Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].[B-]C#[N:24].[Na+]>O1CCCC1.CO>[NH2:24][CH:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [B-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(N)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a solution of tert-butyl 4-acetylpiperidine-1-carboxylate (10 g, 44.05 mmol) in tetrahydrofuran (100 ml) and methanol (100 ml) were added ammonium acetate (20 g, 264.3 mmol) and sodium cyanotrihydroborate (20 g, 264.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuum. The crude product was added water (100 ml), and extracted with ethyl acetate (50 mL×3). The organic layer was dried over sodium sulfate and concentrated to give tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (6 g, yield: 60%) as a colorless liquid. LRMS (M+H+) m/z: calcd 228.15. found 229.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:7]([O:9][CH3:10])=[O:8]>C(#N)C>[N:1]([CH:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:17]([O:19][CH3:20])=[O:18])=[N+:2]=[N-:3]
Reactant: COC(=O)CCCCCCC(Br)C(=O)OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)CCCCCCC(N=[N+]=[N-])C(=O)OC

Procedure:
Sodium azide (4.87 g, 75 mmol) was added to a solution of dimethyl 2-bromoazelate (5.9 g, 20 mmol) prepared according to Auguston, M, et al; Acta Chim. Acad. Sci. Hung; 46:85 (1965) in acetonitrile, and the mixture was heated at reflux temperature for 4 h. The solvent was removed in vacuo, dichloromethane (80 ml) was added to the residue, and the mixture was washed with water. The organic phase was dried over sodium sulfate and the solvent was removed in vacuo to give the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]([N+:7]([O-:9])=[O:8])([CH2:5][OH:6])[CH2:3][OH:4].[C:10]1(=O)OCC[O:11]1>C(OCC)(=O)C>[CH3:1][C:2]1([N+:7]([O-:9])=[O:8])[CH2:5][O:6][C:10](=[O:11])[O:4][CH2:3]1
Reactant: O=C1OCCO1
Reactant: CC(CO)(CO)[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: CC1([N+](=O)[O-])COC(=O)OC1

Procedure:
A solution of 2-methyl-2-nitro-1,3-propanediol and ethylene carbonate is heated overnight. The reaction mixture is diluted with ethyl acetate and the solution is washed with water. The organic phase is dried and concentrated to obtain 5-methyl-5-nitro-1,3-dioxan-2-one. This is dissolved in methanol and hydrogenated under pressure to give the 5amino compound which is acylated with dodecanoyl chloride to give the product.
Reaction SMILES: [Si:1]([O:18][C@H:19]1[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[C@H:22]([NH:30][C:31]2[C:36]([N+:37]([O-])=O)=[CH:35][N:34]=[C:33]([N:40]3[C:44]4[CH:45]=[C:46]([F:49])[CH:47]=[CH:48][C:43]=4[N:42]=[CH:41]3)[N:32]=2)[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CO>[Si:1]([O:18][C@H:19]1[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[C@H:22]([NH:30][C:31]2[C:36]([NH2:37])=[CH:35][N:34]=[C:33]([N:40]3[C:44]4[CH:45]=[C:46]([F:49])[CH:47]=[CH:48][C:43]=4[N:42]=[CH:41]3)[N:32]=2)[CH2:21][CH2:20]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@H](Nc2nc(-n3cnc4ccc(F)cc43)ncc2[N+](=O)[O-])c2cc(F)ccc21)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@H](Nc2nc(-n3cnc4ccc(F)cc43)ncc2N)c2cc(F)ccc21)(c1ccccc1)c1ccccc1
Reaction time: 5 h
Yield: 79 %

Procedure:
N-((1R,4R)-4-(tert-butyldiphenylsilyloxy)-7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-5-nitropyrimidin-4-amine (633 mg, 0.975 mmol) was dissolved in EtOAc (25 mL) and MeOH (25 mL), and mixed with platium on carbon, sulfided (10%, wet) (127 mg, 20% w/w). The reaction mixture was applied to Parr apparatus under H2 (40 psi) for 5 h. TLC showed the reaction completed. The catalyst was filtered off and washed with MeOH. The filtrate and washings were combined and evaporated to dryness to give a white solid product (498 mg, 82%). MS (ESI): 647.5; 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.18 (dd, 1H), 7.63-7.76 (m, 6H), 7.41-7.53 (m, 6H), 7.25-7.30 (m, 1H), 7.02-7.22 (m, 3H), 5.57-5.65 (m, 1H), 4.92 (broad, 2H), 4.87-4.91 (m, 1H), 2.28-2.38 (m, 1H), 1.86-1.98 (m, 2H), 1.72-1.82 (m, 1H), 1.02 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:17][C:16]([F:19])([F:18])[CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:19][C:16]1([F:18])[CH2:17][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC(F)(F)C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC1(F)CN(C2CCNCC2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76.9 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.0 mmol) in DCE (50 mL) was added 3,3-difluoroazetidine hydrochloride (712 mg, 5.5 mmol). The mixture was stirred at RT for 15 min, then sodium triacetoxyborohydride (1.59 g, 7.5 mmol) was added and stirring was continued for 17 h. The reaction mixture was diluted with brine and extracted with DCM. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give 4-(3,3-difluoroazetidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow solid (1.2 g, 88%). To a solution of 4-(3,3-difluoro-azetidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (552 mg, 2.0 mmol) in DCM (4 mL) was added TFA (2 mL) and the resulting mixture was stirred at RT for 45 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a pale yellow solid (271 mg, 77%).
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.C([O-])(=O)C.[NH4+:24].[Cl-].[NH4+]>C(O)(=O)C>[C:1]1(=[O:19])[N:5]([CH2:6][C:7]2[NH:24][C:10]([CH3:11])=[CH:9][CH:8]=2)[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CC(=O)O
Product: Cc1ccc(CN2C(=O)c3ccccc3C2=O)[nH]1

Procedure:
36.3 g (0.14 mol) of 6-phthalimido-2,5-hexanedione, 54 g (0.7 mol) of ammonium acetate and 1 g of ammonium chloride are stirred in 700 ml of acetic acid at 80° C. for 1 hour and the mixture is worked up as in Example 1.
Reaction SMILES: Cl.[CH:2]1([NH:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C[O-].[Na+].CO[C:14]1([CH2:20][CH:21]=[C:22]([C:25]#[N:26])[C:23]#[N:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH2:15]1>C(O)C>[CH:2]1([N:7]2[C:25]([NH2:26])=[C:22]([C:23]#[N:24])[C:21]([CH2:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC1(CC=C(C#N)C#N)C=CC=CC1
Reactant: NNC1CCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(Cc2ccccc2)nn(C2CCCC2)c1N
Yield: 25.8 %

Procedure:
A mixture of cyclopentyl hydrazine hydrochloride (1.4 g, 10.2 mmol), sodium methoxide (0.55 g, 10.2 mmol) and ethanol (30 ml) was heated to reflux and then (1-methoxyphenylethylidene)malononitrile (2.0 g, 10.2 mmol) in ethanol (15 ml) was added dropwise over 1 hour. The reaction mixture was refluxed for 6.5 hours and the solvent was removed in vacuo. The residue was partitioned between chloroform and water, the organic layer was separated and the aqueous layer was extracted with chloroform (3×75 ml). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to afford 0.7 g (26%) of 1-cyclopentyl-3-phenylmethyl-5-amino-1H-pyrazole-4-carbonitrile as white flakes, m.p. 180°-182° C. when recrystallized from ethyl acetate and dried for 18 hours at 90° C. in high vacuum.
Reaction SMILES: CN(C)CCCN=C=NCC.[ClH:12].[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:26][C@@H:25]([F:28])[C@@H:24]3[C@H:20]2[CH2:21][NH:22][CH2:23]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:35][N:36]([CH3:51])[CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][C:48](O)=[O:49].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[ClH:12].[CH3:51][N:36]([CH3:35])[CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][C:48]([N:22]1[CH2:21][C@@H:20]2[C@@H:24]([C@H:25]([F:28])[CH2:26][CH2:27][C:19]2([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:23]1)=[O:49]
Reactant: CN(C)CCCOc1ccccc1CC(=O)O
Reactant: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCCOc1ccccc1CC(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A solution of 0.5 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 50 cm3 of dry dichloromethane is added over 10 minutes to a solution, cooled to +4° C., of 0.72 g of (3aR, 7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride, 0.5 g of 2-(3-dimethylaminopropoxy)phenylacetic acid, 0.03 g of 1-hydroxybenzotriazole in 75 cm3 of dichloromethane, followed by 0.37 cm3 of diisopropylethylamine. The reaction mixture is stirred for 3 hours at 0° C. and then washed twice with 50 cm3 of water and twice with 50 cm3 of a saturated solution of sodium chloride. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 21 cm3 of 0.1N hydrochloric acid, 50 cm3 of diethyl ether and 30 cm3 of water. The aqueous phase is separated and freeze-dried to give 0.85 g of (3aR, 7R,7aR)-2-([2-(3-dimethylaminopropoxy)phenyl]acetyl)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride in the form of a white freeze-dried product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:58])[C@@H:15]([NH:40]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:16][CH2:17][CH2:18][NH:19]/[C:20](/[NH2:39])=[N:21]/[S:22]([C:25]2[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]3[O:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]=3[C:35]=2[CH3:36])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:58])[C@@H:15]([NH2:40])[CH2:16][CH2:17][CH2:18][NH:19]/[C:20](/[NH2:39])=[N:21]/[S:22]([C:25]2[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]3[O:32][C:31]([CH3:33])([CH3:34])[CH2:30][C:29]=3[C:35]=2[CH3:36])(=[O:23])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](N)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of compound A (46.2 mmol) in EtOAc (175 mL) at room temperature was added piperidine (4.57 mL, 46.2 mmol) and the reaction mixture was stirred for 18 h at room temperature. Next the solvent was removed in vacuo and the resulting residue dissolved in minimum amount of EtOAc (˜50 mL) and hexane (˜1 L) was added. The precipitated crude product was filtered off and recrystallised again with EtOAc (˜30 mL) and hexane (˜750 mL). The precipitate was filtered off, washed with hexane and dried in vacuo to afford compound B (28.0 g, 46.2 mmol). LC-MS [M+H] 595.4 (C28H46N6O6S+H, calc: 595.3). Compound B was used without further purification.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:28]([O:31][C:32]1[C:33]([CH2:38]Cl)=[N:34][CH:35]=[CH:36][CH:37]=1)[CH:29]=[CH2:30].O>CN(C)C=O>[CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[N:11]([CH2:38][C:33]3[C:32]([O:31][CH2:28][CH:29]=[CH2:30])=[CH:37][CH:36]=[CH:35][N:34]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Reactant: C=CCOc1cccnc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cccnc1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Temperature: 40 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
((S)-7-Cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester (25 g, 88.2 mmol) is dissolved in dimethylformamide (150 mL) under nitrogen. Cesium carbonate (57.5 g, 176.5 mmol) and 3-allyloxy-2-chloromethyl-pyridine (16.2 g, 88.2 mmol) are added sequentially. The reaction mixture is stirred at 40° C. for 16 h. The reaction is cooled to room temperature and added to water (1250 mL). After one hour of stirring a pale cream solid is filtered. The crude material is purified by recrystallization from i-PrOH and then dried under vacuum to constant weight to afford the title compound (32 g; 84%). LC-ES/MS m/z: 431.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]#[C:22][CH3:23]>>[C:1]([O:5][C:6](=[O:18])[C:7]([S:8]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)(=[O:10])=[O:9])([CH2:16][C:11]#[C:12][CH3:13])[C:20]#[C:21][CH2:22][CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CS(=O)(=O)c1ccc(F)cc1
Reactant: CC#CCBr
Product: CC#CCC(C#CCC)(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(F)cc1
Yield: 77 %

Procedure:
2-(4-Fluoro-benzenesulfonyl)-2-but-2-ynylhexynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. aSctarting from 2-(4fluoro-benzenesulfonyl)-acetic acid tert-butyl ester (4.87 g, 20 mmol) and 1-bromo-2-butyne (5.36 g, 40 mmol), 6.0 g of the product was isolated. Yield 77%; white solid; mp 85° C.; MS: 379.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[CH:6]=[O:7].[CH:11]1([Mg]Br)[CH2:13][CH2:12]1.[Cl-].[NH4+]>C1COCC1>[CH:11]1([CH:6]([C:5]2[CH:8]=[CH:9][N:10]=[C:3]([O:2][CH3:1])[CH:4]=2)[OH:7])[CH2:13][CH2:12]1
Reactant: COc1cc(C=O)ccn1
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C(O)C2CC2)ccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere, to a solution of 2-methoxyisonicotinaldehyde (4.33 g) in THF (100 mL) was added 0.60 M cyclopropylmagnesium bromide (63.1 mL) at 0° C., and the mixture was stirred at 0° C. for 10 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give a crude product of the title compound (5.30 g) as a brown oil. This compound was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][O:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20].[NH3:27]>C(O)C>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][O:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])=[C:2]([NH2:27])[N:10]=1
Reactant: CCOP(=O)(COCCOn1cnc2c(Cl)nc(NC=O)nc21)OCC
Reactant: N
Solvent: CCO
Product: CCOP(=O)(COCCOn1cnc2c(N)nc(N)nc21)OCC
Temperature: 25 °C
Yield: 35 %

Procedure:
A solution of 6-chloro-9-[2-(diethoxyphosphorylmethoxy)ethoxy]-2-formamidopurine (0.80 g, 1.96 mmol) in ethanol (10 ml) saturated with ammonia gas was heated in a sealed steel vessel at 110° C. for 51/2 hours. The reaction mixture was cooled to ambient temperature, evaporated to dryness and the residue chromatographed on silica gel (eluted with dichloromethane:methanol 90:10) to give the title compound (0.25 g, 35%), m.p. 139°-141° (acetonitrile). UV: νmax (EtOH) 256 (ε8,200), 280 (ε10,200)nm:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:13][C:14]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:17][CH2:16][CH2:15]2)=[N:10][C:11]#[N:12])[CH:5]=[N:6][CH:7]=1.[C:24](Cl)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:13][C:14]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:17][CH2:16][CH2:15]2)=[N:10][C:11]#[N:12])[CH:5]=[N:6][CH:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: N#CN=C(Nc1cncc(N)c1)NC1(c2ccccc2)CCC1
Solvent: c1ccncc1
Product: CC(=O)Nc1cncc(NC(=NC#N)NC2(c3ccccc3)CCC2)c1
Temperature: 0 °C
Yield: 8.3 %

Procedure:
A stirred solution of the product from Example 3 (0.87 g, 0.0028 mol) in pyridine (10 ml), was cooled under nitrogen in an ice bath and treated with acetyl chloride (0.22 ml, 0.0031 mol). The mixture was kept in the ice bath for 1 hour and at ambient temperature for 20 hours. It was then concentrated in vacuo. The residue was mixed with saturated NaHCO3 and extracted with CHcl3. The extract was concentrated in vacuo and the residue was chromatographed on silica gel with 5% MeOH-0.25% NH4OH--CHcl3. The product was crystallized from MeOH-EtOAc to give 0.343 g, mp 208°-209° C. and 0.0813 g, mp 207°-208° C. of the titled product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Cl>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([F:13])[CH:15]=3)[C:7]=12
Reactant: Fc1cccc(CCl)c1
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Product: Cc1c(C)n(Cc2cccc(F)c2)c2c(Cl)nccc12
Yield: 72 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and 3-fluorobenzyl chloride, the titled compound was obtained as a white solid. (Yield: 72%)
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[H-].[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.C(OCC)(=O)C>CN(C=O)C>[CH3:17][O:16][CH:3]([O:2][CH3:1])[CH2:4][N:5]([CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: COc1cccc(CBr)c1
Reactant: COC(CNS(=O)(=O)c1ccc(C)cc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(CN(CC(OC)OC)S(=O)(=O)c2ccc(C)cc2)c1
Reaction time: 0.17 h

Procedure:
13.0 g (50 mmol) of N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide was dissolved in 40 ml of DMF. 2.01 g (50 mmol) of sodium hydride was added to the obtained solution at room temperature. After stirring for 10 minutes, 9.18 g (46 mmol) of 3-methoxybenzyl bromide was added to the obtained mixture, and they were stirred for 2 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][C:15]([F:25])=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:17]=1)[N:5]=2.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>N1C=CC=CC=1>[F:25][C:15]1[CH:14]=[CH:13][C:12]([N:11]([CH3:26])[C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:30]([CH:27]4[CH2:29][CH2:28]4)=[O:31])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]=1[NH:18][C:19](=[O:24])[C:20]([F:22])([F:21])[F:23]
Reactant: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc2nc(N)sc2n1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)(methyl)amino]-2-fluorophenyl}-2,2,2-trifluoroacetamide (385 mg, 1.00 mmol) in pyridine (10 mL) was added cyclopropanecarbonyl chloride (144 μL, 1.60 mmol) at 4° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate (10 mL). The obtained suspension was washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=80/20→0/100), and the obtained solution was concentrated under reduced pressure to give the title compound (250 mg, 59%) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]([F:26])([F:25])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:13][C:12]([F:26])([F:25])[F:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: Sc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)CSc1ccc(Br)cc1
Temperature: 0 °C
Yield: 44.5 %

Procedure:
Dissolve 4-bromo-benzenethiol (1.0 g, 5.3 mmol) in dry dimethylformamide (50 mL) and cool to 0° C. under nitrogen. Add dry sodium hydride (152 mg, 6.4 mmol), portionwise. After the vigorous gas evolution stops, add toluene-4-sulfonic acid 2,2,2-trifluoro-ethyl ester (2.0 g, 8.0 mmol) and stir the reaction overnight at room temperature. Slowly pour the reaction into water (400 mL) and extract with ethyl acetate (2×50 mL). Wash the combined organic layers with water (100 mL) and brine (100 mL). Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the resultant residue on a SiO2 column with hexanes to yield 640 mg of 1-bromo-4-(2,2,2-trifluoro-ethylsulfanyl)-benzene (45%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[N:16]([CH3:17])[N:15]=[CH:14][C:13]=1[C:18]#[N:19].[N+](C1C=CC([O:29][C:30]([C:32]2[C:40]3[O:39][C:38]([CH2:41][CH3:42])=[N:37][C:36]=3[C:35]([O:43][CH:44]([F:46])[F:45])=[CH:34][CH:33]=2)=O)=CC=1)([O-])=O>CN(C)C=O>[C:18]([C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[NH:11][C:30]([C:32]1[C:40]2[O:39][C:38]([CH2:41][CH3:42])=[N:37][C:36]=2[C:35]([O:43][CH:44]([F:45])[F:46])=[CH:34][CH:33]=1)=[O:29])#[N:19]
Reactant: Cn1ncc(C#N)c1N
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)Oc3ccc([N+](=O)[O-])cc3)c2o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3c(C#N)cnn3C)c2o1
Reaction time: 1.5 h
Yield: 26.2 %

Procedure:
Sodium bis(trimethylsilyl)amide (0.53 ml) was added to a solution of 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (65 mg) in N,N-dimethylformamide (5 ml) at room temperature under an atmosphere of nitrogen. The mixture was stirred for 10 minutes before addition of 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid 4-nitrophenyl ester (100 mg), then for 90 minutes. It was quenched with water (1 ml) and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 2:1 heptane-ethyl acetate afforded the title compound as a white solid (25 mg).