Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:7])[O:2][CH2:3][CH2:4][O:5][CH3:6].[NH2:9][C@@H:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]([Cl:40])=[C:18]([NH:24][C:25]3[N:30]=[C:29]([NH:31][CH:32]4[CH2:34][CH2:33]4)[C:28]4=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:27]4[N:26]=3)[CH:19]=[C:20]([C:22]#[N:23])[CH:21]=2)[CH2:12][C@H:11]1[O:41][Si:42]([CH:49]([CH3:51])[CH3:50])([CH:46]([CH3:48])[CH3:47])[CH:43]([CH3:45])[CH3:44].C(N(CC)CC)C>ClCCl>[Cl:40][C:17]1[C:18]([NH:24][C:25]2[N:30]=[C:29]([NH:31][CH:32]3[CH2:33][CH2:34]3)[C:28]3=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:27]3[N:26]=2)=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][C@@H:10]([NH:9][C:1](=[O:7])[O:2][CH2:3][CH2:4][O:5][CH3:6])[C@H:11]([O:41][Si:42]([CH:46]([CH3:48])[CH3:47])([CH:49]([CH3:51])[CH3:50])[CH:43]([CH3:44])[CH3:45])[CH2:12]1
Reactant: CC(C)[Si](O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1N)(C(C)C)C(C)C
Reactant: COCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
2-methoxyethyl carbonochloridate (5.08 mg, 0.037 mmol) was added to a solution of 2-((3-((3R,4R)-4-amino-3-((triisopropylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 174D, 19 mg, 0.031 mmol) and triethylamine (8.53 μl, 0.061 mmol) in dichloromethane (1 mL) and the reaction solution was stirred at room temperature overnight. More 2-methoxyethyl carbonochloridate (5.08 mg, 0.037 mmol) was added and stirring continued over the weekend, still about 30% SM left. More triethylamine (100 μL) and 2-methoxyethyl carbonochloridate (20 μl) was added and stirred for another day. Reaction close to completion. The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate, the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 0-40% ethyl acetate/dichloromethane) to give 2-methoxyethyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)carbamate (12 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].CN(C)C=O.[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl>O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2c(Cl)nc(Cl)nc21
Reaction time: 0.25 h

Procedure:
5 g of 2,6-dichloropurine was added to the mixture of 1.54 g of sodium hydride and 100 mL of N,N-dimethylformamide in an ice bath, and stirred at the same temperature for 15 minutes. 6.81 mL of 2-(trimethylsilyl)ethoxymethyl chloride was added to the reaction mixture, and was stirred at the same temperature for 5 hours. The reaction mixture was added with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in the subsequent order, and then dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography, to obtain 6.18 g of 2,6-dichloro-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purine [56-1] as a light brown oily product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15]>C(N(CC)CC)C.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:15]#[C:14][CH2:13][CH2:12][OH:16])[CH:3]=1
Reactant: C#CCCO
Reactant: Brc1cnc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCC#Cc1cnc2ccccc2c1
Yield: 136.9 %

Procedure:
A solution of 3-bromoquinoline (13.57 mL, 0.10 mol) and 3-butyn-1-ol (9.0 mL, 0.12 mol) in 40 mL of triethylamine and 75 mL of dichloromethane is degassed by bubbling dry nitrogen through it for 15 minutes, and 0.7 g (0.001 mol) of bis(triphenylphosphine)palladium dichloride and 0.013 g of cuprous iodide are added. The flask is flushed with nitrogen and the mixture heated to reflux for 5 hours. The cooled mixture is diluted with dichloromethane and washed with water, dried (sodium sulfate), and concentrated to give 27 g of a gold oil. The oil was triturated with diethyl ether to give 18.2 g of the title compound as a tan solid; mp 95.7°-96.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]2[CH2:42][CH2:41][CH2:40][NH:39]2)[CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:39]4[CH2:40][CH2:41][CH2:42][CH:38]4[C:34]4[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=4)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: c1cncc(C2CCCN2)c1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCCC1c1cccnc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(3-pyridinyl)pyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z=577.97 (M+H+); retention time=0.63 minutes.
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:24])([CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH2:4]1.[C:25]1([N:31]2[C:35]([S-:36])=[N:34][N:33]=[N:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Na+]>CN(C)C=O>[CH3:9][C:7]1([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:24])([CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH2:4][C@@H:3]([CH2:2][S:36][C:35]2[N:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:32]=[N:33][N:34]=2)[O:8]1
Reactant: [S-]c1nnnn1-c1ccccc1
Reactant: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CSc2nnnn2-c2ccccc2)OC(C)(C)O1
Temperature: 90 °C
Reaction time: 24 h
Yield: 97.2 %

Procedure:
2-methyl-1-phenylpropan-2-yl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (30 g) prepared in Example 5 was dissolved in dimethylformamide (150 ml), and sodium 1-phenyl-1H-tetrazole-5-thiolate (33.9 g) prepared in Example 7 was added thereto. The reaction liquid was warmed to 90° C. and then stirred for 24 hours. The reaction liquid was cooled to room temperature, and diisopropyl ether (600 ml) and purified water (600 ml) were added thereto. The organic layer was separated, washed with purified water (600 ml), a 10% sodium bicarbonate aqueous solution (600 ml), a saturated ammonium chloride aqueous solution (600 ml) and a saturated sodium chloride aqueous solution (600 ml), dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to give the title compound (40.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24]([N:26]3[CH2:32][CH:31]4[N:33](C(OC(C)(C)C)=O)[CH:28]([CH2:29][CH2:30]4)[CH2:27]3)=[O:25])=[CH:21][N:22]=2)[N:19]=1.[ClH:41]>C(Cl)Cl>[ClH:41].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24]([N:26]3[CH2:27][CH:28]4[NH:33][CH:31]([CH2:30][CH2:29]4)[CH2:32]3)=[O:25])=[CH:21][N:22]=2)[N:19]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)Nc1cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn13)C2
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12)N1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 3-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Example 23, 10 mg, 0.018 mmol) was dissolved in 0.1 mL DCM, followed by addition of 0.5 mL 4 N HCl (dioxane) solution in one portion. After stirring at ambient temperature overnight, the reaction was concentrated to yield the final product salt form as a light yellowish solid. MS (apci) m/z=454.1 (M+H).
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH2:19][CH2:20][CH:21]([CH2:23][C:24]([O:26]CC)=[O:25])[S:22][C:11]1=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C(O)C>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH2:19][CH2:20][CH:21]([CH2:23][C:24]([OH:26])=[O:25])[S:22][C:11]1=2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CC1CCc2c(n(Cc3ccccc3)c3ccccc23)S1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1CCc2c(n(Cc3ccccc3)c3ccccc23)S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
0.5 ml of a 3% w/v aqueous solution of potassium hydroxide was added to a mixture of 44 mg of ethyl 2-(9-benzyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indol-2-yl)acetate (prepared as described in Example 82) in 2 ml of ethanol. The reaction mixture was then stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was made acidic by the addition of a 3% w/v aqueous solution of hydrochloric acid and extracted with ethyl acetate. The ethyl acetate fraction was then washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was recrystallized from hexane and ethyl acetate to afford 37 mg of the title compound as a solid which melted at 164°-167° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:13]=[N:14][C:15]([N:19]([CH3:21])[CH3:20])=[CH:16][C:17]=3[CH3:18])[N:7]([CH2:22][CH2:23][CH2:24]O)[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[C:17]([CH3:18])=[CH:16][C:15]([N:19]([CH3:21])[CH3:20])=[N:14][CH:13]=4)[CH2:24][CH2:23][CH2:22][N:7]3[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3cnc(N(C)C)cc3C)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(N(C)C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 3-[4-chloro-2-{[6-(dimethylamino)-4-methylpyridin-3-yl]amino}-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]propan-1-ol (100 mg, 0.233 mmol) in pyridine (2 mL) was added methanesulfonyl chloride (0.036 mL, 0.465 mmol) dropwise at 0° C. After stirring for 2 hr at room temperature, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude mesylate was dissolved in 1-methyl-2-pyrrolidinone (1.0 mL) and potassium carbonate (64 mg, 0.465 mmol) was added. The mixture was stirred at 50° C. for 4 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-80% ethyl acetate/n-hexane gradient mixture followed by recrystallization from ethyl acetate/n-hexane to afford the title compound (50 mg, 0-12 mmol, 52%) as a colorless solid.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:17]([O:19][C:20](=[O:33])[CH:21]([N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[C:26]1=[O:32])[O:22][CH2:23][CH3:24])[CH3:18].CC1(C)N([O])C(C)(C)CCC1>C(Cl)Cl>[CH2:17]([O:19][C:20](=[O:33])[CH:21]([O:22][CH2:23][CH3:24])[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:26]1=[O:32])[CH3:18]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C(OCC)n1cccc(N)c1=O
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(OCC)n1cccc(Nc2ccccc2)c1=O
Reaction time: 72 h
Yield: 47.6 %

Procedure:
To a 100 ml flask was added in sequence molecular sieves 4Å(200 mg), phenylboronic acid (418 mg), CH2Cl2 (10 ml), triethylamine (0.48 ml), a solution of (RS)-(3-amino-2-oxo-2H-pyridin-1-yl)-ethoxy-acetic acid ethyl ester (412 mg, example 19.2) in CH2Cl2 (10 ml), cupric acetate (31 mg) and TEMPO (295 mg). A CaCl2 trap was placed over the flask. The reaction was then stirred under air for 3 days. The solids were filtered off and washed with CH2Cl2. The filtrate was concentrated. The crude product was purified by chromatography (silica gel, gradient cyclohexane/EtOAc) to give (RS)-ethoxy-(2-oxo-3-phenylamino-2H-pyridin-1-yl)-acetic acid ethyl ester (258 mg) as green oil. MS 317.2 ([M+H]+)
Reaction SMILES: [CH:1]1=[CH:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C=O.C1CCCCCCCCCCC1>C(O)(=O)C>[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=1
Reactant: C1=CCCC=CCCC=CCC1
Agent: C1=CCC/C=C\CCC=CCC1
Agent: C1CCCCCCCCCCC1
Agent: C=O
Solvent: CC(=O)O
Product: C1=CCCCCCCCCCC1
Temperature: 145 °C
Yield: 97 %

Procedure:
A 70 ml autoclave equipped with a magnetic stirrer was charged with 40 g of trans-, trans-, cis-1,5,9-cyclododecatriene, 50 mg of RuCl3*H2O, 400 mg of triphenylphosphine, 0.5 g of 37% strength aqueous formaldehyde solution and 100 mg of acetic acid. The reactor was purged with nitrogen and hydrogen and then brought to a hydrogen pressure of 20 bar and heated up with stirring. At 115° C., the reactor pressure decreased noticeably and the internal temperature rose quickly to 140° C. Thereafter the reactor was constantly maintained at 20 bar and 145° C. by means of hydrogen. After about 2.5 hours the reactor was cooled down and decompressed. The effluent was found by GC to contain a yield of 97% of cyclododecene and 1.8% of cyclododecane. The remainder was cyclododecadiene.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]([F:40])([F:39])[O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][OH:36])=[CH:33][CH:32]=1.O>CN(C)C=O>[N:13]1([C:4]2[N:3]=[C:2]([O:36][CH2:35][C:34]3[CH:37]=[CH:38][C:31]([O:30][C:29]([F:28])([F:39])[F:40])=[CH:32][CH:33]=3)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1Cl
Reactant: OCc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1OCc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 53.2 %

Procedure:
To a solution of ethyl 4-chloro-2-(2,3-dihydro-1H-indol-1-yl)-5-pyrimidinecarboxylate (520 mg, 1.72 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (829 mg, 6 mmol) and 4-(trifluoromethoxy)benzyl alcohol (384 mg, 2 mmol) and the mixture was stirred at 100° C. for 18 h. The reaction mixture was allowed to cool to room temperature and water was added, which was followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the residue was applied to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1) to give the title compound (420 mg, 53%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](Cl)=[O:17])=[CH:10][CH:9]=1>ClCCl.O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:17])=[CH:12][CH:13]=1
Reactant: O=C(Cl)CCc1ccc(Br)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: O
Product: O=C(CCc1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of morpholine (11 g, 126.44 mmol, 2.01 equiv) in dichloromethane (60 mL) 0˜5° C. was added a solution of 3-(4-bromophenyl)propanoyl chloride (15.5 g, 63.01 mmol, 1.00 equiv) in dichloromethane (30 mL) dropwise with stirring. The resulting solution was stirred at 0˜5° C. for 1 h. The reaction mixture was warmed to room temperature. The resulting solution was diluted with 40 mL of water. The mixture was extracted with dichloromethane 2×100 mL. The combined organic layers was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 17.4 g (93%) of 3-(4-bromophenyl)-1-morpholinopropan-1-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](N2CCC(C3N(C)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[N:40]1([CH2:44][CH2:45][N:46]2[CH:50]=[C:49]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH:58]([F:60])[F:59])=[CH:53][CH:52]=3)[N:48]=[C:47]2[CH:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH2:43][CH2:42][CH2:41]1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:64]2[CH2:63][CH2:62][CH:61]([C:47]3[N:46]([CH2:45][CH2:44][N:40]4[CH2:43][CH2:42][CH2:41]4)[CH:50]=[C:49]([C:51]4[CH:52]=[CH:53][C:54]([O:57][CH:58]([F:60])[F:59])=[CH:55][CH:56]=4)[N:48]=3)[CH2:66][CH2:65]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Reactant: FC(F)Oc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(OC(F)F)cc3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using 4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-difluoromethoxy-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate instead of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS: (M+1=495, obsd.=495).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]#[N:19])[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:17]=1>[Ni].N.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][NH2:19])[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:17]=1
Reactant: Cc1nc2c(C#N)cc(Cl)cc2n1C1CCCCO1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1nc2c(CN)cc(Cl)cc2n1C1CCCCO1
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A mixture of 6-chloro-2-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-4-carbonitrile (1.0 g, 3.16 mmol) and Raney nickel (100 mg) in NH3/MeOH (7 N, 10 mL) was stirred under hydrogen for 2 h. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo to afford crude (6-chloro-2-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-4-yl)methanamine (115, 600 mg, 59.0%) as a yellow solid. MS (ESI): m/z=280.3 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:14]1([C:20]2[O:24][N:23]=[CH:22][C:21]=2[CH2:25][CH2:26][C:27](O)=[O:28])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:27](=[O:28])[CH2:26][CH2:25][C:21]3[CH:22]=[N:23][O:24][C:20]=3[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[S:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1cnoc1-c1ccccc1)Nc1nc(-c2ccc(Cl)cc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
A mixture of 2-amino-4-(4-chlorophenyl)thiazole (0.75 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.72 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.55 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.70 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[4-(4-chlorophenyl)-2-thiazolyl]-3-(5-phenyl-4-isoxazolyl)propionamide (0.58 g, yield 43%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 172–173° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[CH3:18])=[CH:15]/[CH2:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH2:50]([O:52][C@@H:53]([CH2:59][C:60]1[CH:65]=[CH:64][C:63](O)=[CH:62][CH:61]=1)[C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH3:51]>>[CH2:57]([O:56][C:54](=[O:55])[C@@H:53]([O:52][CH2:50][CH3:51])[CH2:59][C:60]1[CH:65]=[CH:64][C:63]([O:17][CH2:16]/[CH:15]=[C:14](/[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)\[CH3:18])=[CH:62][CH:61]=1)[CH3:58]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2ccc(Br)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(Br)cc3)cc2)cc1)OCC
Yield: 34.4 %

Procedure:
The title compound was prepared from (E)-3-(4′-bromo-biphenyl-4-yl)-but-2-en-1-ol (0.364 g, 1.2 mmol), triphenylphosphine (0.328 g, 1.3 mmol), diethyl azodicarboxylate (0.173 ml, 1.1 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxy-phenyl)-propionate (0.238 g, 1.0 mmol) by a procedure analogous to that described in example 1c, yielding 0.180 g (34%) of (E)-(S)-3-{4-[3-(4′-bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24](O)=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:7]=1[C:8]#[CH:9].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:43]1([O:52][C:53](N(C)C)=[N+](C)C)[C:47]2C=CC=CC=2N=N1.Cl.CNOC.Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]([N:43]([O:52][CH3:53])[CH3:47])=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:7]=1[C:8]#[CH:9]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C#Cc1c(Cl)cc(C(=O)O)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#Cc1c(Cl)cc(C(=O)N(C)OC)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 91.2 %

Procedure:
A solution of 4-chloro-6-[(1E)-3,3-diethyltriaz-1-en-1-yl]-5-ethynyl-3′-fluorobiphenyl-2-carboxylic acid (2.7 g, 7.1 mmol) in N,N-dimethylformamide (14 mL) was treated with N,N-diisopropylethylamine (4.3 mL, 25 mmol) followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.5 g, 9.3 mmol) and stirred at 20° C. for 5 minutes. The reaction mixture was treated with N,O-dimethylhydroxylamine hydrochloride (0.9 g, 9.3 mmol) and stirred at 20° C. for 1 hour. The reaction mixture was poured into 0.5 M hydrogen chloride in water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with saturated sodium bicarbonate (50 mL), brine (25 mL), dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0% - 40%) gave the desired product (2.7 g, 92% for 2 steps). LCMS for C21H23ClFN4O2 (M+H)+: m/z=417.1; Found: 417.0.