Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[F:6][C:7]1[C:19]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[F:20])[C:11]=2[CH:10]=[CH:9][C:8]=1[OH:21].C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:2]([O:21][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:17](=[C:16]([F:20])[CH:15]=[CH:14][CH:13]=3)[CH2:18][C:19]=2[C:7]=1[F:6])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: Oc1ccc2c(c1F)Cc1c(F)cccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCOc1ccc2c(c1F)Cc1c(F)cccc1-2

Procedure:
56 mmol of 1-bromobutane are added to a mixture of 36 mmol of 1,8-difluorofluoren-2-ol and 109 mmol of anhydrous potassium carbonate in 250 ml of 2-butanone (methyl ethyl ketone) and the mixture is subsequently heated to reflux for 8 h. The still hot solution is then mixed with 50 ml of water. The phases are separated, the organic phase is washed with water and saturated sodium chloride solution and dried over sodium sulfate, and the solvent is removed on a rotary evaporator. The purification is effected by filtration through aluminum oxide (neutral) using toluene as the eluent and recrystallization from heptane. 2-Butoxy-1,8-difluorofluorene is obtained.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].P(=O)(O)(O)[OH:13]>C(OC(=O)C)(=O)C>[C:10]([C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)(=[O:13])[CH3:6].[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: O=P(O)(O)O
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)[c-]1cccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
A mixture of 93.0 g (0.5 mol) of ferrocene, 250 ml of acetic anhydride and 20 ml of 85% strength phosphoric acid was heated to 100° C. for 10 minutes, then cooled and added to ice. After standing overnight, the solid residue was filtered off and washed with water. For further purification, the residue was dissolved in cyclohexane, while warming, animal charcoal/Tonsil being added. The mixture was then filtered and the filtrate was evaporated to dryness under reduced pressure. 64 g (55.4% of theory) of acetylferrocene of melting point 84°-86° C. were obtained in this manner.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:36]=[CH:35][C:29]([CH:30]=[CH:31][C:32](O)=[O:33])=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH:30]=[CH:31][C:32]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:33])=[CH:35][CH:36]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(F)cc1
Yield: 74.7 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (4.0 g), triethylamine (4.8 mL), 4-fluorocinnamic acid (2.9 g), WSC.HCl (3.3 g), and methylene chloride (150 mL), to give the captioned compound (4.3 g, 74%) as an oily product.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:6](=[N:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][C:3]=1[NH2:12].O.O.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[OH:17][C:16]1[C:15]([OH:19])=[N:1][C:2]2[C:10]3=[N:9][N:8]([CH3:11])[N:7]=[C:6]3[CH:5]=[CH:4][C:3]=2[N:12]=1
Reactant: Cn1nc2ccc(N)c(N)c2n1
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: Cn1nc2ccc3nc(O)c(O)nc3c2n1
Yield: 30.1 %

Procedure:
A solution of 4,5-diamino-2-methylbenzotriazole (2.5 g, 15.3 mmol) and oxalic acid dihydrate (2.5 g, 19.8 mmol) in 80 ml of 4M hydrochloric acid was refluxed on an oil bath for 1 h. The cooled mixture was filtered, and the precipitate was washed with water and ethanol. Recrystallization from ethanol with decolourising charcoal afforded 1.0 g (30%) of the title compound; m.p.>300° C.; IR (KBr): 3500-2200, 1690 cm-1 ; 1H-NMR (DMSO-d6) 4.48 (s, 3H, CH3), 7.25 (d, J=9 Hz, 1H, ArH), 7.60 (d, J=9 Hz, 1H, ArH), 12.03 (broad s, 1H, OH), 12.47 (broad s, 1H, OH).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C@@H:11]1[CH2:16][N:15]([C:17]([O:19][CH3:20])=[O:18])[C@H:14]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[C@@H:13]([C:35](OC)=[O:36])[CH2:12]1)=[O:9].[OH:39][NH2:40].Cl.NO.C[O-].[Na+].Cl>CO>[OH:39][NH:40][C:35]([C@H:13]1[CH2:12][C@H:11]([O:10][C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[CH2:2][OH:1])=[O:9])[CH2:16][N:15]([C:17]([O:19][CH3:20])=[O:18])[C@@H:14]1[C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:22])=[O:36]
Reactant: COC(=O)[C@H]1C[C@H](OC(=O)N2CCC[C@H]2CO)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1C[C@@H](OC(=O)N2CCC[C@H]2CO)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of dimethyl (2S,3S,5S)-5-([(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]carbonyloxy)-2-[(4-phenylpiperazin 1-yl)carbonyl]piperidine-1,3-dicarboxylate (66 mg, 0.00012 mol) in methanol (0.57 mL, 0.014 mol) was added 1.640 M of N-hydroxyamine in methanol solution (1.511 mL), made from the hydroxylamine HCl salt and sodium methoxide freshly. The mixture was stirred at rt for 1 h and acidified with 1N HCl. The resulting mixture was applied directly on RP-HPLC to yield the desired compound (61 mg, 76%). MS (ESI): (M+H)+=534.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[O:11]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]3[C:22]4[O:35][C:34]5[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=5[C:23]=4[NH:24][C:25](=[O:32])[C:26]=3[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][C:15]=2[O:14][CH2:13][CH2:12]1>ClCCl.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>[O:11]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]3[C:22]4[O:35][C:34]5[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=5[C:23]=4[N:24]([CH2:5][C:4]4[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=4[O:2][CH3:1])[C:25](=[O:32])[C:26]=3[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][C:15]=2[O:14][CH2:13][CH2:12]1.[O:11]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]3[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([O:32][CH2:5][C:4]4[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=4[O:2][CH3:1])[N:24]=[C:23]4[C:33]5[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=5[O:35][C:22]=34)=[CH:20][C:15]=2[O:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)c1c(-c2ccc3c(c2)OCCO3)c2oc3ccccc3c2[nH]c1=O
Reactant: COc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc3c(c2)OCCO3)c2oc3ccccc3c2n(Cc2ccccc2OC)c1=O
Product: CCOC(=O)c1c(OCc2ccccc2OC)nc2c(oc3ccccc32)c1-c1ccc2c(c1)OCCO2
Reaction time: 10 h

Procedure:
A 50% solution of 1.8 g of 2-methoxybenzyl chloride ("A") in dichloromethane is added to a solution of 2.0 g of ethyl 4-(1,4-benzodioxan-6-yl)-1,2-dihydro-2-oxobenzofuro[3,2-b]pyridine-3-carboxylate (obtainable by reaction of 3-amino-2-(1,4-benzodioxan-6-carbonyl)benzofuran and diethyl malonate in acetone and potassium carbonate, m.p. 255°; 3-amino-2-(1,4-benzodioxan-6-carbonyl)benzofuran is obtainable by reaction of 2-hydroxybenzonitrile and 6-bromoacetyl-1,4-benzodioxane, m.p. 157°) in 15 ml of DMF and 2.5 g of caesium carbonate. The reaction mixture is stirred for 10 hours and worked up in the customary manner. The N-alkylation product ethyl 4-(1,4-benzodioxan-6-yl)-1,2-dihydro-1-(2-methoxybenzyl)-2-oxobenzofuro[3,2-b]pyridine-3-carboxylate, m.p. 105° and the O-alkylation product ethyl 4-(1,4-benzodioxan-6-yl)-2-(2-methoxybenzyloxy)benzofuro[3,2-b]pyridine-3-carboxylate, m.p. 166°, are obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][N:16](C(OCC)=O)[CH2:15][CH2:14]3)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C.O>[C:1]1([C:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)N1CCN(c2ncc(-c3ccccc3)cn2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(-c2cnc(N3CCNCC3)nc2)cc1

Procedure:
0.04 mol of ethyl 1-(5-phenyl-2-pyrimidinyl)-4-piperazinecarboxylate are boiled under reflux with 0.78 mol of KOH in 400 ml of C2H5OH and 40 ml of H2O under N2 protective gas for 15 hours. The mixture is evaporated to dryness, water is added and the residue is taken up in CH2Cl2. After washing with water, the organic phase is separated off and evaporated to dryness, whereupon the amine is obtained as crystals.
Reaction SMILES: [C:1]1([C:7]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([OH:28])[C:25]=1[O:26][CH3:27])[C:20](O)=[O:21].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CO.ClCCl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([OH:28])[C:25]=1[O:26][CH3:27])[C:20]([N:9]1[CH2:10][CH2:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:21]
Reactant: COc1cc(C(=O)O)cc(O)c1OC
Reactant: OCCC1(c2ccccc2)CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(O)c1OC
Reaction time: 18 h

Procedure:
Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.50 g, 2.7 mmol) (prepared by extraction from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and dichloromethane (25 mL). Add 3,4-dimethoxy-5-hydroxybenzoic acid (0.55 g, 2.78 mmol), 1-hydroxybenzotriazole hydrate (0.4 g, 2.9 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.56 g, 2.9 mmol). After 18 hours, dilute the reaction mixture with dichloromethane and extract with saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give residue. Chromatograph the residue on silica gel eluting with methanol/dichloromethane/concentrated aqueous ammonia 1/10/0.1 to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][NH2:9].[NH2:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([NH2:27])=[C:13]2[C:28](=[O:32])N[C:30](=[O:31])[C:12]=12.N>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][N:9]1[C:28](=[O:32])[C:13]2[C:12](=[C:11]([NH2:10])[C:24]3[C:23](=[O:25])[C:22]4[C:17]([C:16](=[O:26])[C:15]=3[C:14]=2[NH2:27])=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:30]1=[O:31]
Reactant: COCCOCCCN
Reactant: Nc1c2c(=O)[nH]c(=O)c2c(N)c2c(=O)c3ccccc3c(=O)c12
Agent: N
Product: COCCOCCCn1c(=O)c2c(N)c3c(=O)c4ccccc4c(=O)c3c(N)c2c1=O
Temperature: 40 °C
Yield: 126.6 %

Procedure:
477.2 g of 3-(2-methoxyethoxy)propylamine are charged to a 750 ml sulfonating flask equipped with paddle stirrer and heated to 40° C. With stirring, 141.2 g of 1,4-diaminoanthraquinone-2,3-dicarboximide are added over 11/4 hours. The ensuing reaction is slightly exothermic, with evolution of NH3. The reaction mixture is heated to 40° C. and further stirred at this temperature for 2 hours. The suspension is then cooled to 20° C. and stirred for a further hour at this temperature and filtered with suction. The filter cake is washed with 300 ml of methanol and then with 300 ml of water, affording 246.3 g of N-[3-(2-methoxyethoxy)propyl]-1,4-diaminoanthraquinone-2,3-dicarboximide with a solids content of 74.7%, corresponding to 180.1 g of this compound (100%). After optional replenishment with fresh 3-(2-methoxyethoxy)propylamine, the mother liquor can be re-used repeatedly.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]([C:15]1[S:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:16]=1[S:24](Cl)(=[O:26])=[O:25])[CH2:12][CH2:13][CH3:14]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:24]([C:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[S:19][C:15]=1[CH2:11][CH2:12][CH2:13][CH3:14])(=[O:25])=[O:26]
Reactant: CCCCc1sc2ccccc2c1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1sc2ccccc2c1S(=O)(=O)Nc1onc(C)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-butylbenzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5 mmoles, 100 mg), 2-n-butylbenzo[b]thiophene-3-sulfonyl chloride (1.2 mmoles, 0.35 g) and THF (6 ml). Recrystallization from ethyl acetate and hexanes provided 0.24 g (56%) of a yellow solid, m.p. 124.5°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CCOC(C)=O>[CH3:16][O:15][N:14]([CH3:13])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a suspension of 3,4-dichlorobenzoic acid (1.0 g, 5.24 mmol) in CH2Cl2 (25 mL) was added N,O-dimethylhydroxylamine hydrochloride (613 mg, 6.28 mmol) followed by N-methylmorpholine (865 μL, 7.85 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.28 mmol) at which point the reaction mixture became homogeneous. After 2 h, the reaction mixture was diluted with EtOAc and washed with 1N HCl, H2O, saturated NaHCO3 solution and brine, sequentially. The organic layer was dried over Na2SO4, and the removal of solvent in vacuo gave the title compound (1.16 g) that required no further purification.
Reaction SMILES: F[C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]1.C[O-].[Na+].O.[C:26](OCC)(=[O:28])C>CN(C)C=O.CO>[CH3:26][O:28][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]1
Reactant: CCOC(C)=O
Reactant: CCCN1CCC(c2cccc(OC(F)(F)F)c2F)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CCCN1CCC(c2cccc(OC(F)(F)F)c2OC)CC1
Temperature: 150 °C

Procedure:
To a solution of 4-[2-fluoro-3-(trifluoromethoxy)phenyl]-1-propylpiperidine (1.92 g, 6.3 mmol) in N,N-dimethylformamide (20 ml) was added a solution of sodium methoxide in methanol (30%, 3 ml) and the mixture was heated to 150° C. for 1 h. Water (50 ml) and ethyl acetate (50 ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic phases was dried (MgSO4) and evaporated under reduced pressure to give an oil. The residue was purified by flash column chromatography (ethyl acetate/methanol, 1:1) to give the title compound (1.32 g). MS m/z (rel. intensity, 70 eV) 317 (M+, 6), 289 (17), 288 (bp), 204 (6), 175 (8).
Reaction SMILES: S1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].Cl.NCCC(OC)=[O:19].C(=O)C1OC=CC=1>>[O:19]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CCN
Reactant: COC(=O)CCNCc1cccs1
Agent: Cl
Solvent: O=Cc1ccco1
Product: COC(=O)CCNCc1ccco1

Procedure:
Methyl 3-[(2-furanylmethyl)amino]propanoate (22) was prepared in the manner methyl 3-[(2-thienylmethyl)amino]propanoate (15) was prepared, as described above in Example 15, on a 6.5 mmol scale from methyl β-alaninate hydrochloride and furfural to yield 0.28 g (28%) of product.
Reaction SMILES: COCCOC.[CH3:7][O:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:24]([O:31][C:32]1[CH:51]=[CH:50][C:49]([CH:52]2[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]2)=[CH:48][C:33]=1[C:34]([NH:36][C:37]1[CH:46]=[C:45](Br)[CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40])=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O>[CH2:24]([O:31][C:32]1[CH:51]=[CH:50][C:49]([CH:52]2[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]2)=[CH:48][C:33]=1[C:34]([NH:36][C:37]1[CH:46]=[C:45]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH3:7])[CH:14]=2)[CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40])=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1cc(C2CCN(C)CC2)ccc1OCc1ccccc1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(-c2cccc(OC)c2)cc1NC(=O)c1cc(C2CCN(C)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
Ethylene glycol dimethyl ether (0.90 mL), water (0.27 mL), 3-methoxyphenylboronic acid (0.030 g), sodium carbonate (0.044 g), and bis(triphenylphosphine)palladium(II) dichloride (2.3 mg) were added to methyl 2-(2-(benzyloxy)-5-(1-methylpiperidin-4-yl)benzamido)-4-bromobenzoate (0.090 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-92% chloroform/methanol] to obtain 0.093 g of methyl 2-(2-(benzyloxy)-5-(1-methylpiperidin-4-yl)benzamido)-4-(3-methoxyphenyl)benzoate as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21](Cl)[N:20]=1.[H-].[Na+].[CH3:31][CH:32]([OH:34])[CH3:33]>>[CH:32]([O:34][C:21]1[N:20]=[C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=1)([CH3:33])[CH3:31]
Reactant: CC(C)O
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1ccc([N+](=O)[O-])c(Nc2ccc3[nH]cc(CC4CCCN4C)c3c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 2,6-dichloro-3-nitropyridine were used. No base was used, and 2-propanol was used as solvent. This reaction mixture was stirred at room temperature was 1 hour. Then a solution of sodium hydride (5 eq) in 2-propanol was added dropwise to the above reaction mixture with cooling at 0° C. The resulting reaction mixture was stirred at room temperature under nitrogen for 2.5 hours. The reaction mixture was then evaporated under reduced pressure. Column chromatography of the residue afforded the title compound (42%) as an orange amorphous solid: 1H NMR (CDCl3) δ10.6 (br s, NH), 8.57 (br s, NH), 8.37 (d, J=9.2 Hz, 1H), 7.71 (s, 1H), 7.34-7.28 (m, 2H), 7.05 (d, J=2.0 Hz, 1H), 6.08 (d, J=9.2 Hz, 1H), 5.14 (sept, J=6.2 Hz, 1H), 3.18-3.10 (m, 2H), 2.61 (dd, J=14.0 and 9.4 Hz, 1H), 2.54-2.45 (m, 1H), 2.44 (s, 3H), 2.23 (dd, J=17.2 and 9.3 Hz, 1H), 1.90-1.53 (m, 4H), 1.25 (d, J=6.1 Hz, 3H), 1.24 (d, J=6.2 Hz, 3H); 13C NMR (CDCl3) δ166.3, 151.8, 138.1, 134.1, 129.5, 127.9, 123.1, 121.7, 119.2, 114.2, 113.9, 111.0, 102.8, 70.4, 66.4, 57.5, 40.8, 31.5, 29.9, 21.9, 14.0, 11.0; FAB HRMS calculated for [C22H27N5O3.H]410.2194, found 409.2187.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[C:21]([F:24])([F:23])[F:22].C(N(CC)CC)C.[C:33]1(=[O:38])[CH2:37][CH2:36][CH:35]=[CH:34]1>O1CCOCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:35]2[CH2:36][CH2:37][C:33](=[O:38])[CH2:34]2)=[CH:8][C:7]=1[C:21]([F:22])([F:23])[F:24]
Reactant: COC(=O)CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Reactant: O=C1C=CCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc([C@H]2CCC(=O)C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
[Rh(S-BINAP)(nbd)]BF4 (0.03 mmol) and 3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluoromethyl-phenyl]-propionic acid methyl ester (preparation 2) (1.5 mmol) were added to a 25 mL-flask containing a magnetic stirring bar and a septum inlet. The flask was flashed with argon. Triethylamine (1.5 mmol) and 2-cyclopenten-1-one (1.0 mmol) dissolved in aqueous 1,4-dioxane (6/1, 3 mL) were then added. The mixture was stirred for 6 h at 25° C. Brine was added, the mixture was extracted with ethyl acetate, and the solvents were removed in vacuo to afford the title compound.
Reaction SMILES: [NH:1]([C:3]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)=[O:4])[NH2:2].[CH3:10]OC(OC)N(C)C.C(OCC)C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[N:6]1[CH:7]=[CH:8][N:9]2[C:5]=1[C:3](=[O:4])[NH:1][N:2]=[CH:10]2
Reactant: COC(OC)N(C)C
Reactant: NNC(=O)c1ncc[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Product: O=c1[nH]ncn2ccnc12
Temperature: 100 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
2-Hydrazinocarbonylimidazole (prepared according to the procedure described in EP-A-0713876) (1.00 g, 7.93 mmol) was suspended in Dowtherm A (6 ml), N,N-dimethylformamide dimethyl acetal (1.89 g, 15.9 mmol) added and the mixture heated at 100° C. for 1.5 h then at 210° C. for 18 h. The mixture was allowed to cool to room temperature, diethyl ether (100 ml) added and the precipitated solid was filtered. The brown solid was purified by dry flash column chromatography on silica eluting with dichloromethane (+0.1% 0.880 ammonia) on a gradient of methanol (5-12%). Collecting appropriate fractions gave 7H-imidazo[1,2-d][1,2,4]triazin-8-one (216 mg, 20%) as an off-white solid: δH (400 MHz, CDCl3) 7.59 (1H, d, J 1), 7.91 (1H, d, J 1), 8.74 (1H, s), 12.39 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(#N)C>[CH:15]1([NH:20][C:13]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])(=[O:10])=[O:11])=[O:14])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C=NS(=O)(=O)c1cccc(Cl)c1Cl
Reactant: NC1CCCC1
Solvent: CC#N
Product: O=C(NC1CCCC1)NS(=O)(=O)c1cccc(Cl)c1Cl
Reaction time: 8 h

Procedure:
To 20 mL of the acetonitrile solution containing 2,3-dichlorobenzenesulfonyl isocyanate, prepared as described in the previous example, was added 2.5 mL of cyclopentylamine. This mixture was allowed to sit overnight. The solid precipitate was filtered off and triturated with 5 mL of acetonitrile. Filtration and drying afforded 5.0 g of the title compound as an off-white solid, m.p. 202°-207° C.; NMR (DMSO-d6): δ1.1-1.8 (m, 8H), 3.7 (m, 1H), 6.5 (br d, 1H), 7.6 (t, 1H), 7.9 (dd, 1H), 8.0 (dd, 1H), 10.8 (br s, 1H); IR (nujol): 3343, 1660, 1375, 1170 cm-1.