Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[S:16]([NH-:19])(=[O:18])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29](C2C=CC=CC=2)[C:30](=O)[O-:31])[N:23]=1.N12CCCN=C1CCCCC2.Cl>O.O1CCOCC1>[C:1]1([C:7]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[S:16]([NH:19][C:30]([NH:29][C:24]2[N:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([CH3:28])[N:25]=2)=[O:31])(=[O:18])=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH-]S(=O)(=O)c1c(-c2ccccc2)sc2ccccc12
Reactant: COc1cc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2c(-c3ccccc3)sc3ccccc23)n1
Reaction time: 4 h
Yield: 78.2 %

Procedure:
A mixture of 1.1 g (3.8 mmol) of 2-phenylbenzo[b]thiophen-3-ylsulfonylamide, 1.0 g (3.8 mmol) of N-(4-methoxy-6-methylpyrimidin-2-yl)phenylcarbamate, 0.6 g (4 mmol) of 1.8-diazabicyclo[5.4.0]undec-7-ene and 15 ml of dioxane is stirred for 4 hours at 20°-25° C. The reaction mixture is then taken up in 100 ml of water, acidified to pH 3 by adding 2N hydrochloric acid dropwise and then extracted with 3×30 ml of ethyl acetate. The combined extracts are dried and concentrated by evaporation. The residue is crystallised from ether, affording 1.35 g (78% of theory) of N-(2-phenylbenzo[b]thiophen-3-ylsulfonyl)-N'-(4-methoxy-6-methylprimidin-2-yl)urea with a melting point of 199°-202° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.C(Cl)Cl.[Cl-].[Na+].O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:17]2[CH:18]=[C:19]([N:23]3[C:31]4[C:26](=[CH:27][C:28]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:29][CH:30]=4)[CH2:25][CH2:24]3)[N:20]=[CH:21][N:22]=2)[CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(c1cc(N2CCc3cc(S(C)(=O)=O)ccc32)ncn1)C1CCN(Cc2ccccc2)CC1
Temperature: 90 °C

Procedure:
A mixture of 7b (0.14 g, 2.1 eq), 6a (0.1 g, 0.3 mmol) and potassium carbonate (0.1 g, 2.2 eq) in 1 mL of DMA was heated up to 90° C. for 48 h then cooled down to room temperature and diluted with DCM (2 mL) and brine (2 mL). The layers were separated and the aqueous extracted with DCM (2×2 mL). The combined extracts were washed with brine (2×50 mL), dried over magnesium sulfate, filtered and evaporated. The residue was diluted with acetonitrile and purified on preparative HPLC to afford 7c.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[C:11]=2[CH3:19])[CH:6]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:30]=[C:29]([C:31](O)=[O:32])[NH:28][N:27]=2)[CH:21]=1.C1C=C2N=NN(O)C2=CC=1.O.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:18][C:12]1[C:11]([CH3:19])=[C:10]([C:7]2[CH:6]=[C:5]([CH2:4][CH2:3][NH:2][C:31]([C:29]3[NH:28][N:27]=[C:26]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[CH:30]=3)=[O:32])[O:9][N:8]=2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: O=C(O)c1cc(-c2cccnc2)n[nH]1
Reactant: Cc1c(-c2cc(CCN)on2)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1c(-c2cc(CCNC(=O)c3cc(-c4cccnc4)n[nH]3)on2)ccc(C#N)c1Cl
Yield: 16.3 %

Procedure:
N-(2-(3-(3-chloro-4-cyano-2-methylphenyl)isoxazol-5-yl)ethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxamide was prepared from 4-(5-(2-aminoethyl)isoxazol-3-yl)-2-chloro-3-methylbenzonitrile hydrochloride (54.8 g, 0.184 mmol), 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid (34.8 mg, 0.184 mmol), HOBt hydrate (42.2 mg, 0.276 mmol), DIPEA (0.096 ml, 0.551 mmol) and EDCI (53 mg, 0.276 mmol) using DCM as solvent as described in previous Example. The crude product was purified by preparative HPLC to give the title compound 13 mg. 1H-NMR (400 MHz; CDCl3): δ 2.47 (s, 3H), 3.23 (t, 2H), 3.89 (m, 2H), 6.30 (s, 1H), 7.09 (bs, 1H), 7.22 (bs, 1H), 7.40 (m, 2H), 7.57 (d, 1H), 7.98 (d, 1H), 8.62 (bs, 1H), 8.95 (bs, 1H).
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=1N.[I-:18].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.S(=O)(=O)(O)O>[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=1[I:18]
Reactant: [I-]
Reactant: COC(=O)c1cc(C#N)ccc1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Solvent: O
Product: COC(=O)c1cc(C#N)ccc1I
Temperature: 25 °C
Yield: 85.6 %

Procedure:
Sodium nitrite (0.8 g, 11.4 mmol) in water (10 ml) was added dropwise over 10 minutes to a stirred solution of 2-amino-5-cyanobenzoic acid methyl ester (2.0 g, 11.4 mmol) in water (30 ml) and conc. sulphuric acid (15 ml) at 0° C. After a fiber 15 minutes at 5° C., a solution of potassium iodide (3.5 g, 21 mmol) in water (30 ml) was quickly added and the mixture allowed to warm to room temperature. 10% Aqueous sodium thiosulphate was added, the mixture extracted with ethyl acetate, the extract dried over magnesium sulphate and evaporated. The residue was purified by flash column chromatography on silica eluting with 20% ethyl acetate in hexane to yield the title compound as a colourless oil (2.8 g). MS (+EI) m/z 287 [M+].
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19](=[O:21])[CH3:20]>CC(C)=O>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][CH2:18][C:19](=[O:21])[CH3:20])=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: CC(=O)CCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 82.1 %

Procedure:
Into acetone (300 ml ) were suspended 41.7 g (0.3 mol) of p-nitrophenol and 41.4 g (0.3 mol) of anhydrous potassium carbonate. Under stirring and reflux, 27.7 g (0.3 mol) of chloroacetone were added dropwise therein over five hours. After the resulting mixture was reacted for two hours as it was, it was cooled down, and the reaction liquid was dispersed into ice water (500 ml). After the extract obtained by extraction therefrom with ethyl acetate (500 ml) was washed with water and dried, the solvent was distilled off under reduced pressure. The thus-obtained light-yellow crystalline residue was recrystallized from ethyl acetate/n-hexane, whereby 48.1 g of the title compound were obtained. (Yield: 82.2%)
Reaction SMILES: [Br-].[CH3:2][C:3]([CH3:11])=[CH:4][CH2:5][S+]1CCCC1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][CH:13]=1.[H-].[Na+]>>[CH3:11][C:3]([CH3:2])=[CH:4][CH:5]1[O:19][CH:18]1[C:15]1[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=1
Reactant: CC(C)=CC[S+]1CCCC1
Reactant: O=Cc1ccncc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: CC(C)=CC1OC1c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 1-(3-methyl-but-2-enyl)-tetrahydrothiophenium bromide (381 mg in 5 mL dry tetrahydrofuran) at 0° C. was added 0.31 mL pyridine-4-carboxaldehyde followed by 111 mg sodium hydride and the mixture allowed to warm to room temperature. After 1.5 hours, an additional 0.15 mL pyridine-4-carboxaldehyde was added and after 30 minutes the reaction quenched by the addition of water. The mixture was partitioned between ethyl acetate and water and the organic portion washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 1:2) gave the title compound (138 mg). Step 4C
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[NH:20]1[CH2:23][CH:22]([C:24]([OH:26])=[O:25])[CH2:21]1.C(N(CC)CC)C.Cl>CN(C=O)C.O>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:20]2[CH2:23][CH:22]([C:24]([OH:26])=[O:25])[CH2:21]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: O=C(O)C1CNC1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CC(C(=O)O)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (2.84 g, 10.5 mmol) and azetidine-3-carboxylic acid (1.06 g, 10.5 mmol) in DMF (100 mL) was added triethylamine (3.18 g, 4.39 mL, 31.5 mmol). The reaction was stirred at room temperature overnight then diluted with H2O (400 mL). The pH of the solution was adjusted to 3-4 by addition of an aqueous 1 M HCl solution. The white precipitate then obtained was filtered, washed with H2O, and purified by silica gel chromatography using 0-15% MeOH—CH2Cl2 giving 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)azetidine-3-carboxylic acid. LC/MS: m/z 336.3 (M+H)+ at 1.97 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[N:7]3[CH2:14][CH:13]([CH3:15])[CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1.[CH2:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC>CN(C=O)C.O.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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][CH:13]1[CH2:14][N:7]2[C:8](=[N:9][C:10]3[CH:11]=[C:2](/[CH:17]=[CH:18]/[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:3]=[CH:4][C:5]=3[C:6]2=[O:16])[CH2:12]1
Reactant: C=Cc1ccccc1
Reactant: CC1Cc2nc3cc(Br)ccc3c(=O)n2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1Cc2nc3cc(/C=C/c4ccccc4)ccc3c(=O)n2C1
Temperature: 25 °C
Yield: 61.6 %

Procedure:
A solution of 6-bromo-2-methyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (100 mg, 0.36 mmol), styrene (75 mg, 0.72 mmol), Pd (PPh3)4 (45 mg, 0.036 mmol), PPh3 (1 mg, 0.0036 mmol) and Et3N (182 mg, 1.8 mmol) in DMF (10 mL) was stirred at 140° C. under N2 for 8 hours. After cooled to room temperature, the mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2SO4. Then the filtrate was concentrated and purified by column chromatography to give the desired product (67 mg). MS (ESI): 303 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 8.13-8.10 (d, J=8.3 Hz, 1H), 7.87-7.84 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.70-7.68 (d, J=7.5 Hz, 2H), 7.56-7.47 (m, 2H), 7.44-7.40 (m, 2H), 7.35-7.30 (m, 1H), 4.29-4.22 (dd, J=11.7, 7.8 Hz, 1H), 3.68-3.62 (dd, J=11.7, 6.8 Hz, 1H), 3.38-3.29 (dd, J=17.2, 8.1 Hz, 1H), 2.91-2.83 (dd, J=17.2, 7.5 Hz, 1H), 2.75-2.67 (m, 1H), 1.18-1.16 (d, J=6.7 Hz, 3H). mGluR5 PAM EC50: +++.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:29]=[CH:28][N:14]3[C:15](=[O:27])[C:16]([CH:25]=O)=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[C:12]=2[O:30][CH3:31])[S:7][CH:8]=1)([CH3:3])[CH3:2].[C:32]([O:36][C:37]([CH:39]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>O1CCCC1.CN(C)C=O>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:29]=[CH:28][N:14]3[C:15](=[O:27])[C:16](/[CH:25]=[CH:39]/[C:37]([O:36][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:38])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[C:12]=2[O:30][CH3:31])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1c(CCc2nc(C(C)C)cs2)ccn2c(=O)c(C=O)c(N3CCOCC3)nc12
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1c(CCc2nc(C(C)C)cs2)ccn2c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N3CCOCC3)nc12
Temperature: 80 °C
Reaction time: 15 h
Yield: 57 %

Procedure:
The 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-9-methoxy-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde (300 mg) obtained in (H) was dissolved in tetrahydrofuran (4 ml) and dimethylformamide (1 ml), added with (tert-butoxy-carbonylmethylene)triphenylphosphorane (767 mg), and stirred at 80° C. for 15 hours. After the solvent was evaporated, the residue was purified by silica gel column chromatography to obtain the title compound (209 mg) as yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[CH:11][C:12]2[C:17](Br)=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[Br:20])=[CH:5][CH:4]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:20][C:13]1[CH:14]=[C:15]([CH3:19])[CH:16]=[C:17]2[C:12]=1[CH:11]=[N:10][N:9]2[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(NN=Cc2c(Br)cc(C)cc2Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(-n2ncc3c(Br)cc(C)cc32)cc1
Yield: 23.9 %

Procedure:
Crude 2,6-dibromo-4-methylbenzaldehyde[4-(methyloxy)phenyl]hydrazone (Intermediate 14 prepared from 2.62 g of 2,6-dibromo-4-methylbenzaldehyde) was dissolved in toluene (100 mL) and treated with tripotassium phosphate (5 g, 23.55 mmol), tris(dibenzylideneacetone)dipalladium(0) (196 mg, 0.214 mmol) and racemic BINAP (122 mg, 0.196 mmol). The mixture was heated under reflux for 17 hours and then cooled, filtered through celite and evaporated under reduced pressure. The residue was purified by silica gel chromatography using the Flashmaster II (100 g cartridge) eluting with a 100:0 to 0:100 cyclohexane:dichloromethane gradient over 60 minutes to give crude product (801 mg). Further purification by silica gel chromatography using the Flashmaster II (50 g cartridge) eluting with a 100:0 to 75:25 cyclohexane:ethyl acetate gradient over 50 minutes gave the title compound as a colourless solid (499 mg).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2.O[Li].O>C1COCC1.O>[CH3:25][O:24][C:23]1[CH:22]=[CH:21][NH:20][C:19]=1/[CH:18]=[C:10]1\[C:11](=[O:17])[NH:12][C:13]2[C:9]\1=[C:8]([C:7]#[C:6][CH2:5][CH2:4][C:3]([OH:26])=[O:2])[CH:16]=[CH:15][CH:14]=2
Reactant: COC(=O)CCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCC(=O)O)c21

Procedure:
Using Method F above, (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester (50 mg, 0.14 mmol) (from Example 8 above) was hydrolyzed with LiOH.H2O (118 mg, 2.8 mmol) in THF (3 mL) and water (3 mL) for 22 h. (Yield 40 mg, 85%).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C:3]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]([O:20]C)=[O:19])[N:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)=[CH:24][CH:23]=2)[C:7](=[O:33])[C:6]=1[OH:34])=[O:4].C1COCC1.[OH-].[Li+].Cl>O.CO>[OH:20][C:18]([CH2:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:9]1[N:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)=[CH:24][CH:23]=2)[C:7](=[O:33])[C:6]([OH:34])=[C:5]1[C:3](=[O:4])[C:2]([CH3:35])([CH3:1])[CH3:36])=[O:19]
Reactant: COC(=O)COc1ccccc1C1C(C(=O)C(C)(C)C)=C(O)C(=O)N1c1ccc(-c2ccsc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C(=O)C1=C(O)C(=O)N(c2ccc(-c3ccsc3)cc2)C1c1ccccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a mixture of 4-(2,2-dimethylpropionyl)-3-hydroxy-5-(2-methoxycarbonylmethyloxyphenyl)-1-(4-thiophene-3-ylphenyl)-1,5-dihydropyrrole-2-one (0.172 g, 0.34 mmol), THF (1.72 mL), and methanol (1.72 mL) was added 1 mol/L aqueous lithium hydroxide solution (1.02 mL), and the resulting mixture was stirred at room temperature for 1 hour. After the reaction was completed, 2 mol/L hydrochloric acid (0.52 mL) and water (14 mL) were added to the reaction mixture, and the precipitated aimed compound was collected by filtration. The resulting aimed compound was dissolved in ethyl acetate, and the mixture was dried over anhydrous sodium sulphate and then concentrated in vacuo. The resulting residue was triturated with ethyl ether and diisopropyl ether to give 5-(2-hydroxycarbonylmethyloxyphenyl)-4-(2,2-dimethylpropionyl)-3-hydroxy-1-(4-thiophene-3-ylphenyl)-1,5-dihydropyrrole-2-one (0.137 g, yield: 82%) as pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][CH:12]3[CH:8]2[CH2:9][NH:10][CH2:11]3)[CH:2]=1.[C:14]([OH:21])(=[O:20])/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18]>CO.C(OC(=O)C)(C)C>[C:14]([OH:21])(=[O:20])/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][C@@H:12]3[C@H:8]2[CH2:9][NH:10][CH2:11]3)[CH:2]=1
Reactant: c1cncc(N2CC3CNCC32)c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CC(=O)OC(C)C
Product: c1cncc(N2C[C@H]3CNC[C@H]32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
The product of Example 40C (65 mg, 0.37 mmol) was treated with fumaric acid (46.4 mg, 0.4 mmol) in methanol/isopropylacetate (1:10 v/v, 20 mL). The mixture was stirred at room temperature overnight. The precipitate was collected by filtration and dried under reduced pressure at 40-50° C. to provide the title compound (47 mg, 44% yield). 1H NMR (MeOH-d4, 300 MHz) δ 3.18 (dd, J=12.6, 3.4 Hz, 1H), 3.35 (m, 1H), 3.46 (m, 1H), 3.75 (m, 3H), 4.04 (t, J=7.5 Hz, 1H), 4.90 (m, 1H), 6.58 (s, 2H), 7.04 (ddd, J=8.2, 2.7, 1.3 Hz, 1H), 7.27 (dd, J=8.2, 4.8 Hz, 1H), 7.87 (d, 2.7 Hz, 1H), 7.95 (dd, J=4.8, 1.1 Hz, 1H); m/z 176 (M+H)+; Anal. calculated for C10H13N3.1.25C4H4O4.0.6H2O: C, 54.41; H, 5.84; N, 12.69. Found: C, 54.96; H, 5.50; N, 12.10.
Reaction SMILES: C(OC(CN[C@H](C)[C@@H](C1C=CC(OC2C=CC=CC=2)=CC=1)CCC1C=CC=CC=1)=O)(C)(C)C.[CH2:34]([O:41][C:42]([CH2:44][NH:45][C@H:46]([CH3:69])[C@@H:47]([C:56]1[CH:61]=[CH:60][C:59]([O:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:58][CH:57]=1)[CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O1[C@@H](C(OC(C)(C)C)=O)[C@H](C([O-])=O)OC1(C(OCC)=O)C(OCC)=O.[O:95]1[C@H:99]([C:100]([O:102][C:103]([CH3:106])([CH3:105])[CH3:104])=[O:101])[C@@H:98]([C:107]([O-])=[O:108])[O:97][C:96]1([C:119]([O:121][CH2:122][CH2:123][Si:124]([CH3:127])([CH3:126])[CH3:125])=[O:120])[C:110]([O:112][CH2:113][CH2:114][Si:115]([CH3:118])([CH3:117])[CH3:116])=[O:111]>>[CH2:34]([O:41][C:42]([CH2:44][N:45]([C@H:46]([CH3:69])[C@@H:47]([C:56]1[CH:57]=[CH:58][C:59]([O:62][C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)=[CH:60][CH:61]=1)[CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:107]([C@@H:98]1[C@@H:99]([C:100]([O:102][C:103]([CH3:106])([CH3:105])[CH3:104])=[O:101])[O:95][C:96]([C:119]([O:121][CH2:122][CH2:123][Si:124]([CH3:125])([CH3:126])[CH3:127])=[O:120])([C:110]([O:112][CH2:113][CH2:114][Si:115]([CH3:116])([CH3:118])[CH3:117])=[O:111])[O:97]1)=[O:108])=[O:43])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: C[C@@H](NCC(=O)OCc1ccccc1)[C@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)[C@H]1OC(C(=O)OCC[Si](C)(C)C)(C(=O)OCC[Si](C)(C)C)O[C@@H]1C(=O)[O-]
Agent: CCOC(=O)C1(C(=O)OCC)O[C@@H](C(=O)[O-])[C@H](C(=O)OC(C)(C)C)O1
Agent: C[C@@H](NCC(=O)OC(C)(C)C)[C@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Product: C[C@H]([C@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1)N(CC(=O)OCc1ccccc1)C(=O)[C@H]1OC(C(=O)OCC[Si](C)(C)C)(C(=O)OCC[Si](C)(C)C)O[C@@H]1C(=O)OC(C)(C)C

Procedure:
The above identified compound was obtained by carrying out the same reaction as in Example 19(1) except that instead of N-(tert-butoxycarbonylmethyl)-{(1R,2R)-1-methyl-2-(4-phenoxyphenyl)-4-phenylbutyl}amine used as the starting material in Example 19(1), N-(benzyloxycarbonylmethyl)-{(1R,2R)-1-methyl-2-(4-phenoxyphenyl)-4-phenylbutyl}amine obtained in Example 52, was used, and instead of 5-tert-butyl 2,2-diethyl (4R,5R)-1,3-dioxolane-2,2,4,5-tetracarboxylate, 5-tert-butyl 2,2-bis{2-(trimethylsilyl)ethyl} (4S,5S)-1,3-dioxolane-2,2,4,5-tetracarboxylate obtained in Example 73, was used.
Reaction SMILES: [CH2:1](OC(=O)COC1C2C(=CC=CC=2)C(=O)N1CC1C=CC=CC=1)C.[CH2:25]([N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]1[O:42][CH2:43][C:44]([NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1)=[O:45])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][C:36]([CH3:1])=[CH:37][CH:38]=2)[CH:33]1[O:42][CH2:43][C:44]([NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1)=[O:45])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(COC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1ccccn1
Reactant: CCOC(=O)COC1c2ccccc2C(=O)N1Cc1ccccc1
Product: Cc1ccc2c(c1)C(OCC(=O)Nc1ccccn1)N(Cc1ccccc1)C2=O

Procedure:
Compound 61 was prepared using the synthetic sequence in a manner analogous to the method described for the conversion of compound 21 to compound 23 and illustrated in Scheme 2. NMR (300 MHz, CDCl3): δ 8.8 (br s, 1H), 8.45 (m, 1H), 8.1 (m, 1H), 7.75 (m, 2H), 7.4-7.2 (m, 7H), 7.05 (m, 1H), 5.9 (s, 1H), 5.0 (d, J=15 Hz, 1H), 4.4 (d, J=15 Hz, 1H), 3.65 (d, J=19 Hz, 1H), 3.5 (d, J=19 Hz, 1H), 2.4 (s, 3H). MS: m/z (MNa+) 410.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23]([OH:25])=O)[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.Cl.[F:28][C:29]([F:38])([F:37])[CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([C:16]4[CH:19]=[C:20]([C:23]([N:34]5[CH2:33][CH2:32][N:31]([CH2:30][C:29]([F:37])([F:38])[F:28])[CH2:36][CH2:35]5)=[O:25])[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12]3)[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)O)ccc1OCC2
Reactant: FC(F)(F)CN1CCNCC1
Agent: Cl
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)N3CCN(CC(F)(F)F)CC3)ccc1OCC2

Procedure:
Following the procedure for 116, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid was reacted with 1-(2,2,2-trifluoroethyl)piperazine dihydrochloride to give 124 as a white solid. 1H NMR (CDCl3, 400 MHz): δ 8.02 (d, J=2.1 Hz, 1 H); 7.95 (s, 1 H); 7.35 (dd, J=8.3, 2.1 Hz, 1 H); 7.23 (d, J=8.3 Hz, 1 H); 6.88 (s, 1 H); 5.73-5.60 (m, 1 H); 4.58 (t, J=5.8 Hz, 2 H); 3.94-3.44 (br m, 4H); 3.20 (t, J=5.8 Hz, 2 H); 3.04 (q, J=9.4 Hz, 2 H); 2.74 (br s, 4 H); 1.58 (d, J=6.6 Hz, 6 H). LCMS: RT=10.93 min, M+H+=490
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[C:16]([NH2:18])=[O:17].[C:19](=O)(OCC)[O:20]CC.[O-]CC.[Na+]>C(O)C>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:6]2[C:2]3[NH:1][C:19](=[O:20])[NH:18][C:16](=[O:17])[C:3]=3[N:4]=[N:5]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)OCC
Reactant: COc1ccc(Cn2nnc(C(N)=O)c2N)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Cn2nnc3c(=O)[nH]c(=O)[nH]c32)cc1
Yield: 50.9 %

Procedure:
A mixture of 5-Amino-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (example 1, step a) (7.59 g, 30.7 mmol), diethyl carbonate (4.72 g, 39.9 mmol) and sodium ethoxide (3.76 g, 55.3 mmol) in ethanol (97.1 mL) was heated to reflux overnight. The solid was filtered, washed with EtOH and dried to give 3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (8.542 g, 15.6 mmol, 50.9% yield) which was used in the consecutive step without further purification. MS (m/e): 272.0 (MH+).