Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:24]2[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[CH:14]=2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]([F:54])([S:50](F)(=[O:52])=[O:51])[C:40]([F:49])([F:48])[C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43]>>[F:54][C:39]([F:38])([S:50]([O:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:9]3[CH:8]=[C:7]([N:24]4[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]4=[O:31])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=3[O:11][CH3:12])[CH:14]=2)[CH:19]=1)(=[O:52])=[O:51])[C:40]([F:48])([F:49])[C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43]
Reactant: COc1c(-c2ccc3cc(O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1c(-c2ccc3cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C

Procedure:
A reactor was equipped with an overhead stirrer in the central neck and charged with 45.0 g of 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (97.8 weight %, 106 mmol, 1.0 equivalent) and 21.9 g of 325 mesh potassium carbonate (159 mmol, 1.5 equivalents). The atmosphere was purged with nitrogen gas while the solids were stirred. The flask was charged with 445 mL of N,N-dimethylformamide, and the slurry was stirred to dissolve the 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione. The purge was stopped and the reaction was conducted under a slight positive pressure of nitrogen gas. Perfluorobutanesulfonyl fluoride (35.2 g, 117 mmol, 1.1 equivalents) was added in one portion, and the mixture was stirred vigorously to mix the immiscible liquids overnight.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1Cl)[C:5]([CH2:13][CH3:14])([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.NC1C=CC=CC=1C(CC)(O)C1C=CC=CC=1>CO.[OH-].[K+]>[NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([CH2:13][CH3:14])([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCC(O)(c1ccccc1)c1ccc(Cl)c(N)c1
Agent: CCC(O)(c1ccccc1)c1ccccc1N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCC(O)(c1ccccc1)c1cccc(N)c1

Procedure:
2.6 g. of 3-amino-4-chloro-α-ethyl-benzhydrol are dissolved in methanol containing 3.9 g of potassium hydroxide. 8.7 g. of an 5% palladium-on-calcium carbonate catalyst are added to the mixture, and the suspension is hydrogenated at room temperature under atmospheric pressure. After the uptake of the calculated amount of hydrogen the catalyst is filtered off and washed with 15 ml. of methanol. The filtrate and the wash are combined and concentrated to 40 ml. under reduced pressure. The product is precipitated from the concentrate with water. The solids are filtered off, washed until neutral, and dried until constant weight. The crude product is recrystallized from alcohol to yield 1.7 g. of 3 amino-α-ethyl-benzhydrol, melting at 92-93° C.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][NH:22][C@H:21]([C:24]([NH2:26])=[O:25])[C:20]([CH3:27])=[C:19]1[CH3:28])S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(ON[C@@H]1C(C)=C[C@@H](CO[Si](C(C)(C)C)(C)C)NC1)C=C>CO.ClCCl>[CH2:1]([O:4][NH:5][C@H:18]1[CH2:23][NH:22][C@H:21]([C:24]([NH2:26])=[O:25])[C:20]([CH3:27])=[C:19]1[CH3:28])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN[C@H](C(N)=O)C(C)=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON[C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C
Solvent: CO
Solvent: ClCCl
Product: C=CCON[C@H]1CN[C@H](C(N)=O)C(C)=C1C
Yield: 68.8 %

Procedure:
The title compound was prepared from (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-3,4-dimethyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 196, 0.82 g, 2.00 mmol) following the procedure described for Intermediate 12. Silica gel chromatography (0%-10% methanol/dichloromethane) afforded the desired product as a white solid (0.31 g, 68.9%).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([CH:11]([NH:16][C:17](=[O:36])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])=[O:27])=[CH:21][CH:20]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])[CH:7]=1>C(O)(C)(C)C.[OH-].[Na+]>[CH3:14][CH:13]([CH3:15])[CH2:12][CH:11]([C:8]1[CH:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:37])=[O:2])[O:10][N:9]=1)[NH:16][C:17](=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[O:27])=[CH:21][CH:20]=1
Reactant: COC(=O)CCc1cc(C(CC(C)C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)c2cc(CCC(=O)O)on2)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-[3-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}butyl)-isoxazol-5-yl]-propionic acid methyl ester (17 mg) in tert-BuOH (1 ml) and 0.1 N NaOH (1 ml) was stirred at room temperature. After 20 h the mixture was concentrated under reduced pressure, dissolved in water (5 ml) and extracted with EtOAc (5 ml×3). The aqueous layer was then acidified to pH 3 with 1N HCl and extracted with EtOAc. The combined organics were washed with brine; dried over Na2SO4; filtered and concentrated under reduced pressure to give the title compound as a white amorphous solid. MP=?; MS [M+1]+ 493.2; 1H nmr (400 MHz, CD3OD) δ0.87 (d, 3H), 0.91 (d, 3H), 1.53-1.66 (m, 3H), 2.26 (s, 3H), 2.64 (t, J=7.4 Hz, 2H), 2.97 (t, J=7.5 Hz, 2H), 3.44 (s, 2H), 5.08 (m, 1H), 6.00 (s,1H), 6.99 (t, 1H), 7.11-7.36 (m, 6H), 7.59 (d, J=7.9 Hz, 1H).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:20]=[C:14]2[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][N:13]2[N:12]=1.[CH3:21][N:22]1[C:26]([C:27](O)=[O:28])=[C:25]([C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH:24]=[N:23]1>>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:20]=[C:14]2[CH:15]=[C:16]([NH:19][C:27]([C:26]3[N:22]([CH3:21])[N:23]=[CH:24][C:25]=3[C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])=[O:28])[CH:17]=[CH:18][N:13]2[N:12]=1
Reactant: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)O
Reactant: Nc1ccn2nc(-c3ccccc3OCCF)nc2c1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3ccccc3OCCF)nc2c1

Procedure:
This compound was prepared in analogy to 2-methyl-2H-pyrazole-3,4-dicarboxylic acid 4-dimethylamide 3-({2-[2-(2-fluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-amide) (Example 100) from 2-[2-(2-fluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine 104 mg, 0.38 mmol) and 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid (130 mg, 0.54 mmol). Yield: 76 mg (28%); off-white solid; LC-MS: m/z=494.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[C:4]([N:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=1)=[O:5].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl>ClCCl>[Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[C:4]([N:6]([C:7]1[S:8][CH:9]=[C:10]([C:12]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:14])[N:11]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=1)=[O:5]
Reactant: O=C(O)c1csc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(OC(F)(F)F)cc2)n1
Reactant: C1CCNC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(c1csc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(OC(F)(F)F)cc2)n1)N1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
A mixture of 250 mg (0.52 mmol) 2-[(2,4-dichloro-benzoyl)-(4-trifluoromethoxy-phenyl)-amino]-thiazole-4-carboxylic acid, 57 μL (0.68 mmol) pyrrolidine and 110 mg (0.68 mmol) 1,1′-carbonyldiimidazole in 10 mL dichloromethane was stirred for 16 h at room temperature. The mixture was poured onto 0.5 N hydrochloric acid and extracted with dichloromethane. Organic phases were pooled, washed with water and brine and dried with MgSO4. Volatiles were removed in vacuo and the residue was purified by silica gel chromatography (n-heptane/ethyl acetate 1:1) to yield 182 mg (65%) of the title compound as colorless solid. MS (m/e): 530.0 (MH+)
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28]([CH:30]1[O:32][CH2:31]1)Br>CS(C)=O>[NH:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:28][CH:30]3[O:32][CH2:31]3)=[CH:19][CH:20]=2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CO1
Reactant: Oc1ccc(Nc2nccc(Nc3ccccc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: c1ccc(Nc2ccnc(Nc3ccc(OCC4CO4)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
4-Anilino-2-(4-hydroxyanilino)pyrimidine (Reference Example H-1, 0.541 g, 1.95 mmol) was dissolved in DMSO (2 ml) and treated with K2CO3 (0.537 g, 3.89 mmol) and epibromohydrin (0.33 ml, 0.53 g, 3.9 mmol). The reaction was allowed to stir at ambient temperature overnight. After warming to 40° C. for 5 hours the reaction was partitioned between EtOAc and water. The organic phase was washed four times with water, dried over MgSO4 and evaporated at reduced pressure. The residue was purified by chromatography (1–5% MeOH in DCM) to give the title product as an oil (0.614 g, 94%). NMR (300 MHz): 2.69 (m, 1H), 2.83 (m, 1H), 3.88 (m, 1H), 4.25 (m, 1H), 6.15 (d, 1H), 6.85 (d, 2H), 7.97 (t, 1H), 7.27 (t, 2H), 7.58 (d, 2H), 7.66 (d, 2H), 7.95 (d, 1H), 8.9 (s, 1H), 9.23 (s, 1H); m/z: (ES+) 335 (MH+).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17]>C(Cl)Cl>[CH2:20]([O:19][C:15](=[O:18])[CH2:16][CH2:17][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:21]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: C=CC(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)CCN(CC(=O)OCC)Cc1ccccc1
Yield: 76.3 %

Procedure:
Ethyl N-benzylglycinate (0.1295 mol, 1 eq), ethyl acrylate (0.142 mol, 1.1 eq) and 155 μL of Triton™ B (available from Sigma-Aldrich, St. Louis, Mo.) were combined at room temperature under N2. The mixture was then heated to reflux overnight. An aliquot was removed and NMR spectrum was taken of the crude material. The product was present plus both starting materials. The excess of the ethyl acrylate was removed under vacuum at 10 mmHg (60° C. water bath). The crude amber oil that resulted was dissolved in 50 mL of CH2Cl2 and was charge onto a Biotage™ 75L cartridge and eluted with the following gradient 0.5% by volume acetone in hexanes, 1% (1200 mL), 1.5% (1200 mL) and 2.5% (3600 mL). The fractions containing the desired product were combined and concentrated to a colorless oil which was dried under high vacuum for 2 hours to afford 29 g (76%) of product (I-4a). 1H NMR spectrum (CDCl3) and LC/MS (294) were consistent with the compound I-4a.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([C:20](Cl)=[O:21])[CH2:18][CH3:19]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:10][C:20](=[O:21])[CH2:17][CH2:18][CH3:19])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC(=O)Cl
Reactant: NC(=O)C(c1ccccc1)c1ccccc1
Product: CCCC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 205° C. and MS: m/e=281 (M+) was prepared in accordance with the general method of example 39 from 2,2-diphenylacetamide and propanecarboxylic acid chloride.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[C:23]([O:28]C)=[N:24][CH:25]=[CH:26][CH:27]=5)[C:19]([CH3:30])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl>O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:30])=[C:20]([C:22]5[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1ncccc1-c1nc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)ccc1C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1-c1ccc[nH]c1=O
Temperature: 90 °C
Yield: 34.8 %

Procedure:
To 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (87 mg, 0.2 mmol) in 1,4-dioxane (1 mL) was added 0.5 mL of an aqueous 4 M hydrochloric acid solution. The reaction mixture was heated to 90° C. for 30 minutes before being quenched with triethlyamine (0.5 mL) and evaporated to dryness. The residue was dissolved in N,N-dimethylformamide (1 mL) and purified by reverse-phase preparative liquid chromatography. The resulting trifluoroacetic acid salt was dissolved in dichloromethane (5 mL) and washed with a saturated sodium bicarbonate solution. The organics were dried over sodium sulfate and evaporated to dryness to yield the product (27 mg, 32%) ESI-MS m/z calc. 387.43. found 388.5 (M+1)+. Retention time 1.23 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.02 (s, 1H), 7.94 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.45 (m, 1H), 7.37-7.35 (m, 2H), 7.24 (m, 1H), 6.80 (d, J=8.2 Hz, 1H), 6.24 (m, 1H), 4.54 (t, J=8.7 Hz, 2H), 3.19 (t, J=8.7 Hz, 2H), 2.07 (s, 3H), 1.50-1.47 (m, 2H), 1.11-1.08 (m, 2H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:13]=[C:12]([CH2:14][O:15][C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[NH:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[O:25]>>[O:25]=[C:24]1[NH:23][CH:29]([CH:12]([CH3:11])[C:14]([NH:20][C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=[C:4]([CH3:3])[CH:13]=3)=[CH:22][CH:21]=2)=[O:15])[C:27](=[O:28])[NH:26]1
Reactant: O=C1CNC(=O)N1
Reactant: Cc1cc(COc2ccc(N)cc2)c2ccccc2n1
Agent: Cl
Product: Cc1cc(COc2ccc(NC(=O)C(C)C3NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 13 %

Procedure:
2-(4-hydantoinyl)propionic acid (50 mg, 0.30 mmol) and 4-[(2-methyl-4-quinolinyl)methoxy]-aniline bis-HCl salt (101 mg, 0.30 mmol) were coupled using general coupling method A to give 20 mg (13%) of the product hydantoin. MS found: (M+H)+=419.
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[N:15]([O-])=O.[Na+]>Cl.O>[ClH:1].[ClH:1].[N:3]1([C:8]2[CH:14]=[CH:13][C:11]([NH:12][NH2:15])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=N[O-]
Reactant: Nc1ccc(-n2ccnc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(-n2ccnc2)cc1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 567.9 %

Procedure:
To a cooled (-15° C.) and stirred suspension of 4-(imidazol-1-yl)aniline dihydrochloride (20 g, 86.16 mmol) in concentrated hydrochloric acid (100 ml) was added dropwise, over 1 hour, a solution of sodium nitrite (6.25 g, 9.05 mmol) in water (40 ml). After a further 10 minutes of stirring at -12° C., the mixture was quickly filtered to remove a solid, and the filtrate was added portionwise to a cooled (-20° C.) and stirred solution of tin (II) chloride dihydrate (100 g) in concentrated hydrochloric acid (50 ml) at such a rate as to maintain the internal temperature below -10° C. (15 minutes). The mixture was allowed to warm to 5° C. over 30 minutes, and the solid was collected and washed with diethyl ether (4×100 ml). The above solid was suspended in water (200 ml) and basified with 4N sodium hydroxide solution and extracted with ethyl acetate (5×500 ml). The combined organic solutions were dried (Na2SO4) and filtered. The filtrate was vigorously stirred while hydrogen chloride was being bubbled through the solution until a deep red mixture was obtained. Stirring was continued for a further 20 minutes to give a cream solid which was collected by filtration and dried over phosphorus pentoxide-potassium hydroxide under high vacuum to leave 12.7 g (60%) of the title compound: δH (360 MHz, DMSO-d6) 7.20 (2H, d, J=9.0 Hz), 7.73 (2H, d, J=9.0 Hz), 7.91 (1H, t, J=1.5 Hz), 8.23 (1H, t, J=1.7 Hz), 9.71 (1H, t, J=1.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18](Cl)=[C:13]3[C:12]([CH:20]([CH3:22])[CH3:21])=[N:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>CN(C=O)C.C(Cl)(Cl)Cl.[Cu]=O>[N:29]1([C:18]2[CH:17]=[CH:16][N:15]=[C:14]3[N:10]([C:8]4[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Br:1])[CH:9]=4)[N:11]=[C:12]([CH:20]([CH3:22])[CH3:21])[C:13]=23)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: CC(C)c1nn(-c2ccc(C#N)c(Br)c2)c2nccc(Cl)c12
Reactant: c1c[nH]cn1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)c1nn(-c2ccc(C#N)c(Br)c2)c2nccc(-n3ccnc3)c12
Yield: 81.4 %

Procedure:
A solution of compound (36a) (0.196 g), potassium carbonate (0.145 g), copper(II) oxide (nanopowder) (0.021 g), and imidazole (0.042 g) in DMF (2.0 mL) was stirred at 120° C. for 20 hr. The reaction solution was diluted with chloroform, and insoluble matters were filtered through celite. The solvent was distilled away, and ethyl acetate and ether were added to the residue. The precipitate was collected by filtration to obtain compound (36b) (0.173 g, 81%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7](Br)[N:8]2[CH2:11][O:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[C:4]([OH:19])[N:3]=1.[NH2:20]N>O.[Ni]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([NH2:20])[N:8]2[CH2:11][O:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[C:4]([OH:19])[N:3]=1
Reactant: Nc1nc(O)c2nc(Br)n(COC(CO)CO)c2n1
Reactant: NN
Agent: [Ni]
Solvent: O
Product: Nc1nc(O)c2nc(N)n(COC(CO)CO)c2n1

Procedure:
A mixture of 2-[(2-amino-8-bromo-6-hydroxy-9H-purin-9-yl)methoxy]-1,3-propanediol (13.7 g; 41 mmole) and 97% hydrazine (6.07 ml) in water (300 ml) is heated to reflux for 48 hours. At the end of this time, the solution is cooled and filtered to give 9.15 g of crude solid. The crude product is suspended in water (120 ml) and Raney nickel (9 g) is added. The mixture is heated at reflux for 6 hours, filtered hot and cooled. The crystals are collected and dried to give 7.15 g of the product, mp>280° dec.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][C:3]=1[C:12]#[N:13].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19](=[O:22])[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[NH2:13][C:12]1[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[O:1][C:20]=1[C:19]([C:18]1[CH:23]=[CH:24][CH:25]=[C:16]([O:15][CH3:14])[CH:17]=1)=[O:22])[O:9][CH2:8][CH2:7][CH2:6]3
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: N#Cc1cc2c(cc1O)OCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(C(=O)c2oc3cc4c(cc3c2N)CCCO4)c1
Temperature: 100 °C
Reaction time: 17 h
Yield: 54.9 %

Procedure:
To a stirred solution of 7-Hydroxy-chroman-6-carbonitrile from method II-3 (30 mg, 0.17 mmol) and 3-methoxyphenacyl bromide (78.5 mg, 0.34 mmol, 2.0 eq) in anhydrous N,N-dimethylformamide (1.0 mL) was added potassium carbonate (47.3 mg, 0.34 mmol, 2.0 eq), and the orange reaction mixture was stirred at 100° C. for 17 h. The resulting dark wine colored reaction was poured into ethyl acetate (10 mL) and water (10 mL). This mixture was then extracted with EtOAc (2×10 mL). The combined organic layers were then dried (Na2SO4), filtered, and evaporated in vacuo. The residue was purified by pre-HPLC to afford the desired product as a yellow solid (30.7 mg, 54.9%). 1H-NMR (CD3CN) δ 7.73 (d, J=7.3 Hz, 1H), 7.66 (s, 1H), 7.50 (s, 1H), 7.44 (t, 1H), 7.34 (dd, J=2.8, 8.5 Hz, 1H), 6.80 (s, 1H), 4.25 (t, 2H), 3.89 (s, 3H), 2.93 (t, 2H), 2.03 (m, 2H); MS LC-MS (MH+=324).
Reaction SMILES: FC(F)(F)C1[NH:4][C:5]2[C:6]([N:27]=1)=[C:7]1[C:12](=[CH:13][CH:14]=2)[CH2:11][CH2:10][CH:9]([CH2:15][O:16]S(C2C=CC(C)=CC=2)(=O)=O)[O:8]1.[BH4-].[Li+]>C1COCC1>[NH2:4][C:5]1[C:6]([NH2:27])=[C:7]2[C:12]([CH2:11][CH2:10][CH:9]([CH2:15][OH:16])[O:8]2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1N)OC(CO)CC2
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a solution of toluene-4-sulfonic acid 2-trifluoromethyl-3,6,7,8-tetrahydro-9-oxa-1,3-diazacyclopenta[a]naphthalen-8-ylmethyl ester (500 mg, 2.11 mmol) in THF (50 mL) was added lithium borohydride (2.11 mL, 2 M, 4.22 mmol). The resulting solution was stirred for 30 min at 50° C. and then evaporated in vacuo to a residue. The residue was dissolved in ethyl acetate (100 mL) and then washed with water (2×30 mL), dried over anhydrous Na2SO4. The solvent was removed in vacuo to afford 352 mg (86% yield) of the title compound: 1H NMR (400 MHz), CDCl3) δ1.90 (m, 2H), 2.78 (m, 2H), 3.18 (bs, 4H), 3.78 (m, 1H, OH), 3.82 (m, 2H), 4.18 (m, 1H), 6.33 (d, J=8 Hz), 6.42 (d, J=8 Hz); MS 195 [M+H]+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(CC1C=CC=CC=1)(C1C=CC=CC=1)=O.[OH:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O.CN(C=O)C>[CH2:1]([O:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:34][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C(Cc1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
35 mmol of benzyl bromide (BzBn, 35 mmol of ethyl 4-hydroxybenzoate (10), 14 g of Cs2CO3 and 40 ml of DMF were combined and stirred at RT ove night. Then the reaction mixture was poured into water and the product was collected by extraction. The organic solution was washed with brine and dried over MgSO4. After evaporation of solvent, pure product was obtained in yield of 100%.
Reaction SMILES: [F:1][C:2]([F:27])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH2:18][F:19])([CH2:16][F:17])[CH:13]=[C:12]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=S)[C:11]=2[CH:26]=1)[C:3]([F:6])([F:5])[F:4].IC.[N+:30]([CH3:33])([O-:32])=[O:31].[H-].[Na+]>O1CCCC1>[F:1][C:2]([F:27])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH2:18][F:19])([CH2:16][F:17])[CH:13]=[C:12]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[CH:33][N+:30]([O-:32])=[O:31])[C:11]=2[CH:26]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: FCC1(CF)C=C(N2CCCC2=S)c2cc(C(F)(F)C(F)(F)F)ccc2O1
Reactant: C[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: O=[N+]([O-])C=C1CCCN1C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21
Temperature: 0 °C
Yield: 11.7 %

Procedure:
To a mixture of 0.16 g of 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(2-thioxo-1-pyrrolidinyl)-2H-1-benzopyran, 0.78 g of iodomethane, 0.41 g of nitromethane and 6 ml of tetrahydrofuran was added 0.10 g of sodium hydride (60%) at room temperature with stirring. The mixture was refluxed with heating for 2 hours. After addition of ice water, the mixture was extracted with methylene chloride. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.02 g of 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(2-nitromethylene-1-pyrrolidinyl)-2H-1-benzopyran represented by the following formula having a melting point of 195-197° C.