Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
Reactant: OB(O)c1ccc(Cl)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Cn1nc2c(-c3ccc(Cl)cc3)c(Br)ccn2c1=O
Temperature: 100 °C
Reaction time: 15 h
Yield: 40 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (100 mg, 0.25 mmol), 4-chlorophenylboronic acid (40 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol) in dioxane (2.0 mL) at 20° C. was added K2CO3 (40 mg, 0.28 mmol) in water (0.6 mL). The resulting reaction mixture was stirred at 100° C. for 15 h under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (38 mg, 0.10 mmol) as a yellow solid. MS: [M+H]+=380. 1H NMR (CD3OD): δ 7.73 (d, J=1.8 Hz, 1H), 7.50 (q, 4H), 6.93 (d, J=1.9, 1H), 3.71 (d, J=1.8, 2H), 2.12 (m, 1H), 0.90 (d, J=1.7, 6H).
Reaction SMILES: [Cl:1]Cl.[CH3:3][N:4]1[C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=[C:5]1[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[Ca+2]>C(Cl)(Cl)Cl>[Cl:1][C:6]1[CH:7]=[C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:10])[N:4]([CH3:3])[C:5]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)Cc1ccc(C(=O)c2ccc(C)cc2)n1C
Reactant: ClCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1c(Cl)cc(C(=O)c2ccc(C)cc2)n1C

Procedure:
A solution of 4.26g (0.06 mole) of chlorine in 75 ml. of chloroform is added rapidly to a mixture of 16.2g. (0.06 mole) of methyl 1-methyl-5-(p-toluoyl)- pyrrole-2-acetate, 16g (0.12 mole) of calcium carbonate, and 0.48g. (0.003 mole) of ferric chloride in 75 ml. of chloroform. The temperature rose somewhat. After an hour, when the chlorine has been consumed, the solids are removed by filtration and the filtrate is evaporated in vacuo to yield a red oil. The oil is chromatographed on 2lb. of Silica (Mallinkrodt SILIC-AR CC-4) 100-200 mesh and eluted successively with hexane, benzene, and chloroform. The first compound-bearing fraction is eluted with chloroform. The solvent is evaporated and the residue is recrystallized from methanol to give white crystalline methyl 3-chloro-1-methyl-5-(p-toluoyl)pyrrole-2-acetate; m.p. 144°-146° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.ClC(OCC)=O.[F:20][C:21]1[CH:39]=[CH:38][C:24]([O:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH:31]([O:36][CH3:37])[CH2:30]2)=[CH:23][CH:22]=1>C(N(CC)CC)C>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([NH2:1])[C:10]([Cl:11])=[CH:9][C:5]=1[C:6]([NH:35][CH:32]1[CH:31]([O:36][CH3:37])[CH2:30][N:29]([CH2:28][CH2:27][CH2:26][O:25][C:24]2[CH:38]=[CH:39][C:21]([F:20])=[CH:22][CH:23]=2)[CH2:34][CH2:33]1)=[O:8]
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: COC1CN(CCCOc2ccc(F)cc2)CCC1N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CCCOc2ccc(F)cc2)CC1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (20.2 g) in MIK (250 ml) and triethyl amine (15.3 ml) was slowly dropped ethyl chloroformate (9.6 ml). The reaction mixture was stirred for 30 minutes at room temperature. To the formed mixed anhydride was then added intermediate 2 (28.2 g) and the reaction mixture was stirred for 2 hours at room temperature. Subsequently, the reaction mixture was washed with water (80 ml) and a NaOH solution (6.5% w/v, 50 ml). The organic layer was warmed to 65° C. and methanol (50 ml) and water (8.5 ml) were added. The solution was cooled slowly and stirred for 2 days during which crystallisation occurred, yielding cisapride having a cis/trans ratio higher than 99/1.
Reaction SMILES: [O:1]=[C:2]([C@@:18]1([OH:59])[CH2:35][C@H:34]([O:36][C@@H:37]2[O:51][C@@H:50]([CH3:52])[C@H:40]3[O:41][C@H:42]4[N:47]([C@H:39]3[CH2:38]2)[CH2:46][CH2:45][O:44][C@@H:43]4[O:48][CH3:49])[C:33]2[C:20](=[C:21]([OH:58])[C:22]3[C:23](=[O:57])[C:24]4[C:29]([C:30](=[O:54])[C:31]=3[C:32]=2[OH:53])=[C:28]([O:55][CH3:56])[CH:27]=[CH:26][CH:25]=4)[CH2:19]1)[CH2:3][O:4][C:5]1([O:11][CH2:12][C:13]([O:15]CC)=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[OH-].[Na+]>O.C(O)(=O)C>[O:1]=[C:2]([C@@:18]1([OH:59])[CH2:35][C@H:34]([O:36][C@@H:37]2[O:51][C@@H:50]([CH3:52])[C@H:40]3[O:41][C@H:42]4[N:47]([C@H:39]3[CH2:38]2)[CH2:46][CH2:45][O:44][C@@H:43]4[O:48][CH3:49])[C:33]2[C:20](=[C:21]([OH:58])[C:22]3[C:23](=[O:57])[C:24]4[C:29]([C:30](=[O:54])[C:31]=3[C:32]=2[OH:53])=[C:28]([O:55][CH3:56])[CH:27]=[CH:26][CH:25]=4)[CH2:19]1)[CH2:3][O:4][C:5]1([O:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CCOC(=O)COC1(OCC(=O)[C@]2(O)Cc3c(O)c4c(c(O)c3[C@@H](O[C@H]3C[C@H]5[C@H](O[C@@H]6[C@@H](OC)OCCN65)[C@H](C)O3)C2)C(=O)c2c(OC)cccc2C4=O)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)COC1(OCC(=O)O)CCCCC1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
To 30 mg of 45, 5 mL of in 01N NaOH was added. The suspension was cooled at 5° C. and stirred under argon for 3 hours. The aqueous solution was brought to pH≅8 with 10% acetic acid water solution and extracted with dichloromethane (2×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, the solvent removed under vacuum and the residue purified by flash chromatography (DCM/MeOH 90:10) to give 5 mg (y=8% 2 steps) of the acid intermediate 46 as a red solid. MS (ESI): 798 [M+H]+. Retention time=3.94 min. Method 2
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([CH3:18])([CH3:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:24]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([CH3:18])([CH3:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:24])=[O:5]
Reactant: CO
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C(C)(C)CC(C)(C)C)ccc1O
Yield: 92 %

Procedure:
A solution of 4 9.8 g (0.199 mol) of 2-hydroxy-5-(1,1,3,3-tetramethylbutyl)benzoic acid in 200 ml of methanol was heated to 50° C. and then treated dropwise with about 80 g of sulfuric acid at a rate to maintain the reaction under reflux. The reaction mixture was heated under reflux for an additional 11 hours, then cooled and partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, then with brine, dried over sodium sulfate and taken to dryness to give 48.6 g (92%) of methyl 2-hydroxy-5-(1,1,3,3-tetramethylbutyl]benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:11]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:47][N:48]([CH3:53])[S:49](Cl)(=[O:51])=[O:50]>N1C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([NH:1][S:49]([N:48]([CH3:53])[CH3:47])(=[O:51])=[O:50])[CH:3]=[C:4]([C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:11]=2)[CH:5]=1
Reactant: COc1cc(N)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(NS(=O)(=O)N(C)C)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Temperature: 45 °C
Reaction time: 48 h
Yield: 44 %

Procedure:
(S)-2-(1-((5-(3-Amino-5-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with dimethylsulfamoyl chloride (25 μL, 0.23 mmol) and 200 μL pyridine according to the method described in Preparation 15b but stirring at 45° C. during 48 h. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 30 mg (44% yield, 85% purity) of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][NH:11][C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]4[O:21][CH2:22][CH2:23][O:24][C:17]=4[CH:16]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH3:32])[C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]4[O:21][CH2:22][CH2:23][O:24][C:17]=4[CH:16]=3)[CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(Cc2ccc3c(c2)OCCO3)CN(C(c2ccccc2)c2ccccc2)CCN1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN1CCN(C(c2ccccc2)c2ccccc2)CC1(C)Cc1ccc2c(c1)OCCO2
Yield: 83.2 %

Procedure:
15 g of 1-diphenylmethyl-3-methyl-3-(3,4-ethylenedioxybenzyl)-piperazine (3a) are dissolved in 200 ml of acetone, combined with 10 g of potassium carbonate, and heated to boiling with stirring. 5.6 g of methyl iodide in 50 ml of acetone are added dropwise in the course of two hours. After a further five hours at reflux with stirring, the mixture is filtered and the filtrate evaporated to dryness in vacuum. The residue is taken up in 200 ml of diethyl ether, washed free of halogen with water, dried over sodium sulfate, and the filtrate is evaporated to dryness is vacuum. 12.9 g (83%) of 1-diphenylmethyl-3-methyl-3-(3,4-ethylenedioxybenzyl)-4-methylpiperazine (4a) are obtained.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[NH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:6](=[O:8])[CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:10])[F:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)CCCC(F)(F)F
Product: O=C(CCCC(F)(F)F)N1C(=O)OC[C@@H]1Cc1ccccc1

Procedure:
Preparation 1N was prepared from 5,5,5-trifluoropentanoic acid (3.35 g, 21.46 mmol) and (4S)-4-benzyl-1,3-oxazolidin-2-one (3.80 g, 21.46 mmol) by the general methods shown for Preparation 1B. Preparation 1N (5.67 g, 84%) was obtained as a colorless viscous oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.32-7.39 (2H, m), 7.30 (1H, d, J=7.05 Hz), 7.18-7.25 (2H, m), 4.64-4.74 (1H, m), 4.17-4.27 (2H, m), 3.31 (1H, dd, J=13.35, 3.27 Hz), 3.00-3.11 (2H, m), 2.79 (1H, dd, J=13.35, 9.57 Hz), 2.16-2.28 (2H, m), 1.93-2.04 (2H, m).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[CH:9]=2)=[O:5])C.[OH-].[Li+].Cl>C1COCC1.O>[CH3:16][O:15][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2ccc(OC)cc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2cc(C(=O)O)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.5 %

Procedure:
6-Methoxy-1H-indole-2-carboxylic acid ethyl ester (5.0 g) was treated with lithium hydroxide (2.33 g) in THF (90 mL) followed by water (30 mL) and stirred at ambient temperature for 16 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford 6-Methoxy-1H-indole-2-carboxylic acid (4.60 g). This material (4.64 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.60 g) in dichloromethane (200 mL) were treated with N-methylpiperazine (3.23 mL) and stirred at ambient temperature for 16 h. The reaction mixture was poured into dichloromethane (200 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% 2 M ammonia in methanol/dichloromethane) to give (6-Methoxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (6.60 g). This material (0.16 g) was dissolved in dichloromethane (10 mL). At room temperature, 1 M boron tribromide (1.5 mL) was added dropwise. The reaction mixture was heated to reflux overnight, and then cooled, quenched with saturated sodium hydrogencarbonate solution, and extracted with dichloromethane. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (0-10% 2 M ammonia in methanol/dichloromethane) to give the title compound (0.12 g). 1H NMR (400 MHz, CDCl3/CD3OD): δ 7.22 (d, J=8.41 Hz, 1H), 6.62 (d, J=2.15 Hz, 1H), 6.5′-6.47 (m, 2H), 3.69 (br s, 4H), 2.30 (t, J=5.09 Hz, 4H), 2.13 (s, 3H). MS (electrospray): exact mass calculated for C14H17N3O2, 259.13; m/z found, 260.1 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:13]3=[N:18][N:19]([CH3:21])[N:20]=[C:12]3[CH:11]=[CH:10][C:9]=2[N:8]=1>>[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:13]3=[N:18][N:19]([CH3:21])[N:20]=[C:12]3[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]=2[N:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cn1nc2ccc3nc(O)c(O)nc3c2n1
Agent: [K+]
Product: Cn1nc2c([N+](=O)[O-])cc3nc(O)c(O)nc3c2n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
Finely powdered potassium nitrate (0.47 g, 4.6 mmol) was added to an ice-cooled solution of 7,8-dihydroxy-2-methyl-2H-1,2,3-triazolo[4,5-f]quinoxaline (1.0 g, 4.6 mmol). The mixture was stirred at 0° C. for 11/2 h, then at room temperature for 4 h and finally poured into ice/water. The resulting solution was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated to dryness giving 0.27 g (22%) of the nitro compound; m.p.>300° C.; IR (KBr): 1700 cm-1 ; 1H-NMR (DMSO-d6): 4.63 (s, 3H, CH3), 8.15 (s, 1H, ArH), 12.1 (broad s, 1H, OH), 13.0 (broad s, 1H, OH).
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][NH:6][C:7]([C:9]1[N:17]=[C:16]2[N:11]([N:12]=[C:13]([NH:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:24][CH2:23]3)[CH:14]=[CH:15]2)[N:10]=1)=[O:8])C.[OH-].[Na+]>C(O)C>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:13]3[CH:14]=[CH:15][C:16]4[N:11]([N:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:42])=[O:3])=[O:8])[N:17]=4)[N:12]=3)[CH2:27][CH2:26]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)CNC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
928 mg of N-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[1,5-b]pyridazine-2carbonyl]glycine ethyl ester was dissolved in 7 ml of ethanol; 2.2 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure; the residue was diluted with water; 1 N hydrochloric acid was added to bring the mixture to pH 4.5. The crystal obtained was collected by filtration, washed with water, acetone and ethyl acetate and dried to yield 443 mg of the title compound.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C@H:28]([CH3:55])[O:29][C:30]1[CH:31]=[C:32]([CH:41]=[C:42]([O:44][C:45]2[CH:50]=[CH:49][C:48]([S:51]([CH3:54])(=[O:53])=[O:52])=[CH:47][CH:46]=2)[CH:43]=1)[C:33]([NH:35][C:36]1[S:37][CH:38]=[CH:39][N:40]=1)=[O:34])(C(C)(C)C)(C)C>C1COCC1.C(OCC)C.Cl>[OH:26][CH2:27][C@H:28]([CH3:55])[O:29][C:30]1[CH:31]=[C:32]([CH:41]=[C:42]([O:44][C:45]2[CH:50]=[CH:49][C:48]([S:51]([CH3:54])(=[O:52])=[O:53])=[CH:47][CH:46]=2)[CH:43]=1)[C:33]([NH:35][C:36]1[S:37][CH:38]=[CH:39][N:40]=1)=[O:34]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2nccs2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2nccs2)c1
Reaction time: 1.5 h
Yield: 59 %

Procedure:
Tetra-n-butyl ammonium fluoride (1.0M in THF, 0.832 mL, 0.832 mmol) was added to a solution of 3-((1S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-N-1,3-thiazol-2-ylbenzamide (425 mg, 0.756 mmol) in THF (5 mL) and the reaction stirred for 1.5 h. A further portion of tetra-n-butyl ammonium fluoride (0.83 mL) in THF was added and the reaction was stirred for a further 1.5 h. The reaction was then diluted with diethyl ether (40 mL) and 1M aqueous hydrochloric acid (20 mL) and the aqueous layer was re-extracted with diethyl ether (20 mL). The combined organic layers were dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 50% to 100% ethyl acetate in hexanes, afforded the title compound as a foam (200 mg, 60%). 1H NMR δ (CDCl3): 1.30 (d, 3H), 3.08 (s, 3H), 3.77 (m, 2H), 4.47 (m, 1H), 6.85 (s, 1H), 7.00 (d, 1H), 7.13 (d, 2H), 7.20 (s, 1H), 7.32 (d, 1H), 7.37 (s, 1H), 7.92 (d, 2H). m/z 467 (M−H)−
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8](=[NH:12])OCC.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>O1CCCC1>[ClH:1].[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:8](=[NH:12])[CH2:7][C:3]1[S:2][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=N)Cc1cccs1
Reactant: COC(CN)OC
Agent: Cl
Solvent: C1CCOC1
Product: COC(CNC(=N)Cc1cccs1)OC
Yield: 117.8 %

Procedure:
A mixture of ethyl 2-thiopheneethanimidate monohydrochloride (ester) (0.05 mol) in tetrahydrofuran (100 ml) was stirred under nitrogen. 2,2-dimethoxyethanamine (0.05 mol) was added portionwise upon cooling and the mixture was stirred overnight. The mixture was evaporated, yielding 15.6 g (100%) of N-(2,2-dimethoxyethyl)-2-thiopheneethanimidamide monohydrochloride (interm. 1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[I:34][C:35]1[CH:36]=[C:37]([CH2:41][OH:42])[CH:38]=[CH:39][CH:40]=1.[Cl:43][C:44]1[C:45]([OH:54])=[C:46]([C:51](=[O:53])[CH3:52])[CH:47]=[CH:48][C:49]=1O>ClCCl.O1CCCC1>[Cl:43][C:44]1[C:45]([OH:54])=[C:46]([C:51](=[O:53])[CH3:52])[CH:47]=[CH:48][C:49]=1[O:42][CH2:41][C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([I:34])[CH:36]=1
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Reactant: OCc1cccc(I)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2cccc(I)c2)c(Cl)c1O
Reaction time: 18 h
Yield: 64.5 %

Procedure:
Add triphenylphosphine (13.6 g, 51.7 mmol) and DIAD (10.5 g, 51.7 mmol) to a solution of (3-iodo-phenyl)-methanol (11.0 g, 47.0 mmol) and 1-(3-Chloro-2,4-dihydroxyphenyl)-ethanone (8.77 g, 47.0 mmol) in dichloromethane:tetrahydrofuran (250 ml:250 ml) and stir. After 18 hours, concentrate the reaction, and load directly onto silica. Purify the residue by flash chromatography eluting with acetone:hexanes to yield the title product as a white solid (12.2 g, 64%): 1H NMR (DMSO-d6) δ 2.62 (s, 3H), 5.34 (s, 2H), 6.88 (d, 1H), 7.23 (t, 1H), 7.48 (d, 1H), 7.72 (d, 1H), 7.87 (s, 1H), 7.96 (d, 1H), 13.14 (s, 1H)
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:31]([O:32]C(=O)C)[C@H:30]([O:36]C(=O)C)[C@@H:29]([CH2:40][O:41]C(=O)C)[O:28][C@H:9]1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]=[CH2:27])=[CH:20][CH:19]=1)(=O)C>CO.O1CCCC1>[O:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]=[CH2:27])=[CH:22][CH:23]=1)[C@@H:9]1[O:28][C@H:29]([CH2:40][OH:41])[C@@H:30]([OH:36])[C@H:31]([OH:32])[C@H:8]1[OH:7]
Reactant: C=CCOc1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCOc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.1 %

Procedure:
Sodium methoxide (28% methanol solution; 0.030 mL) was added to a solution of 2-(4-allyloxybenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.44 g) in methanol (2.5 mL) and tetrahydrofuran (1.5 mL), and the mixture was stirred at room temperature for 4 hours. The solvent of the reaction mixture was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 2-(4-allyloxybenzyl)phenyl β-D-glucopyranoside (0.23 g).
Reaction SMILES: O=[C:2]1[NH:7][C:6]2[CH2:8][CH2:9][O:10][CH2:11][C:5]=2[CH:4]=[C:3]1[C:12]#[N:13].C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][O:10][CH2:11][C:5]2=[CH:4][C:3]=1[C:12]#[N:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc2c([nH]c1=O)CCOC2
Agent: O=C([O-])O
Agent: [Na+]
Product: N#Cc1cc2c(nc1Cl)CCOC2
Temperature: 25 °C
Yield: 66 %

Procedure:
step 2 2-Oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridine-3-carbonitrile (2.50 g, 14.4 mmol) obtained in step 1 was dissolved in phosphoryl chloride (20 mL), and the mixture was stirred with heating under reflux for 4 hr. The mixture was allowed to cool to room temperature, and slowly added to a saturated aqueous sodium hydrogen carbonate solution at 0° C., then the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50) to give 2-chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile (1.85 g, 66%) as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N[NH:22][C:23]([NH2:25])=[S:24].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C1(C)C=CC=CC=1>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH:1]1([N:7]2[CH2:8][CH2:9][CH:10]([C:13]3[CH:14]=[CH:15][C:16]([C:17]4[S:24][C:23]([NH2:25])=[N:22][N:18]=4)=[CH:19][CH:20]=3)[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(C2CCN(C3CCCCC3)CC2)cc1
Reactant: NNC(N)=S
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(-c2ccc(C3CCN(C4CCCCC4)CC3)cc2)s1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
A mixture of 4-(1-cyclohexyl-4-piperidyl)benzonitrile (0.68 g), thiosemicarbazide (0.58 g) and trifluoroacetic acid (3.5 ml) in toluene (7 ml) was stirred for 7 hours at 70° C. After being cooled to room temperature, the solvent was evaporated in vacuo. Then the residue was dissolved in tetrahydrofuran and poured into water. The solution was adjusted to pH 8 with 1N aqueous sodium hydroxide. The resulting precipitate was collected by filtration and washed with water and isopropyl ether to give 5-[4-(1-cyclohexyl-4-piperidyl)phenyl]-1,3,4-thiadiazol-2-amine trifluroacetate (0.80 g).