Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([O:9][C:10]([CH3:23])([CH2:21][CH3:22])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:20])=[CH:16][CH2:17][CH2:18][OH:19])[CH3:8].[H][H]>[Pd].CO>[CH2:7]([O:9][C:10]([CH3:23])([CH2:21][CH3:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])[CH3:8]
Reactant: CCOC(C)(CC)CCCCC(C)=CCCO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: c1ccccc1
Product: CCOC(C)(CC)CCCCC(C)CCCO

Procedure:
A suspension of 0.5 g. of 5% palladium-on-carbon catalyst in 50 ml. of benzene is hydrogenated for 30 minutes. A mixture of 1.5 g. of 9-ethoxy-4,9-dimethylundec-3-en-1-ol in 75 ml. of methanol is added and hydrogenated with agitation until the theoretical amount of hydrogen is absorbed. The catalyst is removed by filtration and the solution evaporated to yield 9-ethoxy-4,9-dimethylundecan-1-ol which is purified by chromatography. The product is treated with phosphorus tribromide to yield 1-bromo-9-ethoxy-4,9-dimethylundecane which can be used as the alkylating agent for preparation of compounds of the present invention of formula I.
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([N+:18]([O-:20])=[O:19])=[CH:12][C:11]=2[CH3:21])[CH2:6][CH2:5]1.[CH3:22][S-:23].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:21][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[C:14]([O:16][CH3:17])=[CH:15][C:10]=1[N:7]1[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][S:23][CH3:22])[CH2:5][CH2:6]1
Reactant: COc1cc(N2CCC(CCI)CC2)c(C)cc1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCC(CCSC)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
To 4-(2-iodoethyl)-1-[2-methyl-5-(methyloxy)-4-nitrophenyl]piperidine (40.6 g, 100 mmol) was added sodium thiomethoxide (7.75 g, 111 mmol) and diluted with DMF (201 mL). The reaction was stirred at 50° C. overnight. The solution was diluted with EtOAc and washed with H2O. The organic layer was dried (MgSO4), filtered, and rotovapped down to provide the title compound of step H (33.5 g) which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 6.64 (s, 1H), 3.86 (s, 3H), 3.23 (d, J=12.1 Hz, 2H), 2.60-2.72 (m, 2H), 2.46-2.52 (m, 2H), 2.14 (s, 3H), 2.01 (s, 3H), 1.75 (d, J=12.1 Hz, 2H), 1.50 (t, J=5.7 Hz, 3H), 1.16-1.35 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:13])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)[N:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:13][C:6]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[N:3]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:33]=[CH:32][C:27]4[C:26](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)[N:5]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1Cl
Reactant: C1CCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N1CCCC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 92.5 %

Procedure:
A mixture of methyl {4,6-dichloro-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate (0.100 g, 0.21 mmol), pyrrolidine (0.019 mL, 0.23 mmol), and N,N-diisopropylethylamine (0.109 mL, 0.62 mmol) in anhydrous DMF (2 mL) was stirred at 80° C. for 5 hours. After cooling to room temperature, the solvent was evaporated and the remaining residue dissolved in EtOAc. This organic solution was sequentially washed with 1N HCl, water, and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by preparative TLC then afforded methyl {4-chloro-2-[4-(2-naphthoylamino)benzyl]-6-pyrrolidin-1-ylpyrimidin-5-yl}-acetate (0.100 g, 95% yield) as a white powder.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29].[Cl-].[Na+]>C(Cl)Cl>[C:28]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[O:9])[CH2:4][CH2:3]1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: NC1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2 Grams of 6-(4-amino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril and 3.06 ml of triethylamine were dispersed in 40 ml of methylene chloride, then under ice-cooling conditions, 0.78 ml of acetyl chloride was added dropwise thereto, and stirred at room temperature for 4 hours. The reaction mixture was poured into an aqueous solution saturated with sodium chloride, then extracted with chloroform. The extract was dried with anhydrous sodium carbonate, the solvent was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol=10:1), then recrystallized from methanol-diethyl ether to yield 0.3 g of 6-(4-acetylamino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril.1/4-hydrate. White powdery substance. Melting point: 228°-229° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][N:22]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[N:16]3[CH:20]=[CH:19][N:18]=[C:17]3[CH2:21][N:22]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1
Reactant: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nccn1-2

Procedure:
In the manner given in Example 33, 2',5-dichloro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone (4.76 g., 10.0 mmol) is dissolved in 60 ml. of ethanol, treated with 1.00 ml. of hydrazine hydrate and heated to 73° C. for 2 hours. After filtration of the reaction mixture, the mother liquids are concentrated and the residue is recrystallized from ethyl acetate/hexane mixtures to give 8-chloro-6-(o-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine of melting point 178°-180° C.
Reaction SMILES: [CH2:1]([NH:4][C:5]([N:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[OH:8])=[O:6])[CH:2]=[CH2:3].[OH-].[Na+].Cl[C:19](OCC)=[O:20]>O1CCOCC1.O>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([N:7]2[C:5](=[O:6])[N:4]([CH2:1][CH:2]=[CH2:3])[C:19](=[O:20])[O:8]2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: C=CCNC(=O)N(O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=CCn1c(=O)on(-c2ccc(Cl)cc2)c1=O
Reaction time: 0.5 h

Procedure:
1-Allyl-3-(4'-chlorophenyl)-3-hydroxyurea (6.0 g.) was dissolved in cooled dioxane (50 ml.) and a solution of sodium hydroxide (1.3 g.) in water (15 ml.) was added thereto. Ethyl chloroformate (3.2 g; 2.9 ml.) was added dropwise at 10°-15° C. with stirring and the stirring continued for about 1/2 hour after the addition was completed. The reaction mixture was poured into cold water (300 ml.), stirred and filtered to separate the precipitate. The precipitate was recrystallized from ethanol and dried in vacuo at room temperature to yield 2-(4'-chlorophenyl)-4-allyl-1,2,4-oxadiazolidine-3,5-dione as white needle-like crystals melting 56°-57° C. and having the following elemental analysis as calculated for C11H9ClN2O3 :
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:33])=[C:8](C(O)=O)[NH:9][C:10]=1[CH:11]=[C:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:29])([OH:3])=[O:2].[OH-].[K+].O.Cl>C(O)CO>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([C:17]2[CH:16]=[C:15]3[C:20]([C:12](=[CH:11][C:10]4[NH:9][CH:8]=[C:7]([CH3:33])[C:6]=4[CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:13](=[O:29])[NH:14]3)=[CH:19][CH:18]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C(=O)O)c(C)c2CCC(=O)O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]cc(C)c2CCC(=O)O)c1
Temperature: 90 °C
Yield: 20.1 %

Procedure:
4-(2-Carboxyethyl)-5-[6-(3-methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (413 mg) suspended in ethylene glycol (5 mL) was held in sealed tube in a pre-heated oil bath at 200° C. for 2 M hours. The reaction mixture was cooled to 90° C. and potassium hydroxide (4 pellets) was added. It was then stirred at 100° C. for 2 more hours. The reaction mixture was cooled, poured into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water and dried in a vacuum oven overnight. The crude solid was purified on a silica gel column using 33:66:1 ethyl acetate:hexanes:glacial acetic acid as eluent to give 75 mg (20%) of 3-{2-[6-(3-methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-4-methyl-1H-pyrrol-3-yl}-propionic acid as an orange-red solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7].O[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[C:13](=[O:17])[CH:12]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1c1ccccc1
Reactant: OCCN1CCOCC1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCN1CCOCC1)C(=O)C2c1ccccc1

Procedure:
The title compound, MS: m/e=598.1 (M+H+), was prepared in accordance with the general method of example 121 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decane-1,3-dione and N-(2-hydroxyethyl)-morpholine.
Reaction SMILES: [F:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1F)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1F)[nH]c(=O)n2C1CCNCC1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
1,1-Dimethylethyl 4-(5-fluoro-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidine-carboxylate (D29) (0.68 mmol, 239 mg) in dichloromethane (5 mL) was treated under argon at room temperature with trifluoroacetic acid (1 mL) and allowed to stir for 1 h. The mixture was concentrated, treated with 10% Na2CO3 aqueous solution, extracted 3 times with ethyl acetate. Organics were combined, dried on MgSO4, and concentrated under vacuum to give the title compound (0.64 mmol, 160 mg, 94% yield). M+H=250.2.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([C:9]3[CH:19]=[CH:18][C:12]4C(C)CN[O:16][C:11]=4[CH:10]=3)[NH:8][C:4]=2[CH:3]=1.[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>>[CH3:7][N:6]1[CH2:5][CH2:4][O:16][C:11]2[CH:10]=[C:9]([C:7]3[NH:6][C:5]4[CH:20]=[CH:21][C:2]([NH:1][C:32](=[O:34])[C:31]5[CH:30]=[CH:29][C:28]([N:25]6[CH2:24][CH2:23][O:22][CH2:27][CH2:26]6)=[CH:36][CH:35]=5)=[CH:3][C:4]=4[N:8]=3)[CH:19]=[CH:18][C:12]1=2
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: CC1CNOc2cc(-c3nc4ccc(N)cc4[nH]3)ccc21
Product: CN1CCOc2cc(-c3nc4cc(NC(=O)c5ccc(N6CCOCC6)cc5)ccc4[nH]3)ccc21

Procedure:
Compound 169 was prepared according to the procedure similar to that described in Scheme III from 5-amino-2-(4-methyl-3,4-dihydrobenzoxazin-7-yl)benzimidazole and 4-morpholinobenzoic acid. [M+H]+ calcd for C27H27N5O3: 470.21; found: 496.96.
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]([C:22](O)=[O:23])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:14]=2)[C:7]([CH3:25])=[N:6][N:5]=1)([CH3:3])[CH3:2].[N:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[CH:32]([NH2:34])[CH3:33]>>[N:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[CH:32]([NH:34][C:22]([C:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH:14]=[C:9]([N:8]2[C:7]([CH3:25])=[N:6][N:5]=[C:4]2[CH:1]([CH3:3])[CH3:2])[CH:10]=1)=[O:23])[CH3:33]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-n3c(C)nnc3C(C)C)c2)cc1
Reactant: CC(N)c1cnccn1
Product: Cc1ccc(-c2cc(C(=O)NC(C)c3cnccn3)cc(-n3c(C)nnc3C(C)C)c2)cc1

Procedure:
5-(3-Isopropyl-5-methyl-[1,2,4]triazol-4-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide was prepared from 5-(3-isopropyl-5-methyl-[1,2,4]triazol-4-yl)-4′-methyl-biphenyl-3-carboxylic acid and 1-pyrazin-2-yl-ethylamine using the procedure of step 4 of Example 6.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[N:10]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[C:28]([CH2:30][C:31]#[N:32])[CH:27]=[CH:26][C:25]=1[O:33][CH3:34])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:36]([Si](C)(C)C)=[N+:37]=[N-:38].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:35])[N:10]([CH2:11][CH3:12])[CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[C:28]([CH2:30][C:31]2[N:36]=[N:37][NH:38][N:32]=2)[CH:27]=[CH:26][C:25]=1[O:33][CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC#N)ccc1OC)C(=O)OCc1ccccc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cc2nn[nH]n2)ccc1OC)C(=O)OCc1ccccc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
(5′-Cyanomethyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-ethyl-carbamic acid benzyl ester (0.209 g, 0.43 mmol), azidotrimethylsilane (0.07 mL, 0.52 mmol), and dibutyltin oxide (0.015 g, 0.04 mmol) were combined in toluene (2.1 mL) and stirred at 110° C. overnight Analytical LCMS indicated that the reaction wasn't proceeding, so additional azidotrimethylsilane (0.04 mL, 0.26 mmol), and dibutyltin oxide (catalytic) was added, and the reaction was stirred at 100° C. overnight. The mixture was cooled to room temperature and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound. M+H is 526.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCN1CCN(c2ccc(N)cn2)CC1
Yield: 102.8 %

Procedure:
A mixture of 2.47 g (10 mmol) 1-ethyl-4-(5-nitro-pyridin-2-yl)-piperazine and 0.247 g Pd/C (10%) in 25 ml methanol was treated with 1 bar hydrogen at room temperature for 2 h. After filtration the mixture was evaporated to dryness to yield 2.12 g (98%) of the title compound as colorless solid. (m/e): 207.3 (MH+; 100%).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH:34](=O)[C:35]1[O:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[O:39]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH:34]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=C(O)CCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccco1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCCC=Cc1ccco1
Yield: 45 %

Procedure:
This compound was synthesized from 10-carboxydecyltriphenylphosphonium bromide (10.50 g, 20 mmol) and furfural (1.92 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization afforded the product (2.38 g, 45%) as pale yellow crystals (mp 38°-39° C.); IR: 3450-2500, 1715, 695 cm-1 ; 1H-NMR: 1.35 (m, 14H), 2.35 (t, 4H), 5.60 (m, 1H), 6.30 (m, 3H), 7.35 (s, 1H), 9.40 (bs, 1H). Anal. Calcd. for C16 H24O3 : C, 72.69, H, 9.15; Found: C, 72.44, H, 9.06%. Z:E=43:57.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([NH2:16])[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:32])[CH2:26][O:27][CH2:28][C:29](O)=[O:30])=[C:20]([C:33]([O:35]C)=[O:34])[CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:32])[CH2:26][O:27][CH2:28][C:29](=[O:30])[NH:16][C:11]2[CH:10]=[C:9]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=3)[CH:14]=[CH:13][C:12]=2[CH3:15])=[C:20]([CH:19]=1)[C:33]([OH:35])=[O:34]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Cc1cc(C)cc(-c2ccc(C)c(N)c2)c1
Product: Cc1cc(C)cc(-c2ccc(C)c(NC(=O)COCC(=O)Nc3ccc(Cl)cc3C(=O)O)c2)c1

Procedure:
Using the same method as in Example 1-(ii), 3′,4,5′-trimethylbiphenyl-3-amine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-[((2-oxo-2-[(3′,4,5′-trimethylbiphenyl-3-yl)amino]ethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:15][CH2:16][C:17](=[O:20])[NH:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([NH:12][NH2:13])=[O:11].[CH:21](=O)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:15][CH2:16][C:17](=[O:20])[NH:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10](=[O:11])[NH:12][N:13]=[CH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NNC(=O)COc1ccc(C2=NNC(=O)CC2)cc1Cl
Solvent: CN(C)C=O
Product: COc1ccc(C=NNC(=O)COc2ccc(C3=NNC(=O)CC3)cc2Cl)cc1
Reaction time: 8 h
Yield: 91.6 %

Procedure:
1.00 g of 6-[3-chloro-4-(hydrazinocarbonylmethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (Compound No. 18a, prepared following the procedure described in Example 4) was dissolved in 55 ml of dimethylformamide, and 2.3 g of p-anisaldehyde were added, at room temperature, to the resulting solution. The mixture was then stirred at the same temperature for 8 hours. At the end of this time, the solvent was distilled off in vacuo and chloroform was added to the resulting residue. The resulting precipitate was filtered off to give 1.28 g of the title compound melting at 220°-222° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:14]([Zn]CC)[CH3:15]>O1CCOCC1>[Cl:13][C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([CH2:14][CH3:15])[CH:3]=[N:4][CH:5]=1
Reactant: CC[Zn]CC
Reactant: CCOC(=O)c1c(Cl)cncc1Br
Solvent: C1COCCO1
Product: CCOC(=O)c1c(Cl)cncc1CC
Temperature: 70 °C
Yield: 54.9 %

Procedure:
To a solution of ethyl 3-bromo-5-chloropyridine-4-carboxylate (5.84 g, 22.08 mmol) in anhydrous dioxane (40 mL) at room temperature was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (323 mg, 0.441 mmol). Then, diethylzinc (2.72 g, 18 mL, 22.09 mmol, 15% solution in toluene) was added dropwise and the reaction was heated at 70° C. for 45 minutes. The mixture was cooled to room temperature, quenched with MeOH, and extracted with ethyl acetate (2×100 mL). The organic layer was washed with water, 0.1 N HCl, and brine, and then dried over anhydrous sodium sulfate. The filtered solution was evaporated, and the residue was purified by CombiFlash using 0-30% ethyl acetate in hexane to provide ethyl 5-chloro-3-ethylpyridine-4-carboxylate as a pale yellow oil (2.59 g, 55% yield); 1H NMR (400 MHz, CDCl3): δ 1.25 (t, 3H), 1.45 (t, 3H), 2.65 (q, 2H), 4.47 (q, 2H), 8.41 (s, 1H), 8.49 (s, 1H); M+ 214.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH3:16])[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[O:27].C(N(CC)CC)C>CN(C)C=O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25][C:26](=[O:27])[N:15]([C:13]1[CH:14]=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:10]=[CH:11][N:12]=1)[CH3:16]
Reactant: CNc1cc(Nc2ccc(F)cc2)ncn1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)Nc1c(Cl)cccc1Cl)c1cc(Nc2ccc(F)cc2)ncn1
Temperature: 90 °C
Reaction time: 14 h

Procedure:
A mixture of N-(4-fluoro-phenyl)-N′-methyl-pyrimidine-4,6-diamine (218.2 mg, 1 mmol), 2,6-dichlorophenyl isocyanate (188 mg, 1 mmol) and triethylamine (1.11 mL, 8 mmol) in dry dimethylformamide (2.5 mL) is shaken for 14 h at 90° C. The reaction mixture is evaporated in vacuo and the residue is distributed between ethyl acetate and half-saturated Na2CO3 solution. The organic layer is dried over Na2SO4, evaporated, and the residue purified by flash chromatography (CH2Cl2/CH3OH). The combined pure fractions are evaporated, the residue triturated with CH2Cl2 and the solid filtered off and dried in vacuo to afford the title compound.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(#N)C.C([O-])([O-])=O.[K+].[K+].Br[C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1>CCOC(C)=O>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([C:39]5[N:44]=[CH:43][CH:42]=[CH:41][N:40]=5)[CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Reactant: Brc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(c5ncccn5)C4)c3)n2)cn1
Temperature: 45 °C
Yield: 20.2 %

Procedure:
To a solution of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62; 30 mg, 0.069 mmol) in acetonitrile (690 μL, 0.069 mmol) was added K2CO3 (38 mg, 0.28 mmol) and 2-bromopyrimidine (12 mg, 0.076 mmol). The reaction mixture was heated to 45° C. for 3 days. After diluting in EtOAc, the mixture was washed with water and brine. The organic layer was dried with MgSO4, filtered and concentrated in vacuo to a clear colorless oil. The oil was purified by reverse phase HPLC using 0-100% acetonitrile/water gradient to afford 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(pyrimidin-2-yl)azetidin-3-yl)acetonitrile (6.1 mg, 20% yield) as a white solid. MS (apci) m/z=438.2 (M+H).
Reaction SMILES: [Mg].CCOCC.BrBr.C([O:16][C:17]1[C:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20])C1C=CC=CC=1>C1C=CC=CC=1>[CH2:26]([O:25][C:24]1[C:17]([OH:16])=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: BrBr
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=Cc1cccc(OCc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To magnesium (2.9 g, turnings, 0.12 mol) in a mixture of anhydrous ether (85 mL) and benzene (85 mL) at 0° C., bromine (3.4 mL, 0.066 mol) was added dropwise. When the reaction had started, stirring was commenced and the addition of bromine continued until complete. The ice bath was removed and the reaction mixture was heated until the solution was almost colorless. After cooling down, the reaction mixture was slowly added to a solution of 2,3-bis-benzyloxy-benzaldehyde (128, 20 g, 0.063 mol) in benzene (415 mL) at room temperature while stirring vigorously. Upon completion of the addition, the reaction mixture was stirred at room temperature overnight, and then refluxed for 36 hours. After the reaction mixture was cooled down to room temperature, a solid was collected by filtration and washed with benzene, then boiled in hydrochloric acid (100 mL, 1.0 M) for 30 minutes. After cool down, the solution was extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. A light tan solid was obtained after removal of the solvent (129, 12.5 g, 87%).