Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[OH:1][C:2]1([C:9]2[S:13][C:12]([CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:17]2[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:23])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CC(C)c1ncc(C2(O)CCC(=O)CC2)s1
Product: CC(C)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(2-iso-Propyl-thiazol-5-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:12]O)[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:7]=2)[CH:3]=1.C(#N)C.C(N(C(C)C)CC)(C)C.F.F.F.C(N(C(C)C)CC)(C)C.[F:68]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C([O-])(O)=O.[Na+]>CCOCC>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]2)[CH2:12][F:68])[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:43])[CH3:41])[N:7]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(CO)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(COC(CF)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-hydroxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (440 mg, 0.694 mmol) in ACETONITRILE (0.1 mL, 1.915 mmol) at room temperature was added diisopropylethylamine (0.545 mL, 3.12 mmol), Diisopropylethylamine trihydrofluoride (197 mg, 1.041 mmol), and perfluoro-1-butanesulfonyl fluoride (0.249 mL, 1.387 mmol). The reaction was stirred at room temperature overnight. It was then poured into sat'd NaHCO3 and diluted with ether. The ether layer was washed with water and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (15%-20% EtOAc/Hex) to give title compound (420 mg, 0.660 mmol, 95% yield) as a colorless film. LC/MS (HPLC method 3): tR=4.33 min, 636.3(MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Br[CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27].C(=O)([O-])O.[Na+]>CN(C)C=O>[F:27][C:26]([F:29])([F:28])[CH2:25][CH2:24][N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: FC(F)(F)CCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CCC(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperazine (5.00 g) and N,N-diisopropylethylamine (4.68 ml) in N,N-dimethylformamide (13 ml) was added 1-bromo-3,3,3-trifluoropropane (5.00 ml) at 60° C. The mixture was stirred at 60° C. for 4 hours. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with hexane. The organic layer was washed successively with saturated aqueous ammonium chloride solution, aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated to give the title compound (5.38 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:13]([N:15]=[C:16](SC)[S:17][CH3:18])#[N:14]>CO>[C:13]([NH:15][C:16](=[N:12][CH2:11][CH2:10][S:9][CH2:8][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1)[S:17][CH3:18])#[N:14]
Reactant: CSC(=NC#N)SC
Reactant: NCCSCc1ncccc1Cl
Solvent: CO
Product: CSC(=NCCSCc1ncccc1Cl)NC#N

Procedure:
A solution of 2-[(3-chloro-2-pyridyl)methylthio]ethylamine (5.77 g; 28.44 mmoles) and dimethyl cyanodithioimidocarbonate [prepared according to the procedure described in J. Org. Chem., 32, 1566 (1967)] (4.16 g; 28.44 mmoles) in methanol (50 ml) was stirred at ambient temperature under a positive pressure of nitrogen for 16 hours and then at reflux for 0.5 hours to complete the reaction. The reaction mixture was evaporated under reduced pressure and the crude product was recrystallized from isopropyl alcohol with activated carbon treatment to give N-cyano-N'-{2-[(3-chloro-2-pyridyl)methylthio]ethyl}-S-methylisothiourea; mp 119.5°-121°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O-:12])=[O:11])=[C:8]([CH3:13])[S:7][C:6]=2[CH:14]=1.Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:25]([N:27]3[CH2:31][CH2:30][C@@H:29]([O:32][CH3:33])[CH2:28]3)=[O:26])[S:24][C:17]=12.[C:34]([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:33][O:32][C@@H:29]1[CH2:30][CH2:31][N:27]([C:25]([C:23]2[S:24][C:17]3[C:18](=[N:19][CH:20]=[CH:21][C:16]=3[O:1][C:2]3[CH:3]=[CH:4][C:5]4[C:9]([C:10]([O:12][CH3:34])=[O:11])=[C:8]([CH3:13])[S:7][C:6]=4[CH:14]=3)[CH:22]=2)=[O:26])[CH2:28]1
Reactant: O=C([O-])[O-]
Reactant: Cc1sc2cc(O)ccc2c1C(=O)[O-]
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: [Cs+]
Product: COC(=O)c1c(C)sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](OC)C5)sc34)ccc12
Yield: 99.5 %

Procedure:
This material was prepared from the reaction of 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (267 mg, 1.20 mmole) with 7-chloro-2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine 4b (297 mg, 1.00 mmole) and Cs2CO3 (977 mg, 3.00 mmole) in a manner similar to that previously described for example 1 to give a brown solid (480 mg, 100%). 1H NMR (DMSO-d6, 300 MHz) δ 8.58 (1H, d, J=5.46 Hz), 8.39 (1H, d, J=8.85 Hz), 8.07 (1H, s), 8.02 (1H, d, J=2.26 Hz), 7.42 (1H, dd, J=2.35, 8.95 Hz), 6.79 (1H, d, J=5.46 Hz), 4.12–3.80 (3H, m), 3.91 (3H, s), 3.68–3.46 (2H, m), 3.27, 3.24 (3H, s), 2.82 (3H, s), 2.17–1.92 (2H, m).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.[CH:24]([C:26]1[S:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[NH2:23][C:9]1[N:8]=[CH:7][C:6]2[C:2]([C:29]3[S:30][C:26]([CH:24]=[O:25])=[CH:27][CH:28]=3)=[CH:3][O:4][C:5]=2[C:10]=1[O:11][C@@H:12]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=1[Cl:22])[CH3:13]
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: O=Cc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2c(-c3ccc(C=O)s3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridine-6-ylamine (100.0 mg, 0.238 mmol), 5-formyl-2-thiopheneboronic acid (55.7 mg, 0.357 mmol), Pd(PPh3)4 (10.0 mg, 0.01 mmol), potassium carbonate (98.7 mg, 0.714 mmol) and 4:1 dioxane:water (10 mL) was heated to 90° C. overnight. The material was concentrated in vacuo, redissolved in DCM and transferred to a separatory funnel, extracting with sat. NaHCO3. The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 2% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=1.90 (d, J=6.8 Hz, 3H), 6.53 (q, J=6.7 Hz, 1H), 7.20-7.25 (m, 1H), 7.41 (dd, J=8.8, 4.8 Hz, 1H), 7.59 (d, J=3.8 Hz, 1H), 7.94 (d, J=4.0 Hz, 1H), 8.13 (s, 1H), 8.28 (s, 1H), 9.89 (s, 1H). MS (ES+): m/z 450.92 (100) [MH+]. HPLC: tR=3.75 min (ZQ3, polar—5 min).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([CH2:12][N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH3:15])=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[Br:22].N1C=CC=CC=1.[OH-].[Na+].[CH2:31]([OH:34])[CH2:32][OH:33]>O>[NH2:2][C:3]1[C:11]([CH2:12][N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH3:15])=[CH:10][C:6]([C:7]([O:33][CH2:32][CH2:31][OH:34])=[O:8])=[CH:5][C:4]=1[Br:22]
Reactant: CCN(Cc1cc(C(=O)Cl)cc(Br)c1N)C1CCCCC1
Reactant: OCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCN(Cc1cc(C(=O)OCCO)cc(Br)c1N)C1CCCCC1
Temperature: 105 °C

Procedure:
41 gm (0.1 mol) of 4-amino-3-bromo-5-(N-ethylcyclohexylaminomethyl)-benzoyl chloride hydrochloride were dissolved in 250 ml of ethylene glycol, and after addition of 17 gm (0.22 mol) of pyridine the solution was heated to 105° C. for one hour. After cooling to room temperature, the mixture was diluted with 1 liter of water. After addition of aqueous sodium hydroxide the mixture was extracted with ether, the ether extract was dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silicagel (eluant: ethyl acetate). After evaporation of the eluate, a resin was obtained which was converted into crystals by trituration with petroleum ether. The crystals obtained were recrystallized from ethanol.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([NH:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([O:23]C)=O)=[O:14])=[CH:8][CH:7]=1>C(O)C.[Cl-].[Na+].O>[NH:2]([C:21]([C:17]1[S:18][CH:19]=[CH:20][C:16]=1[NH:15][C:13](=[O:14])[CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][CH:8]=1)=[O:23])[NH2:3]
Reactant: NN
Reactant: COC(=O)c1sccc1NC(=O)Cc1ccc(OC)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CC(=O)Nc2ccsc2C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.1 %

Procedure:
Hydrazine monohydrate (0.825 mL, 17.1 mmol) was added to a solution of methyl 3-(2-(4-methoxyphenyl)acetamido)thiophene-2-carboxylate (3.48 g, 11.4 mmol) in ethanol (40 mL) and the resulting solution was stirred at room temperature for 24 h. The mixture was diluted with brine and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/ethyl acetate, 1/1 to 1/9) to give N-(2-(hydrazine-carbonyl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide (1.71 g, 5.60 mmol, 49%). Retention time (min)=1.300, method [1], MS(ESI) 306.0 (M+H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:11]([NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])([CH3:10])([CH3:9])[CH3:8].[C:25]1(=[O:29])[O:28][CH2:27][CH2:26]1.C(OCC)(=O)C>C1COCC1.O>[C:7]([C:11]([NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:27][CH2:26][C:25]([OH:29])=[O:28])[C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])([CH3:10])([CH3:8])[CH3:9]
Reactant: COC(=O)c1c(O)cccc1NC(=O)C(C)(C)C
Reactant: O=C1CCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(NC(=O)C(C)(C)C)cccc1OCCC(=O)O
Reaction time: 8 h
Yield: 67.2 %

Procedure:
Potassium tert-butoxide (1.81 g) was added to a solution of methyl 2-tert-butylcarbonylamino-6-hydroxybenzoate (Intermediate 79, 4.06 g) in THF (30 mL) and the mixture was heated at 60° C. β-propiolactone (1.16 g) was added dropwise and the resultant mixture was heated at 60° C. for 25 minutes, then left to stand at room temperature overnight. Ethyl acetate and water were added and the layers were separated. The aqueous phase was extracted with more ethyl acetate and acidified to pH 2 using 1M hydrochloric acid. This was extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 50-100% to give methyl 2-tert-butylcarbonylamino-6-(2-carboxyethoxy)-benzoate (3.5 g) as a white solid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([NH:18]C(OCC2C=CC=CC=2)=O)[CH:6]=1)(=[O:4])=[O:3]>O1CCCC1.[C].[Pd]>[NH2:18][C:7]1[CH:6]=[C:5]([S:2]([NH2:1])(=[O:3])=[O:4])[CH:17]=[CH:16][C:8]=1[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10]
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To tert-butyl 4-aminosulfonyl-2-(benzyloxycarbonyl)aminobenzoate (5.0 g) in tetrahydrofuran solution (50 ml), 5% palladium carbon (500 mg) was added and the mixture was stirred under hydrogen atmosphere at room temperature for 1 hour. The insoluble compound was filtered out, and the filtrate was concentrated. The residue was diluted with ethyl acetate, then the insoluble compound was again filtered out. The filtrate was concentrated, and the residue was recrystallized from ethyl acetate/hexane to obtain the title compound (2.9 g).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[OH:8]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:8]
Reactant: OC(c1ccc2ccccc2c1)c1ccsc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=C(c1ccc2ccccc2c1)c1ccsc1Cl
Temperature: 50 °C
Yield: 52.1 %

Procedure:
To a solution of 1.18 g of (2-chlorothiophen-3-yl)-(naphthalen-2-yl)-methanol in 12 mL of toluene was added 1.12 g of activated manganese dioxide at room temperature, and after stirring at 50° C. for a day, manganese dioxide was filtered off through Celite. The solvent was distilled off, and the resultant crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:50), to afford 0.61 g of the title compound as a colorless oil.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH:21]3[CH:19]([CH:20]3[N:23]([CH3:37])[S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[CH2:18]2)=[N:15][CH:16]=1)=[O:10].C(O)(C(F)(F)F)=O.C(Cl)Cl.CO>>[OH:7][NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH2:22][CH:21]3[CH:19]([CH:20]3[N:23]([CH3:37])[S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[CH2:18]2)=[N:13][CH:12]=1)=[O:10]
Reactant: CN(C1C2CN(c3ncc(C(=O)NOC4CCCCO4)cn3)CC21)S(=O)(=O)c1ccc2ccccc2c1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C1C2CN(c3ncc(C(=O)NO)cn3)CC21)S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3 %

Procedure:
To N-(tetrahydro-2H-pyran-2-yloxy) 2-{6-[methyl(naphthalene-2-sulfonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide was added TFA/DCM/MeOH (5 ml, 1:1:1 mixture). The solution was stirred at r.t. for 2 h. The mixture was then concentrated under reduced pressure, and purified by reverse phase HPLC to yield the title compound (34 mg, 3% yield over 2 steps). LCMS purity >98%, m/z 440 [M−+H]+, 1H NMR (300 MHz, d6-DMSO) δ: 1.55 (1H, m), 2.25 (2H, m), 2.77 (3H, s), 3.58 (2H, m), 3.78 (2H, d, J=11.8 Hz), 7.66-7.84 (2H, m), 7.82 (1H, dd, J=1.8, 8.6 Hz), 8.06 (1H, m), 8.18 (1H, d, J=8.7 Hz), 8.22-8.28 (1H, m), 8.49-8.52 (1H, m), 8.61 (2H, s), 9.01 (1H, br s), 11.05 (1H, br s).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]2[N:8]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:27][CH3:28])=[C:23]([Cl:26])[CH:24]=4)[N:19]=[C:18]([CH3:29])[C:17]=3[CH3:30])[CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[C:31]([Cu])#[N:32]>CN(C=O)C>[Cl:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:27][CH3:28])[N:19]=[C:18]([CH3:29])[C:17]([CH3:30])=[C:16]2[N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([C:31]#[N:32])[CH:7]=2)[C:10]2([CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:9]1
Reactant: N#C[Cu]
Reactant: COc1cc2nc(C)c(C)c(N3CC4(CCOCC4)c4ccc(Br)cc43)c2cc1Cl
Solvent: CN(C)C=O
Product: COc1cc2nc(C)c(C)c(N3CC4(CCOCC4)c4ccc(C#N)cc43)c2cc1Cl
Temperature: 150 °C
Reaction time: 48 h

Procedure:
A mixture of 6-bromo-1-(6-chloro-7-methoxy-2,3-dimethylquinolin-4-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (0.1 g, 0.205 mmol) and CuCN (0.0367 g, 0.41 mmol) in DMF (1 mL) was stirred at 150° C. After 48 h, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using 0 to 100% gradient of EtOAc in hexane as eluent to give 1-(6-chloro-7-methoxy-2,3-dimethyl-4-quinolinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]-6-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.67 (1H, s), 7.59 (1H, s), 7.47 (1H, d, J=7.4 Hz), 7.12 (1H, dd, J=7.6, 1.4 Hz), 6.16 (1H, d, J=1.6 Hz), 4.10 (1H, d, J=9.8 Hz), 4.00 (3H, s), 3.82-3.94 (3H, m), 3.42-3.56 (2H, m), 2.66 (3H, s), 2.15 (3H, s), 1.98-2.11 (2H, m), 1.89 (1H, dd, J=13.7, 1.6 Hz), 1.74 (1H, dd, J=13.5, 1.0 Hz); Mass Spectrum (ESI) m/e=434.2 (M+1).
Reaction SMILES: COC1C=CC([CH:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[OH:10])=CC=1[N+]([O-])=O.COC1C=C(Br)C=C(OC)C=1OC.[Mg].[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[N+:50]([O-:52])=[O:51])C=O>>[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:9]([C:11]2[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=2)[OH:10])[CH:47]=[CH:48][C:49]=1[N+:50]([O-:52])=[O:51]
Reactant: COc1cc(C=O)ccc1[N+](=O)[O-]
Reactant: COc1ccc(C(O)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: COc1cc(Br)cc(OC)c1OC
Agent: [Mg]
Product: COc1cc(C(O)c2cc(OC)c(OC)c(OC)c2)ccc1[N+](=O)[O-]
Yield: 60 %

Procedure:
(3-Methoxy-4-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol was prepared analogously to (4-methoxy-3-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol using 3,4,5-trimethoxy-bromobenzene (3.0 g, 12.1 mmol), magnesium turning (1.0 g, 24.3 mmol) and 3-methoxy-4-nitro-benzaldehyde (1.8 g, 10.1 mmol). The crude product was purified by flash chromatography (silica gel, Hexane:EtOAc 7:3) to afford (3-methoxy-4-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol (2.1 g, 60%): 1H NMR (CDCl3) δ 7.82 (d, J=8 Hz, 1H), 7.23 (s, 1H), 6.97 (d, J=8 Hz, 1H), 6.54 (s, 2H), 5.76 (s, 1H), 4.76 (s, 1H), 3.96 (s, 3H), 3.85 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[N:3]1[C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[N:9]=1.C1CCCCC=1>[Pd].C(O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[N:3]1[C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[N:9]=1
Reactant: COc1ccc([N+](=O)[O-])c(N2C(C)CCC2C)n1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COc1ccc(N)c(N2C(C)CCC2C)n1

Procedure:
4.2 g (0.017 mol) of the product 2-(2,5-dimethylpyrrolidin-1-yl)-6-methoxy-3-nitropyridine synthesized according to the above procedure, 40 ml of ethanol, 10 ml of cyclohexene and 1.5 g of palladium-on-charcoal were placed in a fully equipped round-bottomed flask.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH2:20]([S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:21]1[O:23][CH2:22]1>O1CCCC1.O>[C:25]1([S:24][CH2:20][CH:21]([OH:23])[CH2:22][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cccnc1
Reactant: c1ccc(SCC2CO2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: OC(CCc1cccnc1)CSc1ccccc1
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
Under argon gas, a solution of diisopropylamine (0.835 g, 8.25 mmol) in tetrahydrofuran (5 mL) was added dropwise to n-butyllithium (1.53 M in hexane, 4.9 mL, 7.5 mmol) at 5° C. and the mixture was stirred for 30 minutes. To this was further added a solution of 3-methylpyridine (1.40 g, 15 mmol) in tetrahydrofuran (5 mL) dropwise at 5° C., and the mixture was stirred for 30 minutes. Then, a solution of phenyl glycidyl thioether (0.83 g, 5 mmol) in tetrahydrofuran (5 mL) was added at 5° C. and the reaction was carried out for 2 hours. This reaction mixture was diluted with 10 mL of water for hydrolysis, and extracted with 20 mL of ethyl acetate. The organic layer was washed with 10 mL of water twice and the solvent was distilled off under reduced pressure to give a deep-red oil. This oil was purified by silica gel column chromatography (Merck's Kieselgel 60, hexane/ethyl acetate=1/2) to give 0.521 g (isolation yield: 41%) of 1-(phenylsulfanyl)-4-pyridin-3-ylbutan-2-ol (yellow oil).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][C:28](O)=[O:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[CH2:34][NH:35][CH3:36]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][C:28](=[O:29])[N:35]([CH2:34][C:33]4[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=4[F:31])[CH3:36])=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)O)cc3)cc2)CC1
Reactant: CNCc1ccccc1F
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)N(C)Cc4ccccc4F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-[4′-(4-carboxymethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (2-fluoro-benzyl)-methyl-amine.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[N:24]1([CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:29][CH2:30][CH2:31][C:32]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:33])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)CCCN1CCCC1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCCN1CCCC1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-pyrrolidin-1-yl-butyric acid to yield (3aR,4S,7aR)-methyl 4-(4-(pyrrolidin-1-yl)butanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=453; RT=0.96 min; UPLC Method I
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11]C)=[O:10])[CH:3]=1.O.[OH-].[Li+]>CO.O>[F:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([OH:11])=[O:10])[CH:3]=1
Reactant: COC(=O)c1c[nH]c(=O)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c[nH]c(=O)c(F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylate (0.876 g, 5.12 mmol) in MeOH (33 mL) and water (11 mL), was added lithium hydroxide hydrate (1.074 g, 25.6 mmol). The resulting mixture was then stirred at rt for 5 h. The mixture was concentrated and the pH was adjusted to pH=5 using concentrated HCl. The mixture was then concentrated and dried in vacuo. The resulting residue was dissolved in MeOH (20 mL) and silica gel was added. The mixture was concentrated and dried. The solid mixture was then purified by silica gel flash column chromatography (30%-100% EtOAc/hexane, then 0%-100% MeOH/DCM) to give the title compound as an off-white solid. MS (ESI, positive ion) m/z: 158 (M+H).