Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:27])[C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:16]N(C)C)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[O:29]1CCCC1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:27])[C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:16][OH:29])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)C(=CN(C)C)c2ccc(C)cc2)cc1OC
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Product: COc1ccc(CCNC(=O)C(=CO)c2ccc(C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
One gram (1.0 g) of crude N-[2-(3,4-dimethoxyphenyl)ethyl]-3-dimethylamino-2-(4-methylphenyl)acrylamide (2.7 mmol), 12 ml of 5% hydrochloric acid and 20 ml of tetrahydrofuran were mixed and stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate twice, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 0.76 g of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(4-methylphenyl)acrylamide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[C:9]=2[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.[CH2:22](O)[CH3:23]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[C:9]=2[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)CCc1c(-c2ccc(O)cc2)[nH]c2nccnc12
Product: CCOC(=O)CCc1c(-c2ccc(O)cc2)[nH]c2nccnc12

Procedure:
A solution of 3-{6-(4-hydroxyphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl}propionic acid (0.02 g) [Example 30] in ethanol (2 mL) was treated with a catalytic amount of paratoluenesulfonic acid. The mixture was refluxed for 4 hours, the solvent removed by evaporation and the precipitate filtered. The solid was then taken in ethyl acetate, the organic layer washed with water, brine, dried over magnesium sulfate and evaporated to give a yellow solid which was subjected to flash chromatography on silica, eluting with ethyl acetate) to give the title compound. MS: 298 (MH+).HPLC (Method C): RT=2.58 minutes.
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[C:32]([C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1)=O.C(OP([CH2:57][C:58]#[N:59])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:57][C:58]#[N:59])[CH:44]=[CH:45][C:46]=1[O:47][CH3:48]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2ccc3ccccc3c2)cc1OC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2ccc3ccccc3c2)cc1OC

Procedure:
3-(3,4-Dimethoxyphenyl)-3-naphth-2-ylacrylonitrile was prepared analogously to methyl 3,3-bis-(3',4'-dimethoxyphenyl)acrylate using 2-(3,4-dimethoxybenzoyl)naphthalene (2.9 g, 10 mmol), diethylcyanomethylphosphonate (1.8 mL, 11 mmol) and lithium hexamethyldisilazide (8.5 mL, 11 mmol, 1.3M) with a reaction time of 1 hour at reflux. The crude product was purified by chromatography (silica gel, methylene chloride) to afford 2.93 g (93%) of a mixture of the E and Z isomers as a white solid: mp 121-123° C.; 1H NMR (CDCl3) δ 8.11-6.78 (m, 20H), 5.76 (s, 1H), 5.75 (s, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H); 13C NMR (CDCl3) δ 162.7, 162.7, 151.2, 150.6, 148.9, 148.7, 136.6, 134.5, 134.0, 133.8, 132.8, 131.5, 129.7, 129.4, 129.0, 128.6, 128.6, 128.3, 128.1, 127.7, 127.7, 127.4, 127.2, 126.8, 126.6, 125.4, 123.2, 122.2, 118.4, 118.2, 112.7, 111.1, 110.8, 93.9, 93.4, 56.0, 56.0, 55.9; Anal. Calcd for C21H17NO2. Theoretical: C, 79.98; H, 5.43; N, 4.44. Found: C, 79.90; H, 5.65; N, 4.46.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:28])[C:24]([OH:27])([CH3:26])[CH3:25])=[CH:19][CH:18]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[C:12]([OH:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1.[P:29]([O:36]CC)([O:33][CH2:34]C)[O:30][CH2:31]C>>[CH3:31][O:30][P:29]([CH2:2][CH2:3][CH:4]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:28])[C:24]([OH:27])([CH3:26])[CH3:25])=[CH:19][CH:18]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[C:12]([CH3:14])([OH:15])[CH3:13])=[CH:7][CH:6]=1)(=[O:36])[O:33][CH3:34]
Reactant: CC(C)(O)C(=O)c1ccc(C(CCBr)c2ccc(C(=O)C(C)(C)O)cc2)cc1
Reactant: CCOP(OCC)OCC
Product: COP(=O)(CCC(c1ccc(C(=O)C(C)(C)O)cc1)c1ccc(C(=O)C(C)(C)O)cc1)OC
Yield: 106.8 %

Procedure:
1-(4-{3-Bromo-1-[4-(2-hydroxy-2-methylpropionyl)phenyl]propyl}phenyl)-2-hydroxy-2-methylpropan-1-one (5.0 g, 0.0112 moles) is reacted with 4.6 grams of triethyl phosphite following the procedure of Example 23 to give 5.7 g (98% yield) of {3,3-bis-[4-(2-hydroxy-2-methylpropionyl)phenyl]propyl}phosphonic acid dimethyl ester, a yellow oil. The ester is reacted with trimethylsilyl bromide in chloroform and methanol, following the procedure of Example 22, to give 5.0 g of the title compound, an amorphous solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)c(F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)c(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 38.9 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3,4,5-trifluorobenzyl)piperidine-1-carboxylate (309 mg, 0.77 mmol) (from example 143, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.203 mL, 0.77 mmol) in water (0.500 mL) was added and the mixture was stirred at −40° C. for 20 min. Hydroxylamine (50% in water, 0.047 mL, 0.77 mmol) was added and stirring continued at −40° C. for 3 h. The reaction mixture was then transferred to a preheated 80° C. solution of 6 M hydrogen chloride (3.98 mL, 23.87 mmol) and heating was continued for 20 min. The solvent was then evaporated. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 10-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer, over 30 minutes with a flow of 19 mL/min. Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3,4,5-trifluorobenzyl)-piperidine-1-carboxylate (111 mg, 38.9%) was isolated. MS m/z 371 (M+H)+
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Br:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[C:15]([CH3:25])[CH:16]2[Si:21](Cl)([CH3:23])[CH3:22].O>CCOCC>[Br:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[C:15]([CH3:25])[CH:16]2[Si:21]([CH:4]1[CH:3]=[CH:2][CH:1]=[CH:5]1)([CH3:23])[CH3:22]
Reactant: CC1=Cc2c(Br)cccc2C1[Si](C)(C)Cl
Reactant: C1=CCC=C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC1=Cc2c(Br)cccc2C1[Si](C)(C)C1C=CC=C1
Temperature: 0 °C

Procedure:
To a solution of 1.32 g (20.0 mmol) of freshly distilled cyclopentadiene in 120 ml of ether, 8.00 ml of 2.5 M (20.0 mmol) nBuLi in hexanes was added dropwise, while vigorously stirring, at 0° C. This mixture was stirred for 2 h at room temperature, and then 6.03 g (20.0 mmol) of (4-bromo-2-methyl-1H-inden-1-yl)(chloro)dimethylsilane was added dropwise over 30 min at −80° C. The resulting mixture was stirred for 1 h at this temperature, for 12 h at room temperature, and then 100 ml of water was added. The organic layer was separated. The aqueous layer was extracted with 2×100 ml of dichlorodimethylsilane. The combined organic fractions were dried over Na2SO4 and evaporated to dryness. The product was isolated using flash-chromatography on Silica Gel 60 (40-63 um, d 30 mm, 1 300 mm, eluent: hexanes). Yield 5.50 g (83%) of colorless oil of a mixture of isomers I, II, and III.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](C1NC=CN=1)([C:21]1[NH:22][CH:23]=[CH:24]N=1)=O.C(NCC)C.O>O1CCCC1>[CH2:21]([N:22]([CH2:23][CH3:24])[C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([NH:9][CH2:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:11]=1)[CH3:19]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)OC(=O)CNc1cccc(C(=O)O)c1
Solvent: CCNCC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cccc(NCC(=O)OC(C)(C)C)c1
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of 3-(N-tert-butoxycarbonylmethylamino)benzoic acid (10.0 g, 39.8 mmol) in 100 mL of tetrahydrofuran was added carbonyl diimidazole (6.78 g, 41.8 mmol) under Argon. After 2 h of stirring, diethylamine (5.82 g, 79.4 mmol) was added, and the reaction mixture was stirred for 18 h and then refluxed 3 h. After cooling, water (50 mL) was added to the reaction flask, and the contents were concentrated on a rotary evaporator. The resulting mixture was extracted three times with dichloromethane (50 mL). These extracts were combined, washed twice with 1 N aqueous hydrochloric acid solution (50 mL) and twice with water (50 mL), dried (Na2SO4), and concentrated to give 11.9 g (98%) of N,N-diethyl 3-(N-tert-butoxycarbonylmethylamino)benzamide as a yellow oil. MS (ES), m/z 307 (MH+). 300 MHz 1H NMR (CDCl3) δ1.03-1.19 (br m, 3H), 1.15-1.30 (br m, 3H), 1.45 (s, 9H), 3.14-3.31 (br m, 2H), 3.45-3.62 (br m, 2H), 4.33 (d, J=5.6 Hz, 1H), 4.95 (br s, 1H), 7.19-7.38 (m, 4H).
Reaction SMILES: C([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.C(=O)=O>>[CH:11]#[C:10][C:9]1[CH:12]=[CH:13][C:6]([OH:5])=[CH:7][CH:8]=1
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Agent: O=C=O
Product: C#Cc1ccc(O)cc1
Reaction time: 0.5 h

Procedure:
Further 10 g of p-tert-butoxystyrene was added to the reaction solution. With stirring, polymerization reaction was effected for 30 minutes. Polymerization was stopped by adding 0.1 mol of carbon dioxide gas to the reaction solution.
Reaction SMILES: [C:1](=[O:27])(ON1C(=O)CCC1=O)[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:18])[NH:16][CH3:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:28][NH:29][CH2:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:35][CH:36]=1.C(N(CC)CC)C>ClCCl>[CH3:28][N:29]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:32]=1)[C:1](=[O:27])[O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:18])[NH:16][CH3:17])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CNCc1cccc(-c2ccccc2)c1
Reactant: CNC(=O)c1ccc(-c2ccc(OC(=O)ON3C(=O)CCC3=O)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(-c2ccc(OC(=O)N(C)Cc3cccc(-c4ccccc4)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask was placed a solution of 4-[4-(methylcarbamoyl)phenyl]phenyl 2,5-dioxopyrrolidin-1-yl carbonate from Example 1 Step 4 (560 mg, 1.5 mmol, 1 equiv) in dichloromethane (40 mL), N-methyl (3-biphenyl)methylamine (301 mg, 1.5 mmol, 1 equiv) and triethylamine (153 mg, 1.5 mmol, 1 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was washed with 2×20 mL of water and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The crude product (650 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-002(Agilent)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water and acetonitrile (10.0% acetonitrile up to 80.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 2 min); Detector, uv 220 & 254 nm. The title compound was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([O:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Oc2ccc(F)c(Cl)c2)cc1
Yield: 92.7 %

Procedure:
To a solution of 3-chloro-4-fluorophenol (1.46 g, 10 mmol) and 1-fluoro-4-nitrobenzene (1.41 g, 10 mmol) in acetonitrile (40 mL) was added potassium carbonate (2.76 g, 20 mmol). The reaction mixture was heated at reflux for 4 hours. After filtration, the solvent was removed to give a residue. The residue was washed with n-hexane (2 times 15 mL) and dried to afford the title compound (2.48 g) which was directly used in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][N:19]=[C:18]([Cl:27])[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].O.Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=[C:18]([Cl:27])[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)nc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CNc2nc(Cl)ncc2C(=O)O)CC1
Reaction time: 20 h
Yield: 97.2 %

Procedure:
To a solution of ethyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-2-chloropyrimidine-5-carboxylate (0.390 g, 0.979 mmol) in THF (5 mL), aq. 1N LiOH (1.10 mL, 1.10 mmol) was added. After being stirred for 20 h, water (10 mL) was added. The solution was acidified with 1N HCl (2 mL) to pH 1-2. The product was extracted with EtOAc. The EtOAc solution was washed with brine, dried over Na2SO4, concentrated in vacuo to give 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-2-chloropyrimidine-5-carboxylic acid as a solid (0.353 g).
Reaction SMILES: C(O[C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17])C.[Br:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23].C(OC(=O)C)C>CS(C)=O>[Br:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17]
Reactant: CCOc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O
Reactant: Nc1ccccc1Br
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(Nc2c(Nc3ccccc3Br)c(=O)c2=O)c(O)c1
Temperature: 25 °C
Yield: 3.3 %

Procedure:
A mixture of 3-ethoxy-4-(2-hydroxy-4-cyanoanilino)-3-cyclobutene-1,2-dione (0.7 g, 2.71 mmol) and 2-bromoaniline (0.47 g, 2.73 mmol) were heated in 6 ml DMSO for overnight. The reaction mixture was cooled to room temperature, and ethylacetate was added and precipitates formed. The filtrate was partitioned between ethylacetate and water. The organic layer was dried over sodium sulfate and concentrated. After Gilson HPLC, 34 mg (3%) of purified product was obtained. LC/MS (H+) 386
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH3:12])[CH2:5][CH:6]2[Cl:11].C(N(CC)CC)C.[Cl:20][C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>O1CCCC1>[Cl:20][C:21]1[C:22]([C:23]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]([CH3:12])[CH2:5][CH:6]3[Cl:11])=[O:24])=[CH:26][CH:27]=[CH:28][N:29]=1
Reactant: CC1CC(Cl)c2cccc(N)c21
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1CC(Cl)c2cccc(NC(=O)c3cccnc3Cl)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of 1 g (5.5 mmol) of 4-amino-1-chloro-3-methylindane and 0.7 g (6.9 mmol) of triethylamine in 15 ml of tetrahydrofuran was added 1.1 g (6.2 mmol) of 2-chloronicotinic acid chloride under ice cooling, and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried over Glauber's salt and then concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography (eluent: n-hexane/ethyl acetate=2/1) to obtain 1.3 g of white crystals (Compound No. 6 shown in Table 2) in a yield of 75%.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([Br:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[CH3:12][C:13]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]=1>>[CH3:12][C:13]1[CH:18]=[C:17]([NH:19][C:3]([C:5]2[C:10]([Br:11])=[N:9][CH:8]=[CH:7][N:6]=2)=[O:4])[CH:16]=[CH:15][N:14]=1
Reactant: COC(=O)c1nccnc1Br
Reactant: Cc1cc(N)ccn1
Product: Cc1cc(NC(=O)c2nccnc2Br)ccn1

Procedure:
The title compound, MS: m/e=294.9 (M+H+), was prepared in accordance with the general method of example 1, step 2 from 3-bromo-pyrazine-2-carboxylic acid methyl ester (Example A) and 2-methyl-pyridin-4-ylamine (Example B).
Reaction SMILES: Br[CH2:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:15]3[C:10]([N:11]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:12](=[O:26])[N:13]([CH3:25])[C:14]3=[O:24])=[N:9]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>C1COCC1>[CH2:27]([N:11]1[C:10]2=[N:9][N:8]([CH2:7][C:6]3[CH:31]=[CH:32][C:3]([CH2:2][N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:4][CH:5]=3)[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:15]2[C:14](=[O:24])[N:13]([CH3:25])[C:12]1=[O:26])[CH:28]([CH3:29])[CH3:30]
Reactant: C1CCNC1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(CBr)cc3)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(CN4CCCC4)cc3)nc21

Procedure:
2-(4-(bromomethyl)benzyl)-7-isobutyl-5-methyl-3-(phenylamino)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (30 mg, 0.06 mmol), K2CO3 (16 mg, 0.12 mmol) and pyrrolidine (10 μL, 0.12 mmol) in THF is stirred at room temperature for 2 days. The mixture is then purified by HPLC to give final product as white powder. MS (ESI) m/z 487.3 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:16][C:17]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:16][C:17]1[CH:29]=[C:28]([O:30][C:31]2[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=2)[CH:27]=[CH:26][C:18]=1[C:19]([OH:21])=[O:20])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(Oc2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3ccccc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Oc2ccc(C(=O)O)c(NC(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.0 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(benzamido)-4-(4-methylphenoxy)benzoate and stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure and methanol was added to the obtained residue and a solid substance was separated by filtration to obtain 6.2 mg of 2-(benzamido)-4-(4-Methylphenoxy)benzoic acid as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[N:6][CH:7]=1.[CH:12]([NH:15][CH:16](C)C)(C)C.C(Cl)(=O)C(C)(C)C.CNC>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:15]([CH3:16])[CH3:12])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: CC(C)NC(C)C
Agent: CC(C)(C)C(=O)Cl
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)Cc1cncc(Br)c1
Reaction time: 0.42 h
Yield: 79.2 %

Procedure:
(5-Bromopyridin-3-yl)acetic acid (500 mg, 2.31 mmol) was dissolved in dichloromethane (5 mL), treated with di-iso-propylamine (402.4 μL, 2.31 mmol) and cooled in an ice water bath. Pivaloyl chloride (284.7 μL, 2.31 mmol) was added and the mixture was stirred for 25 minutes. 2 M dimethylamine (1.73 mL, 3.46 mmol) was added and the reaction was stirred 15 h. The mixture was washed with saturated ammonium chloride (1×), saturated sodium bicarbonate (1×), and dried over sodium sulfate to yield 2-(5-bromopyridin-3-yl)-N,N-dimethylacetamide as a brown oil (445 mg, 79%). MS: m/z 562 (M+H+).
Reaction SMILES: [CH2:1]([Sn:5]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH:6]=[CH:7][CH2:8][CH2:9][C:10]([O:12][Sn](CCCC)(CCCC)CCCC)=[O:11])[CH2:2][CH2:3][CH3:4].[F:34][C:35]1[C:40]([F:41])=[CH:39][C:38]([F:42])=[C:37]([F:43])[C:36]=1O>C1COCC1>[CH2:30]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:26][CH2:27][CH2:28][CH3:29])[CH:6]=[CH:7][CH2:8][CH2:9][C:10]([O:12][C:36]1[C:35]([F:34])=[C:40]([F:41])[CH:39]=[C:38]([F:42])[C:37]=1[F:43])=[O:11])[CH2:31][CH2:32][CH3:33]
Reactant: Oc1c(F)c(F)cc(F)c1F
Reactant: CCCC[Sn](C=CCCC(=O)O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C=CCCC(=O)Oc1c(F)c(F)cc(F)c1F)(CCCC)CCCC
Reaction time: 8 h

Procedure:
To a solution of tri-n-butylstannyl 5-(tri-n-butylstannyl)-4-pentenoate acid (1.0 equiv.) in anhydrous THF at room temperature is added dicyclohexy (1.2 equiv.) (Aldrich) and 2,3,5,6-tetrafluorophenol (1.2 equiv.) (Aldrich). The resulting solution is stirred overnight. The mixture is filtered, the filtrate is concentrated, and the residue is chromatographed to provide 2,3,5,6-tetrafluorophenyl 5-(tri-n-butylstannyl)-4-pentenoate.
Reaction SMILES: [ClH:1].CCOCC.[CH2:7]([N:14]1[C:20](=[O:21])[CH:19]([NH:22][C:23](=[O:35])[C@@H:24]([N:26](C)[C:27](=O)OC(C)(C)C)[CH3:25])[CH2:18][S:17][C:16]2[CH:36]=[CH:37][CH:38]=[CH:39][C:15]1=2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[ClH:1].[CH2:7]([N:14]1[C:20](=[O:21])[CH:19]([NH:22][C:23](=[O:35])[C@@H:24]([NH:26][CH3:27])[CH3:25])[CH2:18][S:17][C:16]2[CH:36]=[CH:37][CH:38]=[CH:39][C:15]1=2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@@H](C(=O)NC1CSc2ccccc2N(Cc2ccccc2)C1=O)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CN[C@@H](C)C(=O)NC1CSc2ccccc2N(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
1 M HCl in Et2O (2 mL, 2.00 mmol, Eq: 26.7) was added to a solution of tert-butyl (S)-1-(5-benzyl-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (35 mg, 75 μmol, Eq: 1.00) in MeOH (1 mL). After 2 h at RT, the mixture was stored in a freezer overnight, removed from the freezer and stirred an additional 2 h at RT. The mixture was concentrated, the residue dissolved in MeCN/H2O, and lyophilized to afford the title compound (25 mg, 83%). MS m/z 370.0 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[F:15][C:16]([F:29])([F:28])[CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.FC1C(OC)=C(F)C=C2C=1C=CN2C.[BH4-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][CH:4]=1)[NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([O:19][CH2:18][CH2:17][C:16]([F:15])([F:29])[F:28])[CH:21]=1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: O=Cc1cccc(OCCC(F)(F)F)c1
Agent: COc1c(F)cc2c(ccn2C)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2[nH]cc(CCNCc3cccc(OCCC(F)(F)F)c3)c2c1

Procedure:
Combine 350 mg (1.8 mmol) 5-methoxytryptamine, 401 mg 3-trifluoropropoxybenzaldehyde (1.8 mmol) and 4 g 4 A molecular sieves in 35 mL EtOH and reflux overnight. Decant the liquid into a separate flask and treat with 209 mg (5.5 mmol) NaBH4. Stir the reaction at ambient temperature for 1 hour. Concentrate under vacuum, and partition between 50 mL 1 N NaOH and 25 mL dichloromethane. Extract the aqueous layer with 25 ml dichloromethane and combine the organic layers and concentrate to dryness. Purify the resulting oil by radial chromatography (SiO2; 1% MeOH in CHCl3 mixed with conc. NH4OH) to afford 705 mg (1.8 mmol; 100%) of the desired compound as an oil. Conversion to it's HCl salt by stirring a solution of the compound in 50 mL 50/50 THF/EtOH with 1 g polyvinyl pyridine hydrochloride overnight, filtering and concentrating to a solid. Recrystallize the product from EtOAc: Analysis for C21H23F3N2O2 HCl: calcd: C, 58.81; H, 5.64; N, 6.53; found: C, 58.42; H, 5.44; N, 6.51; ISMS 393 (M+1).