Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) (100 g, 398 mmol) and triethylamine (166 ml, 1.2 mol) are added to toluene (1 L) at room temperature. The mixture is heated to 60° C. Pivaloyl chloride (73.5 ml, 597 mmol) is added over 2 h. After a further 1 h, citric acid solution (237 g in 1 L) is added and the phases are separated. The water phase is washed with toluene (0.5 L). The organic portions are combined, washed with water (0.5 L) and then dried (MgSO4). The mixture is concentrated in vacuo. The residue is suspended in heptane (550 ml) and is heated to reflux. The mixture is then cooled to room temperature. After 1 h, the mixture is cooled to 0° C., and then filtered to give (S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1, R1=pivaloyl)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=[O:11]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: COc1cc2ncnc(N)c2cc1OC
Product: COc1cc2ncnc(NC(=O)Nc3c(Cl)cccc3Cl)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 3, 2,6-dichlorophenyl isocyanate was reacted with 4-amino-6,7-dimethoxyquinazoline (European Patent Application No. 30156, Chemical Abstract volume 95, abstract 187290) to give the title compound; NMR Spectrum: (DMSOd6) 3.96 (s, 3H), 7.31 (m, 2H), 7.38 (t, 1H), 7.5 (d, 2H), 7.6 (d, 2H), 8.43 (s, 1H), 8.7 (s, 1H), 10.61 (s, 1H), 12.09 (s, 1H); Mass Spectrum: M+H+ 393 & 395.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.[N:46]1([S:51](C2C=CC(N)=CC=2)(=[O:53])=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47]1>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([S:51]([N:46]5[CH2:50][CH2:49][CH2:48][CH2:47]5)(=[O:53])=[O:52])=[CH:22][CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Nc1ccc(S(=O)(=O)N2CCCC2)cc1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: O=S(=O)(c1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1)N1CCCC1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 4-(tetrahydro-(1H)-pyrrol-1-ylsulfonyl)aniline were reacted to yield N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-(tetrahydro-(1H)-pyrrol-1-ylsulfonyl)phenyl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.11 (bs, 1H), 9.76 (bs, 1H), 8.19 (d, 1H, J=3.9 Hz), 7.82 (d, 2H, J=8.7 Hz), 7.62 (d, 2H, J=8.7 Hz), 7.27 (d, 1H, J=2.4 Hz), 7.08 (dd, 1H, J=2.4 and 8.7 Hz), 6.85 (d, 1H, J=8.7 Hz), 4.23 (s, 4H), 3.10-3.06 (m, 4H), 1.64-1.58 (m, 4H); LCMS: ret. time: 22.68 min.; purity: 93%; MS (m/e): 472 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1)=[O:10])(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]#[C:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:13]=1)=[O:10]
Reactant: Cc1cc(C#Cc2ccccc2)nc(NC(=O)C(C)NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C#Cc2ccccc2)nc(NC(=O)C(C)N)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of tert-butyl-N-[1-[[4-methyl-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate D3b (2 mg, 5 μmol) and DCM:TFA (9:1, 400 μl) is stirred at RT for 4 hours. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. Yield: 1.5 mg (quant.). HPLC-MS: M+H=280; tR=1.77 min (*Method—1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[Cl:13][C:14]1[C:15]([CH3:34])=[N:16][O:17][C:18]=1[N:19](COC)[S:20]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28](Cl)=[O:29])(=[O:22])=[O:21]>ClCCl>[C:10]([C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=1[NH:1][C:28]([C:24]1[S:25][CH:26]=[CH:27][C:23]=1[S:20]([NH:19][C:18]1[O:17][N:16]=[C:15]([CH3:34])[C:14]=1[Cl:13])(=[O:21])=[O:22])=[O:29])(=[O:12])[CH3:11]
Reactant: CC(=O)c1cc(C)cc(C)c1N
Reactant: COCN(c1onc(C)c1Cl)S(=O)(=O)c1ccsc1C(=O)Cl
Solvent: ClCCl
Product: CC(=O)c1cc(C)cc(C)c1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 43.3 %

Procedure:
To a solution of 2′-amino-3′,5′-dimethylacetophenone (1.9 g, 11.66 mmol) in dichloromethane (20 mL) at room temperature was added N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2-thiophenecarbonyl chloride (Example 51) (1 g, 2.86 mmol). The mixture was stirred for 10 h during which much yellow precipitate formed. The reaction was then concentrated and the residue was diluted with ethyl acetate (50 mL) and washed with 1 N HCl (50 mL). The organic layer was concentrated and the residue was dissolved in methanol (30 mL) followed by the addition of concentrated HCl (15 mL). The mixture was then heated under reflux for 2 h before it was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with water (2×200 mL). The organic layer was separated, dried (MgSO4), the solids filtered and the filtrate concentrated. The residue was then purified by reverse phase HPLC to give N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide (580 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9](F)=[CH:10][C:11]#N)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C([O:28]CC)C>CCCCCC.O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[CH:9]=[CH:10][CH:11]=[O:28])=[CH:4][CH:3]=1
Reactant: CC(C)(C(F)=CC#N)c1ccc(Cl)cc1
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C=CC=O)c1ccc(Cl)cc1
Temperature: -40 °C
Reaction time: 0.58 h
Yield: 97 %

Procedure:
A solution of 4-(p-chlorophenyl)-3-fluoro-4-methyl-2-pentenenitrile, (Z)- (15.6 g, 69.7 mmol) in diethyl ether is treated dropwise with diisobutylaluminum hydride (83.6 mmol, 83.6 mL of a 1M solution in hexane) over 90 minutes at -45° C. under nitrogen, stirred at -40° C. for 35 minutes, and diluted sequentially with water and 2N hydrochloric acid at -10° C. The resultant aqueous mixture is stirred at room temperature for one hour and extracted with diethyl ether. The organic extracts are combined, washed.sequentially with water, 2N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a brown oil (15.34 g, 97% yield).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-:23].[Mn+2:24].[Cl-:25]>CO>[Cl:23][C:8]1([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]1[Cl:25].[Mn+2:24]
Reactant: [Cl-]
Reactant: C1CCC(CC2CNCCNCCNCCNCCN2)CC1
Agent: [Mn+2]
Solvent: CO
Product: ClN1CCNCCNCCNCCNCC1(Cl)CC1CCCCC1
Temperature: 0 °C
Yield: 65 %

Procedure:
A solution of 2-cyclohexylmethyl-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 7A (0.43 g, 1.4 mmole) and anhydrous manganese(II) chloride (0.17 g, 1.4 mmole) in anhydrous methanol (30 ml) was refluxed under a dry nitrogen atmosphere overnight. The solution was filtered and concentrated in vacuo to a volume of 3 ml. Ethyl ether (20 ml) was added. Upon cooling to 0° C., 0.39 g (65% yield) of the product was obtained as a white solid: FAB mass spectrum (NBA) m/z (relative intensity) 401/403 [(M-Cl)+, 100/33]: Anal. Calcd. for C17H37Cl2MnN5 : C, 46.69; H, 8.53; N, 16.09. Found: C, 45.87; H, 8.40; N, 15.55.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]([NH2:13])=[S:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([CH:16](Cl)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=O>ClC(Cl)C>[C:1]([O:9][CH2:10][C:11]1[S:12][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][N:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)COC(=O)c1ccccc1
Reactant: CCOC(=O)C(Cl)C=O
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cnc(COC(=O)c2ccccc2)s1
Yield: 91.7 %

Procedure:
A mixture of 9.14 g of 2-benzoyloxythioacetamide, 9 g of ethyl α-formyl-chloroacetate and 100 ml of dichloroethane was refluxed for 4 hours and after the addition of 4.5 g of ethyl β-formyl-chloroacetate, reflux was maintained for 2 hours. The mixture was cooled and was washed first with aqueous sodium carbonate and then water. The mixture was dried and the solvent was evaporated to obtain 14 g of raw product which was chromatographed over silica gel. Elution with a benzene-ethyl acetate mixture yielded 12.5 g of ethyl 2-benzoyloxymethyl-thiazole-5-carboxylate in the form of an oil.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH2:27][CH:28]([OH:39])[CH2:29][NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][C:21]([Br:26])=[CH:20][CH:19]=3.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[Br:26][C:21]1[CH:20]=[CH:19][C:18]2[N:17]([CH2:27][CH:28]([OH:39])[CH2:29][N:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[C:8](=[O:10])[CH3:9])[C:16]3[C:24]([C:23]=2[CH:22]=1)=[CH:25][C:13]([Br:12])=[CH:14][CH:15]=3
Reactant: CC(=O)Cl
Reactant: COc1cccc(NCC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cccc(N(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)C(C)=O)c1
Temperature: 150 °C

Procedure:
Following a literature procedure (Morcuende, A.; Ors, M.; Valverde, S.; Herradón, B. J. Org. Chem. 1996, 5264-5270) triethylamine (14 μl, 0.10 mmol) and acetyl chloride (8 μl, 0.11 mmol) were added to a heterogeneous mixture of 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol (53 mg, 0.11 mmol) and dibutyltin oxide (5.5 mg, 0.022 mmol) in anhydrous toluene (1.5 ml). The reaction vessel was purged with nitrogen, sealed and heated under microwave radiation to 150° C. for 9 minutes. The reaction was monitored by 1 c/ms and all SM had been consumed. The heterogeneous solution was filtered under vacuum to yield a white solid. The crude product was used without purification.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.Cl.[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([O:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([OH:30])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:60]1([CH2:65][CH2:66]O)[CH:64]=[CH:63][N:62]=[CH:61]1.C(O)(=O)C>C(Cl)Cl>[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([O:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:66][CH2:65][N:60]3[CH:64]=[CH:63][N:62]=[CH:61]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: OCCn1ccnc1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)Oc1cc(Nc2ncnc3cc(OCCn4ccnc4)c(OC)cc23)c(F)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
Diethyl azodicarboxylate (160 mg, 1.4 mmol) was added to a solution of 4-(2-fluoro-5-methoxycarbonyloxy4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (261 mg, 0.7 mmol), (prepared as described for the starting material in Example 22), triphenylphosphine (367 mg, 1.4 mmol) and 2-(imidazol-1-yl)ethanol (94 mg, 0.84 mmol), (J. Med. Chem. 1993, 25, 40524060), in methylene chloride (5 ml) and the mixture stirred for 1 hour at ambient temperature. Acetic acid (42 mg, 0.7 mmol) was added and the solvent was removed by evaporation. The residue was triturated with ether, the solid collected by filtration, dried under vacuum and purified by chromatography eluting with methylene chloride/methanol (9/1 followed by 8/2) to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (250 mg, 76%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.O>CS(C)=O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: BrCCCCCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(OCCCCCCBr)cc1
Reaction time: 0.08 h
Yield: 71.4 %

Procedure:
To a solution of 232 g of ethyl 4-hydroxybenzoate [XII; Alk=C2H5 ] in 1.2 liters of dimethylsulfoxide was added 100 g of potassium hydroxide. The mixture was stirred for five minutes, 678 g of 1,6-dibromohexane was then added, and the mixture stirred for four hours during which an exothermic reaction occurred (max. temp. 46° C.). The reaction mixture was added to 1500 ml of water and extracted three times with 800 ml of cyclohexane. The cyclohexane layer was washed with 800 ml of water, 200 ml 2N potassium hydroxide and 800 ml concentrated sodium chloride solution, then filtered and concentrated in vacuo. The residue was triturated with ether to give 328.1 g of ethyl 4-(6-bromohexyloxy)benzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](O)[C:9]2[C:4](=[CH:5][C:6]([C:13]([F:16])([F:15])[F:14])=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:19]>>[CH3:1][C:2]1[CH:11]=[C:10]([Cl:19])[C:9]2[C:4](=[CH:5][C:6]([C:13]([F:16])([F:15])[F:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c2ccc(C(F)(F)F)cc2n1
Product: Cc1cc(Cl)c2ccc(C(F)(F)F)cc2n1
Reaction time: 8 h

Procedure:
2-Methyl-7-(trifluoromethyl)quinolin-4-ol (1 g, 4.4 mmol) was heated in phosphoroxychloride (3 ml) for under reflux for one hour. The mixture was poured on ice and left at 4° C. overnight. The mixture was extracted with ethylacetate, the organic phase was washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure to yield 1.1 g (4.4 mmol, quantitative) which were used directly in the next step.
Reaction SMILES: [Li].[C:2]([C:6]#[CH:7])([CH3:5])([CH3:4])[CH3:3].[CH:8]([CH:10]=[CH2:11])=[O:9].C(O)(C)C>O1CCCC1>[CH3:3][C:2]([CH3:5])([CH3:4])[C:6]#[C:7][CH:8]([OH:9])[CH:10]=[CH2:11]
Reactant: C=CC=O
Reactant: C#CC(C)(C)C
Agent: [Li]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C=CC(O)C#CC(C)(C)C
Temperature: 40 °C
Reaction time: 24 h
Yield: 73.9 %

Procedure:
Under a blanket of dry nitrogen, at 0° C., metallic lithium (0.667 gr., 0.096 mole) was added to a mixture of t-butylacetylene (9.94 gr., 0.121 mole) and tetrahydrofuran (75 ml). The mixture was heated to 40° C. for 5 hours and kept at room temperature for 24 hours. The lithium was almost completely consumed. A second amount of t-butylacetylene (9.94 gr., 0.121 mole) was added and the reaction mixture was stirred for 21 hours. The mixture was cooled to 0° C. and a solution of freshly distilled acrolein (6.634 gr., 0.118 mole) in tetrahydrofuran (10 ml) was added gradually during 30 minutes. The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 3 hours. Isopropanol (6 ml) was added to quench the remaining lithium. The mixture was quenched using saturated ammonium chloride aqueous solution (30 ml) at 0° C. The pH was brought to 6 by 10% sulfuric acid (ca. 45 ml). The tetrahydrofuran and excess t-butylacetylene were evaporated and the mixture was extracted 3 times by dichloromethane (70 ml each time). The organic phase was washed with water (2×20 ml), dried and the solvent evaporated to give 10.2 gr. of an almost pure 6,6-dimethylhept-1-en-4-yn-3-ol (73.9% yield).
Reaction SMILES: C([N:8]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([CH:17]([NH2:33])[CH2:18][C:19]([NH:21][CH2:22][C:23]2([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH2:25][CH2:24]2)=[O:20])[CH2:13][CH2:12]1)=[O:10])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:33][CH:17]([C@H:14]1[CH2:15][CH2:16][C@H:11]([C:9]([NH:8][C:34]2[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=2)=[O:10])[CH2:12][CH2:13]1)[CH2:18][C:19]([NH:21][CH2:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)=[O:20]
Reactant: CC(C)(C)OC(=O)N(c1ccncc1)C(=O)[C@H]1CC[C@H](C(N)CC(=O)NCC2(c3ccc(Cl)cc3)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(CC(=O)NCC1(c2ccc(Cl)cc2)CC1)[C@H]1CC[C@H](C(=O)Nc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Boc-trans-4-[1-Amino-2-[[[1-(4-chlorophenyl)cyclopropyl]methylamino]carbonyl]ethyl]-N-4-pyridinyl-cyclohexylcarboxamide (2-4) (0.51 g) was dissolved in anhydrous DCM (10 mL). A 20% TFA/CH2Cl2 (10 mL, 2 mL of TFA in 8 mL of anhydrous CH2Cl2) solution was added. The reaction mixture was stirred at RT and monitored by LC/MS. After 60 minutes, the reaction mixture was poured into 20% Na2CO3 (100 mL). The white solid was collected by filtration, and washed with H2O (2×20 mL). The solid was dried under vacuum at <50° C. to give 260 mg (62.6%) of trans-4-[1-Amino-2-[[[1-(4-chlorophenyl)cyclopropyl]methylamino]-carbonyl]ethyl]-N-4-pyridinyl-cyclohexylcarboxamide (2). 99% pure by HPLC (254 nm); MS (ESI) m/z=441.27 [M+H]+ 1H NMR (DMSO-d6) data is depicted in FIG. 21.
Reaction SMILES: BrC[C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[C:6]2=[N:5][C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=3.[P:26]([O:33]CC)([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29]>>[CH2:24]([O:23][C:21]([C:4]1[N:5]=[C:6]2[C:15](=[O:16])[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:17]([F:20])([F:18])[F:19])[CH:12]=3)[N:7]2[C:3]=1[P:26]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:33])=[O:22])[CH3:25]
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CBr
Reactant: CCOP(OCC)OCC
Product: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1P(=O)(OCC)OCC
Yield: 63 %

Procedure:
1-Bromomethyl-2-ethoxycarbonyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 3) (840 mg, 2.0 mmol) and triethyl phosphite (12 ml) was heated at 120° C. for 16 h. The mixture was concentrated in vacuo and the residue submitted to flash chromatography on silica gel, eluting with dichloromethane/methanol (9:1). The purified product was washed with ether to give 600 mg (63%) of the title compound. M.p. 198°-199° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=O)[CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:30]1COCC1>>[CH3:30][N:21]1[CH2:22][CH2:23][CH:18]([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[CH:2][NH:1]4)[CH2:11][CH2:12]2)[CH2:19][CH2:20]1
Reactant: C1CCOC1
Reactant: O=C(C1CCNCC1)N1CCN(c2cccc3[nH]ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN1CCC(CN2CCN(c3cccc4[nH]ccc34)CC2)CC1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a sample of the carbamate (1.5 g, 3.63 mmol) from example 11 in THF (20 mL) was treated with the dropwise addition of 1.0M lithium aluminium hydride in THF (35 mL, 10 equivalents) at 0° C. and the solution refluxed for 16 hours. After cooling to ambient temperature, the excess hydride was destroyed by the addition of ammonium chloride solution and the mixture filtered. Ethyl acetate (50 mL) was added, the solution washed with water (50 mL), brine (25 mL) and dried over anhydrous sodium sulfate. Filtration and concentration gave the titled product, which was converted to its hydrochloride salt by the action of ethereal-HCl.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:4]([O:5][C:6]([CH:9]=[CH2:10])=[CH:7]2)[CH2:3]1.[H][H]>O1CCCC1.[Pt]>[CH:9](=[C:6]1[O:5][C@H:4]2[N:8]([C:2](=[O:1])[CH2:3]2)[CH2:7]1)[CH3:10]
Reactant: C=CC1=CN2C(=O)C[C@H]2O1
Reactant: [H][H]
Agent: [Pt]
Solvent: C1CCOC1
Product: CC=C1CN2C(=O)C[C@H]2O1
Yield: 12 %

Procedure:
(5R)-7-oxo-3-vinyl-4-oxa-1-azabicyclo[3.2.0]hept-2-ene (2.4 mmole) in tetrahydrofuran (20 ml) was shaken with 5% platinum on charcoal (150 mg) under 1 atmosphere of hydrogen at room temperature for 1.5 hours. The catalyst was removed by filtration and was washed with tetrahydrofuran. The solvent was evaporated from the filtrate and the residue was chromatographed on silica gel using 1:7 ethyl acetate/petroleum ether (b.p. 60-80°). A mixture of E- and Z- isomers of the title compound was thus obtained as a colourless oil(40 mg).
Reaction SMILES: [CH:1]([SiH:4]([CH:14]([CH3:16])[CH3:15])[C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].S(Cl)([Cl:19])=O>>[CH:1]([SiH:4]([CH:14]([CH3:16])[CH3:15])[C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:19])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)[SiH](c1ccc(C(=O)O)cc1)C(C)C
Reactant: O=S(Cl)Cl
Product: CC(C)[SiH](c1ccc(C(=O)Cl)cc1)C(C)C

Procedure:
4-diisopropylsilanyl benzoic acid (1) (6.7 g, 28.4 mmol) and thionyl chloride (3.2 mL, 42.6 mmol) were mixed together and heated to reflux for 2 hours. a desired compound was then purified and identified by distillation under a reduced pressure (1 mmHg, 102-104° C.) (5.6 g, 77%). Its NMR data are as follows:
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[CH2:24][CH2:23][C@@H:22]([C:25]([O:27]C)=[O:26])[C@H:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[C:32]([O:31][C:29]([C@@H:21]1[CH2:20][C@H:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:23][C@H:22]1[C:25]([OH:27])=[O:26])=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC[C@H]1C(=O)O
Yield: 63 %

Procedure:
A solution of compound 37 (4.2 mmol) and LiOH (16.8 mmol) in THF/H2O 1/1 (40 mL) was stirred at room temperature for 16 hrs. The reaction mixture was neutralized with 1N HCl to pH 2, and then extracted with DCM (100 mL). Organics were concentrated under reduced pressure and purified by chromatography on silica gel (Cyclohexane/EtOAc) to yield compound 38 as pale yellow oil in 63% yield.