Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][N:35]3[C:43](=[O:44])[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]3=[O:45])=[CH:28][CH:27]=2)O1.C(=O)(O)[O-].[Na+].O1CCOCC1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:15][C:14]([F:17])([F:16])[O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[N:6][C:2]([C:26]3[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][CH2:34][N:35]4[C:36](=[O:45])[C:37]5[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:43]4=[O:44])=[CH:30][CH:31]=3)=[N:3]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Reactant: CC1(C)OB(c2ccc(CCCN3C(=O)c4ccccc4C3=O)cc2)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: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1CCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 140 °C

Procedure:
To 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1) (0.50 g, 1.6 mmol), 2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)isoindoline-1,3-dione (C58) (0.64 g, 1.6 mmol), sodium bicarbonate (0.27 g, 3.3 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.19 g, 0.16 mmol) in a 10-20 mL microwave vial equipped with a stir bar was added dioxane (12 mL) and water (4.1 mL). The reaction was capped and heated at 140° C. for 30 minutes in a Biotage Initiator® microwave reactor with external IR-sensor temperature monitoring from the side of the vessel. The mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography using 0-30% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent provided a solid which was dried under house vacuum overnight. The title compound was obtained as a white solid (0.42 g, 53%): mp 145-148° C.; 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J=0.8 Hz, 1H), 8.08 (d, J=8.1 Hz, 2H), 7.84 (ddd, J=5.5, 3.0, 0.8 Hz, 2H), 7.82-7.77 (m, 2H), 7.69 (ddd, J=5.5, 3.0, 0.8 Hz, 2H), 7.38 (dt, J=9.0, 1.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 3.78 (t, J=7.2 Hz, 2H), 2.79-2.71 (m, 2H), 2.08 (p, J=7.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 493 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][CH:5]([C:7]([OH:9])=O)[CH2:4]1.[CH3:10][O:11][NH:12][CH3:13].Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O.ClCCl>[CH3:10][O:11][N:12]([CH3:13])[C:7]([CH:5]1[CH2:4][CH:3]([O:2][CH3:1])[CH2:6]1)=[O:9]
Reactant: COC1CC(C(=O)O)C1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC1CC(C(=O)N(C)OC)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dichloromethane (20 mL) was added to the vial containing 3-methoxycyclobutanecarboxylic acid (1:1 isomers, 1500 mg, 11.53 mmol), N-methoxymethanamine.HCl (1514 mg, 15.53 mmol) and HATU (6570 mg, 17.3 mmol). Hunig's base (8.03 mL, 46.1 mmol) was then added. The mixture was stirred at room temperature overnight. The mixture was diluted with H2O and extracted with EtOAc three times. Insoluble solids were observed in the aqueous layer. The combined organic layers were washed with brined, dried over Na2SO4 and concentrated. The crude was dissolved in EtOAc and loaded to the column and purified by CombiFlash (40 g silica gel, EtOAc/heptane: 0->50%), leading to less polar diastereomer A and slightly more polar diastereomer B. Diastereomer A: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.09-2.25 (m, 2H) 2.43-2.57 (m, 2H) 3.17 (s, 3H) 3.23 (s, 3H) 3.43 (m, 1H) 3.63 (s, 3H) 3.98-4.09 (m, 1H). GCMS: observed 173 for C8H15NO3.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:19]1[C:20]([CH3:36])=[C:21]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:23][CH:24]=1)[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:11]=2)[NH:6][CH:5]=1.O=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C1(C)C=CC=CC=1.Cl.O1CCOCC1>O1CCOCC1.CC1C=CC(C)=CC=1.[Pd]>[CH2:28]([O:27][C:26]([NH:25][C:21]1[C:20]([CH3:36])=[C:19]([C:3]2[C:4]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)[CH:11]=4)[NH:6][C:5]=3[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N:1][CH:2]=2)[CH:24]=[CH:23][CH:22]=1)=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)C=O
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2ccc(N3CCOCC3)cc12
Agent: [Pd]
Agent: Cl
Solvent: Cc1ccc(C)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1ccc(N3CCOCC3)cc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
To a solution of benzyl 3-(2-amino-1-(5-morpholino-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate (0.713 g, 1.471 mmol) and 50% ethyl 2-oxoacetate (0.583 mL, 2.94 mmol)/toluene in 1,4-dioxane (61.3 mL) was added 4 N hydrochloric acid/1,4-dioxane (0.736 mL, 2.94 mmol)/dioxane under nitrogen. After stirring overnight, more 50% ethyl 2-oxoacetate (0.583 mL, 2.94 mmol) was added. After 2 hr, the reaction was heated to 40° C. After another 2 hr, the reaction was cooled to room temperature, concentrated in vacuo, and dissolved in water (50 mL) and EtOAc (50 mL). The mixture was basified with saturated NaHCO3 solution to pH ˜10. The layers were separated and the aqueous layer was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine, dried over MgSO4, and concentrated in vacuo to give crude product used in subsequent step. This was added to 10% Pd/C (0.377 g, 0.354 mmol) in p-xylene (39.4 mL), and the reaction was heated at 125° C. After 9 h, the reaction was cooled to room temperature, filtered through a wad of CELITE®, rinsed with EtOAc, and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with brine (25 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography using an ISCO 40 g column eluting with 0-50% EtOAc/CH2Cl2 to give the desired product (0.1558 g, 0.276 mmol, 23.4% yield) as a light orange foam.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.Cl[C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([N+:16]([O-:18])=[O:17])=[CH:10][N:9]=1.[OH-].[K+].O>CS(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([N+:16]([O-:18])=[O:17])=[CH:10][N:9]=2)[CH:6]=1
Reactant: Clc1c[nH]cn1
Reactant: COc1cc([N+](=O)[O-])cnc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])cnc1-n1cnc(Cl)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 77.4 %

Procedure:
A mixture of 4-chloro-1H-imidazole (2.72 g, 26.5 mmol), 2-chloro-3-methoxy-5-nitropyridine (5.0 g, 26.5 mmol), and KOH flakes 1.488 g, 26.5 mmol) in anhydrous DMSO (25 mL) was heated at 80° C. for 5 h. The reaction mixture was allowed to cool to rt and was poured into 1.0 L of water with vigorous stirring. The mixture was stirred at rt for 16 h. The precipitate was collected by vacuum filtration using a coarse sintered glass funnel The solid was dried under high vacuum for 24 h to provide 2-(4-chloro-1H-imidazol-1-yl)-3-methoxy-5-nitropyridine (5.22 g, 20.50 mmol, 77% yield) as a light brown solid. LC-MS (M+H)+=255.0. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.94 (d, J=2.44 Hz, 1H) 8.51 (d, J=1.83 Hz, 1H) 8.42 (d, J=2.44 Hz, 1H) 8.02 (d, J=1.83 Hz, 1H) 4.12 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH2:23]O)[N:22]=2)[CH2:14][C@@H:13]1[O:30][CH3:31])=[O:10].C1(P([N:46]=[N+:47]=[N-:48])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:46]([CH2:23][C:21]1[N:22]=[C:18]([N:15]2[CH2:16][CH2:17][C@@H:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[C@@H:13]([O:30][CH3:31])[CH2:14]2)[S:19][C:20]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N+:47]=[N-:48]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)nc1CO
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)nc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of ethyl 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate (0.10 g, 0.2 mmol, Example 143) in anhydrous toluene was added diphenylphosphorylazide (0.053 mL, 0.24 mmol). The reaction was cooled to 0 deg and DBU was added slowly. After stirring at 0 deg for 30 min the reaction was warmed to room temperature and stirred overnight. The biphasic reaction mixture was washed with water (×3), 1NHCl (×1), brine (×1), dried with MgSO4 and concentrated (0.048 g). MS (ES) M+H: 516 for C19H23Cl2N7O4S.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][CH3:16])[CH2:12][O:11]2)=[CH:4][CH:3]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.[OH-].[Na+].O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH2:12][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)([OH:11])[C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CCCC(C)(C)C1(CCc2ccc(Cl)cc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCC(C)(C)C(O)(CCc1ccc(Cl)cc1)Cn1cncn1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
A solution of 20.5 g (0.077 mol) of 2-(4-chlorophenylethyl)-2-(1,1-dimethylbutyl)-oxirane, 5.3 g (0.077 mol) of 1,2,4-triazole, 1.0 g (0.025 mol) of sodium hydroxide, 1 ml of water and a spatula tipful of α,α'-azoisoutyronitrile in 50 ml of N-methylpyrrolidone is heated at 120° C. for 5 hours. After this, the solution is cooled to room temperature and concentrated by stripping off the solvent under reduced pressure, the remaining residue is dissolved in acetic acid and washed three times with water, the organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is purified by column chromatography (silica gel; dichloromethane:ethyl acetate=4:1). In this manner 16.0 g (61.9% of theory) of 1-(4-chlorophenyl)-4,4-dimethyl-3-(1,2,4-triazol-1-yl-methyl)-3-heptanol are obtained in the form of a yellow oil.
Reaction SMILES: O=C1NCCN1C1C=CC([C:13]23[CH2:32][CH:17]4[CH2:18][C:19]([NH:21][CH2:22][C:23]([N:25]5[CH2:29][CH2:28][CH2:27][C@H:26]5[C:30]#[N:31])=[O:24])([CH2:20]2)[CH:15]([CH2:16]4)[CH2:14]3)=CC=1.[Si](Cl)(C)(C)C.[CH3:38][OH:39]>>[O:39]=[C:38]1[CH2:17][CH2:18][CH2:19][N:21]1[C:13]12[CH2:32][CH:17]3[CH2:18][C:19]([NH:21][CH2:22][C:23]([N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[C:30]#[N:31])=[O:24])([CH2:20]1)[CH:15]([CH2:16]3)[CH2:14]2
Reactant: CO
Reactant: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccc(N4CCNC4=O)cc1)(C3)C2
Agent: C[Si](C)(C)Cl
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(N1CCCC1=O)(C3)C2
Reaction time: 0.5 h

Procedure:
To a stirred solution of the compound obtained from example 19 (36 mg, 0.1 mmol) in methanol (2 mL) cooled to 0° C. was added TMS-Cl (25 μL, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue was triturated several times with ether to obtain the hydrochloride salt of (2S)-1-{N-[2-(2-oxopyrrolidin-1-yl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as off-white solid (38 mg).
Reaction SMILES: O1C[CH2:4][CH2:3][CH2:2]1.[CH2:6]([C:19]1[NH:23][CH:22]=[C:21]([C:24]([OH:26])=[O:25])[CH:20]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>C(O)CC>[CH2:6]([C:19]1[NH:23][CH:22]=[C:21]([C:24]([O:26][CH2:2][CH2:3][CH3:4])=[O:25])[CH:20]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCc1cc(C(=O)O)c[nH]1
Reactant: C1CCOC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CCCO
Product: CCCCCCCCCCCCCc1cc(C(=O)OCCC)c[nH]1
Temperature: 60 °C
Yield: 73 %

Procedure:
To 25 ml of tetrahydrofuran were added 1.50 g (5.11 mmol) of 5-tridecylpyrrole-3-carboxylic acid and 1.27 g (6.15 mmol) of dicyclohexylcarbodiimide, followed by adding 3.8 ml of n-propyl alcohol and 62 mg of dimethylaminopyridine. Then the mixture was heated at 60° C. for 10 hours under stirring. After cooling, the resulting precipitates were filtered off and washed well with ether. The filtrate and the washing liquid were combined and concentrated. The residue was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/20) to obtain 1.26 g (73% yield) of propyl 5-tridecylpyrrole-3-carboxylate, m.p. 51°-52° C.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][NH:9][CH3:10])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.Br[CH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25].O>C(#N)C>[C:2]([O:6][C:7](=[O:11])[CH2:8][N:9]([CH2:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:23]([C:24]#[N:25])[CH:22]=1)[CH3:10])([CH3:5])([CH3:4])[CH3:3]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: N#Cc1cccc(CBr)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CN(CC(=O)OC(C)(C)C)Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
To a stirred solution of sarcosine tert-butyl ester hydrochloride (8.1 g, 44.9 mmol) and triethylamine (17 mL, 122.4 mmol) in ACN (100 mL) was added 3-(bromomethyl)benzonitrile (8.0 g, 40.8 mmol) portionwise over a period of 10 minutes at 0° C. After being stirred at RT for 3 hours, the reaction mixture was poured into water and extracted with DCM. Then the organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a pale green liquid (9.0 g, 85%). 1H NMR (DMSO-d6, 400 MHz) δ 7.72 (2H, m), 7.64 (1H, m), 7.54 (1H, m), 3.66 (2H, s), 3.18 (2H, s), 2.22 (3H, s), 1.41 (9H, s).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:11]1([C:17]2[CH:21]=[C:20]([NH2:22])[N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(CC#N)(=O)C1C=CC=CC=1.N(C1C=CC=CN=1)N>>[C:11]1([C:17]2[C:21]3[C:4](=[O:6])[C:3]4[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:22][C:20]=3[N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccccc1I
Reactant: Nc1cc(-c2ccccc2)nn1-c1ccccn1
Agent: N#CCC(=O)c1ccccc1
Agent: NNc1ccccn1
Product: O=c1c2ccccc2[nH]c2c1c(-c1ccccc1)nn2-c1ccccn1

Procedure:
Following the procedures described in Reference Example 2-5 and Example 2-12, the title compound was prepared from o-iodobenzoic acid and 3-phenyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine which was previously prepared from benzoylacetonitrile and 2-hydrazinopyridine following the method described in Reference Example 2-72 (58% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].CN(C)C1C=CC=CC=1.[O:22]1CC[CH2:24][CH2:23]1.ClCC(Cl)=O>C(OCC)(=O)C>[NH:1]1[C:23](=[O:22])[CH2:24][O:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11]([C:2]1=2)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: C1CCOC1
Reactant: Nc1c(O)ccc2ccccc12
Agent: O=C(Cl)CCl
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C1COc2ccc3ccccc3c2N1
Reaction time: 1 h

Procedure:
To a mixture of 1-amino-2-naphthol (16.9 g), N,N-dimethylaniline (19.3 g) and tetrahydrofuran (200 ml) is added dropwise chloroacetyl chloride under ice cooling, and the mixture is stirred at the same temperature for one hour. To the reaction mixture is added ethyl acetate, and the ethyl acetate layer is washed, dried and distilled to remove the solvent. The resulting oil is dissolved in acetone (500 ml) and thereto is added potassium carbonate (75 g), and the mixture is refluxed for 2 hours, and acetone is distilled off. To the residue is added water, and the precipitate is separated by filtration, washed, dried and recrystallized from tetrahyrofuran to give 1H-naphtho[2,1-b][1,4]oxazin-2(3H)-one (13.1 g). M.p. 219°-220.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].[C:13]([OH:22])(=O)[CH2:14]/[CH:15]=[CH:16]/[CH2:17][C:18]([OH:20])=O.[CH3:23][CH2:24][OH:25]>CCOC(C)=O>[C:1]([O:5][C:6]([C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:18](=[O:20])[CH2:17]/[CH:16]=[CH:15]/[CH2:14][C:13]([N:8]1[CH2:7][CH2:11][CH2:10][C@@H:23]1[C:24]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:25])=[O:22])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Reactant: O=C(O)C/C=C/CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)C/C=C/CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Yield: 77 %

Procedure:
Using General Procedure A with 1.5 g (8.76 mmol) D-Proline tert-butyl ester and 630 mg (4.37 mmol) trans-3-hexenedioic acid afforded, after flash chromatography (10% EtOH in EtOAc), 1.59 g (77%) of the title compound as a white crystalline solid. MS m/e (%): 568 (M+NH4+, 35), 451 (M+H+, 100), 395 ([M+H—C3H8]+, 32), 339 (M+H—2C3H8]+, 40).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([C:12]([NH:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][OH:17])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32].CN(C=O)C>O>[OH:17][CH2:16][C@H:15]([NH:14][C:12]([C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[C:3]2=[N:10][C:9]=1[CH3:11])=[O:13])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC(C)CCI
Reactant: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(O)cccn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCCC(C)C)cccn12
Reaction time: 0.5 h

Procedure:
100 mg (0.34 mmol) of 8-hydroxy-N-[(2R)-1-hydroxyhexan-2-yl]-2-methylimidazo[1,2-a]-pyridine-3-carboxamide, 246 mg (0.76 mmol) of caesium carbonate and 75 mg (0.38 mmol) of 1-iodo-3-methylbutane were added to 4.9 ml of dry DMF, and the mixture was stirred for 30 min in an oil bath preheated to 60° C. After cooling, about 40 ml of water were added to the reaction mixture and the solution formed was extracted three times with ethyl acetate. The combined organic phases were concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: water/methanol gradient with addition of 0.1% TFA). All product-containing fractions were combined and concentrated. Saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered, concentrated and dried under high vacuum. This gave 82 mg of the target compound (66% of theory, purity 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([OH:11])[CH:5]=1)([O-:3])=[O:2].FC(S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O)(F)F.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([O:11][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-nitro-2-hydroxytoluene (5 g, 33 mmol) in DMF (75 mL) at 0° C. was added 2,2,2-trifluoroethyl trifluoromethylsulfonate (13 g, 62 mmol) and Cs2CO3 (20 g, 62 mmol). The mixture was stirred at 0° C. for 30 min and then at ambient temperature for 2 h. The mixture was diluted with EtOAc (150 mL) and filtered. The filtrate solvents were removed under reduced pressure and the residue was dissolved in EtOAc (200 mL) and washed with saturated aqueous NaHCO3 (2×100 mL) and brine (50 mL). The organic phase was dried (MgSO4), filtered, and the volume was reduced to ~50 mL under reduced pressure, at which point the product had begun to crystallize. The mixture was cooled to -20° C. for 14 h, filtered, and the solids were washed with cold EtOAc. 4-Nitro-2-(2,2,2-trifluoroethoxy)toluene was obtained as a crystalline solid (HPLC retention time=10.0 min (method A)).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][S:14]([C:17]1[N:22]=[C:21]2[N:23]([CH3:33])[N:24]=[C:25]([C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=3)[C:20]2=[CH:19][N:18]=1)(=[O:16])=[O:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]2[C:20]3[C:21](=[N:22][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[N:18][CH:19]=3)[N:23]([CH3:33])[N:24]=2)=[CH:31][CH:30]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Cn1nc(-c2ccc(N)cc2)c2cnc(S(C)(=O)=O)nc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc2)c2cnc(S(C)(=O)=O)nc21
Reaction time: 2 h

Procedure:
2,3-Dichlorobenzenesulfonyl chloride (342 mg, 1.5 equiv.) was added to a mixture of 4-(6-Methanesulfonyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenyl amine (283 mg., 0.93 mmol) and DIEA (325 μl, 2 equiv.) in CH2Cl2 (10 ml) at room temperature. After 2 hrs, the mixture was diluted by CH2Cl2 (10 ml) and washed by 10% NaHCO3, brine, drying and concentration left 420 mg as a golden yellow solid; LC/MS(m/e)=512.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([S:31][C:32]1[S:33][C:34]3[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=1)[N:6]2[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:30])[C@@H:20]([NH:22]C(=O)OC(C)(C)C)[CH3:21])[CH2:15][CH2:14]1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl>[NH2:22][C@@H:20]([CH3:21])[C:19]([N:16]1[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11][N:6]2[C:5]([S:31][C:32]3[S:33][C:34]4[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=3)=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[NH2:1])[CH2:18][CH2:17]1)=[O:30].[F:45][C:44]([F:47])([F:46])[C:42]([O-:48])=[O:43]
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(CCn2c(Sc3nc4cccc(Cl)c4s3)nc3c(N)ncnc32)CC1
Solvent: ClCCl
Product: C[C@H](N)C(=O)N1CCC(CCn2c(Sc3nc4cccc(Cl)c4s3)nc3c(N)ncnc32)CC1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Boc protected product from example 773 in DCM was added TFA and stirred at room temperature for 3 h. The solvent and excess TFA was evaporated under reduced pressure and the residual TFA was removed by co-evaporating with toluene to give title product as trifluoroacetate salt. 1H NMR δ (CD3OD), 8.35 (s, 1H), 7.84-7.82 (m, 1H), 7.50-7.40 (m, 2H), 4.40 (t, J=7.2 Hz, 2H), 4.00-3.90 (m, 1H), 1.80-1.70 (m, 4H), 1.41-1.37 (m, 4H), 1.32-1.30 (m, 3H), 1.20 (s, 3H); LC-MS [M+H]+ 517.1
Reaction SMILES: [CH3:1][C:2]([CH3:10])=[CH:3][CH2:4][CH2:5][C:6]([CH:8]=[CH2:9])=[CH2:7].[CH2:11]([SiH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12].C([Si](CC(=CC)CCC=C(C)C)(CC)CC)C>>[CH2:11]([Si:13]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:9][CH:8]=[C:6]([CH3:7])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:10])[CH3:1])[CH3:12]
Reactant: CC[SiH](CC)CC
Reactant: C=CC(=C)CCC=C(C)C
Agent: CC=C(CCC=C(C)C)C[Si](CC)(CC)CC
Product: CC[Si](CC)(CC)CC=C(C)CCC=C(C)C
Temperature: 100 °C
Yield: 91 %

Procedure:
A mixture of 0.170 ml (1.0 mmol) of myrcene, 0.192 ml (1.2 mmol) of triethylsilane, and 5.2 mg (0.01 mmol) of tetraethylammonium μ-hydridebis(pentacarbonylchromium) was heated in a sealed tube at 100° C. for 60 hours while being stirred. GLC analysis of the reaction mixture revealed that 6-(triethylsilyl)methyl-2-methyl-2,6-octadiene and 8-triethylsilyl-2,6-dimethyl-2,6-octadiene were produced at a ratio of about 7:3 in a yield of 91%. 6-(Triethylsilyl)methyl-2-methyl-2,6-octadiene: