Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:17]([F:18])=[CH:16][C:5]2[O:6][C:7]([F:15])([F:14])[C:8](=[O:13])[N:9]([CH2:10][C:11]#[CH:12])[C:4]=2[CH:3]=1.[C:19]1(=O)[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[C:21](=[O:28])[O:20]1>C(O)(=O)C>[F:15][C:7]1([F:14])[C:8](=[O:13])[N:9]([CH2:10][C:11]#[CH:12])[C:4]2[CH:3]=[C:2]([N:1]3[C:19](=[O:20])[C:27]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=4[C:21]3=[O:28])[C:17]([F:18])=[CH:16][C:5]=2[O:6]1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N)cc21
Solvent: CC(=O)O
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Yield: 15.3 %

Procedure:
6-amino-2,2,7-trifluoro-4-(prop-2-ynyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (20 g, 78 mmol) and 4,5,6,7-tetrahydroisobenzofuran-1,3-dione (12.47 g, 82 mmol) in acetic acid (500 ml) were stirred at 120° C. overnight, after which time tlc (thin layer chromatography) analysis indicated that the reaction was complete. The reaction mixture was concentrated in vacuo and triturated with toluene to yield 34.6 g of crude product. This material was combined with a further quantity (6.23 g) of crude product which had been obtained in a similar manner, and the combined product was coated on isolute absorbens (˜70 g). Filtration over silica afforded 2 fractions: F1: 12.9 g and F2: 19.35 g. Both fractions were triturated with di-isopropyl ether to yield: T1: 6.04 g (88% purity) and T2: 14.7 g (>95% purity). T1 was recrystallised from MeOH to yield a further 4.65 g of product (>95% purity).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[C:28](OCC)(=[O:34])[C:29](OCC)=[O:30]>C(OCCO)C>[CH:23]1([N:22]2[C:3]3[N:4]=[C:5]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([N:15]5[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]5)=[CH:11][CH:10]=4)[N:6]=[CH:7][C:2]=3[NH:1][C:29](=[O:30])[C:28]2=[O:34])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CN1CCN(c2ccc(Nc3ncc(N)c(NC4CCCC4)n3)cc2)CC1
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCOCCO
Product: CN1CCN(c2ccc(Nc3ncc4[nH]c(=O)c(=O)n(C5CCCC5)c4n3)cc2)CC1
Yield: 52.2 %

Procedure:
A mixture of 0.367 g (1 mmol) of 5-amino-4-(cyclopentylamino)-2-[[4-(4-methylpiperazin-1-yl)phenyl]amino]pyrimidine and 5 mL (32 mmol) of diethyl oxalate in 20 mL of 2-ethoxyethanol is heated under reflux for 3 hours, and cooled, to give 0.22 g (52%) of the title compound (Compound 24): mp (EtOH) 266–270° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=4)[NH2:22])[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>ClCCl>[CH2:37]([O:36][C:34](=[O:35])[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][CH:8]3[CH2:7][CH2:6][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:10][CH2:9]3)[CH2:18][CH2:17]2)[CH:20]=1)[CH3:38]
Reactant: Nc1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
To a cooled solution of 1 g (3 mmol) of 3-{4-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]piperazin-1-yl}aniline in 30 mL of dichloromethane and 0.3 g (3 mmol) of triethylamine, is slowly added 0.32 g (3 mmol) of ethyl chloroformate. The mixture is stirred overnight at room temperature then concentrated under reduced pressure. The product is dissolved in ethyl acetate, washed twice with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The oily residue is purified over 10 g of silica gel (eluant dichloromethane/methanol 95/5) to give 0.35 g (29%) of (3-{4-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]piperazin-1-yl}phenyl)carbamic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([Cl:14])[N:5]=[C:4]([S:15][CH3:16])[N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Cl:14][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)[N:3]=[C:4]([S:15][CH3:16])[N:5]=1
Reactant: CSc1nc(Cl)c(-c2ccccc2)c(Cl)n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1nc(Cl)c(-c2ccccc2)c(-c2ccc(Cl)cc2)n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 35.1 %

Procedure:
To a mixture of 4,6-dichloro-2-(methylthio)-5-phenylpyrimidine (2.71 g, 10.0 mmol), 4-chlorophenylboronic acid (1.72 g, 11.0 mmol) and tetrakis(triphenylphosphine)palladium (578 mg, 0.50 mmol) in toluene (25 mL) at room temperature under argon was added aqueous Na2CO3 solution (2 M, 10 mL, 20.0 mmol). The resulting reaction mixture was stirred at 100° C. under argon for 6 h, after which time analysis by HPLC/MS indicated that the reaction was complete. After cooling the reaction mixture to room temperature, water (50 mL) was added. The resulting mixture was extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NaCl, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to obtain 1.22 g of the title compound as a white solid. HPLC/MS: retention time=4.32 min, [M+H]30 =347.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:5]=[C:4]([N+:12]([O-])=O)[N:3]=1>C(O)C.[Pd]>[NH2:12][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([O:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:5]=1
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])nc1C
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Oc1ccc(N)nc1C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 94.4 %

Procedure:
Acetic acid 2-methyl-6-nitro-pyridin-3-yl ester (0.30 g, 1.53 mmol) was dissolved in ethanol. 10% Pd/C (0.04 g, 0.38 mmol) was added, and the mixture was put under an atmosphere of hydrogen and stirred vigorously for 50 min at room temperature. The catalyst was filtered off, washing with ethanol, and the solvent removed under vacuum to yield acetic acid 6-amino-2-methyl-pyridin-3-yl ester (0.24 g, 95%) as a white solid, MS (ISP): m/e=166.2 (M+), which was used crude.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[OH:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[C:34]([CH3:41])[CH:33]=1)=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=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>[C:13]([O:12][C:11]([N:10]([CH2:18][C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[OH:20])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:30]([O:29][CH3:28])=[O:31])=[CH:33][C:34]=2[CH3:41])=[CH:3][CH:4]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)c(C)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of tert-butyl [2-(4-bromophenyl)ethyl]-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (400 mg) in 1,2-dimethoxyethane (6 ml) was added (4-methoxycarbonyl-2-methylphenyl)boronic acid (171 mg), tetrakis(triphenylphosphine)palladium (55 mg) and aqueous solution of sodium carbonate (2M, 0.92 ml), and the mixture was stirred at 80° C. for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give methyl 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]ethyl]-2-methyl-1,1′-biphenyl-4-carboxylate (320 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:26]3[S:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)[OH:25])=[C:11]([C:35]3[CH2:39][CH2:38][CH2:37][CH:36]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I:40]I.C(=O)(O)[O-].[Na+]>O1CCCC1.C(#N)C.C(OCC)C>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]3[C@@H:24]([C:26]4[S:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=4)[O:25][C:35]4([CH2:39][CH2:38][CH2:37][CH:36]4[I:40])[C:11]=3[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)c1nc2c(c(C3=CCCC3)c1[C@H](O)c1ccc(C(F)(F)F)s1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)s1)OC31CCCC1I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
To a solution of 67 mg (S)—((S)-5-(tert-butyldimethylsilyloxy)-4-cyclopentenyl-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(5-(trifluoromethyl)thiophen-2-yl)methanol in 1 ml tetrahydrofurane and 1 ml acetonitrile are added under nitrogen 29 mg sodium bicarbonate and a solution of 88 mg of iodine in 200 μl tetrahydrofurane and the reaction is monitored by thin layer chromatography. In the case of low conversion the same amounts of sodium bicarbonate and iodine solution are added up to two times. The mixture is then diluted with diethylether and washed with saturated aqueous sodium sulfite solution and brine. After drying with sodium sulphate the solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 98:2 to 80:20).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23](O)=[O:24])[NH:18]4)=[CH:10][O:11][C:7]=2[CH:6]=[C:5]([O:26][CH3:27])[CH:4]=1.Cl.Cl.Cl.[NH2:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]2)[CH2:34][CH2:33]1>>[OH:46][CH:43]1[CH2:42][CH2:41][N:40]([CH2:39][CH2:38][N:35]2[CH2:34][CH2:33][CH:32]([NH:31][C:23]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[C:14]([O:13][CH2:12][C:9]3[C:8]5[C:3]([O:2][CH3:1])=[CH:4][C:5]([O:26][CH3:27])=[CH:6][C:7]=5[O:11][CH:10]=3)[CH:22]=[CH:21][CH:20]=4)=[O:24])[CH2:37][CH2:36]2)[CH2:45][CH2:44]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: COc1cc(OC)c2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Agent: Cl
Product: COc1cc(OC)c2c(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CCC(O)CC6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-(4,6-dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 126 (see example 99) and amine 21.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[NH2:13][C:14]([CH3:25])([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1)[CH3:15]>C(O)C>[CH3:25][C:14]([NH:13][CH2:12][C@@H:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[N:2][N:1]=2)[CH:9]=1)[OH:11])([CH3:15])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: CC(C)(N)CCc1cccc(O)c1
Solvent: CCO
Product: CC(C)(CCc1cccc(O)c1)NC[C@H](O)c1ccc2nnnn2c1
Yield: 36.9 %

Procedure:
A solution of 194 mg (1.21 mmol) of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane and 195 mg of 2-amino-2-methyl-4-(3-hydroxyphenyl)butane in 25 ml of absolute ethanol was heated at reflux for 6.5 hours. The reaction mixture was concentrated and the residue chromatographed on silica gel (4:1:2:1 ethyl acetate:n-propanol:water:ammonium hydroxide) to give 137 mg of product.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)([N:15]1C=CN=C1)=O.N>O1CCCC1>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:15])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: N
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Ex-92A: To a solution of 4-acetyl-benzoic acid (0.5 g, 3.05 mmol) in tetrahydrofuran (10 mL) was added carbonyldiimidazole (0.74 g, 4.75 mmol). The solution was allowed to stir at ambient temperature for one hour and cooled to 0° C. followed by addition of ammonia (28% in water, 3 mL, 21 mmol). The solution was continued to stir at 0° C. for another one hour. The solvent was removed under reduced pressure. The residue was treated with water, filtered, washed with water, dried in vacuo to give 4-acetyl-benzamide (0.25 g, 50%) as a white solid. 1H NMR (DMSO-d6) δ 8.11 (bs, 1H), 8.00 (d, J=9 Hz, 2H), 7.95 (d, J=9 Hz, 2H), 7.53 (bs, 1H), 2.59 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[C:15]1([CH:12]2[CH2:13][CH2:14][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]([F:33])([F:32])[F:21])=[CH:3][CH:4]=3)=[O:9])[CH2:11]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1ccc(Br)cc1)N1CCC(c2ccccc2)C1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2ccccc2C(F)(F)F)cc1)N1CCC(c2ccccc2)C1
Temperature: 120 °C

Procedure:
The above compound could be made in the following manner: 1 eq. of (4-Bromo-phenyl)-(3-phenyl-pyrrolidin-1-yl)-methanone would be combined with 1.5 eq. of 2-(Trifluoromethyl)phenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine)palladium(0), 6.7 eq. of 2M sodium carbonate solution, toluene and ethanol. The reaction mixture would be heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture would be filtered through Celite and concentrated in vacuo. The residue would be diluted with water and extracted with ethyl acetate. The combined organic phases would be washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material would be purified by flash chromatography to afford product.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH2:13][C:14]([O:16]CC)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=[N:3]1.[OH-].[Na+]>CO>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=[N:3]1
Reactant: CCOC(=O)Cc1cccc(-c2ccnn2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nccc1-c1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(3-(1-methyl-1H-pyrazol-5-yl)phenyl)acetate (300 mg, 1.2 mmol) in MeOH (6 mL) was added aqueous NaOH (1.5 mL, 40 W %). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and the residue dissolved in water and adjusted pH to 5-6 with 2N of HCl. The solution was then extracted with EtOAc and the combined organic layers were concentrated to give the crude product which was used directly in the next step. LCMS (m/z): 231.1 (M+1).
Reaction SMILES: [K+].[K+].O[C:4]1[C:14](N(CC(O)=O)C)=[CH:13][CH:12]=[CH:11][C:5]=1[CH2:6][CH2:7][C:8]([O-:10])=O.OC1[C:32]([N:33](CC(O)=O)[CH3:34])=CC=CC=1CCC([O-])=O>CO>[OH:10][C:8]1[CH:7]=[C:6]([C:5]2[CH:4]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:33]([CH3:34])[CH:32]=1
Reactant: CN(CC(=O)O)c1cccc(CCC(=O)[O-])c1O
Agent: [K+]
Solvent: CO
Product: Cn1cc(O)cc1-c1ccccc1
Reaction time: 0.25 h

Procedure:
To a mixture of deoxygenated methanol (15.5 ml) and 3-acetoxy-1-methyl-5-phenylpyrrole (5) (1.3 g, 6.2 mmole), under argon, was added deoxygenated NaOH (2N, 12.5 ml). The reaction mixture was stirred in an icebath for 15 minutes. Then deoxygenated citric acid (2M, 7 ml) was added and the resulting mixture was stirred and an ice bath for 8 minutes. The reaction mixture was concentrated under reduced pressure, then 20 ml of water was added and was extracted twice with ethylacetate (EtOAc) (50 ml). The EtOAc layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to give 3-hydroxy-N-methyl-5-phenylpyrrole (7) as an orange residue. Under argon, a cold solution of anhydrous THF (12.4 ml), pyridine (0.6 ml, 7.4 mmole, 1.2 eq) and trifluoroacetic acid (1.2 ml, 15 mmole, 2.4 eq) was added to the orange residue, followed immediately by the addition of a solution of freshly prepared N-tosyl-L-alaninyl chloride (1.2 g, 7.4 mmole, 1.2 eq) in anhydrous THF 12.4 ml). The resulting mixture was stirred for one hr at 0° C. Then the reaction was quenched by the addition of aqueous citric acid (1M, 5 ml) and EtOAc (30 ml). After a brief mixing, the layers were separated and the organic layer was successively washed with saturated NaCl solution, twice with 5% NaHCO3 solution and again with saturated NaCl solution. the EtOAc extract was then dried over MgSo4, treated with Norit 211, filtered and concentrated under reduced pressure to give the crude product (8) as an orange residue. This was dissolved in hexane:EtOAc (1:1) (5 mL) and chromatographed on a column (SiO2, 100 g) by elution with hexane:EtOAc (7:3) to give 1 g of (8) as a thick light orange oil. A portion of this crude product was further purified by semi-preparative HPLC (column, IBM silica, 1 cm×25 cm; mobile phase, hexane:EtOAc 8:2; flow rate, 4.0 ml/min; pressure, 0.2 psi) to yield a honey color thick oil (8)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14]>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[NH2:8]
Reactant: CS(=O)(=O)CCc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CCc1ccc(N)cc1F
Reaction time: 2 h
Yield: 96 %

Procedure:
2-Fluoro-1-(2-(methylsulfonyl)ethyl)-4-nitrobenzene (700 mg, 2.83 mmol) was dissolved in ethyl acetate (7 mL), and to the solution was added (10%) Pd/C (70 mg) under argon atmosphere which was subjected to hydrogenation in a Parr apparatus and the reaction was continued to stir for 2 h. The reaction mixture was filtered through celite and was washed thoroughly with ethyl acetate and was concentrated under reduced pressure to obtain 3-fluoro-4-(2-(methylsulfonyl)ethyl)aniline (590 mg, 96%).
Reaction SMILES: [CH2:1]([N:8]([CH3:27])[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]12[O:26][CH2:25][CH2:24][CH2:23][O:22]1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[CH2:29]([N+:36](C)(C)C)[C:30]1C=CC=C[CH:31]=1.C(#N)C=C>CCO>[CH2:1]([N:8]([CH3:27])[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:31][CH2:30][C:29]#[N:36])[C:16](=[O:21])[C:15]12[O:26][CH2:25][CH2:24][CH2:23][O:22]1)(=[O:10])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCO
Solvent: C=CC#N
Product: CN(Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2CCC#N
Temperature: 78 °C
Yield: 348.7 %

Procedure:
A mixture of N-benzyl-N-methyl-2′-oxo-1′,2′-dihydrospiro[1,3-dioxane-2,3′-indole]-5′-sulfonamide (1.00 g, 2.57 mmol) and benzyltrimethylammonium hydroxide (40% aqueous sol'n, 0.112 mL, 0.617 mmol, 0.24 mole % ) in absolute EtOH (20 mL) was heated to 78° C. and acrylonitrile (0.424 mL, 6.44 mmol, 2.5 eq) was added drop-wise. The reaction mixture was heated for 40 minutes longer, cooled to room temperature and filtered. The product was washed with ethanol and dried to give the title compound as a white solid (0.95 g, 84% yield). NMR (300 MHz, DMSO-d6): consistent.
Reaction SMILES: CO[CH2:3][C:4]1[N:39]=[C:7]2[N:8]([CH:35]([CH3:38])[CH2:36][CH3:37])[C:9](=[O:34])[C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[N:6]2[N:5]=1.B(Br)(Br)[Br:41].C(=O)([O-])O.[Na+].Cl>ClCCl>[Br:41][CH2:3][C:4]1[N:39]=[C:7]2[N:8]([CH:35]([CH3:38])[CH2:36][CH3:37])[C:9](=[O:34])[C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[N:6]2[N:5]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C(C)CC)c2nc(COC)nn12
Reactant: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C(C)CC)c2nc(CBr)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 2 %

Procedure:
A mixture of 2-(methoxymethyl)-4-(1-methylpropyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.07 g), boron tribromide (1.0 M dichloromethane solution, 0.4 mL) and dichloromethane (5 mL) was stirred at room temperature for 2 hr, saturated aqueous sodium hydrogen carbonate (10 mL) was added, and the mixture was further stirred for 1 hr. The reaction mixture was adjusted to pH 5 with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.013 g, 2%).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:17]([OH:19])=O.CN(C)C=O.S(Cl)([Cl:27])=O>>[CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:17]([Cl:27])=[O:19]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1C2=O

Procedure:
30 g (0.12 mol) of 2-anthraquinonecarboxylic acid are suspended in 100 ml of thionyl chloride at 0° C., with exclusion of moisture. After 2 ml of N,N-dimethylformamide (DMF) have been added, the mixture is heated slowly to the reflux temperature. A clear solution is formed. Excess thionyl chloride is removed by distillation in vacuo, and the residue is recrystallised from toluene. 27 g of 2-anthraquinonecarboxylic acid chloride are obtained. A mixture of 17 g (0.15 mol) of hydroxyethyl methacrylate, 30 ml (0.2 mol) of triethylamine and 50 ml of methylene chloride is added dropwise to a solution of 27 g (0.1 mol) of 2-anthraquinonecarboxylic acid chloride in 200 ml of methylene chloride such that the temperature of the reaction mixture does not exceed 10° C. Acidified ice-water is then added and the organic phase is washed several times with water and sodium bicarbonate solution and dried over sodium sulfate. After the methylene chloride has been stripped off and the residue has been recrystallised from ethanol, the hydroxyethyl methacrylate of 2-anthraquinonecarboxylic acid is obtained in a yield of 72% of theory, melting point: 119°-120° C.