Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@:4]1(O)[C:9](=[CH2:10])[CH2:8][C@H:7]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:5]12[CH3:6])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[C:13](=[CH2:25])[CH2:12]3)(=[O:3])[CH3:2].CN(C)C.[C:31]1([S:37](Cl)(=[O:39])=O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>C(Cl)Cl>[CH2:25]=[C:13]1[C:14]2[C@:19]([CH3:20])([CH2:18][CH2:17][C:16](=[O:24])[CH:15]=2)[C@@H:21]2[C@H:11]([C@H:7]3[C@:5]([CH3:6])([CH2:23][CH2:22]2)[C:4]([C:1](=[O:3])[CH3:2])=[C:9]([CH2:10][S:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:39])[CH2:8]3)[CH2:12]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC(=C)[C@@]3(O)C(C)=O)[C@@]2(C)CCC(=O)C=C12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)C
Agent: Cl
Solvent: ClCCl
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(C(C)=O)=C(CS(=O)c4ccccc4)C[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Reaction time: 0.17 h

Procedure:
17α-Acetyl-17β-hydroxy-6,16-dimethyleneandrosta-4-en-3-one (VII, Preparation 5, 8.0 g) is dissolved in methylene chloride (66 ml) and cooled to -20°. Trimethylamine (2.56 ml) at -20° and methylene chloride (5 ml) are mixed and the trimethylamine mixture transferred by syringe to the steroid solution. To the cold steroid solution was added phenylsulfonylchloride (1.0 equivalence) by a syringe pump over 1 hr. TLC shows the reaction approximately 80-85% complete. Phenylsulfonylchloride (0.25 equivalence) was added over approximately 10 min, TLC showing the reaction to be approximately 95% complete. Phenylsulfonylchloride (0.10 equivalence) was then added for a total of 1.35 equivalence, at which time TLC shows the reaction to be complete. Hydrochloric acid (10%, 40 ml) was added all at once, the temperature now being 7°, and the mixture stirred for about 10 min. The phases are separated. The aqueus portion is back extracted with methylene chloride (10 ml). The organic extracts are washed with phosphate buffer (25 ml) and back extracted with methylene chloride (10 ml). The organic extracts are combined, dried over sodium sulfate overnight at 20°-25°. This mixture is filtered and the filtrate concentrated under reduced pressure to an oil, which is the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]2[CH:17]=[CH:18][O:19][C:4]=2[C:3]1=[O:20].[CH:21]1([CH2:24][O:25][C:26]2[C:27](I)=[N:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=2)[CH2:23][CH2:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:21]1([CH2:24][O:25][C:26]2[C:27]([C:6]3[C:5]4[CH:17]=[CH:18][O:19][C:4]=4[C:3](=[O:20])[N:2]([CH3:1])[CH:7]=3)=[N:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=2)[CH2:22][CH2:23]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccoc2c1=O
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(I)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cn1cc(-c2nc(S(C)(=O)=O)ccc2OCC2CC2)c2ccoc2c1=O
Temperature: 70 °C
Reaction time: 12 h
Yield: 62.3 %

Procedure:
A mixture of 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[2,3-c]pyridin-7-one (50 mg, 0.18 mmol), 3-(cyclopropylmethoxy)-2-iodo-6-methylsulfonylpyridine (53 mg, 0.15 mmol), K3PO4 (114 mg, 0.54 mmol), Pd(dppf)Cl2 (13 mg, 0.018 mmol) in dioxane (5 mL) was bubbled with nitrogen for 5 min and then stirred at 70° C. for 12 h. The reaction mixture was concentrated, treated with DCM (30 mL), washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (35 mg, yield: 52%) as an off-white solid.
Reaction SMILES: C[O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16]C)=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:30])=[CH:25][CH:24]=1)[CH2:7]2.N1C(C(O)=O)=CC=CC=1C(O)=O.C1COCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O>[CH3:13][O:12][C:11]1[C:3](=[O:2])[C:4]2[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:30])=[CH:25][CH:24]=3)[CH2:7][C:8]=2[C:9](=[O:16])[C:10]=1[O:14][CH3:15]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCOc1ccc(C(=O)N3CCOCC3)cc1)C2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: C1CCOC1
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCOc3ccc(C(=O)N4CCOCC4)cc3)C2)C1=O
Reaction time: 0.25 h
Yield: 68.5 %

Procedure:
To a mixture of 4,5,6,7-tetramethoxy-2-[4-[4-(morpholinocarbonyl)phenoxy]butyl]indan (1.50 g), pyridine-2,6-dicarboxylic acid (1.60 g), THF (30 ml), and water (15 ml) was added an water (15 ml) solution of CAN (7.02 g) with cooling with ice. After being stirred for 15 min, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was recrystallized from ethyl acetate to obtain the entitled compound (965 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[CH:25]1([O:30][C:31]2[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([O:30][C:31]2[N:36]=[CH:35][C:34]([N:7]3[C:8]4[C:13](=[CH:12][C:11]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][N:16]=5)=[CH:10][CH:9]=4)[CH:14]=[C:6]3[C:4]([OH:3])=[O:5])=[CH:33][CH:32]=2)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: OB(O)c1ccc(OC2CCCC2)nc1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(F)(F)F)cn3)ccc2[nH]1
Product: O=C(O)c1cc2cc(-c3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC2CCCC2)nc1

Procedure:
The title compound was prepared in accordance with Example 36(d) from 5-(5-trifluoromethylpyrid-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see Example 8(b)) and 6-cyclopentoxypyridine-3-boronic acid (see Example 36(c)), followed by ester hydrolysis (see Example 36(e)).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[F:39]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:35]4[CH:36]=[CH:37][C:38]([F:39])=[C:33]([F:32])[CH:34]=4)(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(F)c(F)c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3,4-difluoro-benzenesulfonyl chloride. Purity (ELSD, based on MW=597.6)=95%.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1.Cl[C:28]1[N:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:30][N:29]=1.BrC1C=NC(N2C3C(=CC=C(C(N4CCOCC4)=O)C=3)C(SC)=C2)=NC=1>>[CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)=[O:13])=[CH:9][CH:10]=2)[N:5]([C:28]2[N:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:32][N:33]=2)[CH:4]=1
Reactant: Clc1ncc(-c2ccccc2)cn1
Reactant: CSc1c[nH]c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc12
Agent: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Product: CSc1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc12

Procedure:
Prepared from the product of 12b) (1.2 g, 3.2 mmol, 1.0 eq) and 2-chloro-5-phenylpyrimidine (0.604 g, 3.2 mmol, 1.0 eq) following the instructions of 1c). Yield: 700 mg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[C:5]([C:4]1[CH:3]=[C:2]([O:1][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: N#Cc1cccc(O)c1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.1 %

Procedure:
A suspension of 3-hydroxybenzonitrile (5.00 g, 42.0 mmol) and 60% sodium hydride (oil dispersion, 2.01 g, 50.3 mmol) in DMF (200 mL) was stirred at room temperature for 30 min, ethyl 4-bromobutanoate (9.82 g, 50.3 mmol) was added thereto, and the mixture was stirred at room temperature for 15 hr. The mixture was allowed to cool to room temperature, and concentrated under reduced pressure. The residue was extracted with ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (0-10% ethyl acetate/hexane) to give the title compound as a colorless oil (10.2 g, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccccn1)c1ccc(N)cc1
Reaction time: 14 h

Procedure:
To a solution of tert-butyl (4-nitrophenyl)(pyridin-2-ylmethyl)carbamate, 11a, (0.58 g, 1.76 mmol) in methanol (17 mL) was added Pd/C (50 mg) and an atmosphere of H2 was applied. After 14 h, the r×n was filtered through a plug of Celite and concentrated. The residue, 12a, was carried on without further purification.
Reaction SMILES: O.[F:2][C:3]([F:43])([C:39]([F:42])([F:41])[F:40])[C:4]([F:38])([F:37])[C:5]([P:8]([C:24]([F:36])([F:35])[C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])([C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(F)F)([F:7])[F:6]>>[P:8]([C:5]([C:4]([C:3]([C:39]([F:40])([F:41])[F:42])([F:2])[F:43])([F:37])[F:38])([F:6])[F:7])([C:24]([C:25]([C:26]([C:27]([F:30])([F:29])[F:28])([F:32])[F:31])([F:34])[F:33])([F:36])[F:35])[C:11]([C:12]([C:13]([C:14]([F:17])([F:16])[F:15])([F:19])[F:18])([F:21])[F:20])([F:23])[F:22]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)P(F)(F)(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)P(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 120 °C
Reaction time: 7.5 h

Procedure:
0.28 g (15.5 mmol) of water is added to 14.04 g (19.3 mmol) of tris(nonafluorobutyl)difluorophosphorane, (C4F9)3PF2, in a 100 ml glass round-bottomed flask and warmed (120° C. oil-bath temperature). A cooled (−30° C. to −35° C.) intensive reflux condenser is connected downstream of the flask. Liquid SO2 (about 5 ml), which is slowly released into the system, is via a T-piece connected in between with connected Young trap. The emulsion is stirred at 120° C. for 7.5 h before the intensive condenser is warmed to −5° C. in order to discharge excess SO2 in gaseous form. Virtually complete consumption (98.4%) of (C4F9)3PF2 and formation of (C4F9)3P═O (78.0%), (C4F9)2P(O)OH (14.0%) can be detected. The entire suspension is condensed at 75° C. in vacuo (10−3 mbar). Clear and colourless (C4F9)3P═O (8.81 g; 12.5 mmol; 79%) can be isolated in 92% purity. Pure, crystalline, clear and colourless (C4F9)2P(O)OH can be isolated from the solid residue by sublimation at 75° C. in vacuo (10−3 mbar).
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[C:31](=[O:32])[N:23]3[CH:24]([C:29]#[N:30])[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:33]=[N+:34]=[N-:35].[Na+].CN1CCCCC1.Cl.CN1CCCCC1>C(O)C.O>[C:1]1([C:7]([NH:20][CH:21]2[C:31](=[O:32])[N:23]3[CH:24]([C:29]4[NH:35][N:34]=[N:33][N:30]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C#N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN1CCCCC1
Product: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Temperature: 25 °C

Procedure:
A mixture of 6-triphenylmethylamino-2,2-dimethyl-3-cyanopenam (4.39 g. 0.01 mole), anhydrous ethanol-free chloroform (20 ml.), powdered sodium azide (650 mg., 0.01 mole) and dry N-methylpiperidine (2.98 g., 0.03 mole) is heated to 58°-60° C. (internal temperature). To the mixture is added with stirring 5 ml. of a solution of dry N-methylpiperidine hydrochloride (1.5 g., 0.011 mole) in ethanol-free chloroform (20 ml.) every 15 minutes over a period of one hour. The mixture is stirred and heated for 1.5 hours at 58°-60° C. following the additions of N-methylpiperidine and is then charged with finely powdered sodium azide (650 mg.) and N-methylpiperidine hydrochloride (1.5 g., 0.011 mole) in ethanol-free chloroform (20 ml.). The reaction mixture is heated for an additional hour and is then cooled to room temperature and diluted with water (150 ml.) and ethanol-free chloroform (250 ml.). The mixture is thoroughly shaken and the chloroform phase then separated and washed with successively with 1N HCl (1 × 250 ml.) and water (1 × 150 ml.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:6][CH:7]=1.BrBr.BrC1C=CC2N=C(N)SC=2C=1>CC#N.C(O)(=O)C>[Br:1][C:2]1[C:3]2[S:10][C:9]([NH2:11])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1cccc(Br)c1
Agent: BrBr
Agent: Nc1nc2ccc(Br)cc2s1
Solvent: CC#N
Solvent: CC(=O)O
Product: Nc1nc2cccc(Br)c2s1
Temperature: 25 °C
Yield: 101.7 %

Procedure:
1-(3-Bromophenyl)-2-thiourea (Oakwood Products, Inc., West Columbia, S.C.; 2.479 g, 10.73 mmol) was suspended in MeCN (200 mL) and cooled in an ice water bath under nitrogen. Then, a solution of bromine (1.1 mL, 21 mmol) in acetic acid (10 mL) was added dropwise over 15 minutes. The reaction was stirred while being cooled in an ice water bath for 30 minutes, then allowed to warm to RT while stirring over the weekend. The resulting precipitate was filtered and the solid was washed with Et2O to afford the mixture (2.5 g, 100% yield) of 7-bromobenzo[d]thiazol-2-amine and 6-bromobenzo[d]thiazol-2-amine in a 1:2 ratio. MS (ESI pos. ion) m/z: 229 (MH+, 79Br), 231 (MH+, 81Br). Calculated exact mass for C7H5BrN2S: 228 (79Br), 230 (81Br).
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH:19]=[CH:20][C:21]([OH:23])=[O:22])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[F:32]>C1COCC1.C(OCC)(=O)C.[Pd]>[CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[F:32]
Reactant: COc1ccc(F)c(-c2ccc(COc3cc(C=CC(=O)O)nc(C)n3)nc2CC(C)(C)C)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(F)c(-c2ccc(COc3cc(CCC(=O)O)nc(C)n3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
To a solution of 3-(6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-2-methylpyrimidin-4-yl)acrylic acid (330 mg) in THF (5.0 mL) and ethyl acetate (5.0 mL) was added 10% palladium-activated carbon (30 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (153 mg) as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[CH:39]([O:38][C:36]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[C:17]([N+:18]([O-:20])=[O:19])=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[N:13]=[CH:14][N:15]=2)[CH2:23][CH2:24]1)=[O:37])([CH3:41])[CH3:40]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
General procedure for the syntheses of carbamates, pyridinamides, and sulfonamides. In a 16 mL reaction vessel was placed (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Comound A2) (42 mg, 0.1 mmol), triethylamine (90 μl) and DMF (1.5 mL) was added to completely dissolve the solid material. Isopropyl chloroformate (0.15 mL, 1.0M in toluene) was added to the solution and the mixture was stirred 30 min under N2 at room temperature. After all of the starting amine was completely converted as indicated by LCMS, the reaction was stopped by quenching with water. The reaction mixture was concentrated under vacuum and purified by preparative HPLC to give Compound A22, 1H NMR (CDCl3, 400 MHz) δ 1.26 (d,6H), 1.89 (m, 2H), 1.93 (m,2H), 3.07 (s, 3H), 3.63 (m, 2H), 3.67 (m, 2H), 4.94 (m, 1H), 5.61 (m, 1H), 7.87 (d, 2H), 7.97 (d, 2H), 8.40 (s, 1H), 10.18 (s, 1H). Exact mass calculated for C20H25N5O7S 479.15, found 480.4 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH2:9])[S:5][CH:6]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][N:9]2[C:13](=[O:14])[C:12]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]3[C:10]2=[O:15])[S:5][CH:6]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCc1cc(Br)cs1
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCc1cc(Br)cs1

Procedure:
A mixture of 2(4-bromo-2-thienyl)-ethylamine (37 g) and phthalic anhydride (26.7 g) in glacial acetic acid (500 ml) is heated at reflux over 15 hours. It is concentrated at reduced pressure, the residue is triturated with ethanol and collected. The solid is recrystallized from ethanol to afford N-[2-(4-bromo-2-thienyl)ethyl]-phthalimide, m.p. 115°-117°.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[C:21]([C:26]1[O:27][C:28]2[C:33]([C:34](=[O:44])[C:35]=1[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[C:32]([OH:45])[CH:31]=[C:30]([OH:46])[CH:29]=2)([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:21]([C:26]1[O:27][C:28]2[CH:29]=[C:30]([O:46][CH2:2][C:3]3[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]4[CH:18]=[CH:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)=[CH:5][CH:4]=3)[CH:31]=[C:32]([OH:45])[C:33]=2[C:34](=[O:44])[C:35]=1[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)([O:23][CH2:24][CH3:25])=[O:22]
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CCOC(=O)c1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1oc2cc(OCc3ccc(OCc4ccc5ccccc5n4)cc3)cc(O)c2c(=O)c1-c1ccc(OC)cc1

Procedure:
0.62 g of 2-(4-chloromethylphenoxy)methyl quinoline, 0.78 g of 2-carboethoxy-5,7-dihydroxy-4'-methoxy isoflavone and 0.31 g potassium carbonate are refluxed in 30 ml of acetone for 17 hours. The mixture was concentrated and the crude product purified by flash chromatography on silica gel and crystallized from toluene to give 2-carboethoxy-5-hydroxy-3-(4-methoxyphenyl)-7-(4-(quinolin-2- ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][C:24](O)=[O:25])[CH2:18][CH2:17]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(=S)=S>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:24](=[O:25])[CH2:23][CH2:22][CH:19]2[CH2:18][CH2:17][N:16]([C:8](=[O:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCC1CCN(C(=O)c2ccccc2)CC1
Reactant: Clc1ccccc1
Solvent: S=C=S
Product: O=C(CCC1CCN(C(=O)c2ccccc2)CC1)c1ccc(Cl)cc1
Yield: 187.6 %

Procedure:
The procedure is as in Example 1, starting from 18 g of chlorobenzene instead of 9.9 g of anisol, 350 ml of carbon disulfide instead of 157 ml and 35 g instead of 15.7 g of 3-(1-benzoyl 4-piperidyl) propionic acid. 40.1 g of crude 1-(4-chlorophenyl) 3-(1-benzoyl 4-piperidyl) 1-propanone are obtained in the form of an oil which crystallizes.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].Cl.[CH2:13]([N:15]=C=NCCCN(C)C)C.Cl.CN.C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH3:13])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N)c(C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 18.4 %

Procedure:
To a solution of 4-amino-3-methylbenzoic acid (1 equiv), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (1.2 equiv), methanamine hydrochloride (1.2 equiv) in DMF (1.3 M) was added sodium hydrogencarbonate (2 equiv). The reaction was stirred at 25° C. for 15 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-90% ethyl acetate (with 10% 1N ammonia in methanol) in hexane). Concentration of the desired fractions afforded the title compound (18.4% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.06 (s, 3 H) 2.71 (d, J=4.69 Hz, 3 H) 5.33 (s, 2 H) 6.56 (d, J=8.59 Hz, 1 H) 7.41 (dd, J=8.39, 2.15 Hz, 1 H) 7.45 (s, 1 H) 7.87-7.99 (m, 1 H); MS (ESI) m/z 165.4 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[N:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1>C(OC(=O)C)(=O)C>[N+:11]([C:8]1[CH:7]=[C:4]([CH:5]=[CH:20][C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[CH:3]=[C:2]([OH:1])[C:9]=1[OH:10])([O-:13])=[O:12]
Reactant: Cc1ccncc1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cc(C=Cc2ccncc2)cc(O)c1O

Procedure:
A solution containing 2.0 g (0.011 mole) of 3,4-dihydroxy-5-nitrobenzaldehyde and 2.23 g (0,024 mole) of 4-picoline in9.0 ml of acetic anhydride was refluxed for 1 h. About 15 ml of isopropanolwas then added and the solution was cooled to 0° C. where upon the diacetyl-derivative of the desired product crystallized. After filtration the product was suspended in 100 ml of 0.5 N hydrochloric acid and refluxed for 1.5 h. After cooling the precipitate was filtered, washed with water and acetone and dried. Yield 1.89 g (67%), m.p. above 350° C.