Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.S([O-])([O-])(=O)=[O:7].[Na+].[Na+].[CH2:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14]>>[CH2:13]([C:15]1[CH:20]=[C:19]([OH:7])[CH:18]=[CH:17][CH:16]=1)[CH3:14]
Reactant: CCc1ccccc1
Reactant: O=S(=O)([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCc1cccc(O)c1
Temperature: 170 °C
Reaction time: 0.5 h
Yield: 396.7 %

Procedure:
A four-necked flask (2 liters-volume) was charged with 98% sulfuric acid (1200 g). Anhydrous sodium sulfate (102 g, 6 mol %) and then ethylbenzene (424 g) were added thereto in 30 minutes while stirring. Temperature was gradually elevated to 200° C. over 2 hours while evaporated water was withdrawn. The heating was continued with stirring for 4 hours at the same temperature in order to isomerize. Then, the mixture was cooled to 170° C. Water (2000 g) was dropped at a uniform rate into the stirred mixture at the same temperature over 10 hours in order to hydrolyze. The obtained reaction mass was left to stand at 150° C. for 30 minutes to form layers. The layer of sulfuric acid (854 g) was removed. The layer of sulfonic acid (1074 g) was neutralized to pH 7.8 with 50% potassium hydroxide and added dropwise to a mixture of sodium hydroxide (563 g) and potassium hydroxide (83 g) mutually melting at 330° C. in a 2 liter reaction vessel. The mixture was heated to 340° C. and maintained with stirring at this temperature for 1 hour. Then, the mixture was dissolved in water (2000 ml) and neutralized to pH 7.2 with 35% hydrochloric acid. The produced phenols were extracted with ether and distilled to give crude m-ethylphenol (348 g, 71% yield based on consumed ethylbenzene), which showed a purity of 98.2% after fractional distillation.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[O:7][CH3:8].CO.[NH2:19][OH:20].[C-]#N.[K+]>C1COCC1.O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:6]([O:7][CH3:8])[CH2:5][CH2:4][C:3]([NH:19][OH:20])=[O:2])=[CH:10][CH:11]=1
Reactant: COC(=O)CCC(OC)c1ccc(Cl)cc1
Reactant: NO
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(CCC(=O)NO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-(4-chloro-phenyl)-4-methoxy-butyric acid methyl ester (62.5 mg, 0.25 mmol) dissolved in 2 mL of THF, methanol, and 50 wt % NH2OH in H2O (2:2:1) mixture was added KCN (4.0 mg, 0.06) and the resulting mixture stirred for 3 days at room temperature. The reaction was quenched by the addition of 1M aqueous HCl (10 mL) and the resulting mixture extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (2×5 mL). The product was isolated by flash column chromatography eluting with 0% to 10% methanol/DCM to give the title compound (34 mg) as colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[N:13]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c1
Yield: 13.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chlorophenyl)-2-(3-chloro-4-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-92, 0.300 g, 0.852 mmol), pivaloyl chloride (0.108 g, 0.852 mmol), DIPEA (2.0 mL), dry THF (10 mL) to afford 0.050 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.13 (s, 9H), 4.29 (d, J=5.4 Hz, 2H), 7.40 (d, J=7.8 Hz, H-0, 7.52-7.59 (m, 3H), 7.91-8.18 (m, 3H), 12.65 (s, 11-0; MS (m/z): 437.23 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[C:3]=1[O:4][C:5]1[CH:14]=[CH:13][C:8]([NH:9][CH2:10][C:11]#[N:12])=[C:7]([N+:15]([O-])=[O:16])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:11]([C:10]1[NH:9][C:8]2[CH:13]=[CH:14][C:5]([O:4][C:3]3[C:18]([F:26])=[CH:19][C:20]([C:22]([F:24])([F:23])[F:25])=[CH:21][C:2]=3[Cl:1])=[CH:6][C:7]=2[N+:15]=1[O-:16])#[N:12]
Reactant: N#CCNc1ccc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1[nH]c2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc2[n+]1[O-]
Reaction time: 8 h
Yield: 83.9 %

Procedure:
4-(2-chloro-4-trifluoromethyl-6-fluorophenoxy)-2-nitro-N-cyanomethylaniline (1 g) was suspended in hot ethanol (50cm3) and anhydrous potassium carbonate (0.18 g) added. The mixture was then stirred under reflux for 4 hours and left at room temperature overnight. The solvent was evaporated from the mixture under vacuum and the residue dissolved in water (75cm3), filtered and acidified with 2M hydrochloric acid. The yellow precipitate was collected and washed with water, then hexane and air dried to give 2-cyano-5-(2-chloro-4-trifluoromethyl-6-fluorophenoxy)-1H-benzimidazole-3-oxide (0.8 g). M+ =370.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C[O:10][C:11]([C:13]1[S:17][C:16](/[CH:18]=[CH:19]/[C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:15][C:14]=1[CH3:32])=O>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([NH:4][C:11]([C:13]1[S:17][C:16](/[CH:18]=[CH:19]/[C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:15][C:14]=1[CH3:32])=[O:10])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: COC(=O)c1sc(/C=C/c2c(-c3ccccc3)noc2C)nc1C
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1nc(/C=C/c2c(-c3ccccc3)noc2C)sc1C(=O)NC(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a stirred solution of isopropylamine (56 mg, 0.95 mmol) in dioxane (2 mL) under argon and at room temperature was added trimethylaluminium (0.47 mL of a 2M solution in toluene, 0.94 mmol). After 1 h, a solution of 4-methyl-2-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid methyl ester (80 mg, 0.24 mmol) in dioxane (2 mL) was added and the reaction mixture warmed to 90° C. After 24 h, the reaction mixture was cooled, quenched with ice and Seignettes's salt solution, then extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, 10 to 80% ethyl acetate in heptane) gave the title compound (40 mg, 46%) as an off white solid. MS: m/e=368.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)=O.C([NH2:25])C1C=CC=CC=1.C(N(CC)CC)C>C(OCC)C.CCCCCC.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:17])([F:16])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)[NH2:25]
Reactant: O=C(c1ccc(F)c(C(F)(F)F)c1)C(F)(F)F
Reactant: NCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCCCCC
Product: NC(c1ccc(F)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.7 %

Procedure:
2,2,2-Trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (21.0 g, 81 mmol) was initially charged in diethyl ether (200 ml), and benzylamine (9.1 g, 85 mmol) and triethylamine (16.4 g, 162 mmol) were added at 0° C. Subsequently, a solution of titanium tetrachloride (7.8 g, 41 mmol) in hexane (100 ml) was added dropwise. The reaction mixture was stirred at room temperature for 3 h. The resulting suspension was filtered, and the solids were washed with diethyl ether and discarded. The solvent of the filtrate was removed under reduced pressure and the residue was taken up in triethylamine (100 ml). The solution was left to stand at room temperature for 16 h. The triethylamine was removed under reduced pressure, and the residue was taken up in dichloromethane and acidified with 10% hydrochloric acid. The mixture was stirred at room temperature for 16 h and then the phases were separated. The organic phase was washed with water and the combined aqueous phases were adjusted to pH 12 with 33% sodium hydroxide solution while cooling with ice. The aqueous phase was extracted three times with dichloromethane and the combined organic phases were dried over magnesium sulphate. The solvent was removed under reduced pressure. 6.5 g (31% of theory) of 2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanamine were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[O:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[NH2:21])[CH:14]=[CH:13]1.NC1N=CC(C2SC(CN3CCCCC3)=CC=2)=CC=1C(NC1C=CN=CC=1)=O>>[NH2:1][C:2]1[C:7]([C:8]([NH:21][C:19]2[CH:18]=[CH:17][N:16]=[C:15]3[CH:14]=[CH:13][O:12][C:20]=23)=[O:10])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1
Reactant: Nc1ccnc2ccoc12
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: Nc1ncc(-c2ccc(CN3CCCCC3)s2)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(Br)cc1C(=O)Nc1ccnc2ccoc12

Procedure:
7.1 Reaction of 2-amino-5-bromo-pyridine-3-carboxylic acid with furo[3,2-b]pyridin-7-amine according to the synthesis described for “A1” step 1, gives 2-Amino-5-bromo-N-furo[3,2-b]pyridin-7-yl-pyridine-3-carboxamide.
Reaction SMILES: FC1C=C(C=CC=1F)C(O)=[O:6].[CH2:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][C:22]3[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>>[NH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18]=2[CH2:19][CH2:20][C:12]3=[O:6])=[N:27][CH:26]=1
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC3)nc1
Product: Nc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
According to the same manner as that described in Example 1 except for using an equimolar amount of 3,4-difluorobenzoic acid in place of 3,4-dichlorobenzoic acid and using an equimolar amount of 6-[(2,3-dihydro-1H-inden-5-yl)oxy]-3-pyridinylamine obtained in Reference Example 19 in place of 4-[(5-amino-2-pyridinyl)oxy]-1-indanone, the reaction was carried out to obtain the titled compound.
Reaction SMILES: [CH2:1]([N:3]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:4]1[C:5]([CH3:33])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([CH:31]=O)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH2:17][CH2:18][CH3:19])=[O:8])[CH3:2].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl>[CH2:1]([N:3]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:4]1[C:5]([CH3:33])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([CH2:31][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH2:17][CH2:18][CH3:19])=[O:8])[CH3:2]
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(C=O)nc2)cc(N(CC)C2CCOCC2)c1C
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(CN3CCOCC3)nc2)cc(N(CC)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
To a stirred solution of 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(6-formylpyridin-3-yl)-2-methyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)benzamide (0.315 g, 0.59 mmol) in EDC (8 mL) at 0° C., was added morpholine (0.1 g, 1.18 mmol) and stirred at rt for 10 min. NaBH(OAc)3 (0.377 g, 1.78 mmol) was then added and stirred for 16 h. On completion, reaction was quenched with water. MeOH (8 mL) was added and layers were separated and extracted with 10% MeOH in DCM, and purified on column chromatography to afford the title compound (0.2 g, 56%).
Reaction SMILES: [CH2:1]([O:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:10]=[C:9]([N:19]2[CH2:24][CH2:23][S:22][CH2:21][CH2:20]2)[C:8]=1[N+:25]([O-:27])=[O:26])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[OH:29]O.[OH-].[Na+]>O>[CH2:1]([O:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:10]=[C:9]([N:19]2[CH2:20][CH2:21][S:22](=[O:29])[CH2:23][CH2:24]2)[C:8]=1[N+:25]([O-:27])=[O:26])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)COc1nc(N2CCNCC2)nc(N2CCSCC2)c1[N+](=O)[O-]
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)COc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4.5 gm (0.011 mol) of 6-neopentyloxy-5-nitro-2-piperazino-4-thiomorpholino-pyrimidine were suspended in a mixture of 60 ml of water and 11.4 ml (0.022 mol) of 2 N hydrochloric acid. 1.66 gm (0.011 mol) of 30% hydrogen peroxide were added to the suspension, and the mixture was stirred for 24 hours at room temperature, whereby a clear solution was obtained. The solution was made alkaline by careful addition of 12 ml of 2 N sodium hydroxide, and the yellow precipitate formed thereby was suction-filtered off, washed with water and recrystallized from a mixture of 30 ml of methanol and 20 ml of water. Yield: 2.4 gm (51.2% of theory); m.p. 156°-158°C.
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([CH2:10][C:11]2[NH:12][C:13](=[O:29])[C:14]3[CH:19]=[N:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26]CC)[C:15]=3[N:16]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1>ClCCl>[CH:5]1([CH2:10][C:11]2[NH:12][C:13](=[O:29])[C:14]3[CH:19]=[N:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[OH:26])[C:15]=3[N:16]=2)[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CCOc1ccccc1-n1ncc2c(=O)[nH]c(CC3CCCC3)nc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1[nH]c(CC2CCCC2)nc2c1cnn2-c1ccccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 ml of 1 M boron tribromide solution in dichloromethane are added to 0.2 g (0.59 mmol) of 6-cyclopentylmethyl-1-(2-ethoxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 12), and the reaction mixture was stirred at room temperature for 1 h. Aqueous hydrolysis is followed by extraction with dichloromethane. The product is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 μm; eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B). 0.167 g (91% of theory) of the product is obtained as a colourless solid.
Reaction SMILES: [CH2:1]([C@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:40][CH2:39][C:36]2[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C=CC[C@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNCc2ccc(OC)cc2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (300 mg, 0.675 mmol; Example 91, Step C) and (4-methoxyphenyl)methanamine (131 μL, 1.01 mmol) in DCE (4.5 mL) was added sodium triacetoxyborohydride (429 mg, 2.03 mmol) at 0° C. in several portions. After being stirred at 25° C. for 18 h, the reaction was quenched by adding ice-cold saturated aqueous NaHCO3 and extracted (2×DCM). The combined organic layers were washed (1×sat. aq. NaCl solution) and concentrated under reduced pressure to provide the title compound as a yellow film. The product was used in the next step without further purification.
Reaction SMILES: C(OC([NH:8][C:9]([NH:26]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][N:19]=2)[CH:12]=1)=O)(C)(C)C.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[ClH:34].[CH3:25][O:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:26])=[NH:8])[CH:16]=[CH:15][C:14]=2[CH3:17])[CH:23]=1
Reactant: COc1ccnc(-c2cc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)ccc2C)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccnc(-c2cc(NC(=N)N)ccc2C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(4-methoxypyridin-2-yl)-4-methylphenyl)guanidine (0.2 g) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (50 ml), and the precipitate was collected by filtration and dried under reduced pressure to give (3-(4-methoxypyridin-2-yl)-4-methylphenyl)-guanidine dihydrochloride (137 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]1)[C:5]2=[O:33].[CH2:34](I)[CH3:35]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:34][CH3:35])[C:7](=[O:12])[N:6]([CH:13]1[CH2:14][CH2:15][N:16]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)[CH2:17][CH2:18]1)[C:5]2=[O:33]
Reactant: CCI
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc(Cl)cc5c4=O)CC3)c2cc1OC
Product: CCn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc(Cl)ccc21
Yield: 45 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.64 mmol) of Compound h was used in place of Compound 24 and ethyl iodide was used in place of methyl iodide. As a result, 145.9 mg (yield: 45%) of Compound 41 was obtained as white crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[S:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]#[CH:19]>CC(C)=O>[CH2:19]([S:10][C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:18]#[CH:17]
Reactant: C#CCBr
Reactant: S=C1Cc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCSc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of the product (14.9 g) of the above (1) in acetone (250 ml) are added potassium carbonate (16.5 g) and propargyl bromide (14.3 g) successively and the mixture is stirred at room temperature for three hours. The precipitate is filtered off. The filtrate is condensed and extracted with ether after addition of water. The extract is washed with water, dried and evaporated to remove the solvent yielding an oily residue (23 g). The residue is chromatographed on a column of silica gel (100 g) and eluted with benzene-hexane. The eluate is condensed to give the tile compound as an oil (18.3 g). Yield: 98%
Reaction SMILES: C(OC1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.C(O[C:18]([O:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].C1COCC1>C(Cl)Cl>[C:24]([O:23][C:21]([O:20][C:18]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Reaction time: 22 h

Procedure:
In 200 mL of methylene chloride was dissolved 6.91 g (0.043 m) of 4-acetoxystyrene and 13.10 g (0.060 m) of di-t-butyldicarbonate under nitrogen. To the solution at room temperature was added 14.0 g (0.101 m) of potassium carbonate and the mixture was vigorously stirred for 22 hours, following the reaction by thin layer chromatography. After 22 hours at room temperature 100 mL of THF was added and the reaction was further stirred for 142 hours. It was worked up as in the above Examples. There was a very low yield (less than 10 %) of the product, 4-(t-butoxycarbonyloxy)styrene, under these conditions as analyzed by NMR, HPLC and TLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[CH3:20])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[N:6][CH:7]=1.[OH-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=2)[CH3:20])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1cccc(F)c1)c1ccc(C(=O)O)cc1
Temperature: 65 °C
Reaction time: 5 h
Yield: 59.1 %

Procedure:
To a stirred solution of methyl 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoate (step 2, 180 mg, 0.42 mmol) in tetrahydrofuran (3 mL) was added 2 N sodium hydroxide aqueous The reaction mixture was stirred at 65° C. for 5 h. After cooling, the reaction mixture was acidified by the addition of 2 N hydrochloric acid (2 mL). The aqueous mixture was partitioned between water (50 mL) and dichloromethane (50 mL) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (50 mL). The combined organic layer was washed with brine (100 mL), dried (sodium sulfate), and concentrated. The residual solids were recrystallized from ethyl acetate to afford 103 mg (60%) of the title compound as white solids: 1H-NMR (CDCl3) δ 8.56 (1H, d, J=3.0 Hz), 8.16 (1H, d, J=3.0 Hz), 8.08–8.05 (3H, m), 7.47–7.40 (3H, m), 7.07–6.91 (3H, m), 5.43–5.33 (1H, m), 1.60 (3H, d, J=7.1 Hz), a peak of COOH was not observed; MS (ESI) m/z 415 (M+H)+, 413 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][C:38]#[CH:39])[CH2:9][C@@H:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:41]1[CH:42]=[C:43]([S:47]([NH2:50])(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1>C(#N)C.C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]([CH2:9][C@@H:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=1)[OH:11])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][C:38]#[C:39][C:41]1[CH:42]=[C:43]([S:47]([NH2:50])(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cccc(I)c1
Reactant: C#CCCOCCCCCCN(Cc1ccccc1)C[C@H](O)c1ccc(OCc2ccccc2)c(NC=O)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cccc(C#CCCOCCCCCCN(Cc2ccccc2)C[C@H](O)c2ccc(OCc3ccccc3)c(NC=O)c2)c1
Yield: 51 %

Procedure:
A stirred solution of 5-((1R)-2-{benzyl[6-(but-3-ynyloxy)hexyl]amino}-1-hydroxyethyl)-2-(benzyloxy)phenylformamide (500 mg) and 3-iodobenzenesulfonamide (340 mg) in acetonitrile (10 ml) and triethylamine (10 ml) with cuprous iodide (50 mg) and bis(triphenylphosphine) palladium dichloride (100 mg) was stirred at ambient temperature under nitrogen for 2 h. The mixture was evaporated in vacuo and the residue was purified by chromatography on Biotage (40 g) cartridge eluting with light petroleum 40-600/ethyl acetate (9:1) to give the title compound (330 mg). LCMS RT=3.04 min.