Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])(=O)/[C:2](=[CH:4]/[CH3:5])/[CH3:3].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Cl-].[Li+].[CH:24]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1)([CH3:26])[CH3:25]>O1CCCC1>[CH:24]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[N:28]1[C:1](=[O:7])/[C:2](/[CH3:3])=[CH:4]/[CH3:5])([CH3:26])[CH3:25]
Reactant: C/C=C(\C)C(=O)O
Reactant: CC(C)[C@@H]1COC(=O)N1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C/C=C(\C)C(=O)N1C(=O)OC[C@H]1C(C)C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A cooled (−20° C.) solution of tiglic acid (2.005 g, 20.031 mmol) in anhydrous tetrahydrofuran (50 mL) was sequentially treated with triethylamine (6.1 mL, 44.068 mmol) and dropwise pivaloyl chloride (2.7 mL, 22.034 mmol). After stirring at −20° C. for 30 min, lithium chloride (1.019 g, 24.037 mmol) and (R)-(+)-4-isopropyl-2-oxazolidinone (2.587 g, 20.031 mmol) were added. The reaction mixture was allowed to slowly warm to room temperature, stirred for 3 days and was then quenched with saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (3.307 g, 78%) as a colourless solid. 1H NMR (300 MHz, CDCl3): δ 0.92 (d, J=6.9 Hz, 3H), 0.94 (d, J=7.1 Hz, 3H), 1.83 (d, J=6.9 Hz, 3H), 1.93 (s, 3H), 2.38 (d of heptet, J=6.9, 4.2 Hz, 1H), 4.19 (dd, J=8.9, 4.6 Hz, 1H), 4.33 (app t, J=8.9 Hz, 1H), 4.49-4.58 (m, 1H), 6.23 (q, J=7.1 Hz, 1H).
Reaction SMILES: BrC1C=CC(O)=C([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.C([C:40]1[CH:41]=[CH:42][C:43]2[O:48][CH2:47][C:46](=[O:49])[NH:45][C:44]=2[CH:50]=1)(=O)C.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:40]2[CH:41]=[CH:42][C:43]4[O:48][CH2:47][C:46](=[O:49])[NH:45][C:44]=4[CH:50]=2)[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1COc2ccc(-c3ccc4cc(-c5nc6cc(C(=O)O)ccc6n5C5CCCCC5)ccc4n3)cc2N1
Yield: 8 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 6-acetyl-4H-benzo[1,4]oxazin-3-one (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (11 mg, 8% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:16]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:17]=[CH2:18]>>[CH:7]1([NH:6][CH2:5][C:4]2[CH:3]=[C:2](/[CH:18]=[CH:17]/[CH2:16][NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:15]=[CH:14][CH:13]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C=CCNC(=O)C(F)(F)F
Reactant: Brc1cccc(CNC2CCCCC2)c1
Product: O=C(NC/C=C/c1cccc(CNC2CCCCC2)c1)C(F)(F)F

Procedure:
Heck coupling of N-(3-bromobenzyl)cyclohexanamine and N-allyl-2,2,2-trifluoroacetamide following the method described in Example 118 gave (E)-N-(3-(3-((cyclohexylamino)methyl)phenyl)allyl)-2,2,2-trifluoroacetamide as a colorless oil. Yield (0.20 g, 22%): 1H NMR (400 MHz, CD3OD) δ 7.55 (s, 1H), 7.48-7.50 (m, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.35-7.37 (m, 1H), 6.61 (d, J=16.0 Hz, 1H), 6.32 (dt, J=16.0, 6.4 Hz, 1H), 4.19 (s, 2H), 4.05 (d, J=6.4 Hz, 2H), 3.07-3.16 (m, 1H), 2.14-2.22 (m, 2H), 1.66-1.82 (m, 2H), 1.68-1.76 (m, 1H), 1.16-1.50 (m, 5H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:28])[C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH:6]=1)([CH3:3])[CH3:2].Br[C:30]1[N:31]=[C:32]([N:40]2[CH2:45][CH2:44][N:43]3[C:46]([C:49]([F:52])([F:51])[F:50])=[N:47][N:48]=[C:42]3[CH2:41]2)[N:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH2:39])[C:34]=12.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1>[NH2:39][C:35]1[C:34]2[N:33]([C:32]([N:40]3[CH2:45][CH2:44][N:43]4[C:46]([C:49]([F:52])([F:51])[F:50])=[N:47][N:48]=[C:42]4[CH2:41]3)=[N:31][C:30]=2[C:16]2[CH:15]=[CH:14][C:13]([C:12]([NH:11][C:7]3[CH:6]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:10]=[CH:9][N:8]=3)=[O:28])=[CH:18][CH:17]=2)[CH:38]=[CH:37][N:36]=1
Reactant: Nc1nccn2c(N3CCn4c(nnc4C(F)(F)F)C3)nc(Br)c12
Reactant: CC(C)Oc1ccnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: C1COCCO1
Product: CC(C)Oc1ccnc(NC(=O)c2ccc(-c3nc(N4CCn5c(nnc5C(F)(F)F)C4)n4ccnc(N)c34)cc2)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 18.7 %

Procedure:
A seal 4 ml vial containing N-(4-isopropoxypyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, (31.3 mg, 0.082 mmol), 1-bromo-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)imidazo[1,5-a]pyrazin-8-amine, (30 mg, 0.074 mmol), and 2nd Generation Xphos Precatalyst (11.71 mg, 0.015 mmol) was treated with Dioxane (372 μl) via a syringe and needle. The resulting suspension was then degassed with house vacuum and back filled with N2. Potassium phosphate tribasic (112 μl, 0.223 mmol) was then added via a syringe and needle and the resulting cream suspension stirred at 60° C. for 5 h. Purification on the Mass Directed HPLC (method: 5 to 35% MeCN/Water w/0.05% TFA on a 30 mm×100 mm, 5 m Waters SunFire RP C-18 Column) afforded 8 mg of the Title compound as a yellow solid/LC-MS (M+1) 579.39.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[O:17]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH2:19][CH:18]1[C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28]>C(O)CCC>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:2]([NH2:1])=[N:3][C:4]([N:32]3[CH2:33][CH2:34][N:29]([C:27]([CH:18]4[O:17][C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[O:20][CH2:19]4)=[O:28])[CH2:30][CH2:31]3)=[N:5][C:6]2=[CH:7][C:8]=1[O:14][CH3:15]
Reactant: O=C(C1COc2ccccc2O1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(C(=O)C4COc5ccccc5O4)CC3)nc(N)c2cc1OC
Temperature: 75 °C
Yield: 80.6 %

Procedure:
4-amino-2-chloro-6,7-dimethoxyquinazoline (3.2 g, 13.35 mmol) and compound 1 (3.4 g, 13.75 mmol) prepared from Example 3 were dissolved in 72 mL of n-butanol. The mixture was refluxed under nitrogen for 3.5 hours. After cooling to 75° C., the solid product was obtained by filtration and dried to afford 5.25 g of hydrochloride salt of Doxazosin (10.76 mmol, 81% yield). 1 N NaOH solution was added to the salt. The mixture was heated to help the salt dissolved. After cooling, the mixture was extracted with 150 mL of dichloromethane twice. The organic layer was dried with anhydrous sodium sulfate and concentrated to afford 4.61 g of Doxazosin.
Reaction SMILES: I[C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[CH2:13]([O:20][C:21]1[CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:25][C:26]=1[Cl:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCO.C([O-])(O)=O.[Na+]>C(COC)OC.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>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([C:2]2[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=2)[CH:24]=[CH:25][C:26]=1[Cl:27])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1c[nH]c(=O)c(I)c1
Reactant: CC1(C)OB(c2ccc(Cl)c(OCc3ccccc3)c2)OC1(C)C
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COC(=O)c1c[nH]c(=O)c(-c2ccc(Cl)c(OCc3ccccc3)c2)c1
Temperature: 90 °C

Procedure:
Stir a solution of 4 g (14.35 mmol) of methyl 5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylate and 6.42 g (18.64 mmol) of 2-[3-(benzyloxy)-4-chlorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in a mixture of 160 mL of dimethoxyethane (DME), 80 mL of EtOH and 120 mL of a saturated aqueous solution of NaHCO3 for 15 minutes under argon, then add 662 mg of Pd(PPh3)4 and heat the reaction mixture for 4 h 30 min at 90° C. After concentration under reduced pressure, distribute the residue obtained in a mixture of 200 mL of DCM and 10 mL of water. Extract the aqueous phase again with 100 mL of DCM, combine the organic phases, dry over MgSO4, filter and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a DCM/methanol gradient from 0 to 2% of methanol. After concentration under reduced pressure, solidify the residue in a 5/95 methanol/ether mixture, then filter and wash with ether. We thus obtain 1.99 g of methyl 5-[3-(benzyloxy)-4-chlorophenyl]-6-oxo-1,6-dihydropyridine-3-carboxylate in the form of a beige solid.
Reaction SMILES: C1(C#CC2CC3(CCNCC3)ON=2)C=CC=CC=1.[F:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][C:28]2[CH2:42][C:31]3([CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)[O:30][N:29]=2)[CH:23]=[CH:24][CH:25]=1>C(Cl)(Cl)Cl>[F:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][C:28]2[CH2:42][C:31]3([CH2:34][NH:33][CH2:32]3)[O:30][N:29]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CC(C#Cc3cccc(F)c3)=NO2)C1
Agent: C(#Cc1ccccc1)C1=NOC2(CCNCC2)C1
Solvent: ClC(Cl)Cl
Product: Fc1cccc(C#CC2=NOC3(CNC3)C2)c1
Yield: 33.4 %

Procedure:
The title compound was synthesized following the method reported for Compound 1c, substituting Compound 1b with Compound 40a and running the reaction in chloroform. The crude brownish oily residue was used without further purification in the next reaction step. Yield: 33.4%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:11]1.[C-:27]#[N:28].[Na+].O>CS(C)=O>[C:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:11]1)#[N:28]
Reactant: [C-]#N
Reactant: BrCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
2-(8-Bromooctyl)-4,5-diphenyltriazole (7 g) in dimethylsulphoxide (220 ml) was added to a suspension of sodium cyanide (1 g) in dimethylsulphoxide (60 ml) over 15 minutes. The reaction mixture was stirred at 24° C. for 1 hour and at 50° C. for 2 hours. The cooled reaction mixture was poured into water (600 ml), extracted with diethyl ether (4×200 ml). The extracts were combined, washed with water (100 ml), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Column chromatography on silica gel eluted with a hexane:ethyl acetate gradient gave 2-(8-cyanooctyl)-4,5-diphenyl-triazole (5.6 g, 92%) as an oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]2[N:38]=[CH:37][C:36]([NH:39][C:40]([C:42]3[CH:43]=[N:44][N:45]([C:48]4[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][N:49]=4)[C:46]=3[CH3:47])=[O:41])=[CH:35][C:34]=2[CH3:58])[CH2:29][CH2:28]1)(C(C)(C)C)(C)C>O1CCCC1>[OH:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]2[N:38]=[CH:37][C:36]([NH:39][C:40]([C:42]3[CH:43]=[N:44][N:45]([C:48]4[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][N:49]=4)[C:46]=3[CH3:47])=[O:41])=[CH:35][C:34]=2[CH3:58])[CH2:29][CH2:28]1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1[C@H]1CC[C@H](O)CC1
Temperature: 85 °C
Reaction time: 6 h

Procedure:
1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (0.2 ml) was added to trans-N-[6-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-methylpyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (41 mg) and stirred at 85° C. for six hours. After the reaction, the solvent was evaporated and the resulting residue was purified with a silica gel column chromatography (chloroform/methanol). Ethanol was added to the purified product, the precipitated solid was washed with water and dried at 60° C. in vacuo to give the titled compound (29 mg) as a white solid.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:15]([CH3:17])=[CH2:16])[CH:14]=1)[C:10]#[N:11])(=[O:6])=[O:5])([CH3:3])[CH3:2].C(CC(N)=O)(C)=C>>[CH:15]([C:13]1[CH:12]=[C:9]([CH2:10][NH2:11])[CH:8]=[C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[CH:14]=1)([CH3:17])[CH3:16]
Reactant: C=C(C)c1cc(C#N)cc(S(=O)(=O)C(C)C)c1
Agent: C=C(C)CC(N)=O
Product: CC(C)c1cc(CN)cc(S(=O)(=O)C(C)C)c1

Procedure:
(3-isopropyl-5-(isopropylsulfonyl)phenyl)methanamine was synthesized from 3-(isopropylsulfonyl)-5-(prop-1-en-2-yl)benzonitrile following the general procedure as described above for the isopropenyl acetamide.
Reaction SMILES: Cl.Cl.[NH:3]1[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][CH:5]=[N:4]1.CCN(C(C)C)C(C)C.C(O)(=O)C.[CH2:27]([N:29]1[C:41]2[CH:40]=[CH:39][C:38]([CH:42]=O)=[CH:37][C:36]=2[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]1=2)[CH3:28].[BH3-]C#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.ClCCl.CO>[NH:3]1[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([CH2:42][C:38]3[CH:39]=[CH:40][C:41]4[N:29]([CH2:27][CH3:28])[C:30]5[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=5[C:36]=4[CH:37]=3)[CH2:9]2)=[CH:6][CH:5]=[N:4]1
Reactant: c1cc(C2CCCNC2)[nH]n1
Reactant: CCn1c2c(c3cc(C=O)ccc31)CCCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(=O)O
Product: CCn1c2c(c3cc(CN4CCCC(c5ccn[nH]5)C4)ccc31)CCCC2
Temperature: 40 °C
Yield: 31.3 %

Procedure:
A 250-mL round-bottomed flask was charged a solution of 3-(1H-pyrazol-5-yl)piperidine dihydrochloride (2.9 g, 13.00 mmol, 1.50 equiv) in ethanol (150 mL) and DIPEA (4.55 g, 35.23 mmol, 4.00 equiv), acetic acid (3.17 g, 52.83 mmol, 6.00 equiv), 9-ethyl-6,7,8,9-tetrahydro-5H-carbazole-3-carbaldehyde (2 g, 8.81 mmol, 1.00 equiv) and NaBH3CN (1.665 g, 26.43 mmol, 3.00 equiv). The resulting mixture was heated to 40° C. in an oil bath for 16 hours. The reaction progress was monitored by TLC (DCM: MeOH=10:1). Upon completion, the mixture was diluted with dichloromethane (200 mL). The pH was adjusted to 9 with aqueous sodium bicarbonate. The mixture was then extracted with dichloromethane (3×100 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (10/1) affording 3-((3-(1H-pyrazol-5-yl)piperidin-1-yl)methyl)-9-ethyl-6,7,8,9-tetrahydro-5H-carbazole as white solid (1 g, 30%). LCMS: [M+H]+: 363. 1H NMR (CDCl3, 300 MHz) δ 7.45 (d, 1H), 7.43 (s, 1H), 7.26 (d, 1H), 7.19 (d, 1H), 6.06 (d, 1H), 4.05 (m, 2H), 3.92 (m, 2H), 3.36 (br, 1H), 2.73 (m, 4H), 2.65 (br, 2H), 2.11 (s, 2H), 1.86 (m, 5H), 1.75 (br, 1H), 1.55 (m, 1H), 1.47 (m, 1H), 1.31 (t, 3H).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:19])/[CH2:17]O)=[CH:11][CH:10]=2)[CH:3]=1.S(Cl)([Cl:22])=O>C(Cl)Cl>[ClH:22].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:19])/[CH2:17][Cl:1])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: C/C(=C\c1ccc(Oc2cccnc2)cc1)CO
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: C/C(=C\c1ccc(Oc2cccnc2)cc1)CCl

Procedure:
In 5 ml of methylene chloride was suspended 350 mg of (E)-3-[4-(pyridin-3-yloxy)phenyl]-2-methylallyl alcohol hydrochloride and to the suspension was added 0.18 ml of thionyl chloride with ice-cooling, after which the resulting mixture was subjected to reaction under reflux for 30 minutes. The solvent and the excessive thionyl chloride were removed by distillation under reduced pressure to obtain oily (E)-3-[4-(pyridin-3-yloxy)phenyl]-2-methylallyl chloride hydrochloride. This was dissolved in 2 ml of methylene chloride.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:25])C=1>ClCCl>[C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[C:8]1[CH:13]=[CH:12][N+:11]([O-:25])=[C:10]([CH3:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)O[SiH2]C(C)(C)C)ccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C(C)(C)O[SiH2]C(C)(C)C)cc[n+]1[O-]
Yield: 92.3 %

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-2-methyl-pyridine (11.47 g, 0.248.4 mmol) was stirred with 57-80% m-CPBA (25.8 g) in dichloromethane (100 ml) in a water bath for 24 hr. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (3:1)) to afford 11.3 g (93%) of 4-(tert-butyl-dimethyl-silanyloxymethyl)-2-methyl-pyridine 1-oxide as a white solid. 1H NMR (200 MHz, CDCl3) δ 0.11 (6H, s), 0.94 (9H, s), (3H, s), 2.52 (3H, s), 4.67 (2H, s), 6.97 (1H, d, J=6.7 Hz), 7.08 (1H, s), 8.10 (1H, d, J=6.7 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:19]=1)=[O:13].CCN(CC)CC.[NH:39]1[CH2:43][CH2:42][CH:41]([C:44](O)=[O:45])[CH2:40]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:44]([CH:41]3[CH2:42][CH2:43][NH:39][CH2:40]3)=[O:45])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: O=C(O)C1CCNC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CCNC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
N-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was dissolved in DMSO, to it Et3N (3 equiv.) and pyrrolidine-3-carboxylic acid (2 equiv.) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equiv.) was added to it and stirring was continued overnight. After completion of the reaction, water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.Br[CH2:28][CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>COCCOC>[CH3:10][O:9][C:3](=[O:8])[CH:4]([CH2:28][CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:5](=[O:6])[CH3:7]
Reactant: COC(=O)CC(C)=O
Reactant: BrCCOCc1ccccc1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C(CCOCc1ccccc1)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (2.0 g, 60% in mineral oil) in DME (50 ml) at 0° C. is added dropwise a solution of methyl acetoacetate (5.8 g, 50 mmol) in DME (10 mL). The solution is stirred at room temperature for 30 minutes. Nal (7.5 g) is added in one portion and then benzyl bromoethyl ether (10.7 5 g, 50 mmol). The mixture is stirred at 70–80° C. overnight. After the formed solid is removed, the solvent is removed. The residue is purified by column with 4:1 of hexane to ethyl acetate to a colorless oil (159).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=1.[F:14][C:15]([F:20])([F:19])[C@H:16]([OH:18])[CH3:17]>>[CH:8]1([C:7]2[C:2]([O:18][C@H:16]([CH3:17])[C:15]([F:20])([F:19])[F:14])=[CH:3][C:4]([C:11]([OH:13])=[O:12])=[N:5][CH:6]=2)[CH2:10][CH2:9]1
Reactant: C[C@@H](O)C(F)(F)F
Reactant: O=C(O)c1cc(Cl)c(C2CC2)cn1
Product: C[C@@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 68a, using 4-Chloro-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48b) and (R)-1,1,1-trifluoropropan-2-ol (CAN 17628-73-8) as starting materials and isolated (231 mg, 41%) as light brown solid; MS (ESI, m/z): 276.5 (M+H+).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:42]=[CH:43][CH:44]=1)[CH2:7][O:8][CH2:9][C:10]1[CH:41]=[C:13]2[N:14]=[C:15]([CH3:40])[C:16]([C@H:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:17]([N:18]3[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH:27]=[CH2:28])([CH3:24])[CH2:20][CH2:19]3)[N:12]2[N:11]=1)C=C.[BH4-].[Na+]>C(Cl)Cl.[NH4+].[Cl-]>[C:36]([O:35][C@@H:29]([C:16]1[C:15]([CH3:40])=[N:14][C:13]2=[CH:41][C:10]3=[N:11][N:12]2[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:24])([O:25][CH2:26][CH2:27][CH2:28][CH2:1][C:4]2[CH:5]=[C:6]([CH2:7][O:8][CH2:9]3)[CH:42]=[CH:43][CH:44]=2)[CH2:20][CH2:19]1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:38])([CH3:39])[CH3:37]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4cccc(CC=C)c4)nn23)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCc1cccc(c1)COC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
A mixture of (S)-ethyl 2-(2-(((3-allylbenzyl)oxy)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.083 mmol) and Grubb's II catalyst (70.2 mg, 0.083 mmol) in DCM (50 mL) was refluxed for 2 h. It was then concentrated. The residue was dissolved in MeOH (2 mL). Sodium borohydride (3.13 mg, 0.083 mmol) was added and the reaction was stirred at rt for 2 h. It was then diluted with NH4Cl, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 20% EtOAc/hexane to isolate ethyl (2S)-2-(tert-butoxy)-2-{4,23-dimethyl-11,22-dioxa-1,5,7,8-tetraazapentacyclo[21.2.2.16,9.113,17.02,7]nonacosa-2,4,6(29),8,13(28),14,16-heptaen-3-yl}acetate (20 mg, 0.035 mmol, 41.8% yield) as a white solid. LCMS (M+1)=579.7.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]([F:9])([F:8])[F:7])[CH3:3].C(N(CC)CC)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Cl:17][CH2:18][C:19]([N:4]([CH2:2][CH3:3])[CH2:5][C:6]([F:9])([F:8])[F:7])=[O:20]
Reactant: O=C(Cl)CCl
Reactant: CCNCC(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC(F)(F)F)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a cooled (0° C.) solution of N-ethyl-2,2,2-trifluoroethanamine hydrochloride, (0.45 g, 2.8 mmol) in DCM (10 mL) was added triethylamine (1.6 mL, 11.2 mmol) followed by 2-chloroacetyl chloride (0.22 mL, 2.8 mmol). The reaction was warmed to RT and stirred for 2 h. The reaction mixture was concentrated, redissolved in EtOAc (20 mL) and washed with brine (25 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to yield 0.6 g of crude product which was further purified by flash column chromatography using 1:1 EtOAc:hexanes as the eluent. 0.5 g of 2-chloro-N-ethyl-N-(2,2,2-trifluoroethyl)acetamide, (yield: 88%) was isolated.