Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][N:7]1[CH2:13][CH2:12][CH2:11][N:10]([CH:14]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]=O)=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[CH2:9][CH2:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC.C1COCC1>[CH3:6][N:7]1[CH2:13][CH2:12][CH2:11][N:10]([CH:14]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]=[CH2:1])=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[CH2:9][CH2:8]1
Reactant: CN1CCCN(C2CCCc3cc(C=O)ccc32)CC1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1ccc2c(c1)CCCC2N1CCCN(C)CC1
Reaction time: 2 h

Procedure:
A dry flask under nitrogen was charged with 0.25 g (0.69 mmol) of methyltriphenyl phosphonium bromide and 2.1 ml of anhydrous THF. To this suspension at ambient temperature was added 0.30 ml (0.69 mmol) of a 2.3 M solution of n-butyllithium in hexane. This was followed by the addition of a solution of 0.18 g (0.67 mmol) of 1-methyl-4-(6-formyl-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine in 1.4 ml THF. After two hours, analysis by 1H-NMR of a worked-up aliquot revealed the presence of the desired product (vinyl proton resonances) as well as residual aldehyde (CHO resonance). A second portion of the triphenylphosphonium ylid (0.070 mmol) was generated in 4 ml THF and added to the mixture containing the residual aldehyde. After four hours, analysis by 1H-NMR of a worked-up aliquot indicated only a trace of aldehyde. The reaction mixture was concentrated invacuo to semisolid which was treated with water and extracted several times with ether. The combined ether extract was dried (MgSO4), filtered and concentrated invacuo to a semisolid, 0.34 g. This material was triturated with hexane, filtered and the hexane was removed invacuo. The resulting residue was again titurated with hexane, filtered and concentrated invacuo to give the title compound, 0.18 g, as a yellow oil; 1H-NMR(300 Hz, CDCl3) δ 5.17-5.20 (1H, d), 5.68-5.74 (1H, d), 6.62-6.71 (1H, q).
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][O:7][C:8]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:22][C:23]#[N:24].[C:25](=O)([O:29]CC)[O:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1.C(O)C>[C:23]([CH:22]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:8]=1[O:7][CH3:6])[C:25]([O:26][CH2:27][CH3:28])=[O:29])#[N:24]
Reactant: COc1c(CC#N)cccc1Oc1ccccc1F
Reactant: CCOC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2F)c1OC
Yield: 109.4 %

Procedure:
A mixture of sodium ethoxide prepared from sodium metal (470 mg) and ethanol (20 ml), 2-[2-methoxy-3-(2-fluorophenoxy)phenyl]acetonitrile (5 g) and diethyl carbonate (9.2 g) in toluene (50 ml) was treated in a similar manner to that of Example 10-(4) to give oily ethyl 2-cyano-2-[2-methoxy-3-(2-fluorophenoxy)phenyl]acetate (7 g).
Reaction SMILES: [CH3:1][C:2]1[S:15][C:5]2[S:6][CH2:7][CH:8]([CH2:11][C:12]([OH:14])=O)[C:9](=O)[C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:12](=[O:14])[CH2:11][CH:8]3[CH2:7][S:6][C:5]4[S:15][C:2]([CH3:1])=[CH:3][C:4]=4[C:9]3=[N:24]2)=[CH:19][CH:18]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: Cc1cc2c(s1)SCC(CC(=O)O)C2=O
Solvent: CCO
Product: Cc1cc2c(s1)SCC1CC(=O)N(c3ccc(Cl)cc3)N=C21
Yield: 46.3 %

Procedure:
A mixture of 3.0 g of 2-methyl-4-oxo-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-acetic acid and 2.0 g of 4-chlorophenylhydrazine in 50 ml of ethanol is refluxed under heating for 9 hours. After cooling, the mixture is concentrated under reduced pressure, the residue is subjected to column chromatography on silica gel and eluted with chloroform. The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 2.0 g of 2-(4-chlorophenyl)-8-methyl-4a,5-dihydro-2H-thieno[2',3':2,3]thiopyrano[4,5-c]pyridazin-3(4H)-one as pale brown crystals, melting at 142°-144° C.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)([O:13][CH2:14][CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1)[CH3:17])(=O)=O>CN(C)C=O.O>[CH2:25]([O:24][C:20]1[CH:19]=[C:18]([CH:16]([CH3:17])[CH2:15][CH2:14][O:13][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)c2cccc(OCc3ccccc3)c2)cc1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCOc1ccccc1)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of phenol (4.56 g., 48.6 mmole) in dimethylformamide (40 ml.) is added under a nitrogen atmosphere to a suspension of sodium hydride (2.32 g., 48.6 mmole) of 50% previously washed with pentane) in dimethylformamide (70 ml.) at 60° C. The reaction mixture is stirred for one hour at 60°-70° C., after which a solution of 3-(3-benzyloxyphenyl)butyl tosylate (18.9 g., 46 mmole) in dimethylformamide (80 ml.) is added. The reaction mixture is stirred at 80° C. for a half hour and is then cooled to room temperature, diluted with cold water (2500 ml.) and extracted with ether (4 × 400 ml.). The combined extracts are washed successively with cold 2N hydrochloric acid (2 × 300 ml.) and saturated sodium chloride solution (3 × 300 ml.) and then dried (Na2SO4). Removal of the solvent under reduced pressure affords the product as an oil. The oily residue is dissolved in benzene and filtered through silica gel (100 g.). Concentration of the filtrate under reduced pressure gives the product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[C:9]([C:26]([O:28]C)=[O:27])[CH:10]=[C:11]([CH:25]=3)[O:12][CH2:13][CH2:14][S:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][CH:17]=3.[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[C:9]([C:26]([OH:28])=[O:27])[CH:10]=[C:11]([CH:25]=3)[O:12][CH2:13][CH2:14][S:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][CH:17]=3
Reactant: COC(=O)c1cc2cc(c1)OCCSc1cccc(c1)Nc1nc(ncc1Cl)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2cc(c1)OCCSc1cccc(c1)Nc1nc(ncc1Cl)N2
Temperature: 60 °C
Yield: 92 %

Procedure:
A solution of methyl 6-chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).1(9,13)]tetracosa-1(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxylate (450 mg, 1.1 mmol) in methanol (2.3 mL) and tetrahydrofuran (4.5 mL) was treated with 1 M sodium hydroxide (2.1 mL, 2.1 mmol) dropwise and heated at 60° C. for 16 h. The reaction mixture was cooled to 0° C. and quenched with 1 M HCl (3.2 mL). The resultant suspension was diluted with a small amount of water, filtered, and washed with cold acetonitrile to give the desired product (420 mg, 97%) as a white solid. LCMS for C19H16ClN4O3S (M+H)+: m/z=414.9.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[NH:16][C:15](=[O:21])[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:7][CH2:8][C@H:9]([C:10]1[C:11]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]([C:38]1[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=1)[C:15](=[O:21])[CH:14]=[CH:13]2)[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4]
Reactant: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2c(ccc(=O)n2-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reaction time: 120 h
Yield: 86.1 %

Procedure:
To the solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate (8J) (23 mg, 0.05 mmol) and 4-chlorophenylboronic acid (16 mg, 0.10 mmol) in dichloromethane (2 mL) was added copper (II) acetate (9 mg), followed by molecular sieve 4 Å and pyridine (82 μL). The mixture was stirred for 5 days, and filtered and washed with ethyl acetate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave (S)-2-(1,5-bis(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyethyl pivalate (25 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H36Cl2NO4: 580.2. Found: 580.0.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].[Br:22][C:23]1[N:27]=[C:26](Cl)[S:25][N:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.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>[Br:22][C:23]1[N:27]=[C:26]([C:10]2[CH:11]=[CH:12][C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[C:6]([CH:9]=2)[C:7]#[N:8])[S:25][N:24]=1
Reactant: CC(C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C#N
Reactant: Clc1nc(Br)ns1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1C#N
Temperature: 120 °C
Yield: 48.2 %

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (D39) (280 mg), 3-bromo-5-chloro-1,2,4-thiadiazole (194 mg) and tripotassium phosphate (517 mg) in 1,2-dimethoxyethane (DME) (4 mL) and water (1 mL) under nitrogen was added Pd(Ph3P)4 (113 mg). The reaction vessel was sealed and heated under microwave at 120° C. for 10 min. Water was added, the reaction mixture was filtered through the celite. The aqueous layer was extracted with EA for 3 times. the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated and purified by column chromatography to give 5-(3-bromo-1,2,4-thiadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile (D44) (152 mg) as a white solid. MS (ES): C12H10BrN3OS requires 323. found 324.0 (M+H+).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[C:21]([C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:34](C)[C:35](=O)OC(C)(C)C)=[CH:29][C:28]=3[F:43])[CH:23]=2)=[CH:20][C:19]([C:44]2[CH:49]=[CH:48][C:47]([S:50]([CH:53]([CH3:55])[CH3:54])(=[O:52])=[O:51])=[CH:46][N:45]=2)=[CH:18][N:17]=1)=O)(C)(C)C>C(Cl)Cl>[F:43][C:28]1[CH:29]=[C:30]([CH2:33][NH:34][CH3:35])[CH:31]=[CH:32][C:27]=1[C:24]1[CH:23]=[C:22]([C:21]2[C:16]([NH2:15])=[N:17][CH:18]=[C:19]([C:44]3[CH:49]=[CH:48][C:47]([S:50]([CH:53]([CH3:54])[CH3:55])(=[O:51])=[O:52])=[CH:46][N:45]=3)[CH:20]=2)[O:26][N:25]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4F)no3)c2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccc(-c2cc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3N)on2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.5 %

Procedure:
TFA (1.724 g, 1.165 mL, 15.12 mmol) was added to a stirred solution of tert-butyl N-[[4-[5-[2-[bis(tert-butoxycarbonyl)amino]-5-(5-isopropylsulfonyl-2-pyridyl)-3-pyridyl]isoxazol-3-yl]-3-fluoro-phenyl]methyl]-N-methyl-carbamate (198.7 mg, 0.1652 mmol) in DCM (7 mL) and the reaction stirred at ambient temperature for 16 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (6 mg, 7% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.22 (d, J=6.8 Hz, 6H), 2.20-2.30 (m, 3H), 3.50-3.60 (m, 1H), 3.75 (s, 2H), 7.05 (br s, 2H), 7.35-7.45 (m, 2H), 7.50 (s, 1H), 7.90-8.00 (m, 1H), 8.25-8.40 (m, 2H) and 8.80 (s, 1H) ppm; MS (ES+) 482.0.
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:22])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[CH3:25][C:26]1[O:27][C:28]([C:34]2[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=2)=[C:29]([C:31](Cl)=[O:32])[N:30]=1>C1COCC1.O>[C:3]([O:7][C:8](=[O:22])[N:9]([C:31]([C:29]1[N:30]=[C:26]([CH3:25])[O:27][C:28]=1[C:34]1[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=1)=[O:32])[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=O)CCCCc1nc(NC(=O)OC(C)(C)C)co1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)Cl)c1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)CCCCc1nc(N(C(=O)OC(C)(C)C)C(=O)c2nc(C)oc2-c2cccc(C)c2)co1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (50 mg, 0.18 mL) in THF (1.0 mL) was added to a suspension of NaH (19 mg, 0.43 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 2-methyl-5-m-tolyl-oxazole-4-carbonyl chloride in THF (1.0 mL). The resulting suspension was stirred for 30 min at 0° C. followed by 2 h at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (1:1 hept-EA)=0.32. LC-MS-conditions 02: tR=1.10 min, [M+H]+=482.06.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C@H:4]([NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17]>C1(C)C=CC=CC=1>[CH3:12][C@H:11]1[C:13](=[O:15])[O:14][C:16](=[O:17])[N:10]1[C@@H:4]([CH2:3][CH2:2][CH3:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCC[C@@H](C(=O)OCC)N1C(=O)OC(=O)[C@@H]1C
Temperature: 20 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Introduce into a reactor, at 0° C., 200 g of N-[(S)-ethoxycarbonyl-1-butyl]-(S)-alanine, 1.5 litres of toluene, and then 184 g of 1,1′-carbonyldiimidazole, then bring the temperature of the reaction mixture to 20° C. After stirring for 1 hour at 20° C., cool the mixture to 0° C. again, filter off the precipitate obtained, then evaporate the filtrate to yield the title product in a yield of 90%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([CH:13]([CH3:15])[CH3:14])[C:6]=2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.[NH2:23][C:24]1[C:29]([C:30]#[N:31])=[C:28](Cl)[N:27]=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:23][C:24]1[C:29]([C:30]#[N:31])=[C:28]([NH:12][C@H:10]([C:8]2[N:7]([CH:13]([CH3:14])[CH3:15])[C:6]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:27]=[CH:26][N:25]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(C)n1c([C@H](C)N)nc2ccc(F)c(-c3ccccn3)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)n1c([C@H](C)Nc2ncnc(N)c2C#N)nc2ccc(F)c(-c3ccccn3)c21
Temperature: 90 °C
Yield: 60 %

Procedure:
(S)-1-(6-Fluoro-1-isopropyl-7-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (0.166 g, 0.56 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (86 mg, 0.56 mmol) and DIPEA (497 μL, 2.78 mmol) in IPA (5 mL) were added and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue purified by flash chromatography (SiO2, eluting with 0-10% methanol in DCM) to give 408 as a white solid (140 mg, 61%). LCMS (Method K): RT 3.28 min [M+H]+ 417. 1H NMR (DMSO-d6, 400 MHz): δ 8.70 (1H, ddd, J=4.8, 1.7, 0.8 Hz), 7.99 (1H, s), 7.93 (1H, td, J=7.8, 1.8 Hz), 7.67 (1H, dd, J=8.8, 4.9 Hz), 7.61 (1H, d, J=7.6 Hz), 7.48 (1H, ddd, J=7.6, 4.8, 1.2 Hz), 7.29 (3H, br s), 7.12 (1H, dd, J=10.3, 8.8 Hz), 5.64 (1H, sept, J=7.1 Hz), 4.01-3.89 (1H, m), 1.55 (3H, d, J=6.6 Hz), 1.27-1.11 (6H, m)
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[O:2].N1CC[CH:16]([N:19]2[CH2:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[NH:21][C:20]2=[O:30])[CH2:15]C1.C(OC)(C)(C)C>CN(C)C=O>[N:8]1([C:1]([N:3]2[CH2:4][CH2:15][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:6][CH2:7]2)=[O:2])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2CCN1C1CCN(C(=O)n2ccnc2)CC1
Temperature: 25 °C

Procedure:
10 g (44.8 mmol) of carbonyldiimidazole (I) are in 40 mL dimethylformamide at 40 to 50° C. dissolved. Then 10.0 g (40.8 mmol) of 1,3,4,5-tetrahydro-3-(4-piperidinyl)-2H-1,3-benzodiazepin-2-one (H) are added batchwise. The suspension formed is liquefied by the addition of 40 mL tert.butyl-methylether and cooled to ambient temperature. After the addition of another 40 mL tert.butyl-methylether the suspension is filtered, the isolated solid is washed with 100 mL tert.butyl-methylether and dried.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13](O)=[N:14][CH:15]=[C:16]([Br:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>C(#N)C>[CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13]([Cl:22])=[N:14][CH:15]=[C:16]([Br:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ncc(Br)n2nc(SCc3ccccc3)nc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Clc1ncc(Br)n2nc(SCc3ccccc3)nc12

Procedure:
A suspension of 1.04 g (3.08 mmol) of crude 2 -benzylthio-5-bromo-8 -hydroxy[1,2,4]triazolo[1,5 -a]pyrazine in 40 mL of dry acetonitrile was prepared in a flask equipped with a condenser and a drying tube and to this was added with stirring 4.0mL (43mmol) of phosphorus oxychloride. The mixture was heated at reflux for 3 hours and the solvent was then removed by evaporation under reduced pressure. The dark residue was dissolved in dichloromethane and the resulting solution was washed with water and dried over sodium sulfate. The residue obtained after removal of the solvent by evaporation under reduced pressure was purified by flash column chromatography on silica gel using dichloromethane as the eluent to obtain 0.26 g (24 percent of theory) of the title compound as an off-white solid melting at 109°-110° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17][NH2:18])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCl>ClCCCl>[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17][NH:18][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
Benzaldehyde (3.3 ml, 32.4 mmol) was added to a stirred solution of tert-butyl-N-(2-aminoethyl)carbamate (5.19 g, 32.4 mmol) in 1,2-dichloroethane (50 ml). After stirring for 1 h sodium triacetoxyborohydride (10.3 g, 48.6 mmol) was added in two portions and the reaction mixture stirred at room temperature for a further 3 h. Dichloromethane (300 ml) was added and the mixture washed with 1N sodium hydroxide. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 50–100% ethyl acetate in hexane then 1–5% methanol in ethyl acetate to afford the title compound (4.9 g, 60%). Mass spectrum (AP+): Found 251 (MH+). C14H22N2O2 requires 250.
Reaction SMILES: I[C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C([O-])([O-])=O.[K+].[K+].CO.CO[CH2:22][CH2:23]OC>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>[CH3:7][C:5]1[NH:6][C:2]([CH:22]=[CH2:23])=[C:3]([C:8]([F:11])([F:10])[F:9])[N:4]=1
Reactant: Cc1nc(C(F)(F)F)c(I)[nH]1
Reactant: COCCOC
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: CO
Solvent: O
Product: C=Cc1[nH]c(C)nc1C(F)(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of 5-iodo-2-methyl-4-(trifluoromethyl)-1H-imidazole (1.98 g, 7.2 mmol) in DME (20 mL) and H2O (4 mL) was added K2CO3 (10 g, 71.9 mmol), trivinylboronic anhydride pyridine complex (1.73 g, 7.19 mmol) and Pd(PPh3)4 (830 mg, 0.719 mmol). The resulting reaction mixture was stirred at 80° C. for 3 h. MeOH (100 mL) was then added to the reaction mixture and the mixture was filtered, concentrated in vacuo, and purified by flash chromatography (SiO2, 10% MeOH/CH2Cl2) to obtain 2-methyl-4-(trifluoromethyl)-5-vinyl-1H-imidazole (911 mg, 5.17 mmol, 72% yield) as a brown syrup.
Reaction SMILES: C([O:6][C:7]1[CH:12]=CC(OC)=[CH:9][C:8]=1[CH:15](C)C(C)=C)(=O)CCC.[C:20]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:24])[CH2:21][CH2:22][CH3:23].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Ca+2].[OH-]>ClCCl>[C:20]([O:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][C:31]=1[C:8]([CH3:15])([CH3:9])[CH:7]1[O:6][CH2:12]1)(=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: CCCC(=O)Oc1ccc(OC)cc1
Reactant: C=C(C)C(C)c1cc(OC)ccc1OC(=O)CCC
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: CCCC(=O)Oc1ccc(OC)cc1C(C)(C)C1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a mixture of E61, o-(1,2-dimethylallyl)-p-methoxyphenyl n-butyrate and p-methoxyphenyl n-butyrate (39.5 gm) in dichloromethane (900 mL) was added in portions metachloroperbenzoic acid (52 gm; 300 mmoles). The mixture was stirred at room temperature overnight. The reaction mixture was cooled in an ice-water bath and calcium hydroxide (150 gm) was added. After stirring for 15 minutes the mixture was filtered through a celite pad and the filtrate concentrated in vacuo. The residue was chromatographed in silica gel using 10% ethyl acetate in hexane to obtain 20 gm (47%) of o-(1,1-dimethyl-2,3-epoxypropyl)-p-methoxyphenyl n-butyrate, E62, as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:16]([CH3:28])[CH:15]=1)(C)(C)C>ClCCl>[CH3:27][O:26][C:24]([CH2:23][CH2:22][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([OH:29])=[O:12])=[CH:15][C:16]=1[CH3:28])=[O:25]
Reactant: COC(=O)CCCCc1ccc(C(=O)OC(C)(C)C)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCCCc1ccc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Trifluoroacetic acid (20 ml) was added to a solution of 4-(4-methoxycarbonyl-butyl)-3-methyl-benzoic acid tert-butyl ester from Example E31.3 (1.43 g, 4.7 mmol) in di-chloromethane (40 ml) and the mixture was stirred for 2 h at room temperature. Solvents were concentrated in vacuo and azeotroped with dichloromethane to yield the title compound (1.07 g, 92%).