Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=O.C(O)(=O)C.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([S:28]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]2[CH2:37][O:38][CH2:39][C:40]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[O:41])(=[O:30])=[O:29])=[C:23]([CH3:48])[CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[NH:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][C:6]=1[CH2:7][N:45]1[CH2:46][CH2:47][N:42]([C:40](=[O:41])[CH2:39][O:38][CH2:37][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][N:31]2[S:28]([C:24]2[C:23]([CH3:48])=[CH:22][C:21]([O:20][CH3:19])=[CH:26][C:25]=2[CH3:27])(=[O:29])=[O:30])[CH2:43][CH2:44]1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCNCC2)c(C)c1
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCN(Cc3nc(-c4ccccc4)[nH]c3Cl)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
4-Chloro-2-phenyl-1H-imidazole-5-carbaldehyde (1.5 eq.) and acetic acid (cat.) were added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(piperazin-1-yl)ethanone (1 eq.) in dichloromethane (25 ml/mmol). The reaction mixture was stirred for 30 min. at 25° C., then sodium triacetoxyborohydride (4 eq.) was added and stirring was carried out for a further 16 h at 25° C. The mixture was diluted with dichloromethane and washed with saturated bicarbonate solution and saturated sodium chloride solution. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography using 3% methanol in ethyl acetate. Yield: 50%; MS, m/z 630.2 (MH+)
Reaction SMILES: C([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])C.[F:16][C:17]([F:21])([F:20])[CH2:18]I>C1COCC1>[CH2:12]([O:11][C:9]([C:7]1([CH2:18][C:17]([F:21])([F:20])[F:16])[CH2:8][CH2:3][N:4]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:5][CH2:6]1)=[O:10])[CH3:13]
Reactant: FC(F)(F)CI
Reactant: CCC1CCCCN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC(F)(F)F)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Under a argon atmosphere a vacuum dried 750 mL four necked flask (with mechanical stirrer) was charged with 6.6 mL diisopropylamine and 100 mL THF. The solution was cooled to −5° C./−10° C. 29.1 mL of 1.6M n-butyllithium in hexane was added over a period of 20 min. The light yellow solution was stirred for 30 min at −5°/−10° C. and afterwards cooled to −75° C. A solution of 10 g (38.8 mmol) ethyl 1-tert-butoxycarbonylpiperidine in 75 mL THF was added over a period of 50 min. The yellow solution was stirred at −75° C. for 2 h. A solution of 9.8 g (46.7 mmol) 2,2,2-trifluoroethyl iodide in 25 mL THF was added dropwise over a period of 45 min. The reaction was stirred for 1 h at −75° C. and allowed to warm up over night to ambient temperature. The reaction was cooled down to 0° C., quenched with 250 mL 10% citric acid aq. solution The aqueous layer was separated and extracted twice with 200 mL ethyl acetate. The organic layers were washed once with 200 mL brine, dried over Na2SO4, filtered and evaporated.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH:25][NH2:26])[CH3:24]>>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][C:14]1[C:19]([CH2:20][CH3:21])=[N:26][N:25]([CH2:23][CH3:24])[C:15]=1[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)C(Cc1nccn1Cc1ccccc1)C(=O)CC
Reactant: CCNN
Product: CCc1nn(CC)c(CC)c1Cc1nccn1Cc1ccccc1

Procedure:
4-(1-Benzyl-1H-imidazol-2-ylmethyl)-1,3,5-triethyl-1H-pyrazole was prepared from 4-(1-benzyl-1H-imidazol-2-ylmethyl)-heptane-3,5-dione and ethylhydrazine in analogy to Example 190 b): light yellow viscous oil; MS (ISP): 323.2 ((M+H)+.).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=O)[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:12][C:11]=2[N:23]=1)=O.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:14]1[N:15]=[C:10]2[CH:9]=[CH:8][C:7]3=[N:6][N:5]=[C:3]([CH2:2][Cl:1])[N:23]3[C:11]2=[N:12][C:13]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CCl)NNc1ccc2[nH]c(=O)c(-c3ccccc3)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: ClCc1nnc2ccc3nc(Cl)c(-c4ccccc4)nc3n12
Temperature: 150 °C

Procedure:
A mixture of 2-chloro-N′-(2-oxo-3-phenyl-1,2-dihydropyrido[2,3-b]pyrazin-6-yl)acetohydrazide (104) (230 mg, 0.698 mmol) and phosphoryl chloride (4 mL, 42.9 mmol) was heated under microwave irradiation at 150° C. for 1.5 hours. The solvent was evaporated, and the residue was diluted with EtOAc, washed with sat. NaHCO3, dried (MgSO4), filtered, and concentrated under reduced pressure to give 3-chloro-9-(chloromethyl)-2-phenyl[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazine (10-2).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][C:7]1([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.[C:19]([C:21]1[CH:34]=[CH:33][C:24]([CH2:25][N:26]2[C:30]([CH2:31]Cl)=[CH:29][N:28]=[CH:27]2)=[CH:23][CH:22]=1)#[N:20].C(N(C(C)C)CC)(C)C>C(#N)C>[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:26]2[C:30]([CH2:31][N:10]3[CH2:11][CH2:12][C:7]([CH2:6][C:5]4[CH:15]=[CH:16][CH:17]=[C:3]([CH3:2])[CH:4]=4)([C:13]#[N:14])[CH2:8][CH2:9]3)=[CH:29][N:28]=[CH:27]2)=[CH:33][CH:34]=1)#[N:20]
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Reactant: Cc1cccc(CC2(C#N)CCNCC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(CC2(C#N)CCN(Cc3cncn3Cc3ccc(C#N)cc3)CC2)c1

Procedure:
A solution of 4-(3-methylbenzyl)piperidine-4-carbonitrile hydrochloride salt (129 mg, 0.51 mmol), 1-(4-cyanobenzyl)-5-chloro-methylimidazole hydrochloride salt (135 mg, 0.51 mmol; Example 52, Step D), and diisopropylethylamine (440 mL, 2.5 mmol) in anhydrous acetonitrile (5 mL) was heated under reflux overnight. The resultant mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 85:15 v/v mixture of chloroform saturated with ammonia gas and hexane. After collection and concentration of appropriate fractions, the residue was triturated with a mixture of ethyl acetate and diethyl ether. The white solid precipitated was filtered to provide the title compound.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH:4]2[CH:9]=O)[CH2:2]1.[NH2:11][OH:12]>>[CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH:4]2[CH:9]=[N:11][OH:12])[CH2:2]1
Reactant: O=CC1CCCCC12CC2
Reactant: NO
Product: ON=CC1CCCCC12CC2

Procedure:
Spiro[2.5]octane-4-carbaldehyde oxime (I-11I) was prepared by reaction of spiro[2.5]octane-4-carbaldehyde and hydroxylamine following the same procol as described for I-6c. MS m/z 154.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]3[C:8]([C:9]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1.[CH2:25]([NH2:28])[CH2:26][NH2:27]>CN1C(=O)CCC1>[NH2:27][CH2:26][CH2:25][NH:28][C:2]1[C:14]2[N:13]3[C:8]([C:9]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1
Reactant: NCCN
Reactant: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(Cl)c23)c(C)c1
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(NCCN)c23)c(C)c1

Procedure:
Heat a solution of 4-chloro-2-methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizine (0.3 g, 0.89 mmol), and ethylene diamine (0.6 mL, 8.93 mmol) in dry NMP (3 mL) at 100° C. for 14 h. Pour the cooled mixture onto water (30 mL) and extracted twice with EtOAc (30 mL). Wash the combined extracts with brine (30 mL), dry, and evaporate in vacuo. Purify by preparative TLC (20% MeOH in CH2Cl2 with 0.5% ammonium hydroxide) to obtain the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].C([O:10][C:11]([C:13]1[S:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:20][CH2:19]2)=[N:16][N:17]=1)=O)C>>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH:5][C:11]([C:13]1[S:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:22][CH2:23]2)=[N:16][N:17]=1)=[O:10]
Reactant: CC(C)(C)CCN
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Product: CC(C)(C)CCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 3,3-dimethylbutylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.053 g, yield 93%). 1H NMR (300 MHz, CDCl3) δ 7.72-7.69 (m, 1H), 7.63-7.51 (m, 2H), 7.33-7.31 (m, 1H), 6.99 (br., t, 1H), 4.07-3.99 (m, 1H), 3.89-3.81 (m, 1H), 3.74-3.59 (m, 2H), 3.53-3.49 (m, 2H), 3.44-3.37 (m, 2H), 3.33-3.29 (m, 2H), 1.51-1.49 (m, 2H), 0.92 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 174.4, 167.5, 158.1, 155.9, 133.9, 132.4, 129.6, 127.1, 126.9, 126.8, 126.7, 126.2, 125.3, 121.7, 49.5, 48.9, 45.9, 42.9, 40.7, 36.4, 29.9, 29.3. MS (ES+) m/z 470 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:19]=2)[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.[OH-].[Na+].OO.CC(O)=[O:36]>CCO.CS(C)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:19]=2)[C:12]([C:15]([NH2:16])=[O:36])=[N:13][CH:14]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-c2ncccn2)c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-c2ncccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound 5-((1R,2S)-2-aminocyclohexylamino)-3-(3-(pyrimidin-2-yl)phenylamino)pyrazine-2-carbonitrile (60 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (47 mg). MS 405.3 (M+H); UV 202.9, 254.8, 304.6 nm; t 0.471 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C([O:18][CH2:19][CH2:20][CH2:21]Cl)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:21][CH2:20][CH2:19][OH:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OCCCCl
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCSc1cccc(Br)c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
3-Bromobenzenethiol (0.40 g) and potassium carbonate (0.44 g) were suspended in N,N-dimethylformamide (4.2 mL), 3-chloropropyl acetate (0.34 mL) was added, and the resulting mixture was stirred at 60° C. for 5 hours. The reaction mixture was partitioned between diethyl ether (40 mL) and water (10 mL). The organic layer was washed successively with water (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (8.5 mL), 28% sodium methoxide-methanol solution (0.08 mL) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give the title compound (0.49 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].N[C:10]1N=CC(C2N=NN(C3C=C(C=CC=3C)C(NC3C=C(C(C)(C)C)C=C(NS(C)(=O)=O)C=3OC)=O)C=2)=C[CH:11]=1>>[C:10]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8])#[CH:11]
Reactant: Cc1ccncc1Br
Reactant: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccc(N)nc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: C#Cc1cnccc1C

Procedure:
3-Ethynyl-4-methyl-pyridine was prepared from 3-bromo-4-methyl-pyridine in the same manner as 2-amino-3-ethynyl pyridine (Example 15).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:18][C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:7][C:2]([NH:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=2)=[N:3][CH:4]=1
Reactant: COc1cccc(CNc2nc(Cl)ncc2Cl)c1
Reactant: COc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(CNc2nc(Nc3cccc(OC)c3)ncc2Cl)c1
Temperature: 105 °C
Yield: 34.7 %

Procedure:
Into a reaction flask were added 2,5-dichloro-N-(3-methoxybenzyl)pyrimidin-4-amine (0.20 g, 0.70 mmol) (prepared according to Example 1, step A), 1,4-dioxane (20 mL), 3-methoxy-benzenamine (0.13 g, 1.0 mmol), and p-toluenesulfonic acid monohydrate (49 mg, 0.26 mmol). The mixture was heated at 105° C. for 2 days. To the mixture was added an aqueous solution of NaHCO3 (saturated, 0.5 mL) and the organic solvent was removed under vacuum. The aqueous layer was extracted with DCM twice. The combined organic layers were dried, filtered and concentrated. The crude product was purified by silica gel column chromatography to provide the desired product (90 mg, 30%). LCMS for C19H20ClN4O2 (M+H)+: m/z=371.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[C:17]([CH2:19][N:20]([C@H:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32]2[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=2)[CH2:26]1)[S:21]([CH3:24])(=[O:23])=[O:22])#[N:18]>>[Cl:38][C:37]1[C:32]([NH:31][C@@H:27]2[CH2:28][CH2:29][CH2:30][C@H:25]([N:20]([CH2:19][C:17]#[N:18])[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:26]2)=[N:33][C:34]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:35][CH:36]=1
Reactant: CS(=O)(=O)N(CC#N)[C@H]1CCC[C@@H](Nc2nc(Cl)ncc2Cl)C1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCC[C@H](N(CC#N)S(C)(=O)=O)C4)n3)cc2CC1

Procedure:
rel-N-((1S,3R)-3-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-N-cyanomethyl-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and rel-N-cyanomethyl-N-[(1S,3R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a tan foam (28 mg, 13%). LCMS (m/e) 562 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.92 (s, 1H), 7.42 (d, 1H, J=8.0 Hz); 7.16 (s, 1H), 7.09 (d, 1H, J=8.1 Hz), 6.88 (s, 1H), 5.11 (d, 1H, J=7.2 Hz), 4.30-4.05 (m, 3H), 3.95-3.84 (m, 1H), 3.56 (t, 2H, J=5.8 Hz), 3.38 (s, 3H), 3.05-2.85 (m, 4H), 2.93 (s, 3H), 2.82-2.65 (m, 6H), 2.48-2.39 (m, 1H), 2.22-2.12 (m, 1H), 2.11-1.93 (m, 2H), 1.60-1.42 (m, 3H), 1.34-1.16 (m, 1H).
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]([CH2:10][O:11][CH2:12][C:13]2([CH2:20][CH3:21])[CH2:18][O:17][P:16](Cl)[O:15][CH2:14]2)([CH2:8][CH3:9])[CH2:4][O:3]1.[CH2:22]([NH:26][CH:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]1)[CH2:23][CH2:24][CH3:25]>>[CH2:22]([N:26]([P:2]1[O:7][CH2:6][C:5]([CH2:10][O:11][CH2:12][C:13]2([CH2:20][CH3:21])[CH2:18][O:17][P:16]([N:26]([CH:27]3[CH2:28][C:29]([CH3:36])([CH3:35])[NH:30][C:31]([CH3:33])([CH3:34])[CH2:32]3)[CH2:22][CH2:23][CH2:24][CH3:25])[O:15][CH2:14]2)([CH2:8][CH3:9])[CH2:4][O:3]1)[CH:27]1[CH2:28][C:29]([CH3:35])([CH3:36])[NH:30][C:31]([CH3:34])([CH3:33])[CH2:32]1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Reactant: CCC1(COCC2(CC)COP(Cl)OC2)COP(Cl)OC1
Product: CCCCN(C1CC(C)(C)NC(C)(C)C1)P1OCC(CC)(COCC2(CC)COP(N(CCCC)C3CC(C)(C)NC(C)(C)C3)OC2)CO1

Procedure:
If 1,3-bis(2-chloro-5-ethyl-1,3,2-dioxaphosphorinan-5-yl)-2-oxapropane is reacted with 4-butylamino-2,2,6,6-tetramethylpiperidine in a procedure analogous to Example 2, 1,3-bis[2-(N-butyl-N-(2,2,6,6-tetramethyl-4-piperidyl)amino)-5-ethyl-1,3,2-dioxaphosphorinan-5-yl]-2-oxapropane is obtained as a viscous resin (Compound No. 22, formula below, R3 =H); FD-MS: 730 (M+).
Reaction SMILES: Cl.[CH:2]1([N:7]2[CH2:12][CH2:11][CH2:10][C:9]3([CH2:21][C:20](=O)[C:19]4[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:18]=4)[O:13]3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[NH2:30][OH:31].N1C=CC=CC=1>C(O)C>[CH:2]1([N:7]2[CH2:12][CH2:11][CH2:10][C:9]3([CH2:21][C:20](=[N:30][OH:31])[C:19]4[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:18]=4)[O:13]3)[CH2:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NO
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C3CCCC3)C1)O2)NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C(/C=C/c1ccc2c(c1)C(=NO)CC1(CCCN(C3CCCC3)C1)O2)NO
Temperature: 80 °C
Yield: 12.6 %

Procedure:
A mixture of (E)-3-(1′-cyclopentyl-4-oxospiro[chroman-2,3′-piperidine]-6-yl)-N-hydroxyacrylamide hydrochloride (80 mg, 0.197 mmol), hydroxylamine hydrochloride (27.3 mg, 0.393 mmol) and pyridine (0.032 ml, 0.393 mmol) in ethanol (2 ml) was heated at 80° C. The solvent was removed in vacuo and the crude was purified by preparative LC-MS to give the title compound (9.56 mg) as trifluoroacetate
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:12]([S:25][CH3:26])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([CH2:21][CH2:22][O:23][CH3:24])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CN(C=O)C>[C:2]1([S:8]([C:11]2[C:12]([S:25][CH3:26])=[N:13][N:14]3[C:19]([NH2:1])=[CH:18][C:17]([CH2:21][CH2:22][O:23][CH3:24])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: COCCc1cc(Cl)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Solvent: CN(C)C=O
Solvent: CO
Product: COCCc1cc(N)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
10 ml of a 50% solution of NH3 in MeOH were added to a solution of 0.50 g (1.25 mmol) of 3-benzenesulphonyl-7-chloro-5-(2-methoxy-ethyl)-2-methylsulphanyl-pyrazolo[1,5-a]-pyrimidine in 10 ml of DMF and stirred at RT for 2 hrs. The reaction solution was evaporated in a high vacuum and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2 and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 10:1) and crystallization from EtOH yielded 0.30 g (63%) of 3-benzenesulphonyl-5-(2-methoxy-ethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p. 186-187°.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[S:17][N:16]=[C:15]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[N:14]=1)=O)(C)(C)C>O1CCOCC1.Cl>[N:18]1([C:15]2[N:14]=[C:13]([CH:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)[S:17][N:16]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc(-n2ccnc2)ns1
Agent: Cl
Solvent: C1COCCO1
Product: c1cn(-c2nsc(C3CCCN3)n2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
2-(3-Imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (359 mg, 1.01 mmol) was dissolved in dioxane (2 mL) and 6M HCl (aq) (2 mL). The reaction vessel was sealed and heated to 100° C. for 1 h. The reaction was allowed to return to room temperature while standing overnight. The reaction mixture was transferred to a separatory funnel and washed with 1M NaOH (30 mL). The aqueous layer was back extracted with DCM (50 mL). The organic layers were combined, dried over Na2SO4 to and concentrated in vacuo to afford 179 mg (80.4%) of 3-imidazol-1-yl-5-pyrrolidin-2-yl-[1,2,4]thiadiazole. [M+H]+ 221.87.
Reaction SMILES: [Si]([O:8][C:9]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)(=[O:21])=[O:20])=[C:14]2[C:10]=1[C:11]([Cl:29])=[CH:12][NH:13]2)(C(C)(C)C)(C)C.F.C(#N)C>O>[Cl:28][C:24]1[CH:23]=[C:22]([S:19]([NH:18][C:15]2[CH:16]=[CH:17][C:9]([OH:8])=[C:10]3[C:14]=2[NH:13][CH:12]=[C:11]3[Cl:29])(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(NS(=O)(=O)c2cccc(Cl)c2)c2[nH]cc(Cl)c12
Agent: F
Solvent: O
Solvent: CC#N
Product: O=S(=O)(Nc1ccc(O)c2c(Cl)c[nH]c12)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
220 mg (0.47 mmol) of N-(4-tert-butyldimethylsilyloxy-3-chloro-1H-indole-7-yl)-3-chlorobenzenesulfonamide synthesized in the same manner as in Synthetic Example 1a was added to a mixed solution (2 ml) of an aqueous 40% hydrogen fluoride solution/acetonitrile (1:10). After stirred at room temperature overnight, water was added thereto and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. Then, the residue was purified by silica gel column chromatography, to give 141 mg of the title compound.
Reaction SMILES: Br[C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1.C(C1C=C[C:33](C)=[N:34]C=1)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:33]([C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1)#[N:34]
Reactant: CCc1ccc(C)nc1
Reactant: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1C#N
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 94 %

Procedure:
2.0 g (4.2 mmol) of 3-(4-bromo-5-ethylsulfonylamino-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)pyrimidinedione, 0.3 g of zinc cyanide and 0.5 g of tetrakis(triphenylphosphine)palladium were added to 10 g of 5-ethyl-2-picoline and the mixture was stirred at 80° C. under an argon atmosphere for 3.5 hours. After the reaction was completed, 94% of the title compound was detected as the relative area value in liquid chromatography.
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][C:45](Cl)=[O:46]>N1C=CC=CC=1>[CH3:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][C:45]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7]1)=[O:46]
Reactant: COCCOCCOCC(=O)Cl
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COCCOCCOCC(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Reaction time: 18 h
Yield: 19.8 %

Procedure:
To a solution of 3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-one dihydrochloride (399 mg, 0.92 mmol) in pyridine (10 ml) was added triethylamine (0.31 ml, 2.2 mmol) and 2-(2-(2-methoxyethoxy)ethoxy)acetyl chloride (197 mg, 1 mmol). The mixture was stirred for 18 hours, evaporated to dryness, the residue dissolved in dichloromethane, and purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (95 mg).