Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[CH3:14])=[O:8].C(NC(C1OC=CC=1C)=O)C1C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>>[Br:34][C:11]1[S:10][C:9]([C:7]([NH:6][CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=2)=[O:8])=[C:13]([CH3:14])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccsc1C(=O)NCc1cccc(F)c1
Agent: Cc1ccoc1C(=O)NCc1ccccc1
Product: Cc1cc(Br)sc1C(=O)NCc1cccc(F)c1
Yield: 89 %

Procedure:
Following the procedure as described in Preparation 19, making variations only as required to use N-(3-fluorobenzyl)-3-methylthiophene-2-carboxamide) in place of N-benzyl-3-methylfuran-2-carboxamide to react with N-bromosuccinimide, 5-bromo-N-(3-fluorobenzyl)-3-methylthiophene-2-carboxamide was obtained as a colorless solid in 89% yield: 1H NMR (300 MHz, CD3CN) δ 7.39-7.31 (m, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.08 (d, J=10.2 Hz, 1H), 7.02 (dd, J=8.5, 2.5 Hz, 1H), 6.98 (s, 1H), 4.48 (d, J=6.1 Hz, 2H), 2.42 (s, 3H); MS (ES+) m/z 328.1 (M+1), 330.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][NH:27]2)=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][N:27]2[C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)=[CH:23][CH:22]=1
Reactant: Fc1ccc2c(c1)NCC2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)N2CCc3ccc(F)cc32)nc(N2CCOCC2)cc1=O
Yield: 37.6 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 205 mg of 6-fluoroindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 140 mg of 2-[2-(6-fluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a very pale pink powder, the characteristics of which are the following:
Reaction SMILES: [OH:1][C@H:2]([CH3:37])[C@H:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:10]=1)=[O:8])[CH2:4][OH:5].[OH-].[K+].[CH2:40]1OCCOCCOCCOCCOCCOC1.IC>C1COCC1>[OH:1][C@H:2]([CH3:37])[C@H:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:10]=1)=[O:8])[CH2:4][O:5][CH3:40]
Reactant: C[C@@H](O)[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@@H](C)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
In a 10 mL round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-hydroxymethyl-propyl)-amide (81 mg, 0.152 mmol) was dissolved in THF (1.5 ml) to give a colorless solution. The reaction was cooled in an ice bath and crushed KOH (86 mg, 1.52 mmol), 18-crown-6 (40 mg, 0.152 mmol), and iodomethane (10 μl, 0.152 mmol) were added successively. The reaction mixture was stirred at 0° C. for 1 h after which the ice bath was removed. The reaction mixture was stirred at room temperature for 2 h then diluted with dichloromethane (10 mL) and washed with aqueous ammonium chloride (10 mL), water (10 mL), and saturated sodium bicarbonate (10 mL). The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0%-60% EtOAc) to afford 30 mg (36%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-methoxymethyl-propyl)-amide as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ: 9.22 (s, 1H), 8.78 (dd, J=8.9, 5.5 Hz, 1H), 8.66 (s, 1H), 8.14 (d, J=9.4 Hz, 1H), 7.67 (dd, J=9.8, 2.3 Hz, 1H), 7.17 (td, J=9.2, 2.1 Hz, 1H), 5.75 (s, 2H), 5.21 (d, J=4.2 Hz, 1H), 4.22-4.34 (m, 1H), 4.17 (s, 3H), 3.97-4.12 (m, 1H), 3.61 (app t, J=8.2 Hz, 3H), 3.52 (dd, J=9.8, 6.4 Hz, 1H), 3.28 (s, 3H), 1.14 (d, J=6.4 Hz, 3H), 0.87 (t, J=7.9 Hz, 2H), −0.07 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[NH2:17][C@@H:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20].CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[C:4]([NH:17][C@@H:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[N:3]=1
Reactant: COC(=O)[C@H](C)N
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)Nc1cc(C(=O)OC(C)(C)C)nc(Cl)n1
Temperature: 50 °C
Yield: 88.7 %

Procedure:
To a mixture of tert-butyl 2,6-dichloropyrimidine-4-carboxylate (0.310 g, 1.24 mmol) in acetonitrile (5 mL) was added (S)-methyl 2-aminopropanoate hydrochloride (0.177 g, 1.27 mmol) and iPr2NEt (0.48 mL, 2.8 mmol). The mixture was heated at 50° C. overnight then concentrated in vacuo. The residue was chromatographed over silica gel with 10-50% EtOAc in hexanes. The product fractions were evaporated in vacuo to yield (S)-tert-butyl 2-chloro-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate as a colorless glass (0.347 g, 1.10 mmol, 89% yield). 1H NMR (400 MHz, DMSO-d6): 8.70 (1H, d, J=6.8 Hz), 7.12 (1H, s), 4.56-4.47 (1H, m), 3.65 (3H, s), 1.53 (9H, s), 1.39 (3H, d, J=7.2 Hz). LC/MS: m/z=316.2 [M+H]+.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.Cl[Sn](Cl)(Cl)Cl.[CH2:22]=[O:23]>C1(C)C=CC=CC=1>[OH:23][C:22]1[C:1]([CH3:8])=[CH:2][CH:3]=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: Cc1ccccc1O
Reactant: C=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: Cc1cccc(C=O)c1O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
o-Cresol 20.0 g (185 mmol) was dissolved in toluene 400 ml and thereto was added 2,6-lutidine 18.4 g (171 mmol). SnCl4 4.8 g (18 mmol) was added to the mixture and the mixture was stirred for 30 min. at 20° C. Thereto was added paraformaldehyde (purity: 95 weight %) 12.9 g (409 mmol) and the mixture was stirred at 80° C. for 5 hours to the conversion of 78%. And the reaction was kept for 10 hours at 100° C. to confirm the disappearance of the raw material, o-cresol. The reaction solution was cooled to room temperature, extracted with water-toluene in a separatory funnel and the organic layer was dried over anhydrous magnesium sulfate and dried in vacuo to give 2-hydroxy-3-methylbenzaldehyde 24.9 g (yield: 99%, selectivity: 99%).
Reaction SMILES: C[O-].[Na+].Cl.Cl.[CH2:6]([NH:13][NH2:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15]([C:17](=[C:20](SC)[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]#[N:19])#[N:16]>CO.C(O)C>[NH2:19][C:18]1[N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:14]=[C:20]([NH:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:17]=1[C:15]#[N:16]
Reactant: NNCc1ccccc1
Reactant: CSC(Nc1ccccc1)=C(C#N)C#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: N#Cc1c(Nc2ccccc2)nn(Cc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
With ice-cooling, 19.3 ml of a 5.4N sodium methanolate solution in 20 ml of methanol (purissimum) are added to 9.9 g of benzylhydrazine dihydrochloride in 20 ml of methanol (purissimum) and the reaction mixture is stirred for approx. 15 minutes at room temperature and then introduced into a solution of 4.65 g of 2-cyano-3-methylmercapto-3-phenylamino-acrylonitrile in 150 ml of absolute ethanol. The mixture is heated under reflux for approx. 17 hours and cooled to room temperature and insoluble material is filtered off with suction. The filtrate is concentrated by evaporation using a rotary evaporator and the brown oily residue is chromatographed on 190 g of silica gel, methylene chloride/ethyl acetate mixtures being used as eluant. 5-Amino-1-benzyl-4-cyano-3-phenylamino-pyrazole is obtained; m.p. 139-140° C., FAB-MS: (M+H)+ =290 (C17H15N5).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:18])[CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:18])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/C[C@@H](C)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC[C@@H](C)NC(=O)OC(C)(C)C
Yield: 99.5 %

Procedure:
A suspension of (R,E)-ethyl 5-(tert-butoxycarbonylamino)hex-2-enoate (1.70 g, 6.61 mmol) and 5% Pd/C (350 mg) in ethanol (35 mL) was vigorously stirred under the atmosphere of hydrogen balloon for 1.5 hr. The reaction mixture was filtered and the filtrate were concentrated to give (R)-ethyl 5-(tert-butoxycarbonylamino)hexanoate (1.71 g, 6.58 mmol, 100% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.34 (s, 1H), 4.12 (q, J=7.1 Hz, 2H), 3.66 (s, 1H), 2.31 (td, J=7.5, 1.6 Hz, 2H), 1.75-1.57 (m, 2H), 1.51-1.38 (m, 2H), 1.44 (s, 9H), 1.25 (t, J=7.1 Hz, 3H), 1.12 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH3:13][S:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.Cl>N1C=CC=CC=1>[OH:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[S:14][CH3:13]
Reactant: CSc1ccccc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CSc1ccccc1C(=O)Nc1cc(C(F)(F)F)ccc1O
Temperature: 80 °C
Yield: 17.9 %

Procedure:
A mixture of 2-amino-4-trifluoromethylphenol (1.00 g), 2-methylsulfanylbenzoic acid (0.95 g), WSC (1.41 g), and pyridine (10 ml) was stirred with heating at 80° C. for 2.5 hours. Into the reaction mixture cooled to room temperature, 1 mol/l of hydrochloric acid was poured, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, sequentially, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.33 g of N-(2-hydroxy-5-trifluoromethylphenyl)-2-methylsulfanyl-benzamide (Compound (1B)-515).
Reaction SMILES: Cl[CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:9][C:10]1[CH:23]=[CH:22][C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1>O.C1(C)C(C)=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:2]([CH3:6])[C:3]([OH:5])=[O:4])=[CH:17][CH:16]=2)=[CH:22][CH:23]=1
Reactant: Oc1ccc(Cc2ccc(Cl)cc2)cc1
Reactant: CC(Cl)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(Oc1ccc(Cc2ccc(Cl)cc2)cc1)C(=O)O
Reaction time: 0.25 h

Procedure:
129.8 Parts of 2-chloropropionic acid, 194 parts of 50% sodium hydroxide solution and 80 parts of water are mixed as described in Example 1. The clear, viscous liquid so obtained is added portionwise to a solution of 218.5 parts of 4-(4'-chlorobenzyl)-phenol in 1,000 parts of xylene; the reaction temperature being maintained at 110°-115° C. by azeotropic distillation of water in a water trap. The addition being complete, stirring is continued for 15 minutes at 110° C. Work-up is as described in Example 2. 290.5 Parts of 2-[4'-(4"-chlorobenzyl)-phenoxy]-propionic acid are obtained. The content of pure final product is 99.8%, corresponding to a yield of 99.8% of theory. The residual content of 4-(4'-chlorobenzyl)--phenol is 0.1%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9]Br)=[CH:4][C:3]=1[S:12][CH3:13].[B-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:11][CH2:9]2)=[CH:4][C:3]=1[S:12][CH3:13]
Reactant: CSc1cc(C(=O)CBr)ccc1C
Agent: [B-]
Agent: [Na+]
Solvent: CO
Product: CSc1cc(C2CO2)ccc1C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a mixture of 18 g of 4'-methyl-3'-methylthio-2-bromoacetophenone and 300 ml of methanol was gradually added 8 g of sodium borohydrate and thereafter the mixture was stirred for one hour at 40°-50° C. After distilling off methanol from the reaction mixture, 200 ml of water was added to the residue and the product was extracted with 300 ml of benzene. Then, benzene was distilled off and the residue formed was purified by a silica gel column chromatography (eluant benzene) to provide 8.5 g of oily 4-methyl-3-methylthiostyrene oxide.
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17].[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35]([NH:37][C@H:38]([C:43](O)=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(C(C)C)CC)(C)C.C(NCC(NC[C@]1(CO)O[C@@H](N2C=C(C)C(=O)NC2=O)C[C@@H]1O)=O)(=O)C>CN(C=O)C>[CH:29]1[C:30]2[CH:31]([CH2:33][O:34][C:35]([NH:37][C@H:38]([C:43]([NH:1][CH2:2][C@:3]3([CH2:18][OH:19])[O:7][C@@H:6]([N:8]4[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]4=[O:10])[CH2:5][C@@H:4]3[OH:17])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:36])[C:32]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]=2[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@](CN)(CO)O2)c(=O)[nH]c1=O
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(=O)NCC(=O)NC[C@]1(CO)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn([C@H]2C[C@H](O)[C@](CO)(CNC(=O)[C@H](CC(C)C)NC(=O)OCC3c4ccccc4-c4ccccc43)O2)c(=O)[nH]c1=O

Procedure:
4′-C-(Aminomethyl)thymidine (4) (0.025 g, 0.1 mmol), N-(9-fluorenylmethyloxycarbonyl)leucine (0.071 g, 0.2 mmol), TSTU (0.09 g, 0.3 mmol) and diisopropylethylamine (0.065 g, 0.5 mmol, 0.087 mL) were combined in DMF (1 mL) according to the procedure used to prepare compound (19). The title compound (20) was obtained as an amorphous solid (0.056 g). δH(300 MHz, CD3OD) 7.86–7.37(8H, m, Fmoc), 7.74(1H, s, H-6), 6.24(1H, dd, H-1′), 4.56(1H, dd, H-3′), 3.68(2H, 2d, H-5′), 3.40(2H, 2d, 4′-C—CH2), 2.37(2H, m, H-2′), 1.70(3H, m, leucyl CH, CH2), 1.66(3H, s, 5-CH3), 1.05(3H, d, leucyl CH3), 1.02(3H, d, leucyl CH3); ES +ve m/z 607(M+H)+, 629(M+Na)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13](Br)([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].CN1CCCC1=O>O>[N:18]([C:13]([CH3:15])([CH3:14])[C:12]([NH:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:17])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(Br)C(=O)NCCOCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(N=[N+]=[N-])C(=O)NCCOCc1ccccc1
Temperature: 50 °C

Procedure:
A mixture of the crude amide (104 g), sodium azide (23.6 g) and N-methyl-2-pyrrolidone (500 ml) was heated at 50° C. for 22 h. After cooling to room temperatur water was added and the resulting mixture was extracted with diethyl ether (2×400 ml). The combined organic phases were washed with brine (3×500 ml) and dried (Na2 SO4). Evaporation of the solvents in vacuo gave 2-azido-N-(2-benzyloxyethyl)-2-methylpropionamide as an oil:78 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)[C:5]([CH3:18])=[CH:4][N:3]=1.[CH3:19][N:20]1[CH:24]=[C:23]([NH2:25])[CH:22]=[N:21]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:18][C:5]1[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)=[N:7][C:2]([NH:25][C:23]2[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)nc1NC1COC2C(O)COC12
Reactant: Cn1cc(N)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1COC2C(O)COC12
Temperature: 150 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a suspension of 6-((2-chloro-5-methylpyrimidin-4-yl)amino)hexahydrofuro[3,2-b]furan-3-ol (54 mg, 0.20 mmol) in n-BuOH (1 mL) was added 1-methyl-1H-pyrazol-4-amine (32 mg, 0.24 mmol) and DIPEA (78 mg, 0.60 mmol). Then the mixture was stirred under nitrogen atmosphere at 150° C. overnight and concentrated in vacuo. To the residue was added water (20 mL), and extracted with DCM (20 mL×3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude oil. Then it was purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to give the title compound as an off-white solid (46 mg, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:12])=[N+:7]([O-])[CH:8]=[CH:9][CH:10]=1)=[O:4].O=P(Cl)(Cl)[Cl:15]>>[Cl:15][CH2:12][C:6]1[N:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc[n+]([O-])c1C
Product: COC(=O)c1cccnc1CCl
Yield: 30.8 %

Procedure:
The crude 3-(methoxycarbonyl)-2-methylpyridine-1-oxide (35 g, 210 mmol) was added in small portion to POCl3 (300 g) at room temperature. After the addition, the reaction mixture was refluxed for 3 hours before it was concentrated in vacuo. The residue was poured into ice-water, neutralized with aq. NaHCO3 solution and extracted with AcOEt (125 mL×3). The combined organic layers were washed with brine, dried over anhy. NazSO4, filtered, and concentrated in vacuo to afford a crude product which was then purified by column chromatography to give title compound (12 g, yield 30%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH:11]=[C:12]([C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:13](=O)[CH3:14])[C:6]#[N:7].[NH2:22][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][C:25]#[N:26].CC(C)([O-])C.[K+]>C(O)(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([CH:11]2[C:12]([C:16]3[S:17][CH:18]=[C:19]([CH3:21])[N:20]=3)=[C:13]([CH3:14])[NH:22][C:23]([C:27]([F:30])([F:29])[F:28])=[C:24]2[C:25]#[N:26])=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:7]
Reactant: N#CC=C(N)C(F)(F)F
Reactant: COc1cc(C#N)ccc1C=C(C(C)=O)c1nc(C)cs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1cc(C#N)ccc1C1C(C#N)=C(C(F)(F)F)NC(C)=C1c1nc(C)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.335 mmol) of the compound from example 6A, 46 mg (0.335 mmol) of 3-amino-4,4,4-tri-fluorobut-2-enenitrile [preparation in analogy to U.S. Pat. No. 3,635,977 and K. Krespan, J. Org. Chem. 34, 42-45 (1969)] and 5.6 mg (0.05 mmol) of potassium tert-butoxide are dissolved in 4 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude product is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 119 mg (82% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:11]I>C1COCC1>[CH3:11][N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8]
Reactant: CI
Reactant: O=C1CCCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCCCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of ε-caprolactam (2.0 g, 17.6 mmol) in anhydrous THF (15 mL) at 0° C. was added NaH, 60% dispersion in oil (1.06 g, 26.0 mmol), and the mixture was stirred at 0° C. for 30 minutes. The cold bath was removed and the mixture was stirred at room temperature for 1 hour and then cooled again to 0° C. Methyl iodide (1.65 mL, 26.0 mmol) was added dropwise over 10 minutes, then the cold bath was removed and the mixture was stirred at room temperature for 18 hours. The excess NaH was quenched with methanol, THF was removed in vacuo and the crude was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate (2×30 mL), adding solid NaCl to break the emulsion. Organic washings were combined and dried over Na2SO4. Ethyl acetate was removed in vacuo and the crude product 206 (1.54 g, 68%) was used without further purification. MS (ESI)=128 (MH+).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11](O)=[O:12])[CH2:8]2.S(Cl)(Cl)=O.[NH2:18][N:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C>>[O:29]=[C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:19]1[NH:18][C:11]([CH:2]1[CH:1]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]1[CH2:4]3)[CH2:8]2)=[O:12]
Reactant: Nn1c(-c2ccccc2)nc2ccccc2c1=O
Reactant: O=C(O)C1C2CC3CC(C2)CC1C3
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nn1c(-c2ccccc2)nc2ccccc2c1=O)C1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
A solution of adamantane-2-carboxylic acid (110 mg, 0.61 mmol, prepared as described in J. Med. Chem, (2007), 50(1), 149-164) in thionyl chloride (1.5 mL, 20.6 mmol) was heated at 80° C. for 90 minutes and then cooled to room temperature and concentrated under vacuum. The residue was dissolved in CH2Cl2 (3 mL) and 3-amino-2-phenylquinazolin-4(3H)-one (145 mg, 0.61 mmol, Aldrich) and diisopropylethylamine (0.2 mL, 1.14 mmol) were added. The mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The residue was purified by flash chromatography (SiO2, eluted with hexanes-EtOAc, 90:10-70:30), then by preparative HPLC on a Waters Nova-Pak® HR C18 6 μm 60 {acute over (Å)} Prep-Pak® cartridge column (40 mm×100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/min to provide the title compound as a white powder (56 mg, 23%): 1 H NMR (300 MHz, CD3OD) δ ppm 1.21 (br. d, J=12.9 Hz, 1 H), 1.31 (br. d, J=12.9 Hz, 1 H), 1.51 (br. d, J=12.7 Hz, 1 H), 1.58-1.72 (m, 3 H), 1.73-1.91 (m, 5 H), 1.90-2.01 (m, 2 H), 2.21 (br. s, 1 H), 2.61 (br. s, 1 H), 7.44-7.56 (m, 3 H), 7.56-7.65 (m, 3 H), 7.76 (d, J=8.3 Hz, 1 H), 7.89 (ddd, J=8.4, 7.0, 1.6 Hz, 1 H), 8.27 (dd, J=7.9, 1.6 Hz, 1 H); MS (DCI) m/z 400 (M+H); Elemental analysis calculated for C25 H25N3O2.0.7 H2O: C, 72.86; H, 6.46; N, 10.20. Found: C, 72.72; H, 6.30; N, 10.06.