Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10](Cl)(=[O:16])[CH2:11][CH2:12][C:13](Cl)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([C:6]2[CH:5]=[C:4]([CH3:8])[C:3]([OH:9])=[C:2]([CH3:1])[CH:7]=2)=[O:14])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1cccc(C)c1O
Reactant: O=C(Cl)CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C(=O)CCC(=O)c2cc(C)c(O)c(C)c2)cc(C)c1O
Temperature: 0 °C
Reaction time: 15 h
Yield: 15.3 %

Procedure:
To 300 ml of methylene chloride was dissolved 10 g/82 mmol of 2,6-dimethylphenol and 6.2 g/40 mmol of succinic dichloride, and the solution was cooled to 0° C. in sodium chloride-ice bath. 49 g/368 mmol of anhydrous aluminum chloride was added dropwise to the mixture with thorough stirring while maintaining the temperature to not more than 5° C. After completing the addition, the mixture was stirred at 5° C. for one hour, and at room temperature for 15 hours. The reaction mixture was then added to 50 ml of ice containing conc. hydrochloric acid to decompose excessive anhydrous aluminum chloride, and the mixture was extracted twice with methylene chloride. The organic layer was washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystalized from toluene to obtain 2.0 g of 1,4-bis(3',5'-dimethyl-4'-hydroxyphenyl)butane-1,4-dione. MS: 326 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][NH:10][C:9]=2[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N:27]=[C:28]=[O:29]>O1CCCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[NH:27][C:28](=[O:29])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][NH:10][C:9]=2[C:13]([NH2:15])=[O:14])=[CH:6][CH:7]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: NC(=O)c1[nH]cnc1-c1ccc(N)cc1
Solvent: C1CCOC1
Product: NC(=O)c1[nH]cnc1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 52.4 %

Procedure:
To 0.055 g (0.272 mmol) of 5-(4-aminophenyl)-3H-imidazole-4-carboxamide dissolved in 4 cm3 of tetrahydrofuran is added, at a temperature in the region of 20° C. under an argon atmosphere, 0.040 cm3 (0.272 mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate. After stirring for 16 hours at a temperature in the region of 20° C., the reaction mixture is filtered through a No. 3 sinter funnel. The solid obtained is washed successively with three times 2 cm3 of tetrahydrofuran and three times 2 cm3 of pentane and is then dried under reduced pressure (2.7 kPa) to give 0.058 g of 5-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-3H-imidazole-4-carboxamide in the form of a beige-coloured solid melting at 325° C.; 1H NMR (400 MHz, DMSO d6, δ in ppm) 6.98 (broad m, 1H); 7.30 (broad m, 1H); 7.40 (m, 1H); 7.49 (partially masked m, 1H); 7.51 (d, J=8.5 Hz, 2H); 7.71 (s, 1H); 7.82 (d, J=8.5 Hz, 2H); 8.62 (dd, J=2.0 and 7.5 Hz, 1H); 9.00 (broad s, 1H); 9.37 (broad s, 1H); 12.65 (broad m, 1H); EI: m/z=407: M+; m/z=205 [C8H3NOF4]+ base peak; m/z=179 [C7H5NF4]+.
Reaction SMILES: [C:1]([C:9]1[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=[C:11]([CH3:23])[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[OH:32][CH2:23][C:11]1[N:10]=[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(OCc2ccccc2)c(C(=O)c2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1nc(CO)ccc1OCc1ccccc1
Temperature: 50 °C
Yield: 97.5 %

Procedure:
113 g of 2-benzoyl-3-benzyloxy-6-methylpyridine was dissolved in 600 ml of dichloromethane. 96 g of 3-chloroperbenzoic acid was added thereto, followed by stirring under heating at 50° C. in an oil bath. After cooling in a water bath, an aqueous sodium sulfite solution and further an aqueous saturated sodium bicarbonate solution were added to the reaction solution. The organic phase was separated, further washed with an aqueous saturated sodium bicarbonate solution and brine. Then, it was dried over anhydrous magnesium sulfate and the solvent was removed. The resulting residue was dissolved in 200 ml of acetic acid anhydride, followed by heating under stirring at 150° C. for 3 hours in an oil bath. Then, the solvent was removed and 400 ml of methanol and 200 ml of an aqueous 2N sodium hydroxide solution were further added thereto, followed by heating under stirring at 60° C. for 3 hours in an oil bath. Activated carbon was added to the reaction solution. After stirring for a while, it was filtered off. Water was added to the filtrate to precipitate crystals. The resulting crystals were collected by filtration and vacuum-dried, to give 116 g of the target compound.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:36])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[O:33][CH3:34])[C:17]1=[O:35])C1C=CC=CC=1.[H][H]>CO.CCOC(C)=O.[Pd]>[CH3:34][O:33][C:26]1[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=1[C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[CH2:24][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([NH:9][OH:8])=[O:36])[C:17]2=[O:35]
Reactant: [H][H]
Reactant: COc1ccc(-c2cccc3c2CN(CCCCCC(=O)NOCc2ccccc2)C3=O)c(OC)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cccc3c2CN(CCCCCC(=O)NO)C3=O)c(OC)c1
Reaction time: 5 h

Procedure:
N-(benzyloxy)-6-(4-(2,4-dimethoxyphenyl)-1-oxoisoindolin-2-yl)hexanamide (22 mg, 0.045 mmol) in the Step 3 of Example 39 was dissolved in a mixture solvent of MeOH and EtOAc (mixture ratio=2:1 (v/v), 10 ml). 10% of Pd/C (2.2 mg) was added thereto and the reaction proceeded at room temperature for 5 hrs in state of the connected with hydrogen balloon. The resulting mixture thus obtained was filtered with Celite, and the filtrates were distilled under a reduced pressure to remove the solvent and obtained the title compound quantitatively.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([NH:18][C@@H:19]2[C:37](=[O:38])[N:21]3[C:22]([C:34]([OH:36])=[O:35])=[C:23]([CH:26]([S:28][C:29]4[NH:33][N:32]=[N:31][N:30]=4)[CH3:27])[CH2:24][S:25][C@H:20]23)=[O:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]1([C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[N+]=[N-])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCOCC1>[C:39]1([CH:45]([O:35][C:34]([C:22]2[N:21]3[C:37](=[O:38])[C@@H:19]([NH:18][C:16](=[O:17])[CH2:15][C:13]4[S:14][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:11][CH:12]=4)[C@H:20]3[S:25][CH2:24][C:23]=2[CH:26]([S:28][C:29]2[NH:30][N:31]=[N:32][N:33]=2)[CH3:27])=[O:36])[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccc(CNC(=O)OC(C)(C)C)s3)[C@H]2SC1
Solvent: C1COCCO1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccc(CNC(=O)OC(C)(C)C)s3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The product, containing 7β-[2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetylamino]-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid, is dissolved in 30 ml of dioxane, 1.5 g of diphenyldiazomethane are added to the solution and the mixture is stirred for 12 hours at room temperature and then concentrated. After crystallisation from a mixture of methyl acetate and diethyl ether, the residue gives 7β-[2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetylamino]-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester.
Reaction SMILES: [Al](C)(C)C.CO[C:7]([C:9]1[S:10][C:11]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:12][C:13]=1[C:14]#[C:15][Si](C)(C)C)=[O:8].[C:27]([O:31][C:32]([N:34]1[CH2:37][CH:36]([O:38][C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][C:40]=2[F:46])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:27]([O:31][C:32]([N:34]1[CH2:35][CH:36]([O:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH:15]=[CH:14][C:13]4[CH:12]=[C:11]([C:20]5[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=5)[S:10][C:9]=4[C:7]3=[O:8])=[CH:41][C:40]=2[F:46])[CH2:37]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(N)cc2F)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Al](C)C
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(-n3ccc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2F)C1
Temperature: 0 °C
Yield: 80.1 %

Procedure:
Add 2.0 M Al(CH3)3 (1.28 mL, 2.56 mmol) to a suspension of 5-(4-chloro-phenyl)-3-trimethylsilanylethynyl-thiophene-2-carboxylic acid methyl ester (0.851 g, 2.44 mmol) and 3-(4-amino-2-fluoro-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.688 g, 2.44 mmol) in toluene (20 mL). Stir the reaction at 60° C. for 4 h. Cool the mixture to 0° C., quench with 2.0 M NaOH (5 mL) and water (20 mL) and then extract with CHCl3 (3×50 mL). Dry with Na2SO4, filter, and concentrate. Dissolve the crude material in THF (50 mL), treat with 1.0 M TBAF (2.93 mL, 2.93 mmol) and stir at RT overnight. Dilute with EtOAc (100 mL), wash with water (3×40 mL), dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 5% CH3OH/CHCl3 to give 1.03 g (80%) of the title compound. LC-MS/ES m/z (35Cl) 526.9 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH:17]=O)[CH2:6][CH:5]2[CH:7]([CH3:16])[C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:12])[C:10]([CH3:11])=[C:4]2[O:3]1.[CH2:19]1[C:31]2[NH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH2:22][CH2:21][NH:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[N+:13]([C:8]1[CH:7]([CH3:16])[CH:5]2[CH2:6][C:2]([CH2:17][N:20]3[CH2:21][CH2:22][C:23]4[C:24]5[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=5)[NH:30][C:31]=4[CH2:19]3)([CH3:1])[O:3][C:4]2=[C:10]([CH3:11])[C:9]=1[CH3:12])([O-:15])=[O:14]
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: CC1=C2OC(C)(C=O)CC2C(C)C([N+](=O)[O-])=C1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1=C2OC(C)(CN3CCc4c([nH]c5ccccc45)C3)CC2C(C)C([N+](=O)[O-])=C1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
2.0 g of 2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-aldehyde, 1.52 g of 2,3,4,9-tetrahydro-1H-beta-carboline, 50 ml of methylene chloride, 0.8 ml of acetic acid and 2.04 g of sodium triacetoxyborohydride were added, followed by stirring overnight at room temperature. The mixture was poured into ice-water and an aqueous sodium hydroxide solution was added. The reaction solution was extracted with chloroform, washed with saturated saline and dried over anhydrous magnesium sulfate and, after the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:ethyl acetate=50:1) to obtain 1.49 g of the objective product.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C1(S([N:21]2[C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[C:23]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](Cl)[N:31]=3)=[CH:22]2)(=O)=O)C=CC=CC=1>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:32]1[N:31]=[C:30]([C:23]2[C:24]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:21][CH:22]=2)[CH:35]=[CH:34][N:33]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: FC(F)(F)c1ccccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 6.3 %

Procedure:
Using the procedure of example 1, 2-trifluoromethylaniline (131 mg) was reacted with compound 1f (100 mg) to provide compound 29 (6 mg, 6%). 1H NMR (400 MHz, CD3OD) δ 8.56 (d, J=8.0 Hz, 1H), 8.27 (t, J=5.6 Hz, 1H), 8.24 (s, 1H), 8.22 (d, J=1.6 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.27 (d, J=5.6 Hz, 4.8 Hz, 1H), 7.10 (dd, J=8.0 Hz, 4.8 Hz, 1H). MS (ESI) m/z: 356 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.C(N(CC)CC)C>ClCCl>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[C:7]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)=[O:8])([CH3:3])[CH3:2]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CCCCCCCCCCCCCCCc1cccc(OC(C)C)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCc1cccc(OC(C)C)c1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Isopropoxy-6-pentadecyl-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Isopropoxy-N-(4-nitro-3-trifluoromethyl-phenyl)-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH2:16]([N:18]1[C:24]2[CH:25]=[C:26]([F:30])[C:27]([NH2:29])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20][CH2:19]1)[CH3:17].Cl[C:32]1[N:37]=[C:36]([NH:38][C:39]2[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:40]=2[C:41]([NH:43][CH3:44])=[O:42])[C:35]([Cl:50])=[CH:34][N:33]=1>C(O)(C)C>[Cl:50][C:35]1[C:36]([NH:38][C:39]2[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:40]=2[C:41]([NH:43][CH3:44])=[O:42])=[N:37][C:32]([NH:29][C:27]2[C:26]([F:30])=[CH:25][C:24]3[N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)=[N:33][CH:34]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCCOc2cc(N)c(F)cc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1CCCOc2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)c(F)cc21
Yield: 7.1 %

Procedure:
10-Camphorsulfonic acid (77 mg, 0.33 mmol) was added to 9-Ethyl-2-fluoro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine (62 mg, 0.29 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (95 mg, 0.30 mmol) in Isopropyl alcohol (3 mL). The mixture was irradiated in a CEM microwave (130° C., 40 min), resulting in ˜20% conversion. The reaction was stopped, conc. in vacuo and purified by HPLC then free based with MP-carbonate resin in DCM/MeCN to afford 2-[5-Chloro-2-(9-ethyl-2-fluoro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide as a purple foam (10 mg, 7%). LCMS 489 (M+H), 1H-NMR (CDCl3): 8.78 (s, 1H), 8.05 (s, 1H), 7.65 (d, 1H, J=8.7 Hz), 7.35 (m, 1H), 7.29 (m, 1H), 7.23 (m, 1H), 6.84 (s, 1H), 6.55 (d, 1H, J=13.4 Hz), 6.21 (s, 1H), 3.97 (t, 2H, J=5.5 Hz), 3.12 (m, 4H), 2.91 (d, 3H, J=4.7 Hz), 1.96 (m, 2H), 1.17 (t, 3H, J=6.9 Hz); 19F-NMR: −111, −136.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:31][CH2:30][CH2:29][NH:28]3)=[N:9][C:10]=2[C:11]2[CH:26]=[CH:25][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:32](O)(=[O:36])[C:33]#[C:34][CH3:35]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32](=[O:36])[C:33]#[C:34][CH3:35])=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:25][CH:26]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC#CC(=O)O
Reactant: Cc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCN4)n4ccnc(N)c34)cc2)c1
Product: CC#CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3cc(C)ccn3)cc2)c2c(N)nccn12
Yield: 27.2 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-methylpyridin-2-yl)benzamide (intermediate 7) and 2-butynoic acid, to afford the title compound (6.3 mg, 27.2%). Data: UPLC (C) Rt: 1.56 min; m/z 480.3 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:20])[C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:8][CH:9]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1>[CH3:20][N:6]1[C:5]([C:3]([OH:4])=[O:2])=[CH:9][N:8]=[C:7]1[C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:18])([F:17])[F:19])=[CH:14][CH:15]=1
Reactant: COC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(C(=O)O)cnc1-c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 86.2 %

Procedure:
To a solution of 3-methyl-2-[4-(trifluoromethyl)phenyl]-3H-imidazole-4-carboxylic acid methyl ester (962 mg) in tetrahydrofuran (10 ml) was added 1 N aqueous solution of sodium hydroxide (10 ml) at room temperature, and stirred at 80° C. for 1.5 hours. After completion of the reaction, 1 N hydrochloric acid aqueous solution (10 ml) was added thereto, and the solvent was evaporated. The obtained residue was washed with water, and dried in vacuo to give the titled compound (788 mg) as a gray solid.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:17](/B(O)O)=[CH:18]\[CH2:19][CH2:20][CH2:21][CH3:22].[ClH:26]>CCOCC>[ClH:26].[CH:17](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:18]\[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: OCCCCNc1ccc2ncc(Br)n2n1
Reactant: CCCC/C=C/B(O)O
Agent: Cl
Solvent: CCOCC
Product: CCCC/C=C/c1cnc2ccc(NCCCCO)nn12
Yield: 51 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2. The free base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (61 mg, 51%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.87 (s, 1H), 7.85 (d, J=9.8 Hz, 1H), 7.15 (,J=9.8 Hz, 1H), 6.93 (dt, J=7.0, 16.2 Hz, 1H), 6.66 (d, J=16.2 Hz, 1H), 3.62 (t, J=6.5 Hz, 2H), 3.43 (t, J=7.0 Hz, 2H), 2.37-2.32 (m, 2H), 1.82-1.76 (m, 2H), 1.69-1.64 (m, 2H), 1.56-1.50 (m, 2H), 1.47-1.41 (m, 2H), 0.96 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 157.1, 139.1, 133.3, 130.1, 120.9, 120.7, 117.7, 114.3, 62.6, 42.6, 34.2, 32.3, 31.2, 25.9, 23.3, 14.3; HPLC tR=11.2 min (Luna), 98.3%; ES-MS: (M+H)=289 m/z.
Reaction SMILES: [O:1]=[C:2]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C@H:10]1[CH2:15][O:14][CH2:13][CH2:12][N:11]1CC1C=CC=CC=1)[C:3](OCC)=[O:4]>[Pd].CCOC(C)=O>[C:24]1([CH2:23][N:8]2[C:2](=[O:1])[C:3](=[O:4])[N:11]3[C@H:10]([CH2:15][O:14][CH2:13][CH2:12]3)[CH2:9]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(=O)N(Cc1ccccc1)C[C@H]1COCCN1Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1C(=O)N2CCOC[C@@H]2CN1Cc1ccccc1
Yield: 53.7 %

Procedure:
1-Phenyl-N-{[(3S)-4-(phenylmethyl)-3-morpholinyl]methyl}methanamine (4.35 g, 14.7 mmol) and diisopropylethylamine (3.30 mL, 19.1 mmol) in THF (50 mL) cooled to 0° C. Ethylchlorooxo-acetate (1.80 mL, 16.2 mmol) was added dropwise via syringe. The ice bath was removed and the reaction was stirred at rt for 2 h. The reaction mixture was concentrated, taken up in EtOAc and washed with half saturated NaHCO3. The aqueous layer was back extracted with EtOAc, dried over MgSO4 and azeotroped in EtOH to provide ethyl oxo((phenylmethyl){[(3S)-4-(phenylmethyl)-3-morpholinyl]methyl}amino)acetate (5.83 g, 14.7 mmol, used without further purification). Ethyl oxo((phenylmethyl){[(3S)-4-(phenylmethyl)-3-morpholinyl]methyl}amino)acetate (5.83 g, 14.7 mmol) was hydrogenated (1 atm.) with Pd on carbon (1.18 g, 20% w/w with starting morpholine) for 13 days. The reaction was filtered through Celite® and washed thoroughly with MeOH. The solution was concentrated and subsequently triturated with EtOAc providing the title compound of step E (2.06 g, 7.9 mmol, 54% over two steps). 1H NMR (400 MHz, CDCl3) δ ppm 3.00 (ddd, J=13.9, 12.3, 4.2 Hz, 1H), 3.14-3.23 (m, 3H), 3.49 (td, J=12.1, 2.9 Hz, 1H), 3.72-3.82 (m, J=10.0, 10.0, 6.3, 4.0 Hz, 1H), 3.87 (dd, J=11.4, 3.7 Hz, 1H), 4.02 (dd, J=11.7, 4.4 Hz, 1H), 4.28 (dd, J=13.9, 2.2 Hz, 1H), 4.61-4.67 (m, 1H), 4.70-4.75 (m, 1H), 7.26-7.38 (m, 5H). Chiral HPLC analysis (Chiralpak AS-H, 4.6×150 mm, methanol (0.1% isopropyl amine), 1.0 mL/min, UV 254 nm, 25° C.) ee=99%, retention time, S=2.99 min. [α]D20° C.=−9.0:I=100 mm, c=0.975 in CHCl3.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([N:20]4[CH2:25][CH2:24][C:23]([NH:27]C(=O)OCC5C=CC=CC=5)([CH3:26])[CH2:22][CH2:21]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl>O.C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([N:20]4[CH2:21][CH2:22][C:23]([CH3:26])([NH2:27])[CH2:24][CH2:25]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(c2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC1(N)CCN(c2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 69.4 %

Procedure:
To the product from Step A (0.115 g, 0.233 mmol) was added HCl (1.17 mL, 7.00 mmol, 6.0N aqueous). The mixture was stirred at 90° C. for 45 minutes. The mixture was then cooled to ambient temperature and diluted with water (10 mL) and with CH2Cl2 (10 mL). The layers were mixed and separated and the aqueous phase was washed once more with CH2Cl2 (10 mL) and was then treated with saturated aqueous Na2CO3 until pH=10. The aqueous phase was then extracted with CH2Cl2 (3×10 mL). The combined organic phases were washed with water followed by brine and then dried over Na2SO4, filtered and concentrated to provide 0.058 g (66%) of the product >96% pure by HPLC. MS ESI (+) m/z 359.1 (M+1) detected.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[NH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=1>O>[NH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([S:14]([CH3:15])=[O:2])[N:9]=1
Reactant: CSc1nccc(N)n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Sodium metaperiodate (1.3 g.) in water (5 ml.) was added to a solution of 4-amino-2-methylthiopyrimidine (0.7 g.) in water (10 ml.) at 90°, and the solution kept at 90° for 1 hour. A further 1.3 g. of sodium metaperiodate was added and the solution heated a further 0.5 hours and then cooled to room temperature. The mixture was filtered and the filtrate evaporated to dryness. The residue was triturated with MeOH and the suspension filtered and then the filtrate was evaporated to dryness. The residue was triturated with acetonitrile and the insoluble solid collected to give 4-amino-2-methylsulphinylpyrimidine (0.7 g.) which was used without further purification.