Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=[O:24])C)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[OH-].[Na+].BrBr.[OH:29]S([O-])=O.[Na+].Cl>O1CCOCC1.O.C(Cl)Cl>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:29])=[O:24])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: O=S([O-])O
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(C)=O)cc3)CC2)CC1
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(=O)O)cc3)CC2)CC1
Reaction time: 1 h

Procedure:
A solution of 32.6 g of p-(trans-4-(trans-4-propyl-cyclohexyl)-cyclohexyl)-acetophenone in 100 ml of dioxane is added dropwise to a solution of 40 g of NaOH and 48 g of bromine in 230 ml of water at 20°, while stirring. Stirring is continued for 1 hour. A solution of 14 g of NaHSO3 in 140 ml of water is added and hydrochloric acid is added until the pH is 5. Customary working up (CH2Cl2) gives p-(trans-4-(trans-4-propylcyclohexyl)-cyclohexyl)-benzoic acid. The crude product is boiled with 60 ml of SOCl2 for 2.5 hours. After evaporation, the resulting crude acid chloride is dissolved in 430 ml of dioxane, 200 ml of 25% aqueous ammonia is added and the mixture is poured onto ice and filtered to give p-(trans-4-(trans-4-propylcyclohexyl)-cyclohexyl)-benzamide. 65 g of POCl3 is added dropwise to a solution of 32.7 g of this amide in 500 ml of DMF at 50°, while stirring. After the mixture has been further stirred for 1 hour, it is poured onto ice and worked up in the customary manner (CH2Cl2) to give trans-1-p-cyanophenyl-4-(trans-4-propyl-cyclohexyl)-cyclohexane, m.p. 55°, c.p. 184°.
Reaction SMILES: P([O-])([O-])([O-])=O.[CH3:6][C:7]([CH3:35])=[CH:8][CH2:9][C:10]1[C:15]([OH:16])=[C:14]2[C:17]([C:19]3[C:24]([O:25][C:13]2=[CH:12][C:11]=1[OH:34])=[CH:23][C:22]([OH:26])=[C:21]([O:27][CH3:28])[C:20]=3[CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])=[O:18].CC(C)=CCC1C(O)=CC2OC3C=C(O)C(O)=C(CC=C(C)C)C=3C(=O)C=2[C:45]=1[OH:46].[N+](C1C=CC([C@@]2(O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)O)=CC=1)([O-])=O>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:6][C:7]([CH3:35])=[CH:8][CH2:9][C:10]1[C:11]([OH:34])=[CH:12][C:13]2[O:25][C:24]3[CH:23]=[C:22]([OH:26])[C:21]([O:27][CH3:28])=[C:20]([CH2:29][CH:30]=[C:31]([CH3:32])[CH3:33])[C:19]=3[C:17](=[O:18])[C:14]=2[C:15]=1[OH:16].[CH3:45][OH:46]
Reactant: CC(C)=CCc1c(O)cc2oc3cc(O)c(O)c(CC=C(C)C)c3c(=O)c2c1O
Agent: COc1c(O)cc2oc3cc(O)c(CC=C(C)C)c(O)c3c(=O)c2c1CC=C(C)C
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Product: CO
Reaction time: 0.08 h

Procedure:
α-Glucosidase inhibitory activity was measured using the in vitro method developed by D. Prasanth et al., (Fitoterapia 2001, 72, 686-688). In a micro plate well was taken 50 μL of α-glucosidase enzyme (0.4 U/mL), and treated with 90 μL of 100 mM phosphate buffer (pH 7) and 10 μL test substances (α-mangostin, γ-mangostin and AR 933) or vehicle control. The contents were mixed well and the reaction mixtures were incubated at room temperature for 5 min, and then added 50 μL of p-nitrophenyl α-D-glucopyranose (20 mM) as substrate. The contents were mixed well and again incubated at room temperature for 15 min. The reaction was stopped by the addition of 30 μL of sodium carbonate solution (135 mM). The absorbance was measured at 405 nm using micro plate reader. Control and test blank ODs were obtained by replacing enzyme with buffer. Percentage inhibitions were calculated by comparing mean test OD with mean control OD. {% inhibition=[(COD−TOD)/COD]×100}. The IC50 values were calculated by linear regression analysis of the dose response curve.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:41])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH2:23][O:24][CH3:25])[CH:17]=[C:16]([C:26]([O:28]CC)=[O:27])[C:15]3=[O:31])=[C:8]([C:32]2[S:33][CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[N:36]=2)[CH:7]=1)[CH3:2].[Li+].[OH-].C1COCC1>CO.O>[CH2:1]([NH:3][C:4](=[O:41])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH2:23][O:24][CH3:25])[CH:17]=[C:16]([C:26]([OH:28])=[O:27])[C:15]3=[O:31])=[C:8]([C:32]2[S:33][CH:34]=[C:35]([C:37]([F:39])([F:40])[F:38])[N:36]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CCOC)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3CCOC)cn1
Temperature: 100 °C
Yield: 74.8 %

Procedure:
Ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 51, 0.090 g, 0.15 mmol) and LiOH (0.092 mL, 0.18 mmol) were combined in MeOH (1 mL)/THF (1 mL) and heated to 100° C. in the microwave for 15 min The reaction mixture was cooled to room temperature, diluted with water (1.000 mL) and heated until the compound dissolved. The resulting solution was filtered and the filtrate was then concentrated under reduced pressure to remove methanol. HCl (1 N) was added and the resulting precipitate was collected by filtration, washed with water and dried overnight to yield a white solid (0.063 g).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:26])[CH2:13][CH:14](P(OCC)(OCC)=O)[C:15]([OH:17])=[O:16])([CH3:10])([CH3:9])[CH3:8].[CH:27]1([CH2:33][CH2:34][CH:35]=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[CH:50]1([NH2:56])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>C1COCC1.C(OCC)(=O)C>[CH:50]1([NH2:56])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1.[C:7]([O:11][C:12](=[O:26])[CH2:13]/[C:14](=[CH:35]\[CH2:34][CH2:33][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)/[C:15]([OH:17])=[O:16])([CH3:8])([CH3:9])[CH3:10]
Reactant: O=CCCC1CCCCC1
Reactant: CCOP(=O)(OCC)C(CC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C/C(=C\CCC1CCCCC1)C(=O)O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 67 %

Procedure:
Potassium tert-butoxide (20.2 g, 0.18 mol) was added portionwise over 10 minutes to a solution of 3-(diethoxyphosphoryl)succinic acid 1-tert-butyl ester (25.4 g, 82 mmol) in THF (115 ml), at 0° C., under nitrogen. The mixture was stirred at 0° C. for 40 minutes and then cooled to −20° C. A solution of 3-cyclohexylpropan-1-al (11.5 g, 82 mmol in THF (60 ml) was added dropwise over 10 minutes between −20 and −10° C., under nitrogen. The mixture was stirred between −20 and −5° C. for 3 hours and then aqueous citric acid (10%, 250 ml) and ethyl acetate (200 ml) was added. The organic phase was separated and the aqueous fraction was washed with ethyl acetate (200 ml). The combined organic fractions were washed with saturated sodium bicarbonate solution (2×100 ml), aqueous citric acid solution (10%, 100 ml) and demineralised water (100 ml) and then concentrated in vacuo. The resulting solid was taken up in ethyl acetate (150 ml) and cyclohexylamine (9.4 ml, 82 mmol) was added dropwise over 5 minutes at 20-25° C. The mixture was stirred at 20-25° C. for 16 hours and then filtered. The residue was dried in vacuo at 40° C. for 4 hours to leave the title compound as a colourless solid (21.7 g, 67% yield, 95% pure by NMR).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([O:10][C:11]1[C:12](=O)[C:13](=[O:18])[C:14]=1[O:15]CC)[CH3:9]>CCO>[CH2:8]([O:10][C:11]1[C:14](=[O:15])[C:13](=[O:18])[C:12]=1[NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:9]
Reactant: Nc1cccnc1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2cccnc2)c(=O)c1=O

Procedure:
3-Aminopyridine (12.3 g, 130 mmol) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (21.5 g; 125 mmol) in 130 mL EtOH. The mixture was heated to reflux for 16 h, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (7% EtOH in EtOAc) to give the title compound as a yellow powder.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:30])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH:4]1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])(CC)C.[CH2:36]([O:43][C:44]([C:46]([NH2:59])([C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])[CH:47]=O)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>O1CCCC1.C1CCCCC1>[C:49]([C:46]([NH2:59])([CH:47]=[CH:10][CH:4]1[C:5]([CH3:8])([CH3:9])[CH2:6][CH2:7][C:3]1([CH3:2])[CH3:30])[C:44]([O:43][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:45])([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50]
Reactant: CC1(C)CCC(C)(C)C1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC(C=O)(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Br-]
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)C1C=CC(N)(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
The 2,2,5,5-tetramethyl cyclopentylmethyl triphenylphosphonium bromide is suspended in tetrahydrofuran at 0° C. under argon. Sec-Butyllithium in cyclohexane is added followed by a solution of 2-benzyloxycarbonyl-2-CBZ-aminoacetaldehyde in tetrahydrofuran. After one hour, water is added to the reaction mixture. The organic layer is separated, washed with water and dried over MgSO4 and evaporated to yield the alkene, benzyl 2-CBZ-amino-4-(2,2,5,5-tetramethylcyclopentyl)-3-butenoate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:30]([CH:24]5[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:31])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)C1CCCCC1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)C4CCCCC4)nc3cc21

Procedure:
Cyclohexanecarboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (200 mg, 0.64 mmol) and cyclohexanecarbonyl chloride (258 μl, 1.93 mmol). The title compound was obtained as light brown powder (64 mg, 23%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:10][C:11]=1[C:12](O)=O)=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[BH3-]C#N.[Na+].P([O-])([O-])([O-])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:58]>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:10][C:11]=1[CH2:12][Br:58])=[O:5])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)c1c(C(=O)O)ccn(Cc2ccccc2)c1=O
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])([O-])[O-]
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c(CBr)ccn(Cc2ccccc2)c1=O
Reaction time: 3 h
Yield: 41.1 %

Procedure:
1-Benzyl-2-oxo-1,2-dihydro-pyridine-3,4-dicarboxylic acid 3-ethyl ester (1.8 g, 5.98 mmol) was dissolved in 50 mL of CH2Cl2. Oxalyl chloride (5.2 mL, 59.8 mmol) and DMF (2 drops) were added, and the mixture was stirred for 3 h. Solvent and excess oxalyl chloride were removed by evaporation in vacuo, and to the residue was added a solution of NaCNBH3 (750 mg, 12 mmol) in THF (40 mL). The resulting suspension was stirred at r.t. for 16 h. The reaction mixture was cooled in an ice bath, and then poured into a pre-cooled, vigorously stirring pH 4.9 phosphate buffer (300 mL). The resulting mixture was extracted several times with benzene, and the combined organic layer was washed with ice-cold water and dried over MgSO4. Evaporation of the solvent at reduced pressure gave a yellow oil, which was dissolved in 30 mL of CH2Cl2. The solution was cooled in at ice bath, and triphenylphosphine (1.64 g, 6.27 mmol) and carbon tetrabromide (2.08 g, 6.27 mmol) were added. The mixture was then stirred at r.t. for 16 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (0-60% EtOAc/hexanes) to give 860 mg of the title compound as an orange oil. 1H NMR (CDCl3, 200 MHz): δ=7.20-7.45 (m, 6H), 6.20 (d, 1H, J=7.0 Hz), 5.12 (s, 2H), 4.43 (q, 2H, J=7.0 Hz), 4.28 (s, 2H), 1.42 (t, 3H, J=7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CN(C(O[N:43]1[C:48](=O)[CH:47]=[CH:46]C=C1)=[N+](C)C)C.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH:43][CH:48]3[CH2:46][CH2:47]3)=[O:26])=[CH:28][CH:29]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reaction time: 2 h

Procedure:
rac-4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-benzoic acid (0.70 g, 1.6 mmol) was dissolved in DMF and activated with the coupling reagent TPTU (0.48 g, 1.6 mmol) and Hünig's base (0.55 ml, 3.2 mmol) for 2 min. ⅛ of this activated mixture was delivered to a reaction tube on a parallel synthesizer containing cyclopropylamine (0.013 g, 0.22 mmol) and a further amount of Hünig's base (0.04 ml, 0.22 mmol) in DMF (3 ml). The reaction mixture was shaken for 2 h, concentrated under reduced pressure and purified directly using preparative RP(C18) chromatography: lyophilisate 40 mg; MS: m/e=476.1 (MH+), 493.1 (MNH4+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:46]=[CH:47][C:48]=1[O:49][CH3:50])[CH2:28][O:29][C:30]([NH:32][C:33]1[N:41]=[CH:40][N:39]=[C:38]2[C:34]=1[N:35]=[CH:36][N:37]2[CH2:42][C:43](O)=[O:44])=[O:31]>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:43](=[O:44])[CH2:42][N:37]1[CH:36]=[N:35][C:34]2[C:38]1=[N:39][CH:40]=[N:41][C:33]=2[NH:32][C:30]([O:29][CH2:28][C:27]1[CH:46]=[CH:47][C:48]([O:49][CH3:50])=[C:25]([O:24][CH3:23])[CH:26]=1)=[O:31])[CH3:2]
Reactant: COc1ccc(COC(=O)Nc2ncnc3c2ncn3CC(=O)O)cc1OC
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(NC(=O)OCc3ccc(OC)c(OC)c3)ncnc21
Yield: 97.6 %

Procedure:
The title compound (6.28 g, 96%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (3.26 g, 9.5 mmol) and [6-N-(3,4-dimethoxybenzyloxycarbonyl)-adenin-9-yl]-acetic acid (3.50 g, 9.03 mmol) as per the procedure of Example 27. 1H NMR (500 MHz; DMSO-d6) δ 10.58 (s, 1H), 8.98 (brs, 0.6H), 8.77 (brs, 0.4H), 8.57 (s, 0.4H), 8.53 (s, 0.6H), 8.29 (d, 1H), 8.27 (m, 1H), 8.17 (d, 1H), 7.65 (m, 2H), 7.08 (s, 1H), 6.98 (d, 1H), 6.94 (d, 1H), 5.35 (s, 1.2H), 5.15 (s, 0.8H), 5.12 (s, 2H), 4.45 (s, 0.8H), 4.18 (q, 0.8H), 4.07 (s, 1.2H), 4.01 (q, 1.2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.70 (t, 1.2H), 3.48 (t, 1.2H), 3.42 (t, 0.8H), 3.22 (t, 0.8H), 1.23 (t, 1.2H), 1.12 (t, 1.8H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[CH:9]=[N:10][CH:11]=1.[CH3:14][NH2:15]>CO>[CH3:14][NH:15][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1
Reactant: COc1cncc(OCCCCl)c1
Reactant: CN
Solvent: CO
Product: CNCCCOc1cncc(OC)c1
Temperature: 100 °C

Procedure:
Crude 5-(3-chloropropoxy)-3-methoxypyridine (0.75 g, 3.73 mmol) was dissolved in methanol (10.5 mL) and added to a 40 wt % aqueous solution of methylamine (10.6 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the solution was concentrated by rotary evaporation. Saturated NaCl solution (50 mL) was added, and the mixture was basified with 10% NaOH solution to pH 11. The mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered and concentrated by rotary evaporation to give 0.54 g of a brown oil. The product was purified by column chromatography on silica gel (18 g) eluting with CHCl3—CH3OH (1:1, v/v) to remove impurities, followed by CHCl3—CH3OH-Et3N (50:50:2, v/v/v) to collect the product. Selected fractions containing the product were combined and concentrated by rotary evaporation. The resulting brown oil was dissolved in CHCl3 (25 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to give 0.228 g (31.2%) of a brown oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)C1C=CC=CC=1.CS(O)(=O)=O>C(Cl)Cl>[CH2:21]([NH:20][C:18]([NH:17][C:15]1[S:16][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:23][C:13]=2[N:14]=1)=[O:19])[CH3:22]
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)ccc2s1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(O)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(5-(benzyloxy)benzo[d]thiazol-2-yl)-3-ethylurea I (1.20 g, 3.66 mmol) in DCM (100.0 mL) was added methanesulfonic acid (4.32 mL, 66.22 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h. After the completion of reaction (TLC monitoring), the solvent was evaporated. The residue was cooled and then basified with saturated NaHCO3 solution followed by extraction with EtOAc (3×100 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (0.90 g) that was carried forward to the next step without further purification. MS: 238.10 (M+H)+.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=C[CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.OC(COC1C=CC([Cl:55])=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:55].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:21]=[CH:26][CH:27]=[CH:28][C:29]=1[CH:24]([CH3:25])[CH3:23])[CH2:4][NH:5][C:6]([CH3:16])([CH3:17])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2cccc3ccccc23)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C(C)C)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M-15,1), 251 (19), 250 (100), 163 (5), 122 (5), 121 (53), 114 (8), 104 (6),103 (6), 91 (24), 77 (14).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH2:29]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[CH2:30][CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7](=[O:8])[C:2]=1[C:36]1[CH:37]=[CH:38][C:33]([O:32][CH2:29][CH2:30][CH3:31])=[CH:34][CH:35]=1)[CH3:28]
Reactant: CCCOc1ccc(B(O)O)cc1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCOc1ccc(-c2c(CC)nc(CCC)n(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 92.3 %

Procedure:
To a solution of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g) and 4-propoxyphenylboronic acid (0.31 g) in 1,4-dioxane (15 mL) were added 2 M aqueous cesium carbonate solution (3 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.52 g, 93%) as a colorless amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:19]=1[F:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[C:22]([N:34]2[CH2:35][CH2:36][CH:31]([C:29]([O:28][CH2:26][CH3:27])=[O:30])[CH2:32][CH2:33]2)[CH:21]=[CH:20][C:19]=1[F:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc2c(c1)nc(-c1cc(Br)ccc1F)n2C(=O)OC(C)(C)C
Reactant: CCOC(=O)C1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCN(c2ccc(F)c(-c3nc4cc(C)ccc4n3C(=O)OC(C)(C)C)c2)CC1
Temperature: 80 °C
Yield: 99.5 %

Procedure:
Method 8—Step a 2-(5-Bromo-2-fluoro-phenyl)-5-methyl-benzoimidazole-1-carboxylic acid tert-butyl ester (obtained as described in general method 6, step c) (0.94 g, 2.40 mmol), piperidine-4-carboxylic acid ethyl ester (0.48 g, 3.12 mmol) and cesium carbonate (3.90 g, 12.01 mmol) were placed into a dried schlenk tube and 3 cycles of vacuum/nitrogen were performed, then dry toluene (4 mL) was added. At the same time palladium(II)acetate (0.82 g, 0.36 mmol), and BINAP (0.45 g, 0.72 mmol) were placed into a dried schlenk tube under nitrogen and 3 cycles of vacuum/nitrogen were performed. Then dry toluene (2 mL) was added, at room temperature under nitrogen, and the mixture was added to the first schlenk. The reaction mixture was heated at 80° C. overnight, water (5 mL) was added, the organic layer was filtered over Na2SO4 and then purified by flash chromatography (eluent: cyclohexane:EtOAc 8:2) to obtain 1.15 g of the title compound in quantitative yield.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[C:8]([OH:17])(=[O:16])[C:9]1C(=C[CH:13]=[CH:14][CH:15]=1)O>>[C:5]([O:4][C:1]1[C:9](=[CH:15][CH:14]=[CH:13][CH:2]=1)[C:8]([OH:17])=[O:16])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccccc1O
Product: CC(=O)Oc1ccccc1C(=O)O

Procedure:
Reactor inlet stream 19 is in fluid communication with reactor 10. Reactor inlet stream 19 as introduced to reactor 10 comprises a molar excess of between about 2% and about 20% acetic anhydride compared to salicylic acid. Reactor 10 may preferably be any reactor configured for the esterification of reaction to produce acetyl salicyclic acid. Further, reactor 10 is preferably configured to distill acetyl salicylic acid. Reactor 10 may preferably be a continuous stirred tank reactor or a batch reactor, without limitation. Further, reactor 10 may preferably comprise a jacketed reactor. In certain embodiments, reactor 10 is configured as a holding tank for increased residence time, distillation, and/or agitation of reaction mixture.