Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH:4]=O)=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[C:9]([NH2:14])[C:8]=1[NH2:15]>CCO>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[C:9]2[C:8]=1[N:15]=[CH:1][C:2]([CH3:4])=[N:14]2
Reactant: Nc1c(Br)ccc(Br)c1N
Reactant: CC(=O)C=O
Solvent: CCO
Product: Cc1cnc2c(Br)ccc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
A 40% aqueous solution of methylglyoxal (6.7 M, 6.3 mL, 112 mmol, 1.48 equiv) was added to a suspension of 3,6-dibromo-benzene-1,2-diamine (Step 1.6) (20 g, 75.5 mmol) in EtOH (400 mL). The reaction mixture was stirred for 2 h at rt and for 0.5 h at reflux, allowed to cool and filtered to afford 7.66 g of the title compound. The filtrate was concentrated and the residue triturated in EtOAc and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (Hex/EtOAc, 1:0→9:1) to provide additional 2.15 g of the title compound. The title compound: ESI-MS: 300.9/302.9/304.9 [M+H]+; tR=4.81 min (System 1); TLC: Rf=0.90 (Hex/EtOAc, 1:1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:25][CH2:26][CH2:27]OC)=[C:17](OCCOC)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2].[OH-:30].[Na+]>C(O)C1C=CC=CC=1>[CH2:8]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:25][CH2:26][C:27]4[CH:7]=[CH:8][CH:3]=[CH:1][CH:2]=4)=[C:17]([O:30][CH2:15][CH2:16][O:25][CH3:26])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:2][CH:1]=1)[CH3:7]
Reactant: [OH-]
Reactant: CCc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Agent: [Na+]
Solvent: OCc1ccccc1
Product: CCc1cccc(Nc2ncnc3cc(OCc4ccccc4)c(OCCOC)cc23)c1
Temperature: 151 °C

Procedure:
N-(3-ethylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, prepared as described above (4.0 g, 10 mmol), solid anhydrous sodium hydroxide (104 mg, 2.6 mmol) and benzyl alcohol (20 mL) was heated at 150-152° C. for 23 hours. The reaction mixture was allowed to cool to room temperature and purified by column chromatography on silica gel using a gradient system with ethyl acetate/hexane as eluent to give a white solid which was dried under vacuum at 45-50° C. to give the title product. (2.52 g, 58%), mp 156-157° C.
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][CH:37]1[C:41]([NH2:43])=[O:42].O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[N:17]=[CH:16][C:15]([CH:6]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])[N:36]5[CH2:40][CH2:39][CH2:38][CH:37]5[C:41]([NH2:43])=[O:42])=[CH:20][CH:19]=4)=[O:23])[CH2:25][CH2:26]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: NC(=O)C1CCCN1
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N1CCCC1C(N)=O

Procedure:
1-((6-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl)pyrrolidine-2-carboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and pyrrolidine-2-carboxamide in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: NC1C=CC(Cl)=C([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=2)C=1.ClC1C=C(S(C)(=O)=O)C=CC=1C(O)=O>>[C:9]([NH2:8])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1
Reactant: Nc1ccc(Cl)c(NC(=O)c2cccnc2)c1
Agent: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Product: NC(=O)c1cccnc1

Procedure:
N-(5-amino-2-chlorophenyl)nicotinamide (0.40 mmol) was used in general procedure 2 with 2-chloro-4-(methylsulfonyl)benzoic acid (0.48 mmol). The product was purified by RP-HPLC to give N-(2-chloro-4-(methylsulfonyl)benzamido)phenyl)nicotinamide. MS (Q1) 464.0 (M)+
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:2]1.[CH3:25][O:26][CH2:27][C:28](Cl)=[O:29]>C1COCC1>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]3[CH2:17][CH2:18][CH:19]([NH:22][C:28](=[O:29])[CH2:27][O:26][CH3:25])[CH2:20][CH2:21]3)=[CH:23][CH:24]=2)[CH2:2]1
Reactant: COCC(=O)Cl
Reactant: NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Solvent: C1CCOC1
Product: COCC(=O)NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reaction time: 0.17 h

Procedure:
To Intermediate M (75 mg, 0.23 mmol) in THF (1 mL) & TEA (0.128 mL, 0.92 mmol) was added Methoxy-acetyl chloride (0.042 mL, 0.46 mmol). The reaction was stirred for 10 min then quenched with MeOH and purified by reversed phase HPLC eluting with 0-60% MeCN in water (+0.1% TFA) to provide the title compound 252. (LC/MS method 16: ES+ m/z 398.4 [M+H]+, Rt=0.31 min)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH:12][C:13](=[O:30])[CH:14]([NH:22]C(OC(C)(C)C)=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][S:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH:12][C:13](=[O:30])[CH:14]([NH2:22])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:6][S:7][C:8]([CH3:11])([CH3:9])[CH3:10])[CH3:2]
Reactant: CCOC(=O)C(CSC(C)(C)C)NC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(CSC(C)(C)C)NC(=O)C(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 23 (6.63 g, 25.0 mmol) in CH2Cl2 (30 mL) was added TFA (30 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h, then concentrated. EtOAc (150 mL) was added, washed successively with sat. NaHCO3 (2×20 mL) and brine (20 mL), dried (Na2SO4), and concentrated to give D as a light yellow oil (6.83 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.94 (br d, 1H), 7.30 (m, 5H), 4.80 (m, 1H), 4.21 (q, 2H), 3.70 (dd, 1H), 3.28 (dd, 1H), 2.99 (m, 2H), 2.74 (dd, 1H), 2.25 (br s, 2H), 1.30 (m, 12H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:31])[NH:20][C:21]([CH3:30])=[CH:22][C:23]=2[C:24]2C=CC=[CH:26][CH:25]=2)=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[H][H]>[Pd].CCO.C1COCC1>[CH3:12][CH:11]([N:8]1[C:9]2[CH:10]=[CH:2][CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:31])[NH:20][C:21]([CH3:30])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:13]
Reactant: [H][H]
Reactant: Cc1cc(-c2ccccc2)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cccc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
6-Bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (70.3 mg, 0.15 mmol) in 3:1 EtOH/THF (4 mL) was hydrogenated using Pd/C (10% wet Degussa type) and a balloon of hydrogen. The reaction mixture was stirred at room temperature overnight. It was filtered through Celite, washed with EtOAc and EtOH and the solvent was evaporated. DMF was added with some water and white solids that crashed out were filtered off, air-dried for 15 min and dried in a vacuum oven for 3 h. The residue was purified by Gilson reversed-phase HPLC (30×100 Varian Polaris C18, 15-80% gradient of MeCN in water with 0.1% TFA over 12 minutes). Most of the solvent was removed and saturated NaHCO3 was added. The solids that crashed out were filtered off, air-dried for 15 min and dried in vacuum oven overnight to give the title compound (19 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (br. s., 1H) 8.63 (br. s., 1H) 8.34 (s, 1H) 7.85 (d, J=8.34 Hz, 1H) 7.39-7.51 (m, 7H) 5.99 (s, 1H) 5.03 (quin, J=6.57 Hz, 1H) 4.22 (d, J=4.29 Hz, 2H) 2.21 (s, 3H) 1.49 (s, 3H) 1.47 (s, 3H). MS (ES) [M+H]+ 367.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.[CH3:35][O:36][C:37]1[CH:42]=[C:41]([O:43][C:44]([F:47])([F:46])[F:45])[CH:40]=[CH:39][C:38]=1[S:48](Cl)(=[O:50])=[O:49]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:48]([C:38]1[CH:39]=[CH:40][C:41]([O:43][C:44]([F:45])([F:46])[F:47])=[CH:42][C:37]=1[O:36][CH3:35])(=[O:49])=[O:50])[C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:15][CH2:16][CH:17]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: COc1ccccc1C1(CC(=O)N2CCC(c3ccncc3)CC2)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1cc(OC(F)(F)F)ccc1S(=O)(=O)Cl
Product: COc1ccccc1C1(CC(=O)N2CCC(c3ccncc3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2OC)c2ccc(Cl)cc21
Yield: 38.9 %

Procedure:
With 290 mg of 5-chloro-3-(2-methoxyphenyl)-3-[2-oxo-2-(4-pyridin-4-yl piperidin-1-yl)ethyl]-1,3-dihydro-2H-indol-2-one obtained in Step 51-2 and 195 mg of 2-methoxy-4-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 173 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 1.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=CC3C=NC=CC=3)[CH:16]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(OC(N1CCO[C@H](CC2C=[CH:47][CH:46]=[C:45]([CH2:49][OH:50])C=2)C1)=O)(C)(C)C.BrCC1CC1>>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:50][CH2:49][CH:45]3[CH2:46][CH2:47]3)[CH:16]=2)[CH2:9]1)=[O:2])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(CO)c2)C1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Agent: BrCC1CC1
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(COCC3CC3)c2)C1

Procedure:
The title compound was synthesized in analogy to example 95, intermediate (a), from (R)-2-(3-hydroxymethyl-benzyl)-morpholine-4-carboxylic acid tert-butyl ester and (bromomethyl)cyclopropane to give the compound as colorless oil (56%).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:21]([O-])=O)=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:9](=[O:19])(=[O:18])[CH2:8][O:7][C:6]=2[CH:20]=1.O.O.Cl[Sn]Cl.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[C:3]([NH2:21])=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:9](=[O:18])(=[O:19])[CH2:8][O:7][C:6]=2[CH:20]=1
Reactant: O=[N+]([O-])c1cc2c(cc1F)OCS(=O)(=O)N2Cc1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc2c(cc1F)OCS(=O)(=O)N2Cc1ccccc1
Reaction time: 12 h
Yield: 67.2 %

Procedure:
A mixture of 6-fluoro-7-nitro-1-(phenylmethyl)-1H-4,2,1-benzoxathiazine 2,2-dioxide (1.96 g, 5.79 mmol) and SnCl2.2H2O (6.55 g, 29 mmol) in ethyl acetate (40 mL) was heated at reflux for 3 h. After the reaction was complete, ethyl acetate (400 mL) and then Na2CO3 (18.5 g) were added, and the mixture was stirred for 12 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give 1.20 g of the title compound of Step G.
Reaction SMILES: [CH3:1][N:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([C:5]1[C:6](=[O:18])[N:7]([CH3:17])[C:8]2[C:13]([C:14]=1O)=[C:12]([CH3:16])[CH:11]=[CH:10][CH:9]=2)=[O:4].O=P(Cl)(Cl)[Cl:27]>>[CH3:1][N:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([C:5]1[C:6](=[O:18])[N:7]([CH3:17])[C:8]2[C:13]([C:14]=1[Cl:27])=[C:12]([CH3:16])[CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc2c1c(O)c(C(=O)N(C)c1ccccc1)c(=O)n2C
Product: Cc1cccc2c1c(Cl)c(C(=O)N(C)c1ccccc1)c(=O)n2C

Procedure:
N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-1,5-dimethyl-2-oxo-quinoline-3-carboxamide (3.5 g) was heated in phosphorus oxytrichloride (7 ml) at 100° C. for 2 hours. The mixture was concentrated, dissolved in dichloromethane and washed with water. The organic phase was dried (Na2SO4) and concentrated. The residue was triturated with ethyl acetate and filtered to give the title compound (2.3 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4].[CH:9](N)([CH3:11])[CH3:10]>CN(C=O)C>[CH:9]([N:8]1[CH2:2][C:3](=[O:4])[NH:5][C:6]1=[O:7])([CH3:11])[CH3:10]
Reactant: CC(C)N
Reactant: NC(=O)NC(=O)CCl
Solvent: CN(C)C=O
Product: CC(C)N1CC(=O)NC1=O
Temperature: 135 °C

Procedure:
(2-Chloroacetyl)-urea (0.68 g, 5.00 mmol) and isopropylamine (0.86 mL, 10.0 mmol) in DMF (10 mL) was stirred for 6 h at room temperature and then heated to 135° C. for 4 hours. DMF was removed under vacuum and the residue was purified by column chromatography (silica gel 230-400 mesh; eluting with hexane:dichloromethane:ethyl acetate 2.5:1.0:0.5) to give 1-isopropyl-imidazolidine-2,4-dione as a white solid. Yield: 0.20 g (28%).
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]([N:16]2[C@H:20]([C:21](O)=[O:22])[CH2:19][CH2:18][N:17]2[C:24](OCC2C=CC=CC=2)=O)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.S(Cl)(C)(=O)=O.[F:51][C:52]1[CH:53]=[CH:54][C:55]([NH2:58])=[N:56][CH:57]=1>CN(C=O)C>[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:14]([N:16]2[C@H:20]([C:21]([NH:58][C:55]3[CH:54]=[CH:53][C:52]([F:51])=[CH:57][N:56]=3)=[O:22])[CH2:19][CH2:18][N:17]2[CH3:24])=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: Nc1ccc(F)cn1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Product: CN1CC[C@@H](C(=O)Nc2ccc(F)cn2)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 68.3 %

Procedure:
1-Methylimidazole (38.2 μl, 0.479 mmol) was added into a solution of (3S)-2-[(2R)-3-cyclopentyl-2({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidine carboxylic acid (100 mg, 0.240 mmol) in 1.0 ml of DMF. The solution was cooled to 0° C., and then mesyl chloride (24.26 μl, 0.311 mmol) was added dropwise at 0° C. and then 5-fluoro-2-pyridinamine (40.3 mg, 0.359 mmol) dissolved in another 1.0 ml of DMF was added. The reaction mixture was stirred for 3.5 h at rt. The reaction mixture was concentrated and purified by RP-HPLC to afford (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-N-(5-fluoro-2-pyridinyl)-1-methyl-3-pyrazolidinecarboxamide (84 mg, 0.164 mmol, 68.6% yield) as a white solid. LC-MS (ES) m/e 512.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:35][CH2:36][N:37]1C(=O)C2=CC=CC=C2C1=O.O.NN>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][CH:10]1[O:11][CH2:35][CH2:36][NH2:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: NN
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: c1ccccc1
Product: NCCOC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 10 °C

Procedure:
A mixture that consists of 42.1 g (100 mmol) of 2,3,5-tri-O-benzyl-ribofuranose, 3.40 g (10 mmol) of tetrabutylammonium hydrogen sulfate and 33.7 g (600 mmol) of fine-powder potassium hydroxide in 3050 ml of benzene is cooled to 10° C. At 10° C., 38.1 g (150 mmol) of N-(2-bromoethyl)-phthalimide, dissolved in 100 ml of benzene, is added in drops over 40 minutes while being stirred vigorously. It is stirred for three hours at 10° C. 300 ml of benzene is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The filtrate residue is dissolved in 500 ml of ethanol, 25.03 g of hydrazine hydrate (500 mmol) is added, and it is refluxed for six hours. It is allowed to cool to 0° C., deposited precipitate is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is dissolved in 400 ml of dichloromethane, and this solution is washed twice with 5% aqueous sodium hydroxide solution and then once with water (in each case 300 ml). The organic phase is evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/ethanol/triethylamine=20:2:0.1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[S:7][C:8]3[N:9]=[C:10]([N:21]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[N:23]=[C:22]4[CH2:30][CH3:31])[N:11]=[C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:13]=3[N:14]=2)[CH2:2]1.[OH:32][C:33]([CH3:38])([CH3:37])[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:30]([C:22]1[N:21]([C:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:13]3[N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:34](=[O:35])[C:33]([OH:32])([CH3:38])[CH3:37])[CH2:4]4)[S:7][C:8]=3[N:9]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)sc2n1
Reactant: CC(C)(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)(C)O)C3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
A mixture of 2-azetidin-3-ylmethyl-5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (209 mg, 0.48 mmol), 2-hydroxyisobutyric acid (56 mg, 0.54 mmol), HATU (200 mg, 0.53 mmol) and DIPEA (94 μL, 0.54 mmol) in DCM (5 mL) was allowed to stir at r.t. for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-2%) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 5-98%) affording 814 as a white solid (89 mg, 35%). LCMS (method I): RT 3.39 min, [M+H]+ 522.2. 1H NMR (CDCl3, 400 MHz): δ 8.00-7.99 (1 H, m), 7.75-7.74 (1 H, m), 7.28-7.28 (2 H, m), 4.62-4.12 (7 H, m), 4.05-3.92 (1 H, m), 3.88 (4 H, t, J=4.76 Hz), 3.45 (1 H, s), 3.43-3.38 (2 H, m), 3.33 (2 H, q, J=7.47 Hz), 3.27-3.21 (1 H, m), 1.43-1.42 (9 H, m)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:2][C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: CC(=O)c1cc(C)ccn1
Reactant: COC(OC)N(C)C
Product: Cc1ccnc(C(=O)C=CN(C)C)c1

Procedure:
A suspension of 2-acetyl-4-methylpyridine (0.65 g) in N,N-dimethylformamide dimethyl acetal (4 ml) was refluxed for 10 hours and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, filtered and dried under reduced pressure to give 3-dimethylamino-1-(4-methylpyridin-2-yl)prop-2-en-1-one (777 mg).
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[N:32]1([C:37]2[N:42]=[CH:41][C:40]([C:43]([OH:45])=O)=[CH:39][N:38]=2)[CH:36]=[CH:35][N:34]=[CH:33]1.[CH:46]1([NH:49][CH:50]2[CH2:55][CH2:54][N:53]([C:56]3[O:60][N:59]=[C:58]([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)[N:57]=3)[CH2:52][CH2:51]2)[CH2:48][CH2:47]1>CN(C)C=O>[CH:46]1([N:49]([CH:50]2[CH2:51][CH2:52][N:53]([C:56]3[O:60][N:59]=[C:58]([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)[N:57]=3)[CH2:54][CH2:55]2)[C:43]([C:40]2[CH:41]=[N:42][C:37]([N:32]3[CH:36]=[CH:35][N:34]=[CH:33]3)=[N:38][CH:39]=2)=[O:45])[CH2:48][CH2:47]1
Reactant: c1ccc(-c2noc(N3CCC(NC4CC4)CC3)n2)cc1
Reactant: O=C(O)c1cnc(-n2ccnc2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cnc(-n2ccnc2)nc1)N(C1CC1)C1CCN(c2nc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (75 mg) and ethyldiisopropylamine (74 μL) are added to a solution of 2-imidazol-1-yl-pyrimidine-5-carboxylic acid (40 mg) in N,N-dimethylformamide (5 mL) at room temperature. The solution is stirred for 10 min prior to the addition of cyclopropyl-[1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]amine (60 mg). The resulting mixture is stirred at 60° C. for 3 h, cooled to room temperature over night, and concentrated in vacuo. The crude product is purified by HPLC(H2O/MeOH/TFA). LC (method 1): tR=1.50 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[CH3:27][C:28]([NH2:42])([CH3:41])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=1.FC(F)(F)C([O-])=O>>[CH3:41][C:28]([NH:42][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:27])[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=1
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: CC(C)(N)Cc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])C(F)(F)F
Product: CC(C)(Cc1ccc(OC(F)(F)F)cc1)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
The target compound is obtained by reacting 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one with 233 mg (1 mmol) 1,1-dimethyl-2-(4-trifluoromethoxy-phenyl)-ethylamine using the method described for Example 2c). Beige solid. Yield: 279 mg (50%, trifluoroacetate); mass spectroscopy: [M+H]+=441.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([Cl:8])[N:7]=1.[CH3:14][S:15]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])(=[O:17])=[O:16].C(N(CC)C(C)C)(C)C>O1CCOCC1>[Cl:8][C:6]1[N:7]=[C:2]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:18]([S:15]([CH3:14])(=[O:17])=[O:16])[CH:19]=2)[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]=1[CH2:9][CH3:10]
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Reactant: CS(=O)(=O)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCc1nc(C(N)=O)c(Nc2cccc(S(C)(=O)=O)c2)nc1Cl
Temperature: 170 °C
Reaction time: 17 h
Yield: 42.6 %

Procedure:
A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (600 mg), 3-(methylsulfonyl)aniline (467 mg), N,N-diisopropylethylamine (0.48 mL) and dioxane (18 mL) was stirred in a sealed tube at 170° C. for 17 hours. After cooling, the mixture was partitioned using ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was washed with chloroform, and the solid was collected by filtration and dried to give 5-chloro-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (412 mg) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:25][N:24]=[CH:23][N:22]=2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:33])[NH:12][C:11]([C:21]2[S:25][N:24]=[CH:23][N:22]=2)=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2ncns2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CBr)NC(c2ncns2)=NC1c1ccc(F)cc1Br
Yield: 40 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(1,2,4-thiadiazol-5-yl)-1,4-dihydropyrimidine-5-carboxylate (5.7 g, 13.4 mmol) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (2.7 g, 40%). The compound was characterized by the following spectroscopic data: