Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6](=[NH:9])OC)(=[NH:4])[NH2:3].[CH2:10]([NH2:13])[CH:11]=[CH2:12]>C(O)C>[ClH:1].[CH2:10]([NH:13][C:6]([NH:5][C:2]([NH2:4])=[NH:3])=[NH:9])[CH:11]=[CH2:12]
Reactant: COC(=N)NC(=N)N
Reactant: C=CCN
Agent: Cl
Solvent: CCO
Product: C=CCNC(=N)NC(=N)N

Procedure:
Into 3 ml of ethanol were dissolved 5 g of guanyl-O-methylisourea hydrochloride and 3 ml of allylamine. The resulting solution was reacted at room temperature for 24 hours in a nitrogen stream. The reaction mixture was then filtered and the precipitates were washed with ethanol to give 3.14 g of allylbiguanide hydrochloride as needle like crystals (m.p.: 178°-179° C.).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:5]=2[O:4][C:3]=1[C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].ClS([N:33]=[C:34]=[O:35])(=O)=O>ClCCl>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:19]([C:3]1[O:4][C:5]2[CH:10]=[C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:8]=[CH:7][C:6]=2[C:2]=1[NH:1][C:34]([NH2:33])=[O:35])=[O:28]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(OCc3ccccc3)ccc12
Solvent: ClCCl
Product: NC(=O)Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(OCc3ccccc3)ccc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
30.9 g (75 mmol) of the compound of example IV or IVa are dissolved in 750 ml dichloromethane and cooled to 0°C. 11.6 g (82 mmol) chlorosulfonyl isocyanate in dichloromethane are added and the mixture is stirred at 0° C. for 30 min and at room temperature for 3 h. The solvent is removed in vacuo, the residue suspended in water and stirred vigorously for 3 h at 60° C. After cooling to r.t. the suspension is filtered, the crude product dried in a desiccator in the presence of phosphorus pentoxide and triturated with diisopropylether at 40° C.;.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][NH:6][C:7](=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:17]=[N:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>C(O)C>[F:30][C:28]([F:29])([F:31])[C:25]1[CH:24]=[CH:23][C:22]([C:19]2[N:18]=[CH:17][C:16]([CH2:15][O:14][C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:33])=[O:2])=[O:32])=[CH:9][CH:10]=3)=[CH:21][CH:20]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)CCNC(=O)c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCNC(=O)c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1

Procedure:
To a solution of [6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (120 mg, 0.47 mmol) in THF (2 mL) and toluene (4 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 179.5 mg, 0.71 mmol) at 0° C., followed by the addition of tributylphosphine (0.18 mL, 0.71 mmol) and 3-(4-hydroxy-benzoylamino)-propionic acid methyl ester (127 mg, 0.57 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 3-{4-[6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-benzoylamino}-propionic acid methyl ester. The ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 3-{4-[6-(4-Trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-benzoylamino}-propionic acid (33 mg). MS (ES): 443.2 [M+H]−.
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:6]([OH:8])=[O:7])[CH3:5].[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11].Cl>O.C1COCC1>[C:9]([NH:3][C@H:4]([C:6]([OH:8])=[O:7])[CH3:5])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)Cl
Reactant: C[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)C(=O)N[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydroxide (1.24 g) and L-alanine (2.76 g) were dissolved in pure water and, under cooling with ice, a solution where methacryloyl chloride (3 ml) was dissolved in THF (15 ml) and an aqueous solution (17 ml) containing sodium hydroxide (1.21 g) were simultaneously dropped thereinto. After that, the mixture was stirred at room temperature for 4 hours, acidified with 2M hydrochloric acid and extracted with ethyl acetate. The organic phase was dried, concentrated in vacuo, washed with ether and dried in vacuo to give the aimed product. Yield: 1.76 g (36%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=1[O:37][CH3:38]>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[C:29]([O:37][CH3:38])[CH:30]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: COc1cc(B(O)O)ccc1F
Product: COC(=O)C(CC(C)C)c1cc(Oc2ccc(F)c(OC)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 30 %

Procedure:
The title compound was prepared in 30% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester and 4-fluoro-3-methoxyphenylboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:13][CH2:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[N:17]=[C:7]3[C:6]=2[CH2:5]1)#[N:2].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+]>CN(C)C=O>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:7]2[N:8]([C:9](=[O:14])[NH:10][C:11]3[CH2:12][CH2:13][N:4]([CH2:3][C:1]4[NH:27][N:26]=[N:25][N:2]=4)[CH2:5][C:6]=32)[N:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCN1CCc2[nH]c(=O)n3nc(-c4ccccc4F)nc3c2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(c3nc(-c4ccccc4F)nn13)CN(Cc1nnn[nH]1)CC2
Reaction time: 3 h

Procedure:
A mixture of the product of Example 50 (640 mg), sodium azide (1.41 g), ammonium chloride (120 mg) and dimethylformamide (10 mL) is stirred at 90° over 3 hours under nitrogen. The mixture is cooled and quenched in ice-water (40 mL), stirred 1/2 hour, and cautiously acidified with glacial acetic acid to afford the solid product 2-(2-fluorophenyl)-9-tetrazolylmethyl-7,8,9,10-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-c]pyrimidine-5(6H)one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)OCO2

Procedure:
To a solution of 38 gms. of 1-nitro-3,4-methylenedioxybenzene in 75 mls. of absolute ethanol is added 1.5 gms. of 5% palladium on carbon. The resulting mixture is hydrogenated at approximately 4 atmospheres pressure of hydrogen and ambient temperature for 4 hours. The catalyst is removed by filtration and the filtrate concentrated to a syrup. Trituration of the syrup with petroleum ether (b.p. 30°-60°C.) causes solidification and recrystallization from the same solvent provides 1-amino-3,4-methylenedioxybenzene, m.p. 37°C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[S:9][CH:8]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(OCC)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]2[S:9][CH:8]=[C:7]([C:27]3([OH:30])[CH2:26][CH2:25][N:24]([C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH2:29][CH2:28]3)[C:11]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1ccc2scc(Br)c2c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2csc3ccc(Cl)cc23)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
A solution of 1.55 mL (1.86 mMol) n-butyllithium in 5.0 mL diethyl ether was cooled to -78° C. under a nitrogen atmosphere. To this cooled solution was added a solution of 0.418 gm (1.68 mMol) 3-bromo-5-chlorobenzothiophene in 10.0 mL diethyl ether. The reaction mixture was stirred at -78° C. for 1 hour and then to it was added dropwise a solution of 0.401 gm (2.0 mMol) 1-tert-butoxycarbonyl-4-piperidone in 5.0 mL diethyl ether. The reaction was stirred an additional 2 hours at -78° C. and was then gradually warmed to -20° C. over 55 minutes. The reaction mixture was then quenched with saturated aqueous sodium bicarbonate, diluted with additional diethyl ether and the phases separated. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica chromatography, eluting with toluene containing 10% ethyl acetate. Fractions shown to contain product were combined and concentrated under reduced pressure to give 0.36 gm (58.4%) of the desired compound as a colorless foam.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12]O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)Cl>[Br:33][CH2:12][CH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1ccc2c(c1)CCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCc1ccc2c(c1)CCO2
Reaction time: 15 h
Yield: 89.4 %

Procedure:
Compound 76-1 (1.91 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (2.97 g) and N-bromosuccinimide (2.01 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and further at room temperature for 15 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (2.31 g) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[B:9]([OH:11])[OH:10].[CH3:12][S:13]([O-:15])=[O:14].[Na+].Cl>CN(C=O)C>[CH3:12][S:13]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[B:9]([OH:11])[OH:10])(=[O:15])=[O:14]
Reactant: OB(O)c1ccccc1CBr
Reactant: CS(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccccc1B(O)O
Reaction time: 2.5 h
Yield: 28.9 %

Procedure:
A solution in DMF (2.0 ml) of [2-(bromomethyl)phenyl]boronic acid (399 mg) was added in one portion to a stirred slurry of sodium methanesulphinate (200 mg) in DMF (2.0 ml). The mixture was stirred for 2.5 h i nd then poured into 1M hydrochloric acid (100 ml) and extracted with EA (3×50 ml). the combined extracts were dried and evaporated. On standing a solid material precipitated, which was washed with ER to give white crystals of the title compound (115 mg), m.p. 133°-137°. T.l.c. (A) ER:hexane (3:2) Rf 0.51.
Reaction SMILES: O=C1CCCN1[C:7]12[CH2:26][CH:11]3[CH2:12][C:13]([NH:15][CH2:16][C:17]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[C:24]#[N:25])=[O:18])([CH2:14]1)[CH:9]([CH2:10]3)[CH2:8]2.[Si](Cl)(C)(C)C>CO>[C:7]1([C:7]23[CH2:26][CH:11]4[CH2:12][C:13]([NH:15][CH2:16][C:17]([N:19]5[CH2:23][CH2:22][CH2:21][C@H:20]5[C:24]#[N:25])=[O:18])([CH2:14]2)[CH:9]([CH2:10]4)[CH2:8]3)[CH:26]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(N1CCCC1=O)(C3)C2
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccccc1)(C3)C2
Reaction time: 0.5 h
Yield: 217.5 %

Procedure:
To a stirred solution of the compound obtained from example 26 (35 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 diethyl ether to obtain the hydrochloride salt of (2S)-1-[N-(2-phenylhexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl]pyrrolidine-2-carbonitrile as an off-white solid (38 mg).
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])[O:3][CH2:4][C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[CH3:17])[N:8]=[C:7]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[N:6]=1.[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31]>O1CCOCC1>[CH3:29][Si:2]([CH3:1])([C:25]([CH3:28])([CH3:27])[CH3:26])[O:3][CH2:4][C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[CH3:17])[N:8]=[C:7]([C:18]2[CH:19]=[CH:20][C:21]([NH:22][C:33]([NH:32][CH2:30][CH3:31])=[O:34])=[CH:23][CH:24]=2)[N:6]=1
Reactant: CCN=C=O
Reactant: C[C@H]1COCCN1c1cc(CO[Si](C)(C)C(C)(C)C)nc(-c2ccc(N)cc2)n1
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ccc(-c2nc(CO[Si](C)(C)C(C)(C)C)cc(N3CCOC[C@@H]3C)n2)cc1
Temperature: 120 °C

Procedure:
4-[4-[(Dimethyl-tert-butyl-silyl)oxymethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (250 mg) was dissolved in 1,4-dioxane (4 mL) and ethyl isocyanate (0.144 mL) added. The reaction was heated to 120° C. for 1 hour in a microwave reactor. The reaction was concentrated in vacuo then the residue chromatographed on silica, eluting with 2.5% methanol in DCM, to give the desired compound (106 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=1.[C:11]1([CH:18]=CC(O)=[CH:14][CH:13]=1)O.CCOCC>C1(C)C=CC=CC=1.C=CC=C>[CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]2[CH:6]([C:7](=[O:9])[CH:8]=1)[CH2:14][CH:13]=[CH:11][CH2:18]2
Reactant: Oc1ccc(O)cc1
Reactant: COC1=CC(=O)C=CC1=O
Agent: C=CC=C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC1=CC(=O)C2CC=CCC2C1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of 2-methoxybenzoquinone (17, 750 mg, 5.43 mmol, TCI, used as received), hydroquinone (38 mg, Matheson, used as received) in toluene (7.5 mL) and butadiene (54, 7.5 mL, Matheson, used as received; Note: condensed butadiene into the toluene with ice bath cooling) contained in a screw top, sealed robe (Ace) was stirred overnight in a 60° C. oil bath. The resulting solution was allowed to cool to rt, then was further cooled in an ice bath. A precipitate formed. The sealed tube was opened. The solid was collected by filtration, washed with hexanes and allowed to air dry (930 mg). The solid was crystallized from hexanes (dissolved in 350 mL, hot filtered, concd to 200 mL, re-filtered, allowed to cool to rt) to yield a yellow powder (703 mg, 68%, >95% pure by 1H NMR analysis); mp 120°-122° C. (hexanes), lit. (Cavill et al., Aust. J. Chem. 26:595-601 (1993)) 126.5°-128° C. (ether); 1H NMR (CDCl3) δ2.21 (m, 2H), 2.51 (m, 2H), 3.16 (m, 1H), 3.26 (m, 1H), 3.79 (s, 3H), 5.69 (m, 2H), 5.90 (s, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)=[CH:13][CH:12]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)O1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[NH:35]1[CH:34]=[C:33]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=4)=[CH:13][CH:12]=3)=[N:6][CH:7]=2)[CH:37]=[N:36]1
Reactant: Cc1cc(-c2ccc(CC(=O)Nc3ccc(I)cn3)cc2)ccn1
Reactant: CC1(C)OB(c2cn[nH]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: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(-c4cn[nH]c4)cn3)cc2)ccn1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
N-(5-Iodopyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 65-2 (20 mg, 0.046 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (13.5 mg, 0.07 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol) was mixed in toluene (3 mL)/ethanol (1 mL)/Na2CO3(2M, 1 mL). The reaction mixture was stirred at 90° C. for 10 hours. The solvent was removed by rotary evaporation and the residue was dissolved in DMSO. The inorganic salt was removed by filtration. The crude product in DMSO was purified by reverse phase HPLC to give N-(5-(1H-pyrazol-4-yl)pyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 65 as off-white solid. MS m/z 370.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([OH:26])[CH2:16][C:17]#[C:18][Si](CC)(CC)CC)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:28]1[CH:34]=[C:33]([N:35]2[CH:39]=[N:38][N:37]=[CH:36]2)[CH:32]=[CH:31][C:29]=1[NH2:30]>>[N:37]1[N:38]=[CH:39][N:35]([C:33]2[CH:32]=[C:31]3[C:29](=[CH:28][CH:34]=2)[NH:30][CH:18]=[C:17]3[CH2:16][CH:15]([OH:26])[CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:36]=1
Reactant: CC[Si](C#CCC(O)CC1CCN(C(=O)OC(C)(C)C)CC1)(CC)CC
Reactant: Nc1ccc(-n2cnnc2)cc1I
Product: CC(C)(C)OC(=O)N1CCC(CC(O)Cc2c[nH]c3ccc(-n4cnnc4)cc23)CC1

Procedure:
Prepared according to the procedure described for Example 49 step d, using (±)-5-[N-(tert-butyloxycarbonyl)piperidin-4-yl]-4-hydroxy-1-triethylsilyl-1-pentyne (Example 49, step b) and 2-iodo-4-(1,2,4-triazol-4-yl)aniline. 1H NMR (250 MHz, CDCl3) δ 1.04-1.19 (3H, m), 1.44 (9H, s), 1.68 (4H, m), 2.69 (2H, bt), 2.82 (1H, dd), 3.0 (1H, dd), 4.08 (3H, m), 7.17 (1H, dd), 7.25 (2H, m), 7.50 (1H, d), 7.59 (1H, d), 8.44 (2H, s), 8.46 (1H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH2:21][CH2:22][CH:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[OH:24])[C:10]2=[O:32])=[CH:5][CH:4]=1.[S:33]([CH2:37][C:38](O)=[O:39])([OH:36])(=[O:35])=[O:34].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH:23]([OH:24])[CH2:22][CH2:21][CH:11]2[C:10](=[O:32])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:38]([CH2:37][S:33]([OH:36])(=[O:35])=[O:34])=[O:39])=[CH:4][CH:5]=3)[CH:12]2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CN)cc2)cc1
Reactant: O=C(O)CS(=O)(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CNC(=O)CS(=O)(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 60 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]4-(4-methoxyphenyl)azetidin-2-one (5) in 1 ml of dimethylformamide was added to a solution of 20 mg of sulfoacetic acid, 55 μl of diisopropylcarbodiimide, 38 mg of hydroxybenzotriazole in 1 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). This gave the product of molecular weight 556.61 (C28H29F1N2O7S1); MS (ESI) 539.05 (M+H+—H2O)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[N:47]([C:50]1[CH:57]=[CH:56][C:53]([C:54]#[N:55])=[CH:52][CH:51]=1)=[C:48]=[O:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:48]([NH:47][C:50]2[CH:57]=[CH:56][C:53]([C:54]#[N:55])=[CH:52][CH:51]=2)=[O:49])[CH2:42][CH2:41]1)=[O:39]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Reactant: N#Cc1ccc(N=C=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NC(=O)N2CCC(C(=O)Nc3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cc1
Yield: 44 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 4-isocyanatobenzonitrile as starting materials in 44% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.33 (m, 2H), 9.01 (s, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 7.75 (s, 1H), 7.65 (s, 4H), 7.20 (d, 1H), 7.04 (m, 2H), 6.87 (d, 1H), 6.78 (d, 1H), 4.20 (d, 2H), 2.90 (m, 6H), 2.69 (m, 1H), 1.89 (m, 2H), 1.61 (m, 2H). LCMS for C32H30ClN8O2 (M+H)+: m/z=593.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]([CH3:16])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][C:6]=1[C:7]#[N:8].N>C(O)C.[Ni].[Pd]>[NH2:1][CH:2]1[CH:6]([CH2:7][NH2:8])[CH2:5][N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]1[CH3:16]
Reactant: CC1C(N)=C(C#N)CN1Cc1ccccc1
Agent: [Ni]
Agent: [Pd]
Agent: N
Solvent: CCO
Product: CC1C(N)C(CN)CN1Cc1ccccc1

Procedure:
In a manner to that in Example 1, 106.6 g of 3-amino-4-cyano-1-benzyl-2-methyl-3-pyrroline in 200 ml of ethanol and 200 g of gaseous ammonia is hydrogenated, in the presence of 6 g of Raney nickel containing 2% of palladium, for 4 hours at 120°C at a pressure of 100 atmospheres. The crude amine contains, on the basis of the gas-chromatogram, about 10% of low-boiling by-product. Fractional distillation through a packed column yields 52.1 g (47.6%), B.P. 126°-127°C/0.3 mm Hg.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[CH:14]=[CH:13][CH:12]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C(=O)C.O>[O:23]=[C:21]1[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[S:18][C:17]([C:15]2[N:16]=[C:11]([CH2:10][CH2:9][NH:8][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:12]=[CH:13][CH:14]=2)=[N:22]1
Reactant: NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 25.8 %

Procedure:
2-[6-(2-Aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (0.53 g, 1.3 mmol) was dissolved in N,N-dimethylacetamide (10 ml), and benzoyl chloride (0.38 g, 2.7 mmol) and potassium carbonate (0.18 g, 1.3 mmol) were added thereto. The reaction mixture was stirred at 60° C. for 4 hrs, combined with ethyl acetate and water. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with methanol-ethyl acetate (1:20, v/v) were collected, concentrated and recrystallized from hexane-ethanol to give the titled compound (0.13 g, 26%) as white crystals.