Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:9][C:10]1[C:11]([C:19]2[S:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=2)=[N:12][O:13][C:14]=1[C:15]([F:18])([F:17])[F:16]>C1COCC1>[Cl:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][C:24]([C:22]1[S:23][C:19]([C:11]2[C:10]([CH3:9])=[C:14]([C:15]([F:17])([F:18])[F:16])[O:13][N:12]=2)=[CH:20][CH:21]=1)=[O:25]
Reactant: Nc1cnccc1Cl
Reactant: Cc1c(-c2ccc(C(=O)Cl)s2)noc1C(F)(F)F
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)Nc3cnccc3Cl)s2)noc1C(F)(F)F
Reaction time: 1 h
Yield: 16 %

Procedure:
A solution of 3-amino-4-chloropyridine (129 mg, 1.0 mmol) in THF (2 mL) was treated with solid 5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl chloride (148 mg, 0.5 mmol, as prepared in Example 2 Method B) and allowed to stir for 1 hr. The reaction was then evaporated and the residue chromatographed on silica gel with EtOAc/hexanes (70%) as eluant to afford product as a colorless solid (31 mg, 16%). 1H NMR (CDCl3) 2.39 (d, J=1.5, 3H), 7.39 (d, J=5.3, 1H), 7.56 (d, J=7.56, 4.1, 1H), 7.72 (d, J=4.1, 1H), 8.22 (s, 1H), 8.33 (d, J=4.7, 1H), 9.61 (s, 1H). 13C NMR 8.0, 114.8, 118.7 (q, J=271), 129.0, 129, 7, 132.9, 134.6, 140.5, 143.8, 146.1, 157.7, 159.0, 19F NMR −63.1. LC/MS 6.34 min, [M+1]+ 388.
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][C:8]([C:11](O)([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:12][CH:13]([CH3:15])[CH3:14])=[C:7]1[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.C(Cl)Cl>O>[CH2:12]([C:11]1([CH2:16][CH:17]([CH3:19])[CH3:18])[C:25]2[CH:24]=[CH:23][S:22][C:21]=2[C:7]2[S:6][CH:10]=[CH:9][C:8]1=2)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CC(O)(CC(C)C)c1ccsc1-c1cccs1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CC(C)CC1(CC(C)C)c2ccsc2-c2sccc21
Temperature: 25 °C

Procedure:
H2SO4 (1.45 mL) was added dropwise to 4-(2,2′-bithiophene-3-yl)-2,6-dimethylheptan-4-ol (IIb) (0.688 g, 2.23 mmol) under stirring at room temperature. After stirring for 12 h, CH2Cl2 (15 mL) and water (15 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were successively washed with saturated NaHCO3 and brine. After drying over MgSO4, the solvent was removed in vacuo. The crude oil was purified with column chromatography (eluent hexane) to afford a pure dark yellow oil (Ib) (0.240 g, 35.0%). 1H-NMR (CDCl3): δ=7.12 (d, J=4.8 Hz, 2H), 6.92 (d, J=4.8 Hz, 2H), 1.85 (d, J=5.8 Hz, 4H), 1.08-0.78 (m, 2H), 0.50 (d, J=7.1 Hz, 12H). 13C-NMR (CDCl3): δ=158.45, 137.29, 124.99, 122.66, 53.69, 49.30, 25.46, 25.14.
Reaction SMILES: [F:1][C:2]([F:6])([CH3:5])[CH2:3]O.N1C=CC=CC=1.C(#N)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][C:39]1[C:49]([N+:50]([O-:52])=[O:51])=[CH:48][C:42]2[CH2:43][CH2:44][NH:45][CH2:46][CH2:47][C:41]=2[CH:40]=1>>[F:1][C:2]([F:6])([CH3:5])[CH2:3][N:45]1[CH2:46][CH2:47][C:41]2[CH:40]=[C:39]([O:38][CH3:37])[C:49]([N+:50]([O-:52])=[O:51])=[CH:48][C:42]=2[CH2:43][CH2:44]1
Reactant: CC(F)(F)CO
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(CC(C)(F)F)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To mixture of 2,2-Difluoro-propan-1-ol (0.26 g, 0.0027 mol) and Pyridine (0.27 mL, 0.0034 mol) in Acetonitrile (25 mL, 0.48 mol) at 0-5° C. was added dropwise Trifluoromethanesulfonic anhydride (0.48 mL, 0.0028 mol). The mixture was stirred for 30 minutes then Potassium carbonate (0.37 g, 0.0027 mol) and 7-Methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.30 g, 0.0013 mol) were added. The reaction mixture was warmed to room temperature then heated to 50° C. for 18 hours. The mixture was evaporated. The residue was dissolved in dichloromethane (50 mL) and washed with water (50 mL), dried over magnesium sulfate, filtered and evaporated. The material was purified via silica gel chromatography using 0%→10% Methanol:Dichloromethane solvent gradient. 3-(2,2-Difluoro-propyl)-7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine isolated as a yellow solid (0.316 g, 78%).
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15]O)=[NH:5].N[N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:20]=[C:19]1[NH2:31]>C(O)(C)C>[ClH:1].[ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15][N:18]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:20]=[C:19]1[NH2:31])=[NH:5]
Reactant: COc1ccc(-c2cn(N)c(N)n2)cc1
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(-c2cn(N=C3CCc4c(C(=N)NO)cccc43)c(N)n2)cc1

Procedure:
7.2 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) are added, with stirring, to a mixture of 4.92 g (0.024 mol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 4.9 g (0.024 mol) of 1,2-diamino-4-(4-methoxyphenyl)-imidazole (see Hetzheim A. et al., Chem. Ber. 100, 3418 (1967)) and 120 ml of isopropanol, and the reaction mixture is stirred at 80° C. for 19 hours. The reaction mixture is filtered while hot and the filtrate is cooled. The pale-yellow title product that has crystallised out is filtered off with suction and dried. It crystallizes in the form of the monohydrate, m.p. >220° C., MS (FAB): (M+H)+ =377, 1H-NMR (DMSO/D2O): δ=8.23 (d, 1H); 7.74 (s, 1H); 7.72 (d, 1H); 7.57-7.63 (m, 3H); 7.02 (d, 2H); 3.75 (s, 3H), 3.26 (s, 4H).
Reaction SMILES: BrBr.[CH2:3]([O:5][C:6]([CH:8]1[CH2:19][N:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:11]2[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=2[C:9]1=[O:25])=[O:7])[CH3:4].C(N(CC)CC)C>C(Cl)Cl>[CH2:3]([O:5][C:6]([C:8]1[C:9](=[O:25])[C:10]2[CH:15]=[N:14][C:13]([S:16][CH3:17])=[N:12][C:11]=2[N:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[CH:19]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C1CN(C2CCCC2)c2nc(SC)ncc2C1=O
Agent: BrBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cn(C2CCCC2)c2nc(SC)ncc2c1=O
Reaction time: 0.25 h

Procedure:
Bromine (0.13 g, 0.82 mmol) was added to a solution of 8-Cyclopentyl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.34 g, 0.82 mmol) in DCM (5 mL). After 15 min, the solution was concentrated and the crude residue was redissolved in DCM (5 mL) and triethylamine (0.16 mL, 0.24 mmol) was added. After 15 h, the reaction mixture was partitioned between water and DCM, the organic layer was separated, dried (MgSO4) and concentrated to provide the title compound. Mass Spectrum (LCMS, ESI pos.) Calcd. For C16H19N3O3S: 333.11, found: (M+H) 334.1.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2].[CH2:46]([O:53][C:54]([NH:56][C:57](N1C=CC=N1)=[NH:58])=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>O1CCCC1>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:41][C:57]([NH2:58])=[N:56][C:54]([O:53][CH2:46][C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[O:55])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N=C(NC(=O)OCc1ccccc1)n1cccn1
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCNC(N)=NC(=O)OCc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 55.9 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (70 mg) in tetrahydrofuran (3 mL) was added N-(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (0.27 g), and the mixture was stirred at 60° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-ethyl acetate-ethyl acetate/ethanol=10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[3-(N′-benzyloxycarbonylguanidino)propoxy]-2-methylphenyl)methyl}-5-isopropyl-1H-pyrazole (50 mg). This material was dissolved in methanol (1 mL). To the solution was added sodium methoxide (28% methanol solution, 0.01 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give 4-({4-[3-(N′-benzyloxycarbonylguanidino)propoxy]-2-methylphenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (35 mg). This material was dissolved in methanol (2 mL). To the solution was added 10% palladium-carbon powder (15 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (27 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[C:12](S)[NH:13][CH:14]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2]>[Ni].CN(C)C=O>[CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCNc1cc(-c2c[nH]c(S)n2)ccn1
Agent: [Ni]
Solvent: CN(C)C=O
Product: CCNc1cc(-c2c[nH]cn2)ccn1

Procedure:
A mixture of 1.1 g. (5 mmoles) of 4-(2-ethylamino-4-pyridyl)imidazole-2-thiol and 4.0 g. of Raney nickel in 30 ml. of dimethylformamide was heated at 120° C. for 4 hours. The catalysts was filtered through celite and the filtrate concentrated under reduced pressure to remove the solvent. The residual oil solidified on trituration with diethyl ether affording 830 mg. (88%) of the desired product. Purification by chromatographing over 35 g. of silica gel using chloroform-methanol (19:1, v:v) as the eluent gave 384 g. (41%) of pure product, m.p. 135°-137° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:5]2[C:6](=[O:11])[C:7]=1[CH2:8][CH2:9]Cl.[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:5]2[C:6](=[O:11])[C:7]=1[CH2:8][CH2:9][N:27]1[CH2:26][CH2:25][N:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=2)[CH2:29][CH2:28]1
Reactant: Cc1nc2ccc(Cl)cn2c(=O)c1CCCl
Reactant: Clc1cccc(N2CCNCC2)c1
Solvent: Cc1ccccc1
Product: Cc1nc2ccc(Cl)cn2c(=O)c1CCN1CCN(c2cccc(Cl)c2)CC1
Yield: 23.7 %

Procedure:
A mixture of 1.3 g of 2-methyl-3-(2-chloroethyl)-7-chloro-4H-pyrido[1,2-a]pyrimidin-4-one, 4.2 g of 1-(m-chlorophenyl)piperazine and 20 ml of toluene was refluxed with heating for 30 hours. After completion of the reaction, the reaction mixture was then treated in the same manner as in Example 8. The crude crystals thus obtained were recrystallized from ethanol to give 0.5 g of the desired compound as pale orangeyellow needles, m.p. 152° - 154°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[H][H]>CCOC(C)=O.CO.[Pd]>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: [H][H]
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(CCC(=O)O)cc(OC)c1
Yield: 96.5 %

Procedure:
To a solution of 3-(3,5-Dimethoxy-phenyl)-acrylic acid (12 g, 57.7 mmol) in EtOAc (100 ml) and MeOH (100 ml) was added carefully 10% Pd/C (1.3 g), the reaction mixture was shaken in Parr apparatus for 5 hs under 30-40 psi of hydrogen, then the solution was passed through a celite pad, the filtrate was concentrated and dried at 50° C. under reduced pressure to give product (11.7 g, 96.55%). LC-MS: m/e 209 (M−1)
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[Cl:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][N:28]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:29]3[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:27]([Cl:26])=[N:28]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Clc1n[nH]c2ccccc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3nc(Cl)c4ccccc43)nc12
Temperature: 125 °C

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (136 mg, 318 μmol), 3-chloro-1H-indazole (48.6 mg, 318 mmol) in dioxane (3.5 mL) was added sodium tert-butoxide (67.3 mg, 700 μmol) and bis(tri-tert-butylphosphine)palladium(0) (16.3 mg, 31.8 μmol). The mixture was degassed then heated in sealed tube at 125° C. for two days. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-butyl-2-(3-chloro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide. 1H NMR (CDCl3) δ: 9.12 (s, 1H), 8.61 (d, J=8.5 Hz, 1H), 8.36 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.58 (ddd, J=8.5, 7.2, 1.1 Hz, 1H), 7.42 (ddd, J=8.1, 7.1, 0.9 Hz, 1H), 5.72 (s, 2H), 3.55-3.62 (m, 2H), 1.61 (s, 9H), 0.95 (d, J=16.6 Hz, 2H), −0.03 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C@:11]1([CH3:22])[CH2:16][S:15](=[O:18])(=[O:17])[C:14]([CH3:20])([CH3:19])[C:13]([NH2:21])=[N:12]1.C(N(CC)CC)C>C(O)C.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:11]2([CH3:22])[CH2:16][S:15](=[O:17])(=[O:18])[C:14]([CH3:19])([CH3:20])[C:13]([NH2:21])=[N:12]2)[CH:4]=1
Reactant: CC1(C)C(N)=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)CS1(=O)=O
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)C(N)=N[C@](C)(c2cc(N)ccc2F)CS1(=O)=O
Temperature: 23 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a solution of (R)-5-(2-fluoro-5-nitro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (950 mg, 2.88 mmol, Eq: 1.00) in ethanol (50 ml) was added at 23° C. under inert atmosphere triethylamine (292 mg, 402 μl, 2.88 mmol, Eq: 1.00) and after inertisation Pd/C 10% (307 mg, 288 μmol, Eq: 0.1). The suspension was set under hydrogen (balloon) and stirred at 23° C. for 1 hour. The catalyst was filtered off, washed three times with ethanol and a mixture of dichloromethane and methanol and evaporated the combined filtrate to give the crude and nearly pure (R)-5-(5-amino-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (760 mg, 2.54 mmol, 88.0% yield) as an off-white solid. MS (ISP): m/z=300.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:11])[CH3:10].[CH:12]1([N:15]=[C:16]=[O:17])[CH2:14][CH2:13]1>O1CCCC1>[CH:12]1([NH:15][C:16](=[O:17])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:9](=[O:11])[CH3:10])[CH2:14][CH2:13]1
Reactant: CC(=O)Nc1ccccc1F
Reactant: O=C=NC1CC1
Solvent: C1CCOC1
Product: CC(=O)N(C(=O)NC1CC1)c1ccccc1F
Temperature: 100 °C

Procedure:
A mixture of 5.8 g of 3A, 50 ml of tetrahydrofuran and 5.0 g of 1A was heated in a sealed glass cylinder for 12 hours at 100° C. Then the solvent was evaporated, and the residue was recrystallized from ether/hexane to give 3, as a white solid, m.p.: 43°-45° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]([CH2:18][OH:19])[CH2:15][CH:16]=[CH2:17])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]([CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH:16]=[CH2:17])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCC(CO)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(COS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A solution of methanesulphonyl chloride (2.3 g) in dichloromethane (10 ml) was added to an ice-cooled solution of 4-(3,4-dichlorophenyl)-5-hydroxypent-1-ene (4.3 g) (see Preparation 22) and triethylamine (2.5 g) in dichloromethane (50 ml) over 10 minutes. The mixture was stirred for a further 30 minutes before being washed sequentially with water (3×25 ml) and brine (25 ml), then dried over anhydrous sodium sulphate. Removal of the solvent under reduced pressure gave 4-(3,4-dichlorophenyl)-5-(methanesulphonyloxy)pent-1-ene (5.4 g) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:39][CH2:38][CH2:37][N:36]2[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[C:31]([F:47])[CH:30]=1>C(Cl)(Cl)Cl>[F:47][C:31]1[CH:30]=[C:29]([NH:28][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH:34]=[CH:33][C:32]=1[CH:35]1[CH2:39][CH2:38][CH2:37][N:36]1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(N)cc1F
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(NC(=O)c2cnccn2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.5 g of pyrazine-2-carboxylic acid and 3.1 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride were added to a pyridine (50 ml) solution of 3 g of t-butyl 2-(4-amino-2-fluoro-phenyl)-pyrrolidine-1-carboxylate obtained in Example 338 (step 2), and the reaction liquid was stirred at room temperature for 3 hours. The reaction liquid was diluted with chloroform, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=50/1) to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[N:25]=[CH:26][S:27][C:21]=2[N:20]=[C:19]1[CH:28]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH2:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[N:25]=[CH:26][S:27][C:21]=2[N:20]=[C:19]1[CH:28]([N:31]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCC(NCCN(C)C)c1nc2scnc2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(c1nc2scnc2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (1 equiv) in dichloromethane is added to a solution of 6-benzyl-5-(1-{[2-(dimethylamino)ethyl]amino}-propyl)[1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one (1-4, 1 equiv) and N,N-diisopropylethylamine (1 equiv) in dichloromethane, and the resulting mixture is stirred under ambient conditions for 1 h. The reaction mixture is washed with saturated aqueous NaHCO3 solution, and brine, then dried (MgSO4) and concentrated. The residue is purified by flash chromatography. Elution with CH2Cl2 to 5% NH3—EtOH/CH2Cl2 gives N-[1-(6-benzyl-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-5-yl)propyl]4-bromo-N-[2-(dimethylamino)ethyl]benzamide (1-5).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:27])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:20]=2)[C:16]=1Cl)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH2:28]1[C:32]2([CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][NH:29]1.C(N(CC)C(C)C)(C)C.[OH-].[Li+]>CN1C(=O)CCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:27])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=2)[C:16]=1[N:29]1[CH2:30][CH2:31][C:32]2([CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:28]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: C1CCC2(C1)CCNC2
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3ccccc3)nn2c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(-c3ccccc3)nn2c(N2CCC3(CCCC3)C2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
(S)-methyl 2-(tert-butoxy)-2-(7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetate was dissolved in NMP (1 mL) and combined with 2-azaspiro[4.4]nonane (8.72 mg, 0.070 mmol) and N,N-diisopropylethylamine (27 mg, 0.21 mmol). This mixture was stirred at rt for 24 h. A 1M lithium hydroxide solution (0.348 mL, 0.348 mmol) was added to the reaction mixture and it was heated at 50° C. for 4 h to complete the ester hydrolysis. The reaction mixture was concentrated in vacuo and purified by Biotage (4 g column, 0-10% MeOH/CH2Cl2 ramp) to give 11.1 mg (27% yield) of S)-2-(tert-butoxy)-2-(5-methyl-2-phenyl-7-(2-azaspiro[4.4]nonan-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic (1:1 solvate with NMP) as a yellow waxy solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:5]=1[CH2:6][O:7]C=O)=[O:2]>C(#N)C.C(O)CCC>[OH:7][CH2:6][C:5]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:4]=1[NH:3][CH:1]=[O:2]
Reactant: COc1ccc(NC=O)c(COC=O)c1
Solvent: CCCCO
Solvent: CC#N
Product: COc1ccc(NC=O)c(CO)c1
Temperature: 20 °C
Reaction time: 65 h

Procedure:
1.70 g of Candida antarctica B lipase (CAL-B) were added to a solution of 5.90 g of the product from stage 1 in a mixture of 190 ml of anhydrous acetonitrile and 10.3 ml of n-butanol and stirred for 65 hours at 20° C. The mixture was then filtered and washed with acetonitrile. After concentrating the filtrate by evaporation in vacuo, 5.00 g (98% of theory) of the title compound remained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][CH:6]=1.CN.[CH2:16]([N:18](CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:18][CH3:16])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Product: CNCc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 15 in tetrahydrofuran (0.4 M) at room temperature under nitrogen was added methylamine (7.5 eq) and triethylamine (12.0 eq). The reaction was stirred at room temperature overnight. The tetrahydrofuran was removed under reduced pressure and the resulting oil was diluted with H2O. The aqueous layer was acidified with 6N hydrochloric acid, extracted with ethyl acetate (3×), made basic with saturated sodium bicarbonate and extracted with dichloromethane (3×). The dichloromethane was dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. (66%) 1H NMR (400 MHz, CDCl3) δ 7.31 (d, 2H), 7.25 (d, 2H), 3.77 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H), 2.45 (s, 3H).