Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]#[N:8].[OH-:9].[K+].OO>O>[NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:8])=[O:9]
Reactant: N#Cc1cccn1N
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: O
Product: NC(=O)c1cccn1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
1-Amino-1H-pyrrole-2-carbonitrile (2.52 g, 23.5 mmole) was suspended in 75 ml water, treated with potassium hydroxide (32 g, 0.57 mole), 30% hydrogen peroxide (2 ml) and stirred overnight at room temperature. Cooled reaction mixture to 0° C. for 30 min and isolated product by filtration, washed with cold water and dried under vacuum to give 2.55 g product (yield: 87%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][N:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@@H:12]2[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[O:34][N:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC1(C)CCNC(=O)[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C1
Reactant: BrCc1ccc(-c2ccno2)cc1
Product: CC1(C)CCNC(=O)[C@H](N(Cc2ccc(-c3ccno3)cc2)S(=O)(=O)c2ccc(Cl)cc2)C1

Procedure:
4-Chloro-N-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 5-(4-bromomethyl-phenyl)-isoxazole analogous to Example 2c to afford 4-chloro-N-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-N-(4-isoxazol-5-yl-benzyl)-benzenesulfonamide MS: m/e=488.1 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[CH:15][N:16]3C(OC(C)(C)C)=O)[CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])#[N:2].C1(C)C=CC=CC=1.C([Sn](CCCC)=O)CCC.C[Si]([N:58]=[N+:59]=[N-:60])(C)C>O.C(O)(=O)C>[NH:16]1[C:17]2[C:13](=[C:12]([C:10]3[CH:9]=[C:8]4[C:4]([CH:5]=[N:6][N:7]4[S:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)(=[O:29])=[O:30])=[C:3]([C:1]4[NH:2][N:60]=[N:59][N:58]=4)[CH:11]=3)[CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: CC(C)(C)OC(=O)n1ccc2c(-c3cc(C#N)c4cnn(S(=O)(=O)c5ccccc5)c4c3)cccc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnn[nH]3)cc(-c3cccc4[nH]ccc34)cc21
Temperature: 90 °C
Yield: 33 %

Procedure:
To a round bottomed flask was charged 1,1-dimethylethyl 4-[4-cyano-1-(phenylsulfonyl)-1H-indazol-6-yl]-1H-indole-1-carboxylate (6.16 g, 12.36 mmol) followed by toluene (250 ml). The resulting solution was then treated with dibutyl(oxo)stannane (0.554 g, 2.224 mmol) and trimethylsilyl azide (3.3 ml, 25.09 mmol). The mixture was heated to 90° C. overnight, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in methanol/DCM and preabsorbed onto silica (20 g). This was placed on the top of a silica cartridge (750 g) and eluted with 0-40% methanol in DCM. The product containing fraction was evaporated to give a green foam which was placed into acetic acid (50 ml) and the mixture heated to 100° C. overnight. The mixture was heated for a further 24 h, then cooled to room temperature and water (250 ml) added. A precipitate formed, which was collected by filtration and air dried over the weekend to give the title compound as a pale grey solid (1.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[C:4]([CH3:16])[CH:3]=1.O.C1(C)C=C[C:21]([S:24](O)(=O)=O)=CC=1>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH:13]([CH3:14])[CH3:15])[C:21]2=[S:24])=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1NCCCNC(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)ccc1N1CCCN(C(C)C)C1=S
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
To a solution of the diamine of Step A (6 g) in dioxane (100 mL) under nitrogen was added N,N′-thiocarbonyl-di-1,2,4-triazole (4.5 g). After stirring at room temperature for 3 hours, para-toluene sulfonic acid monohydrate was added in one portion (9.5 g) and the mixture was heated at reflux for 8 hours. Additional para-toluene sulfonic acid monohydrate was added (1 g) and reflux was resumed for another 2 hours. The mixture was cooled and diluted with ethyl acetate. The precipitate was collected and washed with ethyl acetate. The combined filtrates were washed with brine, dried over magnesium sulfate, and evaporated to dryness. The residue was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 20% ethyl acetate in hexane provided the title compound as a white crystalline solid (5.26 g, 74.6%). The material was slurried in hexane-ether, sonicated and collected to provide 4.91 g of pure product, m.p. 147-149° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH:19][C@@H:20]([CH2:33][NH2:34])[CH2:21][O:22][C:23]1[C:31]2[NH:30][C:29](=[O:32])[NH:28][C:27]=2[CH:26]=[CH:25][CH:24]=1.C(O)(=O)C>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([NH:34][CH2:33][C@H:20]([OH:19])[CH2:21][O:22][C:23]3[C:31]4[NH:30][C:29](=[O:32])[NH:28][C:27]=4[CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1
Yield: 48.4 %

Procedure:
A mixture of 1-(4-ethoxycarbonylphenyl)-4-piperidone (0.25 g, 1 mmol) (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (0.22 g, 1 mmol) U.S. Pat. No. 5,786,356/1988) in 100 mL of ethanol and 0.5 mL of acetic acid was hydrogenated in the presence of 400 mg of 10% palladium on carbon under hydrogen (5˜20 psi) for overnight. The catalyst was then removed by filtering through a short pad of silica gel. The filtrate was concentrated and purified by thin layer chromatography (12% methanol/methylene chloride) to give the title compound as a white solid (0.22 g, 48%); mp>170° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.28 (t, J=7.0 Hz, 3 H), 1.30–1.55 (m, 2 H), 1.80–2.10 (m, 2 H), 2.80–3.10 (m, 5 H), 3.80–4.10 (m, 5 H), 4.23 (q, J=7.0 Hz, 2 H), 6.58 (d, J=7.8 Hz, 1 H), 6.62 (d, J=8.4 Hz, 1 H), 6.86 (dd, J=8.4, 7.8 Hz, 1 H), 6.98 (d, J=8.6 Hz, 2 H), 7.77 (d, J=8.6 Hz, 2 H), 10.60 (s, 1 H), 10.75 (s, 1 H); MS (ES) m/z: 455.1 (MH+); HRMS Calcd. for C24H30N4O5(MH+): 454.2216. Found: 454.2211.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[C:28]([CH:38]([CH3:40])[CH3:39])[NH:27][N:26]=1)(=[O:3])[CH3:2].[N+](C1C=C(S(O[CH2:54][C@@H:55]2[O:57][CH2:56]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:54][C@@H:55]3[O:57][CH2:56]3)=[CH:35][CH:36]=2)=[C:28]([CH:38]([CH3:40])[CH3:39])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OC[C@H]3CO3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.1 %

Procedure:
A mixture of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-hydroxyphenyl)methyl]-5-isopropyl-1H-pyrazole (0.55 g), (R)-1-(3-nitrobenzenesulfonyloxy)-2,3-epoxypropane (0.38 g) and cesium carbonate (0.57 g) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(R)-2,3-epoxypropoxy]phenyl}methyl)-5-isopropyl-1H-pyrazole (0.4 g). This material (43 mg) was dissolved in ethanol (1.5 mL). To the solution was added 2-amino-2-methyl-1,3-propanediol (51 mg), and the mixture was stirred at 75° C. for 14 hours. To the reaction mixture was added 1 mol/L aqueous sodium hydroxide solution (0.28 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μm, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient, water/methanol 90/10-10/90) to give the title compound (12 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:32])([F:31])[C:18]1[N:23]=[CH:22][C:21](/[CH:24]=[CH:25]\[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:31][C:17]([F:16])([F:32])[C:18]1[N:23]=[CH:22][C:21]([CH2:24][CH:25]([N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CCOC(=O)/C=C\c1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)nc1)n1c2c(c3cc(C)ccc31)CN(C)CC2

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, (Z)-ethyl 3-(6-(trifluoromethyl)pyridin-3-yl)acrylate and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C@H:14]([OH:16])[CH3:15])[C:11]([OH:13])=O)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].[C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1)#[N:22].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[C:21]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:29][NH:30][C:11](=[O:13])[C@H:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:5]=2)[C@H:14]([OH:16])[CH3:15])=[O:28])=[CH:31][CH:32]=1)#[N:22]
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Reactant: N#Cc1ccc(C(=O)NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a pre-cooled (−30° C.) solution of (2R,3R)-2-(4-cyano-3-(trifluoromethyl)-phenylamino)-3-hydroxybutanoic acid (1.05 g, 3.64 mmol) and 4-cyanobenzohydrazide (587 mg, 3.64 mmol) in anhydrous THF (60 mL) was added 1-Hydroxybenzotriazole monohydrate (563 mg, 3.64 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide-HCl (1.40 g, 7.29 mmol) at −30° C. followed by triethylamine (1.02 mL, 7.29 mmol). The reaction mixture warmed to room temperature and stirred for 17 h, then quenched with 5% aq. citric acid (150 mL). The solution was extracted with EtOAc (150 mL). The organic extract was washed with 5% aq. citric acid (2×80 mL), sat. aq. NaHCO3 (3×80 mL), H2O (2×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as an off white solid (1.57 g, 100%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.10 (dm, J=8.8 Hz, 2H), 7.94 (dm, J=8.8 Hz, 2H), 7.73 (d, J=8.6 Hz, 1H), 7.31 (d, J=2.3 Hz, 1H), 7.07 (dd, J=2.3, 8.6 Hz, 1H), 6.66 (d, J=7.2 Hz, 1H), 4.26-4.18 (m, 2H), 1.35 (d, J=6.3 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[CH3:25][N:26]1[C:30]2[CH2:31][CH2:32][CH2:33][C:29]=2[C:28]([Sn](CCCC)(CCCC)CCCC)=[N:27]1>CN(C=O)C.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.[Cu]I>[CH:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:29]4[CH2:33][CH2:32][CH2:31][C:30]=4[N:26]([CH3:25])[N:27]=3)[N:3]=2)[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1)=[O:12])([CH3:16])[CH3:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCC2
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4c3CCC4)nc12
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 33.6 %

Procedure:
2-Bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (184 mg, 446 μmol) and 1-methyl-3-(tributylstannyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole (293 mg, 714 μmol) were dissolved in DMF (2.5 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (25.8 mg, 22.3 μmol) and CuI (17.0 mg, 89.2 mmol) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 2.5 h. The reaction mixture was concentrated under high vacuum and the residue was purified by chromatography (40 g column, 50 μm from Analogix, 0-50% EtOAc in hexanes over 30 min) to give N-isopropyl-2-(1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (68 mg, 150 μmol, 34%) as a light yellow solid. MS (M+Na)+=477; 1H NMR (CDCl3) δ: 9.06 (s, 1H), 8.28 (s, 1H), 8.13 (d, J=8.3 Hz, 1H), 5.68 (s, 2H), 4.44 (dq, J=14.5, 6.6 Hz, 1H), 3.89 (s, 3H), 3.47-3.64 (m, 2H), 3.04 (t, J=7.0 Hz, 2H), 2.62-2.86 (m, 4H), 1.34 (d, J=6.8 Hz, 6H), 0.86-0.96 (m, 2H), −0.06 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][OH:7].[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1>>[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([O:7][CH2:6][C:5]2[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:15]=1
Reactant: COc1cc(CO)cc(OC)c1
Reactant: Clc1cncc(Cl)n1
Product: COc1cc(COc2cncc(Cl)n2)cc(OC)c1

Procedure:
The title compound was prepared according to the procedure of example 50, step 1, starting from 3,5-dimethoxybenzyl alcohol (2.16 g, 12.8 mmol), K-t-BuO (1.34 g, 11.9 mmol) and 2,6-dichloropyrazine (1.59 g, 10.7 mmol). The yield of the title compound was 2.56 g (84%) and was obtained as a white solid. HRMS m/z calcd for C13H13ClN2O3 (M)+ 280.0615, found 280.0627. Anal. (C13H13CIN2O3) C, H, N.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([CH2:14][CH:15]=[O:16])[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1CCC[C@@H]1C(O)=O.[Cl:25]N1C(=O)CCC1=O>ClCCl>[Cl:25][CH:14]([C:11]1([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)[CH2:12][CH2:13]1)[CH:15]=[O:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=CCC1(c2ccc3ncccc3c2)CC1
Agent: O=C(O)[C@H]1CCCN1
Solvent: ClCCl
Product: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Temperature: 0 °C

Procedure:
To a mixture of (1-quinolin-6-ylcyclopropyl)acetaldehyde (410 mg, 1.94 mmol), D-proline (45 mg, 0.39 mmol) in dichloromethane (10 mL) cooled (0° C.) was added N-chlorosuccinimide (311 mg, 2.33 mmol) with stirring. The reaction mixture was stirred at 0° C. for 1 h, then gradually warmed to RT. The reaction mixture was quenched with water, extracted with dichloromethane. The combined organic extracts were concentrated and the residue purified by flash chromatography eluting with ethyl acetate in hexanes (0-25% in 18 min) to afford the desired product. (320 mg, 67.1%) LCMS: (M+H)=246.2; (M+H2O+H)=264.2.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=2[NH:7][CH:6]=1)C.CI.[Si]([C:22]#[N:23])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1(C)C=CC=CC=1.ClCCl>[CH3:15][O:14][C:12]1[CH:13]=[C:8]2[C:9]([C:5]([CH2:4][C:22]#[N:23])=[CH:6][NH:7]2)=[CH:10][CH:11]=1
Reactant: COc1ccc2c(CN(C)C)c[nH]c2c1
Reactant: C[Si](C)(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CI
Product: COc1ccc2c(CC#N)c[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
To a solution of 6-methoxygramine (1.0 g, 4.9 mmol, 1.0 eq.) in a mixture of anhydrous dichloromethane (16 mL) and toluene (30 mL) was added, under an argon atmosphere, methyl iodide (610 μL, 9.8 mmol, 2.0 eq.). The mixture was stirred at room temperature for 16 hours and then, concentrated under reduced pressure. To the residue taken up in anhydrous THF (40 mL) were added, under an argon atmosphere, TMSCN (920 μL, 7.3 mmol, 1.5 eq.) and TBAF (14.7 mL, 1M, 14.7 mmol, 3.0 eq.). The mixture was stirred at room temperature for 4 hours and then, concentrated under reduced pressure. The crude was taken up in ethyl acetate and the organic layer was washed with aqueous bicarbonate solution and then dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel pad filtration (eluent: EtOAc) to afford (6-methoxy-1H-indol-3-yl)-acetonitrile as a beige powder (0.87 g, 95%). mp: 100° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[C:26]([CH3:35])=[C:27]([CH:32]=[CH:33][CH:34]=4)[C:28]([O:30]C)=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.O1CCOCC1.[OH-].[Na+].Cl>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[C:26]([CH3:35])=[C:27]([CH:32]=[CH:33][CH:34]=4)[C:28]([OH:30])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)cccc1C(=O)O
Temperature: 70 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of methyl 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-2-methylbenzoate (100 mg) in MeOH-1,4-dioxane (1:2, 4.5 ml) was added iN NaOH solution (1.0 ml) and the mixture was stirred at 70° C. for 1 hour. After cooling, the mixture was acidified with iN HCl and extracted with EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate, evaporated in vacuo to give 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]-methyl}-2-methylbenzoic acid (97.0 mg) as a solid.
Reaction SMILES: CCN(C(C)C)C(C)C.C(Cl)CCl.[Br:14][C:15]1[C:16]([S:22]([NH2:25])(=[O:24])=[O:23])=[C:17]([Cl:21])[S:18][C:19]=1[Cl:20].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([C:39]([NH:25][S:22]([C:16]2[C:15]([Br:14])=[C:19]([Cl:20])[S:18][C:17]=2[Cl:21])(=[O:23])=[O:24])=[O:40])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NS(=O)(=O)c1c(Cl)sc(Cl)c1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NS(=O)(=O)c2c(Cl)sc(Cl)c2Br)CC1
Reaction time: 16 h

Procedure:
60 mg of DMAP, 130 mg of DIEA and 192 mg of EDC are added to a solution of 155 mg of 4-bromo-2,5-dichloro-thiophene-3-sulfonamide and 230 mg of 1-(tert.butyloxycarbonyl)-piperidine-4-carboxylic acid in 8 ml of DMF. The mixture obtained is stirred for ca. 16 h at ca. 30°, solvent is evaporated and the evaporation residue is treated with EtAc. The mixture obtained is washed with aqueous 1 N HCl, aqueous saturated NaHCO3 and brine, and dried. Solvent from the organic phase obtained is evaporated and the evaporation residue is subjected to chromatography. 4-(4-Bromo-2,5-dichloro-thiophene-3-sulfonylaminocarbonyl)-piperidine-1-carboxylic acid tert.-butyl ester is obtained and lyophilized from 1,4-dioxane.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[NH:11][CH:10]=[N:9][N:8]=1.II.[I:14](O)(=O)(=O)=O.C(O)(=O)C.O.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:6]=[C:5]([I:14])[S:4][C:3]=1[C:7]1[NH:11][CH:10]=[N:9][N:8]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: Brc1ccsc1-c1nnc[nH]1
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Brc1cc(I)sc1-c1nnc[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a mixture of 3-(3-bromo-2-thienyl)-4H-1,2,4-triazole (1.12 g, 4.87 mmol), iodine (1.12 g, 4.41 mmol) and periodic acid (4.80 g, 24.8 mmol) in acetic acid (11.0 mL, 200 mmol) were added water (8.0 mL, 400 mmol) and sulfuric acid (2.0 mL, 40 mmol) and the reaction mixture was stirred at rt for two days. The resulting white precipitate was collected by filtration. The solid cake was washed with water and dried under high vacuum at 40° C. to yield product as a white solid (1.74 g, 100% yield, as a white solid). LCMS: (FA) ES+, 357.7. 1H NMR (400 MHz, d6-DMSO) δ: 8.63 (s, 1H), 7.43 (s, 1H)
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H][H].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])CBr)[CH3:14]>CN(C)C=O>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[O:10][C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)[CH3:14]
Reactant: CCOC(CBr)OCC
Reactant: Oc1ccc(F)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(OCC)Oc1ccc(F)cc1
Temperature: 120 °C
Yield: 89.8 %

Procedure:
To a suspension of sodium hydride (11.24 g, 281.00 mmol) in anhydrous N,N-dimethylformamide (500 mL) was added 4-fluorophenol (26.21 g, 233.96 mmol) at 0° C. After hydrogen evolution had ceased, bromo-acetaldehyde diethyl acetal (55 g, 280.60 mmol) was added. The reaction was heated at 120° C. overnight. The mixture was poured into ice-water, extracted with ethyl acetate (3×150 mL), washed with 1N sodium hydroxide (3×100 mL), and brine (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum to give the residue, which was purified by a silica gel column (1% ethyl acetate in petroleum ether) to afford 1-(diethoxymethoxy)-4-fluorobenzene as oil (45 g, 84%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[CH2:5][OH:6].[H-].[Na+].Cl[C:10]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([F:27])[CH:21]=2)[CH:17]=[C:16]([C:28]([F:31])([F:30])[F:29])[C:11]=1[C:12]([O:14]C)=[O:13].Cl>O1CCCC1>[F:27][C:22]1[CH:21]=[C:20]([C:18]2[CH:17]=[C:16]([C:28]([F:31])([F:29])[F:30])[C:11]([C:12]([OH:14])=[O:13])=[C:10]([O:6][CH2:5][CH:3]3[CH2:4][CH:2]3[CH3:1])[N:19]=2)[CH:25]=[CH:24][C:23]=1[CH3:26]
Reactant: CC1CC1CO
Reactant: COC(=O)c1c(C(F)(F)F)cc(-c2ccc(C)c(F)c2)nc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(F)(F)F)c(C(=O)O)c(OCC3CC3C)n2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
37 mg (0.431 mmol) of (2-methylcyclopropyl)methanol and 17 mg (0.431 mmol) of sodium hydride (60% strength dispersion in mineral oil) were initially charged in 5 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 60 minutes. 100 mg (0.288 mol) of methyl 2-chloro-6-(3-fluoro-4-methylphenyl)-4-(trifluoromethyl)nicotinate (Example 2A) in 2 ml of tetrahydrofuran were then added. The mixture was stirred at reflux temperature for 3 h and then at room temperature overnight. For work-up, the reaction mixture was adjusted to pH 1 using 1N hydrochloric acid. After removal of the volatile components on a rotary evaporator, the product was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 10:90→90:10). This gave 20 mg (18% of theory) of the target compound.