Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:19][C:20]=2[CH2:21][CH3:22])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:29]([CH2:37][C:38](=O)[CH3:39])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:21]([C:20]1[O:19][C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:17][C:16]=1[CH2:15][CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C@H:2]([NH:1]/[C:38](/[CH3:39])=[CH:37]\[C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:3]([OH:5])=[O:4])=[CH:8][CH:9]=1)[CH3:22]
Reactant: CCc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC(=O)CC(=O)c1ccccc1
Product: CCc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N/C(C)=C\C(=O)c2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared (as described above for the preparation of example 1) from a suspension of 205 mg (0.54 mmol) of Intermediate 52 and 87 mg (0.54 mmol) of benzoylacetone to yield 145 mg (51%) of example 55: TLC (DCM/MeOH, 4/1): Rf=0.60; 1H NMR (DMSO-d6, 300 MHz) δ11.42 (d, 1H, J=9.0), 7.89-7.86 (m, 2H), 7.77-7.74 (m, 2H), 7.48-7.32 (m, 6H), 7.11 (d, 2H, J=8.4), 6.77 (d, 2H, J=8.4), 5.53 (s, 1H), 4.1 (t, 1H, J=6.3), 3.2-3.14 (m, 2H), 2.86 (t, 2H, J=6.3), 2.79-2.74 (m, 1H), 2.67 (q, 2H, J=7.5), 1.65 (s, 3H), 1.17 (t, 3H, J=7.5); low resolution MS (ES+)m/e 525.2 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:12]2[C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][O:15][C:11]=2[CH:10]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[CH:21]=[CH:20][C:12]2[CH:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][O:15][C:11]=2[CH:10]=1
Reactant: COC(=O)c1coc2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1COc2cc(O)ccc21
Reaction time: 8 h
Yield: 102.9 %

Procedure:
To a mixture of methyl 6-(benzyloxy)-1-benzofuran-3-carboxylate (10 g) and MeOH (200 mL) was added 10% Pd—C (2 g). The mixture was stirred under hydrogen atmosphere overnight. The catalyst was removed by filtration. The filtrate was concentrated in vacuo to give the title compound (7.08 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][OH:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:14][C:15]=1[CH3:16].O[C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:14][C:15]=1[CH3:16])[CH2:23][O:24][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COc1cc(CO)ccc1OCc1nc(N2CCOCC2)sc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(N2CCOCC2)sc1C
Reaction time: 15 h
Yield: 56.5 %

Procedure:
To a mixture of {3-methoxy-4-[(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]phenyl}methanol (2.00 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (1.19 g), tributylphosphine (1.74 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (2.17 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (1.68 g, yield 57%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 149-150° C.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH:15]=[CH:16][CH:17]=1.[N+]([O-])(O)=O.[OH-].[NH4+]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH:15]=[CH:16][C:17]=1[N+:6]([O-:9])=[O:7]
Reactant: COc1cccc(Cn2ccnc2)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc(Cn2ccnc2)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
To 184 parts of cold (10° C., ice bath) concentrated sulfuric acid were added portionwise 75 parts of 1-[(3-methoxyphenyl)methyl]-1H-imidazole mononitrate during 1 hour. Upon complete addition, stirring was continued for 30 minutes at 10° C. 15 Parts of concentrated nitric acid were added dropwise during 30 minutes at 15° C. Upon completion, the whole was stirred for 30 minutes at 10° C. The reaction mixture was poured into 1500 parts of crushed ice and the whole was treated with an ammonium hydroxide solution. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of ethyl acetate, methanol and methanol, saturated with ammonia, (95:2.5:2.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was stirred in 45 parts of ethyl acetate. The precipitated product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 28.2 parts (40.3%) of 1-[(3-methoxy-4-nitrophenyl)methyl]-1H-imidazole (int. 145).
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:11]([O:13]CC)=O)[C:6](=[O:7])[N:5]([CH3:16])[C:3]1=[S:4].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([O:25][C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])[CH:19]=1.C(O)C>CN(C)C=O>[CH3:16][N:5]1[C:6](=[O:7])[CH:8]([C:11](=[O:13])[NH:22][C:21]2[CH:23]=[CH:24][C:18]([Cl:17])=[CH:19][C:20]=2[O:25][C:26]2[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=2[Cl:32])[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[S:4]
Reactant: Nc1ccc(Cl)cc1Oc1c(Cl)cccc1Cl
Reactant: CCOC(=O)C1C(=O)N(C)C(=S)N(C)C1=O
Solvent: CN(C)C=O
Solvent: CCO
Product: CN1C(=O)C(C(=O)Nc2ccc(Cl)cc2Oc2c(Cl)cccc2Cl)C(=O)N(C)C1=S
Reaction time: 6 h

Procedure:
2.5 g (10 mmol) of 1,3-dimethyl-5-ethoxycarbonyl-2-thiobarbituric acid, 2.9 g (10 mmol) of 4-chloro-2-(2,6-dichlorophenoxy)aniline, 40 ml of ethanol and 3 ml of dimethylformamide are mixed and then boiled under reflux with stirring for 6 hours. The reaction mixture is then cooled and the resultant crystalline precipitate is isolated by filtration. If necessary, the crystalline precipitate can be recrystallised from a mixture of dioxane and ethanol. Melting point 254°-257° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Br[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:17]([C:14]1[CH:15]=[CH:16][C:11]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[F:1])=[CH:12][CH:13]=1)[CH2:18][CH2:19][CH3:20]
Reactant: Nc1ccc(F)cc1F
Reactant: CCCCc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCCCc1ccc(Nc2ccc(F)cc2F)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
2,4-difluoroaniline (44 m mol)), 1-bromo-4-butylbenzene (30 m mol)), palladium(II)acetate (0.4 m mol)), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.9 m mol)), and potassium-tert-butoxide (44 m mol)) were dissolved in toluene (100 ml) in a 250 ml tri-neck-round bottom flask and then stirred in a bath of 100° C. for 24 hours. After the reaction was terminated, the toluene was removed from the solution. After extraction was performed on the solution using dichloromethane and water, the resulting solution was reduced in pressure and distilled. After a silica gel column chromatography, the solvent was reduced in pressure and distilled, thereby obtaining 4-butyl-N-(2,4-difluorophenyl)benzeneamine liquid having 0.3 g.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2C=O)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([OH:25])=[CH:11][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1ccccc1Oc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
The crude aldehyde from step 1 (23.3 g, 0.10 mmol) was dissolved in dichloromethane (500 mL), and m-chloroperbenzoic acid (70%, 50.0 g, 0.20 mmol) and sodium bicarbonate (25.2 g, 0.30 mmol) were added. The resulting heterogeneous mixture was stirred and heated under reflux for 2 h and then quenched with an aqueous solution of sodium sulfite (0.5 M, 500 mL). After stirring at 25° C. for 30 min, the organic phase was separated and the aqueouse phase was extracted with dichloromethane (2×200 mL). The combined organic phases were washed with a saturated solution of sodium bicarbonate (2×200 mL), dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel, eluting with an 8:2 mixture of hexane and ethyl acetate to give the title phenol.
Reaction SMILES: [CH2:1]([O:19][CH:20]([CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:21][OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:1]([O:19][CH:20]([CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:21]=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOCC(CO)OCCCCCCCC/C=C\C/C=C\CCCCC
Agent: O=[Cr](=O)([O-])Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCC(C=O)OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 38.9 %

Procedure:
To a solution of 2,3-bis((9Z,12Z)-octadeca-9,12-dienyloxy)propan-1-ol (4.0 g, 7.0 mmol) and PCC (4.5 g, 21.0 mmol) in dichloromethane (75 mL) was added sodium carbonate (375 mg, 3.5 mmol). The solution was stirred for 6 hours at room temperature then filtered through silica with diethyl ether rinses (250 mL). The filtrate was concentrated in vacuo to dryness and purified by column chromatography on silica gel 60 (eluted with a gradient of 100% hexanes to 5% ether in hexanes) to afford 2,3-bis((9Z,12Z)-octadeca-9,12-dienyloxy)propanal as a colorless oil (1.6 g, 39%)
Reaction SMILES: ClC1C=C[CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].ClCC[N:14]1C[CH2:18][CH2:17][CH2:16][CH2:15]1>CS(C)=O>[N:10]1([CH2:18][CH2:17][CH2:16][C:15]#[N:14])[CH2:5][CH2:4][CH2:3][CH2:8][CH2:9]1
Reactant: N#CCc1ccccc1Cl
Reactant: ClCCN1CCCCC1
Solvent: CS(C)=O
Product: N#CCCCN1CCCCC1

Procedure:
A process for the preparation of a compound of the formula ##STR25## which comprises (a) reacting 2-chlorobenzeneacetonitrile with 1-(2-chloroethyl)piperidine in the presence of a base and DMSO to produce a piperidinebutanenitrile of the formula ##STR26## (b) alkylating the resulting piperidinebenzene-butanenitrile with an alkylating agent in the presence of a base and DMSO to produce a piperidinebutanenitrile of the formula ##STR27## (c) hydrolyzing the resulting piperidine-butanenitrile in toluene with hydrochloric acid to produce a compound of the formula ##STR28## (d) reacting the resulting compound with isopropylamine in a solvent to form an imine of the formula ##STR29## (e) reducing the imine with sodium borohydride in ethanol to form an amine of the formula ##STR30## (f) acetylating the resulting amine with acetic anhydride in a solvent to produce an acetylated amine of the formula ##STR31## (g) hydrolyzing the acetylated amine with sulfuric acid to produce ##STR32## (h) recovering the compound so produced.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][CH2:26]2>CN(C=O)C>[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:26]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Nc1cccc2c1CNC2
Solvent: CN(C)C=O
Product: Nc1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Temperature: 120 °C
Yield: 64.5 %

Procedure:
A mixture of 136 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 180 mg of 4-aminoisoindoline, and 1.5 ml of anhydrous DMF was heated at 120° C. for 1.5 hours while stirring. The resulting reaction mixture was evaporated under reduced pressure to dryness. 20 ml of chloroform and 10 ml of 5% acetic acid was added to the residue, and the mixture was stirred. Deposited crystals were collected by filtration, washed with water and ethanol. The chloroform layer was separated, washed with brine, dried over anhydrous sodium sulfate, and condensed. The residue was crystallized by the addition of hot ethanol. After cooling the mixture, the crystals were collected by filtration. These crystals were combined with those collected above and were recrystallized from a mixed solvent of chloroform, methanol, and ethanol to obtain 123 mg of the target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][C:17]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=1)=[O:27])([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][C:17]([C:19]4[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=4)=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=[CH:31][N:30]=1)=[O:27]
Reactant: O=C(Cc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1[N+](=O)[O-])Nc1cc(C(F)(F)F)ccn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1cc(-c2cnc3cc(-c4ccncc4)ccn23)ccc1CC(=O)Nc1cc(C(F)(F)F)ccn1
Yield: 14.3 %

Procedure:
Suspend 2-[2-nitro-4-(7-pyridin-4-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-N-(4-trifluoromethyl-pyridin-2-yl)-acetamide (0.18 g, 0.35 mmol) and ammonium formate (0.11 g, 1.82 mmol) in anhydrous methanol (5 mL) and bubble nitrogen through the solution for 5 minutes. Under a positive stream of nitrogen, add 10% Pd-on carbon (0.03, 0.03 mmol) to the solution and stir the reaction at ambient temperature for 18 hours. Filter the reaction contents through a pad of Celite® and wash the pad with methanol (40 mL). Concentrate the solution and then chromatograph the residue on silica using a gradient of (0→2→5%) methanol in dichloromethane to yield the title compound (0.03 g, 0.05 mmol). MS(ES), m/z 489 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][OH:18])=[CH:11][C:10]=1[O:19][CH3:20])(C)(C)C.Cl>C(O)(=O)C>[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][OH:18])=[CH:11][C:10]=1[O:19][CH3:20]
Reactant: COc1cc(OCCO)ccc1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(OCCO)ccc1CN
Temperature: 80 °C
Yield: 9.3 %

Procedure:
The above [4-(2-hydroxy-ethoxy)-2-methoxy-benzyl]-carbamic acid tert-butyl ester (10.3 mg, 0.35 mmol) is treated with 37% aq. HCl (0.1 mL) and acetic acid (1 mL) for 1.5 h at rt. The solvents are removed by lyophilisation. The residue is dissolved in 2 N aq. NaOH (1 mL) and ethanol (0.25 mL) and heated to 80° C. for 1 h. The mixture is cooled to rt and extracted twice with EA. The organic extracts are combined, dried over Na2SO4, filtered and evaporated to give 2-(4-aminomethyl-3-methoxy-phenoxy)-ethanol (6.4 mg) as a beige oil. LC-MS: tR=0.58 min, [M+1]+=198.11.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[Cl:5][C:6]1[N:11]=[C:10](Cl)[N:9]=[C:8]([N:13]([CH:39]2[CH2:44][C:43]([CH3:46])([CH3:45])[NH:42][C:41]([CH3:48])([CH3:47])[CH2:40]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([C:31]2[N:36]=[C:35]([Cl:37])[N:34]=[C:33](Cl)[N:32]=2)[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[N:7]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:5][C:6]1[N:11]=[C:10]([NH:4][CH2:1][CH:2]=[CH2:3])[N:9]=[C:8]([N:13]([CH:39]2[CH2:40][C:41]([CH3:47])([CH3:48])[NH:42][C:43]([CH3:45])([CH3:46])[CH2:44]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([C:31]2[N:36]=[C:35]([Cl:37])[N:34]=[C:33]([NH:4][CH2:1][CH:2]=[CH2:3])[N:32]=2)[CH:21]2[CH2:22][C:23]([CH3:29])([CH3:30])[NH:24][C:25]([CH3:28])([CH3:27])[CH2:26]2)[N:7]=1
Reactant: CC1(C)CC(N(CCCCCCN(c2nc(Cl)nc(Cl)n2)C2CC(C)(C)NC(C)(C)C2)c2nc(Cl)nc(Cl)n2)CC(C)(C)N1
Reactant: C=CCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCNc1nc(Cl)nc(N(CCCCCCN(c2nc(Cl)nc(NCC=C)n2)C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)n1
Reaction time: 19 h

Procedure:
17.2 g (0.3 mole) of anhydrous allylamine are added dropwise, in the course of one hour, at 30°-40° and while stirring, to a solution of 103.6 g (0.15 mole) of N,N'-bis-(2,4-dichloro-1,3,5-triazin-6-yl)-N,N'-bis-(2,2,6,6-tetramethylpiperid-4-yl)-hexamethylenediamine in 500 ml of toluene. A solution of 12.0 g (0.3 mole) of sodium hydroxide in 100 ml of water is then added at approx. 30°, and stirring is continued for a further 19 hours at 50°. The mixture is worked up by separating off the aqueous phase in a separating funnel, washing the organic phase with three times 200 ml of water, drying it over sodium sulfate and removing the solvent by vacuum distillation. The solid residue is recrystallised from ethyl methyl ketone, which gives pure N,N'-bis-(2-chloro-4-allylamino-1,3,5-triazin-6-yl)-N,N'-bis-(2,2,6,6-tetramethylpiperid-4-yl)-hexamethylenediamine of melting point 210°-211°.
Reaction SMILES: CS(OC1C=CC(/C=[CH:13]/[C:14]([OH:16])=[O:15])=CC=1)(=O)=O.[F:17][C:18]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:19]=1[CH:20]=O.C(C1C=CC(OS(C)(=O)=O)=CC=1)=O>>[F:17][C:18]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:19]=1/[CH:20]=[CH:13]/[C:14]([OH:16])=[O:15]
Reactant: CS(=O)(=O)Oc1ccc(/C=C/C(=O)O)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Agent: CS(=O)(=O)Oc1ccc(C=O)cc1
Product: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1F

Procedure:
5.12 g of (E)-2-Fluoro-4-(trifluoromethyl)cinnamic acid were synthesized as described for (E)-3-(4-(methanesulfonyloxy)phenyl)acrylic acid using 2-fluoro-4-trifluoromethylbenzaldehyde (commercially available from Aldrich) instead of methanesulfonic acid 4-formylphenyl ester.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].Br[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23]>CS(C)=O>[CH3:23][C:22]([CH3:24])=[CH:21][CH2:20][O:7][N:8]1[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]2[C:12]1=[O:13]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)=CCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium carbonate (7.55 g, 54.6 mmol) was added to a solution of N-hydroxyphthalimide (13.93 g, 85.4 mmol) in 150 mL of DMSO to give a wine-red colored solution. 4-Bromo-2-methyl-2-butene (20 g, 134 mmol) was added to the solution dropwise and the reaction was stirred for 16 hours at room temperature. The reaction was poured into 600 mL of ice water to give a white crystalline solid. The crude crystalline product was filtered, washed with ice water, and air dried. The crystalline product was recrystallized from ethanol to give 15.7 g, m.p. 97°-98° C.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[C:18]([CH3:24])=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[CH:14][C:9]=2[S:8][CH:7]=1)C.[OH-].[Na+].Cl>O.CO.CCO.C1COCC1>[CH3:24][C:18]1[C:17]([CH2:16][O:15][C:13]2[CH:12]=[CH:11][C:10]3[C:6]([CH2:5][C:4]([OH:25])=[O:3])=[CH:7][S:8][C:9]=3[CH:14]=2)=[CH:22][CH:21]=[C:20]([CH3:23])[N:19]=1
Reactant: CCOC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1ccc(COc2ccc3c(CC(=O)O)csc3c2)c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
To a mixture of ethyl(6-((2,6-dimethylpyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (7.73 g), EtOH (75 mL) and THF (dry) (75 mL) was added 1N NaOH (45 mL). The mixture was stirred at room temperature for 2 h. To the mixture were added EtOH (50 mL) and MeOH (75 mL). The mixture was neutralized with 1N HCl (45 mL), and then water (500 mL) was added dropwise to the mixture. The precipitate was collected by filtration and washed with water. The solid was recrystallized from acetone-hexane to give the title compound (4.85 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:5]2=[N:6][CH:7]=1.[Cl:13]C1C=CC=CC=1>>[Cl:13][CH2:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:5]2=[N:6][CH:7]=1
Reactant: Clc1ccccc1
Reactant: Cc1cnc2c(c1)C(=O)OC2=O
Product: O=C1OC(=O)c2ncc(CCl)cc21
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
106.8 g (0.65 mol) of 5-methyl-2,3-pyridine dicarboxylic acid anhydride were dissolved in 427 g chlorobenzene and heated up to 85° C. A solution of 0.64 g (0.004 mol) AlBN in 99.0 g (0.66 mol) SO2Cl2 was added during 45 min. The mixture was stirred for additional 90 min at 85° C. Chlorobenzene was partly distilled off and the solution was cooled to 10° C. via 10 h ramp. The precipitate was filtered off and washed with chlorobenzene/hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl.[NH2:31][CH2:32][C:33]1[C:34](=[O:41])[NH:35][C:36]([CH3:40])=[CH:37][C:38]=1[CH3:39].CN1CCOCC1>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([NH:31][CH2:32][C:33]2[C:34](=[O:41])[NH:35][C:36]([CH3:40])=[CH:37][C:38]=2[CH3:39])=[O:16])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:12])[CH3:13])[C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Cl)nc21
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-Chloro-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.12 g, 0.501 mmol), 1-hydroxy-7-azabenzotriazole (0.102 g, 0.751 mmol), EDC (0.144 g, 0.751 mmol), and 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (0.123 g, 0.651 mmol) were dissolved in dimethyl sulfoxide (3.0 mL) and stirred at room temperature. Added next to the stirring contents was N-methylmorpholine (0.220 mL, 2.003 mmol) via syringe at once. After stirring at room temperature overnight, the reaction mixture was slowly added to water (75 mL) and stirred for 10 min. After sitting for 10 min. at room temperature, the contents were filtered to afford a tan solid which was washed with water and then cold 50% aq EtOH. The contents were filtered, air-dried for 10 min., and then dried under vacuum for 1 hr. The collected solid was then further dried in a vacuum oven at 45° C. for 4 hr. The title compound was collected as 0.105 g (55%). LCMS E-S (M+H)=373.9. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49 (d, J=6.82 Hz, 6 H), 2.13 (s, 3 H), 2.20 (s, 3 H), 4.35 (d, J=4.80 Hz, 2 H), 5.07-5.20 (m, 1 H), 5.89 (s, 1 H), 7.66 (s, 1 H), 8.39 (s, 1 H), 8.91 (t, J=4.80 Hz, 1 H), 11.55 (s, 1 H).