Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][N:9]([OH:20])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NO.N1C=CC=[CH:25][C:24]1=[O:29].C(OC(=O)C)(=O)C>>[C:24]([O:20][N:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12](=[O:13])[C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10]1)(=[O:29])[CH3:25]
Reactant: O=c1cccc[nH]1
Reactant: O=c1c(-c2ccccc2)cn(O)cc1-c1ccccc1
Agent: NO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)On1cc(-c2ccccc2)c(=O)c(-c2ccccc2)c1

Procedure:
A 2.4 g. portion of 3,5-diphenyl-1-hydroxy-4(1H)-pyridone was made by the process of Example 23, using hydroxylamine as the aminating agent. The pyridone was added to 25 ml. of acetic anhydride and the mixture was heated on the steam bath for about 1 hour. The volatiles were then evaporated under vacuum, and the residue was washed with benzene and then recrystallized, first from benzene and then from chloroform-hexane. The yield was 2.1 g. of 1-acetoxy-3,5-diphenyl-4(1H)-pyridone, m.p. 197°-199° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O.N1CCCCC1.C(O)(=O)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[CH:18][C:14]1[S:13][CH:17]=[CH:16][CH:15]=1)[C:7]2=[O:12]
Reactant: O=Cc1cccs1
Reactant: COc1cccc2c1CCC2=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COc1cccc2c1CC(=Cc1cccs1)C2=O
Temperature: 130 °C
Yield: 88.1 %

Procedure:
To 4-methoxy-1-indanone (0.1 g; 0.62 mmol) were added thiophene-2-carboxaldehyde (87.5 μl ; 0.93 mmol), piperidine (18.5 μl ; 0.18 mmol) and acetic acid (10.7 μl ; 0.18 mmol). After heating at 130° C. for 90 minutes the mixture was taken up in CH2Cl2, washed with water and purified by flash chromatography, eluting with petroleum ether/ethyl acetate (95/5) to give 4-methoxy-2-(2-thienylmethylene)-1-indanone (140 mg; 90%).
Reaction SMILES: [I:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.N1C(C)=CC=CC=1C.[CH:18]([N:21]1[C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=[N:22]1)([CH3:20])[CH3:19]>>[NH2:9][C:3]1[N:4]=[C:5]([NH:8][C:26]([C:25]2[N:21]([CH:18]([CH3:20])[CH3:19])[N:22]=[CH:23][CH:24]=2)=[O:27])[CH:6]=[CH:7][C:2]=1[I:1]
Reactant: Nc1ccc(I)c(N)n1
Reactant: CC(C)n1nccc1C(=O)O
Solvent: Cc1cccc(C)n1
Product: CC(C)n1nccc1C(=O)Nc1ccc(I)c(N)n1
Yield: 38 %

Procedure:
Method A using 3-Iodo-pyridine-2,6-diamine (Preparation 44), 1.6 equivalents of lutidine and 1.5 equivalents of acid chloride prepared from 2-isopropyl-2H-pyrazole-3-carboxylic acid. Purified by trituration with methanol:ethylacetate 1:2 to afford the title compound as a colourless oil (608 mg, 38%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](Cl)([OH:12])[C:6](O)=[C:5]2Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH2:20].Cl.O1CCOCC1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[C:5]2[NH:20][C:19]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:17]([Cl:16])[CH:18]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: OC1=C(Cl)c2cc(F)ccc2NC1(O)Cl
Agent: Cl
Solvent: C1COCCO1
Product: Oc1cc(Nc2ccc(Cl)c(Cl)c2)c2cc(F)ccc2n1
Yield: 47.4 %

Procedure:
Prepared using general procedure 1; 6-Fluoro-2,4-dichloroquinolinediol (2.5 g, 13.95 mmol), 3,4-dichloroaniline (4.5 g, 27.91 mmol), 5 mL of 4 M HCl in dioxane (20 mmol) were irradiated to 180° C. (400 W max) for 40 min. Pouring onto methanol followed by collection of the solids, afforded 2.136 g of material (6.61 mmol, 47%). 1H NMR (300 MHz, DMSO): 11.48(s, 2H), 8.74(s, 1H), 7.92(dd, 1H, J=10.70, 2.60 Hz), 7.65(d, 1H, J=8.88 Hz), 7.56(d, 1H, J=2.42 Hz), 7.49(d, 1H), 7.33(m, 2H), 5.89(s, 1H).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8]([O:11]S(C)(=O)=O)(=O)=[O:9].[NH2:16][C:17]1[C:26]([Cl:27])=[C:25]([CH3:28])[CH:24]=[C:23]2[C:18]=1[N:19]=[C:20]([O:31][CH3:32])[C:21]([O:29][CH3:30])=[N:22]2.O>O1CCCC1.C(OCC)(=O)C>[Cl:27][C:26]1[C:17]([NH:16][S:8]([CH3:7])(=[O:11])=[O:9])=[C:18]2[C:23](=[CH:24][C:25]=1[CH3:28])[N:22]=[C:21]([O:29][CH3:30])[C:20]([O:31][CH3:32])=[N:19]2
Reactant: COc1nc2cc(C)c(Cl)c(N)c2nc1OC
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: COc1nc2cc(C)c(Cl)c(NS(C)(=O)=O)c2nc1OC
Reaction time: 1 h
Yield: 84.1 %

Procedure:
Pyridine (80 μl, 78 mg, 0.985 mmol) and methanesulphonic anhydride (172 mg, 0.985 mmol) were added to a solution of 5-amino-6-chloro-2,3-dimethoxy-7-methylquinoxaline (Example 3 step (e), 50 mg, 0.197 mmol) in dry tetrahydrofuran (1.6 ml) at room temperature under nitrogen. After stirring for 24 hours further pyridine (32 μl, 31 mg, 0.394 mmol) and methanesulphonic anhydride (69 mg, 0.394 mmol) were added. After a further 16 hours water (0.6 ml) was added and stirring continued for 1 hour. The mixture was diluted with ethyl acetate (15 ml) and washed with 2M hydrochloric acid (5 ml), water (5 ml), saturated sodium bicarbonate solution (5 ml) and brine (5 ml) and then dried (MgSO4), filtered and concentrated under reduced pressure. The solid residue was purified by flash chromatography on silica gel eluting with 3:1 hexane:ethyl acetate to give N-(6-chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)methanesulphonamide (55 mg, 84%) as a white solid mp 198° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[F:13].[C:14]([O:18][C:19]([N:21]1[CH2:28][CH:27]2[O:29][CH:23]([CH2:24][NH:25][CH2:26]2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH:23]2[O:29][CH:27]([CH2:26][N:25]([CH2:2][CH2:3][O:4][C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=3[F:13])[CH2:24]2)[CH2:28]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: N#Cc1ccc(OCCBr)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CCOc3ccc(C#N)cc3F)CC(C1)O2
Temperature: 60 °C
Reaction time: 120 h
Yield: 65.8 %

Procedure:
A suspension of 4-(2-Bromo-ethoxy)-3-fluoro-benzonitrile (21.6 g, 0.0885 mol, from step (v) above), 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (21.1 g, 0.07965 mol; see WO 01/28992) and dry K2CO3 (48.9 g, 0.354 mol) in 200 ml of dry acetonitrile was stirred at 60° C. for five days under N2 atmosphere. The reaction mixture was filtered through celite and filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 27% ethyl acetate in petroleum ether, as eluent to yield the sub-title compound (20.5 g) as a solid.
Reaction SMILES: [CH:1]1[C:6]2[O:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH2:10][C:11](=O)[CH2:12][C:5]=2[CH:4]=[CH:3][CH:2]=1.O.O.O.O.O.O.[Cl-].[Mg+2].[Cl-].[CH3:27][NH:28][CH:29]=[O:30]>C(O)=O.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:27][NH:28][C:29]([CH:11]1[CH2:12][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=2[O:7][C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[CH2:10]1)=[O:30]
Reactant: O=C1Cc2ccccc2Oc2ccccc2C1
Reactant: CNC=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: O=CO
Product: CNC(=O)C1Cc2ccccc2Oc2ccccc2C1

Procedure:
5H-Dibenz[b,g]oxocin-6(7H)-one (3 g - as prepared in B) was dissolved in a mixture of formic acid (3 ml) and methylformamide (12 ml) containing magnesium chloride hexahydrate (0.6 g), and the solution was refluxed for three hours. The cooled reaction mixture was diluted with water and neutralised with sodium carbonate solution, then the product was extracted into 1,1'-oxybisethane. The extract was washed with water, sodium carbonate solution and water then dried over sodium sulphate, and evaporated to give 6,7-Dihydro-N-methyl-5H-dibenz[b,g]oxocine-6-formamide.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH3:18])[N:12]=1.CCN(C(C)C)C(C)C.CCO>O>[Cl:10][C:11]1[N:16]=[C:15]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)[CH:14]=[C:13]([CH3:18])[N:12]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Temperature: 70 °C
Reaction time: 72 h
Yield: 59.1 %

Procedure:
A mixture of 5-cyclopropyl-1H-pyrazol-3-amine (1.98 g, 16.07 mmol), 2,4-dichloro-6-methyl-pyrimidine (2.62 g, 16.07 mmol), DIPEA (5.7 mL, 32.15 mmol) and anhydrous EtOH (50 mL) was stirred at 70° C. under N2 for 3 d. The reaction mixture was cooled and poured into water (ca. 700 mL). The reaction was stirred at RT overnight until solid precipitated out. The solid was filtered, washed with additional water and pumped dry under high-vacuum to afford 2.37 g (59%) of 189 as a solid: 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 10.08 (s, 1H), 7.04 (br s, 1H), 5.93 (br s, 1H), 2.27 (s, 3H), 1.93 to 1.84 (m, 1H), 0.96-0.88 (m, 2H), 0.70-0.64 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23][CH2:24]O)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7].[CH:38]([NH2:41])([CH3:40])[CH3:39]>>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23][CH2:24][NH:41][CH:38]([CH3:40])[CH3:39])[C:12]2=[O:26])[CH2:27][CH2:28]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCCO)CN2c1ccccc1
Reactant: CC(C)N
Product: CC(C)NCCCN1CN(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=571.1 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(3-hydroxy-propyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and isopropylamine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[CH:39][N:40]=[CH:41][CH:42]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1

Procedure:
The title compound was prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester [CAS-No. 335255-65-7] and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) according to the general procedure M. Obtained as a yellow solid (410 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1I.C([Mg]Cl)(C)C.CN([CH:19]=[O:20])C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)c(I)c(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: Cc1ccccc1
Product: O=Cc1c(Br)cc(F)cc1Br
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 53.7 %

Procedure:
To a solution of 1,3-dibromo-5-fluoro-2-iodobenzene (50 g, 132 mmol) in anhydrous toluene (300 mL) cooled at −35° C. was added the solution of isopropylmagnesium chloride (84 mL, 171 mmol, 2.0M in Et2O) over 30 minutes while maintaining the internal temperature below −25° C. A clear brown solution was obtained and the stirring was continued for 1.5 h at −25° C. Then anhydrous DMF (34 mL, 436 mmol) was added over a period of 30 minutes. The reaction mixture was warmed to 10° C. (room temperature) over 1 h and stirred at this temperature for 1.5 h. It was then quenched with 3.0M HCl and followed by the addition of ethyl acetate. The organic layer was separated and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (from 50:1 to 20:1) to give 101h as a white solid (20 g, 54%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12](=[O:15])[NH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].[CH2:16](Br)[CH2:17][CH3:18]>>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc2n[nH]c(=O)n2n1
Reactant: CCCBr
Product: CCCCNc1ccc2nn(CCC)c(=O)n2n1
Yield: 86 %

Procedure:
By reacting the product of Example 3 with propyl bromide according to the procedure of Example 4, 6-n-butylamino-2-propyl-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one is obtained, yield 86%, m.p. 183°-185° (ethyl acetate with some drops of absolute ethanol). The hydrochloride is obtained by treatment with ethanolic HCl.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[C:14](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1ccc(OC)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Methyl 3-cyano-4-hydroxybenzoate (1.00 g) was dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (1.56 g) and dimethylsulfuric acid (0.70 mL) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. After the reaction solution was filtered, water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (923 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[CH3:16][N:17]=[C:18]=[O:19]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:18]([NH:17][CH3:16])=[O:19])[CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1CNCCN1Cc1ccc(F)cc1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)N1CCN(Cc2ccc(F)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Fluorobenzyl)piperazin-2-one (0.40 g, 1.9 mmol, Example 1, Step 4) was dissolved in anhydrous THF (20 mL) under nitrogen and methyl isocyanate (0.96 mL, 1.9 mmol, 2M solution in THF) was added. The reaction was allowed to stir for two hours at room temperature. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel using a 0-5% MeOH/CHCl3 gradient elution. Collection and concentration of the appropriate fractions provided the title compound as a white solid. 1H NMR (400 MHz, d6 DMSO) δ 7.29 (m, 2H), 7.16 (m, 2H), 6.55 (d, 1H, J=4.2 Hz), 4.51 (s, 2H), 3.97 (s, 2H), 3.50 (t, 2H, J=5.4 Hz), 3.22 (t, 2H, J=5.4 Hz), and 2.56 (d, 3H, J=4.4 Hz); ES MS (M+1)=266.
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]([N:23]2[CH:27]=[N:26][N:25]=[CH:24]2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[Cl:30])C1C=CC=CC=1>[Pd].CO.C1COCC1.CCOC(C)=O>[Cl:30][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][C:9]=1[OH:8])[CH2:13][N:14]([N:23]1[CH:24]=[N:25][N:26]=[CH:27]1)[C:15]1[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)c(Cl)c2)n2cnnc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(N(Cc2ccc(O)c(Cl)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Palladium on charcoal (50 mg, 10% Pd) was added to a solution of 4-[(4-benzyloxy-3-chloro-benzyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB02129, 1.04 g, 2.50 mmol) in MeOH/THF/EtOAc (25 mL/25 mL/25 mL). The mixture was stirred under hydrogen atmosphere (balloon) for 18 hours at room temperature. The reaction mixture was filtered through celite and the clear colourless filtrate was concentrated under reduced pressure. The residue was suspended in 2-propanol (20 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 484 mg (59%). 1H-NMR (400 MHz, d6-DMSO) δ=4.93 (s, 2H), 6.76 (d, J=9.0 Hz, 2H), 6.86 (d, J=8.6 Hz, 1H), 7.02 (dd, J=8.2, 2.0 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.76 (d, J=9.0 Hz, 2H), 8.77 (s, 2H), 10.29 (s, 1H, —OH). 13C-NMR (100 MHz, d6-DMSO) δ=56.87, 103.55, 114-48, 117.28, 119.73, 120.25, 126.72, 129.19, 130.91, 134.56, 144.02, 152.03, 153.50. LRMS (FAB+): 325.0 (100, [M+H]+).
Reaction SMILES: C([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH-:38])(=O)CCCCCCC/C=C\CCCCCCCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.O>C1COCC1.C(Cl)Cl>[CH2:20]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]/[CH:29]=[CH:28]\[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)CCCCCCCC/C=C\CCCCCCCC[NH-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCCNCCCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C

Procedure:
A solution of N-oleoyloleylamide (prepared above) in THF (100 mL) was warmed to 40° C. Lithium aluminum hydride was slowly added until violent evolution of gas ceased. The reaction mixture was heated to reflux for one hour and then cooled to room temperature. Methanol (100 mL) was slowly added, followed by water (200 mL). Methylene chloride was added and the resultant suspension was stirred for fifteen minutes. The slurry was filtered and the precipitate was washed with ethanol.backslash.methylene chloride (50:50, 50 mL, 2×). The combined filtrates were washed with methylene chloride. The organic fraction was dried over magnesium sulphate, filtered and the solvent was removed under vacuum. The residue was passed down a silica gel column (150 g) using 5% methanol in methylene chloride as the eluent, to provide dioleylamine as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(C)([O-])C.[K+]>CS(C)=O>[CH2:24]([N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][CH2:3][C:2]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:1])[CH3:15])[C:6]1=[O:14])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)(CCn1c(=O)[nH]c2ccccc21)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(CCn1c(=O)n(Cc2ccccc2)c2ccccc21)NC(=O)OC(C)(C)C

Procedure:
tert-butyl [1,1-Dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propyl]-carbamate, benzyl chloride and potassium-tert-butoxide are stirred overnight at ambient temperature in dimethylsulphoxide. The alkylation product tert-butyl [3-(3-benzyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-propyl]-carbamate obtained from the reaction is then treated with trifluoroacetic acid/dichloromethane in order to cleave the protective group. Mass spectroscopy [M+H]+=310.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:6]([CH2:8][CH2:9][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])([OH:7])=[O:5]
Reactant: CCOC(=O)C(CCC(=O)OC(C)(C)C)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(CCC(=O)O)C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of compound 10 (19.6 g, 68.05 mmol), in 400 mL CH2Cl2 is added 400 mL of TFA. The mixture is stirred under during 48 h at room temperature. The reaction mixture is concentrated under vacuum, coevaporated two times with cyclohexane to eliminate excess TFA yielded 15.8 g compound 11 as oil used without further purification.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=1.N[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[CH:8]([CH:4]1[O:3][C:2]([NH:1][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[N:6][C:5]1=[O:7])([CH3:10])[CH3:9]
Reactant: NCCN1CCOCC1
Reactant: CC(C)C1OC(N)=NC1=O
Product: CC(C)C1OC(NCCN2CCOCC2)=NC1=O

Procedure:
Synthesis was performed from 2-amino-5-isopropyl-1,3-oxazol-4(5H)-one and N-(2-aminoethyl)morpholine according to Method G+H.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17])=[C:7]([OH:19])[CH:6]=1)(=[O:3])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].IC>C(C(C)=O)C>[C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17])=[C:7]([O:19][CH3:20])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(O)c(C(=O)CCCCCl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CI
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)CCCCCl
Yield: 67.7 %

Procedure:
1-(4-Acetylamino-5-chloro-2-hydroxyphenyl)-5-chloropentan-1-one (1.07 g, 3.5 mmol), potassium carbonate (1.38 g, 10.0 mmol) and iodomethane (0.62 mL, 10.0 mmol) were combined in methyl ethyl ketone (20 mL) and stirred at reflux temperature for 4 hours, 15 minutes. The mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed in brine, dried over sodium sulfate, and then evaporated to leave a solid residue. Crystallization of the residue from ethyl acetate-hexanes gave 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloro-pentan-1-one (0.720 g, 2.37 mmol), m.p. 98°-100° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=3)[N:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)[O:25][B:24](B2OC(C)(C)C(C)(C)O2)[O:23]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:18][C:17]([F:20])([F:19])[C:16]1[C:11]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([B:24]([OH:25])[OH:23])=[C:3]3[CH:10]=[N:9]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: FC(F)(F)c1cccnc1-n1ncc2c(I)ccnc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OB(O)c1ccnc2c1cnn2-c1ncccc1C(F)(F)F

Procedure:
To a 48 mL pressure bottle containing Intermediate 73A (495 mg, 1.269 mmol) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (569 mg, 2.241 mmol), potassium acetate (571 mg, 5.82 mmol) and anhydrous DMSO (10 mL). The reaction mixture was purged with argon, treated with PdCl2(dppf).CH2Cl2 (56 mg, 0.077 mmol), and heated to 85° C. for 2 h 15 min to give conversion to the desired product. LC/MS (Condition B): ret. T=2.5 min, (M+H)+ 309.07.