Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[I:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl)=[CH:10][CH:9]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[I:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)=[CH:10][CH:9]=1
Reactant: O=C(CCCCCl)c1ccc(I)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(I)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(4-iodophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 533 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]2[O:19][CH2:18]2)[O:4][N:3]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>>[CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])[O:4][N:3]=1
Reactant: Cc1cc(C=Cc2ccccc2OCC2CO2)on1
Reactant: CC(C)(C)N
Product: Cc1cc(C=Cc2ccccc2OCC(O)CNC(C)(C)C)on1

Procedure:
This compound is obtained by the method described for Example 1 from 5.0 g (0.019 mole) of 3-methyl-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazole and 1.56 g (0.2 mole) of tert.-butylamine. 3.1 g (48% of theory) of colorless crystals, melting point 83°-85° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:32]2[CH2:33][CH2:34][N:29]([C:23]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[CH2:30][CH2:31]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: Cc1cccc(C)c1N1CCNCC1
Product: COc1ccc2nc(NC(=O)N3CCN(c4c(C)cccc4C)CC3)c(OC)nc2c1
Yield: 91 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 2.36 (s, 6H), 3.17-3.21 (m, 4H), 3.68-3.71 (m, 4H), 3.91 (s, 3H), 4.14 (s, 3H), 6.95-7.03 (m, 3H), 7.14-7.21 (m, 3H), 7.77-7.80 (m, 1H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)=[N:6][CH:5]=1)=[O:3].Cl.[Cl:24]C1C(Cl)=C(C)NC=1C(NC1CCNCC1)=O>>[ClH:24].[NH2:15][CH:12]1[CH2:13][CH2:14][N:9]([C:7]2[S:8][C:4]([C:2]([NH2:1])=[O:3])=[CH:5][N:6]=2)[CH2:10][CH2:11]1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncc(C(N)=O)s2)CC1
Agent: Cl
Product: NC(=O)c1cnc(N2CCC(N)CC2)s1

Procedure:
Title compound was synthesized from tert-butyl 1-[5-(aminocarbonyl)-1,3-thiazol-2-yl]piperidin-4-ylcarbamate (Intermediate 82) by an analogous method to Intermediate 1.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C:6]1[O:10][N:9]=[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][C:13]=2[CH2:25][S:26][C:27]([CH3:30])([CH3:29])[CH3:28])[N:7]=1)C.[Li+].[OH-]>CO.O>[C:27]([S:26][CH2:25][C:13]1[CH:14]=[C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[N:7]=[C:6]([CH2:5][C:4]([OH:31])=[O:3])[O:10][N:9]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)Cc1nc(Cc2ccc(NC(=O)C(C)(C)C)cc2CSC(C)(C)C)no1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1Cc1noc(CC(=O)O)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-benzyl]-[1,2,4]oxadiazol-5-yl}-acetic acid ethyl ester (0.28 mmol) in MeOH (5 mL) was treated with 1N aqueous LiOH (0.5 mL), and the reaction was stirred for 6 hours at room temperature. The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried and concentrated to give the title compound.
Reaction SMILES: C([NH:7][C:8]1[N:13]=[N:12][C:11]([CH2:14][C:15]([O-:17])=[O:16])=[CH:10][CH:9]=1)(=O)C(C)(C)C.[CH3:18][Si](C=[N+]=[N-])(C)C.C(OCC)C>Cl.O>[NH2:7][C:8]1[N:13]=[N:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(CC(=O)[O-])nn1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: COC(=O)Cc1ccc(N)nn1
Reaction time: 1 h

Procedure:
A solution of 2-(6-pivalamidopyridazin-3-yl)acetate (740 mg, 2.52 mmol) in 6 N hydrochloric acid (24 mL) was heated to 105° C. for 12 h, then cooled and concentrated in vacuo. The resulting crude residue was redissolved in methanol (10 mL) and treated dropwise with a 2 N solution of trimethylsilyldiazomethane in diethylether (2.52 mL, 5.04 mmol). After 1 h, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried (sodium sulfate), filtered and concentrated to provide title compound. LC-MS (IE, m/z): 168 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].OS(O)(=O)=O.[N+:15]([O-])([OH:17])=[O:16].O>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([OH:8])=[C:6]([N+:15]([O-:17])=[O:16])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(Br)c(F)cc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of 4-bromo-3-fluorophenol (89 g, 465.9 mmol) in a mixture of CH2Cl2 (940 mL) and H2SO4 (52.1 mL, 978 mmol) at 0° C., HNO3 (65%) (32.9 ml, 468 mmol) was added dropwise (the mixture turned from colourless to black). The resulting mixture was stirred at 0 ° C. for 1 h and then poured into water. The organic layer was washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure to afford the crude compound which was purified by flash chromatography (SiO2, heptane/toluene 1:3) to give 4-bromo-5-fluoro-2-nitrophenol (49.5 g, 45%). 1H-NMR (400 MHz, CDCl3) 6.95 (d, J=9.0, 1H), 8.38 (d, J=6.2, 1H), 10.69 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]3=[C:16]([OH:25])[C:15]=2[C:14]2[C:13]([C:26]([NH2:28])=[O:27])=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]3=[C:16]([O:25][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:26](=[O:27])[NH2:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc2c1c1c(O)c3ccccc3cc1n2Cc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1c2ccccc2cc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 53.7 %

Procedure:
40% Methanolic Triton B (0.378 mL, 0.832 mM) was added to a solution of 5-benzyl-11-hydroxy-5H-benzo[b]carbazole-1-carboxylic acid amide, (0.235 g, 0.64 mM) in 5 mL DMF at room temperature. After 2 minutes, methyl bromoacetate (0.125 mL, 0.202 g, 1.28 mM) was added and the resultant mixture stirred at room temperature for 2 h. Cesium carbonate (0.105 g, 0.32 mM) was then added as a solid, and the mixture allowed to stir at room temperature for an additional 1 h. The mixture was diluted with ethyl acetate, washed with H2O, 1N HCl, saturated aqueous NaHCO3 solution, and saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting brown residue-was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 0.151 g (53%) of the title compound (5-benzyl-1-carbamoyl-5H-benzo[b]carbazol-11-yloxy)-acetic acid, methyl ester as a brown foam (MP 120–125° C., MW 438.49).
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=2)[C:4](=[O:17])[N:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[Cl:25]C1C=C(NN)C=CC=1.C(N(CC)CC)C>C1(C)C=CC=C(C)C=1>[Cl:25][C:20]1[CH:19]=[C:18]([N:3]2[C:4](=[O:17])[C:5]([C:7]3[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=3)=[CH:6][NH:2]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cn1cc(-c2cccc(C(F)(F)F)c2)c(=O)n1-c1ccccc1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Solvent: Cc1cccc(C)c1
Solvent: CCN(CC)CC
Product: O=c1c(-c2cccc(C(F)(F)F)c2)c[nH]n1-c1cccc(Cl)c1

Procedure:
A 3.5 gram portion of the atropic ester of Example 1 was reacted with 2.3 grams 3-chlorophenylhydrazine hydrochloride in the presence of 1.3 grams triethylamine in about 50 ml. meta-xylene. The mixture was then stirred at reflux overnight, and the reaction mixture evaporated to dryness under vacuum. The residue was partitioned between ethyl acetate and water, and the organic layer was dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel with ethyl acetate as the eluant. The product containing fractions were combined and evaporated to dryness to produce a crude product, which was recrystallized from methanol to produce 2 grams 1-(3-chlorophenyl)-4-(α,α,α-trifluoro-3-tolyl)-3-pyrazolin-5-one, m.p. 182°-184° C.
Reaction SMILES: [CH2:1]=O.[OH:3][CH2:4][CH:5]1[CH2:9][NH:8][CH2:7][CH:6]1[NH:10][CH3:11]>C(O)CCC>[CH3:11][N:10]1[CH2:1][O:3][CH2:4][CH:5]2[CH:6]1[CH2:7][NH:8][CH2:9]2
Reactant: C=O
Reactant: CNC1CNCC1CO
Solvent: CCCCO
Product: CN1COCC2CNCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.1 g (0.1 mol) of 37% strength formaldehyde solution in 20 ml of n-butanol are added dropwise to 13 g (0.101 mol) of 4-hydroxymethyl-3-methylaminopyrrolidine in 100 ml of n-butanol at room temperature. The mixture is stirred at room temperature overnight and concentrated and the residue is distilled.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2].[CH3:21][C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:33][CH2:34]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][C:23]2[N:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:26][C:22]=2[CH3:21])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1OCC)OCC
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1OCC)OCC

Procedure:
In analogy to the procedure described in example 7 c], [rac]-2-ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester (example 47 c]) was reacted with 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol in tetrahydrofuran in the presence of triphenylphosphine and DBAD (di-tert-butyl azodicarboxylate) to yield [rac]-2-ethoxy-3-{2-ethoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 1 g], to yield [rac]-2-ethoxy-3-{2-ethoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless oil, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[CH:3]1.C([Li])CCC.[CH2:13]=[O:14]>>[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:13][OH:14]
Reactant: Cc1cn(C)cn1
Reactant: C=O
Agent: [Li]CCCC
Product: Cc1cn(C)c(CO)n1

Procedure:
The reaction of 1,4-dimethylimidazole (5.65 g.) with n-butyl lithium followed by treatment with formaldehyde according to the method described for the preparation of 3-hydroxymethyl-5,6,7,8-tetrahydromidazo[1,5-a]pyridine (used for Example 224) gave 1,4-dimethyl-2-hydroxymethylimidazole (2.71 g.), m.p. 125-126° (ethyl acetate-petroleum ether).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(OOC(C)(C)C)(C)(C)C>>[CH:10]1([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCCCC1
Reactant: CCCCCCCCO
Agent: CC(C)(C)OOC(C)(C)C
Product: CCCCCCCCOC1CCCCC1
Temperature: 90 °C
Yield: 42 %

Procedure:
Into a pressure vessel 1-octanol (160 μL, 1 mmol, 1 eq) was added and diluted with cyclohexane (1.080 mL, 10 mmol, 10 eq). To this stirring solution was added 1 mol % of a stock solution of {[Cl2NN]Cu}2(benzene) from the catalyst stock solution described in Example 4 (200 μL=0.01 mmol). After adding of tert-butyl peroxide (220 μL, 1.2 mmol), the pressure vessel was sealed and heated to 90° C. for 24 hr. The catalyst was separated by exposing the mixture to air and filtering through Celite®. After removing cyclohexane under vacuum, the residue was analyzed by 1H NMR and GC/MS to determine the yield and consumption of starting materials. 1H NMR Yield: 42%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH:17]1([NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24](I)[CH:23]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.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>[CH:17]1([NH:20][C:21]([C:22]2[CH:27]=[C:26]([C:6]3[CH:5]=[CH:4][C:3]([C:9](=[O:10])[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:2]([NH2:1])[CH:7]=3)[C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:30])[CH2:18][CH2:19]1
Reactant: Nc1cc(Br)ccc1C(=O)c1ccccc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)c2ccccc2)c(N)c1
Temperature: 95 °C
Reaction time: 4 h
Yield: 48.6 %

Procedure:
To a solution the (2-Amino-4-bromo-phenyl)-phenyl-methanone (276 mg, 1.0 mmol) and N-Cyclopropyl-3-iodo-4-methyl-benzamide (301 mg, 1.0 mmol) in 5 mL of methyl sulfoxide was added potassium carbonate (276 mg, 2.0 mmol) and followed by Pd(PPh3)4 (58 mg, 0.05 mmol). After the reaction mixture was stirred at 95° C. for 4 hours, the reaction mixture was allowed to cool to room temperature and 10 mL of water was added to the mixture. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers washed with water (10 mL) and brine (10 mL), dried over MgSO4, and the solvents were evaporated. The residue was purified by chromatography (hexanes:ethyl acetate=1:1) to give the desired compound as a colorless solid (180 mg, 49%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.I[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:12]=1>C1COCC1.C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:20][Si:19]([C:18]#[C:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:12][CH:13]=1)([CH3:22])[CH3:21]
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Reactant: C#Cc1ccc(C)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.1 %

Procedure:
Into a 50 ml round bottom flask was placed a mixture of 0.64 g (0.0054 mole) of 4-methylphenylacetylene, 1.50 g (0.005 mole) of 4-iodophenyltrimethylsilylacetylene, 0.011 g (0.0058 mmole) of CuI, 0.103 g (0.146 mmole) of bis(triphenylphosphine)palladium(II)dichloride in 10 ml of THF and 10 ml of triethylamine. The brown solution turned to an orange-yellow suspension when solid started to form. The mixture was stirred at room temperature under nitrogen for 3 days. It was filtered and the filtrate concentrated under reduced pressure. The residue was redissolved in 25 ml of chloroform and the solution was washed two times with water (15 ml each) and then dried over anhydrous MgSO4, filtered and concentrated, 1.43 g (quantitative yield) of solid was obtained. 1HNMR indicated ˜10% of by product present. The solid product was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)Cl.C(OCC)(=O)C.[CH:21]([NH2:23])=O>>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:23][CH:21]=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC=O
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1[nH]cnc2cc(F)ccc12
Yield: 82 %

Procedure:
A solution of 2-amino-4-fluorobenzoic acid (3 g, 19.3 mmol) in formamide (30 ml) was heated at 150° C. for 6 hours. The reaction mixture was poured onto icetwater 1/1 (250 ml). The precipitated solid was collected by filtration, washed with water and dried to give 7-fluoro-3,4-dihydroquinazolin-4-one (2.6 g, 82%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C(OCC)(=O)C.C(O)C.[CH3:22][NH2:23]>>[CH3:22][NH:23][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: CN
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1ccc(C(=O)OC)cc1
Yield: 74.4 %

Procedure:
Methyl 4-(bromomethyl)benzoate was dissolved in methylamine ethanol solution and the mixture was stirred at reflux for 3 hr. The mixture was condensed under vacuum and poured into ethyl acetate and filtered. The cake was dried to get methyl 4-((methylamino)methyl)benzoate (2.5 g, 74.4%), LC-MS (ESI) m/e 180 [M+1]−.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([C:22]([NH:24][NH2:25])=[O:23])[N:6]=1)([CH3:4])[CH3:3].[C:26](C1NC=CN=1)(C1NC=CN=1)=[O:27].C(N(CC)CC)C>C1COCC1>[CH3:3][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:18]([CH3:19])([CH3:20])[CH3:21])[N:8]=[C:7]([C:22]2[O:23][C:26](=[O:27])[NH:25][N:24]=2)[N:6]=1)([CH3:4])[CH3:1]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COCCOCOc1c(C(C)(C)C)nc(C(=O)NN)nc1C(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(-c2n[nH]c(=O)o2)nc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 64 h

Procedure:
4,6-Bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy) methoxy]-2-pyrimidine carboxylic acid hydrazide (1.0 g, 2.8 mmoles), carbonyl diimidazole (0.7 g, 4.2 mmoles), and triethylamine (0.6 g, 5.9 mmoles) are combined in 20 mL of THF and the reaction mixture is stirred at room temperature under argon for 64 hours. The reaction is quenched with 50 mL of 10% HOAc/H2O. The organics are extracted into ether (3×30 mL) and washed with 50 nil of brine. The solvent is evaporated and the residue is taken up in 20 mL of acetic acid. The reaction mixture is warmed to reflux for 18 hours. It is cooled to room temperature and diluted with 150 mL of H2O. The organics are extracted into EtOAc (3×100 mL) and washed with H2O (3×100 mL) followed by brine (3×100 mL). The solvent is evaporated, and the remaining oil is purified by flash chromatography (50% EtOAc|Hexane). Yield of 5-[4,6-bis (1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]-1,3,4-oxadiazole-2 (3H)-one=0.11 g (13%), mp 230°-232° C.
Reaction SMILES: [Na].[C:2]([NH:4][C:5]([NH:10][CH3:11])=[N:6][CH2:7][CH2:8][SH:9])#[N:3].Cl.[CH3:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH2:19]Cl>C(O)C>[C:2]([NH:4][C:5]([NH:10][CH3:11])=[N:6][CH2:7][CH2:8][S:9][CH2:19][C:15]1[N:16]=[CH:17][NH:18][C:14]=1[CH3:13])#[N:3]
Reactant: Cc1[nH]cnc1CCl
Reactant: CNC(=NCCS)NC#N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CNC(=NCCSCc1nc[nH]c1C)NC#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium (1.43 g) was added, with stirring under nitrogen, to dry ethanol (100 ml). After the sodium had dissolved a solution of N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine (4.90 g) in dry ethanol (50 ml) was added and the mixture was stirred at room temperature for one hour. 5-Methyl-4-chloromethylimidazole hydrochloride (5.18 g) was added in batches over a period of 1 hour at room temperature. The mixture was then stirred at room temperature, for a further hour and heated at reflux temperature for 1/2 hour. After cooling the mixture was filtered and the filtrate was evaporated to a glassy solid (8.8 g). This crude product was chromatographed on silica gel with acetonitrile as eluant and the solid product obtained (3.60 g) was recrystallised from acetonitrile to give N-cyano-N'-methyl-N"-[2-(5-methyl-4-imidazolylmethylthio)ethyl]guanidine, m.p. = 140°-142° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=CC(C(O)=O)=C[C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[CH3:34][CH:35]([CH3:39])[C:36]([NH2:38])=[O:37]>C(#N)C>[C:1]([C:5]1[CH:10]=[CH:39][C:35]([C:36]([NH:38][C:24](=[O:31])[CH:23]([CH3:28])[CH3:17])=[O:37])=[CH:34][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C(N)=O
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Solvent: CC#N
Product: CCCCCC(CC(=O)Nc1cc(C(=O)NC(=O)C(C)C)ccc1C(C)(C)C)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 139, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 7) and 2-methylpropanamide, the title compound was obtained as crystals, melting at 157-159° C. (from acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27]>ClCCl.CN(C1C=CN=CC=1)C>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([C:12](=[O:14])[CH2:11][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]3[CH2:18][N:17]([CH3:19])[CH2:16][CH2:15][C:6]2=3)[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNCC1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)O)C1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)CC1
Reaction time: 3 h
Yield: 12 %

Procedure:
A mixture of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetic acid (125 mg, 0.45 mmol) and oxalyl chloride (2 ml) in dichloromethane (6.0 ml) was stirred at 25 deg C. for 3 h. The reaction mixture was concentrated to dryness. The resulting crude was dissolved in dichloromethane (6.0 ml) and DMAP (64 mg, 0.52 mmol) was added followed by addition of acetyl piperazine (56 mg, 0.43 mmol). The resulting mixture was stirred at 25 deg C. for 14 h. The solvent was removed in vacuo and purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 20 mg of 1-(4-Acetyl-piperazin-1-yl)-2-(8-chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanone as trifluoroacetic acid salt.