Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH2:11][CH:12]3[CH2:17][O:16][CH2:15][CH2:14][NH:13]3)[CH2:7][NH:8]2)=[CH:4][CH:3]=1>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH:12]3[CH2:17][O:16][CH2:15][CH2:14][NH:13]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1)NCC2CC1COCCN1
Solvent: C1CCOC1
Product: Fc1ccc2c(CC3COCCN3)c[nH]c2c1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Intermediate 49 (0.726 g, 2.92 mmol) was dissolved in THF (100 mL) and cooled to 0° C. in an ice bath. BH3.Me2S complex (0.61 mL, 6.40 mmol) was added dropwise and the reaction mixture allowed to warm to r.t. The reaction mixture was heated to reflux for 5 h and allowed to cool to r.t. The reaction mixture was quenched with aqueous 2N NaOH (25 mL) and stirred at r.t. for 72 h. The reaction mixture was concentrated in vacuo and dissolved in EtOAc (100 mL), washed with aqueous 2N HCl (2×50 mL) and the combined aqueous fractions basified with solid NaOH pellets (ca 10 g) to raise the pH to pH 12. The aqueous fraction was extracted with EtOAc (3×50 mL) and the combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. The material from the initial EtOAc extraction was combined with the concentrated material and purified by column chromatography (SiO2, 0-25% [MeOH/DCM/NH4OH (50:50:1)]/DCM) to afford 0.493 g as a mixture of 6-fluoro-3-(morpholin-3-ylmethyl)indoline and title compound (1:3). The resulting mixture was dissolved in THF (7.5 mL) followed by the addition of DDQ (0.102 g, 0.452 mmol). The reaction mixture was irradiated in the microwave at 100° C. for 10 minutes. The reaction mixture was diluted with EtOAc (50 mL), washed with aqueous 2N NaOH (20 mL), brine (20 mL), dried (MgSO4), filtered, concentrated in vacuo and purified by column chromatography (SiO2, 0-25% [MeOH/DCM/NH4OH (50:50:1)]/DCM) to give the title compound (0.430 g, 61%) as an amber oil. δH (CDCl3) 8.04 (1H, br. s), 7.52 (1H, dd, J 8.7 and J 5.3 Hz), 7.00-7.09 (2H, m), 6.85-6.95 (1H, m), 3.90 (1H, dd, J 10.9 and J 2.8 Hz), 3.76-3.85 (1H, m), 3.49-3.61 (1H, m), 3.24-3.36 (1H, m), 3.17-3.03 (1H, m), 2.95-2.76 (3H, m), 2.62 (1H, dd, J 14.3 and J 9.0 Hz), 1.78 (1H, br. s). LCMS (ES+) 235.0 (M+H)+, RT 1.85 minutes (Method 2).
Reaction SMILES: N1(C([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:25][C@@H:24]([O:26][CH2:27][CH2:28][CH3:29])[C@H:23]([NH:30][C:31](=[O:46])[CH2:32][NH:33][C:34](=[O:45])[C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=5)[CH2:22]4)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=O)CCOCC1.N1(C(C2C=CC(N3CCC(=O)CC3)=CC=2)=O)CCOC[CH2:48]1>>[CH3:48][C:10]1[CH:11]=[C:12]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:25][C@@H:24]([O:26][CH2:27][CH2:28][CH3:29])[C@H:23]([NH:30][C:31](=[O:46])[CH2:32][NH:33][C:34](=[O:45])[C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:43])([F:44])[F:42])[CH:36]=4)[CH2:22]3)[CH2:17][CH2:16]2)[CH:13]=[CH:14][CH:9]=1
Reactant: O=C1CCN(c2ccc(C(=O)N3CCOCC3)cc2)CC1
Reactant: CCCO[C@@H]1CN(C2CCN(c3ccc(C(=O)N4CCOCC4)cc3)CC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Product: CCCO[C@@H]1CN(C2CCN(c3cccc(C)c3)CC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1

Procedure:
The title compound was synthesized in similar fashion to rel-N-{2-[((3R,4R)-1-{1-[4-(morpholin-4-ylcarbonyl)phenyl]piperidin-4-yl}-4-propoxypyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide substituting 1-(3-methylphenyl)piperidin-4-one for 1-[4-(morpholin-4-ylcarbonyl)phenyl]piperidin-4-one and was isolated as a white solid. 1H-NMR (CDCl3) δ: 0.84 (m, J=7.6 Hz, 3H), 1.42-1.70 (m, 3H), 1.87-1.96 (m, 3H), 2.23 (s, 3H), 2.30-2.35 (m, 2H), 2.62-2.82 (m, 4H), 3.29-3.41 (m, 2H), 3.50-3.60 (m, 3H), 3.70-3.74 (m, 1H), 4.07 (d, J=4.8 Hz, 2H), 4.26-4.30 (m, 1H), 6.58-6.67 (m, 4H), 7.04-7.09 (m, 2H), 7.49 (t, J=7.9 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.95 (d, J=7.5 Hz, 1H), 8.04 (s, 1H). MS m/z: 547 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:32][C:33]1([CH3:41])[O:37][C@@H:36]([CH2:38][CH2:39][NH2:40])[CH2:35][O:34]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:32][C:33]1([CH3:41])[O:37][C@@H:36]([CH2:38][CH2:39][NH:40][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:30])[CH2:35][O:34]1
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)c(F)c1
Yield: 63.6 %

Procedure:
A mixture rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (125 mg, 0.267 mmol), 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.2 mg, 1.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 114.1 mg, 0.3 mmol) and iPr2NEt (0.3 mL, 3.22 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide (101 mg, 63.5%) as an off-white powder. HRMS (ES+) m/z Calcd for C30H35Cl2N3O3S+H [(M+H)+]: 594.2097. found: 594.2096.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20].[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:19]([C:18]3[C:17]([Cl:16])=[N:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(F)c1)c1ccc[nH]1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: O=C(Nc1cccc(F)c1)c1ccc(C(=O)c2cccnc2Cl)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.3 %

Procedure:
To a solution of 1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide (1.56 g, 7.6 mmol) and 2-chloronicotinoyl chloride (1.925 g, 10.9 mmol) in benzene (15 mL) at 0° C. was added dropwise a solution of tin (IV) chloride (3.5 g) in dry benzene (5 mL). The mixture was allowed to warm up slowly to room temperature and stirred for 4 hours. The reaction was added with NaOH (100 mL) and extracted with ethyl acetate, washed with brine (2×), dried and concentrated. The residue was purified on a silica gel column to give 477 mg (18%) of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.[CH:10]1(B(O)O)[CH2:12][CH2:11]1.C([O-])([O-])=O.[Cs+].[Cs+].C1COCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[Cl:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH:10]2[CH2:12][CH2:11]2)[C:7]=1[NH2:8]
Reactant: OB(O)C1CC1
Reactant: Nc1c(Cl)ccnc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1c(Cl)ccnc1C1CC1
Temperature: 50 °C

Procedure:
Following a modified synthetic procedure reported in J. Org. Chem. 2003, 68, 5534 a mixture of 2-bromo-4-chloropyridin-3-amine (prepared as described in US2002/0119982) (1.0 eq.), cyclopropylboronic acid (2.0 eq.), Cs2CO3 (3.0 eq.) and PdCl2(dppf)-CH2Cl2 adduct (0.1 eq.) in 10:1 solution THF:H2O (0.14 M) was put in a 10-mL glass vial equipped with a small magnetic stirring bar. The reaction vessel was fitted with a rubber septum, was evacuated and back-filled with argon and sealed with an aluminum/Teflon crimp top. The reaction mixture was then irradiated for 1 h at 120° C., using an irradiation power of 100 W. After completion of the reaction, the vial was cooled to 50° C. with air jet cooling before it was opened. The reaction mixture was diluted with EtOAc and filtered on a pad of Solca Floc®200FCC. The crude product was purified by flash chromatography eluting with 5-100% EtOAc/petroleum ether affording the titled compound as yellow oil. 1H-NMR (400 MHz, DMSO-d6, 300K) δ 7.59 (1H, d, J=5.1 Hz), 7.04 (1H, d, J=5.1 Hz), 5.42 (2H, br. s), 2.24-2.15 (1H, m), 0.92-0.82 (4H, m). MS (ES) C8H9ClN2 requires: 168, found: 169, 171 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].Cl[CH2:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>CN(C)C=O>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[CH2:15][O:13][C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([CH3:3])[CH:5]=1
Reactant: ClCc1nc2ccccc2s1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2nc3ccccc3s2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
23.0 g of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 80.0 g of 3-methyl-4-nitrophenol in 700 ml of dimethylformamide cooled in an ice-water bath. The resulting mixture was stirred at the same temperature for 20 minutes, at the end of which time a solution of 95.9 g of 2-chloromethylbenzothiazole in 50 ml of dimethylformamide was added to the reaction mixture. The temperature of the resulting mixture was elevated to 80° C. and the mixture was then stirred for 2 hours. At the end of this time, the reaction mixture was poured into ice-water and the precipitated crystalline solid was washed with water. The crude crystalline solid thus obtained was recrystallised from toluene to give 98.8 g (yield 63%) of the title compound as a solid having a melting point of 145° to 147° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.[Br:12]Br>O1CCOCC1>[Br:12][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][C:4]=1[CH3:11])=[O:10]
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: BrBr
Solvent: C1COCCO1
Product: Cc1cc(O)ccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a stirred solution of 4′-hydroxy-2′-methylacetophenone (4.5 g, 30.0 mmol) in dioxane (7 ml) was added a solution of bromine (4.87 g, 30.5 mmol) in dioxane (28 ml) dropwise at room temperature. After addition, the mixture was stirred at room temperature for 30 minutes. The volatile was evaporated in vacuo, and the residue was used for next reaction without further purification. (5.57 g, 81% yield).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:11]3[CH2:15][CH2:16][CH2:17][C@H:18](O)[C:10]=3[CH:9]=[CH:8][C:7]=2[CH2:6]1)=[O:4].C1C=CC(P([N:36]=[N+:37]=[N-:38])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>C1(C)C=CC=CC=1>[N:36]([C@H:18]1[C:10]2[CH:9]=[CH:8][C:7]3[CH2:6][N:5]([C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])[CH2:14][CH2:13][C:12]=3[C:11]=2[CH2:15][CH2:16][CH2:17]1)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(N1CCc2c(ccc3c2CCC[C@@H]3O)C1)C(F)(F)F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=N[C@@H]1CCCc2c1ccc1c2CCN(C(=O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2,2,2-trifluoro-1-(7-hydroxy-1,2,7,8,9,10-hexahydrobenzo[f]isoquinolin-3(4H)-yl)ethanone (299 mg, 1 mmol) in 3 mL of toluene at −10° C. was added DPPA (0.26 mL, 1.2 mmol). To this stirred solution was then added DBU (0.18 mL, 1.2 mmol) dropwise while keeping the temperature below 0° C. After stirring at room temperature for 3 h, 0.5 mL of 10% HCl was added and the resulting solution was evaporated to dryness and directly submitted to flash chomatography (SiO2, hexane/EtOAc=100:10 to 100:15 to 100:18) to afford (R)-1-(7-azido-1,2,7,8,9,10-hexahydrobenzo[f]-isoquinolin-3(4H)-yl)-2,2,2-trifluoroethanone as a colorless oil which was directly used in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][C:32]([CH:38]([C:40]2[CH:45]=[CH:44][C:43]([S:46][CH3:47])=[CH:42][CH:41]=2)[CH3:39])=[CH:31][N:30]=1.C([O-])(=O)C.[K+]>O1CCOCC1>[F:28][C:29]1[C:34]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:3]=2)=[CH:33][C:32]([CH:38]([C:40]2[CH:41]=[CH:42][C:43]([S:46][CH3:47])=[CH:44][CH:45]=2)[CH3:39])=[CH:31][N:30]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Reactant: CSc1ccc(C(C)c2cnc(F)c(B(O)O)c2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)c4ccc(SC)cc4)cnc3F)n2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
4-Chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.4126 g, 3.6704 mmol), 2-fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridin-3-ylboronic acid (1.2342 g, 4.2390 mmol), Am-Phos (140.4 mg, 0.1983 mmol), and potassium acetate (1.531 g, 15.60 mmol) were suspended in 1,4-dioxane (20 mL) and water (4 mL), and nitrogen was bubbled through the suspension for 15 s. Then, the flask was fitted with a reflux condenser and placed in a preheated oil bath (100° C.), and stirred under nitrogen overnight. Then, the reaction was cooled to room temperature, diluted with water (40 mL), and extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered through a Celite® (diatomaceous earth) pad, concentrated, and purified on a silica gel filter (600 mL fritted filter with about 3 inches of silica gel; DCM to 100:1 DCM/MeOH to 75:1 DCM/MeOH). The fractions with product were collected, concentrated, and dried under high vacuum, first at room temperature, and then in a water bath (about 50° C.) to give 4-(2-fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.797 g). 1H NMR (CDCl3, 400 MHz) δ 8.34 (dd, J=8.90 Hz, 2.45 Hz, 1H), 8.15 (d, J=1.96 Hz, 1H), 7.24-7.17 (m, 6H), 7.16-7.11 (m, 2H), 6.86 (dd, J=10.17 Hz, 8.61 Hz, 4H), 4.82 (s, 2H), 4.78 (s, 2H), 4.20 (q, J=7.30 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 2.53 (s, 3H), 2.45 (s, 3H), 1.67 (d, J=7.24 Hz, 3H). m/z (ESI, pos. ion) 596 (M+H)+.
Reaction SMILES: CN(C)C(=O)C[NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl[CH2:47][C:48]([NH:50][CH:51]([CH3:53])[CH3:52])=[O:49]>>[CH:51]([NH:50][C:48](=[O:49])[CH2:47][NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)([CH3:53])[CH3:52]
Reactant: CC(C)NC(=O)CCl
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCC(=O)NC(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-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)benzoic acid using 2-chloro-N-isopropylacetamide as the alkylating reagent in Step 1. The product was isolated as a white solid (50 mg, 81%). LCMS: m/e 629.46 (M+H)+, 2.60 min (method 10). 1H NMR (400 MHz, Acetic acid d4) δ ppm 7.99 (d, J=8.53 Hz, 2H), 7.26 (d, J=8.53 Hz, 2H), 5.34 (d, J=4.77 Hz, 1H), 4.84 (s, 1H), 4.72 (s, 1H), 4.15 (d, J=15.31 Hz, 1H), 4.06 (dt, J=13.11, 6.62 Hz, 1H), 3.85 (d, J=15.31 Hz, 1H), 3.07-2.77 (m, 1H), 2.41-1.26 (m, 22H), 1.74 (s, 3H), 1.24 (s, 3H), 1.16 (d, J=6.53 Hz, 6H), 1.10 (s, 3H), 1.06 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: O[C:2]1[C:7]([Br:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:13])=O.[OH-].[Na+]>>[Cl:13][C:2]1[C:7]([Br:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1
Reactant: CCc1ncnc(O)c1Br
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1ncnc(Cl)c1Br
Temperature: 70 °C

Procedure:
29.7 g (0.146 mol) of 4-hydroxy-5-bromo-6-ethylpyrimidine are introduced slowly into 27.3 g (0.178 mol) of phosphorus oxychloride. The suspension dissolves on heating to 70° C.; the reaction is slightly exothermic. The temperature is kept at 70° C. for 11/2 hours and, after cooling, the solution is poured onto ice-water and neutralised carefully to pH 5-7, at 0° C., with 30% sodium hydroxide solution. Extraction with ethyl acetate yields, after removal of the solvent, 30.4 g of crude product. Distillation yields 23.9 g (73.9% of the theoretical yield) of pure substance having a boiling point of 112°-114° C./24 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16](C#N)[CH:15]=2)[CH:5]=[C:6](F)[CH:7]=1.BrC1C=C(C(OCC)=O)OC=1C1C=CC=C([Cl:39])C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:39])[CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(Br)c(-c2cccc(Cl)c2)o1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2cccc(C#N)c2)o1
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(-c2cccc(Cl)c2)o1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 11A starting with the compound from Example 5A. Extraction is carried out with dichloromethane and purification is by preparative HPLC (RP18 column; eluent: acetonitrile/water gradient). 452 mg (34% of theory) of the title compound are obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[PH2]([O-])=O.[Na+].O1[CH2:16][CH2:15][CH2:14][CH2:13]1>O.[Pd]>[C:13]1([C:14]2[CH:13]=[CH:16][CH:15]=[CH:16][CH:15]=2)[CH:14]=[CH:13][CH:16]=[CH:15][CH:14]=1
Reactant: C1CCOC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: O=[PH2][O-]
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 50 °C

Procedure:
4 Grams of polychorinated biphenyl transformer oil (ASKAREL) containing approximately up to 70% PCBs was dissolved in 25 ml of tetrahydrofuran and mixed with 25 g potassium carbonate dissolved in 50 ml water, and 0.5 g of 5% palladium on carbon. The mixture was stirred and warmed to 50° C. To this mixture, while stirring, was added a solution of 10 g sodium hypophosphite monohydrate in 20 ml water dropwise over a period of one hour. Subsequently, an additional 5 g of sodium hypophosphite monohydrate in 10 ml water was added dropwise over a period of 30 minutes. The catalyst was filtered off, the reaction mixture was mixed with 100 ml diethyl ether, the phases separated, the aqueous phase was extracted with 100 ml diethyl ether in 50 ml portions and the organic phases combined. After drying the organic phase with magnesium sulfate, the organic phase was concentrated to yield 0.85 g of biphenyl. A GC analysis made on both the starting material and the reaction product established that all detectable PCB's had been removed.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH:10]S(O)(=O)=O.N([O-])=O.[Na+]>O>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:10])=[CH:7][N:6]=1)#[N:9]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(N)cn1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(O)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
In a 100 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 5-amino-2-cyano pyridine (1.0 g, 8.38 mmol), conc. H2SO4 (4.2 mL), water (15 mL) and the mixture was cooled to 0° C. A solution of NaNO2 (636 mg, 9.22 mmol) in water (5.7 mL) was added slowly at 0° C. Then the reaction mixture was stirred for 30 min at 0° C. The reaction mixture was poured into a boiling mixture of water (11 mL) and H2SO4 (1 mL) and stirred for 30 min. The mixture was cooled and extracted with EtOAc. The organic layer was washed with water, dried and concentrated to give 2-cyano-5-hydroxy pyridine (900 mg, 89%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[CH:26]1([C:29]2[C:34](OS(C(F)(F)F)(=O)=O)=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:28][CH2:27]1>>[CH:26]1([C:29]2[C:34]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:28][CH2:27]1
Reactant: O=S(=O)(Oc1cccnc1C1CC1)C(F)(F)F
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cccnc4C4CC4)c3n2)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and trifluoro-methanesulfonic acid 2-cyclopropyl-pyridin-3-yl ester (Example B.10) (294 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (220 mg, 46%). MS (ISP) 473.3 [(M+H)+]; mp 202° C.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N1C=CC=CC=1.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C1COCC1.O>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#Cc1nc2ccc(O)cc2s1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc2nc(C#N)sc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.2 %

Procedure:
A solution of 2-cyano-6-hydroxybenzothiazole (2.1 g, 12.5 mmol) in 30 mL of dry THF under inert atmosphere was treated with pyridine (2.0 g, 25 mmol) followed by pivaloyl chloride (1.95 g, 16.2 mmol). This reaction was stirred 15 h at room temperature. The reaction mixture was then diluted with 100 mL of distilled water, and this solution was extracted with ethyl acetate (4×50 mL). The combined organics were washed with aqueous sodium bicarbonate (2×100 mL) and distilled water (1×100 mL), then dried over Na2SO4 and concentrated under reduced pressure to afford 3.0 g of a thick oil. This material was chromatographed on silica gel and 1.8 g of the product was eluted with 10% ethyl acetate/hexanes. 1H NMR (CDCl3): δ 1.39 (s, 9H); 7.34-7.38 (m, 1H); 7.74-7.75 (d, 1H); 8.20-8.23 (d, 1H).