)SCCC2NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NC1CCSc2cc(C(=O)O)ccc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.1 %

Procedure:
To a mixed solution of 4-(benzyloxycarbonylamino)thiochromane-7-carboxylic acid methyl ester (3.20 g) in methanol (50 ml), tetrahydrofuran (100 ml) and water (50 ml) was added 1N aqueous sodium hydroxide solution (20 ml), and the mixture was stirred at room temperature for 5 hr. Dilute hydrochloric acid was added to the reaction mixture until the pH became 1, and the precipitated crystals were collected by filtration. The crystals were recrystallized from acetone-hexane to give the objective 4-(benzyloxycarbonylamino)thiochromane-7-carboxylic acid (2.74 g) as colorless crystals.