Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9][C@H:8]2[NH:16][C:17](=[O:19])[CH3:18])[C:3]1=[O:20].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C(N(CC)CC)C>C(O)(C)C>[CH3:14][N:13]([CH3:15])[C@H:10]1[CH2:9][C@@H:8]([NH:16][C:17](=[O:19])[CH3:18])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:34])([F:35])[F:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[C:3]2=[O:20])[CH2:12][CH2:11]1
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CC(=O)N[C@@H]1C[C@H](N(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)N[C@@H]1C[C@H](N(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.5 %

Procedure:
To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(dimethylamino)cyclohexyl)acetamide (40 mg, 0.14 mmol) in isopropanol (6 mL) was added 4-chloro-6-(trifluoromethyl)quinazoline (39 mg, 0.17 mmol) and triethylamine (0.02 mL, 0.14 mmol). The mixture was stirred at RT for 16 h and concentrated in vacuo to a crude oil, which was purified by semi-preparative reverse phase HPLC (gradient elution, water/methanol/TFA) to give the title compound (70 mg, 71% yield). LC/MS found [M+H]+=479. 1H-NMR (400 MHz, CD3OD), δ ppm: 8.87 (s, 1H), 8.72 (s, 1H), 8.22 (m, 1H), 7.87 (m, 1H), 5.49 (m, 1H), 4.23 (m, 1H), 4.2 (m, 1H), 4.12 (m, 1H), 3.75 (m, 1H), 3.65 (m, 1H), 3.38 (m, 1H), 2.82 (s, 6H), 2.51 (m, 1H), 2.35 (m, 1H), 2.15 (m, 1H), 2.14-1.86 (m, 5H), 1.84 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5][CH2:4]1.O.NN>C(O)C>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH2:9])[CH2:5][CH2:4]1
Reactant: CO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CO[C@H]1CC[C@H](N)CC1

Procedure:
A mixture of 2-(trans-4-methoxycyclohexyl)-1H-isoindole-1,3(2H)-dione (0.27 g, 1.0 mmol), and hydrazine hydrate (63.3 uL, 0.00130 mol) in ethanol (2.0 mL) was heated at reflux for 1 h. After cooling, the solid was filtered off, and the filtrate was concentrated to yield the desired product (0.12 g, 89%).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]([O:16][CH3:17])=[O:15])=O)(C)(C)C.[ClH:18].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:18].[NH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)[C@H]1CCC[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCC[C@H]1N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of methyl (1S,2R)-2-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylate (0.84 g) and ethyl acetate (2.5 ml) was added a 4 M hydrogen chloride/ethyl acetate solution (5.0 ml) under ice-cooling, followed by stirring at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure to obtain methyl (1S,2R)-2-aminocyclopentanecarboxylate hydrochloride (0.72 g).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[OH:27][CH2:28][C:29]1[N:30]=[CH:31][N:32]2[CH:36]=[CH:35][S:34][C:33]=12>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:30]3[C:29]([CH2:28][OH:27])=[C:33]4[S:34][CH:35]=[CH:36][N+:32]4=[CH:31]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: OCc1ncn2ccsc12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3c[n+]4ccsc4c3CO)[C@H](C)[C@H]12
Yield: 0.9 %

Procedure:
The same procedure as in Example 1 was repeated except that 149 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 201 mg of 7-hydroxymethylimidazo[5,1-b]thiazole were used, thereby obtaining 1.4 mg of the title compound.
Reaction SMILES: Br.Cl[C:3]1[C:4]2[CH2:15][CH2:14][CH2:13][C:5]=2[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.[O-:16][CH2:17][CH3:18].[Na+]>C(O)C>[CH2:17]([O:16][C:3]1[C:4]2[CH2:15][CH2:14][CH2:13][C:5]=2[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1)[CH3:18]
Reactant: CC[O-]
Reactant: Nc1nnc2c3c(c(Cl)nn12)CCC3
Agent: Br
Agent: [Na+]
Solvent: CCO
Product: CCOc1nn2c(N)nnc2c2c1CCC2

Procedure:
6-Chloro-8,9-dihydro-7H-cyclopenta[d][1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.017, 1.0 g) was dissolved in ethanol (50 ml) while stirring and under argon. Thereafter, the reaction mixture was admixed with sodium ethoxide (1.41 g) and stirred at 60° C. for 1 h. After the solvent had been drawn off, the residue was purified using a 40 g silica gel cartridge (0-20% dichloromethane-ethanol gradient in 60 min). The clean product fractions were combined and dried. 662 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6]O.N1C=CC=CC=1.P(Br)(Br)[Br:22]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Br:22]
Reactant: COc1cc(CO)cc(OC)c1OC
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(CBr)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 202.8 %

Procedure:
To a solution of 3,4,5-trimethoxybenzyl alcohol (20.2 g, 0.108 mol) in 300 ml of dry tetrahydrofuran was added 4.12 ml (0.052 mol) of pyridine, and cooled to 0° C. A solution of phosphorous tribromide (4.8 ml, 0.051 mol) in 20 ml of dry tetrahydrofuran was added dropwise to the above solution at 0 ° C. The mixture was stirred for 1 hr. Tetrahydrofuran was concentrated. The residue was then diluted with 200 ml of 10% hydrochloric acid, and then extracted with 200 ml of ethyl acetate. The extract was dried over magnesium sulfate, filtered, concentrated, and dried in vacuum overnight. 3,4,5-Trimethoxybenzyl bromide (27 g, 100% yield) was obtained as a white solid, which can be used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][S-:14].[Na+]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([S:14][CH3:13])[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: C[S-]
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CSc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of the 2,4-dichloro-5-(trifluoromethyl)pyrimidine (2.50 g, 11.5 mmol) in THF (50 mL) in an ice bath under nitrogen was added zinc(II) chloride (1.0 M in ether, 13.8 mL, 13.8 mmol) dropwise. The mixture was stirred in the ice bath for two hours, then sodium methanethiolate (0.888 g, 12.7 mmol) was added. The mixture was stirred overnight, allowing the reaction to slowly come to room temperature. After 18 hours the reaction was quenched with 2 M HCl (15 mL), and the organics removed by evaporation under reduced pressure. The aqueous residue was diluted with brine (15 mL), and extracted with DCM (3×30 mL). The combined organic phases were dried (phase separator) and carefully evaporated to give a pale yellow oil. Chromatography (Biotage Isolera, 2×40 g silica cartridge, 0-20% DCM/n-hexane) followed by carefully evaporation of solvent (40° C.@400 mmHg then room temperature @200 mmHg) gave the title compound (I13) (2.149 g, 82% yield) as a colourless oil; 1H NMR (600 MHz, CDCl3) δ 8.66 (s, 1H), 2.61 (s, 3H). LCMS Method C: rt: 7.95 min; m/z 229.1[M+H]+. Note: I13 is volatile.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>ClCCl>[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=4)[NH:9]3)=[CH:6][CH:7]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)c3ccc(F)cc3)cc1)N2
Yield: 37 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (70 mg, 0.23 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.52 mmol,) in dichloro methane (5 mL) was added 4-fluorobenzoyl chloride (54 mg, 0.34 mmol). The resultant mixture was stirred at room temperature for 16 hrs under nitrogen. The solvent was removed in vacuo and the residue was washed with dichloromethane/petroleum ether, the precipitate was collected to afford methyl 2-(4-(4-fluorobenzamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid, 43 mg, yield: 37%.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=1[C:11]#[N:12])=[O:5])C.[H-].[Na+].Br[CH2:19][C:20]1[CH:24]=[C:23]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[O:22][N:21]=1.[OH-].[Na+]>CN(C=O)C>[Cl:30][C:27]1[S:26][C:25]([C:23]2[O:22][N:21]=[C:20]([CH2:19][N:7]3[C:6]([C:4]([OH:3])=[O:5])=[C:10]([C:11]#[N:12])[C:9]([CH2:13][CH2:14][CH3:15])=[N:8]3)[CH:24]=2)=[CH:29][CH:28]=1
Reactant: CCCc1n[nH]c(C(=O)OCC)c1C#N
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCc1nn(Cc2cc(-c3ccc(Cl)s3)on2)c(C(=O)O)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
112 mg (0.5 mmol) of 4-cyano-5-propyl-2H-pyrazole-3-carboxylic acid ethyl ester was dissolved in 2 ml of DMF and 23.8 mg (0.6 mmol) of sodium hydride (60% in mineral oil) were added at RT. After stirring for 20 min at room temperature the solution was cooled to −70° C. and 166 mg (0.6 mmol) of 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole were added. The reaction was stirred at room temperature for 3 h. The reaction solution was treated with 1 ml of 2N aqueous NaOH for 16h at room temperature. The product was purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8](O)=[O:9])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:25])=O.CN(C)C=O>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8]([Cl:25])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C(=O)O)cc(OC(C)=O)c1OC(C)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Oc1cc(C(=O)Cl)cc(OC(C)=O)c1OC(C)=O
Reaction time: 2 h

Procedure:
3,4,5-Triacetoxybenzoic acid (296.23 g, 1 mol) was slurried in a 2 L flask in CH2Cl2 (1.0 L), and oxalyl chloride (113 mL, 1.3 mol) as added, followed by slow, dropwise addition of N,N-dimethylformamide (1.5 mL). After 2 hours at RT, gas evolution had ceased, and 3,4,5-triacetoxybenzoyl chloride was isolated by evaporation under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5](O)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH2:6][CH2:7][CH3:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.OS(O)(=O)=O.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH2:6][CH2:7][CH3:8]
Reactant: CCCC(O)(CC(=O)OC)c1ccccc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC(CC(=O)OC)c1ccccc1C

Procedure:
A solution of 58.9 g of 3-hydroxy-3-(o-tolyl)-hexanoic acid methyl ester, 1.1 g p-toluene sulphonic acid and 2.5 ml concentrated H2SO4 in 400 ml toluene is boiled in a water separator under reflux. The resultant reaction solution is concentrated, taken up in CHCl3, washed with NaHCO3 solution, H2O and then NaCl solution and then concentrated. The crude product in CHCl3 is filtered through silica gel and the filtrate concentrated. The product containing 3-(o-tolyl)-hex-2-and/or 3-enoic acid methyl ester is taken up in 400 ml methanol and hydrogenated in the presence of 2.1 g 10% (by weight) Palladium on charcoal at 20° and at 1.1 atmospheres to yield 3-o-tolyl-hexanoic acid methyl ester, which is further worked up as such.
Reaction SMILES: CO.Cl.[CH3:4]N(C)CCCN=C=NCC.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[C:31]([OH:33])=[O:32])(=[O:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C1C=CN=CC=1.ClCCl>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[C:31]([O:33][CH3:4])=[O:32])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 56 h
Yield: 79.4 %

Procedure:
4-Dimethylaminopyridine (61 mg), methanol (45 μl) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (192 mg) were added to a solution of (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid (287 mg) [see Preparation 38] in dichloromethane (6 ml). The reaction mixture was stirred at room temperature for 56 hours after which time it was diluted with dichloromethane and washed with 1N aqueous hydrochloric acid solution followed by saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 50:50, by volume, hexane:ethyl acetate, to afford methyl (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylate (239 mg) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:11](CC2C=CC(OC)=CC=2OC)[CH2:10][C:9]2[N:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=3)[S:25][C:8]=2[C:7]1=[O:36])=[O:5])[CH3:2].S(Cl)(Cl)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:23]=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:30][CH:31]=3)[S:25][C:8]=2[C:7]=1[OH:36])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)c2sc(-c3ccc(C(C)(C)C)cc3)nc2CN1Cc1ccc(OC)cc1OC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ncc2nc(-c3ccc(C(C)(C)C)cc3)sc2c1O
Reaction time: 5 h
Yield: 60.1 %

Procedure:
2-(4-tert-Butyl-phenyl)-5-(2,4-dimethoxy-benzyl)-7-oxo-4,5,6,7-tetrahydro-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (0.5 g, 0.98 mmol) was dissolved in 6.7 mL of anhydrous dichloromethane. To the solution was added 108 μL of thionyl chloride, and the reaction was stirred for 5 h. The solution was filtered on a fine glass frit filter to collect a white solid precipitate. The solid was washed twice with cold dichloromethane and then partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic fraction was washed with brine, dried over anhydrous sodium sulfate, and concentrated to produce 0.21 g of a yellow solid. MS: (+) m/z 357.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([CH2:18][CH2:19][C:20](O)=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:23].[CH3:24][NH:25][CH3:26]>ClCCl>[CH3:24][N:25]([CH3:26])[C:20](=[O:21])[CH2:19][CH2:18][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:23])[N:2]([CH3:1])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cn1c(-c2ccccc2)c(CCC(=O)O)c2ccccc2c1=O
Reactant: CNC
Solvent: ClCCl
Product: CN(C)C(=O)CCc1c(-c2ccccc2)n(C)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 0.9 g (2.93 mmol) of 2-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-4-propanoic acid in 150 ml of dichloromethane is prepared in a 500 ml round-bottomed flask placed under an argon atmosphere, 0.7 g (4.3 mmol) of N,N'-carbonyldiimidazole is added, the mixture is stirred at room temperature for 2 h, is saturated for 1 min with gaseous dimethylamine and stirring is continued for 12 h. The solvent is evaporated under reduced pressure, the residue is taken up in 200 ml of dichloromethane, 100 ml of water and 1M hydrochloric acid, the organic phase is separated, washed with water, dried over sodium sulphate and filtered and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate ranging from 100/0 to 70/30 and then with a 95/5 mixture of dichloromethane and methanol. After recrystallizing from a mixture of dichloromethane, methanol and acetonitrile, 0.72 g (2.15 mmol) of white solid is obtained. Melting point: 165.5°-166° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]([NH2:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[Cl:12][C:13]1[N:14]=[C:15]([NH:11][C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH3:10])[CH:16]=[N:17][CH:18]=1
Reactant: Clc1cncc(Cl)n1
Reactant: C[C@H](N)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1cncc(Cl)n1)c1ccc(F)c(F)c1
Temperature: 110 °C
Yield: 35.1 %

Procedure:
(1S)-1-(3,4-Difluorophenyl)ethanamine (977 mg, 6.2 mmol) and 2,6-dichloropyrazine (1.236 g, 8.3 mmol, 1.3 eq) was dissolved in dioxane (5 mL) and potassium carbonate (1.73 g, 2.0 eq) added to the solution. The mixture was then heated at reflux (110° C.) under a nitrogen atmosphere for 65 hours. The crude reaction mixture was then poured onto cold water (30 mL) and extracted with diethyl ether (3×30 mL). The combined organic extracts were concentrated and subjected to flashmaster chromatography (20 g silica cartridge (8:2 petroleum spirits:ethyl acetate, followed by ethyl acetate flush) to afford the desired pyrazine-adduct as an off-white solid (587 mg, 35%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH:37]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:35][CH:34]=2)[CH2:29][CH2:30][CH2:31]1
Reactant: Nc1ccc(CN2CCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(azetidin-1-yl-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol/ammonia=9:1:0.5) C27H25N3O3
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]([CH2:24][CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:9]1[C:10]([N+:21]([O-:23])=[O:22])=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)(=[O:4])=[O:3].CN(C=O)C.[NH2:36][CH2:37][CH2:38][CH2:39][OH:40].Cl>O=S(Cl)Cl>[CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]([CH2:24][CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:9]1[CH:17]=[C:13]([C:14]([NH:36][CH2:37][CH2:38][CH2:39][OH:40])=[O:16])[C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cc(C(=O)O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: NCCCO
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cc(C(=O)NCCCO)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 68 %

Procedure:
5-(Bis{2-[(methylsulfonyl)oxy]ethyl}amino)-2,4-dinitrobenzoic acid [A method of preparing this compound is disclosed in co-pending NZ Application No. 521851] (9) was heated under reflux in excess SOCl2 (60 mL) and catalytic DMF for1 h. Evaporation under reduced pressure, followed by azeotroping in benzene, gave the crude acid chloride. This was dissolved in dry Me2CO and treated at 0° C. with 3-amino-1-propanol at 0° C. for 5 min. The mixture was acidified to pH 2-3 with 0.2 N HCl, concentrated to half volume, and then solid NaBr was added, followed by extraction with EtOAc (2×). Evaporation, and chromatography of the residue on silica gel, eluting with EtOAc/MeOH (9:1), gave give 2-(5-{[(3-hydroxypropyl)amino]carbonyl } {2-[(methylsulfonyl)oxy]ethyl}-2,4-dinitroanilino)ethyl methanesulfonate (8) (68%) as a yellow gum; 1H NMR [(CD3)2SO] δ 8.54 (t, J=5.7 Hz, 1 H), 8.53 (s, 1 H), 7.45 (s, 1 H), 4.43 (t, J=5.1 Hz, 1 H), 4.33 (t, J=5.2 Hz, 4 H), 3.69 (t, J=5.2 Hz, 4 H), 3.57 (q, J=5.9 Hz, 2 H), 3.26 (after D2O exchange, t, J=7.0 Hz, 2 H), 3.12 (s, 6 H), 1.66 (pent, J=6.7 Hz, 2 H). HRMS (FAB) calcd. for C16H25N4O12S (MH+) m/z 529.0910; found 529.0904.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[CH:18]=O>>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[CH:18]=[CH:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: C=CCOc1ccc(C(C)=O)cc1
Product: C=CCOc1ccc(C(=O)C=Cc2cc(OC)ccc2OC)cc1
Reaction time: 2.5 h
Yield: 77.1 %

Procedure:
1.76 g (10 mmol) of 4-allyloxyacetophenone and 1.66 g (10 mmol) of 2,5-dimethoxy-benzaldehyde were under an inert atmosphere (argon) dissolved in 10 ml of dry freshly distilled ethanol, and 100 mg of sodium hydroxide was added to the solution. The mixture was left under stirring for 2.5 h and filtered. The precipitate was recrystallized from methanol to give 2.50 g (83%) of 2,5-dimethoxy-4′-prop-2-enyloxychalcone, m.p. 86-87° C.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[C:14]([CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:36]=[CH:37][CH:38]=1)[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31](O)=[O:32])=[CH:28][CH:29]=2)[C:24]([CH3:34])=[C:23]1[CH3:35])#[N:15]>>[C:14]([CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:36]=[CH:37][CH:38]=1)[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]([NH:13][C@H:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=3)[CH3:12])=[O:32])=[CH:28][CH:29]=2)[C:24]([CH3:34])=[C:23]1[CH3:35])#[N:15]
Reactant: Cc1c(C)n(Cc2cccc(OCC#N)c2)c2ccc(C(=O)O)cc12
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: Cc1c(C)n(Cc2cccc(OCC#N)c2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the 1-(3-(cyanomethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 480 [M+H]+.