Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[O:17][N:16]=[C:15]([CH:18]([OH:20])[CH3:19])[N:14]=2)[CH:10]=[CH:11][CH:12]=1>C(Cl)Cl>[CH3:1][S:2]([O:20][CH:18]([C:15]1[N:14]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=2)[O:17][N:16]=1)[CH3:19])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1noc(-c2cccc(Cl)c2)n1
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1noc(-c2cccc(Cl)c2)n1
Reaction time: 0.25 h

Procedure:
Methane sulfonyl chloride (40 μl, 0.49 mmol) was added to a mixture of TEA (95 μl, 0.67 mmol) and 1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethanol (100 mg, 0.45 mmol) in DCM (5 ml). After stirring for 15 min the mixture was washed with water and brine, dried and concentrated and the title compound was obtained in 135 mg yield. 1H NMR: 1.9 (d, 3H), 3.1 (s, 3H), 5.9 (q, 1H), 7.5 (t, 1H), 7.6 (m, 1H), 8.0 (m, 1H), 8.1 (t, 1H)
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:18]([CH2:19][CH2:20][OH:21])[N:17]=[CH:16][N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:24][C:25]([OH:42])([CH3:41])[CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>>[OH:21][CH2:20][CH2:19][N:18]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[N:28][N:27]([CH2:26][C:25]([CH3:41])([OH:42])[CH3:24])[CH:31]=5)[CH:23]=[CH:22][C:5]=4[C:6]=3[N:7]=2)=[N:15][CH:16]=[N:17]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: OCCn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CCO)nc2-3)cn1

Procedure:
Following the procedure for 114, 2-[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-ethanol was reacted with 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 442. MS(ESI+) 453.1. 1H NMR (400 MHz, DMSO) δ 8.35 (d, J=8.3, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.42 (dd, J=8.3, 1.8, 1H), 7.30 (d, J=1.7, 1H), 4.94 (t, J=5.5, 1H), 4.89 (t, J=5.9, 2H), 4.71 (s, 1H), 4.39 (t, J=5.0, 2H), 4.04 (s, 2H), 3.91 (q, J=5.8, 2H), 3.44 (t, J=5.0, 2H), 1.10 (s, 6H)
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].CC1(C)C(C)(C)OB([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)O1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:2]2[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=2[C:4]#[N:5])=[CH:20][CH:21]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: N#Cc1c(Cl)cncc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: N#Cc1c(Cl)cncc1-c1ccc(N)cc1
Temperature: 85 °C
Yield: 35.2 %

Procedure:
The product from Example 1B (3 g, 17.3 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (4.18 g, 19 mmol), PdCl2dppf.CH2Cl2 (300 mg), and Na2CO3 (4.5 g) were combined in DMF (25 mL) and water (10 mL). The mixture was degassed with nitrogen and heated to 85° C. overnight The mixture was allowed to cool to room temperature and partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with hexanes:ethyl acetate (1:1) to provide 1.4 g of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.67 (s, 2H) 6.70 (d, J=8.48 Hz, 2H) 7.40 (d, J=8.82 Hz, 2H) 8.76 (s, 1H) 8.79 (s, 1H).
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:33][CH3:34])=[C:13]([CH:32]=1)[C:14]([NH:16][CH:17]1[CH:26](O)[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=2)[O:19][C:18]1([CH3:31])[CH3:30])=[O:15].S(=O)(O)[O-].[Na+]>C(#N)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:33][CH3:34])=[C:13]([CH:32]=1)[C:14]([NH:16][CH:17]1[CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=2)[O:19][C:18]1([CH3:30])[CH3:31])=[O:15]
Reactant: COc1ccc2c(c1)OC(C)(C)C(NC(=O)c1cc(Cl)ccc1OC)C2O
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])O
Agent: [I-]
Solvent: CC#N
Product: COc1ccc2c(c1)OC(C)(C)C(NC(=O)c1cc(Cl)ccc1OC)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
44 g (300 mmol) of sodium iodide and 38 ml (300 mmol) of chlorotrimethylsilane were added to 19.6 g (50 mmol) of 3-(5-chloro-2-methoxybenzamido)-2,2-dimethyl-7-methoxy-4-chromanol in 120 ml of acetonitrile. The temperature rose temporarily to 32° C. After the mixture had been stirred at about 25° C. for three hours, it was poured into ice/water, decolorized with concentrated sodium bisulfite solution and extracted several times with methylene chloride. The combined organic solutions were washed with water, dried and evaporated and the residue was chromatographed over a silica gel column using methylene chloride/ethyl acetate 95:5. The 3-(5-chloro-2-methoxybenzamido)-2,2-dimethyl-7-methoxychroman was obtained as an oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1.[Cl:27][CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>>[Cl:27][CH2:28][CH2:29][CH2:30][S:31]([N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1)(=[O:33])=[O:32]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCN(S(=O)(=O)CCCCl)CC2)c(F)c1

Procedure:
(5R)-3-(4-(1,2,5,6-Tetrahydropyridin-4-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (380 mg, 1 mM) was treated with 3-chloropropylsulfonyl chloride essentially as in Example 76. After the reaction, the precipitate was filtered, washed with water (10 ml), diethyl ether (2×10 ml), and dried to give the desired product (245 mg).
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[Sn](CCCC)(CCCC)CCCC)[CH3:2].Br[C:24]1[S:25][CH:26]=[CH:27][N:28]=1.C([O-])(O)=O.[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>[CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH3:2]
Reactant: Brc1nccs1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1COCC
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
Product: CCOCn1ccnc1-c1nccs1
Temperature: 25 °C
Yield: 26 %

Procedure:
A solution of crude 1-ethoxymethyl-2-tributylstannanyl-1H-imidazole (previous experimental), 2-bromothiazole (1.05 mL, 11.6 mmol, 1.0 eq based on integration of 1H NMR of crude 1-ethoxymethyl-2-tributylstannanyl-1H-imidazole), and Pd(PPh3)4 (0.67 g, 0.58 mmol) in toluene (20 mL) is stirred at 80° C. for 18 hours. After cooling to room temperature, the reaction mixture is poured into saturated aqueous NaHCO3 and extracted twice with CH2Cl2. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 2:1 hexanes-EtOAc (+0.5% Et3N). Fractions containing product are concentrated and resubjected to flash chromatography on silica gel. Elution with 2:1 hexanes-EtOAc (+0.5% Et3N) affords (26%) of 2-(1-ethoxymethyl-1H-imidazol-2-yl)-thiazole as a bright yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=3.2 Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 7.20 (d, J=1.2 Hz, 1H), 7.15 (d, J=1.2 Hz, 1H), 6.03 (s, 2H), 3.56 (q, J=7.2 Hz, 2H) 1.17 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH:12]1[NH:18][C:17](=[NH:19])[CH2:16][CH2:15][CH2:14][CH2:13]1)([O-])=O.[H][H]>C(O)C.[Pd]>[ClH:1].[ClH:1].[NH:19]=[C:17]1[NH:18][CH:12]([CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH2:2])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: N=C1CCCCC(Cc2ccccc2[N+](=O)[O-])N1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N=C1CCCCC(Cc2ccccc2N)N1
Yield: 155.9 %

Procedure:
The product of Example 270 (0.150 g, 0.59 mmol) was dissolved in ethanol and treated with 5% Palladium on Carbon under 5 psi of Hydrogen to give the title product (141 mg, 0.46 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.CI.[C:22](=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([N:12]3[CH2:17][CH2:16][N:15]([CH3:22])[CH2:14][CH2:13]3)[NH:8][S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1
Reactant: O=S1(=O)NC(N2CCNCC2)=Nc2ccc(Cl)cc21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCN(C2=Nc3ccc(Cl)cc3S(=O)(=O)N2)CC1
Reaction time: 2 h
Yield: 38.2 %

Procedure:
To a solution of 1.0 g of 7-chloro-3-(1-piperazinyl)-2H-1,2,4-benzothiadiazine 1,1-dioxide in 15 ml of dimethylformamide is added dropwise at 0° C. 0.56 g of 93% methyl iodide, in the presence of 0.7 g of anhydrous sodium carbonate. The mixture is stirred for 2 hours, while the temperature is kept at 0° C. After removal of dimethylformamide by distillation under reduced pressure, the resulting residue is triturated with 10 ml of water to precipitate the crystals. The collected precipitate is recrystallized from a mixture of dimethylformamide and water to give 0.4 g of the desired product, m.p. above 300° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12
Reactant: Brc1ccccn1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccccn4)c3n2)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 2-bromopyridine [CAS 109-04-6; commercially available] (237 mg, 1.5 mmol) according to general procedure II. Obtained as a yellow solid (345 mg, 80%). MS (ISP) 433.2 [(M+H)+]; mp 158-159° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O>>[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6]
Reactant: O=Cc1ccccc1O
Reactant: COC(=O)CN
Product: COC(=O)CNCc1ccccc1O
Yield: 40 %

Procedure:
Prepared as in example 10-10a from glycine methyl ester and 2-hydroxybenzaldehyde. Yield 40%. MS M+H calculated 196.1. found 196.1.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7](F)[CH:6]=1)[CH:2]=[CH2:3].[CH3:15][NH2:16]>C1COCC1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([CH:6]=1)[NH:16][CH3:15])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc([N+](=O)[O-])c(F)c1
Reactant: CN
Solvent: C1CCOC1
Product: C=CCOc1ccc([N+](=O)[O-])c(NC)c1

Procedure:
The title compound of Example 11 Step A (15.2 mmol, 3.01 g) was stirred in 15 mL of 2 M methylamine in THF at 0° C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was partitioned into DCM/brine. The organic phase was concentrated under reduced pressure affording the product as a bright yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.03 (d, 1H), 6.30-6.36 (overlapping m, 2H), 6.06 (m, 1H), 5.44 (m, 1H), 5.31 (m, 1H), 2.96 (d, 3H). MS (ESI): m/z 209 (M+H). HPLC A: 2.20 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:13]O.C([O-])=O.[Na+]>C(O)=O>[C:4]([C:3]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=1[OH:1])#[N:13]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: COc1ccc(O)c(C#N)c1
Yield: 51.5 %

Procedure:
To a solution of 2-hydroxy-5-methoxybenzaldehyde (4.00 g) in formic acid (30 ml) were added hydroxylamine hydrochloride (2.01 g) and sodium formate (3.22 g) at room temperature and the mixture was refluxed for 2 hours. The reaction mixture was concentrated. the residue was diluted with water and was extracted with t-butyl methyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with a mixture of t-butyl methyl ether and hexane to give the title compound (2.02 g) having the following physical data.
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH:8]([CH3:12])[CH2:9][CH:10]=[CH2:11])[CH2:3][C:4]([O:6]C)=[O:5]>[OH-].[K+].CO>[CH3:1][C:2]([OH:13])([CH:8]([CH3:12])[CH2:9][CH:10]=[CH2:11])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: C=CCC(C)C(C)(O)CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCC(C)C(C)(O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3,4-dimethyl-3-hydroxy-6-heptenoate (11.7 g, 62.8 mmol) was dissolved in a 2 N potassium hydroxide-methanol solution (44 mL), and the solution was stirred overnight at room temperature. The reaction solution was concentrated, then dissolved in water (30 mL), and washed with ether. The aqueous layer was made acidic (<pH=2) using aqueous hydrochloric acid, followed by two extractions with ethyl acetate. The ethyl acetate layer was washed with saturated saline, then dried, and then concentrated to obtain the compound of interest as an oil substance (10.1 g, 93%). This compound was used in the next reaction without being purified.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].I[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].CN(C)C=O>O1CCCC1.ClCCl>[CH3:15][CH:14]([CH3:16])[CH2:13][CH2:12][N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10]
Reactant: O=C1NC(=O)C2CC12
Reactant: CC(C)CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)CCN1C(=O)C2CC2C1=O
Reaction time: 0.08 h

Procedure:
Sodium hydride (0.11 g) was added to a solution of 3-azabicyclo[3.1.0]hexane-2,4-dione (0.3 g) in dry tetrahydrofuran (10 ml) under a nitrogen atmosphere at room temperature. The suspension was stirred for 5 minutes and 1-iodo-3-methylbutane (0.53 g) was then added in one portion to the reaction mixture. After stirring for two hours at room temperature, dimethylformamide (5 ml) was added and the reaction mixture was stirred for a further 16 hours at room temperature. The reaction mixture was diluted with dichloromethane and then partitioned with water (20 ml). The aqueous phase was extracted with dichloromethane (20 ml) and the combined organic extracts were washed with water (2×20 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography on silica gel (50 g) using 25% ethyl acetate/hexane as eluant to give the title compound as a colourless oil.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[CH2:16][CH:15]([CH2:17][NH2:18])[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23.C(N(CC)CC)C.[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl>CN(C=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[CH2:16][CH:15]([CH2:17][NH:18][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23
Reactant: O=C(O)c1ccccc1
Reactant: NCC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.7 %

Procedure:
A mixture of 8-bromo-5-aminomethyl-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione hydrochloride (134 mg, 0.405 mmol), triethyl amine (124 μL, 0.892 mmol), benzoic acid (54 mg, 0.446 mmol), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (69 mg, 0.446 mmol) and N-hydroxybenzotriazole (68 mg, 0.446 mmol) in DMF (6 mL) was stirred for 20 h at room temperature and 0.1N hydrochloric acid (20 mL) was added. The precipitates formed were collected by filtration, washed with distilled water, and dried in vacuo to give 87 mg of the title compound (52%): mp 180.5°~182° C.; 1H NMR (270 MHz, DMSO-d6) δ11.86 (s, 1H), 8.56 (t, 1H, J=6 Hz), 7.34~7.54 (m, 5H), 7.12 (s, 1H), 7.17 (s, 2H), 4.96~5.06 (m, 1H), 3.90~4.00 (m, 1H), 3.72~3.82 (m, 1H), 3.43 (dd, 1H, J=17, 10 Hz), 3.19 (dd, 1H, J=17, 3 Hz).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]1=[O:10].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH:20]=O)[CH:18]=2)[CH:13]=[N:12]1>CO.N1CCCCC1>[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](/[CH:20]=[C:3]3/[C:2](=[O:10])[NH:1][C:5]4[C:4]/3=[CH:9][CH:8]=[CH:7][N:6]=4)[CH:18]=2)[CH:13]=[N:12]1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: O=C1Cc2cccnc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2ncccc2/C1=C\c1ccc2cn[nH]c2c1
Temperature: 70 °C
Yield: 70.5 %

Procedure:
To a mixture of 1H-pyrrolo[2,3-b]pyridin-2(3H)-one (26.8 mg, 0.2 mmol) and 1H-indazole-6-carbaldehyde (29.2 mg, 0.2 mmol) in MeOH (2 mL) was added 1 drop of piperidine via syringe needle. The resulting mixture was refluxed for 2 h (oil temp. 70° C.) and then cooled to rt. The resulting precipitate was collected by suction filtration to give the title compound as a yellow solid (37 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H, NH), 11.25 (s, 1H, NH), 8.16 (s, 1H), 8.10 (d, J=5.2 Hz, 1H), 7.93-7.87 (m, 4H), 7.44 (d, J=8.8 Hz, 1H), 6.90 (dd, J=7.6 Hz, 5.6 Hz, 1H); MS ESI 263.0 [M+H]+, calcd for [C15H10N4O+H]+ 263.1.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([OH:15])[C:6]=1[C:16]([O-:18])=O)=[N+]=[N-].[H][H]>CN(C)C=O.[Pd]>[OH:15][C:7]1[C:6]2[C:16](=[O:18])[NH:1][CH2:4][C:5]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: [N-]=[N+]=NCc1c(C(=O)[O-])c(O)nc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C1NCc2c1c(O)nc1ccccc21
Yield: 30 %

Procedure:
0.27 g (0.0010 mol) of 4-azidomethyl-2-hydroxy-quinoline-3-carboxylate was dissolved in 20 ml of hot dimethylformamide and treated with 14 mg of 10% Pd/C. A stream of hydrogen was introduced slowly during 11/2 hrs. The suspension was filtered under argon and the filtrate was partially concentrated under a high vacuum. The residue was treated with 25 ml of de-gassed ethanol, filtered off, dried in a vacuum and there were obtained ~60 mg (30%) of 4-hydroxy-2,3-dihydro-1 H-pyrrolo[3,4-c]quinolin-3-one as an air-sensitive, grey solid. The mother liquor was concentrated totally. The residue was dissolved in 75 ml of methanol and a stream of oxygen was conducted in slowly during 21/2 hrs. The mixture was filtered, concentrated, chromatographed over silica gel with ethyl acetate/methanol 9:1 as the eluent and the product was recrystallized from hot ethyl acetate. Yield: 0.033 g (15%) of 4-hydroxy-2,3-dihydro-1H-pyrrolo[3,4-c]-quinoline-1,3-dione as yellow crystals; m.p. 340°-350° C. (dec., subl.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13].[CH2:15]([O:17][P:18]([CH2:23][PH:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:16].C(N(CC)CC)C>C(#N)C.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>[CH2:27]([O:26][P:24]([CH2:23][P:18]([O:17][CH2:15][CH3:16])([O:19][CH2:20][CH3:21])=[O:22])([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13])=[O:25])[CH3:28]
Reactant: CCO[PH](=O)CP(=O)(OCC)OCC
Reactant: CC1(C)CC(=O)Oc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(=O)(CP(=O)(OCC)c1ccc2c(c1)C(C)(C)CC(=O)O2)OCC
Temperature: 100 °C
Yield: 73.9 %

Procedure:
A mixture of 6-bromo-4,4-dimethylchroman-2-one (3.5 g, 9.7 mmol), diethyl(ethoxyphosphinyl)methylphosphonate (1.7 g, 9.7 mmol), triethylamine (4.1 mL, 29 mmol) and Pd(PPh3)4 (0.56 g, 0.48 mmol) in acetonitrile (20 mL) was heated to 100° C. for 18 hr. The reaction mixture was cooled and diluted with acetonitrile (50 mL) followed by washing with aqueous HCl (10%), water and saturated aqueous NaCl. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (0-10% methanol in CH2Cl2) on a Biotage™ flash chromatography system, resulting in 120 as pale yellow oil (3.0 g, 73%): 1H NMR (400 MHz, CDCl3) δ 1.21 (t, J=7.2, 3H), 1.30-1.37 (m, 6H), 1.40 (s, 6H), 2.61 (dd, J=1.7, 17.2, 20.7, 2H), 2.66 (s, 2H), 3.95-4.08 (m, 2H), 4.11-4.21 (m, 4H), 7.16 (dd, J=3.1, 8.3, 2H), 7.73 (dd, J=3.1, 8.3, 2H): 31P (162 MHz, CDCl3) δ 20.07 (d, J=7.7, 1 P), 33.74 (d, J=7.7, 1 P).
Reaction SMILES: [C:1]([C:5]1[NH:14][C:8]2=[CH:9][N:10]=[C:11](Cl)[CH:12]=[C:7]2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:15].O>>[C:1]([C:5]1[NH:14][C:8]2=[CH:9][N:10]=[C:11]([NH2:15])[CH:12]=[C:7]2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc2cc(Cl)ncc2[nH]1
Reactant: N
Solvent: O
Product: CC(C)(C)c1cc2cc(N)ncc2[nH]1
Temperature: 200 °C
Yield: 27 %

Procedure:
To a solution of 2-tert-butyl-5-chloro-1H-pyrrolo[2,3-c]pyridine (5.0 g, 24 mmol) in NH3.H2O (400 mL) was added CuSO4.5H2O (595 mg, 2.39 mmol). The mixture was heated at 200° C. (3 MPa pressure) for 24 h. After cooling, the mixture was extracted with CH2Cl2 (150 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give a residue, which was purified by column (petroleum ether/ethyl acetate=10/1) to obtain 2-tert-butyl-1H-pyrrolo[2,3-c]pyridin-5-amine (1.2 g, 27%). 1H NMR (400 MHz, DMSO) δ 10.66 (br s, 1H), 8.02 (s, 1H), 6.39 (s, 1H), 5.86 (d, J=1.2 Hz, 1H), 4.85 (br s, 2H), 1.29 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C:19]3[CH:30]=[CH:29][C:22]4[O:23][CH:24]([CH2:27][OH:28])[CH2:25][O:26][C:21]=4[CH:20]=3)=[N:14][CH:15]=2)[N:10]([CH3:31])[C:9]1=[O:32].[S:33](Cl)([C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)(=[O:35])=[O:34].N1C=CC=CC=1>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C:19]3[CH:30]=[CH:29][C:22]4[O:23][CH:24]([CH2:27][O:28][S:33]([C:36]5[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=5)(=[O:35])=[O:34])[CH2:25][O:26][C:21]=4[CH:20]=3)=[N:14][CH:15]=2)[N:10]([CH3:31])[C:9]1=[O:32]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1C(=O)N(c2ccccc2Br)Cc2cnc(Nc3ccc4c(c3)OCC(CO)O4)nc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC2COc3cc(Nc4ncc5c(n4)N(C)C(=O)N(c4ccccc4Br)C5)ccc3O2)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 26.4 %

Procedure:
520 mg of the product from example 1 were dissolved in 20 ml CHCl3. 213 mg tosyl chloride and 13 mg 4-dimethylaminopyridine were added and the mixture was cooled to 5° C. 166 mg pyridine were added dropwise and stirring was continued at room temperature for 3 hrs. The mixture was stirred 1 hr at 60° C., then another 105 mg tosyl chloride were added and stirring was continued at room temperature for 16 hrs. The mixture was diluted with 50 ml CHCl3 and washed with 0.5 M HCl, dried and evaporated. Chromatography on silica yielded 180 mg of the title compound.