Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[N:2].C[O:11][C:12]([C:14]#[C:15][C:16](OC)=[O:17])=[O:13].[OH-].[Na+].Cl>CO.C1(OC2C=CC=CC=2)C=CC=CC=1.O>[C:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:5]2[C:4]=1[C:16](=[O:17])[CH:15]=[C:14]([C:12]([OH:13])=[O:11])[NH:6]2)#[N:2]
Reactant: N#Cc1cccc(N)c1
Reactant: COC(=O)C#CC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: N#Cc1cccc2[nH]c(C(=O)O)cc(=O)c12
Yield: 0.5 %

Procedure:
3-Cyanoaniline (21.3 g, 0.18 mol) and dimethylacetylene dicarboxylate (10.9 ml, 0.12 mol) were dissolved in dry methanol and heated at reflux for 14 h. After cooling, the solvent was removed in vacuo and the residue partitioned between diethyl ether and 1N hydrochloric acid. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to leave an oil which was heated in diphenyl ether (100 ml) at 250° C. for 15 minutes. On cooling, a solid precipated which was collected and recrystallised successively from acetic acid/diethyl ether, then from pyridine, to give a pure material by t.l.c. (0.165 g). This was dissolved in water (20 ml) and methanol (10 ml) with sodium hydroxide (0.13 g) and the solution heated at 100° C. for 2 h. Addition of 1N hydrochloric acid caused precipitation of a white solid which was collected by filtration and washed successively with water, ethanol and diethyl ether to give 5-cyano-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.14 g) m.p. 278°-279° C., δ (360 MHz, NAOD) 6.96 (1H, s, 3-H), 7.64 (1H, dd, 7-H), 7.83 (1H, dd, 6-H) and 8.05 (1H, dd, 8-H). (Found: C, 60.23; H, 3.03; N, 12.46%. C11H6N2O3. 0.3H2O requires C, 60.17; H, 3.03; N, 12.78%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([C:10]1[O:16][C@H:15]2[N:12]([C:13](=[O:33])[C@@H:14]2[C@@H:17]([O:19]C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH3:18])[C:11]=1[C:34]([O:36]CC1C=CC([N+]([O-])=O)=CC=1)=[O:35])([CH3:9])[CH3:8])=[N+]=[N-].[H][H]>[Pd].C(OCC)(=O)C.O>[NH2:1][CH2:4][CH2:5][CH2:6][C:7]([C:10]1[O:16][C@H:15]2[N:12]([C:13](=[O:33])[C@@H:14]2[C@@H:17]([OH:19])[CH3:18])[C:11]=1[C:34]([OH:36])=[O:35])([CH3:8])[CH3:9]
Reactant: [H][H]
Reactant: C[C@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(C(C)(C)CCCN=[N+]=[N-])O[C@H]12
Agent: [Pd]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(C(C)(C)CCCN)O[C@H]12
Reaction time: 0.33 h
Yield: 74.7 %

Procedure:
In a 100 ml two necked flask fitted with a magnetic stirrer, a rubber septum and connected to a hydrogenation apparatus palladium on carbon catalyst (10%, 300 mg) in ethyl acetate (13 ml) and water (13 ml) was prehydrogenated for 20 min at 0° C. A solution of p-nitrobenzyl (5R,6R)-3-[4-azido-1,1-dimethylbutyl]-6-[(S)-1-p-nitrobenzyloxycarbonyloxyethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (280 mg, 0.44 mmol) in ethyl acetate (10 ml) was then added with a syringe at 0° C. with stirring. After 50 min of stirring at 0° C. hydrogen uptake came to an end (90 ml of hydrogen was consumed). The catalyst was removed by filtration, washed with a small portion of ethyl acetate and water and the chilled two phase mixture allowed to separate. The aqueous phase was washed twice with portions (3 ml) of cold ethyl acetate and water and the ethyl acetate phases were reextracted twice with portions (3 ml) of water. Residual ethyl acetate was removed from the combined water phases in vacuum and then in high vacuum at 0° C. and the volume was reduced to 13 ml in high vacuum. The solution was lyophilized at −25° C. for three days to give (5R,6R)-3-[4-amino-1,1-dimethylbutyl]-6-[(S)-1-hydroxyethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (YOB) as a colourless voluminous powder (98 mg, 75%)
Reaction SMILES: FC(F)(F)S(O[CH:7]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.[CH3:21][N:22]([C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([CH:7]([N:32]2[CH2:33][CH2:34][C@H:30]([N:22]([CH3:21])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:31]2)[C:8]([F:11])([F:10])[F:9])=[CH:17][CH:16]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Reactant: O=S(=O)(OC(c1ccc(Cl)nc1)C(F)(F)F)C(F)(F)F
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCN(C(c2ccc(Cl)nc2)C(F)(F)F)C1
Yield: 66.8 %

Procedure:
Prepared as described in Example 1, Step C, using 1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (1.50 g, 4.37 mmol) and (S)-tert-butyl methyl(pyrrolidin-3-yl)carbamate (1.2 g, 6.11 mmol) to afford tert-butyl (3S)-1-(1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-yl(methyl)carbamate (1.15 g, 67%).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[NH:9][C:10]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[NH:9][C:10]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: Cc1ccc2nc(SCCCCCO)[nH]c2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc2nc(SCCCCCBr)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
1.4 g of the compound obtained in Example 14a and 2.8 g of carbon tetrabromide were added to 15 ml of tetrahydrofuran and then gradually added with 2.2 g of triphenylphosphine. After the reaction mixture was stirred at room temperature for 1 hour, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 2:2) to obtain 1.18 g of the title compound as yellow crystals (yield: 67%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([S:12][C:13]2[S:14][C:15]([CH2:19][C:20]([O:22]CC)=[O:21])=[C:16]([CH3:18])[N:17]=2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])C.CO.[OH-].[Na+]>O>[C:20]([CH2:19][C:15]1[S:14][C:13]([S:12][C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:17][C:16]=1[CH3:18])([OH:22])=[O:21]
Reactant: CCOC(=O)Cc1sc(Sc2ncccc2C(=O)OCC)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(Sc2ncccc2C(=O)O)sc1CC(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To a mixture of 737 mg (2.09 mmol) of the title compound of Example 1, 70 ml of methanol, and 30 ml of water chilled to 0° C. in an ice bath was added 210 mg (5.22 mmol, 2.5 equivalents) of sodium hydroxide. After the sodium hydroxide had dissolved, the ice bath was removed and the mixture was allowed to stir at room temperature for 3 hours. The solvent was removed by rotary evaporation and the residue was diluted with water, chilled to 0° C. in an ice bath, and acidified with aqueous 6N HCl solution until precipitation had ceased. The precipitate was collected by filtration (washed with cold water) and was dried under vacuum to yield 554 mg (85%) of the title compound, mp 233°-235° C. 1H NMR (DMSO-d6): δ 2.29 (3H, s), 3.85 (2H, s), 7.38 (1H, dd, J=8, 5), 8.33 (1H, d, J=8), 8.63 (1H, d, J=5). FAB MS (m/e): 311 (M+ +1), 265, 233, 119 (base).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(CCO)[CH2:9][CH2:10]O>>[NH:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=[CH:9]1
Reactant: Nc1ccccc1
Reactant: OCCNCCO
Product: c1ccc2[nH]ccc2c1
Yield: 24.5 %

Procedure:
Reaction was carried out in the same manner as described in Example 1 except that granular activated carbon was used in place of the Pd-C catalyst, 6.1 g (0.1 mole) of monoethanolamine or 9.3 g (0.1 mole) of diethanolamine was used as the ethanolamine, and the reaction temperature was raised to 400° C. When monoethanolamine was used, 2.7 g of indole was obtained in a 23.5% yield based on the aniline. Similarly, when diethanolamine was used, 2.9 g of indole was obtained in a 24.5% yield based on the aniline.
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][C:7]([B:11]3[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]3)=[CH:8][CH:9]=2)C(C2C=CC=CC=2)=[N:3]1.BrC1C=CC2N=N[N:32](C)[C:31]=2C=1>>[CH3:31][N:32]1[C:5]2[CH:6]=[C:7]([B:11]3[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:18])([CH3:19])[O:12]3)[CH:8]=[CH:9][C:10]=2[N:2]=[N:3]1
Reactant: Cn1nc(-c2ccccc2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Cn1nnc2ccc(Br)cc21
Product: Cn1nnc2ccc(B3OC(C)(C)C(C)(C)O3)cc21

Procedure:
Prepared in a manner similar to 1-methyl-3-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole, but using 6-bromo-1-methyl-1H-benzo[d][1,2,3]triazole instead of 5-bromo-1-methyl-3-phenyl-1H-indazole. 1H NMR (400 MHz, CDCl3) δ 8.04 (dd, J=6.8, 1.6 Hz, 2H), 7.79 (d, J=8.6 Hz, 1H), 4.33 (s, 3H), 1.39 (s, 12H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(O)C.[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH2:27].C(O)(=O)C>N>[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC(=O)c1nnc2cc(OC)c(OC)cc2c1Cl
Agent: N
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1nnc2cc(OC)c(OC)cc2c1Nc1ccc(F)cc1F
Temperature: 75 °C
Yield: 87.9 %

Procedure:
To a 50 mL round bottom flask charged with a magnetic stir bar and ethyl 4-chloro-6,7-dimethoxycinnoline-3-carboxylate (0.200 g, 0.675 mmol) (Method 7) was added anhydrous ethanol (10 mL), 2,4-difluoroaniline (0.087 g, 0.675 mmol), and glacial acetic acid (˜100 μL). The reaction mixture was then heated to 75° C. for 1 h, cooled to rt, and diluted with concentrated aqueous ammonia (˜5 mL). The crude product precipitated from this reaction mixture and was collected via vacuum filtration using a Buchner funnel. The solid was washed water (1×100 mL) and diethyl ether (1×100 mL) to yield the crude product which was purified on 40 g silica using EtOAc as eluent providing 0.231 g (88%) of the title compound as a yellow solid. 1H NMR: 9.25 (s, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 7.40 (m, 1H), 7.30 (m, 1H), 7.10 (m, 1H), 4.02 (s, 3H), 3.95 (q, 2H), 3.85 (s, 3H), 1.20 (t, 3H); m/z 390.
Reaction SMILES: [NH2:1][NH2:2].[N+:3]([C:6]([N+:15]([O-:17])=[O:16])([N+:12]([O-:14])=[O:13])[CH2:7][CH2:8][C:9](Cl)=[O:10])([O-:5])=[O:4]>CO>[N+:3]([C:6]([N+:15]([O-:17])=[O:16])([N+:12]([O-:14])=[O:13])[CH2:7][CH2:8][C:9]([NH:1][NH:2][C:9](=[O:10])[CH2:8][CH2:7][C:6]([N+:3]([O-:5])=[O:4])([N+:15]([O-:17])=[O:16])[N+:12]([O-:14])=[O:13])=[O:10])([O-:5])=[O:4]
Reactant: NN
Reactant: O=C(Cl)CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Solvent: CO
Product: O=C(CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])NNC(=O)CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]

Procedure:
Low temperatures also reduce side reactions with hydrazine as well as the reaction of the acid chloride with methanol Therefore the hydrazine solution and the 4,4,4-trinitrobutyryl chloride solution are mixed together at a temperature in the range of preferably about -40° C. to -100° C., more preferably from -60° C. to -90° C., and still more preferably from -70° C. to -85° C., with about -78° C. being most preferred. The resulting reaction solution is then put in ambient (room) temperature environment and allowed to warm up to a temperature in the range of from about -5° C. to about 25° C. The product N,N'-bis(4,4,4-trinitrobutyryl)hydrazine is then isolated using conventional techniques as illustrated in the example.
Reaction SMILES: [CH:1](O)=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:16]1[N:20]2[C:21]3[C:26]([NH:27][CH2:28][C:19]2=[N:18][C:17]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][CH:24]=[CH:23][CH:22]=3.CCOCC>ClCCl>[CH:1]([CH:28]1[NH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]2[CH:16]=[C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:18]=[C:19]12)=[O:2]
Reactant: CCOC(=O)c1cn2c(n1)CNc1ccccc1-2
Reactant: O=CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1cn2c(n1)C(C=O)Nc1ccccc1-2
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.5 %

Procedure:
A solution of 0.70 g of 98% formic acid in 70 ml of dichloromethane was stirred under dry nitrogen with 2.5 g of carbonyldiimidazole for 15 minutes and 1.4 g of ethyl 4,5-dihydroimidazo[1,2-a]quinoxaline-2-carboxylate were added. The mixture was stirred at room temperature for 6 hours under nitrogen and was then poured into ice/aqueous bicarbonate and filtered. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to a low volume. Dilution with ether gave 1.1 g (70% yield) of ethyl 4-formyl-4,5-dihydroimidazo[1,2-a]quinoxaline-2-carboxylate as colorless crystals after crystallization from dichloromethane/diethyl ether.
Reaction SMILES: Cl.[NH:2]([C:4](=[S:6])[NH2:5])[NH2:3].[F:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH2:18][C:19]1[N:23]2[N:24]=[C:25]([C:28](=O)[CH3:29])[CH:26]=[CH:27][C:22]2=[N:21][CH:20]=1>>[F:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH2:18][C:19]1[N:23]2[N:24]=[C:25](/[C:28](=[N:3]/[NH:2][C:4](=[S:6])[NH2:5])/[CH3:29])[CH:26]=[CH:27][C:22]2=[N:21][CH:20]=1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: NNC(N)=S
Agent: Cl
Product: C/C(=N\NC(N)=S)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 60 %

Procedure:
The title compound was prepared from hydrazine carbothioamide hydrochloride and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 60% yield as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.53 (s, 1H), 8.88 (dd, 1H), 8.53 (s, 1H), 8.47 (d, 1H), 8.34 (m, 2H), 8.10 (d, 1H), 7.99 (d, 1H), 7.85 (s, 1H), 7.79 (d, 1H), 7.50 (q, 1H), 4.59 (s, 2H), 2.34 (s, 3H). LCMS (method A): [MH]+=394, tR=4.91 min.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)=[C:4]([N:22]=[N+:23]=[N-:24])[N:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCn2cnc3c(N=[N+]=[N-])nc(N)nc32)CO1
Temperature: 105 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
To a solution of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.47 g, 1.5 mmol) in dry N,N-dimethylformamide (5 ml), sodium azide (0.20 g, 3.0 mmol) was added and the mixture was stirred at 100-110° C. for 4 hours. The solvent was removed and the residue washed with water to leave 2-amino-6-azido-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine as a crystalline solid (0.36 g, 75%), m.p. decomposed at 200° C.; λmax (MeOH) 272 (ε 8,210) and 301 (ε 10,100) nm; νmax (KBr) 1670, 1625, and 1560 cm−1; δH (CDCl3-CD3OD) 1.44 (6H, s, C(CH3)2), 1.6-2.2 (3H, m, CH2CHCH2), 3.5-3.8 (2H, dd (ABX), J 7 Hz and J 11 Hz, 2×Hax), 3.85-4.15 (2H, dd (ABX), J 4 Hz and J 11 Hz, 2×Heq), 4.29 (2H, t, J 7 Hz, CH2N), and 7.93 (1H, s, 8-H) (Found: C, 48.96; H, 5.66; N, 35.15%; M+ 318.1553. C13H18N8O2 requires C, 49.05; H, 5.70; N, 35.20%; M+ 318.1546).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[C:9]([O:13][CH2:14][CH2:15][NH2:16])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][CH2:14][CH2:15][NH:16][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: O=Cc1ccncc1
Reactant: CC(C)(C)OCCN
Product: CC(C)(C)OCCNCc1ccncc1

Procedure:
Using 4-pyridine carboxaldehyde and O-tert butyl ethanolamine, and the synthetic procedure described for Intermediate 16, a crude sample of the title compound was prepared, which was used directly in the next stage of the synthetic sequence.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:23])=[O:22]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Cl)cc2Cl)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,4-dichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (45.8 mg) with purity >90%. MS (pos) m/z 395.2, 397.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([CH3:12])=[CH:4][C:3]=1[OH:13].C=O.S(=O)(=O)(O)O.[O:21]1[CH2:26]COC[CH2:22]1>>[CH3:12][C:5]1[C:4]2[CH2:26][O:21][CH2:22][O:13][C:3]=2[C:2]([CH3:1])=[CH:7][C:6]=1[C:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: C1COCCO1
Reactant: Cc1cc(C(C)(C)C)c(C)cc1O
Agent: C=O
Agent: O=S(=O)(O)O
Product: Cc1cc(C(C)(C)C)c(C)c2c1OCOC2
Yield: 59 %

Procedure:
Reaction of 2,5-dimethyl-4-(1,1-dimethylethyl)-phenol (20.2 g, GLC purity 88%, 0.1 mol, which may be prepared as described by W. Weinrich, Ind. Eng. Chem. (1943) 35, 264-272), 40% formaldehyde solution (80 mL, 1.07 mol), p-dioxane (170 mL) and sulfuric acid (10 mL) according to the procedure described in Example 2, provided after distillation 13.05 g (59% yield, GLC purity 97%) of 5,8-dimethyl-6-(1,1-dimethylethyl)-4H-1,3-benzodioxin, bp 139° C., 3 mm; 1H-NMR (CDCl3)δ 1.40 (9H, s), 2.21 (6H, s), 4.79 (2H, s), 5.14 (2H, s); 7.01 (1H, s); IR (film)νmax 2940, 1580, 1475 cm-1 ; MS m/e 220, 205, 190, 185, 147; UVλmax (ethanol) 225 nm (ε=4270), 281 nm (ε=1490).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.C[N:11]([CH:13](OC)OC)C.N[OH:19].Cl>CC(O)C>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][CH:13]=[N:11][OH:19])[CH:4]=1
Reactant: Nc1cc(CCl)ccn1
Reactant: COC(OC)N(C)C
Reactant: NO
Agent: Cl
Solvent: CC(C)O
Product: ON=CNc1cc(CCl)ccn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
To a solution of 4-(chloromethyl)pyridin-2-amine (4-1) (1.56 g, 8.7 mmol) in propan-2-ol (15 mL) was added DMF-DMA (1.56 mL, 11.3 mmol) at room temperature under N2. The reaction mixture was heated to 90° C. for 3 h. After cooled to 50° C., the mixture was treated with NH2OH.HCl (0.781 g, 11.3 mmol), then stirred at 50° C. overnight. After cooled to room temperature, the mixture was concentrated and purified by chromatography on silica gel to afford the title compound (820 mg). MS (m/z): 186 (M+1)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:23]C(OC(Cl)C)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[O:14]2)[CH2:10][CH2:9]1.[ClH:23]
Reactant: CC(Cl)OC(=O)Cl
Reactant: O=C1OC2(CCN(Cc3ccccc3)CC2)c2ccccc21
Solvent: ClCCl
Product: Cl
Product: O=C1OC2(CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 484 %

Procedure:
To a solution of 1′-benzyl-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one 1b (6 g, 20.4 mmol) in dichloromethane (30 mL) was added dropwise 1-chloroethyl chloroformate (2.9 g, 20.4 mmol). The mixture was stirred at 25° C. for 5 hr and then was concentrated to dryness under reduced pressure. The residue was dissolved in methanol and the mixture was heated to reflux for 30 min. The mixture was concentrated to dryness and ether was added. The precipitated solid was collected by filtration and washed with ether, dried in air to obtain 3H-spiro[isobenzofuran-1,4′-piperidin]-3-one 1c as its HCl salt (3.6 g). 1H-NMR (400 MHz, DMSO-d6) δ 9.16 (br, 2H), 7.86-7.81 (m, 2H), 7.63 (t, J=7.6 Hz, 1H), 7.56 (d, J=7.2 Hz, 1H), 3.39-3.42 (m, 2H), 3.11-3.14 (m, 2H), 2.47-2.48 (m, 2H), 1.85 (d, J=14.4 Hz, 2H). MS (ESI) m/z (M+H+): 203.24.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]1[C:10]([NH2:29])=[N:11][CH:12]=[C:13]([C@@H:15]2[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:16]2)[N:14]=1.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:8][C:9]1[C:10]([NH:29][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[N:11][CH:12]=[C:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH:17]([O:21][Si:22]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:23])[CH3:24])[CH2:16]2)[N:14]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCC[C@@H](c2cnc(N)c(Br)n2)C1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)Nc1ncc(C2CCCC(O[Si](C)(C)C(C)(C)C)C2)nc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Pivaloyl chloride (71.5 μL, 0.569 mmol) was added dropwise to a stirred, cooled (0° C.) mixture of (+/−)-3-bromo-5-((1R,3S)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazin-2-amine (110 mg, 0.285 mmol) and TEA (159 μL, 1.139 mmol) in CH2Cl2 (949 μL). The red mixture was stirred at 0° C. for 1 h, then at room temperature for 2 h. EtOAc and Sat NaHCO3 was added and stirred well. Organic layer was separated and the aqueous layer was extracted well with EtOAc. Combined EtOAc layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with EtOAc/heptane to give (+/−)-N-(3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazin-2-yl)pivalamide 97 mg in 72.4% yield. LCMS (m/z): 472.3 (MH+), 1.19 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (100 mg, 0.27 mmol) and 4-fluorobenzylamine (40 mg, 0.32 mmol). The title compound was obtained as a solid (60 mg, 48% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.37 (1H, m), 9.03 (2H, s), 8.46 (1H, s), 7.32 (2H, dd), 7.20 (2H, dd), 4.43 (2H, m). MS m/z: 456.04, 458.00 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Li+].[CH3:30]I>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[C:5](=[O:8])[N:6]([CH3:30])[CH:7]=1
Reactant: CI
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cn(C)c3=O)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a suspension of (R)-ethyl 5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.73 g, 1.97 mmol) in DMF (10 mL) at 0° C. was added LiH (20 mg, 2.36 mmol). After stirring for 30 minutes, a solution of MeI (0.56 g, 3.93 mmol) in DMF (2 mL) was added and the reaction was stirred at ambient temperature for 17 hours. The reaction mixture was cooled to 0° C. and quenched with ice-water (30 mL). The mixture was extracted with EtOAc (3×), washed with water and brine, dried with MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography, eluting with 2.5% MeOH/DCM to yield the title product (0.64 g, 85%). MS (apci) m/z=386.0 (M+H).