Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]=[N:17][CH:18]([NH:24][C:25](=O)[CH2:26][Cl:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C>[C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:25]([CH2:26][Cl:27])=[N:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(N=Nc1ccc(Cl)cc1C(=O)c1ccccc1)NC(=O)CCl
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1

Procedure:
A solution of 1.5 part of ethyl (2-benzoyl-4-chlorophenylazo)-chloroacetylaminoacetate in 30 volume parts of acetic acid is refluxed for 10 minutes, and then the acetic acid is distilled off under reduced pressure. The residue is neutralized with a saturated aqueous solution of sodium bicarbonate and, then, extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue is treated with n-hexane to obtain ethyl 1-(2-benzoyl-4-chlorophenyl)-5-chloromethyl-1H-1,2,4-triazole-3-carboxylate as crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6](=[O:9])[C:7]=1[OH:8].CC1(C)[O:15][CH:14]([CH2:16]O)[CH2:13][O:12]1.CC1NC=CC(=O)C=1OCC1C=CC=CC=1>OCC(CO)O>[CH2:16]([N:3]1[CH:4]=[CH:5][C:6](=[O:9])[C:7]([OH:8])=[C:2]1[CH3:1])[CH:14]([CH2:13][OH:12])[OH:15]
Reactant: CC1(C)OCC(CO)O1
Reactant: Cc1[nH]ccc(=O)c1O
Agent: Cc1[nH]ccc(=O)c1OCc1ccccc1
Solvent: OCC(O)CO
Product: Cc1c(O)c(=O)ccn1CC(O)CO
Yield: 90 %

Procedure:
The 2-methyl-3-hydroxypyridine-4(1H)-one of glycerol is prepared starting from the 2-methyl-3-hydroxypyridine-4(1H)-one of solketal according to the method described in example 15. The extraction and purification protocol is the following: filtration of the catalyst, addition of water, followed by elimination of the organic solvent, lyophilization, retake-up of the residue by an organic solvent, neutralization using Dowex OH− resin, filtration, and finally evaporation of the solvent. Starting from 1.00 g (3.04 mmol) of 2-methyl-3-benzyloxypyridine-4(1H)-one of solketal, 790 mg (2.73 mmol) of 2-methyl-3-hydroxypyridine-4(1H)-one of glycerol is isolated, which is pure at chromatographic and NMR analyses. Yield: 90%.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][CH:8]1[CH:20]=[C:21]([CH3:25])[C:22](=[O:24])[CH3:23])=[O:6])[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH:20]=[C:21]([CH3:25])[C:22](=[O:24])[CH3:23])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C=C(C)C(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C=C(C)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a solution of 2S,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (9.9 g) in tetrahydrofuran (99 ml) was added 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (32.3 ml) at 0° C. After stirring at room temperature for 1 hour, the reaction mixture was poured into a mixture of ethyl acetate (200 ml) and water (100 ml). The aqueous layer was separated and extracted with ethyl acetate. The combined organic layer was washed twice with 1N hydrochloric acid (25 ml) and then with saturated aqueous sodium bicarbonate, water and brine successively, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (100 ml) eluting with a mixture of n-hexane and ethyl acetate (1:1-1:2 V/V) to give (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-(2-methyl-3oxo-1-butenyl)pyrrolidine (5.65 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N:5]1[CH:6]=[CH:7][C:2]([O:1][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:3][CH:4]=1
Reactant: Oc1ccncc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.9 %

Procedure:
To a solution of 4-hydroxypyridine (4.42 g, 45.8 mmol) and 1-fluoro-4-nitrobenzene (4.89 mL, 45.8 mmol) in anhydrous DMF (50 mL) was added anhydrous K2CO3 (13.0 g, 91.6 mmol) in one portion. The mixture was heated at the reflux temperature with stirring for 24 h, cooled to room temperature and poured in water (300 mL). The solid that separated was filtered, washed with water and dried well under high vacuum to yield 8.9 g (90%) of desired product, 4-(4-pyridinyloxy)-1-nitrobenzene. 1H NMR (CDCl3, 300 MHz): δ 8.36 (d, 2H, J=9.0 Hz), 8.11 (d, 2H, J=8.1 Hz), 7.83 (d, 2H, J=9.0 Hz), 6.27 (d, 2H, J=7.8 Hz); LCMS (m/z): 217 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[C:6]([CH3:14])=[CH:5][C:4]1=[O:15])[CH3:2].[C:16]([NH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33]Cl)[CH2:27][CH2:26]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([NH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][O:13][C:10]2[CH:11]=[C:12]3[C:7]([C:6]([CH3:14])=[CH:5][C:4](=[O:15])[N:3]3[CH2:1][CH3:2])=[CH:8][CH:9]=2)[CH2:27][CH2:26]1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(NC1CCN(CCCCl)CC1)c1ccccc1
Reactant: CCn1c(=O)cc(C)c2ccc(O)cc21
Product: CCn1c(=O)cc(C)c2ccc(OCCCN3CCC(NC(=O)c4ccccc4)CC3)cc21
Yield: 59 %

Procedure:
In a manner analogous to that described in Example 11, by the reaction of 1-ethyl-7-hydroxy-4-methyl-2-oxo-1,2-dihydroquinoline with 3-(4-benzamidopiperidino)-propyl chloride, there is obtained, in a yield of 59% of theory, 7-[3-(4-benzamido-piperidino)-propoxy]-1-ethyl-4-methyl-2-oxo-1,2-dihydroquinoline; m.p. 164°-165° C. (after recrystallization from dichloromethane/diethyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7](=[O:17])[N:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([C:29]2[CH:39]=[C:38]([CH3:40])[C:32]3[N:33]([CH3:37])[C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)=[O:28])[CH:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7](=[O:17])[N:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:21]4[CH:22]=[C:23]([C:27]([C:29]5[CH:39]=[C:38]([CH3:40])[C:32]6[N:33]([CH3:37])[C:34](=[O:36])[O:35][C:31]=6[CH:30]=5)=[O:28])[N:24]=[CH:25][N:26]=4)[CH2:13][CH2:12]3)[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(Cl)cc2CCN1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(N4CCc5cc(Cl)ccc5NC4=O)CC3)ncn2)cc2oc(=O)n(C)c12

Procedure:
56 mg (0.20 mmol) 7-chloro-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 61 mg (0.20 mmol) 6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.070 mL (0.40 mmol) DIPEA were stirred overnight in 1.5 mL DMF at RT. The mixture was diluted with 1.5 mL MeOH, suction filtered, washed with DIPE and dried.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: COCCOC
Product: N#Cc1c(-c2ccco2)nc(N)nc1N1CCN(c2ccccc2)CC1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and 1-phenylpiperazine in DME. ES-MS m/e (%): 347 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[NH:11][CH:12]=[CH:13][C:14]=2[C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:24][NH2:25]>C(O)C>[Cl:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=1[C:14]1[CH:13]=[CH:12][NH:11][C:10]=1[C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:25][N:24]=1
Reactant: NN
Reactant: O=C(c1cccnc1Cl)c1[nH]ccc1-c1c(Cl)cccc1Cl
Solvent: O
Solvent: CCO
Product: Clc1cccc(Cl)c1-c1cc[nH]c1-c1n[nH]c2ncccc12

Procedure:
A mixture of (2-chloro-pyridin-3-yl)-[3-(2,6-dichloro-phenyl)-1H-pyrrol-2-yl]-methanone (160 mg) and hydrazine hydrate (0.5 mL) in ethanol (8 mL) was heated at 90–100° C. for 24 hours. The reaction was concentrated, the residue was purified on a silica gel column to give 30 mg of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10](Cl)[N:9]=[C:8]2Cl.[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH3:15][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]1[N:9]=[C:8]([N:11]([C:12]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:10])[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: CNc1ccccc1
Reactant: COc1cccc2c(Cl)nc(Cl)nc12
Solvent: C1CCOC1
Product: COc1cccc2c(N(C)c3ccccc3)nc(N(C)c3ccccc3)nc12
Yield: 15 %

Procedure:
8-Methoxy-2,4-dichloroquinazoline (1.5 g, 0.007 mol) was heated under reflux in a solution of N-methyl aniline (1.43 m), 0.014 mol) in tetrahydrofuran (50 ml) for 16 hours precipitating a solid, which was collected and crystallised from ethanol/water to give 2,4-bis-(N-methylphenylamino)-8-methoxyquinazoline (0.37 g, 15%), m.p. 169°-170°.
Reaction SMILES: S(CCC[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:33]#[N:34])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25]CCCS([O-])(=O)=O)=[CH:21][CH:20]=2)[C:17]#[N:18])=[CH:11][CH:10]=1)([O-])(=O)=O.[Na+].[Na+].COC1C=CC(/C(=C(/C2C=CC(OC)=CC=2)\C#N)/C#N)=CC=1>>[OH:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](=[C:16](/[C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)\[C:17]#[N:18])/[C:33]#[N:34])=[CH:13][CH:14]=1
Reactant: N#CC(=C(C#N)c1ccc(OCCCS(=O)(=O)[O-])cc1)c1ccc(OCCCS(=O)(=O)[O-])cc1
Agent: COc1ccc(/C(C#N)=C(\C#N)c2ccc(OC)cc2)cc1
Agent: [Na+]
Product: N#C/C(=C(/C#N)c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To prepare sodium 1,2-bis[4-(3-sulfonatopropoxyl)phenyl]-1,2-dicyanoethene (3), (1) (0.2903 g, 1 mmol) was dissolved in 10 mL distilled DCM under N2 atmosphere in a 50 mL two-valves round bottom flask. Boron trifluoride methyl sulfide complex (5.26 mL, 50 mmol) was added into the solution slowly. The resulting mixture was stirred at ambient temperature overnight. The solution was concentrated under a stream of N2 and partitioned between 1M HCl and ethyl acetate. The combined organic later were washed with H2O and brine, dried over Na2SO4 and concentrated to give 2,3-bis(4-hydroxyphenyl)fumaronitrile (2) without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([OH:9])[C:5]([Cl:8])=[CH:6][CH:7]=1.Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH:12]([F:17])[F:16])[C:3]=1[F:10]
Reactant: Oc1c(Cl)ccc(Br)c1F
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1c(Br)ccc(Cl)c1OC(F)F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-6-chloro-2-fluorophenol (1.00 g, 4.44 mmol) and sodium chlorodifluoroacetate in dimethylformamide (DMF; 9 mL) was added potassium carbonate (1.22 g, 5.32 mmol) and water (1.77 mL) and the resulting mixture heated to 100° C. for 4 hours. The solution was cooled to ambient temperature and concentrated hyrdrochlroric acid (2.5 mL) and water (4 mL) were added and stirred at ambient temperature overnight. The solution was cooled in an ice bath and neutralized with 2N sodium hydroxide and then extracted with ethyl ether (2×25 mL). The combined extracts were washed with brine, dried (sodium sulfate), and concentrated to give 1-bromo-4-chloro-2-fluoro-3-difluoromethoxybenzene (1.20 g, 4.2 mmol). This material was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]2[CH2:14][CH2:13]2)=[C:7]([O:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)[N:6]=1)=[O:4].[OH-].[Na+]>CO.C(OCC)(=O)C>[CH:12]1([NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=2[O:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH2:13][CH2:14]1
Reactant: COC(=O)c1ccc(NC2CC2)c(OCC2CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccc(NC2CC2)c(OCC2CC2)n1
Yield: 92.1 %

Procedure:
A solution of 5-(cyclopropylamino)-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester (400 mg, 1.53 mmol), sodium hydroxide (244 mg, 6.1 mmol) in THF/H2O 1/1 (10 mL) was stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure. Water was added and the pH was adjusted to 2 by addition of 1 N HCl. Extraction with ethyl acetate (30 mL) was followed by washing with brine (6×30 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 50 g, 50% ethyl acetate in petroleum ether) to yield the title compound (350 mg, 92%) as yellow solid; MS (EI): m/e=249.3 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:27])=[C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]3)[CH:16]=2)[C:11](=[O:28])[C:10]([C:29]([OH:31])=[O:30])=[CH:9]1.[CH2:32](O)[CH3:33]>>[CH2:32]([O:30][C:29]([C:10]1[C:11](=[O:28])[C:12]2[C:17](=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]3)=[C:14]([F:27])[CH:13]=2)[N:8]([CH2:7][CH2:6][OH:5])[CH:9]=1)=[O:31])[CH3:33]
Reactant: CC(=O)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CCO)CC1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cn(CCO)c2cc(N3CCN(C(C)=O)CC3)c(F)cc2c1=O

Procedure:
Thionyl chloride (2.4 g) was added dropwise to a solution of 1-(2-hydroxyethyl)-6-fluoro-7-(4-acetyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.38 g) in ethanol (20 ml) under cooling with an ice-water bath, and the reaction mixture was refluxed for 5.5 hrs. The reaction mixture was evaporated to dryness, the residue was neutralized with aqueous potassium carbonate solution, and the solution was extracted with chloroform. After removing the chloroform, the residue was recrystallized from a mixture of methylene chloride and ethyl acetate to give 0.36 g of 1-(2-hydroxyethyl)-6-fluoro-7-(4-acetyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([NH:16][NH2:17])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23][N:24](C=NC=[N+](C)C)[CH3:25].[Cl-].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH2:3]([N:10]1[CH2:11][CH2:12][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([N:16]2[CH:25]=[N:24][CH:23]=[N:17]2)[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C=NC=[N+](C)C
Reactant: CCOC(=O)C1(NN)CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(n2cncn2)CCN(Cc2ccccc2)CC1

Procedure:
A stirred suspension of ethyl 1-benzyl-4-hydrazinopiperdin-4-ylcarboxylate dihydrochloride salt (D27, 2.0 g, 0.0057 mol) in absolute chloroform (200 ml) was treated with Gold's reagent ([3-(dimethylamino)-2-azaprop-2-en-1-ylidene]-dimethylammonium chloride) (930 mg, 0.0057 mol) and triethylamine (1.6 ml, 0.0114 mol) and the mixture heated at reflux under nitrogen for 2.5 h. The solution was allowed to cool, treated with concentrated potassium carbonate solution and the organic layer separated, dried (Na2SO4) and concentrated in vacuo to leave an orange oil. This was chromatographed on silica gel eluting first with ethyl acetate to obtain the title compound (D28), then with methanol to obtain a high polar intermediate, which on heating under reflux in toluene for 20 minutes gave a further batch of the triazole product. These two batches were combined to give the title compound (D28) (770 mg, 43%) as an orange oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Br:8].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:4]2[C:3](=[O:9])[C:2]([Br:1])=[C:7]([Br:8])[CH:6]=[N:5]2)=[CH:20][CH:19]=1
Reactant: O=c1[nH]ncc(Br)c1Br
Reactant: COc1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: COc1ccc(Cn2ncc(Br)c(Br)c2=O)cc1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
A mixture of 4,5-dibromopyridazinone (25 g, 98 mmol), anhydrous potassium carbonate (34 g, 246 mmol), 4-methoxybenzylchloride (14 mL, 103 mmol) and tetrabutylammonium bromide (1.6 g, 4.9 mmol) in CH3CN (200 mL) was stirred at 45° C. for 3 h and then at 80° C. for 2 h. The mixture was allowed to cool to 22° C. and filtered through a pad of Celite. The pad was washed with CH2Cl2, followed by EtOAc, and the combined filtrate was evaporated to dryness. The crude product was suspended in MeOH and sonicated. The solid was collected by suction filtration, washed with MeOH, and air-dried to give 2-(4-methoxybenzyl)-4,5-dibromopyridazin-3(2H)-one as a brown solid. The filtrate was concentrated and purified by silica gel chromatography, eluting with 20% hexane in CH2Cl2, to give 2-(4-methoxybenzyl)-4,5-dibromopyridazin-3(2H)-one as a pale yellow solid. 1H NMR (400 MHz, CDCl3) @ ppm 3.78 (s, 3H), 5.25 (s, 2H), 6.85 (d, J=8.53 Hz, 2H), 7.40 (d, J=9.03 Hz, 2H), 7.78 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15](=[CH:25][N:26](C)C)[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=O)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([NH:36]C1C=C(C(=CN(C)C)C(C2C=CC(F)=CC=2)=O)C=CN=1)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[N:36][NH:26][CH:25]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: CN(C)C=C(C(=O)c1cccc(F)c1)c1ccnc(NC(=O)OC(C)(C)C)c1
Product: CC(C)(C)OC(=O)Nc1cc(-c2c[nH]nc2-c2cccc(F)c2)ccn1

Procedure:
The reaction was carried out in the same manner as in Example 2-2) except for using 13.5 g (35.0 mmol) of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-(3-fluorophenyl)-2-propen-1-one obtained in Example 22-1) in place of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-(4-fluorophenyl)-2-propen-1-one to obtain 12.4 g of the title compound as a yellowish white powder. (Yield: quantitative)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)C>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C1CCc2cc(Br)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1CCc2cc(-c3cccc(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3 g (14.2 mmol) of 5-bromoindan-1-one are suspended with 2.22 g (14.2 mmol) of 3-chlorophenylboronic acid and 3 g (28.3 mmol) of sodium carbonate in a mixture of 100 ml of toluene, 20 ml of ethanol and 20 ml of water. Under an argon atmosphere, 160 mg (7.1 mmol) of palladium(II) acetate and 373 mg (14.2 mmol) of triphenylphosphine are added. The mixture is heated under reflux for 3 h, and then the ethanol content of the solvent mixture is removed in vacuo. 40 ml of 0.5 N sodium hydroxide solution are added, and the mixture is stirred at room temperature for 10 min. The precipitate is filtered off with suction; the filtrate is washed with 40 ml of water until neutral and then washed with concentrated brine (3×40 ml), dried over magnesium sulfate, concentrated in vacuo and purified by chromatography on silica gel with toluene/ethyl acetate 20/1. 5-(3-Chlorophenyl)indan-1-one is obtained with a melting point of 113° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](Cl)=[N:11][CH:10]=1.[CH2:34]([CH2:36][NH2:37])[OH:35]>>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([NH:37][CH2:36][CH2:34][OH:35])=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NCCO
Product: Cc1ccccc1-c1cc(NCCO)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 48 h
Yield: 73.9 %

Procedure:
A mixture of 0.837 g (1.72 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide and 5.0 ml (83 mmol) ethanolamine was stirred at 100° C. for 48 h. After cooling to room temperature excess ethanolamine was removed under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with two portions of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and water, dried with sodium sulfate and concentrated to give 0.8 g of crude product. Flash chromatography afforded 0.650 g (73.9%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[H-].[Na+].[C:17]([O:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:20])[CH2:18][CH3:19]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:22]([O:21][C:17](=[O:20])[CH2:18][CH3:19])[C:23](=[O:24])[O:25][C:26]([CH3:28])([CH3:29])[CH3:27])(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: CCC(=O)ONC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CCC(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
tert-Butyl {[2-(methylsulfonyl)phenyl]sulfonyl}(propanoyloxy)carbamate (44) is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino propanoate according to Scheme 2. (1.09 g, 68%), 1H NMR (250 MHz, DMSO-d6) δ ppm 8.16-8.37 (2H, m), 8.00-8.15 (2H, m), 3.46 (3H, s), 2.61 (2H, q, 7.5 Hz), 1.29 (9H, s), 1.15 (3H, t, 7.5 Hz).
Reaction SMILES: [CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[CH2:23][C:24]([NH2:26])=[O:25]>CN(C=O)C>[CH2:1]1[CH:12]2[CH:4]([N:5]([CH2:23][C:24]([NH2:26])=[O:25])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1
Reactant: NC(=O)CCl
Reactant: c1ccc2c(c1)NC1CCCC21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CN1c2ccccc2C2CCCC21
Temperature: 100 °C
Yield: 69.2 %

Procedure:
To a stirred solution of 1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole (130 mmol, 21 g) in DMF (50 mL) was added diisopropylethylamine (400 mmol, 70 mL) followed by 2-chloroacetamide (270 mmol, 25 g). The reaction mixture was heated to 100° C. for 18 h. The reaction was concentrated and the diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash column chromatography through silica gel (elution with 60% ethyl acetate-hexanes) to afford a yellow solid (90 mmol, 20 g, 69%).