Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:23]2[C:24]([F:41])=[C:25]([NH:29][S:30]([C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:42].[OH-].C(Cl)Cl>CO>[NH2:42][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:23]2[C:24]([F:41])=[C:25]([NH:29][S:30]([C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CS(=O)(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(N)n3)s2)CC1
Yield: 101.7 %

Procedure:
A solution of N-(3-{5-(2-chloro-4-pyrimidinyl)-2-[4-(methylsulfonyl)-1-piperazinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide (0.14 g, 0.22 mmol) in NH4OH (2.5 mL, 65 mmol) was sealed in a microwave vial and irradiated at 140° C. for 12 min. LCMS analysis indicates complete conversion to product. The reaction mixture was transferred to a round bottom flask with DCM and MeOH. A precipitate formed while attempting to remove the volatiles in vacuo and it was collected by vacuum filtration. The pale yellow solid was dried in vacuo to afford the title compound (0.14 g, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.76 (br. s., 1H), 7.84 (d, J=5.3 Hz, 1H), 7.46-7.61 (m, 3H), 7.38-7.46 (m, 1H), 7.22-7.34 (m, 2H), 6.59 (br. s., 2H), 5.64 (d, J=5.1 Hz, 1H), 3.60 (br. s., 4H), 3.26 (br. s., 4H), 2.92 (s, 3H). MS (ES+): 626 [M+H]+.
Reaction SMILES: [Na:1].C([O:9][C@@H:10]1[C@@H:15]([O:16]CC2C=CC=CC=2)[C@H:14]([O:24]CC2C=CC=CC=2)[C@@H:13]([CH2:32][S:33]([OH:36])(=[O:35])=[O:34])[O:12][C@@H:11]1[O:37][CH2:38][CH2:39][CH2:40][O:41][C:42](=[O:60])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])C1C=CC=CC=1.[H][H]>C(O)C.ClCCl.[Pd]>[Na:1].[S:33]([CH2:32][C@H:13]1[O:12][C@H:11]([O:37][CH2:38][CH2:39][CH2:40][O:41][C:42](=[O:60])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C@H:10]([OH:9])[C@@H:15]([OH:16])[C@@H:14]1[OH:24])([OH:36])(=[O:34])=[O:35]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCCCO[C@H]1O[C@H](CS(=O)(=O)O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na]
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC(=O)OCCCO[C@H]1O[C@H](CS(=O)(=O)O)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
To a solution of the compound (9) (28.7 g, 33.3 mmol) in ethanol (400 ml) and dichloromethane (150 ml) was added 10% palladium activated carbon (7.00 g), and the mixture was stirred at room temperature for 48 hours in a hydrogen gas atmosphere. After the sufficient progress of the reaction was confirmed, palladium activated carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified with silica gel chromatography (dichloromethane-methanol, 10:1→5:1→3:1→2:1→1:1), and precipitated from 98% heated ethanol to obtain the title compound (10) in the form of a colorless powder {15.6 g (26.4 mmol), 79.4%}.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:11].O>C(Cl)Cl>[Cl:11]/[C:3](/[CH3:5])=[CH:2]/[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)/C=C(\C)Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 7.7 %

Procedure:
In a reaction vessel flushed with argon gas was placed 437.4 grams (3.36 moles) of ethyl acetoacetate in 500 ml of methylene chloride. The stirred solution was cooled to 0° C. and 700 grams (3.36 moles) of phosphorous pentachloride was added in portions at a rate such that the reaction mixture temperature did not exceed 5°. Upon completion of addition, the reaction mixture was stirred at 0°-5° for 16 hours. Five-hundred ml of water was added dropwise, and the layers in the resultant two-phase system were separated. The water layer was made alkaline with solid sodium bicarbonate and extracted with several 100-ml portions of methylene chloride. The organic layer from the reaction mixture was washed with water until all the solid material in it dissolved. The washed organic layer and the methylene chloride washings of the water layer were combined and dried with sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to a residual oil. The oil was first distilled under reduced pressure using a Vigreux column. Fractions boiling at 52°-65°/0.40-1.07×103Pa were combined and subjected to a second distillation under reduced pressure using a spinning band distilling system. Fractions boiling at 66°-70°/0.40-1.07×103Pa from the first distillation and fractions boiling at 66.5°-82°/1.20×103Pa from the second distillation were subjected to a third distillation under reduced pressure using a spinning band distilling system. The fraction, bp 46°/1.33×103Pa from the second distillation was combined with the fractions, bp 42°-45°/1.20×103Pa from the third distillation to give 38.4 grams of ethyl [E]-3-chloro-2-butenoate.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:13]=[C:14](S(C)=O)[NH:15][C:16](=[O:21])[C:17]=2[C:18]([NH2:20])=[O:19])[CH:8]=[CH:9][CH:10]=1)=[O:4].[NH2:25][CH2:26][C:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CN1C(=O)CCC1>C(OCC)(=O)C>[NH2:33][C:27]1([CH2:26][NH:25][C:14]2[NH:15][C:16](=[O:21])[C:17]([C:18]([NH2:20])=[O:19])=[C:12]([NH:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[CH:6]=3)[N:13]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CNC(=O)c1cccc(Nc2nc(S(C)=O)[nH]c(=O)c2C(N)=O)c1
Reactant: NCC1(N)CCCCC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cccc(Nc2nc(NCC3(N)CCCCC3)[nH]c(=O)c2C(N)=O)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
A mixture of 4-{[3-(methylcarbamoyl)phenyl]amino}-2-(methylsulfinyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (Preparation Example 311) (234 mg), 1-(aminomethyl)cyclohexaneamine (172 mg) and NMP (2 mL) was stirred at 80° C. for 30 minutes. After cooling, the reaction liquid was diluted with ethyl acetate, and the precipitated solid was collected by filtration. This solid was heated with ethanol-water and washed to give 2-{[(1-aminocyclohexyl)methyl]amino}-4-{[3-(methylcarbamoyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide (215 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:2].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:2]
Reactant: CCOc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: CCOc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 88.5 %

Procedure:
To 2-(ethyloxy)-4-fluoro-1-nitrobenzene (Example 116, step A) (3.0 g, 16.2 mmol) in 60 mL of dioxane was added, piperazine (4.19 g, 48.61 mmol). The mixture was heated to 120° C. 72 h. The mixture was purified by flash chromatography to give the title compound of step A (3.6 g, 14.33 mmol, 88%). 1H NMR (400 MHz, CDCl3) δ ppm 7.95 (d, J=9.34 Hz, 1H), 6.40 (dd, J=9.34, 2.56 Hz, 1H), 6.30 (d, J=2.56 Hz, 1H), 4.13 (q, J=6.96 Hz, 2H), 3.30-3.33 (m, 4H), 2.95-3.02 (m, 4H), 1.48 (t, J=6.96 Hz, 3H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]([N:36]([C:38]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=2)[CH3:37])=[O:35])[CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[O:27]1[CH2:28][CH2:29][N:30]([CH2:33][C:34]([N:36]([C:38]2[CH:44]=[CH:43][C:41]([NH:42]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:40][CH:39]=2)[CH3:37])=[O:35])[CH2:31][CH2:32]1
Reactant: CN(C(=O)CN1CCOCC1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C(=O)CN1CCOCC1)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(N-morpholinomethylcarbonyl-N-methyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1)=O.Cl.[N:13]1[O:14][N:15]=[C:16]2[CH:21]=[C:20]([CH2:22][O:23][NH2:24])[CH:19]=[CH:18][C:17]=12.N1C=CC=CC=1>C(O)C>[N:13]1[O:14][N:15]=[C:16]2[CH:21]=[C:20]([CH2:22][O:23][N:24]=[C:2]([C:4]3[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=3)[CH3:1])[CH:19]=[CH:18][C:17]=12
Reactant: CC(=O)c1ccc(O)c(F)c1
Reactant: NOCc1ccc2nonc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NOCc1ccc2nonc2c1)c1ccc(O)c(F)c1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A solution of 3-fluoro-4-hydroxyacetophenone (0.061 g, 0.398 mmol), (benzo[c][1,2,5]oxadiazol-5-yl)methoxyamine hydrochloride (0.095 g, 0.470 mmol) and pyridine (0.13 ml, 1.61 mmol) in ethanol (5 ml) was stirred at reflux under nitrogen for 4 h and cooled to room temperature. The solution was concentrated to a pale yellow oil which was diluted with water. The resultant suspension was extracted with dichloromethane (×3). The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and concentrated to an off-white solid. The crude product was purified by column chromatography (SiO2), eluting with 9:1 petrol/ethyl acetate, to give a pale beige solid which was further washed with petrol/dichloromethane to give 3′-fluoro-4′-hydroxyacetophenone-O-[(benzo[c][1,2,5]oxadiazol-5-yl)methyl]oxime (CP9-128) as a pale beige solid (0.098 g, 82%), m.p. 139-140°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[N:5]([CH:12]([C:20]1[CH:25]=[CH:24][C:23]([O:26]CC2C=CC=CC=2)=[C:22]([O:34][CH3:35])[CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)CC(OC)OC)[CH3:2].[C:37](OCC)(=[O:39])C.CCCCCC>C(OCC)(=O)C.C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:36])[NH:5][CH:12]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:34][CH3:35])[CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:39][CH3:37])[CH:15]=1)[CH3:2]
Reactant: CCOC(=O)N(CC(OC)OC)C(Cc1ccccc1)c1ccc(OCc2ccccc2)c(OC)c1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)NC(Cc1cccc(OC)c1)c1ccc(O)c(OC)c1
Reaction time: 15 h
Yield: 56 %

Procedure:
To a stirred solution of [1-(4-benzyloxy-3-methoxy-phenyl)-2-phenyl-ethyl]-(2,2-dimethoxy-ethyl)-carbamic acid ethyl ester (10.5 g, 20 mmol) in ethyl acetate (100 mL) and ethanol (50 mL) was added 10% palladium on activated carbon (2 g). The mixture was hydrogenated at 1 atm for 15 hrs. The solution was filtered through a Celite plug and evaporated to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) afforded (2,2-dimethoxy-ethyl)-[1-(4-hydroxy-3-methoxy-phenyl)-2-(3-methoxy-phenyl)-ethyl-carbamic acid ethyl ester as a colorless oil. (4.87 g, 56% yield)
Reaction SMILES: COS(OC)(=O)=O.[CH3:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][N+:10]=1[O-].[C-:19]#[N:20].[K+]>O>[CH3:8][C:9]1[N:10]=[C:11]([C:19]#[N:20])[CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: [C-]#N
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C#N)n1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
To 10.2 ml (13.5 g, 104 mmol, 1.1 equiv.) of dimethylsulfate were added 15.0 g (94.4 mmol) of 2-Methyl-4-nitropyridine-N-oxide at 60° C. The reaction mixture was then stirred for 90 min at 70° C., and allowed to cool to room temperature. The solidified residue was triturated with 30 ml of ether. The product was filtered, washed with 20 ml of ether, and dried. The product was then dissolved in 100 ml of water and added dropwise over a period of 30 min. to a at −8° C. cooled solution of 24.6 g (377 mmol, 4.0 equiv.) of potassium cyanide in 100 ml of water. The reaction mixture was stirred for a further 15 min. at −8° C. The product was filtered off, washed twice with 15 ml of water and dried in vaccuo to yield the title compound (11.1 g, 72%) as a light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][C:14]3([CH2:17][OH:18])[CH2:16][CH2:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C:19](=[O:20])[O:18][CH2:17][C:14]43[CH2:15][CH2:16]4)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCC1(Nc2nc(-c3ccc(Br)cc3)cs2)CC1
Solvent: CC#N
Product: O=C1OCC2(CC2)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 165 °C
Reaction time: 0.03 h
Yield: 74 %

Procedure:
A mixture of (1-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}cyclopropyl)methanol (0.7598 g 2.34 mmol), prepared in previous step, and 15 mL of anhydrous acetonitrile were sonicated for 1 min and then stirred on a vortex stirrer for 2 min. To the resulting solution, carbonyldiimidazole (0.5683 g, 3.5 mmol) was added and the mixture again sonicated for 1 min and stirred on a vortex stirrer for 2 min. The resulting solution was then heated in an Emrys™ Optimizer microwave oven at 165° C. for 20 min. Upon cooling to room temperature crystals began to form. The crystals were collected by filtration and the filtrate was concentrated under reduced pressure. The residue was partitioned between methylene chloride and 2N HCl. The organic layer was separated, washed with water, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material obtained was combined with the crystalline material previously isolated to give the title compound (607.9 mg 75%) as a white solid, mp 201-202° C.; MS (ESI) m/z 351. HRMS: calcd for C14H11BrN2O2S+H+, 350.97973; found (ESI, [M+H]+), 350.9806.
Reaction SMILES: CS[C:3]1[C:4]2[C:5](=[CH:14][S:15][CH:16]=2)[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)(=O)C>[N:17]1([C:3]2[C:4]3[C:5](=[CH:14][S:15][CH:16]=3)[NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CSC1=Nc2ccccc2Nc2cscc21
Reactant: C1CNCCN1
Solvent: CC(=O)O
Product: c1ccc2c(c1)N=C(N1CCNCC1)c1cscc1N2

Procedure:
A bomb charged with 2.5 g. of 10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine, 8.6 g. of piperazine, and three drops of acetic acid is placed in an oil bath and heated at 155°-160° C. for 4 days. The bomb is then cooled and the contents are dissolved in 2N acetic acid. The solution is filtered and the filtrate is made alkaline with ammonium hydroxide and extracted with chloroform. The extracts are dried, filtered and evaporated to give a yellow solid. Recrystallization from ethanol gives the product as light tan crystals which melt at 228°-231° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[N:33]([C:34]([C:36]4[C:37]([CH3:41])=[N:38][O:39][CH:40]=4)=[O:35])[CH2:32][CH2:31][N:10]2[C:11](=[O:30])[C:12]2[N:13]([C:15]4[N:20]=[C:19]([CH3:21])[N:18](COCC[Si](C)(C)C)[C:16]=4[CH:17]=2)[CH2:14]3)=[CH:5][CH:4]=1.COC1C=CC([C@]23N(C(C4C(C)=NOC=4)=O)CCN2C(=O)C2N(C4N(COCC[Si](C)(C)C)C=NC=4C=2)C3)=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]23[N:33]([C:34]([C:36]4[C:37]([CH3:41])=[N:38][O:39][CH:40]=4)=[O:35])[CH2:32][CH2:31][N:10]2[C:11](=[O:30])[C:12]2[N:13]([C:15]4[NH:20][C:19]([CH3:21])=[N:18][C:16]=4[CH:17]=2)[CH2:14]3)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@]23Cn4c(cc5c4nc(C)n5COCC[Si](C)(C)C)C(=O)N2CCN3C(=O)c2conc2C)cc1
Agent: COc1ccc([C@@]23Cn4c(cc5ncn(COCC[Si](C)(C)C)c54)C(=O)N2CCN3C(=O)c2conc2C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C23Cn4c(cc5nc(C)[nH]c54)C(=O)N2CCN3C(=O)c2conc2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Either (5aS)-5a-(4-methoxyphenyl)-2-methyl-6-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-5a,6,7,8-tetrahydro-5H-imidazo[1,2-a]imidazo[4′,5′:4,5]pyrrolo[1,2-d]pyrazin-10(1H)-one or its regioisomer (5aS)-5a-(4-methoxyphenyl)-6-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-3-{[2-(trimethylsilyl)ethoxy]methyl}-5a,6,7,8-tetrahydro-5H-imidazo[1,2-a]imidazo[4′,5′:4,5]pyrrolo[1,2-d]pyrazin-10(3H)-one (27 mg, 0.048 mmol) similarly prepared according to steps (a), (b) and (c) was dissolved in dichloromethane (0.9 mL) and treated with trifluoro acetic acid (2.1 mL). The mixture was stirred at room temperature. After one hour the LCMS indicated complete deprotection. The mixture was then concentrated in vacuo and the residue obtained purified by flash chromatography using the biotage SP4 (0-5% MeOH gradient in EtOAc) to yield either 5a-(4-methoxyphenyl)-2-methyl-6-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-5a,6,7,8-tetrahydro-5H-imidazo[1,2-a]imidazo[4′,5′:4,5]pyrrolo[1,2-d]pyrazin-10(1H)-one (2) or its regioisomer 5a-(4-methoxyphenyl)-2-methyl-6-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-5a,6,7,8-tetrahydro-5H-imidazo[1,2-a]imidazo[4′,5′:4,5]pyrrolo[1,2-d]pyrazin-10(3H)-one (8.5 mg, 40% yield). ESI-MI m/z [M+H]+ 447.09. 1H NMR (400 MHz, CDCl3) δ 8.53 (br s, 1H), 8.46 (br s, 1H), 7.43 (br d, J=8.9 Hz, 2H), 6.82-6.73 (m, 2H), 6.69 (s, 1H), 6.05 (d, J=13.1 Hz, 1H), 4.46 (d, J=12.8 Hz, 1H), 4.35 (ddd, J=10.7, 8.8, 4.6 Hz, 1H), 4.00 (td, J=8.9, 5.6 Hz, 1H), 3.83 (tdd, J=13.2, 9.8, 6.6 Hz, 2H), 3.72 (s, 3H), 2.52 (s, 3H), 2.42 (d, J=0.5 Hz, 3H). The compounds in Table 1 were similarly prepared by reference to the general method(s) and/or synthetic examples.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]([CH2:35][CH3:36])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([N+:32]([O-:34])=[O:33])[CH:23]=1)=O)(C)(C)C>C(Cl)Cl>[CH2:35]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([N+:32]([O-:34])=[O:33])[CH:23]=1)[CH3:36]
Reactant: CCN(C(=O)OC(C)(C)C)c1ccccc1-c1ccc(C(=O)OC)c([N+](=O)[O-])c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNc1ccccc1-c1ccc(C(=O)OC)c([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Trifluoroacetic acid (4.5 mL) was added to a methylene chloride (2.0 mL) solution of methyl 4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2-nitrobenzoate (0.39 g) at room temperature, followed by stirring at the same temperature for 1 hour. The solvent was evaporated under reduced pressure, and ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 91-85% hexane/ethyl acetate] to obtain 0.27 g of methyl 4-(2-(ethylamino)phenyl)-2-nitrobenzoate as an orange oily substance.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[N:19]=[C:18]([C:28]([N:30]3[CH2:34][C:33](=[O:35])[NH:32][CH2:31]3)=[O:29])[CH:17]=2)[CH:11]=1)(=O)=O.[CH2:36]([NH2:38])[CH3:37].[CH:39]([OH:41])=[O:40].ClC1C=C(N2C(C3C=CC=C(OCCCN(C)C)C=3)=CC(C(N3CC(=O)NC3)=O)=N2)C=CC=1>O1CCCC1>[CH:39]([OH:41])=[O:40].[Cl:27][C:23]1[CH:22]=[C:21]([N:20]2[C:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][NH:38][CH2:36][CH3:37])[CH:11]=3)=[CH:17][C:18]([C:28]([N:30]3[CH2:34][C:33](=[O:35])[NH:32][CH2:31]3)=[O:29])=[N:19]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)OCCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Reactant: CCN
Agent: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: C1CCOC1
Solvent: O=CO
Product: CCNCCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 120A and ethylamine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 23 mg (21% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([S:16]([CH:19]=[CH2:20])(=[O:18])=[O:17])[CH3:15]>>[CH2:14]([S:16]([CH2:19][CH2:20][P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:18])=[O:17])[CH3:15]
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=CS(=O)(=O)CC
Product: CCS(=O)(=O)CCP(c1ccccc1)c1ccccc1
Reaction time: 1.75 h
Yield: 69 %

Procedure:
A mixture of 64 g (0.34 mole) of diphenyl phosphine and 40.2 g (0.33 mole) of highly reactive, freshly distilled vinyl ethyl sulfone monomer was irradiated in the usual manner. To suppress polymer forming side reactions the temperature of the reaction mixture was kept below 5° C. by an ice-water bath and the u.v. irradiation was limited to 105 minutes. The adduct formed crystallized from the liquid mixture by the end of the reaction period. Consequently, the reaction mixture was filtered with suction to recover the crude, crystalline product, i.e. 2-ethylsulfonylethyl diphenyl phosphine. The crude, dried product (94 g, 94%) was recrystallized from 670 ml methanol to yield 69 g (69%) of the compound (of unpleasant odor) as a white crystalline solid (Table 4).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:13][C:12]=3[F:28])=[CH:6][N:5]2[CH:29]=1.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1.O.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH:30]1([C:33]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:13][C:12]=4[F:28])=[CH:6][N:5]3[CH:29]=2)=[O:34])[CH2:32][CH2:31]1
Reactant: Nc1cn2cc(Oc3ccc(NC(=O)OCc4ccccc4)cc3F)ccc2n1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a solution of benzyl {4-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-3-fluorophenyl}carbamate (10.0 g, 25.5 mmol) in N,N-dimethylacetamide (100 mL) was added cyclopropanecarbonyl chloride (2.77 mL, 30.6 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hr. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate and collected by filtration to give the title compound (9.2 g, 78%) as a thin-brown solid.