Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[Cl:4][C:5]1[C:6]([N:20]([CH2:25][CH2:26][N:27]2C(=O)C3=CC=CC=C3C2=O)[S:21]([CH3:24])(=[O:23])=[O:22])=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]=[C:10]([O:16][CH3:17])[C:9]([O:18][CH3:19])=[N:8]2>ClCCl.CO>[Cl:4][C:5]1[C:6]([N:20]([CH2:25][CH2:26][NH2:27])[S:21]([CH3:24])(=[O:23])=[O:22])=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]=[C:10]([O:16][CH3:17])[C:9]([O:18][CH3:19])=[N:8]2
Reactant: COc1nc2cc(Cl)c(Cl)c(N(CCN3C(=O)c4ccccc4C3=O)S(C)(=O)=O)c2nc1OC
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1nc2cc(Cl)c(Cl)c(N(CCN)S(C)(=O)=O)c2nc1OC
Reaction time: 48 h
Yield: 69.4 %

Procedure:
Hydrazine hydrate (696 μl, 716 mg, 14.3 mmol) was added dropwise to a solution of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-phthalimidoethyl)methanesulphonamide (3.76 g, 7.15 mmol) in a mixture of dichloromethane (71 ml) and methanol (5 ml) at room temperature under nitrogen. The mixture was heated at reflux for 4 days and then further methanol (20 ml) was added. After a further 2 days the mixture was allowed to cool and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and this was extracted 3 times with 10% aqueous citric acid. The combined acid extracts were adjusted to pH 9 with solid potassium carbonate and extracted 3 times with dichloromethane. The combined dichloromethane extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 95:5 dichloromethane:methanol to give N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-aminoethyl)methanesulphonamide (1.96 g, 69%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].C(N(CC)CC)C.[CH2:20]([C:28]1([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:40]2[CH:39]=[C:38]([C:41](Cl)=[O:42])[CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>ClCCCl.CCCCCCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([NH:6][NH:7][C:41]([C:38]1[CH:37]=[CH:36][C:35]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:40]=2[CH:39]=1)=[O:42])=[O:5]
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C(=O)Cl)cc21
Reactant: NNC(=O)c1cc(Cl)ccc1Cl
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Solvent: ClCCCl
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C(=O)NNC(=O)c3cc(Cl)ccc3Cl)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2,5-Dichlorobenzohydrazide (one equivalent) and triethylamine (one equivalent) were warmed in 500 mL of 1,2-dichloroethane until the solid material had dissolved. On cooling, 9,9-dioctyl-9H-fluorene-2-carbonyl chloride (one equivalent) was added and the mixture stirred at RT for two days. The insolubles were filtered off and the filtrate evaporated to give an oil. This was taken up in heptane and the precipitated solid filtered off. The remaining solution was dried (MgSO4) and concentrated to give the desired intermediate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7](SC#N)[N:6]3[N:15]=[C:16]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:5]3[C:4]=2[CH:3]=1.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24].O>CN1CCN(C)C1=O.C(O)C>[C:23]([NH:27][C:7]1[N:6]2[N:15]=[C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:5]2[C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[N:8]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: N#CSc1nc2ccc(Cl)cc2c2nc(-c3ccco3)nn12
Reactant: CC(C)(C)N
Solvent: CCO
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: CC(C)(C)Nc1nc2ccc(Cl)cc2c2nc(-c3ccco3)nn12
Reaction time: 3 h

Procedure:
A solution of 9-chloro-5-thiocyanato-2-(2-furyl)[1,2,4]triazolo-[1,5-c]quinazoline (2 g) in 1,3-dimethylimidazolidone (28 ml) is added to tert-butylamine (2 ml). The mixture is stirred for 3 hours under nitrogen, and then is diluted with ethanol (20 ml), and treated with water (20 ml). The resulting precipitate is collected, recrystallized from 2-methoxyethanol, and dried in high vacuum to afford pure 5-tert-butylamino-9-chloro-2-(2-furyl)-[1,2,4]triazolo-[1,5-c]quinazoline, mp above 330° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15]>C(Cl)Cl>[CH3:16][C:13]([NH:12][C:4](=[O:5])[C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=1[F:11])([CH3:17])[CH2:14][OH:15]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of 2,6-difluorobenzoyl chloride (50 g, 283 mmol) in CH2Cl2 (200 mL) was added rapidly dropwise to an ice water-cooled solution of 2-amino-2-methyl-1-propanol (63.1 g, 708 mmol) in CH2Cl2 (400 mL). The resulting mixture was stirred at RT and monitored to completion by GLC, then was extracted twice with 10% HCl and once with sat aq NaHCO3. The organic phase was dried (MgSO4), and concentrated to afford 61.9 g N-(1,1-dimethyl-2-hydroxyethyl)-2,6-difluorobenzamide as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4]1.Cl[CH2:16][CH2:17][CH:18]([C:22]1[CH:27]=[CH:26][C:25]2[O:28][CH2:29][O:30][C:24]=2[CH:23]=1)[CH2:19][CH2:20]Cl>CC(C)=O.O>[C:9]1([N:5]2[CH2:4][CH:3]([CH2:2][N:1]3[CH2:16][CH2:17][CH:18]([C:22]4[CH:27]=[CH:26][C:25]5[O:28][CH2:29][O:30][C:24]=5[CH:23]=4)[CH2:19][CH2:20]3)[O:7][C:6]2=[O:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NCC1CN(c2ccccc2)C(=O)O1
Reactant: ClCCC(CCCl)c1ccc2c(c1)OCO2
Solvent: O
Solvent: CC(C)=O
Product: O=C1OC(CN2CCC(c3ccc4c(c3)OCO4)CC2)CN1c1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 1.92 g of 5-aminomethyl-3-phenyloxazolidin-2-one [obtainable by reaction of 5-chloromethyl-3-phenyloxazolidin-2-one with potassium phthalimide and subsequent hydrolysis] and 2.63 g of 1,5-dichloro-3-(3,4-methylenedioxyphenyl)pentane in 40 ml of acetone and 40 ml of water is boiled for 24 hours and worked up as usual, giving 3-phenyl-5-[4-(3,4-methylenedioxyphenyl)piperidinomethyl]oxazolidin-2-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:17]1([C:2]2[CH:3]=[C:4]([N:8]3[CH:14]4[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]4)[CH2:10][CH2:9]3)[CH:5]=[N:6][CH:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cncc(N2CCN3CCC2CC3)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: c1ccc(-c2cncc(N3CCN4CCC3CC4)c2)cc1

Procedure:
0.87 g (3.1 mmol) of 4-(5-bromo-3-pyridyl)-1,4-diazabicyclo[3.2.2]nonane is introduced into a 50 ml three-necked round-bottomed flask, 0.39 g (3.15 mmol) of phenylboronic acid, 0.11 g (0.095 mmol) of tetrakis(triphenylphosphine)palladium, 3.3 ml of aqueous 2 M sodium carbonate solution, 6.5 ml of benzene and 0.15 ml of ethanol are added and the mixture is refluxed for 16 h.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:10])=[N:4][CH:5]=[C:6]([F:9])[C:7]=1I.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].C(=O)(O)[O-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([NH2:10])=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[NH:18][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1
Reactant: Nc1ncc(F)c(I)c1F
Reactant: COc1ccc(CN)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2c(F)cnc(N)c2F)cc1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 3,5-Difluoro-4-iodopyridin-2-amine (3.0 g, 11.7 mmol), 4-methoxybenzylamine (1.92 g, 14 mmol), Pd2dba3 (1.07 g, 1.2 mmol), BINAP (1.46 g, 2.3 mmol), sodium t-butoxide (1.46 g, 2.3 mmol), and toluene (600 ml) was heated in a sealed vessel with stirring at 130° C. for 16 h. Aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (30% ethyl acetate in hexanes eluant) to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.[C:30]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:35]=[CH:34][C:33]([CH:36]=[N:37][OH:38])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:38]/[N:37]=[CH:36]/[C:33]2[CH:34]=[CH:35][C:30]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:31][CH:32]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1
Reactant: ON=Cc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCO/N=C/c2ccc(-c3ccccc3)cc2)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Yield: 80 %

Procedure:
This compound was produced using similar methods as those used in Step 5, example 27, starting with 4-(3-bromo-propoxy)-2-(4-trifluoromethoxy-benzoylamino)-benzoic acid methyl ester (0.46 g, 0.97 mmol), biphenyl-4-carbaldehyde oxime (0.20 g, 1.01 mmol) and cesium carbonate (1.26 g, 3.86 mmol) in acetone (35 mL). The crude material was purified by flash chromatography through silica gel using diethyl ether/hexanes (0/100 gradient to 12/88) to give 4-[3-({[(1E)-1,1′-biphenyl-4-ylmethylidene]amino}oxy)propoxy]-2-{[4-(trifluoromethoxy)benzoyl]amino}benzoic acid methyl ester (0.46 g, 80%) as a white solid. 1H NMR (500 MHz, DMSO-d6); δ 11.93 (s, 1H), 8.34 (d, 1H), 8.31 (s, 1H), 8.06 (d, 2H), 7.99 (d, 1H), 7.70-7.66 (m, 6H), 7.60 (d, 1H), 7.46 (t, 2H), 7.38 (t, 1H), 6.85 (dd, 1H), 4.31 (t, 2H), 4.23 (t, 2H), 3.87 (s, 3H), 2.18 (m, 2H).
Reaction SMILES: [NH2:1][C:2](=[S:12])[CH2:3][C:4]([CH3:11])([CH3:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].O.O.O.O.O.[OH-].C(=O)(O)[O-].[Mg+2].[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](=O)[CH2:33]Cl)(=[O:26])[CH3:25]>O1CCOCC1.C(OCC)(=O)C>[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[N:1]=[C:2]([CH2:3][C:4]([CH3:10])([CH3:11])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[S:12][CH:33]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OCCCCC(=O)CCl
Reactant: COC(=O)CC(C)(C)CC(N)=S
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CC(C)(C)Cc1nc(CCCCOC(C)=O)cs1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
Methyl 5-amino-3,3-dimethyl-5-thioxopentanoate (500 mg; 2.64 mmoles) was dissolved in 1,4-dioxane (10 mL) under nitrogen and magnesium carbonate hydroxide pentahydrate (640 mg; 1.32 mmoles) was added. 6-Chloro-5-oxohexyl acetate (685 mg; 3.56 mmoles; Rieke, R. D.; Brown, J. D.; Wu, X. Synth. Commun. 1995, 25(23), 3923.) was added and the mixture was magnetically stirred for 10 hours with heating to 60° C. The mixture was allowed to cool, diluted with ethyl acetate and filtered. The solvent was removed under vacuum and the residue was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (3:1). Following removal of solvent the product, methyl 4-{4-[4-(acetyloxy)butyl]-1,3-thiazol-2-yl}-3,3-dimethylbutanoate, was obtained as pale yellow oil. (820 mg). The material was impure, containing some 6-Chloro-5-oxohexyl acetate. 1H NMR (400 MHz) CDCl3 δ 6.76 (1H, s), 4.04-4.11 (2H, m), 3.68 (3H, m), 3.05 (2H, s), 2.78 (2H, t, J=7.5 Hz), 2.33 (2H, s), 2.04 (3H, s), 1.61-1.82 (4H, m), 1.10 (6H, s).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[N+](=[CH2:12])=[N-]>C(OCC)C>[CH3:12][O:8][C:7]([CH:4]1[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]1)=[O:9]
Reactant: C=[N+]=[N-]
Reactant: O=C1CCC(C(=O)O)C1
Solvent: CCOCC
Product: COC(=O)C1CCC(=O)C1

Procedure:
To a solution of 2.8 g of 3-oxocyclopentanecarboxylic acid in 20 ml of diethyl ether was added ethereal solution of diazomethane under cooled with ice until the mixture turned pale yellow, and then the reaction mixture was concentrated under reduced pressure to give about 3.1 g of 3-oxocyclopentanecarboxylic acid methyl ester as crude product. Obtained methyl ester compound was dissolved in 20 ml of methanol and after the mixture was cooled to -50° C., 820 mg of sodium borohydride was added thereto at a time and the mixture was stirred for 20 minutes at the same temperature. After 1.3 ml of acetic acid was dropped slowly to the reaction mixture, methanol was removed under reduced pressure. To the residue was added 10 ml of water and the mixture was extracted with ethyl acetate and the extract was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3 g of the title compound as crude product having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14](N3CCN(C(OC(C)(C)C)=O)C[C@@H]3C)=[CH:13]C=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:31][N:32]1CCC2N=C(N)[S:40][C:34]=2[CH2:33]1.BrC1C(=O)N(C)C=C(Br)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:40][C:34]3[CH2:33][N:32]([CH3:31])[CH2:13][CH2:14][C:15]=3[N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CN1CCc2nc(N)sc2C1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Agent: Cn1cc(Br)cc(Br)c1=O
Product: CN1CCc2nc(Nc3cc(Br)cn(C)c3=O)sc2C1
Yield: 44 %

Procedure:
Following the procedures described for 191g and starting with 203a (4.0 g, 23.5 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (3.0 g, 17.8 mmol) afforded 203b as yellow solid (2.8 g, 44%). MS: [M+H]+ 357.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[C:36]([F:37])=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][C:29]=3[F:38])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:40][O:41][C:42](=[O:46])[CH2:43][CH2:44][NH2:45].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[C:36]([F:37])=[CH:35][C:31]([C:32]([NH:45][CH2:44][CH2:43][C:42]([O:41][CH3:40])=[O:46])=[O:33])=[CH:30][C:29]=3[F:38])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(-n2c(C(C)(C)c3ccc(Cl)c(Cl)c3)cnc2SCc2c(F)cc(C(=O)O)cc2F)ccc1F
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)c(OC)c2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzoic acid (0.85 mmol from previous step) and β-alanine methyl ester hydrochloride (139 mg, 1.0 mmol) in DCM (10 mL) was treated with Et3N (0.36 mL, 2.6 mmol) and HATU (390 mg, 1.0 mmol) at ambient temperature. After stirring for 16 h at ambient temperature the reaction mixture was quenched by the addition of H2O, 1N HCl, and DCM. The aqueous layer was extracted with DCM. The combined extracts were washed with satd NaHCO3, dried over Na2SO4 and concentrated under reduced pressure to afford crude product. This material was purified by flash chromatography (silica gel, EtOAc/Hex, 0:100 to 100:0) to give methyl 3-(4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzamido)propanoate as a clear syrup, that was carried on to the next step directly. 1H NMR (400 MHz, CDCl3) δ 7.31-7.23 (m, 2H), 7.19 (s, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.99 (t, J=5.5 Hz, 1H), 6.88 (ddd, J=10.7, 9.6, 5.4 Hz, 2H), 6.26 (ddd, J=8.5, 3.8, 2.5 Hz, 1H), 5.91 (dd, J=7.5, 2.4 Hz, 1H), 4.16-4.08 (m, 2H), 3.76-3.66 (m, 5H), 3.50 (s, 3H), 2.66 (t, J=5.9 Hz, 2H), 1.89 (s, 1H), 1.54 (s, 3H), 1.47 (s, 3H); MS (EI) m/z 666 (MH+).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:14]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]3([CH:26]=[CH:25][C:24](=[O:27])[CH:23]=[CH:22]3)[N:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].ClC1C=CC(Cl)=CC=1Cl.[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39]>C(Cl)(Cl)Cl.CC(C)=O>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]3[CH:26]=[CH:25][C:24](=[O:27])[CH:23]=[CH:22][C:12]3=[C:13]([S:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(C2=NC3(C=CC(=O)C=C3)C(Sc3ccccc3)=C2)CC1
Agent: O=C(O)C(=O)O
Solvent: Clc1ccc(Cl)c(Cl)c1
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: C=CCN1CCN(c2cc(Sc3ccccc3)c3ccc(=O)ccn23)CC1
Yield: 41.6 %

Procedure:
By working as in Example 5, but starting with 2-(4-allyl-1-piperazinyl)-4-phenylthio-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (15.2 g) and 1,2,4-trichlorobenzene (150 cc), a residue is obtained which is redissolved in chloroform (300 cc). The solution obtained is poured into silica (300 g) contained in a column 4.2 cm in diameter. Elution is first performed with chloroform (1 liter) and this eluate is rejected. Elution is then performed with a mixture of chloroform and methanol (90:10 by volume) (3 liters) and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in acetone (15 cc). Oxalic acid (1.9 g), dissolved in acetone (15 cc), is added to the solution obtained. The precipitate formed is separated by filtration and washed with ethyl ether (10 cc). 3-(4-Allyl-1-piperazinyl)-1-phenylthio-7H-pyrrolo[1,2-a]azepin- 7-one dioxalate (2.45 g), m.p. 225° C., is thereby obtained.
Reaction SMILES: C(C1C=CC(C)=[N:7]C=1)C.[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:45]=[CH:44][C:24]([C:25]([NH:27][C:28]3[C:37]4[O:36][C:35]([C:38](OCC)=[O:39])=[CH:34][C:33](=[O:43])[C:32]=4[CH:31]=[CH:30][CH:29]=3)=[O:26])=[CH:23][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CS(O)(=O)=O>CO>[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:45]=[CH:44][C:24]([C:25]([NH:27][C:28]3[C:37]4[O:36][C:35]([C:38](=[O:39])[NH2:7])=[CH:34][C:33](=[O:43])[C:32]=4[CH:31]=[CH:30][CH:29]=3)=[O:26])=[CH:23][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc(=O)c2cccc(NC(=O)c3ccc(OCCCCc4ccccc4)cc3)c2o1
Reactant: CCc1ccc(C)nc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: NC(=O)c1cc(=O)c2cccc(NC(=O)c3ccc(OCCCCc4ccccc4)cc3)c2o1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a mixture containing 120 ml of 5-ethyl-2-methylpyridine and 75 ml of methanol was added 29.5 g of 8-[4-(4-phenyl-1-butoxy)benzoyl]amino-2-ethoxycarbonyl-4-oxo-4H-benzopyran, into which 8.2 g of ammonia gas was bubbled around 0° C., and the mixture was stirred below 30° C. for 3 hours. Then, the temperature was increased to 80° C., and excess ammonia and part of the methanol were removed and recovered into methanol in another vessel. The recovered ammonia and/or methanol can be used again in the subsequent production. The temperature was increased to 80° C., and the remaining methanol and part of 5-ethyl-2-methylpyridine were removed by reducing a pressure down to 30 mmHg. Subsequently, 60.8 mmol (5.84 g) of methane sulfonic acid was added, and the mixture was stirred at 100° C. for 6 hours. Then, the temperature was decreased to 60° C., and methanol was added dropwise at 50° to 60° C. The mixture Was cooled to 0° C., and the deposited crystals were collected by filtration, which afforded 27.7 g of 8-[4-(4-phenyl-1-butoxy)benzoyl]amino-2-carbamoyl-4-oxo-4H-benzopyran (yield 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[N:15]([CH:19]=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1.Cl.[CH3:24][NH:25][CH3:26].C=O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[N:15]([C:19]([CH2:24][NH:25][CH3:26])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CNC
Reactant: Cc1cn2cccc(OCCCc3ccc(Cl)cc3Cl)c2n1
Agent: C=O
Agent: Cl
Solvent: CO
Product: CNCc1c(C)nc2c(OCCCc3ccc(Cl)cc3Cl)cccn12
Yield: 53.7 %

Procedure:
A mixture of 8-[3-(2,4-dichlorophenyl)propoxy]-2-methylimidazo[1,2-α]pyridine (703 mg, 2 mmol, see example 1), dimethylamine hydrochloride (700 mg, 8.48 mmol) and paraformaldehyde (256 mg, 8.48 mmol) in methanol (5 mL) was refluxed for 40 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between dichloromethane (15 mL) and saturated aq sodium bicarbonate solution (5 mL) and water (5 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×10 mL). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by dry column (60 mL funnel, silica gel 10–40μl, Sigma cat. S-6628) eluted with increasingly polar mixtures of ethyl acetate-hexanes (v/v: 1:1.4, 1.2:1, 2:1, 2.9:1, 5:1, containing 0.5% v/v isopropylamine) yielded 406 mg (52% yield) of 8-[3-(2,4-dichlorophenyl)propoxy]-3-[(methylamino)methyl]-2-methylimidazo[1,2-α]pyridine in the first fraction (Rf=0.20 in ethyl acetate-hexanes, 2:1 v/v, containing 0.5% v/v isopropylamine) and 221 mg (27% yield) of 8-[3-(2,4-dichlorophenyl)propoxy]-3-[(dimethylamino)methyl]-2-methylimidazo[1,2-α]pyridine in the second fraction (Rf=0.07 in ethyl acetate-hexanes, 2:1 v/v, containing 0.5% v/v isopropylamine).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[F:17].C([O-])([O-])=O.[Cs+].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C(OC(=O)C)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:2]2[N:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: COc1cnnc(Cl)c1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cnnc(-c2ccc(F)c(Cl)c2)c1
Temperature: 90 °C

Procedure:
3-Chloro-5-methoxy-pyridazine (Bryant, R. D.; Kunng, F.-A.; South, M. S. J. Heterocycl. Chem. (1995), 32(5), 1473-6.), 3-chloro-4-fluorophenylboronic acid, Cs2CO3 and tris(dibenzylideneacetone)dipalladium chloroform complex are mixed and a solution of tri-tert-butylphosphine in degassed dioxane is added. The mixture is heated at about 90° C. for 22 hours then cooled to room temperature, ethylacetate is added, the solid is filtered and the filtrate is concentrated in vacuo to provide 3-(3-chloro-4-fluoro-phenyl)-5-methoxy-pyridazine (a compound of formula XI).