Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:17])[N:11]([CH2:15][CH3:16])[C:12](=[O:14])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]1[CH2:23][CH2:22][CH:21]=[CH:20][CH:19]=1>ClCCl.CN(C1C=CC2N=C3C(=CC(C=C3)=[N+](C)C)SC=2C=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:20]4[CH2:21][CH2:22][CH:23]([CH:18]=[CH:19]4)[CH:13]2[C:12](=[O:14])[N:11]([CH2:15][CH3:16])[C:10]3=[O:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1=CCCC=C1
Reactant: CCN1C(=O)C=C(c2ccc(Cl)c(Cl)c2)C1=O
Agent: CN(C)c1ccc2nc3ccc(=[N+](C)C)cc-3sc2c1
Solvent: ClCCl
Product: CCN1C(=O)C2C3C=CC(CC3)C2(c2ccc(Cl)c(Cl)c2)C1=O
Yield: 57.4 %

Procedure:
A solution of 7.5 g of the above maleimide, 2.25 g of 1,3-cyclohexadiene, and 10 mg of methylene blue in 25 ml of dichloromethane was heated at reflux for 5 hours, then an additional one ml of the diene was added and the solution was heated for 24 hours. The cooled reaction mixture was subjected to high pressure liquid chromatography on a silica gel column eluting with hexane:ethyl acetate (4:1) and gave 5.58 g of 3a-(3,4-dichlorophenyl)-2-ethyl-3a,4,7,7a-tetrahydro-4,7-ethano-1H-isoindol-1,3(2H)-dione as a white solid, mp 122°-126° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][C:7]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H][H]>[Pd].C(OCC)(=O)C.C(O)(=O)C.C(O)C>[CH2:14]([NH:1][C@H:2]1[CH2:8][C:7]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:6]=2[CH2:5][CH2:4][CH2:3]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H]1CCCc2ccc(O)cc2C1
Reactant: O=Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)C[C@H](NCc1ccccc1)CCC2
Reaction time: 1 h

Procedure:
A mixture of (R)-8-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (5.8 g; contaminated with ammonium bromide), benzaldehyde (5.3 ml), acetic acid (0.15 ml), 10% palladium on carbon (50% wet; 1.1 g), and ethanol (260 ml) was stirred under hydrogen for 1 hour, and then an additional portion of benzaldehyde (5.3 ml) was added. After aging for 0.5 hour, hydrogen was introduced to the reaction mixture and stirring was continued for an additional 3 hours. To the reaction mixture was added an additional portion of acetic acid (0.15 ml), and the mixture was stirred under 1 atm of hydrogen for an additional 1 hour. The catalyst was filtered off, and washed with ethanol. Removal of the solvent in vacuo afforded the residue, which was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution; chloroform, then 100:1 to 50:1 to 10:1 chloroform-methanol) to give (R)-8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (6.6 g). Physical data are shown for the hydrochloride of the product, which was recrystallized from 3:1 diisopropyl ether-ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>>[ClH:1].[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:14]3[CH2:15][CH2:16][C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:13]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Clc1ccc2c(Cl)ccnc2c1
Product: Cl
Product: Clc1ccc2c(N3CCc4ccccc4C3)ccnc2c1

Procedure:
The title compound, MS: m/e=295.3 (M+H+), was prepared from 4,7-dichloroquinoline and 1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [C:1]([C:5]1[CH:32]=[CH:31][C:8]2[N:9]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:10]([CH2:12][CH:13]3[CH2:16][CH:15]([C:17](N(OC)C)=[O:18])[CH2:14]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:32]=[CH:31][C:8]2[N:9]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:10]([CH2:12][CH:13]3[CH2:16][CH:15]([CH:17]=[O:18])[CH2:14]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C1CC(Cc2nc3cc(C(C)(C)C)ccc3n2COCC[Si](C)(C)C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)nc(CC1CC(C=O)C1)n2COCC[Si](C)(C)C
Reaction time: 2.5 h
Yield: 130.5 %

Procedure:
To a solution of 3-[(5-tert-butyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)methyl]-N-methoxy-N-methylcyclobutane-1-carboxamide (0.61 g, 1.32 mmol) in tetrahydrofuran (15 ml) was added dropwise 1M diisobutylaluminum hydride solution in toluene (3.29 ml) under N2 at −10° C. The reaction was stirred at this temperature for 2.5 h before being quenched by the addition of methanol (2 ml) and stirred for 5 mins. The solution was poured onto saturated aq. Rochelle's salt (20 ml), diluted with Et2O (30 ml) and stirred for 30 min. This was then separated and the organic layer was washed with Rochelle's salt (30 ml), sat. NaHCO3 (30 ml), and brine (30 ml). This was dried (MgSO4) and concentrated to afford the title compound (0.69 g, 130%) as a colourless gum which was used crude in the next reaction.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:9]([CH3:14])=[N:10][NH:11][C:12]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2].CC(=O)CC(=O)C.[F:23][C:24]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:25]=1[CH2:26]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:12]([CH3:13])=[N:11][N:10]([CH2:26][C:25]2[CH:28]=[CH:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][C:24]=2[F:23])[C:9]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1n[nH]c(C)c1CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)CC(C)=O
Product: Cc1nn(Cc2ccc([N+](=O)[O-])cc2F)c(C)c1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (3,5-dimethyl-1H-pyrazol-4-yl)acetic acid tert-butyl ester (10 g, 47.6 mmol, preparation according to WO2007/141267 by using 2,4-pentanedione instead of 3,5-heptanedione) and 2-fluoro-4-nitrobenzyl bromide (11.2 g, 47.9 mmol) in acetonitrile (150 mL) is added K2CO3 (6.615 g, 47.9 mmol) and the mixture is stirred for 24 hours at room temperature. The solid is filtered off and the solvent is removed by evaporation. The residue is dissolved in dichloromethane/water. After extraction with dichloromethane the organic layer is dried over MgSO4 and evaporated under reduced pressure. The residue is purified by MPLC (cyclohexane/ethyl acetate 7:3, silicagel 60) to yield 13.6 g of [3,5-dimethyl-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid tert-butyl ester (ESI mass spectrum: [M+H]+=364 TLC: Rf=0.23 (cyclohexan/ethyl acetate 7:3, solicagel 60 F254)). b) To a solution of [3,5-dimethyl-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid tert-butyl ester (13.6 g, 37.4 mmol) in methanol (250 mL) is added Raney nickel (6 g) and the mixture is hydrogenated at 50 psi and 50° C. for 12 hours. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to yield 11.6 g of the title compound (ESI mass spectrum: [M+H]+=334; TLC: Rf=0.53 (dichloromethane/methanol 95:5, silicagel 60 F254)).
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]([F:38])([F:37])[C:8]1[CH:9]=[C:10]([C:18]([CH3:36])([CH3:35])[C:19]([N:21]([C@H:23]2[C@H:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:26][NH:25][CH2:24]2)[CH3:22])=[O:20])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.N1CCCC1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[F:17][C:14]([F:15])([F:16])[C:12]1[CH:11]=[C:10]([C:18]([CH3:35])([CH3:36])[C:19]([N:21]([C@H:23]2[C@H:27]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:26][N:25]([C:3](=[O:4])[CH2:2][Br:1])[CH2:24]2)[CH3:22])=[O:20])[CH:9]=[C:8]([C:7]([F:38])([F:37])[F:6])[CH:13]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccc(F)cc1
Reactant: O=C(Cl)CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(C(=O)CBr)C[C@H]1c1ccc(F)cc1
Yield: 70 %

Procedure:
To a stirred solution of bromo-acetyl chloride (0.80 g, 4 mmol) in CH2Cl2 (5 ml) at 0° C. was added over 1 hour a solution of rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-[(3S,4R)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-N-methyl-isobutyramide (pyrrolidine interm. VII-4 described herein above, 0.94 g, 1.97 mmol) and ethyl-diisopropyl-amine (0.37 ml, 2.17 mmol) in CH2Cl2 (10 mL). The reaction was stirred over night, quenched by addition of an aqueous solution of NaHCO3, and the product extracted with CH2Cl2. Purification by flash chromatography (SiO2, EtOAc/Hx 1:1) yielded 0.83 g (70%) of rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-[(3S,4R)-1-(2-bromo-acetyl)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-N-methyl-isobutyramide as a white foam.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[N:13][OH:14])=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].ClCCl.[C:22]([O-])(=O)[CH3:23].[Na+].Cl[O-].[Na+]>C=C>[Cl:1][C:2]1[C:11]([C:12]2[CH2:23][CH2:22][O:14][N:13]=2)=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Agent: C=C
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOCC2)c1Cl
Reaction time: 12 h

Procedure:
Ethylene was passed for 30 minutes at 15-20° C. into a solution of 158.0 g (0.54 mol) of methyl 2-chloro-3-hydroxyiminomethyl-4-methylsulfonylbenzoate and 1 l of dichloromethane. After 1.6 g of sodium acetate had been added, 454 ml of sodium hypochlorite solution were added dropwise at 10° C. while simultaneously passing in ethylene. Ethylene was subsequently passed in at 10° C. for a further 15 minutes. After the mixture had been stirred for 12 hours, the phases were separated, and the organic phase was washed with water, dried and concentrated. This gave 156.5 g (90% of theory) of methyl 2-chloro-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoate.
Reaction SMILES: [CH2:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][C@@H:6]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:5]1)[CH:2]=[CH2:3].O.C([O-])(O)=[O:39].[Na+].OO>C1COCC1>[OH:39][CH2:3][CH2:2][CH2:1][C@@H:4]1[C@@H:8]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:7][C@@H:6]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:5]1
Reactant: C=CC[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn([C@H]2C[C@H](CCCO)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Yield: 39.2 %

Procedure:
Compound 37 (0.74 g, 2 mmol) was treated with BH3Me2S (0.388 g, 5.12 mmol) in THF (10 ml). The reaction mixture was quenched with MeOH (0.7 mL). H2O (3 mL) and NaHCO3 (1.11 g, 13.3 mmol) were added to the reaction mixture followed by H2O2 (30%, 1.91 mL, 16.92 mmol). After work-up, the residue was purified by silica gel chromatography. The product was crystallized from ether/hexane to furnish 0.41 g of the product as white needles. mp 150°-151° C.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[C:5]([C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])#[CH:6].[N-:25]=[N+:26]=[N-:27].[Na+].C(O)(C)(C)C>C(OCC)(=O)C.N.[Cu]I.O>[CH:2]([N:25]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[N:27]=[N:26]1)([CH3:4])[CH3:3]
Reactant: C#Cc1cccc(CCOCCC(=O)OC(C)(C)C)c1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)I
Agent: [Cu]I
Agent: N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)n1cc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)nn1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
2-Iodopropane (0.168 mL) was added in one portion to a mixture tert-butyl 3-(3-ethynylphenethoxy)propanoate [Example 4, Step ii)] (383 mg), sodium azide (109 mg), tert-butanol (0.75 mL), water (3 mL) and copper(I) iodide (26.6 mg) and sealed into a microwave tube. The reaction was heated to 80° C., over a period of 3 h in the microwave reactor. The reaction mixture was diluted with ethyl acetate and 35% ammonia (1 mL) and ethyl acetate (2 mL) were added. The mixture was stirred for 30 min. and extracted into ethyl acetate. The organic was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 100% ethyl acetate in isohexane to afford the titled compound (291 mg) as an oil. 1H NMR (300 MHz, CDCl3) δ 7.79 (s, 1H), 7.72-7.64 (m, 2H), 7.33 (t, J=7.6 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 4.89 (septet, J=6.6 Hz, 1H), 3.70 (t, J=6.4 Hz, 2H), 3.697 (t, J=7.3 Hz, 2H), 2.92 (t, J=7.1 Hz, 2H), 2.49 (t, J=6.4 Hz, 2H), 1.63 (d, J=6.7 Hz, 6H), 1.43 (s, 9H)
Reaction SMILES: O=S(Cl)[Cl:3].[CH2:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[N:11]=[N:10][C:9]=1[CH2:17]O)[CH3:6]>C(Cl)Cl>[Cl:3][CH2:17][C:9]1[N:10]=[N:11][C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=1[O:7][CH2:5][CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCOc1cc(OCC)c(CO)nn1
Solvent: ClCCl
Product: CCOc1cc(OCC)c(CCl)nn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Excess SOCl2 is added to a stirred solution of (4,6-diethoxy-pyridazin-3-yl)-methanol (174 mg, 0.88 mmol) in CH2Cl2 (4 mL). The reaction mixture is stirred at room temperature for 4 hours. The solvent is then removed in vacuo; toluene (4 mL) is added and evaporated to dryness. Flash column chromatography purification (silica gel, eluted with 3:1 Hexane, EtOAc) of the residue provides the title compound as a clear oil. H1 NMR δ (CDCl3) 6.28(s, 1H), 4.78 (s, 2H), 4.54 (q, 2H, J=7.2 Hz), 4.11 (q, 2H, J=7.2 Hz), 1.48 (t, 3H, J=7.2 Hz), 1.41 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[NH:7]C(=O)[O:9][C:10](=O)[C:5]=2[CH:4]=1.[NH4+:15].[OH-]>C1COCC1>[NH2:7][C:6]1[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:10]([NH2:15])=[O:9]
Reactant: COc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(N)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-methoxy-1H-benzo[d][1.3]oxazine-2,4-dione (7.0 g, 36.2 mmol) in THF (50 mL) was added NH4OH (20 mL) and the reaction was stirred at rt for 1 h. The solution was concentrated under reduced pressure and dried to give 5.0 g of 2-amino-5-methoxy-benzamide as a dark brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([N:8]([CH2:13][C:14]([N:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH3:17])=[O:15])[CH2:9][C:10](O)=[O:11])[CH:7]=1.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([N:8]([CH2:13][C:14]([N:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH3:17])=[O:15])[CH2:9][C:10]([NH:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:11])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N(CC(=O)O)CC(=O)N(C)N1Cc2ccccc2C1
Reactant: NCCN1CCCC1
Product: Cc1ccc(Cl)cc1N(CC(=O)NCCN1CCCC1)CC(=O)N(C)N1Cc2ccccc2C1
Yield: 73.8 %

Procedure:
Using the compound (300 mg, 0.77 mmol) obtained in step A, and 1-(2-aminoethyl)pyrrolidine (0.11 ml, 0.85 mmol), and according to the method of Example 1, step B, the title compound (275 mg, yield 74%) was obtained as a pale-yellow amorphous solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH2:11].C(N(CC)CC)C>ClCCl>[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH:11][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: COC(CN)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)NCC(OC)OC
Reaction time: 4 h
Yield: 65 %

Procedure:
Over a period of 4 hours, 104.5 parts of methacryloyl chloride dissolved in 105 parts of dichloromethane are added dropwise at a maximum of 15° C., while cooling with ice, to 105.14 parts of aminoacetaldehyde dimethylacetal and 101.2 parts of triethylamine in 200 parts of dichloromethane. When the reaction is complete, the dichloromethane phase is washed with 200 parts of water then with 200 parts of 1N HCl solution, and then twice with 200 parts of water. After drying with anhydrous magnesium sulfate, the dichloromethane phase is concentrated by evaporation and stabilised with 0.1% of 2,6-di-tert-butyl-p-cresol, based on the reaction product. After distillation at 90° C. 10-3 mbar, 112 g of methacrylamidoacetaldehyde dimethylacetal are obtained in the form of a colourless liquid, boiling point 92° C. 10-3 mbar (65% yield).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[CH:6]=[C:5]([CH3:11])[C:3]=1[OH:4].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:16][C:17]([CH3:21])=[CH:18][CH2:19]O>ClCCl>[CH3:16][C:17]1([CH3:21])[CH2:18][CH2:19][C:6]2[C:7](=[C:8]([CH3:9])[C:2]([CH3:1])=[C:3]([OH:4])[C:5]=2[CH3:11])[O:10]1
Reactant: CC(C)=CCO
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C)O2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
257 g (1.69 mol) of 2,3,6-trimethylhydroquinone were introduced into a suspension of 248 g (1.86 mol) of anhydrous aluminum chloride in 850 ml of dry dichloromethane at 5° C. After stirring for 30 min, 160 g (1.86 mol) of 3-methyl-2-buten-1-ol were added dropwise at 5°-10° C. The mixture was stirred at room temperature overnight and then poured into ice-water, the precipitate was filtered off, the filtrate was extracted with dichloromethane, and the organic phase was washed with water to neutrality, dried over magnesium sulfate and evaporated. Distillation of the residue provided a main fraction of 153.3 g of the title compound at 140° C. and 0.4 mbar, and this was recrystallized from heptane with a melting point of 85°-88° C.
Reaction SMILES: Cl[CH:2]([CH:8]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[S:10]([N:20]1[C:28]2[C:23](=[N:24][C:25]([NH2:29])=[CH:26][N:27]=2)[CH:22]=[CH:21]1)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].C(O)CCC>O1CCOCC1>[S:10]([N:20]1[C:28]2[N:27]=[CH:26][C:25]3[N:24]([C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:8][N:29]=3)[C:23]=2[CH:22]=[CH:21]1)([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(N)cnc32)cc1
Reactant: CCOC(=O)C(Cl)C=O
Solvent: CCCCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of ethyl 2-chloro-3-oxopropanoate (1.60 g, 7.65 mmol, prepared as described in US2009005359A1) and 1,4-dioxane (10.0 mL) was added to 5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-amine (1.45 g, 5.03 mmol, Preparation #E.1.1) under nitrogen. Anhydrous butan-1-ol (30.0 mL) was added, a reflux condenser was attached, and the system was sealed. After about 30 min, the mixture was warmed to about 80° C. The solution was allowed to cool to ambient temperature. A solution of ethyl 2-chloro-3-oxopropanoate (2.78 g, 13.3 mmol) and 1,4-dioxane (5 mL) was added. After about 30 min, the reaction mixture was warmed to about 80° C. After about 30 min, the mixture was warmed to about 125° C. After about 48 h, the brown solution was allowed to cool to ambient temperature. The volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 5-50% EtOAc in heptane to give ethyl 3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-carboxylate (1.16 g, 60%): LC/MS (Table 1, Method b) Rt=2.52 min; MS m/z 385 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:24](O)([CH3:26])[CH3:25])[C:7]([O:11][C@@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH:35]2[CH2:40][CH2:39][N:38]([C:41]3[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=3)[CH2:37][CH2:36]2)[CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C.CN1CCCC1=O>O>[C:1]([C:4]1[N:5]=[C:6]([C:24]([CH3:26])=[CH2:25])[C:7]([O:11][C@@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[N:8][C:9]=1[NH:45][C:44]1[CH:46]=[CH:47][C:41]([N:38]2[CH2:39][CH2:40][CH:35]([N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)[CH2:36][CH2:37]2)=[CH:42][CH:43]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2nc(Cl)c(C(N)=O)nc2C(C)(C)O)C1
Reactant: CN1CCN(C2CCN(c3ccc(N)cc3)CC2)CC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C=C(C)c1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1O[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Yield: 65.4 %

Procedure:
A mixture of tert-butyl (3R)-3-{[5-carbamoyl-6-chloro-3-(2-hydroxypropan-2-yl)pyrazin-2-yl]oxy}pyrrolidine-1-carboxylate (300 mg), 4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (680 mg), diisopropylethylamine (400 μL), and N-methylpyrrolidone (1.2 mL) was reacted in a microwave reaction device at 180° C. for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1), and then washed with diisopropyl ether to obtain tert-butyl (3R)-3-{[5-carbamoyl-6-({-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-3-(prop-1-en-2-yl)pyrazin-2-yl]oxy}pyrrolidine-1-carboxylate (304 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][C:24]=1[N+:37]([O-:39])=[O:38]>CN(C=O)C.CCOCC>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][O:12][C:3]2[C:4]([N+:9]([O-:11])=[O:10])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])=[C:24]([N+:37]([O-:39])=[O:38])[CH:25]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1OCCBr
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1OCCOc1c([N+](=O)[O-])ccc(F)c1F
Temperature: 70 °C
Yield: 69.4 %

Procedure:
2,3-Difluoro-6-nitrophenol (0.7 g, 3.7 mmol) was stirred with K2CO3 (0.5 g, 3.7 mmol) in DMF (10 mL) for 10 min. Bromoethane 6 (1.1 g, 3.1 mmol) was added to the reaction mixture and heated at 70° C. for 24 hrs. The reaction mixture was diluted with ether (30 mL) and washed with water (20 mL) and then brine (20 mL). The ether layer was dried (MgSO4) and concentrated under reduced pressure. Fractionation of the crude product by flash chromatography with 4:1 hexane/ethyl acetate provided 7 as a yellow oil (960 mg, 63%). 1H NMR: 4.45 (t, J=5 Hz, 2H), 4.71 (t, J=5 Hz, 2H), 5.05 (s, 2H), 7.0-7.7 (m, 10H)
Reaction SMILES: [CH:1]1([NH:4][C:5](=[NH:14])[C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Br[C:16](=[CH:19]OC(C)C)[CH:17]=[O:18].C([O-])([O-])=O.[K+].[K+].C(Cl)(Cl)Cl>O>[CH:1]1([N:4]2[C:16]([CH:17]=[O:18])=[CH:19][N:14]=[C:5]2[C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(C(=N)NC2CC2)cc1
Reactant: CC(C)OC=C(Br)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(-c2ncc(C=O)n2C2CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.6 %

Procedure:
N-cyclopropyl-4-methoxy-benzamidine (0.90 g, 4.75 mmol), 2-bromo-3-isopropoxy-propenal (1.37 g, 7.12 mmol) and K2CO3 (0.98 g, 7.12 mmol) were mixed with chloroform (10 ml) and water (1.2 ml), followed by stirring at r.t. for 24 h. After drying of the reaction mixture (Na2SO4), filtration and concentration of the filterate in-vacuo, the crude residue was purified via flash chromatography (40% EA in hex.) to isolate the title compound (973 mg, 85%). 1H-NMR: 9.83 (s, 1H), 7.82 (m, 3H), 7.02 (d, 2H), 3.89 (s, 3H), 3.58 (m, 1H), 1.13 (m, 2H), 0.64 (m, 2H).