Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CB(O)O.[C:5]([O-])([O-])=O.[Na+].[Na+].[C:11]([NH:15][C:16]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[C:27](Br)[CH:26]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>C1(C)C=CC=CC=1.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.CCOC(C)=O>[C:11]([NH:15][C:16]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[C:27]([CH3:5])[CH:26]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)NC(=O)C1CCN(Cc2cc(Br)cc([N+](=O)[O-])c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(CN2CCC(C(=O)NC(C)(C)C)CC2)cc([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
Methylboronic acid (23.2 mg, 0.377 mmol) and a solution of 2 M Na2CO3 (0.088 mL, 0.502 mmol) is added to a solution of 1-(3-bromo-5-nitro-benzyl)-piperidine-4-carboxylic acid tert-butylamide BB-10a (100 mg, 0.251 mmol) in anhydrous toluene (3 mL) The mixture is purged under argon for 15 min. Tetrakis(triphenylphosphine)palladium (0) (58 mg, 0.0502 mmol) is added and the mixture is heated to 100° C. overnight. Water (10 mL) and AcOEt (10 mL) are added and the aqueous phase is extracted twice with AcOEt (10 mL). The combined organic phases are dried over MgSO4, filtered and concentrated under reduced pressure. The title compound is obtained by prep. LC-MS F as a colorless powder (61 mg, 73%); LC-MS A: tR=0.63 min; [M+H]+=334.24.
Reaction SMILES: CN(C)[CH:3]=[CH:4][CH:5]=[O:6].P(Cl)(Cl)(Cl)=O.[CH3:13][C:14]1([CH3:33])[CH2:23][CH2:22][C:21]2[C:16]3=[C:17]([C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:25][N:15]13)[CH:18]=[CH:19][CH:20]=2.[OH-].[Na+]>C(#N)C.O>[CH3:13][C:14]1([CH3:33])[CH2:23][CH2:22][C:21]2[C:16]3=[C:17]([C:24]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)=[C:25](/[CH:3]=[CH:4]/[CH:5]=[O:6])[N:15]13)[CH:18]=[CH:19][CH:20]=2
Reactant: CC1(C)CCc2cccc3c(-c4ccc(F)cc4)cn1c23
Reactant: CN(C)C=CC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1(C)CCc2cccc3c(-c4ccc(F)cc4)c(/C=C/C=O)n1c23
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A solution of 3-dimethylaminoacrylaldehyde (3.68 g) in dry acetonitrile (10 ml) was slowly added over a 30-minute period to a solution of phosphorus oxychloride (6.07 g) in dry acetonitrile (10 ml) with stirring at 0°-10° C. under nitrogen. A solution of 5,6-dihydro-4,4-dimethyl-1-(4-fluorophenyl)-4H-pyrrolo[3,2,1-ij]quinoline (3.70 g) in dry acetonitrile (9 ml) was slowly added to the reaction mixture at the same temperature. The reaction mixture was refluxed for 7 l hours under nitrogen, cooled to room temperature and slowly poured into a cold solution of sodium hydroxide (6.34 g) in water (130 ml) with stirring. The reaction mixture was extracted twice with toluene. The extracts were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on a silica gel column eluting with a mixture of n-hexane and ethyl acetate (5:1, V/V). The fractions containing the object compound were collected and evaporated under reduced pressure. The residual oil was triturated with n-hexane to give yellow crystals of (E)-3-[5,6-dihydro-4,4-dimethyl-1-(4-fluorophenyl)-4H-pyrrolo[3,2,1-ij]quinolin-2-yl]acrylaldehyde (3.11 g).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:61]([CH3:63])[CH3:62])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:59])[C@H:47]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:48]7C=CC=C[CH:49]=7)=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:60]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].[CH3:64][O:65][C:66](N[C@@H](C(C)C)C(O)=O)=O.[CH3:76][O:77]C(N[C@H](C1C=CC=CC=1)C(O)=O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:61]1[CH2:63][CH2:66][O:65][CH2:64][CH2:62]1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:59])[C@@H:47]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C@H:48]([O:77][CH3:76])[CH3:49])=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:60]=2)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]4)ccc23)[nH]1)C(C)C
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]4)ccc23)[nH]1)C1CCOCC1

Procedure:
This compound was made in an analogous manner to methyl (R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate, substituting (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid in the first amide coupling, and substituting (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid for (R)-2-(methoxycarbonylamino)-2-phenylacetic acid in the second amide coupling. LCMS-ESI+: calculated for C47H54N8O9: 874.98; observed [M+1]+: 876.01.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10](=[CH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[O:3]1.[CH2:18]([Zn]CC)C.ICI>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[CH2:11][C:10]2([CH2:18][CH2:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[O:3]1
Reactant: CC[Zn]CC
Reactant: C=C1CC(C)(C)Oc2ccc(C(=O)OC)cc21
Solvent: Cc1ccccc1
Solvent: ICI
Product: COC(=O)c1ccc2c(c1)C1(CC1)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 2,2-dimethyl-4-methylidene-3,4-dihydro-2H-chromene-6-carboxylate (34.0 mg, 0.15 mmol) and diethylzinc (1.17 mL, 1.17 mmol) in toluene (2.90 mL) under N2 atmosphere was added diiodomethane (189 μL, 2.34 mmol) dropwise via a syringe at room temperature. The mixture was stirred at room temperature overnight and then partitioned between diethyl ether (10.0 mL) and 5% aqueous HCl (10.0 mL). The aqueous layer was extracted with diethyl ether (20.0 mL, 2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-15% EtOAc/hexanes to afford the desired product as a pale-yellow solid.
Reaction SMILES: [CH3:1][OH:2].[CH:3]([O:8][CH3:9])(OC)OC.OS(O)(=O)=O.[C:15]([C:23]1[C:24](=O)[O:25][C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][C:28]=1[OH:29])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=CC=1>O>[C:23]1([C:24]2[O:25][CH:26]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:27](=[C:28]=[O:29])[C:1](=[O:2])[C:3]=2[O:8][CH3:9])[CH:15]=[CH:16][CH:21]=[CH:20][CH:19]=1
Reactant: CO
Reactant: O=C(c1ccccc1)c1c(O)cc(-c2ccccc2)oc1=O
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Solvent: O
Product: COC1=C(c2ccccc2)OC(c2ccccc2)C(=C=O)C1=O
Yield: 85 %

Procedure:
A 200 ml flask was fitted with a N2 inlet, a magnetic stirring bar and a condenser. 50 mls of methanol, 8.0 gms of trimethyl orthoformate, 5.2 gms of concentrated H2SO4 and 5.0 gms of 3-benzoyl-4-hydroxy-6-phenyl-pyr-2-one were added. The resulting mixture was then refluxed for 3 days, cooled, poured into water and extracted with methylene chloride (300 mls). The organic extracts were combined and washed with water. Removal of the solvent provided 4.4 gms of 2,6-diphenyl-3-methoxy-carbonyl-pyr-4-one (85%). Recrystallization from methylene chloride/ether provide material with a melting point=150°-1°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[C:9]2[C:17](Cl)(Cl)Cl)=[CH:4][C:3]=1[F:21].Cl.[NH:23]1[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-:28].[K+].[K+]>C(#N)C.O>[N:23]1([C:17]([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:21])[CH:4]=3)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1
Reactant: Fc1cc(-n2c(C(Cl)(Cl)Cl)nc3cccnc32)ccc1Cl
Reactant: O=C([O-])[O-]
Reactant: C1CNC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(c1nc2cccnc2n1-c1ccc(Cl)c(F)c1)N1CCC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
3-(4-Chloro-3-fluorophenyl)-2-(trichloromethyl)-3H-imidazo[4,5-b]pyridine (C20) (50 mg, 0.14 mmol) was dissolved in a 3:1 mixture of acetonitrile and water (1.4 mL). Azetidine hydrochloride (25.6 mg, 0.274 mmol) was added, followed by an aqueous solution of potassium carbonate (4 M, 0.15 mL, 0.60 mmol), and the reaction mixture was heated at 50° C. for 22 hours, then at 80° C. for 3 hours, and finally at 100° C. for 18 hours. The layers were separated, and the organic layer was concentrated in vacuo; purification via reversed phase HPLC (Column: Waters Sunfire C18, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 30% to 50% B) afforded the product. Yield: 17 mg, 51 μmol, 36%. LCMS m/z 331.1, 333.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 8.45 (dd, J=4.6, 1.5 Hz, 1H), 8.30 (dd, J=7.9, 1.3 Hz, 1H), 7.76 (dd, J=8.3, 8.3 Hz, 1H), 7.73 (dd, J=10.1, 2.2 Hz, 1H), 7.46 (dd, J=8.1, 4.6 Hz, 1H), 7.40-7.43 (m, 1H), 4.64-4.68 (m, 2H), 4.02-4.07 (m, 2H), 2.29-2.35 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([O:12]CC3C=CC([N+]([O-])=O)=CC=3)=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12.[Sn].Cl>CO.O>[NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: Cl
Agent: [Sn]
Solvent: O
Solvent: CO
Product: NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Reaction time: 1 h

Procedure:
p-Nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (10 gm) was suspended in a mixture of methanol (120 ml) and water (25 ml). Tin powder was charged at 30° C., followed by the addition of concentrated HCl (25 ml) in a methanol (20 ml) and water (5 ml) mixture over a period of 15 minutes. The reaction mixture was stirred for 1 hour. After completion of the reaction, aq. KHCO3 was added to bring the pH to 8.0, followed by the addition of activated carbon. After stirring for 10 minutes, the mixture was filtered. To the filtrate was added aq. HCl to bring the pH to 4.0. The product thus separated was filtered and dried. Yield: 3.9 g (68%).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.C([Li])CCC.CCCCCC.CN([CH:29]=[O:30])C>C1COCC1.[Cl-].[Na+].O.O>[CH3:14][N:5]1[C:4]2[CH:3]=[C:2]([CH:29]=[O:30])[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:13])[CH3:12]
Reactant: CN(C)C=O
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CN1c2cc(C=O)sc2C(=O)NC1(C)C
Reaction time: 0.33 h
Yield: 97.1 %

Procedure:
To a stirred suspension of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (259 mg, 0.941 mmol) in THF (10 mL) at −78° C. was added dropwise 1.6 M n-butyllithium in hexane (1.29 mL, 2.07 mmol). After 20 min, DMF (0.146 mL, 1.88 mmol) was added, and the mixture was allowed to −30° C. for 30 min. The mixture was poured into water (50 mL) and brine (50 mL). Extraction with EtOAc (100 mL), washing with brine, drying over MgSO4, filtration and concentration under reduced pressure gave the title compound (205 mg, 97%) as yellow solid:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:9]1[CH:22]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[C@H:9]1[CH2:22][NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Reactant: Cc1c(N)ccc(C#N)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1c(NC[C@@H]2[C@H](O[Si](C)(C)C(C)(C)C)CCCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
A mixture of 77F (660 mg, 1.92 mmol), 4-amino-2-chloro-3-methylbenzonitrile (384 mg, 2.3 mmol, 1.2 equiv) and HOAc (165 μL, 2.88 mmol, 1.5 equiv) in 1,2-DCE (10 mL) was stirred at rt for 30 min and Na(OAc)3BH (610 mg, 2.88 mmol, 1.5 equiv) was added. The reaction was stirred at rt overnight. Another 407 mg of Na(OAc)3BH (610 mg, 1.92 mmol, 1.0 equiv) was added and stirred at rt for another 24 h. The mixture was concentrated and the residue was diluted with EtOAc (30 mL), washed with saturated sodium bicarbonate solution (2×15 mL), brine (2×15 mL), dried (MgSO4) and evaporated to give the crude product. Purification of the crude product by flash chromatography (0-50% EtOAc/hexane) yield the desired product 77G (192 mg, 20%) as a white foam: Rf (30% EtOAc/hexane) 0.37; HPLC (Phenomenex Luna 5μ C18 4.6×50 mm, linear gradient over 4 min) retention time 4.6 min (100%); MS (ES) m/z 344.1 [M+1]+; HRMS calcd for C25H41N3O3SiCl 494.2606, Found 494.2613.
Reaction SMILES: O[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:12][C:13]([CH3:15])=[O:14].N1CCCC1>C1(C)C=CC=CC=1>[CH3:12][C:13]1([CH3:15])[CH:2]([CH3:11])[C:3](=[O:4])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:14]1
Reactant: CC(O)C(=O)c1ccccc1
Reactant: CC(C)=O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CC1C(=O)c2ccccc2OC1(C)C

Procedure:
A solution of 2-hydroxypropiophenone (500 ml, 3.64 mol), acetone (400 ml), and pyrrolidine (150 ml, 1.8 mol) in toluene (1000 ml) was heated at 85° C. for 66 hours. The cooled solution was then washed successively with water, aqueous hydrochloric acid and aqueous sodium hydroxide solution. The toluene layer was separated and the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane/heptane (50/50), to give 81 g of 2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one as an oil, a compound of Formula (3a); 1H NMR (CDCl3): δ1.3 (d,3H), 1.4 (s,3H), 1.6 (s,3H), 2.5-3.0 (q,1H), 6.8-8.1 (m,4H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[OH-].[Na+].[S:10](Cl)([CH3:13])(=[O:12])=[O:11].Cl>C1COCC1>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CNCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H]1CN(S(C)(=O)=O)CCN1
Temperature: 0 °C
Reaction time: 2 h
Yield: 19.8 %

Procedure:
To a solution of (2R)-2-methylpiperazine (1.00 g, 9.98 mmol) in NaOH (2 M aqueous, 10.5 ml, 21.0 mmol) and THF (15 ml) at 0° C. was added a solution of mesyl chloride (0.817 ml, 10.5 mmol) in THF (5 ml) over 30 seconds. The clear solution was stirred at 0° C. for 2 h. The reaction was poured into 2M aqueous HCl (20 ml), then the mixture washed with EtOAc (2×25 ml). The aqueous was adjusted to pH 12 with solid NaOH (˜1.5 g), then extracted with DCM (2×25 ml). The combined organics were passed through a phase separator and concentrated under vacuum to leave a white solid, (3R)-3-methyl-1-(methylsulfonyl)piperazine (352 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>CO>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:14]([NH:15][N+:16]([O-:18])=[O:17])=[NH:19]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSC(=N)N[N+](=O)[O-]
Solvent: CO
Product: Cc1nc[nH]c1CSCCNC(=N)N[N+](=O)[O-]
Reaction time: 48 h

Procedure:
A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (1.7 g.) and S-methyl-N-nitroisothiourea (1.45 g.) in methanol (35 ml.) was heated at 50°-60° for 2/5 hours and then set aside at room temperature for 48 hours. The crystalline product was filtered off and recrystallised from methanol to give N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-nitroguanidine, m.p. 184°-186°. (Found: C, 37.5; H, 5.7: N, 32.5; S, 12.5. C8H14N6O2S requires: C, 37.2; H, 5.5; N, 32.5; S, 12.4).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].S(Cl)(Cl)=O.[Cl:20][S:21](O)(=[O:23])=[O:22]>>[F:15][C:2]([F:1])([F:14])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([S:21]([Cl:20])(=[O:23])=[O:22])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(N1CCc2ccccc21)C(F)(F)F
Solvent: O=S(Cl)Cl
Product: O=C(N1CCc2cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
A solution of the 1-(trifluoroacetyl)indoline (2-1, 21.5 g), neat in thionyl chloride (65.59 mL, 899.24 mmol), was cooled to 0° C. and treated with chlorosulfonic acid (13.28 mL, 199.83 mmol). The solution was stirred for 50 minutes, then poured directly into a beaker of ice (3 L). The precipitate was filtered and vacuum dried to afford 1-(trifluoroacetyl)indoline-5-sulfonyl chloride (2-2) as an orange solid; 1H NMR (500 MHz, CDCl3) δ 8.42 (d, 1H, J=8.5 Hz), 8.00 (d, 1H, J=6.7 Hz), 7.92 (s, 1H), 4.43 (t, 2H, J=8.2 Hz), 3.41 (t, 2H, J=8.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=2)=[CH:4][CH:3]=1.[N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]=[S:26]>CS(C)=O>[C:18]([O:17][C:16]([NH:15][C:13]1[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=1[CH3:23])[O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25]([NH:24][C:27](=[O:28])[O:29][CH2:30][CH3:31])=[S:26])=[N:7][CH:6]=1)=[O:22])([CH3:19])([CH3:20])[CH3:21]
Reactant: CCOC(=O)N=C=S
Reactant: Cc1ccc(Oc2ccc(N)nc2)cc1NC(=O)OC(C)(C)C
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(C)c(NC(=O)OC(C)(C)C)c2)cn1
Yield: 57.9 %

Procedure:
In the same manner as in Reference Example 30 and using tert-butyl {5-[(6-aminopyridin-3-yl)oxy]-2-methylphenyl}carbamate (17.5 g, 44.5 mmol), DMSO (100 mL) and ethyl isothiocyanatoformate (6.50 mL, 55.0 mmol) as starting materials, the title compound (11.5 g, 49%) was obtained as a white solid.
Reaction SMILES: [Na].[S:2](=[C:5]([CH:13]([OH:16])[CH2:14][OH:15])[CH2:6][C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)(=[O:4])=[O:3].[CH3:17]I.O>CO>[CH3:17][N:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:6][C:5](=[S:2](=[O:3])=[O:4])[CH:13]([OH:16])[CH2:14][OH:15])[CH2:12]1
Reactant: CI
Reactant: O=S(=O)=C(Cc1cnccn1)C(O)CO
Agent: [Na]
Solvent: CO
Solvent: O
Product: CN1C=CN=C(CC(C(O)CO)=S(=O)=O)C1

Procedure:
1.2 g of 2-(2-sulfonyl-3,4-dihydroxybutyl) pyrazine sodium salt (4106 and 4107) was added to a solution of 10 ml of methyl iodide in 25 ml of methanol. 2 ml of water were added and the mixture was refluxed for 5 days. It was then concentrated, taken up in 100 ml of water and washed with methylene chloride. The aqueous layer was concentrated and the residue chromatographed (Biogel P-2/water) giving 1.1 g of 1-methyl-3-(2-sulfonyl-3,4-dihydroxybutyl)pyrazine (4100) as a mixture of diastereoisomers. UV H2O max: 283 (3.88). These were separated using a Biorad AG-50 W×4 (Ca++) column at 65° with water as the eluent. 13C NMR: 163.89, S (C3); 150.36, D (C5); 138.88, D, 135.81, D (C2, C6); 71.05, D (CHOH); 64.41, T (CH2OH); 61.64, D (CHSO3-); 49.65, Q (NCH3); 32.61, T (--CH2 --). 13C NMR of the epimer; 163.49, S (C3); 150.44, D (C5); 138.77, D, 135.92, D (C2, C6); 71.82, D (CHOH); 63.37, T (CH2OH); 63.25, D (CHSO3-); 49.65, Q (NCH3); 33.26, T (-CH2 -).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2.[Na].[CH3:22][SH:23].CN(C=O)C>O>[CH3:22][S:23][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Reactant: CS
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A mixture of 0.20 g of 2-(3-fluoropyridin-4-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine, 47 mg of methylmercaptan sodium salt and 6 ml of DMF was stirred for 1 hour under ice cool. To this mixture was added 47 mg of methylmercaptan sodium salt, and the resultant mixture was stirred further for 1 hour under ice cool. To the reaction mixture was added water, and the resultant mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 0.19 g of 2-[3-(methylthio)pyridin-4-yl]-6-(trifluoromethyl)thiazolo[5,4-b]pyridine (hereinafter, referred to as the present compound 14).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCOCC.[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>C1COCC1>[C:14]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C1=C(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 3.0 M solution of phenylmagnesium bromide in ether (49.7 mL, 149 mmol) was added THF (300 mL). To this solution cooled to 0° C. cyclopentanone (13.23 mL, 149 mmol) was added. The reaction mixture was stirred at room temperature for 30 min, then at reflux for 2 h. Ice (20 g) was added, followed by 6 N HCl, until the precipitate dissolved. The product was extracted with ether. The combined etherial layers were washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel to give cyclopentenylbenzene (21.49 g, 149 mmol, 100% yield) as a colorless oil. LC-MS (M+H)+=145.1. 1H NMR (500 MHz, chloroform-d) δ ppm 7.48 (2H, d, J=7.3 Hz), 7.35 (2H, t, J=7.8 Hz), 7.22-7.27 (1H, m), 6.22 (1H, t, J=2.1 Hz), 2.70-2.80 (2H, m), 2.52-2.64 (2H, m), 2.01-2.12 (2H, m).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C:5]1(=O)[CH2:9][CH2:8][CH2:7][CH2:6]1.[C-:11]#[N:12].[K+]>O>[CH3:2][N:3]([CH3:4])[C:5]1([C:11]#[N:12])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: [C-]#N
Reactant: CNC
Reactant: O=C1CCCC1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CN(C)C1(C#N)CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.4 %

Procedure:
To a suspension of dimethylamine hydrochloride (8.15 g; 0.1 mol) in cyclopentanone (8.4 g; 0.1 mol) cooled (ice bath) was added dropwise a solution of potassium cyanide (6.5 g; 0.1 mol) in water (50 ml) over 10 min. After vigorous stirring at room temperature for 18 h, the crude reaction mixture was extracted three times with diethyl ether (3×200 ml) and the combined extracts washed twice with water (2×50 ml), dried (Na2SO4), and evaporated to afford the title product as a pale yellow oil (12.5 g) which was used without further purification. 1H NMR (CDCl3) δ: 1.7-2.0 (6H, m), 2.15-2.3 (2H, m), 3.3 (6H, s). Mass Spectrum (Electrospray LC/MS): Found 112 (MH+−HCN). C8H14N2 requires 138.