Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:45][CH2:44][C@H:43]([O:46][Si](C(C)C)(C(C)C)C(C)C)[CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:45][CH2:44][C@H:43]([OH:46])[CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CC[C@H](O[Si](C(C)C)(C(C)C)C(C)C)C5)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CC[C@H](O)C5)n4c3)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
To a solution of Intermediate 26d (19 mg, 0.024 mmol) in THF (1 mL) at −30° C. was added TBAF (1M in THF, 36 μL, 0.036 mmol) and the mixture was allowed to warm to RT over 1 h. The reaction mixture was applied to an SCX-2 cartridge (2 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. Purification by HPLC (C6-Ph column, 35-75% MeCN in H2O, 0.1% HCO2H) gave the title compound as an off-white powder after freeze-drying (10.0 mg, 60%). LCMS (Method 5): Rt 4.00 min, m/z 621 [MH+]. 1H NMR (400 MHz, CDCl3): 1.29 (9H, s), 1.89-2.09 (4H, m), 2.13-2.29 (2H, m), 2.34 (3H, s), 3.35 (1H, td, J 9.2, 4.6), 3.45 (1H, d, J 11.1), 3.50 (1H, dd, J 11.1, 4.3), 3.60 (1H, m), 4.51 (1H, m), 5.04 (1H, td, J 8.5, 5.3), 5.15 (1H, t, J 4.1), 5.57 (1H, d, J 8.6), 6.26 (1H, s), 6.67 (1H, br s), 6.89 (1H, dd, J 9.9, 1.7), 7.15 (2H, d, J 7.1), 7.24-7.29 (4H, m), 7.30-7.38 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.Cl[C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH:6][C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([F:10])[CH:3]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: CCOC(=O)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(=O)Nc1c(F)cc(Br)cc1F
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 4-bromo-2,6-difluoroaniline (10 g, 48 mmol) in DCM (15 mL) was added ethyl 3-chloro-3-oxopropanoate (6.8 mL, 53 mmol) and DIEA (9.2 mL, 53 mmol) at room temperature. After 1 hour, the reaction mixture was partitioned between H2O and DCM. The organic phase was washed with saturated NH4Cl, H2O, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give Compound B26a (10 g, 65% yield). HPLC: RT=1.6 (LCMS Method Q). MS (ES): m/z=321.9 [M+H]+. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.89 (br. s., 1H), 7.20-7.15 (m, 2H), 4.29 (q, J=7.2 Hz, 2H), 3.54 (s, 2H), 1.36-1.31 (m, 3H).
Reaction SMILES: [F:1][C:2]1C=C[C:5](Br)=[CH:4][C:3]=1C.[Li]CCCC.CN(C)C=O.[CH2:20]1[CH2:24][O:23][CH2:22][CH2:21]1>>[F:1][C:2]1[CH:24]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]([CH3:5])[CH:3]=1
Reactant: C1CCOC1
Reactant: Cc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A -78° C. solution of 2-fluoro-5-bromotoluene (25.764 gm, 136.3 mmol) in THF (200 ml) was treated with n-BuLi (2.5M in hexane, 60 ml, 150 mmol) over a 12-minute period. After stirring for one hour, the cloudy white mixture was treated with neat dimethylformamide (30 ml, 28.3 gm, 387 mmol) over a two-minute period. Stirring continued for an additional hour. The mixture was then quenched with saturated NH4Cl, warmed to room temperature, and made acidic with 10% HCl. The mixture was extracted with Et2O and the ether extract was washed with H2O and brine, then dried (Na2SO4), filtered, and stripped. The dark residue was distilled (bp 55° C. @ 1 mm) to give the title compound (16.286 gm, 86%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:12](=[O:13])[N:11](CC2C=CC(OC)=CC=2OC)[CH:10]1[C:25]([O:27][CH3:28])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])(O)=O.[Na+].[Na+]>C(#N)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C:12](=[O:13])[NH:11][C@H:10]1[C:25]([O:27][CH3:28])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1C(NC(=O)OC(C)(C)C)C(=O)N1Cc1ccc(OC)cc1OC
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@@H]1NC(=O)[C@@H]1NC(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 30.7 %

Procedure:
A solution of 10.5 g (26.7 mmole) of methyl 3-t-butoxycarbonylamino-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate in 500 ml of acetonitrile is degassed with argon and warmed to 80°. A degassed solution of 15 g (55.5 mmole) of potassium persulfate and 7.5 g (28 mmole) of sodium monohydrogen phosphate in 150 ml of water is added in five portions over 1 hr. The reaction is stirred at 80°-85° under argon for 2-3 hrs until all starting material is consumed (tlc). The reaction mixture is cooled, concentrated in vacuum, shaken with ethyl acetate-water. The organic phase is washed with dilute HCl, NaHCO3 solution and brine; dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed over silica gel with 1:1 benzene-ethyl acetate to afford pure product which crystallized from ethyl acetate-hexane to yield 2.0 g (31%) of the title compound. A less pure fraction from the column, is crystallized from ethyl acetate-hexane to give an additional 0.5 g of product, overall yield, 38%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11](=[O:15])OCC)=[N:2]1.[Cl:16][C:17]1[CH:18]=[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:20]=[CH:21][C:22]=1[Cl:23].C1CCN2C(=NCCC2)CC1>CS(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11]([N:27]2[CH2:26][CH2:25][N:24]([C:19]3[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=3)[CH2:29][CH2:28]2)=[O:15])=[N:2]1
Reactant: CCOC(=O)Nc1n[nH]c2ccccc12
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Nc1n[nH]c2ccccc12)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 100 °C
Yield: 50.5 %

Procedure:
Ethyl 1H-indazol-3-ylcarbamate (250 mg), 1-(3,4-dichlorophenyl)piperazine (KANTO CHEMICAL CO. INC., 310 mg) and DBU (200 μl) were dissolved in dimethyl sulfoxide (4 ml), and the mixture was stirred with heating at 100° C. for 1 hr. By the work-up following the method of Example 12, 4-(3,4-dichlorophenyl)-1-piperazinecarboxylic acid (1H-indazol-3-yl)amide (240 mg, yield 50%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[OH:27][CH2:28][CH2:29][NH:30][CH3:31]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:30]([CH2:29][CH2:28][OH:27])[CH3:31])[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CNCCO
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)C(=O)Oc1ccc(Cl)cc1
Solvent: CC(=O)N(C)C
Product: CN(CCO)CCCCOC[C@H]1CC[C@H](CN(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was reacted with (2-hydroxy-ethyl)-methyl-amine in N,N-dimethylacetamide at 50° C. for 3 hours to yield trans-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-butoxymethyl}-cyclohexylmethyl)-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 441 (MH+, 1Cl).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH2:13][CH3:14])(=O)C.O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[C:13]1([CH:14]2[O:8][CH:1]2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(C)=O
Agent: [Rh]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: c1ccc(C2OC2c2ccccc2)cc1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a rapidly stirred solution of a sulphide of formula (D) wherein Ra is CH2OCH3 and Rb is H (1 equivalent, 80 mg, 0.33 mmol), rhodium (II) acetate dimer (1 mol %, 1.5 mg, 0.003 mmol), benzyltriethylammonium chloride (20 mol %, 15 mg, 0.066 mmol) and benzaldehyde (35 mg, 0.33 mmol) in anhydrous acetonitrile (1 cm3) was added the tosyl hydrazone salt (1.5 equivalents, 147 mg, 0.495 mmol). The heterogeneous mixture was stirred rapidly at room temperature to facilitate even dispersion of the solid, then held at 30° C. (bath temperature) for 32 hours. The mixture was then cooled and ethyl acetate/water (0.5 cm3+0.5 cm3) added. The organic phase was removed and the aqueous phase extracted with ethyl acetate (2×0.5 cm3). The combined organic extracts were then dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified on silica, eluting with 0-25% DCM/petrol, to give stilbene oxide as a white solid (38 mg, 59%) and as a >98:2 mixture (trans:cis) of diastereoisomers; enantiomeric excess 93% (R, R major) as determined by chiral HPLC (see conditions below). The NMR data for this compound is reported above.
Reaction SMILES: [CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH3:28])[CH3:27])[CH:21]=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:27][N:26]([CH3:28])[C:22]1[CH:21]=[C:20]([N:16]2[CH2:15][CH2:14][CH:13]([N:2]([CH3:1])[C:3](=[O:12])[O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:18][CH2:17]2)[CH:25]=[CH:24][N:23]=1
Reactant: CN(C)c1cc(Br)ccn1
Reactant: CN(C(=O)OCc1ccccc1)C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN(C)c1cc(N2CCC(N(C)C(=O)OCc3ccccc3)CC2)ccn1
Temperature: 80 °C
Yield: 63 %

Procedure:
Benzyl methyl(piperidin-4-yl)carbamate (0.862 mmol, 1.0 eq.), 4-bromo-N,N-dimethylpyridin-2-amine (173 mg, 0.862 mmol, 1.0 eq.) and t-BuONa (193 mg, 1.72 mmol, 2.0 eq.) were taken up in toluene (10 ml) and degassed with N2. BI NAP (26 mg, 0.043 mmol, 0.05 eq.) and Pd2(dba)3 (39 mg, 0.043 mmol, 0.05 eq.) were then added and the mixture was heated for 16 hours at 80° C. After monitoring by TLC, the reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, 4% MeOH in DCM). Yield: 63% (200 mg, 03543 mmol)
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])[S:13][N:12]=1)[CH3:2].C([O-])(=O)C.[Na+].[NH:33]1[CH2:38][CH2:37][CH:36]([C:39]([O:41]CC)=[O:40])[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:13][N:12]=[C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:33]4[CH2:34][CH2:35][CH:36]([C:39]([OH:41])=[O:40])[CH2:37][CH2:38]4)[CH:7]=[CH:6][CH:5]=3)[N:15]=2)[CH:17]=[CH:18][C:19]=1[CH2:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1c(C=O)cccc1-c1nsc(-c2ccc(CC(C)C)c(C#N)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1c(CN2CCC(C(=O)O)CC2)cccc1-c1nsc(-c2ccc(CC(C)C)c(C#N)c2)n1
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a solution of 5-[3-(2-ethyl-3-formylphenyl)-1,2,4-thiadiazol-5-yl]-2-(2-methylpropyl)benzonitrile (D63) (100 mg) in dichloromethane (DCM) (15 mL) was added sodium acetate (22.9 mg), ethyl 4-piperidinecarboxylate (46.1 mg) and 5 drops of acetic acid. After stirring for 30 min, sodium triacetoxyborohydride (85 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated. The residue was dissolved in isopropanol/water (10 mL, 1:1), 0.5M sodium hydroxide (2.66 mL) was added. The reaction solution was stirred at room temperature overnight. The isopropanol was removed in vacuo and the residue was acidified to pH=3-4. The resulting solution was extracted with ethyl acetate (2*15 mL), and the combined organic phases were dried over sodium sulphate, concentrated and purified by Mass Directed AutoPrep to afford 1-[(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,2,4-thiadiazol-3-yl}-2-ethylphenyl)methyl]-4-piperidinecarboxylic acid (E28) (43 mg). δH (DMSO-d6, 400 MHz): 0.87 (6H, d), 1.03 (3H, t), 1.47 (2H, m), 1.71 (2H, m), 1.92 (3H, m), 2.01 (1H, m), 2.70 (4H, m), 2.93 (2H, q), 3.47 (2H, s), 7.24 (1H, t), 7.39 (1H, dd), 7.66 (2H, m), 8.26 (1H, dd), 8.47 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])[S:11][C:12]=2[CH2:13][CH2:14][CH2:15][C:16](OCC)=[O:17])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])[S:11][C:12]=2[CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCc1sc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCCO)s1
Reaction time: 1 h
Yield: 71.7 %

Procedure:
Ethyl 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-thiazolebutanoate (2.00 g) was dissolved in 20 ml of tetrahydrofuran, to which was added gradually lithium aluminum hydride (195 mg) under ice-cooling. The resulting mixture was stirred for 1 hour. Water (0.5 ml) was carefully added to the reaction mixture, the resulting mixture was filtered, and the residue on the filter paper was washed with ethyl acetate. The filtrate was concentrated to give crystals of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-thiazolebutanol (1.28g, 72%). Recrystallization from ethyl acetate-hexane gave pale yellow prisms. Melting point 98-99° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]2[C:12]=1[CH:13]=[N:14][NH:15]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:38][CH2:39][CH2:40][OH:41].C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[OH:41][CH2:40][CH2:39][NH:38][C:8](=[O:10])[C:6]1[CH:5]=[CH:4][C:3]([C:11]2[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1nc(C(=O)O)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Reactant: NCCO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1nc(C(=O)NCCO)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.3 %

Procedure:
To 6-methyl-5-(6-(trifluoromethyl)-1H-indazol-4-yl)picolinic acid (1.6 g, 4.98 mmol) in DMF (20 mL) were added HOBt (0.942 g, 6.97 mmol), EDC (1.432 g, 7.47 mmol), 2-aminoethanol (0.913 g, 14.94 mmol), followed by N-ethyl-N-isopropylpropan-2-amine (4.34 mL, 24.90 mmol). The reaction mixture was stirred for 16 hours at room temperature, was subsequently diluted with EtOAc and was washed with brine. Volatiles were evaporated from the organic phase and the residue was purified by CombiFlash® chromatography, eluting with a gradient of 0-20% MeOH in DCM. The product-containing fractions were combined and concentrated in vacuo to give the title compound as a white solid (0.658 g, 36.3%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.43 (s, 3H), 3.44 (q, J=5.98 Hz, 2H), 3.57 (t, J=5.94 Hz, 2H), 7.38-7.44 (m, 1H), 7.90-8.07 (m, 4H), 8.70 (t, J=5.81 Hz, 1H); ESI-MS m/z [M+H]+ calc'd for C17H15F3N4O2, 365.1. found 365.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[CH:16]=[CH:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>[N+](C1C=CC=CC=1)([O-])=O.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[C:16]([S:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=2)(=[O:32])=[O:31])=[CH:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCCC2Cn2ccc3cccnc32)cc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O=[N+]([O-])c1ccccc1
Product: O=S(=O)(c1cccc(Cl)c1)c1cn(CC2CCCN2Cc2ccccc2)c2ncccc12
Temperature: 100 °C
Yield: 27 %

Procedure:
A mixture of 1-[(1-benzylpyrrolidin-2-yl)methyl]-1H-pyrrolo[2,3-b]pyridine (2.0 g, 6.86 mmol), 3-chlorophenylsulfonyl chloride (1.63 g, 7.55 mmol) and silver trifluoromethanesulfonate (AgOTf) (2.32 g, 8.92 mmol) in nitrobenzene is heated at 100° C. under a nitrogen atmosphere for 36 h, cooled to room temperature, quenched with 10% aqueous sodium carbonate, and extracted with CH2Cl2. The extracts are combined, washed sequentially with water and brine and concentrated in vacuo. The resultant residue is purified by flash column chromatography (0–5% methanol in CH2Cl2 as eluent) to afford the title compound as a semi-solid, 865 mg (27% yield), identified by HNMR and mass spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:19][C:20]1[CH:24]=[C:23]([CH:25]=O)[NH:22][N:21]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:25]\[C:23]3[NH:22][N:21]=[C:20]([CH3:19])[CH:24]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: Cc1cc(C=O)[nH]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(C)n[nH]1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (100 mg, 0.404 mmol) in toluene 10 mL was added 3-methyl-1H-pyrazole-5-carbaldehyde 93 (70.8 mg, 0.404 mmol). PTSA (153.8 mg, 0.808 mmol) was added to the reaction mass, then stirred at 120° C. for 6 h, diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude 94 and was purified through flash chromatography by using 100-200 mesh silica gel eluting at 2% MeOH in DCM to afford yellow coloured solid compound (E)-6-methoxy-2-((3-methyl-1H-pyrazol-5-yl)methylene)-5-morpholino-2, 3-dihydro-1H-inden-1-one 94.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[C:21]([CH:31]=1)[CH2:22][NH:23][C:24](=[O:30])[C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10]([N:26]1[CH2:27][CH2:28][CH2:29][C@H:25]1[C:24]([NH:23][CH2:22][C:21]1[CH:31]=[C:17]([Cl:16])[CH:18]=[CH:19][C:20]=1[N:32]1[CH:36]=[N:35][N:34]=[N:33]1)=[O:30])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1

Procedure:
The title compound was prepared from 1-(tert-butoxycarbonyl)-D-proline (49 mg, 0.23 mmol), N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (Example 26, Step B, 70 mg, 0.23 mmol, 1.0 equiv), EDC (66 mg, 0.34 mmol, 1.5 equiv) and HOAt (16 mg, 0.11 mmol, 0.5 equiv) in DMF (500 μl) essentially according to the procedure described in Example 26, Step C. Preparative reverse phase HPLC [gradient elution with 95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 5:95 water (+0.1% TFA)/CH3CN (+0.1% TFA)] afforded the title compound as a clear oil. 1H NMR (400 MHz, CDCl3): δ 9.17 (s, 1 H), 8.11 (br s, 1 H), 7.54 (d, J=2.0 Hz, 1 H), 7.40 (dd, J=2.0, 8.4 Hz, 1 H), 7.23 (d, J=8.4 Hz, 1 H), 4.69–4.66 (m, 1 H), 4.43–4.39 (m, 1 H), 4.18–4.16 (m, 2 H), 4.04–3.99 (m, 1 H), 3.55–3.48 (m, 3 H), 2.27–1.88 (m, 8 H), 1.30 (s, 9 H). LCMS (M+H): 504.3.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([NH:16]C(=O)OC(C)(C)C)[S:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]=[C:14]([NH2:16])[S:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccc(S(C)(=O)=O)cc2)ns1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2nsc(N)n2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl 3-(4-(methylsulfonyl)phenyl)-1,2,4-thiadiazol-5-ylcarbamate (1.57 g, 4.42 mmol) in DCM (20 mL) was added anisol (0.50 mL) and TFA (10 mL). The reaction mixture was stirred at room temperature for 6 h and concentrated. The solid was suspended in saturated NaHCO3 (˜200 mL) and stirred for 30 min. The solid was collected by filtration, washed with water (˜500 mL) followed by hexanes (˜50 mL), and dried under high vacuum to give 3-(4-(methylsulfonyl)phenyl)-1,2,4-thiadiazol-5-amine.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:42])([CH3:41])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:40])([C@@:18]4([CH3:39])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([CH:37]=O)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].C(O)(=O)C(O)=O.[NH2:49][CH2:50][CH2:51][N:52]1[CH2:56][CH2:55][CH2:54][C:53]1=[O:57]>>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:42])([CH3:41])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:40])([C@@:18]4([CH3:39])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([CH2:37][NH:49][CH2:50][CH2:51][N:52]2[CH2:56][CH2:55][CH2:54][C:53]2=[O:57])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: NCCN1CCCC1=O
Agent: O=C(O)C(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCCC3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield following steps 5 and 6, using methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 1-(2-aminoethyl)pyrrolidin-2-one oxalate as the reactant amine MS: m/e 673.6 (MH+), 1.72 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.96 (s, 3H) 0.98 (s, 3H) 1.02 (s, 3H) 1.08 (s, 3H) 1.17 (s, 3H) 1.73 (s, 3H) 2.01-2.21 (m, 4H) 2.44 (t, J=8.16 Hz, 2H) 2.51 (td, J=10.79, 5.52 Hz, 1H) 2.94 (d, J=13.05 Hz, 1H) 3.30 (dt, J=3.26, 1.63 Hz, 3H) 3.55 (t, J=7.15 Hz, 2H) 3.58-3.70 (m, 2H) 4.62-4.67 (m, 1H) 4.76 (d, J=1.76 Hz, 1H) 5.35 (dd, J=6.27, 1.76 Hz, 1H) 6.94 (dd, J=11.92, 1.38 Hz, 1H) 7.02 (dd, J=8.03, 1.51 Hz, 1H) 7.83 (t, J=7.91 Hz, 1H). 19F NMR (376 MHz, MeOD) δ ppm −112.75 (s, 1 F).