Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>COCCOC>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1ccc(Cl)cc1
Yield: 59.4 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (45 mg, 0.12 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 4-chloro-phenylboronic acid (27 mg, 0.17 mmol) and Pd[PPh3]4 (13 mg, 0.012 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (30 mg, 61%). LC-MS m/e 421.26 (M+H+)
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([S:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[CH2:6]2.[C:18]([C:21]1[N:22]=[CH:23][S:24][CH:25]=1)(O)=[O:19].ON1C2C=CC=CC=2N=N1.N=C=N>CN(C=O)C>[CH3:1][N:2]1[CH:3]2[CH2:9][CH2:8][CH:7]1[CH2:6][CH:5]([S:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([C:21]3[N:22]=[CH:23][S:24][CH:25]=3)=[O:19])=[CH:15][CH:16]=1)[CH2:4]2
Reactant: O=C(O)c1cscn1
Reactant: CN1C2CCC1CC(Sc1ccc(N)cc1)C2
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN1C2CCC1CC(Sc1ccc(NC(=O)c3cscn3)cc1)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 76 %

Procedure:
A mixture of 4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenylamine (50 mg), 4-carboxythiazole (52 mg), 1-hydroxybenzotriazole (61 mg) and carbodiimide resin (1.7 mmol/g, 470 mg) in DMF (7 ml) was stirred at room temperature for 3 days. The mixture was filtered then passed through an SCX cartridge, eluting with methanol followed by 2M ammonia in methanol, providing N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-4-thiazolecarboxamide as a white solid (55 mg)
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[Cl:19].N1C=CC=CC=1>C1COCC1>[Cl:19][C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[NH:12][C:2](=[O:3])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cnccc1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cnccc1Cl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 34 %

Procedure:
A solution of benzyl chloroformate (1.1 equiv.) in THF (1.85 M) was slowly added to a solution of 3-amino-4-chloropyridine (1.0 equiv.) and pyridine (1.5 equiv.) in THF (1.0 M) and stirred at rt for 3.5 hours (formation of a precipitate over time). The reaction was quenched with H2O (100 mL), extracted with EtOAc (200 mL), washed with NaCl(sat.) (75 mL), dried over MgSO4, filtered and the volatiles were removed in vacuo. The product precipitated from a mixture of hexane/EtOAc yielding benzyl 4-chloropyridin-3-ylcarbamate (34%). LCMS (m/z): 263.1 (MH+); LC Rt=2.33 min.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].Cl>N1C=CC=CC=1>[CH3:20][C:19]1[CH:21]=[CH:22][C:16]([S:13]([O:1][CH2:2][C@@H:3]([NH:5][C:6]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:12])[CH3:4])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)NC(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A mixture of tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (10.0 g), tosyl chloride (12.0 g) and pyridine (100 mL) was stirred for 30 min under ice-cooling, and at room temperature for 2 hr. Tosyl chloride (6.0 g) was further added to the reaction mixture, and the mixture was stirred at room temperature overnight. 0.5M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a white solid (13.5 g).
Reaction SMILES: [S:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:20])[O:13][C:14]3[CH:19]=CC=CC=3)[S:10][C:6]=2[CH:5]=1)[C:2]#[N:3].[N:23]1(CCN)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[S:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:20])[O:13][CH2:14][CH2:19][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[S:10][C:6]=2[CH:5]=1)[C:2]#[N:3]
Reactant: N#CSc1ccc2nc(NC(=O)Oc3ccccc3)sc2c1
Reactant: NCCN1CCOCC1
Product: N#CSc1ccc2nc(NC(=O)OCCN3CCOCC3)sc2c1

Procedure:
The 2-morpholin-4-ylethyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate was prepared according to the method described in Example 9c, but using 654 mg of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate and 0.27 cm3 of 2-morpholin-4-ylethanamine. The residue obtained is chromatographed on an Analogix cartridge of 40 g of silica 15-40 μm, elution being carried out with a gradient of dichloromethane then 95/5 dichloromethane/methanol. 729 mg of 2-morpholin-4-ylethyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate are thus obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:41])([F:40])[C:27]1[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[N:29]([CH2:36][C:37]([OH:39])=O)[N:28]=1.CCN(C(C)C)C(C)C.[F:51][C:52]1[CH:53]=[C:54]([CH2:59][CH:60]([C:62]2[N:63]=[CH:64][S:65][C:66]=2[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=2[CH3:73])[NH2:61])[CH:55]=[C:56]([F:58])[CH:57]=1>CN(C=O)C>[F:51][C:52]1[CH:53]=[C:54]([CH2:59][CH:60]([NH:61][C:37](=[O:39])[CH2:36][N:29]2[C:30]3[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=3[C:27]([C:26]([F:25])([F:41])[F:40])=[N:28]2)[C:62]2[N:63]=[CH:64][S:65][C:66]=2[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=2[CH3:73])[CH:55]=[C:56]([F:58])[CH:57]=1
Reactant: Cc1ccccc1-c1scnc1C(N)Cc1cc(F)cc(F)c1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1scnc1C(Cc1cc(F)cc(F)c1)NC(=O)Cn1nc(C(F)(F)F)c2c1CCCC2
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (25.0 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 13D (33.1 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired product. 1H NMR (400 MHz, DMSO) δ 9.23 (s, 1H), 8.89 (d, J=8.3 Hz, 1H), 7.35-7.16 (m, 2H), 7.11 (t, J=7.6 Hz, 1H), 6.99 (t, J=9.5 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), 6.51 (d, J=6.4 Hz, 2H), 4.83-4.77 (m, 1H), 4.72 (s, 2H), 3.05 (d, J=7.7 Hz, 2H), 2.46-2.21 (m, 4H), 1.87 (s, 3H), 1.61 (s, 4H). MS (m/z) 561 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:13][C:14](=[CH2:18])[C:15](=[O:17])[CH3:16].CCN(CC)CC>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9](=[O:10])[CH2:13][CH:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: C=C(C)C(C)=O
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)C(C)CC(=O)c1ccc(S(C)(=O)=O)cc1
Reaction time: 3 h
Yield: 4.3 %

Procedure:
To a stirred solution of 4-(methylsulfonyl)benzaldehyde (1.84 g, 10 mmol) in ethanol (8 mL) was added 3-methyl-3-buten-2-one (0.8 g, 9.5 mmol), 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.51 g, 1.9 mmol), and Et3N (2.65 mL, 19 mmol) at room temperature. After stirring for 3 hours, volatiles were removed by evaporation. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/2) to provide the subtitle compound (0.11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:61]([O:63][C:64](=[O:67])[CH2:65][NH2:66])[CH3:62]>CN(C)C=O>[CH2:61]([O:63][C:64](=[O:67])[CH2:65][NH:66][C:19](=[O:21])[C:18]1[CH:17]=[CH:16][C:15]([S:12](=[O:13])(=[O:14])[NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:2]=2[Cl:1])=[CH:23][CH:22]=1)[CH3:62]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
The solution of 4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzoic acid (8.207 g, 18.7 mmol), triethylamine (5.2 mL, 37.4 mmol) and HBTU (8.24 g, 21.7 mmol) in dry dimethyl formamide (150 mL) was stirred at room temperature for five minutes before glycine ethyl ester hydrochloride (Aldrich) (2.614 g, 18.7 mmol) was added. The pH of the reaction mixture was adjusted to 8 by the addition of triethylamine, the so obtained mixture was stirred at room temperature overnight, then concentrated in vacuo. The residue was treated with saturated sodium hydrogencarbonate solution (300 mL), the precipitated crystals were filtered off, washed with water and dried. The crude product was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and n-hexane:ethyl acetate=2:1 as eluent to yield 7.68 g (78%) of the title compound. MS (EI) 524 (MH+).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:17](=[O:33])[CH:18]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH:18]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:17]([NH:16][C@@H:13]2[C@@H:11]3[C@@H:10]([CH2:9][NH:8][CH2:12]3)[CH2:15][CH2:14]2)=[O:33])=[CH:27][CH:28]=1
Reactant: [H][H]
Reactant: O=C(N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(N[C@H]1CC[C@@H]2CNC[C@@H]21)C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
N-((3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-2,2-bis(4-fluorophenyl)acetamide (150 mg, 0.336 mmol) from Example 228 and ethanol (20 ml) were added to 20% Pd(OH)2 on carbon, wet (30.0 mg, 0.214 mmol) in a 50 mL pressure bottle and stirred for 2 hours at under 30 psi hydrogen at 50° C. The mixture was filtered and the solvent removed in vacuo to give 2,2-bis(4-fluorophenyl)-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.09 (d, J=7.1, 1H), 7.60-7.55 (m, 4H), 7.13 (q, J=8.2, 4H), 5.26 (s, 1H), 4.36-4.27 (m, 1H), 3.06 (dd, J=10.9, 2.7, 1H), 2.92 (dd, J=10.9, 7.0, 1H), 2.81 (dd, J=10.7, 7.0, 1H), 2.59 (dd, J=10.8, 2.8, 1H), 2.52-2.41 (m, 2H), 2.33-2.25 (m, 1H), 2.06-1.96 (m, 1H), 1.83 (td, J=12.7, 6.9, 1H), 1.65-1.52 (m, 1H), 1.26 (ddt, J=12.3, 8.7, 6.1, 1H); MS (ESI+) m/z 357 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([N:5]=[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[C:8]2O)=[N:3]1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:8]1[C:9]2[C:4](=[N:3][N:2]([CH3:1])[CH:10]=2)[N:5]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: Cn1cc2c(O)cc(-c3ccccc3)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1cc2c(Cl)cc(-c3ccccc3)nc2n1

Procedure:
39 g. of 2-methyl-6-phenyl-2H-pyrazolo[3,4-b]pyridin-4-ol (0.17 mol.) are refluxed in 195 ml. of phosphorus oxychloride for 90 minutes. The excess phosphorus oxychloride is removed in vacuo and the residue is poured onto ice. Concentrated aqueous ammonia is added under external cooling to adjust the mixture to pH 8-9. Stirring is continued for one additional hour. The collected 4-chloro-2-methyl-6-phenyl-2H-pyrazolo[3,4-b]pyridine is washed with water and dried at 70°, yield: 41 g. (100%); m.p. 177°-179°. Recrystallization from ethyl acetate gives a melting point of 189°-190°.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6](Cl)=[N:7]2.[CH3:14][C:15]([NH2:18])([CH3:17])[CH3:16].O.BrC1C=CC=C2C=1N=C(NC(C)(C)C)C(Cl)=N2>CS(C)=O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6]([NH:18][C:15]([CH3:17])([CH3:16])[CH3:14])=[N:7]2
Reactant: Clc1nc2cccc(Br)c2nc1Cl
Reactant: CC(C)(C)N
Agent: CC(C)(C)Nc1nc2c(Br)cccc2nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)Nc1nc2cccc(Br)c2nc1Cl
Temperature: 100 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
A solution of 5-bromo-2,3-dichloroquinoxaline (LeadGen Labs, LLC, Orange, Conn.) (305 mg, 1.10 mmol) and 2-methylpropan-2-amine (Aldrich) (0.12 mL, 1.10 mmol) in DMSO (5.0 mL) was stirred under argon at 65° C. for 17 h (water-cooled reflux condenser attached to flask). Additional 2-methylpropan-2-amine (0.06 mL, 0.57 mmol) was added, and the resulting solution was stirred at 100° C. for 5 h. The reaction mixture was subsequently cooled to 25° C. and diluted with half-saturated aq. NaHCO3 (80 mL). The resulting mixture was extracted with DCM (2×80 mL), and the combined extracts were sequentially washed with water (2×50 mL), dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-10% EtOAc/hexanes) furnished a ˜2.5:1 mixture of 8-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine and 5-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine (224 mg, 0.71 mmol, 65% yield) as an off-white solid: 8-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine: 1H NMR (400 MHz, CDCl3) δ ppm 7.86 (1H, dd, J=7.6, 1.0 Hz), 7.72 (1H, dd, J=8.2, 1.0 Hz), 7.21 (1H, t, J=7.9 Hz), 5.63 (1H, br. s.), 1.63 (9H, s). m/z (ESI, +ve) 314.0 (M+H)+. 5-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine: 1H NMR (400 MHz, CDCl3) δ ppm 7.65 (1H, d, J=3.7 Hz), 7.63 (1H, d, J=3.3 Hz), 7.39 (1H, t, J=8.0 Hz), 5.60 (1H, br. s.), 1.57 (9H, s). m/z (ESI, +ve) 314.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[C:25](O)=O>>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(Cl)cc(Cl)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3,5-dichlorobenzoic acid: MS (APCl) m/z 439 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:15]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[CH:28](=[O:37])/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[OH:37][CH:28]([CH:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH:14]([CH3:13])[C:19]1=[O:20])/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC1C(=O)CCCN1C(=O)OC(C)(C)C
Reactant: O=C/C=C/c1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC1C(=O)C(C(O)/C=C/c2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2.14 mL (15.3 mmol) of N,N-diisopropylamine in 50 mL of tetrahydrofuran at −78° C. was added 7.96 mL (15.6 mmol, 2.5M in hexane) of n-butyl lithium and the mixture was stirred at −78° C. for 10 min. The reaction was warmed to 0° C. and stirred at 0° C. for 15 min. The mixture was cooled down to −78° C. again, and a solution 2.50 g (11.7 mmol) of tert-butyl 2-methyl-3-oxopiperidine-1-carboxylate (Step C) in 5 mL of tetrahydrofuran was added to the mixture slowly. The mixture was stirred at −78° C. for 1 h. Then 1.77 mL (14.9 mmol) of trans-cinnamaldehyde in 5 mL of tetrahydrofuran (pre-cooled to −78° C.) was added to the reaction mixture and the reaction was stirred at −78° C. for 5 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with three portions of ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. Purification by flash chromatography on a Biotage® system (silica gel, eluting with 10% ethyl acetate/hexane to 30% ethyl acetate/hexane) gave the tide compound. LC/MS 368 (M+23).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[C:5](/[CH3:18])=[CH:6]/[C@@H:7]1[CH2:15][CH2:14][C:13]([CH3:16])=[C:12]2[C@@H:8]1[C@@H:9]([OH:17])[CH2:10][CH2:11]2)[CH3:2].[H][H]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])/[C:5](/[CH3:18])=[CH:6]/[C@@H:7]1[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@@H:12]2[C@@H:8]1[C@@H:9]([OH:17])[CH2:10][CH2:11]2)[CH3:2]
Reactant: CCOC(=O)/C(C)=C/[C@@H]1CCC(C)=C2CC[C@H](O)[C@@H]21
Reactant: [H][H]
Solvent: ClCCl
Product: CCOC(=O)/C(C)=C/[C@@H]1CC[C@@H](C)[C@H]2CC[C@H](O)[C@@H]21
Temperature: 0 °C
Yield: 72.1 %

Procedure:
A solution of compound (10a) (223.8 mg, 0.8466 mmol) and degassed DCM (34) was cooled to 0° C. The flask was flushed with hydrogen over a period of 2 minutes before hydrogen was bubbled through the solution itself for one additional minute. After adding Crabtree catalyst (68.0 mg, 0.0845 mmol) the flask was once again flashed with hydrogen for 3 minutes before hydrogen was bubbled through the solution for 2 minutes until it became colorless. The icebath was removed and the mixture stirred for 2¼ hours. Argon was bubbled through the reaction mixture and the solvent was evaporated. Chromatography (hexane/EtOAc 7/1 to 3/1) of the residue furnished 162.7 mg of compound of (11a) as white solid with 72% yield.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:4]([N:5]=[C:15]=[S:16])[CH:6]=[CH:7][CH:8]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cccc(N)c1N1CCOCC1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(N=C=S)c1N1CCOCC1

Procedure:
Reaction of 3-methyl-2-morpholinoaniline (9.4 g) with thiophosgene (6 ml) in dioxane (50 ml) and water (200 ml) at 0° C. for 30 minutes and at room temperature for 2 hours gave a product which was extracted with dichloromethane to give 3-methyl-2-morpholinophenyl isothiocyanate as a red oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.C1C(=O)N([Cl:21])C(=O)C1.CCOC(C)=O>CN(C=O)C>[Cl:21][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[OH:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2cc(O)ccc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(Cl)c(O)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
To a solution of 6-methoxynaphthalen-2-ol (1.00 g, 5.74 mmol) in DMF (15 mL) was added NCS (843 mg, 6.31 mmol). The reaction mixture was stirred at 25° C. for 16 hours. Diluted the reaction with EtOAc, washed with H2O and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by silica gel column (PE/EtOAc=100/1) gave the product (940 mg, yield 87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:19]([S:21]([C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26](F)[CH:25]=3)(=[O:23])=[O:22])[CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([SH:43])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:1]([O:5][C:6](=[O:35])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:19]([S:21]([C:24]3[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[C:26]([S:43][C:40]4[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=4)[CH:25]=3)(=[O:23])=[O:22])[CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Sc1ccc(Cl)cc1
Reactant: CN([C@@H]1CCCc2c(OCC(=O)OC(C)(C)C)cccc21)S(=O)(=O)c1cc(F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN([C@@H]1CCCc2c(OCC(=O)OC(C)(C)C)cccc21)S(=O)(=O)c1cc(Sc2ccc(Cl)cc2)cc(C(F)(F)F)c1
Temperature: 150 °C
Yield: 70.2 %

Procedure:
A mixture of {(R)-5-[(3-fluoro-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid tert-butyl ester (80.0 mg, 0.15 mmol), 4-chloro-benzenethiol (50 μL), and potassium carbonate (55.0 mg, 0.40 mmol) in N,N-dimethylformamide (1.0 mL) was heated in a microwave oven at 150° C. for 30 minutes. The resulting mixture was neutralized with 1N hydrochloric acid and then extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford ((R)-5-{[3-(4-chloro-phenylsulfanyl)-5-trifluoromethyl-benzenesulfonyl]-methyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (67.5 mg, 70.2%) as a viscous oil, which was used for the next step without any further purification. MS cald. for C30H31ClF3NO5S2 641, obsd. 642 (ESI+) [(M+H)+].
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.[H-].[Na+].I[CH2:28][CH3:29]>C1COCC1>[CH2:28]([N:3]1[CH2:4][CH:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6]2([CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[C:2]1=[O:1])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NCC2c1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CC(c2ccccc2)C2(CCCN(C(=O)OC(C)(C)C)C2)C1=O
Reaction time: 0.17 h

Procedure:
tert-Butyl 1-oxo-4-phenyl-2,7-diazaspiro[4,5]decane-7-carboxylate (ASW MedChem) (1 g, 3.03 mmol) was dissolved in THF (20 ml) under an atmosphere of nitrogen. The solution was cooled (ice/brine bath) and treated with sodium hydride (60% in oil) (0.133 g, 3.33 mmol). The reaction mixture was stirred for 10 minutes and iodoethane (0.269 ml, 3.33 mmol) was added dropwise. The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound. The resulting diastereomeric mixture was used in the next step without further purification.