Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:3]=1.[CH3:14][N:15](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:8]1([C:4]2[N:3]=[C:2]([C:14]#[N:15])[CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Brc1ccnc(N2CCOCC2)n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccnc(N2CCOCC2)n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
In a sealed tube a mixture of 4-(4-bromopyrimidin-2-yl)morpholine (0.40 g, 1.64 mmol), Zn(CN)2 (0.35 g, 3.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.20 mmol) in anhydrous DMF was degassed with argon for 10 minutes and then warmed at 120° C. After 2 hours, the mixture was cooled and diluted with saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 20% ethyl acetate in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford 2-morpholin-4-yl-pyrimidine-4-carbonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]1([CH3:62])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53](=[O:59])[C:54]3[S:58][CH:57]=[CH:56][CH:55]=3)[CH2:44][CH:43]([NH2:60])[C:42]2=[O:61])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1>O1CCCC1.O>[C:32]1([CH3:62])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53](=[O:59])[C:54]3[S:58][CH:57]=[CH:56][CH:55]=3)[CH2:44][CH:43]([NH:60][C:14]([NH:12][C:9]3[CH:10]=[CH:11][C:2]([CH3:1])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=3)=[O:16])[C:42]2=[O:61])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C(=O)c1cccs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(N)ccc1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC(=O)NC2CN(C(=O)c3cccs3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)ccc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 252.6 %

Procedure:
Methyl 2-methyl-5-aminobenzoate (0.37 g) was dissolved in tetrahydrofuran (10 ml), triphosgene (0.22 g) was added at internal temperature 5° C., triethylamine (0.95 g) was added thereto over 10 minutes, the mixture was stirred at room temperature for 10 minutes. A solution of 1-(2-toluoylmethyl)-2-oxo-3-amino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (0.81 g) in tetrahydrofuran (10 ml) was added, the mixture was stirred at room temperature for one hour. Water was added to the reaction mixture, and extracted with chloroform. The organic layer was successively washed with water and saturated brine and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(chloroform:methanol=50:1), to thereby obtain 1.17 g of the title compound as light yellow amorphous (Yield: 100%).
Reaction SMILES: B(Br)(Br)[Br:2].[CH2:5]([C:7]1[CH:12]=[C:11]([O:13]C)[C:10]([F:15])=[CH:9][C:8]=1[C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]3[NH:26][C:27]4[CH2:32][CH2:31][NH:30][CH2:29][C:28]=4[N:33]=3)=[N:21][NH:22]2)=[CH:18][CH:17]=1)[CH3:6]>C(Cl)Cl>[BrH:2].[BrH:2].[BrH:2].[CH2:5]([C:7]1[C:8]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([C:25]4[NH:26][C:27]5[CH2:32][CH2:31][NH:30][CH2:29][C:28]=5[N:33]=4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)=[CH:9][C:10]([F:15])=[C:11]([OH:13])[CH:12]=1)[CH3:6]
Reactant: CCc1cc(OC)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A 1M solution of boron tribromide in DCM (4.54 mL, 4.54 mmol) was added dropwise to a solution of 2-[6-(2-ethyl-5-fluoro-4-methoxy-phenyl)-1H-indazol-3-yl]-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (Preparation 24, 739 mg, 1.13 mmol) in DCM (10 mL) at 0° C. The resulting solution was stirred at room temperature for 18 hours. Further boron tribromide (4.54 mL, 4.54 mmol) was added dropwise and the reaction was allowed to stir at room temperature for 5 hours. Precipitated solid was collected by filtration, washed with tBME, then triturated with EtOAc to yield the title compound as the trihydrobromide salt (665 mg) in a 94% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16]([C:19](Cl)=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:14][CH:15]=1)=[O:20]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc2c(Cl)c(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2s1
Yield: 84 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with 4-biphenylcarbonyl chloride (50 μL, 0.30 mmol) in presence of triethylamine (42 μL, 0.30 mmol) according to method A gave biphenyl-4-carboxylic acid (4-chloro-2-methyl-benzothiazol-5-yl)-amide (79 mg, 0.21 mmol, 84% yield) as a pale pink powder after crystallisation in hexane/DCM.
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][N:6]=[C:5]2[N:14]([CH2:17][C:18]3[O:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[CH:16][C:4]=12)[NH2:2].[CH2:23]([N:25]1[C:29]2=[N:30]C=C(C(OCC)=O)C(NN)=C2C=N1)C>>[CH2:17]([N:14]1[C:5]2[N:6]=[CH:7][C:8]3[C:9](=[O:11])[NH:30][C:29]4[N:1]([N:2]=[CH:23][N:25]=4)[C:3]=3[C:4]=2[CH:16]=[N:15]1)[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1NN
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Product: O=c1[nH]c2ncnn2c2c1cnc1c2cnn1Cc1ccco1

Procedure:
By substituting 4-hydrazino-1-furfurylpyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in Example 1, 8-furfuryl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one is obtained. This compound is now processed as in Example 4, substituting bromobenzene for the methyl iodide. A small amount of copper catalyst is added to obtain 8-furfuryl-4-phenyl-4H-pyrazolo[4',3': 5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:13]=1)[CH2:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.C([Li])CCC.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:7]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)[C:24]2([OH:27])[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH:13]=1
Reactant: Fc1ccc(Cl)cc1Cn1cccc1
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(C(c2cc(Cl)ccc2F)n2cccc2)CC1
Temperature: -80 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(5-chloro-2-fluorobenzyl)pyrrole of Example XVIIIa (15 g, 72 mmole) in 100 ml THF, cooled to -80° C., is added a solution of n-butyllithium (2.5 M in hexane 75 mmole, 30 ml) over a period of ten minutes. The mixture is stirred at -80° C. for one hour, then at -50° C. for 15 minutes. The mixture is again cooled to -80° C., then a solution of 1-methyl-4-piperidone (8.1 g, 72 mmole) in 50 ml THF is added. After stirring at ambient temperature for two hours, the mixture is poured over 500 ml ice water and is extracted with ether. The organic layer is extracted with diluted HCl. The aqueous acidic extract is then basified with sodium carbonate and extracted with ether. The organic extracts are washed twice with water and dried (saturated NaCl, anhydrous MgSO4). The solution is filtered and concentrated to a solid (21 g, 90%, m.p. 110°-115° C.) of which 4 g is recrystallized from hexanes to yield crystals, m.p. 124°-125° C. of 4-[(5-chloro-2-fluorophenyl)-(1-pyrryl)methyl]-1-methyl-4-piperidinol.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[C-:20]#[N:21].[Na+]>C(#N)C>[C:20]([C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1)#[N:21]
Reactant: [C-]#N
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Agent: [Na+]
Solvent: CC#N
Product: Cn1nnnc1-c1cn(C)c2cc(C#N)ccc2c1=O
Reaction time: 70 h

Procedure:
A mixture of 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (5.25 g), sodium cyanide (1.0 g), crown ether (18-crown-6, 5.4 g) and acetonitrile (200 ml) was stirred and boiled under reflux for 79 hours, left at ambient temperature for 70 hours, and boiled under reflux for 24 hours. The mixture was cooled and filtered. The residue was boiled with industrial methylated spirit (200 ml) and the mixture filtered while hot. The residue was further extracted twice with boiling 50% aqueous industrial methylated spirit (400 ml, then 200 ml). Each hot extract precipitated a solid when cooled. The three solids were combined and recrystallised from 50% aqueous industrial methylated spirit to give a crude product. This product was purified by high pressure liquid chromatography on silica, using dichloromethane:methanol 9:1 as the eluent. The eluent was evaporated to give a residue which was recrystallised from 30% aqueous industrial methylated spirit to give the novel compound 7-cyano-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 301°-303°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(OC([NH:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:34][CH:35]([O:41][CH:42]([CH3:44])[CH3:43])[C:36]([O:38]CC)=[O:37])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])=O)(C)(C)C>>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:34][CH:35]([O:41][CH:42]([CH3:44])[CH3:43])[C:36]([OH:38])=[O:37])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])=[O:6]
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1Cl
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(-c2ccccc2)cc1Cl

Procedure:
Using 2-chloro-4-phenylbenzoic acid and ethyl 3-[3-([(tert-butoxycarbonyl)amino]methyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(2-chloro-4-phenylbenzoyl)amino]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 38).
Reaction SMILES: [Br:1][C:2]1[C:7](N)=[C:6]([Br:9])[C:5]([CH3:10])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[N:3]=1.C(ON=O)(C)(C)C>C1COCC1>[Br:9][C:6]1[CH:7]=[C:2]([Br:1])[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[C:5]=1[CH3:10]
Reactant: Cc1c(-c2ccc(F)cc2F)nc(Br)c(N)c1Br
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: Cc1c(Br)cc(Br)nc1-c1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2,4-dibromo-6-(2,4-difluorophenyl)-5-methylpyridin-3-amine (10 g, 26.4 mmol, 1 eq) in THF (100 mL) was added tert-butylnitrite (4.7 mL, 39.6 mmol, 1.5 eq). The solution warmed and gas evolution was evident. After 2 h, the mixture was heated to and maintained at 60° C. for 45 min. The mixture was cooled and concentrated in vacuo. The product was purified by flash column chromatography eluting with 2% Et2O in hexanes to give 4,6-dibromo-2-(2,4-difluorophenyl)-3-methylpyridine. Mass spectrum (ESI) 362.2 (M+1); 364.2 (M+3); 366.2 (M+5).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[N:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:21][C:18]1[CH:17]=[N:16][C:15]([NH:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncc(Br)cn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1cnc(N[C@@H]2CCCNC2)nc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a cold (˜0° C.) solution of (R)-3-(5-bromo-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (775 mg) in dry DCM (10 mL) was added slowly TFA (0.831 mL). The reaction mixture was stirred at RT for 20 h, 5 eq more of TFA (0.831 mL) was added and the stirring was continued for 2 h. The reaction was concentrated in vacuo to yield the title compound as a bis-trifluoroacetate salt which was used for the next step without further purification.
Reaction SMILES: [C:1]1([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]3[CH2:25][CH:24]([CH2:26][C:27]([O:29]CC)=[O:28])[C:23]4[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=4[CH2:21][C:20]=3[CH:36]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.N1C=CC=CC=1NCCCOC1C=CC2C[C@H](CC(OCC)=O)C3C=CC=CC=3CC=2C=1.C(O)(C(F)(F)F)=O>O>[C:1]1([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:36]=[C:20]3[CH2:21][C:22]4[CH:35]=[CH:34][CH:33]=[CH:32][C:23]=4[CH:24]([CH2:26][C:27]([OH:29])=[O:28])[CH:25]=[C:19]3[CH2:18][CH:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCCCNc3nccc4ccccc34)cc2Cc2ccccc21
Agent: CCOC(=O)C[C@H]1Cc2ccc(OCCCNc3ccccn3)cc2Cc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CC1C=C2CC=C(OCCCNc3nccc4ccccc34)C=C2Cc2ccccc21

Procedure:
According to the procedure of Example 6 (c), except substituting ethyl (±)-10,11-dihydro-3-[3-(isoquinoline-1-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate for the ethyl (R)-10,11-dihydro-3-[3-(pyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate, the title compound was prepared as an amber solid: MS (ES) m/e 453.2(M+H)+. Anal. Calcd for C29H28N2O3.1.3 TFA.0.25 H2O: C, 62.71; H, 4.96; N, 4.63. Found: C, 62.45; H, 4.92; N, 4.41.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl>O1CCOCC1>[C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][CH2:21][NH2:22])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)NCCc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCCc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Intermediate 30 (7 g, 17.5 mmol) in dioxane (70 mL) was added hydrogen chloride (1.25M in dioxane, 25 mL). The reaction mixture was stirred at room temperature overnight. The precipitate was filtrated and washed with dioxane and ether. The crude was purified by column chromatography with silica gel, eluting with methylen chloride/methanol/ammonium (40:4:0.2) and the title compound was obtained as an oil (2.6 g, 50%). (M+): 300.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([C:15]([OH:17])=O)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>CCOC(C)=O>[CH:1]1([CH2:7][NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[O:17])[CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(O)c1cc(NCC2CCCCC2)ncn1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(O)cc1)c1cc(NCC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[(cyclohexylmethyl)amino]pyrimidine-4-carboxylic acid (Intermediate 6) and 4-amino-phenol (Aldrich), the title compound was obtained as a white solid after trituration in EtOAc.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[N:17][C:18]=2[O:19][CH3:20])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@H:45]([OH:48])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[OH:48][C@H:45]1[CH2:46][CH2:47][C@H:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:2]3[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:14]=[CH:15][C:16]([CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[N:17][C:18]=4[O:19][CH3:20])[N:3]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH2:43][CH2:44]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)n1)OCC
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@H](O)CC2)C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)n1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl [(5-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-6-methoxypyridin-2-yl)methyl]phosphonate (Compound 286A, 100 mg, 0.22 mmol) and 7-amino-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (115 mg, 0.44 mmol). The crude material was purified by MDP to obtain the title compound (82 mg, 55% yield). 1H NMR (400 MHz, methanol-d4) δ=1.31 (t, J=6.9 Hz, 6 H), 1.38-1.53 (m, 2 H), 1.62-1.77 (m, 2 H), 1.84-1.93 (m, 2 H), 2.04-2.14 (m, 2 H), 2.53-2.64 (m, 1 H), 3.17 (s, 3 H), 3.44 (d, J=21.7 Hz, 2 H), 3.62-3.72 (m, 1 H), 4.01 (s, 3 H), 4.10-4.21 (m, 4 H), 4.51 (s, 2 H), 6.99 (dd, J=8.1, 2.8 Hz, 1 H), 7.39 (d, J=8.6 Hz, 1 H), 8.15 (d, J=7.3 Hz, 1 H), 8.37 (s, 2 H). MS (ES+): m/z 679.31 (100) [MH+]; HPLC: tR=1.06 min (UPLC, purity).
Reaction SMILES: [NH:1]1C2C(=CC=C(C#N)C=2)C=[CH:2]1.[C:12]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](OC(F)(F)F)[CH:22]=2)[N:17]([CH2:29][C:30]([OH:32])=[O:31])[CH:16]=1)(=[O:14])[CH3:13]>>[C:12]([C:15]1[C:23]2[C:18](=[CH:19][C:20]([C:2]#[N:1])=[CH:21][CH:22]=2)[N:17]([CH2:29][C:30]([OH:32])=[O:31])[CH:16]=1)(=[O:14])[CH3:13]
Reactant: N#Cc1ccc2cc[nH]c2c1
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Product: CC(=O)c1cn(CC(=O)O)c2cc(C#N)ccc12

Procedure:
was prepared from 1H-indole-6-carbonitrile in a similar manner as described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. MS: 243 [M+H]+; tR (HPLC conditions k): 2.72 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=O)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:15]([NH2:18])[C:16]#[CH:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.C(N(CC)CC)C>[CH2:15]([NH:18][C:12]([C:9]1[O:8][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=2[CH:10]=1)=[O:14])[C:16]#[CH:17]
Reactant: COc1cccc2oc(C(=O)O)cc12
Reactant: C#CCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCNC(=O)c1cc2c(OC)cccc2o1
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
4-Methoxybenzo(b)furan-2-carboxylic acid (44.0 g) and propargylamine (12 g) were dissolved in dimethylformamide (200 ml), and WSC (48.0 g), HOBt (43.0 g) and triethylamine (50 ml) were added thereto at room temperature. The mixture was stirred for 4 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of ammonium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as yellow crystals (45.0 g).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([C:6]1[C:11]([O:12][CH2:13][O:14][CH3:15])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:16])[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:15][O:14][CH2:13][O:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[CH:4]([CH3:5])[CH2:3][CH2:2][O:16]2
Reactant: COCOc1cccc(O)c1C(C)CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCOc1cccc2c1C(C)CCO2
Yield: 97 %

Procedure:
In a 50 mL round-bottomed flask 2-(3-hydroxy-1-methyl-propyl)-3-(methoxymethoxy)phenol (56.3 mg, 0.249 mmol) was dissolved in Tetrahydrofuran (THF) to give a colourless solution. Triphenylphosphine (59.4 mg, 0.226 mmol) was added and the reaction mixture was stirred until complete solubilization of triphenylphosphine. DIAD (45.8 mg, 0.226 mmol) was added and the reaction mixture was stirred. Additional Triphenylphosphine (59.4 mg, 0.226 mmol) and DIAD (45.8 mg, 0.226 mmol) were added. The reaction mixture evaporated in vacuo and the residue was purified by flash chromatography (Biotage SP1) on silica gel using a 10 g SNAP silica cartridge as column and cyclohexane/ethyl acetate 10:1 as eluents affording the title compound (50.3 mg) as colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][C:12]1[C:13]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[C:12]([CH3:11])=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=3)[CH2:20][CH2:21]2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1cnc(Br)cn1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cn3)CC2)c(C)c1
Yield: 69.5 %

Procedure:
Using 5-bromopyrazine-2-carboxylic acid (203 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (191 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (261 mg) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22]4[O:23][C:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=5)=[N:25][N:26]=4)[CH:20]=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:35])[CH:7]=1.[OH-].[Na+].Cl>CO>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[O:23][C:22]([C:19]3[CH:20]=[CH:21][C:15]4[N:14]=[C:13]([C:9]5[C:8]([CH3:35])=[CH:7][C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:11][C:10]=5[CH3:12])[NH:17][C:16]=4[CH:18]=3)=[N:26][N:25]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)CCc1cc(C)c(-c2nc3ccc(-c4nnc(-c5ccc(OC)cc5)o4)cc3[nH]2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2nnc(-c3ccc4nc(-c5c(C)cc(CCC(=O)O)cc5C)[nH]c4c3)o2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4-{6-[5-(4-Methoxyphenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazol-2-yl}-3,5-dimethylphenyl)-propionic acid methyl ester in MeOH (10 mL) was added 1N NaOH (10 mL). The mixture was stirred at RT for 2 h then the resulting solution was carefully acidified to pH 3-4 with 1N HCl. The resulting precipitate was filtered, washed with water and was dried under reduced pressure to give the title compound. MS: m/z 469.1 (M+1). H1-NMR (MeOD): δ 8.40 (s, broad, 1H), 8.15-8.08 (m, 3H), 7.81 (s, broad, 1H), 7.16 (d, J=8.97 Hz, 2H), 7.10 (s, 2H), 3.91 (s, 3H), 2.93 (t, 2H), 2.55 (t, 2H), 2.15 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[CH2:4][S:5][C:6]#[N:7].[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([O:1][CH2:2][C:3]([CH3:9])([CH3:8])[CH2:4][S:5][C:6]#[N:7])(=[O:12])[CH3:11]
Reactant: CC(C)(CO)CSC#N
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC(C)(C)CSC#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 58.7 g of 3-hydroxy-2,2-dimethyl-1-propylthiocyanate, 400 ml of acetic anhydride and 400 ml of pyridine was stirred for 16 hours at room temperature. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 500 ml of diethyl ether. The solution was washed in turn with 1N-hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. After removing the solvent, the residue was purified by distillation under reduced pressure, thereby affording 53.2 g of 3-acetoxy-2,2-dimethyl-1-propylthiocyanate.