Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13](C3C(S([O-])(=O)=O)=CC=CN=3)[CH2:12]2)=[O:10])=[C:4]([C:33](=[O:40])[NH:34][CH:35]([CH:37]2[CH2:39][CH2:38]2)[CH3:36])[CH:3]=1.C(O)(=O)C.[BrH:45].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([Br:45])[CH2:12]2)=[O:10])=[C:4]([C:33](=[O:40])[NH:34][CH:35]([CH:37]2[CH2:39][CH2:38]2)[CH3:36])[CH:3]=1
Reactant: Br
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(c2ncccc2S(=O)(=O)[O-])=NN1c1ncccc1Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Reaction time: 1 h

Procedure:
400 mg of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl3-pyridine sulfonate was dissolved in 0.7 mL of acetic acid, and 0.4 mL of a 33 mass % hydrogen bromide acetic acid solution was dropwise added, followed by stirring for about 1 hour. After completion of the reaction, ethyl acetate, water and 2.8 mL of 1 N sodium hydroxide were added, followed by stirring and extraction with ethyl acetate. Then, concentration under reduced pressure was carried out to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/2) to obtain 330 mg of the desired product in a paste form.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[C:9]=1Br.C([Sn](CCCC)(CCCC)[C:58]([O:60]CC)=[CH2:59])CCC>O1CCOCC1.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>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:9]=1[C:58](=[O:60])[CH3:59]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 100 °C

Procedure:
A degassed mixture of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (Int-91,154 mg, 0.19 mmoL), Pd(PPh3)4 (22 mg, 0.019 mmoL), tributyl(1-ethoxyvinyl)stannane (103 mg, 0.28 mmoL) in dioxane (3 mL) was heated at 100° C. overnight. The reaction mixture was cooled to room temperature, filtered through 9:1 SiO2:KF plug and concentrated in vacuo. The crude tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (Int-9j) was treated with 50% TEA in H2O (4 mL) until the disappearance of starting material in LCMS. Concentration afforded crude 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone (Int-9k), which was then heated under microwave conditions with N2H4.H2O (800 uL) and NMP (6 mL) first at 100° C. for 30 min and then at 200° C. for 1 h. Purification with prep-LC provided 3-methyl-6-(6-phenylpyridin-3-yl)-4-(piperidin-4-yl)-1H-dipyrazolo[1,5-a:4′,3′-e]pyrimidine (Int-91): LCMS tR=2.49 Min (10 min run, UV254m). Mass calculated for, M+409.2, observed LC/MS m/z 410.6 (M+H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:8][C:7]=1[Br:23])(=[O:3])[CH3:2].[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>ClCCCl.CC#N>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:8][C:7]=1[Br:23])(=[O:3])[CH3:2]
Reactant: CCOc1ccc(C(=O)c2ccc(COC(C)=O)c(Br)c2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Solvent: ClCCCl
Product: CCOc1ccc(Cc2ccc(COC(C)=O)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.6 %

Procedure:
To a stirred solution of 2-bromo-4-(4-ethoxybenzoyl)benzyl acetate (0.41 g, 1.09 mmol) and Et3SiH (0.44 μL, 2.76 mmoL) in 1,2-dichloroethane/MeCN (2.5 mL, 1:2), was added dropwise BF3.Et2O (0.21 mL, 1.66 mmol). The reaction was complete after stirring for about 17 h at 25° C. Upon cooling, the reaction was quenched with 0.5 mL of 28.5% NaOH aqueous solution. The aqueous layer was extracted 2× with CH2Cl2, the combined organic layers were washed once with 2M KOH, 2× with H2O containing 10% brine and 2× with brine prior to drying over Na2SO4. After removal of the volatiles, the residue was purified by silica gel column (10:1 petroleum ether/ethyl acetate) to yield 0.24 g of title compound. 1H NMR (CDCl3, 300 MHz): δ 7.39 (s, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 7.07 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 5.15 (s, 2H), 4.01 (q, J=7.0 Hz, 2H), 3.88 (s, 2H), 2.12 (s, 3H), 1.40 (t, J=7.0 Hz, 3H); MS ESI (m/z) 380 (M+NH4)+, calc. 362.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH:32]([F:34])[F:33])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:9]=2)[CH:7]=1.[C:35]([O:39][C:40](=[O:46])[NH:41][CH2:42][CH2:43][CH2:44]Br)([CH3:38])([CH3:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:35]([O:39][C:40](=[O:46])[NH:41][CH2:42][CH2:43][CH2:44][N:28]1[CH2:27][CH2:26][CH:25]([N:10]2[CH:11]=[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:31][CH:32]([F:33])[F:34])=[N:9]2)[CH2:30][CH2:29]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: O=C(Nc1cn(C2CCNCC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCN1CCC(n2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 60 °C
Yield: 101.5 %

Procedure:
A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [3-(5-chloro-2-difluoromethoxyphenyl)-1-piperidin-4-yl-1H-pyrazol-4-yl]amide (100 mg, 0.20 mmol), (3-bromo-propyl)-carbamic acid tert-butyl ester (71 mg, 0.3 mmol) and potassium carbonate (45 mg, 0.32 mmol) in DMF (2 mL) was heated at 60° C. for 1.5 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried (Na2SO4) and evaporated. The resultant residue was chromatographed on silica eluting with dichloromethane on a gradient of 2M ammonia in methanol (0-6%) to give [3-(4-{3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}piperidin-1-yl)propyl]carbamic acid tert-butyl ester as a yellow oil (131 mg, 100%). LCMS (Method 4) [M+H]+=675.0, RT=2.86 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: O=C1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1CCCN1c1ncc(Br)cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (11.3 g), pyrrolidin-2-one (5 g), and K2CO3 (27.4 g) in 1-methylpyrrolidin-2-one (100 mL) was heated to 80° C. under nitrogen and stirred at this temperature overnight. After cooling to room temperature, the reaction mixture was concentrated to give an oil which was poured into water (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phase was concentrated to afford an oil, which was purified by column chromatography on silica gel to afford the title compound. Yield: 592 mg (4% of theory).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+].O>CC(C)=O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1
Reactant: COC(=O)c1ccc2c(C)c[nH]c2c1
Reactant: BrCCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(C)cn(CCCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.4 %

Procedure:
A stirred solution of methyl 3-methyl-1H-indole-6-carboxylate (0.5 g, Reference Example 30) in acetone (35 ml) was treated with 1-bromo-3-phenylpropane (0.577 g) and sodium hydroxide (0.116 g). The mixture was stirred at room temperature for 12 hours then poured into water (35 ml) and then extracted three times with ethyl acetate (50 ml). The combined extracts were washed with dilute hydrochloric acid (50 ml, 1N) then with saturated sodium bicarbonate solution (50 ml), then dried over magnesium sulphate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (50:1, v/v) to yield the title compound (0.58 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C.O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: Cc1cc(Br)cc(C(=O)O)c1N
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)cc(C)c1N
Yield: 89.1 %

Procedure:
2-Amino-5-bromo-3-methylbenzoic acid (5.0 g, 21.7 mmol) in dry DMF (35 mL) was stirred with Cs2CO3 (10.62 g, 32.6 mmol) at room temperature for 1 h under nitrogen. Iodomethane (3.4 g, 1.5 mL, 23.95 mmol) in dry DMF (7 ml) was added dropwise to the above stirring reaction mixture over a period of 30 min and continued the reaction for 24 h. Reaction mixture was diluted with water (200 mL) and stirred to observe hetergeneous suspension. The purple solid was collected by filtration and dried to obtain methyl 2-amino-5-bromo-3-methylbenzoate (4.72 g, 89%). 1H NMR (DMSO-d6): δ 7.67 (app d, 1H, J=2.1 Hz), 7.34 (s, 1H), 6.60 (s, 2H), 3.78 (s, 3H), 2.09 (s, 3H).LCMS: rt 7.98 min (A), purity 99%, MS (m/e) 245 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]([N+]([O-])=O)=[N:4][S:5][N:6]=1.C(N(CC)CC)C.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C[N:26]1[C:30](=O)[CH2:29][CH2:28][CH2:27]1>C(O)C.[Pd]>[NH2:26][C:27]1[C:3]2[C:2](=[N:6][S:5][N:4]=2)[CH:30]=[CH:29][C:28]=1[NH:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: CN1CCCC1=O
Reactant: O=[N+]([O-])c1nsnc1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1c(NCc2ccccc2)ccc2nsnc12
Temperature: 80 °C

Procedure:
To a solution of 5-chloro-4-nitro-2,1,3-thiadiazole (1.0 g, 4.64 mmol) in anhydrous NMP (5 ml) was added triethylamine (0.65 ml, 4.64 mmol) and benzylamine (0.51 ml, 4.64 mmol). The mixture was heated to 80° C. for 1 hour. The cooled mixture was poured into ice-water (50 ml) and the product was filtered off, washed with water and dried. Yield: 1 g (75%). This product (0.5 g, 1.75 mmol) was suspended in ethanol (20 ml) and hydrogenated at ambient pressure using palladium (5% on activated carbon) as the catalyst. Yield: quantitative.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[CH2:1]([O:19][C:29](=[O:30])[CH2:28][Cl:27])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)CCl
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCCOC(=O)CCl
Temperature: 0 °C

Procedure:
To an ice-cooled solution of z,z,z-octadeca-6,9,12-trienol (2 g, 7.56 mmol) and triethylamine (2.02 g, 20 mmol) in methylene chloride (20 ml) was added dropwise with stirring chloroacetyl chloride (1.13 g, 10 mmol) in methylene chloride (20 ml) under an atmosphere of nitrogen. On completion of the reaction as shown by tlc, the mixture was washed with water (2×100 ml) and saturated sodium chloride solution (100 ml). The organic phase was dried with magnesium sulfate, filtered and concentrated under reduced pressure. Toluene (100 ml) was added to azeotropically remove final traces of water. z,z,z-octadeca-6,9,12-trienyl-(2-chloro)acetate was obtained as a dark brown oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)(C)(C)C>[NH2:17][C:12]1([C:2]2[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCC1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Solvent: CC(C)(C)O
Product: NC1(c2nc(Cl)ccc2C(=O)O)CCCC1
Temperature: 100 °C
Yield: 29.5 %

Procedure:
15 g of 2,6-dichloronicotinic acid (70.31 mmol, Aldrich) and 34.7 ml of cyclopentylamine (351.56 mmol) are placed in a sealed tube containing 40 ml of tert-butanol. The mixture is heated at 100° C. overnight and evaporated to dryness. The residue is taken up in water and the product is acidified by pouring in an aqueous solution of acetic acid at 10%, and the mixture is then extracted with choloroform. The organic phases are combined, dried over sodium sulphate, filtered, and concentrated under vacuum. The solid residue is triturated in an ether/pentane mixture so as to give 5 g of expected product in the form of an off-white solid (yield=29.5%).
Reaction SMILES: C([N:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:5]([C:7]([O:9][N+:10]([O-:12])=[O:11])=[O:8])[CH3:6])(=O)C>O.O.O.O.O.O.[Co](Cl)Cl.[OH-].[Na+]>[N+:10]([O:9][C:7](=[O:8])[C@H:5]([CH3:6])[NH:4][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: CC(=O)N(c1ccccc1)C(C)C(=O)O[N+](=O)[O-]
Agent: Cl[Co]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@H](Nc1ccccc1)C(=O)O[N+](=O)[O-]
Temperature: 37 °C
Reaction time: 48 h
Yield: 37 %

Procedure:
To N-acetyl-O-nitrophenyl-DL-alanine (324 g, 1.28 mol), aqueous solution (1.8 liters) of 1N sodium hydroxide was added to dissolved, and acylase (9.0 g) and cobalt (II) chloride hexahydrate (100 mg) were sequentially added, and the mixture was stirred for 2 days at 37° C. After filtering the insoluble matter, the filtrate was evaporated in vacuo, and precipitating crystals were filtered and washed with a small amount of water, and the captioned compound (99.6 g, 37%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=O.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:50][CH2:51][C@@:52]([OH:59])([C:55]([F:58])([F:57])[F:56])[CH2:53][OH:54]>CN(C)C=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:50][CH2:51][C@:52]([OH:59])([CH2:53][OH:54])[C:55]([F:58])([F:57])[F:56])=[O:16]
Reactant: Nc1c(C(=O)O)cnn1-c1ccc(F)cc1
Reactant: NC[C@](O)(CO)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1c(C(=O)NC[C@](O)(CO)C(F)(F)F)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 117.4 %

Procedure:
5-Amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid (104 mg) was dissolved in dry dimethylformamide (3 ml) and diisopropylethylamine (0.33 ml) was added followed by the addition of O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (196 mg). The reaction was stirred at room temperature, under nitrogen, for 20 minutes. (S)-2-(Aminomethyl)-3,3,3-trifluoro-1,2-propanediol (90 mg) in dry dimethylformamide (2 ml) was added and the reaction was stirred at room temperature for 3 hours. The reaction was partitioned between ethyl acetate (50 ml) and water (50 ml) and the separated aqueous phase was re-extracted with ethyl acetate (50 ml). The combined organics were washed with water, 1M hydrochloric acid, 10% lithium chloride solution (2 times), bicarbonate and brine. The organics were dried using a hydrophobic frit and evaporated to give a pale yellow oil (200 mg). This was dissolved in dichloromethane (ca. 5 ml) and left to stand at room temperature for 4 hours wherein a precipitate formed. The precipitate was filtered and washed with a small amount of dichloromethane to give the title compound as a white solid (93 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:18][C:19]1[CH:24]=[C:23]([C:25]2([CH3:28])[CH2:27][O:26]2)[CH:22]=[C:21]([CH3:29])[N:20]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:28][C:25]([C:23]3[CH:24]=[C:19]([CH3:18])[N:20]=[C:21]([CH3:29])[CH:22]=3)([OH:26])[CH3:27])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1cc(C2(C)CO2)cc(C)n1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(C)(O)Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc(C)n1
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (220 mg, 1 mmol) was dissolved in DMF and sodium hydride (120 mg, 3 mmol) was added. The reaction mixture was stirred for 10 min and 2,6-dimethyl-4-(2-methyloxiran-2-yl)pyridine (210.6 mg, 1.3 mmol) was added dropwise to the reaction mixture with constant stirring. The reaction mixture was stirred at RT overnight. The reaction mixture was poured on crushed ice and the precipitate obtained was filtered under vacuum; washed with water and hexane to obtain 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(2,6-dimethylpyridin-4-yl)propan-2-ol (323 mg) which was dissolved in DCM (3 mL) and cooled to 0° C. Thionylchloride (3 mL) was added dropwise and the reaction mixture was allowed to cool to RT. The reaction mixture was then stirred at RT for 2 h. Thionylchloride was evaporated under vacuum by azeotropic distillation with DCM. 1N NaOH solution was added to basify (pH-12-13) the reaction mixture and the compound extracted with EtOAc (2×30 mL). The organic layer was concentrated under vacuum to get the crude desired product. The crude compound was further purified through reverse phase HPLC. Yield: 17 mg. 1H NMR (CD3OD, D1-HCl salt) δ (ppm): 7.95 (s, 2H), 7.66 (s, 1H), 7.58 (s, 1H), 7.25 (m, 2H), 4.70 (m, 1H), 4.40 (m, 1H), 3.90 (m, 1H), 3.62 (m, 1H), 3.22 (m, 2H), 3.10 (s, 6H), 2.10 (s, 3H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:46]I>C1(C)C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[I:46][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCCCCCCCCCCI
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a suspension of 0.5 g of tert-butyl N-(12-hydroxydodecyl)carbamate in 15 ml of toluene were added 0.28 g of imidazole, 1.09 g of triphenylphosphine and 0.84 g of iodine and the mixture was stirred for 0.5 hour. Then, 5 ml of tetrahydrofuran was further added and the mixture was stirred for 2 hours. To the reaction solution was added ethyl acetate and the mixture was washed successively with a 10% aqueous solution of sodium thiosulfate and water and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue thus obtained was chromatographed over a silica gel column to afford 0.42 g of the title compound.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH2:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[C@@H:8]([C@:9]3([O:28][CH3:29])[CH2:10][CH2:11][C:12]2=[O:27])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([OH:30])[CH:4]=[CH:5]2.[CH3:31][I:32]>O>[I-:32].[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N@@+:18]([CH3:31])([CH2:19][CH2:20][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[C@@H:8]([C@:9]3([O:28][CH3:29])[CH2:10][CH2:11][C:12]2=[O:27])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([OH:30])[CH:4]=[CH:5]2
Reactant: CO[C@@]12CCC(=O)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(CCc1ccccc1)[C@@H]2C5
Reactant: CI
Solvent: O
Product: CO[C@@]12CCC(=O)[C@@H]3Oc4c(O)ccc5c4[C@@]31CC[N@@+](C)(CCc1ccccc1)[C@@H]2C5
Product: [I-]

Procedure:
A solution of 4,5α-epoxy-3-hydroxy-14β-methoxy-17-(2-phenylethyl)morphinan-6-one (0.32 g, 0.7 mmol) and methyl iodide (0.56 g, 3.92 mmol) in 6 ml of water-free acetonitrile was stirred under N2 40° C. (bath temperature) for 2 days and then evaporated down. The residue (0.32 g of brown oil) was purified using column chromatography (silica gel; CH2Cl2/MeOH 250:2). Yield: 0.07 g (16%) of colourless crystals of the compound 52. Fp. 180-181° C.; MS (CI): 420 (M++1); IR (KBr): 1727 (C═O) cm−1; 1H-NMR (D2O, δ in ppm): 7.17-7.14 (m, 5 arom. H), 6.56 (s, 2 arom. H), 5.18 (s, CH-5), 3.64 (s, CH3N+, axial), 3.44 (s, OCH3).
Reaction SMILES: [CH:1]1([S:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:16](O)=[O:17])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[S:28][C:29]([O:32][C:33]2[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=2)[C:36]([O:38][CH3:39])=[O:37])=[CH:30][N:31]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:1]1([S:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:16]([NH:26][C:27]3[S:28][C:29]([O:32][C:33]4[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=4)[C:36]([O:38][CH3:39])=[O:37])=[CH:30][N:31]=3)=[O:17])=[CH:11][CH:10]=2)(=[O:7])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CCCC2)nc1
Reactant: COC(=O)c1cccc(Oc2cnc(N)s2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1cccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CCCC4)nc3)s2)c1
Yield: 42.9 %

Procedure:
The compound of example A10 was obtained by similar method described in example A1 using 2-(6-cyclopentylsulfonyl-3-pyridyl)-2-tetrahydropyran-4-yloxy-acetic acid (Preparation 14; 0.200 g, 0.542 mmol), methyl 3-(2-aminothiazol-5-yl)oxybenzoate (Preparation 20, 0.162 g, 0.650 mmol), HOBt (0.087 g, 0.650 mmol), and EDCl (0.124 g, 0.650 mmol), N-methyl morpholine (0.136 g, 1.35 mmol) in DCM (8 mL) to provide the title compound (0.140 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:5]=1[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:7].Br[CH2:26][C:27]([CH3:29])=[CH2:28]>CN(C=O)C>[Br:3][C:4]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:5]=1[C:6]([N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[CH2:28][C:27]([CH3:29])=[CH2:26])=[O:7]
Reactant: C=C(C)CBr
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)CN(Cc1ccc(OC)cc1)C(=O)c1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of NaH (1.22 g) in DMF (130 ml) was added 2-bromo-N-(4-methoxy-benzyl)-5-nitro-benzamide (6.2 g) in DMF (60 ml) at −78° C. The mixture was warmed to 0° C., 3-bromo-2-methyl-propene (4.57 g) was added and the mixture was stirred for 2 h at 0° C. The reaction was poured into ice water, extracted with EtOAc (2×400 ml), dried over MgSO4, filtered and concentrated to a DMF solution which was used without further purification.