Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([CH2:5][N:6]1[C:12]2[CH:13]=[C:14]([N+:19]([O-])=O)[C:15]([O:17][CH3:18])=[CH:16][C:11]=2[CH2:10][N:9]([CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH2:8][C:7]1=[O:28])=[O:4]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]2[CH2:10][N:9]([CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH2:8][C:7](=[O:28])[N:6]([CH2:5][C:3](=[O:4])[N:2]([CH3:1])[CH3:29])[C:12]=2[CH:13]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(CC(=O)N(C)C)C(=O)CN(CC(=O)N(C)C)C2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc2c(cc1N)N(CC(=O)N(C)C)C(=O)CN(CC(=O)N(C)C)C2
Yield: 100.2 %

Procedure:
A solution of 2-(1-dimethylcarbamoylmethyl-7-methoxy-8-nitro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-N,N-dimethyl-acetamide (150 mg, 0.37 mmol) in ethyl acetate (25 mL) and ethanol (25 mL) was treated with 10% Pd—C and hydrogenated on a Paar apparatus under 40 psi H2. After 14 hours the mixture was filtered and concentrated to give 2-(8-amino-1-dimethylcarbamoylmethyl-7-methoxy-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-N,N-dimethyl-acetamide (140 mg, 99%) as a pale yellow solid, used without further purification; MS (m/e) 378 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([CH3:13])[CH3:12].[Li]CCCC.CN([CH:22]=[O:23])C>C1COCC1>[CH3:12][C:5]1([CH3:13])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:22]=[O:23])[CH:3]=2)[S:8][CH2:7][CH2:6]1
Reactant: CC1(C)CCSc2ccc(Br)cc21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCSc2ccc(C=O)cc21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
1-Bromo-4-[(3-methylbut-3-en-1-yl)sulfanyl]benzene (1.05 g, 4.08 mmol) dissolved in dichloromethane (24.0 mL) was cooled to 0° C., and aluminum chloride (0.60 g, 4.49 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 1 hour and warmed to room temperature for another hour. It was then poured into an Erlenmeyer flask containing a 10% aqueous NaOH solution and ice. The mixture was extracted with dichloromethane (2×, 40.0 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-10% EtOAc/Hexanes to give 6-bromo-4,4-dimethyl-3,4-dihydro-2H-thiochromene as a pale-yellow oil. 6-Bromo-4,4-dimethyl-3,4-dihydro-2H-thiochromene (798 mg, 3.10 mmol) in THF (21.0 mL) was cooled to −78° C. and n-BuLi (1.50 mL, 3.72 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 10 minutes and then DMF (961 μl, 12.4 mmol) was added dropwise via a syringe. The resulting mixture was allowed to warm to room temperature and wet silica gel (5.0 g/0.5 mL of water) was added. The mixture was allowed to stir at room temperature for 10 minutes before it was filtered. The silica gel was rinsed with EtOAc and the filtrate was concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-20% EtOAc/hexanes to obtain the desired product as a pale-yellow oil.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.NC1[N:20]=[CH:21][NH:22][C:23]=1[Cl:24]>C(O)(=O)C>[F:16][C:13]([F:14])([F:15])[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:20]3[CH:21]=[N:22][C:23]([Cl:24])=[C:17]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: Nc1nc[nH]c1Cl
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2ccnc3c(Cl)ncn23)c1

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone, 40 ml. of glacial acetic acid and 0.01 mole of 4-amino-5-chloroimidazole is refluxed for 6 hours. The solvent is removed under reduced pressure and the residue worked up as for Example 29 to give the product of the example.
Reaction SMILES: [Br:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.C(O[Cl:15])(C)(C)C>CO>[Br:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[N:4]1[Cl:15]
Reactant: CC1(CBr)COC(=O)N1
Reactant: CC(C)(C)OCl
Solvent: CO
Product: CC1(CBr)COC(=O)N1Cl
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
A solution of 4-(bromomethyl)-4-methyloxazolidin-2-one (1.33 g, 6.86 mmol) in MeOH (10 ml) was cooled to 0° C. and tert-butylhypochlorite (1.0 ml, 8.4 mmol) as added dropwise. The solution was stirred for 30 min, concentrated in vacuo, and the residue purified by flash chromatography (20% to 60% ethyl acetate in hexanes) to afford the title compound as a white solid (960 mg, 4.20 mmol, 61%). 1H NMR (CDCl3, 400 MHz) δ 1.57 (s, 3H), 3.45 (d, J=10.4 Hz, 1H), 3.60 (d, J=10.8 Hz, 1H), 4.20 (d, J=8.8 Hz, 1H), 4.51 (d, J=8.8 Hz, 1H). LRMS (ESI/APCI): 228 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1([C:21]([OH:23])=O)[CH2:20][CH:11]2[CH2:12][N:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:14][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>CC(C)=O.O>[CH2:1]([C:8]1([C:21]([N:37]=[N+:38]=[N-:39])=[O:23])[CH2:9][CH:10]2[CH2:14][N:13]([C:15](=[O:19])[N:16]([CH3:17])[CH3:18])[CH2:12][CH:11]2[CH2:20]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C(=O)N1CC2CC(Cc3ccccc3)(C(=O)O)CC2C1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN(C)C(=O)N1CC2CC(Cc3ccccc3)(C(=O)N=[N+]=[N-])CC2C1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 96.9 %

Procedure:
5-Benzyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 14c (0.86 g, 2.72 mmol) was dissolved in 30 mL of acetone upon cooling by an ice-water bath. When the mixture was cooled to −5° C., a solution of triethylamine (0.303 g, 2.99 mmol) and ethyl chloroformate (0.325 g, 2.99 mmol) in 15 mL of acetone were added dropwise successively. The reaction mixture was stirred for 15 minutes followed by dropwise addition of a solution of sodium azide (0.353 g, 5.44 mmol) in 15 mL of water. The reaction mixture was stirred for another 30 minutes. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 5-benzyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carbonyl azide 14d (0.9 g, yield 97%) as a light yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([O:20]C)=O.O.[NH2:23][NH2:24]>C(O)C>[O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([NH:23][NH2:24])=[O:20]
Reactant: NN
Reactant: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Solvent: O
Solvent: CCO
Product: NNC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A solution of methyl 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (1.019 g, 3.42 mmol) and hydrazine monohydrate (0.3 mL, 6.19 mmol) in ethanol (10 mL) was heated under microwave conditions for 10 min at 120° C. After that time, the reaction was cooled to room temperature and the product was collected by filtration and washed with cold ethanol to give 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carbohydrazide (0.607 g, 60%) as bright orange crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:9]([CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:11])[CH2:47][CH2:48][CH3:49]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2-(2-chlorophenyl)acetic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (77 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (53 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (50 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.79-0.88 (m, 3 H) 1.19-1.28 (m, 2 H) 1.57-1.69 (m, 2 H) 2.40 (s, 3 H) 3.76-3.81 (m, 2 H) 3.96 (t, 2 H) 5.77-5.85 (m, 1 H) 7.22-7.33 (m, 2 H) 7.34-7.40 (m, 1 H) 7.40-7.47 (m, 1 H); MS (ESI) m/z 323 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:25])=[CH:17][C:16]=1[C:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH3:43][Mg]Br.Cl.C(OCC)(=O)C>C1COCC1>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:25])=[CH:17][C:16]=1[C:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)([OH:27])[CH3:43])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: C[Mg]Br
Reactant: Cc1cc(C(=O)C2CCCCC2)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)cc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(C)(O)C2CCCCC2)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a solution of (2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-5-methyl-4-(trifluoromethyl)phenyl)(cyclohexyl)methanone (52 mg, 0.085 mmol) in anhydrous THF (10 mL) under nitrogen at 0° C. was added methylmagnesium bromide (3.0 M solution in THF, 25.6 mg, 0.114 mL, 0.342 mmol). The solution was stirred at 0° C. for 30 minutes, then warmed to room temperature and stirred for 1.5 hours. The solution was then poured into a mixture of 2 N hydrochloric acid (10 mL) and ethyl acetate (20 mL). The solution was stirred at room temperature for 10 minutes then the layers were separated and the aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organics layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on a 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 1-50% ethyl acetate in heptane) to yield the title compound (97.2%). 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H) 7.68 (s, 2H) 7.33 (s, 1H) 7.17 (s, 1H) 5.39 (d, J=16.17 Hz, 1H) 4.82 (d, J=15.76 Hz, 1H) 4.77(s, 2H) 4.15(s, 3H) 2.39 (s, 3H) 1.62 (m, 6H) 1.24 (s, 3H) 1.04 (m, 5H). LC-MS calc. 623.5, found 624.6 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]([CH2:17][O:18][CH2:19][CH2:20][Cl:21])=[O:16])[CH3:11].N1CCCCC1>C(O)(C)C.C(O)(=O)C.N1CCCCC1>[CH2:10]([O:12][C:13](=[O:22])[C:14](=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])[C:15]([CH2:17][O:18][CH2:19][CH2:20][Cl:21])=[O:16])[CH3:11]
Reactant: CCOC(=O)CC(=O)COCCCl
Reactant: O=Cc1ccccc1Cl
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)COCCCl
Yield: 97 %

Procedure:
16.64 g (0.118 mole) of 2-chloro-benzaldehyde (V) and 24.7 g (0.118 mole) of ethyl-4-(2-chloroethoxy)-acetoacetate (IV) are reacted in 365 ml of isopropanol in the presence of a piperidine acetate catalyst [10 g (11.8 millimoles) of piperidine+0.7 g (11.8 millimoles) of acetic acid] at room temperature for 10 hours. The reaction mixture is evaporated, the residual oil is dissolved in dichloro methane, washed with water and dried. The organic phase is evaporated in vacuo. Thus 37.9 g of the desired product are obtained in the form of a yellow oil, yield 97%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]5([C:29]#[N:30])[CH2:28][CH2:27]5)[CH:21]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>CN(C)C(=O)C.C(OCC)(=O)C>[C:29]([C:26]1([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:19]([NH:18][C:16]2[CH:17]=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:36]([CH:33]5[CH2:35][CH2:34]5)=[O:37])[S:3][C:4]=4[CH:10]=3)[CH:13]=[CH:14][C:15]=2[CH3:32])=[O:31])[CH2:27][CH2:28]1)#[N:30]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 40.4 %

Procedure:
To a solution of N-{5-[(2-amino-1,3-benzothiazol-6-yl)oxy]-2-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (300 mg, 0.681 mmol) in N,N-dimethylacetamide (3.0 mL) was added cyclopropanecarbonyl chloride (65 μL, 0.715 mmol), and the mixture was stirred at room temperature for 10 hr. To the reaction mixture was added cyclopropanecarbonyl chloride (30 μL, 0.33 mmol), and the mixture was further stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogencarbonate solution (100 mL) and saturated brine (100 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/diisopropyl ether to give the title compound (140 mg, 40%) as a colorless solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][C@H:25]2[C@:20]([CH3:32])([CH2:21][CH2:22][C@@H:23]([O:27]S(C)(=O)=O)[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:34])([C@@H:17]([OH:33])[CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1.[CH2:35](O)[CH2:36][OH:37].N1C=CC=CC=1>CCOC(C)=O>[OH:1][C@@H:2]1[CH2:26][C@@H:25]2[C@:20]([CH3:32])([CH2:21][CH2:22][C@H:23]([O:27][CH2:35][CH2:36][OH:37])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:34])([C@@H:17]([OH:33])[CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: OCCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@@H](OCCO)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 120 °C
Yield: 37 %

Procedure:
A pressure vessel (250 mL flask) containing the compound of Example 1A (10.0 g, 20 mmol) was charged with ethylene glycol (20 mL) and pyridine (4 mL) at ambient temperature, sealed and then heated at 120° C. for 4 hours. The reaction was cooled to ambient temperature, diluted with EtOAc (50 mL), and quenched with 1N HCI (30 mL). The layers were separated and the organic layer was washed with 1N HCI (2×30 mL), dried (Na2SO4), and concentrated. Purification by silica gel chromatography (10%->40% acetone/hexanes) provided the title compound (3.5 g, 37%). MS (ESI) m/e 484 (M+NH4)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:22]4[CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][CH2:26][CH2:27][C:21]=4[N:20]([CH3:35])[C:19]=3[N:36]=2)[C:11](=[O:37])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:38]>CO>[ClH:38].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:22]4[CH2:23][NH:24][CH2:25][CH2:26][CH2:27][C:21]=4[N:20]([CH3:35])[C:19]=3[N:36]=2)[C:11](=[O:37])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CCC2
Agent: Cl
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc31)CNCCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of tert-butyl 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (140 mg, 0.028 mmol) in 1.25 M HCl in MeOH (6.0 mL) was stirred under N2 at ambient temperature for 18 h. Additional 1.25 M HCl in MeOH was added, and the solution was stirred at ambient temperature for 18 h. The solution was concentrated to dryness to yield the title compound (130 mg, quant.) as a light-yellow powder: mp 328-332° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.20 (s, 2H), 8.16 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.48-7.41 (m, 4H), 7.38-7.34 (m, 2H), 6.17 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.17 (s, 2H), 4.46 (s, 2H), 3.75 (s, 3H), 3.44-3.43 (m, 2H), 3.14-3.12 (m, 2H), 2.09-2.07 (m, 2H); ESI MS m/z 401 [M+H]+; HPLC (Method A)>99% (AUC), tR=13.3 min.
Reaction SMILES: OC[C@@H]1CCCC[C@H]1[NH:9][S:10]([C:13]1[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)(=[O:12])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].BrCC1C(F)=CC(C2N=CON=2)=C(F)C=1.ClC1C=CC(S(N(CC2C=CC(C3OC=CN=3)=C(F)C=2F)[C@@H]2CCCC[C@H]2CO)(=O)=O)=CC=1>>[F:22][C:19]([F:20])([F:21])[C:16]1[N:15]=[CH:14][C:13]([S:10]([NH2:9])(=[O:12])=[O:11])=[CH:18][CH:17]=1
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(C(F)(F)F)nc1
Agent: Fc1cc(-c2ncon2)c(F)cc1CBr
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)c(F)c1F)[C@@H]1CCCC[C@H]1CO
Product: NS(=O)(=O)c1ccc(C(F)(F)F)nc1
Yield: 82.5 %

Procedure:
The title compound was synthesized from N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)-6-(trifluoromethyl)pyridine-3-sulfonamide (50 mg, 0.15 mmol), cesium carbonate (72 mg, 0.22 mmol), and 3-(4-(bromomethyl)-2,5-difluorophenyl)-1,2,4-oxadiazole (50 mg, 0.18 mmol) according to the procedure described for 4-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 20) to give N-(2,5-difluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)-N-(1R,2R)-2-(hydroxymethyl)cyclohexyl)-6-(trifluoromethyl)pyridine-3-sulfonamide (28 mg, 35%). 1H NMR (400 MHz, CDCl3) δ ppm 9.08 (d, J=2.01 Hz, 1H), 8.82 (s, 1H), 8.25 (dd, J=8.31, 2.01 Hz, 1H), 7.81 (d, J=8.31 Hz, 1H), 7.74 (dd, J=9.82, 5.54 Hz, 1H), 7.55 (dd, J=10.20, 5.92 Hz, 1H), 4.53 (d, J=15.50 Hz, 1H), 4.47 (d, J=15.60 Hz, 1H), 3.70-3.84 (m, 1H), 3.57 (dd, J=11.71, 2.90 Hz, 1H), 321 (d, J=11.58 Hz, 1H), 1.63-1.81 (m, 3H), 1.43-1.56 (m, 2H), 1.33-1.41 (m, 1H), 1.16-1.31 (m, 2H), 1.05-1.14 (m, 1H). Analytical HPLC R.T=21.66. HRMS [M+H]+ calc'd 533.1282, found 533.1277.
Reaction SMILES: COC([C:5]1[C:14]([OH:15])=[N:13][C:8]2=[N:9][CH:10]=[CH:11][N:12]=[C:7]2[C:6]=1[OH:16])=O>Cl.S(=O)(=O)(O)O>[OH:16][C:6]1[C:7]2[C:8](=[N:9][CH:10]=[CH:11][N:12]=2)[NH:13][C:14](=[O:15])[CH:5]=1
Reactant: COC(=O)c1c(O)nc2nccnc2c1O
Agent: Cl
Agent: O=S(=O)(O)O
Product: O=c1cc(O)c2nccnc2[nH]1
Temperature: 100 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a solution of 6,8-dihydroxypyrido[2,3-b]pyrazine-7-carboxylic acid methyl ester (5.0 g) in concentrated hydrochloric acid (36% by weight in water) was added a few drops of concentrated sulfuric acid at ambient temperature. The reaction mixture was then heated to 100° C. for four hours. The reaction mixture was allowed to cool to ambient temperature and stored at ambient temperature for 16 hours. Then the reaction mixture was concentrated and dried under high vacuum to give 8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one as a brown solid (3.02 g).
Reaction SMILES: [C:1]1([S:7]([CH:10]2[CH2:16][CH:15]3[N:17](C(OC(C)(C)C)=O)[CH:12]([CH2:13][CH2:14]3)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[ClH:27]>CO>[ClH:27].[C:1]1([S:7]([CH:10]2[CH2:11][CH:12]3[NH:17][CH:15]([CH2:14][CH2:13]3)[CH2:16]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(S(=O)(=O)c1ccccc1)C2
Agent: Cl
Solvent: CO
Product: O=S(=O)(c1ccccc1)C1CC2CCC(C1)N2
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a methanol (5 mL) solution of tert-butyl 3-phenylsulfonyl-8-azabicyclo[3.2.1]octane-8-carboxylate (174 mg) was added a 4N-hydrogen chloride methanol solution, and the mixture was stirred at 60° C. for 3 hours. The solvent was distilled off under reduced pressure, and the resulting solid was washed with diethyl ether to give a crude product of the title compound as a colorless solid (141 mg).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:5][C@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.[CH3:19]I.[H-].[Na+].Cl>CN(C)C=O>[CH3:19][C:4]1([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:2](=[O:1])[N:6]([C@@H:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH2:5]1
Reactant: COC(=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C)CC(=O)N([C@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl(3R)-5-oxo-1-[(R)-1-phenylethyl]pyrrolidin-3-yl-carboxylate (49.5 g, 200 mmol) and methyl iodide (37.4 mL, 600 mmol) in dimethylformamide (1 L), sodium hydride (in oil; content, 55%; 11.35 g: 260 mmol) was gradually added in 5 minutes at room temperature. After stirring at room temperature for 2 hours, methyl iodide (24.9 mL, 400 mmol) and sodium hydride (in oil; content, 55%; 6.11 g; 140 mmol) were further added, and the mixture was stirred for another 4 hours. The reaction mixture was added to 0.5N hydrochloric acid (1 L) in an ice bath, and extracted with ethyl acetate (2 L+1 L). The organic layers were combined and washed with water (1 L×2) and saturated aqueous solution of sodium chloride (1 L), and dried with anhydrous sodium sulfate. After removing the dessicating agent by filtration, the solvent was removed by distillation under reduced pressure. The thus obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate, 80:20→67:33→50:50→33:67) to obtain stereoisomers at position 3 of the title compound (stereoisomer A: 19.86 g (76.0 mmol, 38%) as a pale yellow oil, stereoisomer B: 20.22 g (77.4 mmol, 39%) as a pale yellow solid, and a mixture of stereoisomers A and B: 9.69 g (37.1 mmol, 19%) as a pale yellow oil.
Reaction SMILES: C(S[C:9](=[S:18])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1)C1C=CC=CC=1.[CH3:19][NH2:20].O>C(O)C>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:9]([NH:20][CH3:19])=[S:18])=[N:12][CH:13]=1
Reactant: CN
Reactant: Cc1ccc(NC(=S)SCc2ccccc2)nc1
Solvent: O
Solvent: CCO
Product: CNC(=S)Nc1ccc(C)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl(5-methyl-2-pyridyl)dithiocarbamate (3 g.) was suspended in ethanol (30 ml.). Methylamine (33% ethanolic solution, 10 ml.) was added and the mixture stirred at room temperature for 1 hour. On the addition of water, the thiourea separated and was collected by filtration, dried and recrystallised from ethanol-petrol ether. Yield 2.5 g., m.pt. 161° C.