Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:3]1.C(N(CC)CC)C.Cl[C:23]1[N:28]=[C:27]([NH2:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][CH:24]=1>C(#N)C>[NH2:29][C:27]1[N:28]=[C:23]([N:2]2[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14]3)=[O:9])[CH2:3]2)[CH:24]=[CH:25][C:26]=1[N+:30]([O-:32])=[O:31]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C([C@@H]1CCCNC1)N1CCCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Temperature: 10 °C
Yield: 104.7 %

Procedure:
To a suspension of (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone hydrochloride (45.56 g, 208.3 mmol) in anhydrous acetonitrile (200 mL) at 10° C. was added triethylamine (50 mL). The suspension was poured into a 2 L 3-neck flask equipped with a thermometer and a magnetic stirrer. To the original flask was added anhydrous acetonitrile followed by sonication and addition of triethylamine (80 mL). The suspensions were combined and cooled to 10° C. and 6-chloro-3-nitropyridin-2-amine (32.97 g, 190 mmol) was added. The bright yellow solution was stirred under nitrogen while the temperature was increased gradually to 80° C. over 1 h. The reaction mixture was cooled to room temperature. The resulting suspension was filtered and the solids were rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure. A saturated aqueous solution of ammonium chloride (500 mL) was added to the residue and the mixture was extracted into ethyl acetate (2×). The combined organics were washed with brine, dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried for 18 h under high vacuum to afford (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone as a yellow foam (63.51 g). 1H NMR (400 MHz, CD3OD) δ 1.47-1.64 (m, 1H) 1.71-2.07 (m, 7H) 2.68 (tt, 1H) 3.01 (q, 2H) 3.33-3.46 (m, 2H) 3.52 (dt, 1H) 3.60-3.70 (m, 1H) 4.41 (br s, 1H) 4.71 (d, 1H) 6.23 (d, 1H) 8.05 (d, 1H); MS (ES+) (M+H) 320.4.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:44])[O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([C:30]([F:33])([F:32])[F:31])=[CH:25][C:24]=3[NH:34][C:35]([C:37]3[CH:41]=[C:40]([CH3:42])[N:39]([CH3:43])[N:38]=3)=O)=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>[OH-].[Na+].C(O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:44])[O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:23]4[CH:28]=[C:27]([Cl:29])[C:26]([C:30]([F:32])([F:31])[F:33])=[CH:25][C:24]=4[N:34]=[C:35]3[C:37]3[CH:41]=[C:40]([CH3:42])[N:39]([CH3:43])[N:38]=3)=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(Nc3cc(Cl)c(C(F)(F)F)cc3NC(=O)c3cc(C)n(C)n3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3c(-c4cc(C)n(C)n4)nc4cc(C(F)(F)F)c(Cl)cc43)cc2)cc1
Temperature: 50 °C
Reaction time: 85 h
Yield: 21.3 %

Procedure:
A mixture of 2-(4-{[5-chloro-2-{[1,5-dimethyl-1H-pyrazol-3-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl (4-methylphenyl)sulfonylcarbamate (step 3, 145 mg, 0.223 mmol) in 2N NaOH (1 ml) and ethanol (2 ml) was stirred at 50° C. for 85 h. After cooling, the pH value was adjusted to 4.0 by addition of 2N HCl. The mixture was diluted with water (80 ml), and extracted with dichloromethane (80 ml×3). The combined organic layer was washed with brine (50 ml), dried (MgSO4), and concentrated. Purification by PTLC eluting with hexane/ethyl acetate (1:3) to afford 30 mg (21%) of the title compound as a red solid.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([CH3:22])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH3:15])[CH:11]=1.Cl.[NH2:24]O.O.O.O.[C:29]([O-:32])(=O)[CH3:30].[Na+]>C(O)C>[CH3:22][C:16]1[CH:17]=[C:18]([C:20]2[N:24]=[C:29]([CH3:30])[O:32][N:21]=2)[CH:19]=[C:2]([CH3:1])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH3:15])[CH:11]=1
Reactant: NO
Reactant: CC(=O)[O-]
Reactant: Cc1cc(CCCCCOc2c(C)cc(C#N)cc2C)on1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(CCCCCOc2c(C)cc(-c3noc(C)n3)cc2C)on1
Yield: 32.4 %

Procedure:
A suspension of 7.0 g 5-[5-(2,6-dimethyl-4-cyanophenoxy)pentyl]-3-methylisoxazole, 1.8 g hydroxylamine hydrochloride and 3.5 g sodium acetate trihydrate in 40 ml 95% ethanol was heated at reflux under nitrogen for two days. The reaction mixture was filtered, concentrated in vacuo, and the residue in 50 ml acetic anhydride was heated at reflux for 3 hrs. The reaction mixture was poured over ice/10% sodium hydroxide and extracted with ether. The ether extracts were washed with water and saturated sodium bicarbonate, dried (K2CO3), concentrated and subjected to flash filtration (silica gel 60, 3:1 hexane/ethyl acetate) followed by chromatography (MPLC, silica gel 60, 3:1 hexane/ethyl acetate). The resulting product was crystallized from isopropyl acetate/hexane to give 2.7 g 5-{5-[2,6-dimethyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]pentyl}-3-methylisoxazole, m.p. 45°-46° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].CC(C)([O-])C.[K+].Cl[C:13]1[C:22]2[C:17](=[C:18]([NH:23][C:24](=[O:33])[C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([Cl:31])[C:25]=1[C:24]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[N:16]=[CH:15][CH:14]=[C:13]2[O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:33]
Reactant: O=C(Nc1cccc2c(Cl)ccnc12)c1c(Cl)cccc1Cl
Reactant: COCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COCCOc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
To a stirred solution of 2-methoxyethanol (130 mg) in N-methylpyrrolidone (2 ml) was added potassium tert-butoxide (172 mg) under ice-cooling, and the mixture was stirred for 30 minutes at ambient temperature. To the mixture was added 4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (200 mg), and the mixture was stirred for 5 hours at 80° C. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-(2-methoxyethoxy)quinoline (175 mg).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1.O1CCOCC1>O>[N+:17]([C:16]1[CH:15]=[CH:14][C:13]([CH:2]2[CH2:3][NH:4][CH:5]3[CH2:8][CH2:9][N:1]2[CH2:7][CH2:6]3)=[N:12][CH:11]=1)([O-:19])=[O:18]
Reactant: C1CN2CCC(CC2)N1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(C2CNC3CCN2CC3)nc1

Procedure:
1,4-diazabicyclo[3.2.2]nonane (6.3 g, 50 mmol) was added to a mixture of 2-chloro-nitropyridine (11.9, 75 mmol), and dioxane (250 ml) at 0° C. The reaction mixture was allowed to reach room temperature. Water (100 ml) was added. The mixture was extracted with dichloromethane (3×50 ml). Chromatography on silica gel with dichloromethane and 10% methanol as solvent gave the title compound as an oil. Yield 8.1 g (65%). Mp. 143-146° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[N:6]([C@@H:8]([C:12]2[O:13][C:14]3[C:19]([C:20](=[O:29])[C:21]=2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=[C:16]([Cl:30])[CH:15]=3)[CH:9]([CH3:11])[CH3:10])[CH:7]=1.N1C=CC=CC=1.[CH3:44][C:45](OC(C)=O)=[O:46]>C(Cl)Cl>[CH2:22]([CH:21]1[C:20](=[O:29])[C:19]2[C:14](=[CH:15][C:16]([Cl:30])=[CH:17][CH:18]=2)[O:13][CH:12]1[C@H:8]([N:6]1[CH:7]=[C:3]([CH2:2][NH:1][C:45](=[O:46])[CH3:44])[N:4]=[C:5]1[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)[CH:9]([CH3:11])[CH3:10])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(-c2nc(CN)cn2[C@@H](c2oc3cc(Cl)ccc3c(=O)c2Cc2ccccc2)C(C)C)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1cn([C@H](C(C)C)C2Oc3cc(Cl)ccc3C(=O)C2Cc2ccccc2)c(-c2ccc(C)cc2)n1
Yield: 88.8 %

Procedure:
To 2-[(R)-1-(4-aminomethyl-2-p-tolyl-imidazol-1-yl)-2-methyl-propyl]-3-benzyl-7-chloro-chromen-4-one (0.17 g, 0.33 mMol) in CH2Cl2 (5 mL) was added with stirring, pyridine (27 uL, 0.33 mMol) and Ac2O (63 uL, 0.67 mMol). After stirring at RT for 4 h the reaction was concentrated under vacuum. The remaining residue was triturated with (1:1) Et2O/pet. ether, filtered and dried under vacuum to give the title compound (163 mg, 89%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=8.6 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.43 (m, 6H), 7.17 (m, 3H), 6.84 (br s, 1H), 6.71 (d, J=2.2 Hz, 1H), 6.69 (s, 1H), 5.07 (d, J=10.9 Hz, 1H), 4.50 (2d, 1H), 4.43 (2d, 1H), 4.07 (d, J=15.5 Hz, 1H), 2.66 (m, 1H), 2.51 (s, 3H), 2.48 (d, J=15.5 Hz, 1H), 2.00 (s, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.34 (d, J=6.7 Hz, 3H); MS (ES) m/e 554.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1.[Li+].CC([N-]C(C)C)C.CC(O)=O>C1COCC1.O>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2cccnc2)nc(N2CCOCC2)n1
Reaction time: 0.08 h
Yield: 43 %

Procedure:
1-[4-Chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (U.S. Pat. Appl. Publ. No. US 2007/244110) (0.183 g, 0.5 mmol) was added to a mixture of 3-aminopyridine (0.20 g, 2 mmol) and LDA (1.0 mL, 2 M in THF, 2 mmol) in 10 mL THF at room temperature. After 5 min, the mixture was neutralized with HOAc, diluted with water, extracted with EtOAc, and dried (Na2SO4). Chromatography on alumina eluting with CH2Cl2/EtOAc (4:1) gave a solid, which was recrystallized from i-Pr2O to give 92 mg (43% yield) of (4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridinyl)-1,3,5-triazin-2-amine: mp (i-Pr2O) 228-230° C.; 1H NMR (CDCl3) δ 8.86 (br, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.38 (d, J=6.2 Hz, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.89 (dd, J=6.2, 2.9 Hz, 1H), 7.58 (br t, JHF=53.8 Hz, 1H), 7.42 (m, 2H), 7.34 (dd, J=8.3, 4.7 Hz, 1H), 7.28 (m, exchangeable with D2O, 1H), 3.93 (m, 4H), 3.82 (m, 4H); Anal. Calcd. for C20H18F2N8O: C, 56.6; H, 4.3; N, 26.4. Found: C, 56.5; H, 4.4; N, 26.1%.
Reaction SMILES: CCC([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12]C(=O)C)[O:9][C@@H:8]([N:16]2[CH:30]=[C:20]3[NH:21][C:22](=[O:29])[C:23]4[C:24](=[O:28])[NH:25][N:26]=[CH:27][C:18]([C:19]=43)=[N:17]2)[C@@H:7]1[O:31]C(=O)C)=O.N.[CH3:36]O>>[CH3:36][C@@:7]1([OH:31])[C@H:6]([OH:5])[C@@H:10]([CH2:11][OH:12])[O:9][C@H:8]1[N:16]1[CH:30]=[C:20]2[NH:21][C:22](=[O:29])[C:23]3[C:24](=[O:28])[NH:25][N:26]=[CH:27][C:18]([C:19]=32)=[N:17]1
Reactant: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc3[nH]c(=O)c4c(=O)[nH]ncc(n2)c34)O[C@@H]1COC(C)=O
Reactant: CO
Agent: N
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2[nH]c(=O)c3c(=O)[nH]ncc(n1)c23
Temperature: 25 °C

Procedure:
To the product from Step 8 is added 7N NH3 in MeOH and the mixture is stirred at ambient temperature until deacetylation is sufficiently complete as determined by TLC. The mixture is concentrated in vacuo and the crude material is taken up and purified by Phenomenex-C18 reverse phase HPLC (Buffer A=H2O, Buffer B=acetonitrile) to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][CH2:10][C@@H:11]([NH:13]C(=O)OC(C)(C)C)[CH3:12])=[CH:5][C:4]=1[NH:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[N:23]=1)#[N:2].[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>C(Cl)Cl>[OH:34][C:32]([C:31]([F:36])([F:35])[F:30])=[O:33].[NH2:13][C@@H:11]([CH3:12])[CH2:10][NH:9][C:6]1[CH:5]=[C:4]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[N:23]=2)[C:3]([C:1]#[N:2])=[N:8][CH:7]=1
Reactant: Cc1cc(C)nc(Nc2cc(NC[C@H](C)NC(=O)OC(C)(C)C)cnc2C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)nc(Nc2cc(NC[C@H](C)N)cnc2C#N)c1
Reaction time: 1 h

Procedure:
To a flask containing tert-butyl [(2S)-1-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)propan-2-yl]carbamate (160 mg, 0.404 mmol) were added DCM (3 mL) and trifluoroacetic acid (0.3 mL). After 1 hour, the reaction mixture was concentrated under reduced pressure to afford 5-{[(2S)-2-aminopropyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile TFA salt. The material was used without further purification. MS ESI calc'd. for C16H21N6 [M+H]+ 297. found 297.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16](=[NH:18])[NH2:17])[CH:12]=2)[CH:7]=1)(=[O:4])=[O:3].[C:19](Cl)(=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[C:19]([O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16](=[NH:18])[NH2:17])[CH:12]=2)[CH:7]=1)(=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)O
Product: N=C(N)c1ccc2cc(OC(=O)C=Cc3ccccc3)ccc2c1
Yield: 91.9 %

Procedure:
To a solution of 9.9 g of 6-amidino-2-naphthol methanesulfonate in 100 ml of anhydrous pyridine, while being cooled in ice and stirred, was added 5.8 g of cinnamoyl chloride. After having been stirred overnight at room temperature, the mixture was admixed with ethyl acetate and the resulting precipitate was collected by filtration. The precipitate was suspended in methanol, mixed with a saturated aqueous sodium hydrogencarbonate solution with stirring, and the precipitate was collected by filtration. After having been washed with water and acetone, the precipitate was suspended in methanol and mixed with methanesulfonic acid. After having been stirred for same time, the mixture was admixed with ethyl ether, the precipitate was collected by filtration and recrystallized from a methanol-ethyl ether mixture to obtain 7.1 g of 6-amidino-2-naphthyl cinnamate methanesulfonate.
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[CH:6]=[C:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:4]=1)=O.[CH3:16][C:17]([S@@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18].O>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:17]([S@@:20](/[N:22]=[CH:1]/[C:3]1[N:7]([CH3:8])[CH:6]=[C:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:4]=1)=[O:21])([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: Cn1cc(C(=O)OC(C)(C)C)cc1C=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: O
Product: Cn1cc(C(=O)OC(C)(C)C)cc1/C=N/[S@@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 64 %

Procedure:
To a solution of tert-butyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate (3.0 g, 14.5 mmol), (S)-2-methylpropane-2-sulfinamide (2.6 g, 21.8 mmol) in DCM (200 mL) was added titanium isopropoxide (24.8 g, 87 mmol). The mixture was stirred at rt for 20 h then water (30 mL) was added to quench the reaction. The solid precipitate was filtered and the filtrate was concentrated and purified by flash column chromatography (petroleum ether:EtOAc, 5:1) to give (S,E)-tert-butyl 5-((tert-butylsulfinylimino)methyl)-1-methyl-1H-pyrrole-3-carboxylate (2.9 g, 63%). 1H NMR (CDCl3, 400 MHz) δ 8.30 (s, 1H), 7.29 (s, 1H), 7.02 (s, 1H), 3.89 (s, 3H), 1.48 (s, 9H), 1.16 (s, 9H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:12]1[N:13]=[C:14]([NH:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:15][CH:16]=1)\[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C)C=O>[N:37]([CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:12]1[N:13]=[C:14]([NH:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:15][CH:16]=1)\[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)/C(=N\OCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OCCN=[N+]=[N-])c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C

Procedure:
A solution of 17.5 g of 2-(tritylamino)-4-thiazoleglyoxylic acid ethyl ester (Z)-O-(2-bromoethyl) oxime and 5 g of sodium azide in 200 ml of N,N-dimethylformamide was stirred at 50° C. for 15 hours. The reaction solution was cooled to 20° C. and partitioned between ethyl acetate and water. The organic phase was dried over sodium sulphate and the solvent was removed in a vacuum. Crude 2-(tritylamino)-4-thiazoleglyoxylic acid ethyl ester (Z)-O-(2-azido-ethyl) oxime was obtained as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:13][C:12]([CH3:14])=[C:11]2[C:7]=1[CH2:8][C@H:9]1[C:15]([CH3:17])([CH3:16])[C@H:10]12)=[O:5])C.[Li+].[OH-]>CCO.O>[CH3:16][C:15]1([CH3:17])[C@@H:9]2[CH2:8][C:7]3[C:11]([C@H:10]12)=[C:12]([CH3:14])[S:13][C:6]=3[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 70 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of crude (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (10.3 g, 41.2 mmol) in EtOH (200 mL) a solution of 2N aq. LiOH (300 mL) is added. The resulting mixture is stirred at 70° C. for 1 h, cooled to rt and diluted with water (250 mL). The aq. solution is extracted three times with DCM (125 mL) before it is acidified to pH 3 by adding citric acid. The acidified solution is extracted twice with DCM (2×250 mL), These second extracts are combined, dried over Na2SO4, filtered and evaporated to give (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (7.0 g) as a yellow solid. LC-MS: tR=0.95 min, [M+1]+=223.00. 1H NMR (CDCl3): δ 3.04-2.92 (m, 1H), 2.83 (d, J=19.3 Hz, 1H), 2.39 (s, 3H), 1.91-1.87 (m, 2H), 1.13 (s, 3H), 0.73 (s, 3H).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[C:13]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:24]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:23]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:33][O:32][C:30](=[O:31])[CH2:29][N:28]([S:2](=[O:4])(=[O:3])[NH:5][C:6]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[C:25]1[CH:26]=[CH:27][C:22]([S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[CH:23][C:24]=1[O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)CNc1ccc(S(=O)(=O)c2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN(c1ccc(S(=O)(=O)c2ccccc2)cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of chlorosulfonylisocyanate (346 mg, 2.45 mmol) in CH2Cl2 (15 mL) at 0° C. is added dropwise a solution of t-butanol (181 mg, 2.45 mmol) in CH2Cl2 (5 mL) and the mixture is stirred at 0-5° C. for 30 min. To this is added dropwise a solution of methyl (4-benzenesulfonyl-2-benzyloxyphenylamino)acetate (620 mg, 1.63 mmol) and triethylamine (281 mg, 278 mmol) in CH2Cl2 (5 mL) and the mixture is stirred at RT for 4 h. The mixture is washed with water and the organic layer is dried over magnesium sulfate. The solvent is removed under reduced pressure to afford an oil that is chromatographed on a Biotage 40M column using CH2Cl2/EtOAc (95:5) as eluent to afford the title compound as an oil: 1H NMR (CDCl3) δ 7.82 (m, 3H), 7.47 (m, 11H), 5.24 (s, 2H), 4.54 (br s, 2H), 3.67 (s, 3H), 1.41 (s, 9H); (M−1)−=589.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:20]([CH3:22])[CH3:21])[C:17](O)=[O:18])[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:20]([CH3:21])[CH3:22])[C:17]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=3)=[O:18])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C(=O)O)C(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: COc1cn(C(C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)C(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
120 mg (333 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoic acid (racemate) and 70.7 mg (366 μmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate mixtures). Yield: 134 mg (75% of theory)
Reaction SMILES: C(C1OC(N)=NC=1)C1C=CC=CC=1.Br[CH:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:16]=[O:17].NC(N)=O>C(O)C>[C:19]1([CH2:18][CH2:15][CH:16]=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=CC(Br)Cc1ccccc1
Agent: NC(N)=O
Agent: Nc1ncc(Cc2ccccc2)o1
Solvent: CCO
Product: O=CCCc1ccccc1

Procedure:
5-Benzyl-oxazol-2-ylamine A mixture of 2-bromo-3-phenylpropionaldehyde (14.2 g, crude from above) and urea (7.2 g, 0.12 mol) were heated at reflux for 15 hours in 200 mL of ethanol. The solvent was evaporated to dryness and the residue was diluted with dichloromethane (250 mL) and then washed with sodium hydroxide (10% aqueous solution, 100 mL) and water (50 mL). The organic layer was washed three times with hydrochloric acid (5% aqueous solution, 250 mL). The combined aqueous layers were brought to pH 9 to 10 with a 10% aqueous solution of sodium hydroxide and then extracted three times with dichloromethane (300 mL). The organic layer was dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to give a pale yellow solid (1.6 g, 9.2 mmol, 9.2% from 3-phenyl-propionaldehyde). ESI-MS m/z calc. 174.1. found 175.1 (M+1)+; 1H NMR (CDCl3) δ 7.32-7.22 (m, 5H), 6.39 (s, 1H), 4.72 (bs, 2H), 3.84 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)[C:3]1[S:4][C:5]2[CH:11]=[C:10]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)=[O:14])[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:34](=O)[CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(Cl)Cl>[CH2:34]([N:31]1[CH2:32][CH2:33][CH:29]([CH2:28][N:2]([CH3:1])[C:3]2[S:4][C:5]3[CH:11]=[C:10]([NH:12][C:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=5)=[CH:19][CH:20]=4)=[O:14])[CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:30]1)[CH3:35]
Reactant: CC=O
Reactant: CN(CC1CCNC1)c1nc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN1CCC(CN(C)c2nc3ccc(NC(=O)c4ccc(-c5ccc(F)cc5)cc4)cc3s2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
Place 4′-fluoro-biphenyl-4-carboxylic acid [2-(methyl-pyrrolidin-3-ylmethyl-amino)-benzothiazol-6-yl]-amide (123 mg, 0.267 mmol) in THF (3 mL) and cool to 0° C. Add acetaldehyde (0.040 mL, 0.716 mmol) and sodium triacetoxyborohydride (88 mg, 0.415 mmol). Stir at 0° C. for 10 min. Dilute with DCM and wash with 1N NaOH. Collect the organic layer and chromatograph (silica gel, eluting with 10% 2M NH3 in MeOH:DCM) to yield 102 mg (78%) of the title compound: mass spectrum (ion-spray): (m/z)=489.0 (M+1).