Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1.C(#N)C.[O:21]([C:23]#[N:24])[Na].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[CH3:1][O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:23]([NH2:24])=[O:21])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Reactant: N#CO[Na]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC#N
Solvent: O
Product: COC1=Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
10-methoxy-5H-dibenz(b,f)azepine (29.9 g, 0.134 mol) was added to 300 ml acetonitrile in a three-neck flask (500 ml) equipped with a mechanical stirring apparatus. The mixture was stirred at room temperature for 15 minutes, and then NaOCN (18 g, 0.277 mol) was added, followed by pyridinium p-toluenesulfonate (75 g, 0.3 mol). The mixture was stirred at room temperature for about 4 hours, at which time TLC indicated that the reaction was complete (disappearance of 10-methoxy-5H-dibenz(b,f)azepine). 30 ml water was added, and the mixture stirred for 15 minutes. The solids were filtered and the filtrate was concentrated under vacuum. The semi-solid residue was triturated with acetone to provide a creamy solid, which was dried at 80° C. to provide 18 g (0.068 mol, 50% yield) of 10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide (10-methoxycarbamazepine).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl.CO>[OH:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCCOCCO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethylene glycol (22 g, 207.5 mmol) in CH2Cl2 (100 ml) was added triethylamine (10.5 g, 103.75 mmol). 9.89 (51.8 mmol) Toluene-4-sulfonyl chloride was added in one portion. The solution was stirred at room temperature for 1 hour. TLC was performed in 5% MeOH in DCM. After ½ hour a TLC showed formation of product. After 1 hour and 15 minutes the reaction mixture was washed with 0.1 M KHSO3 and 5% NaHCO3. The organic phase was dried with Na2SO3 and evaporated under reduced pressure. The crude reaction mixture was trapped on silica and purified by flash chromatography on a CombiFlash companion instrument (330 g column) using Hexane/EtOAc 50/50. Structure confirmed NMR.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:24][C@H:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:26][C:27](O)=[O:28])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(Cl)CCl.CI>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH:11][C:27](=[O:28])[CH2:26][C@H:25]([O:24][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCC
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CI
Product: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)C(=O)OCc1ccccc1)OC(=O)CCCCCCC
Yield: 93.1 %

Procedure:
In the same manner as described in Example 2-(5), L-serine benzyl ester (390 mg, 2.0 mmol) was acylated with (R)-3-octanoyloxytetradecanoic acid (815 mg, 2.2 mmol) in the presence of EDC·MeI (745 mg, 2.5 mmol) in CH2Cl2 to afford 1.02 g (93%) of N-[(R)-3-octanoyloxytetradecanoyl]-L-serine benzyl ester: mp 50-51° C.; 1H NMR (CDCl3) δ 0.88 (t, 6H, J=6.8 Hz), 1.1-1.7 (m, 30H), 2.30 (t, 2H, J=7.7 Hz), 2.51 (d, 2H, J=5.8 Hz), 2.60 (t, 1H, J=6.0 Hz), 3.97 (m, 2H), 4.65 (m, 1H), 5.22 (m, 3H), 6.61 (d, 1H, J=6.9 Hz), 7.35 (br s, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][N:17]([CH3:26])[C:18]1[CH:23]=[CH:22][C:21](C=C)=[CH:20][N:19]=1.[OH-].[K+].CN1C(=O)C[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:31][CH2:32][C:18]3([N:17]([CH3:16])[CH3:26])[CH:23]=[CH:22][CH:21]=[CH:20][NH:19]3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCCC1=O
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1ccc(N(C)C)nc1
Agent: [K+]
Agent: [OH-]
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCC2(N(C)C)C=CC=CN2)C1

Procedure:
The title compound is prepared from: a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, N,N-dimethyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: ClC1C=CC([N+]([O-])=O)=CN=1.N[C:12]1[N:17]=[C:16]([NH:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[NH:29][CH:30]=[CH:31][N:32]=3)=[C:24]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=3[Cl:40])[N:23]=2)[CH:15]=[CH:14][C:13]=1[N+:41]([O-:43])=[O:42]>>[Cl:40][C:34]1[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:33]=1[C:24]1[N:23]=[C:22]([NH:21][CH2:20][CH2:19][NH:18][C:16]2[CH:15]=[CH:14][C:13]([N+:41]([O-:43])=[O:42])=[CH:12][N:17]=2)[CH:27]=[CH:26][C:25]=1[C:28]1[NH:32][CH:31]=[CH:30][N:29]=1
Reactant: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: O=[N+]([O-])c1ccc(Cl)nc1
Product: O=[N+]([O-])c1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]{2-[(5-nitro(2-pyridyl))amino]-ethyl}amine was prepared from 2-chloro-5-(nitro)pyridine using the general method for {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine.
Reaction SMILES: Cl[C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][S:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CN(C=O)C>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[C:6]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)=[N:5][S:4][N:3]=2)[CH2:14][CH2:15]1
Reactant: C1COCCN1
Reactant: Clc1nsnc1-c1cccnc1
Solvent: CN(C)C=O
Product: c1cncc(-c2nsnc2N2CCOCC2)c1

Procedure:
A solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.59 g, 3 mmol) and morpholine (1.3 g, 15 mmol) in DMF (5 ml) was heated at 100° C. for 3 h. After evaporation water was added to the residue and extracted with ether. The combined and dried organic phases were evaporated and the residue purified by column chromatography (SiO2, eluent: ethyl acetate/methylene chloride (1:1)). Yield: 0.68 g (91%).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[OH-].[Li+:21].O1CCCC1>O.C(#N)C>[Li+:21].[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][CH2:4][C:3]([O-:19])=[O:2])[CH2:11][CH2:10]2)=[CH:13][CH:14]=1
Reactant: COC(=O)CCC1CCN(c2ccc(Cl)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: O=C([O-])CCC1CCN(c2ccc(Cl)cc2)CC1
Yield: 90.2 %

Procedure:
To 3-[1-(4-chloro-phenyl)-piperidin-4-yl]-propionic acid methyl ester (345 mg; 1.22 mmol, prepared in accordance with Example 142) is added lithium hydroxide (72 mg; 3.00 mmol) dissolved in water (6.5 mL). After dilution with tetrahydrofuran (10 mL) the reaction mixture is stirred for 2-4 hours. The mixture is then diluted with acetonitrile until a precipitate is formed. The solid is collected by filtration and dried under high vacuum to deliver the desired product (300 mg; 1.10 mmol).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:33])[C@H:21]([CH3:32])[NH:22][C:23](=[O:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[F:34]C1C=CC(CC(O)=O)=CC=1>>[F:34][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C:23]([NH:22][C@H:21]([C:20]([NH:19][C@@H:3]2[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C@@H:4]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:33])[CH3:32])=[O:31])=[CH:30][CH:29]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Product: C[C@H](NC(=O)Cc1ccc(F)cc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (113) was used except that 4-fluorophenylacetic acid (77 mg) was used instead of phenylacetic acid to afford the title compound as a 1:1 mixture with the 2S,3R diastereomer (134 mg), white solid, m.p. 130-140° C. 1H NMR (300 MHz, CDCl3) δ 0.97 (d, 1.5H, J=5 Hz), 1.07 (d, 1.5H, J=5Hz), 3.43 (two peaks, 2H), 4.52 (m, 0.5H), 4.57(m, 0.5H), 4.93 (t, 1H, J=6 Hz), 5.11 (t, 1H, J=6 Hz), 5.78(dd, 1H, J=7 Hz, J=10 Hz), 6.05 (d, 0.5H, J=8 Hz), 6.21(d, 0.5 Hz, J=8 Hz), 6.33 (d, 0.5 h, J=6 Hz), 6.66 (d, 0.5H, J=7 Hz), 6.88-7.60 (m, 13H), 7.96 (s, 1H). MS APCI, m/z=484 (M+Na). LC/MS: 2.10 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)C.[CH2:10]([CH:12]1[O:14][CH2:13]1)[Cl:11]>CC(C)=O>[Cl-:11].[OH:14][CH:12]1[CH2:13][N+:1]2([CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:10]1
Reactant: C1COCCN1
Reactant: ClCC1CO1
Solvent: CCO
Solvent: CC(C)=O
Product: OC1C[N+]2(CCOCC2)C1
Product: [Cl-]
Temperature: 250 °C
Reaction time: 36 h

Procedure:
To a 1 L 3-neck round bottom flask, fitted with a thermocouple, nitrogen inlet and a 250 ml addition funnel, was charged morpholine (91.5 g, 91.5 ml, 1.05 mole, 1.0 eq.) and 100 ml of ethanol. The solution was stirred rapidly while adding epichlorohydrin (100 g, 84.5 ml, 1.08 mole, 1.03 eq.) from the addition funnel over about 30 minutes. The temperature was monitored and when the pot temperature reached 27° C., the reaction was cooled with an ice water bath. The clear solution was stirred for 18 hours. The reaction was assayed by GC (dilute 5 drops of reaction mixture into 1 ml of ethanol and inject onto a 15 m DB-5 capillary GC column with the following run parameters, Injector 250° C., detector 250° C., initial oven temperature 28° C. warming to 250° C. at 10° C. per minute.) The reaction was complete with less than 3% morpholine remaining. The reaction was concentrated on the rotoevaporated at 50° C. with full house vacuum until no more distillate could be condensed. The resulting oil was stored at room temperature for 24-48 hours or until a significant mass of crystals was observed (seeded will speed up the process). The slurry was diluted with 250 ml of acetone and filtered. The solids were dried in the vacuum oven at 60° C. for 18-24 hours. This provided 84 g of crystalline product. The mother liquors could be concentrated and the crystallization process repeated in increase recovery. 1H NMR (400 MHz, DMSO-d6) δ6.55 (d, 1 H), 4.64 (m, 1 H), 4.53 (m, 2 H), 4.18 (m, 2 H), 3.74 (m, 4 H), 3.60 (m, 2 H), 3.48 (m, 2 H). 13C NMR (100 MHz, DMSO-d6) δ70.9, 61.39, 61.04, 60.25, 58.54, 57.80.
Reaction SMILES: [C:1]1([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1>C1COCC1.[Pd]>[C:11]1([CH2:10][CH2:9][C:1]2[CH:2]=[CH:3][C:4]([CH2:7][OH:8])=[CH:5][CH:6]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCc1ccc(C=Cc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: OCc1ccc(CCc2ccccc2)cc1

Procedure:
Hydrogenating 10 g (48 mmol) of 4-stilbenemethanol (Aldrich; Milwankee/U.S.A.) in 100 ml of THF, in the presence of 0.5 g of 5% Pd/C under low pressure and at RT, filtering through ®Celite (filtering aid based on kieselguhr, Johns-Manville Corp., obtainable from Fluka, Buchs, Switzerland) and evaporating the filtrate affords the title compound, approximately 15% of which, according to the 1H-NMR spectrum, consists of p-(2-phenylethyl)toluene: TLC Rf (A)=0.62; 1H-NMR (200 MHz, CDCl3): 2.92 (s, 4H), 4.68 (s, 2H), 7.15-7.35 (m, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]#[N:11])=[CH:4][CH:3]=1.[CH3:12][N:13]1[C:17]([C:18]#[N:19])=[CH:16][CH:15]=[C:14]1B(O)O.C(=O)([O-])[O-].[K+].[K+].COC(OC)COCC(OC)OC.O>O>[C:18]([C:17]1[N:13]([CH3:12])[C:14]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]#[N:11])=[CH:4][CH:3]=2)=[CH:15][CH:16]=1)#[N:19]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: N#CNCc1ccc(Br)cc1
Agent: COC(COCC(OC)OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cn1c(C#N)ccc1-c1ccc(CNC#N)cc1
Temperature: 10 °C
Yield: 27 %

Procedure:
(4-bromophenyl)methyl cyanamide (0.100 g, 0.47 mmol) tetrakis(triphenylphosphine)palladium(0) (0.050 g, 0.043 mmol), N-methyl-5-cyanopyrroleboronic acid (0.150 g, 1 mmol), potassium carbonate (0.345 g, 2.5 mmol) and dimethoxyethylether/water 3:1 were placed in a microwave reaction vial fitted with a septa. The vial was then filled with a continuous flow of nitrogen. Using microwave assisted conditions, the mixture was heated to 10° C. for 15 minutes. The mixture was poured into water, extracted with ethyl acetate, the ethylacetate dried over magnesium sulfate, and evaporated in vacuo. The residue was flash chromatographed using 9/1 Hexane/ethylacetate to give [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]methylcyanamide (0.030 g, 27%). HPLC purity 100% at 210-370 nm, 10 min.; the Xterra™ RP18 instrument, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C14H12N4+H+, 237.11347; found (ESI, [M+H]+), 237.1127.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](Cl)=[O:10])[S:5][C:6]=1[Cl:7].[CH3:12][NH:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[ClH:1].[CH3:12][N:13]([C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C:9](=[O:10])[CH2:8][C:4]1[S:5][C:6]([Cl:7])=[C:2]([Cl:1])[CH:3]=1
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCC1
Reactant: O=C(Cl)Cc1cc(Cl)c(Cl)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C(=O)Cc1cc(Cl)c(Cl)s1)[C@@H]1CCCC[C@H]1N1CCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
A solution of 1,61 g (7,01 mmoles) of 4,5-dichloro-2-thienylacetic acid chloride (formula (II); X=4-Cl, Y=5-Cl, Z=Cl) in 15 ml of absolute chloroform is dropped to a solution of 1,24 g (6,80 mmoles) of trans-N-methyl-2-(1-pyrrolidinyl)cyclohexylamine (formula III; R=methyl, ##STR7## and 0,69 g (6,80 mmoles) of triethylamine in 60 ml of absolute chloroform for 15 minutes at room temperature and then stirred 18 hours at room temperature. Thereafter the reaction solution is shaken out with saturated solution of sodium hydrogen carbonate, the organic phase is washed with water, dried over sodium sulfate and evaporated. The oily residue consisting of the crude base of formula (I) and some ether-insoluble by-product is taken up with 30 ml of ether, filtered over activated charcoal and HCl-gas is introduced into the solution. The precipitated crystalline hydrochloride is sucked off, dissolved in 4 ml of methanol, precipitated with 50 ml of wet ether, sucked off and the operation is repeated once. The colorless crystals are dried at 13,3 Pa and room temperature for 5 hours. Thus the non-hygroscopic hemihydrate of the hydrochloride is obtained. Yield 57%. M.p. 216°-218° C. The compound free of crystal water obtained by drying in vacuo at 13,3 Pa and 140° C. is hygroscopic.
Reaction SMILES: [Cl-].C[O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.[CH2:31]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])CCC.[Cl:40][C:41]1[CH:48]=CC(C#N)=[CH:43][CH:42]=1>O1CCCC1>[Cl:40][C:41]1[CH:48]=[CH:39][C:38]([C:37](=[O:3])[CH2:36][O:35][CH3:31])=[CH:43][CH:42]=1
Reactant: CCCCOCCCC
Reactant: N#Cc1ccc(Cl)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: COCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.8 %

Procedure:
Equipped with magnetic stirring, (methoxymethyl)-triphenylphosphonium chloride (5.2 g, 15.2 mmol) was suspended in anhydrous tetrahydrofuran at 0° C. under N2 flow. Phenyl lithium, in 1.8 M in di-n-butyl ether (8.4 mL, 15.2 mmol), was added such that the temperature did not exceed 4° C. Mixture remained at 0° C. for 15 minutes, and a solution of 4-chlorobenzonitrile (0.56 g, 4.07 mmol) dissolved in 10 mls of anhydrous tetrahydrofuran was added over 15 minutes. Reaction was warmed to room temperature and continued for another 2 hours. Reaction was quenched with 50 ml of water and mixture was extracted (3×100 mls) with ether. Combined ethers were washed (2×20 mls) brine, and dried over MgSO4. Organics were filtered and concentrated to an amber oil. Oil was loaded on a flash silica gel column and eluted with 10-40% EA/Hex gradient to afford 382 mg of 1-(4-chlorophenyl)-2-methoxy-ethanone. (51% yield).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[O:48]1[C:52]([CH2:53][NH2:54])=[CH:51][N:50]=[CH:49]1.CCN(C(C)C)C(C)C>ClCCl.CO>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:54][CH2:53][C:52]3[O:48][CH:49]=[N:50][CH:51]=3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NCc1cnco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NCc1cnco1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a 25 mL 3N round-bottomed flask equipped with nitrogen inlet, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (4) (0.250 g, 1.0 eq.) was dissolved in dichloromethane (5.0 mL, 20 V). The reaction mixture was cooled to 0° C. and then added HOBT (0.119 g, 1.1 eq.) followed by EDC HCl (0.150 g, 1.1 eq.) and oxazol-5-ylmethanamine HCl (0.143 g, 1.1 eq.). DIPEA (0.101 g, 1.1 eq) was added to this reaction mixture dropwise at the same temperature. The clear reaction mixture was stirred at 0° C. for 1.5 h. The progress of the reaction was followed by TLC analysis on silica gel with 5% methanol in dichloromethane as mobile phase and visualization with UV.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([O:14]C)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[OH-].[Na+]>CC(O)=O.O>[CH2:1]([C:8]1[NH:13][C:12](=[O:14])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccnc(Cc2ccccc2)n1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccnc(Cc2ccccc2)[nH]1
Temperature: 95 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of 2-benzyl-4-methoxypyrimidine (0.675 g, 3.37 mmol) in AcOH (15 mL) was added HBr (2.28 mL, 20.2 mmol; 48 wt % in H2O). The reaction mixture was stirred at 95° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with H2O. The pH of the reaction mixture was adjusted to 5-6 with 6 M aqueous NaOH and then partitioned between EtOAc and H2O. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude yellow solid. Purification of the crude product was achieved by trituration with dichloromethane and diethyl ether. The resulting solid was filtered, washed with diethyl ether, collected and dried under vacuum to yield the desired product (0.531 g, 85%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J=6.6 Hz, 1H), 7.31 (m, 4H), 7.23 (m, 1H), 6.10 (d, J=6.6 Hz, 1H), 3.83 (s, 2H). LRMS (ESI pos) m/e 187 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[S:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH:15]([CH3:22])[C:16]3=O)[C:3]1=O.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Mg].Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl>CCOCC.O>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:5][CH:6]=[CH:7][C:8]=2[S:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][C:15]([CH3:22])=[C:16]2[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Brc1ccccc1
Reactant: Br[Mg]c1ccccc1
Reactant: CC1Cc2c(Sc3cccc4c3CC(C)C4=O)cccc2C1=O
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: CC1=C(c2ccccc2)c2cccc(Sc3cccc4c3CC(C)=C4c3ccccc3)c2C1
Temperature: 0 °C

Procedure:
Under an argon atmosphere, to a solution of 3.20 g (9.93 mmol) of 2-methyl-4-[(2-methyl-1-oxo-2,3-dihydro-1H-inden-4-yl)sulfanyl]-1-indanone in 20 ml of ether, a solution of PhMgBr in ether [obtained from 0.73 g (30.0 mmol) of magnesium turnings, 4.77 g (30.4 mmol) of bromobenzene, and 30 ml of ether] was added dropwise with vigorous stirring at 0° C. This mixture was stirred overnight and then added to 50 ml of water. Then, to this mixture 12 M HCl (to pH 1) was added. The organic layer was separated; and the aqueous layer was extracted with 3×20 ml of dichloromethane. The combined extract was evaporated, and a mixture of the residue and 0.5 g para-toluenesulfonic acid in 150 ml benzene was refluxed for 1 hour. The resulting mixture was washed with 50 ml of saturated aqueous NaHCO3. The organic layer was separated, dried over Na2SO4, and evaporated to dryness. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 35 mm, l 300 mm, eluant: hexanes-CH2Cl2=1:2, vol.). Yield, 2.20 g (50%) of a yellowish solid.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C:21]1([NH2:32])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:30]#[N:31])[CH:27]=2)[CH2:22]1)=[O:20])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1([NH:32][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:30]#[N:31])[CH:27]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Reactant: CCOC(=O)C1(N)Cc2ccc(C#N)cc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 2-cyclobutoxy-3-methyl-benzoic acid (400 mg, 1.94 mmol), 2-amino-5-cyano-indan-2-carboxylic acid ethyl ester (670 mg, 2.91 mmol), HATU (1.11 g, 2.91 mmol) in anhydrous DMF (15 mL) is added DIPEA (480 μL, 2.91 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5%-60% EtOAc in heptane) to give a pure product (114) as a white semisolid (682 mg, 84%).