Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:25]2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=[C:21]([NH2:28])[C:20]=2[N:19]=[C:18]1[CH3:29]>>[NH2:28][C:21]1[C:20]2[N:19]=[C:18]([CH3:29])[N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:11]([NH:10][C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:12])[C:25]=2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=1
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Reactant: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Product: Cc1nc(N)c2nc(C)n(CCCNC(=O)N[C@@H]3C[C@H]3c3ccccc3)c2c1C

Procedure:
Using the methods of Examples 75-85, trans-2-phenylcyclopropyl isocyanate was reacted with 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 393.2393.
Reaction SMILES: [C:1]([O:4][C:5](=O)C)(=O)[CH3:2].[F:8][CH:9]([F:18])[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(OCC)(OCC)OCC>>[CH2:1]([O:4]/[CH:5]=[C:11](/[C:10](=[O:17])[CH:9]([F:18])[F:8])\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:2]
Reactant: CCOC(=O)CC(=O)C(F)F
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCO/C=C(\C(=O)OCC)C(=O)C(F)F
Temperature: 95 °C
Reaction time: 8.5 h
Yield: 85.5 %

Procedure:
Add acetic anhydride (166 kg, 1625 mol) to a mixture of ethyl 4,4-difluoroacetoacetate (33 kg, 199 mol) and triethyl orthoformate (60 kg, 407 mol) maintained at 90-100° C. Stir the mixture at 90-100° C. for 8.5 hours and remove ethyl acetate using a Dean-Stark apparatus. Concentrate the reaction mixture to give the title compound (37.8 kg, 86% yield, 97% GC purity). 1H NMR (500 MHz, CDCl3,) δ 7.88 (d, J=6 Hz, 1H), 6.3 (m, 1H), 4.3 (m, 4H), 1.4 (m, 3H), 1.32 (m, 3H).
Reaction SMILES: [N:1]([C@@H:4]([C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]([CH3:14])=[CH2:13])[CH:11]=1)[CH3:5])=[N+]=[N-]>CO.Cl.[Pd]>[CH2:13]=[C:12]([C:10]1[CH:11]=[C:6]([C@H:4]([NH2:1])[CH3:5])[CH:7]=[N:8][CH:9]=1)[CH3:14]
Reactant: C=C(C)c1cncc([C@@H](C)N=[N+]=[N-])c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C=C(C)c1cncc([C@@H](C)N)c1
Reaction time: 12 h
Yield: 83.9 %

Procedure:
To a stirred solution of (R)-3-(1-azidoethyl)-5-(prop-1-en-2-yl)pyridine (340 mg) in MeOH.HCl (1.25M, 10 mL) was added 10% Pd/C (50 mg) and stirred under hydrogen atmosphere for 12 h. The catalyst was filtered off and the residue was dissolved in 5 mL of 25% aqueous NH3 and extracted with CHCl3 and the organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (10% MeOH/90% CHCl3 spiked with 0.25% of Et3N) to provide 246 mg of (R)-1-(5-(prop-1-en-2-yl)pyridin-3-yl)ethanamine.
Reaction SMILES: [OH-].[Na+].[CH:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1.[N+:13]([CH3:16])([O-:15])=[O:14].C(O)(=O)C>CO>[CH3:11][O:10][C:6]1[CH:5]=[C:4]([CH:3]([OH:12])[CH2:16][N+:13]([O-:15])=[O:14])[CH:9]=[CH:8][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1cccc(C=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccc(C(O)C[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
An aqueous sodium hydroxide solution (1.5 g of sodium hydroxide (37 mmol) was dissolved in 15 ml of water) was added dropwise to a solution of m-anisaldehyde (5.0 g, 37 mmol) and nitromethane (4.0 ml, 73 mmol) in methanol (50 ml) keeping the temperature of the solution at not higher than 30° C. The reaction mixture was then stirred at room temperature for 4 hours. Upon cooling on ice, an aqueous acetic acid solution (glacial acetic acid (37 mmol) was dissolved in 250 ml of water) was added, the resulting reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and a 5% aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (6.09 g).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:31])[N:19]([CH2:23][C:24]5([F:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1.Br[CH2:39][CH2:40][OH:41]>>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:31])[N:19]([CH2:23][C:24]5([F:30])[CH2:29][CH2:28][N:27]([CH2:39][CH2:40][OH:41])[CH2:26][CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CC1(F)CCNCC1
Reactant: OCCBr
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CC1(F)CCN(CCO)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[4-fluoro-1-(2-hydroxyethyl)piperidin-4-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(4-fluoropiperidin-4-yl)methyl]-1,3-thiazolidine-2,4-dione (Example 303) and 2-bromoethanol following General Procedure S.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[OH-].[Na+].[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13]>O>[C:12]([O:16][C:17]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)CC1
Yield: 40 %

Procedure:
Water (250 ml) was added to 4-piperidone monohydrate hydrochloride salt (75 g) for dissolution, and 1 N aqueous solution of sodium hydroxide (1000 ml) was added thereto. To the solution, ditertiarybutylcarbonate (120 g) was added dropwise with stirring under cooling on ice, and the mixture was vigorously stirred for 6 hours at room temperature. The reaction mixture was subjected to extraction with ethyl acetate, and the extract was evaporated to dryness under reduced pressure to thereby yield a pale yellow solid. By recrystallization of the solid from hexane, N-t-butyloxycarbonyl-4-piperidone (3) (38.9 g) was obtained in the form of white needle-shaped crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]2=[O:19])(=[O:12])=[O:11])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1.[N:23]1([CH2:32][C:33](O)=[O:34])[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]1=[O:25]>>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:33](=[O:34])[CH2:32][N:23]3[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]3=[O:25])[CH2:15][C:14]2=[O:19])(=[O:12])=[O:11])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: O=C1CNCCN1S(=O)(=O)c1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3c(Cl)cc(Cl)cc3[N+](=O)[O-])C(=O)C2)c(=O)[nH]c1=O
Yield: 88.3 %

Procedure:
The title compound (919 mg, 88%) was synthesized by reaction of 1-(4,6-dichloro-2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (781 mg, 2.0 mmol) with (thymin-1-yl)-acetic acid (368 mg, 2.0 mmol) as per the procedure of example 64. 1H-NMR (500 MHz; DMSO-d6) δ 11.34 (s, 0.6H), 11.32 (s, 0.4H), 8.42 (d, 0.4H), 8.41 (d, 0.6H), 8.32 (d, 0.4H), 8.30 (d, 0.6H), 7.35 (s, 0.6H), 7.27 (s, 0.4H), 4.69 (s, 1.2H), 4.58 (s, 0.8H), 4.42 (s, 0.8H), 4.27 (s, 1.2H), 4.11 (t, 1.2H), 3.97 (t, 0.8H), 3.93 (t, 1.2H), 3.82 (t, 0.8H), 1.74 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]2[C:7]3=[N:8][C:9](C#N)=[C:10]([C:12]#[N:13])[N:11]=[C:6]3[C:5](=[O:19])[C:4]=2[CH:3]=1.[OH:20]O.ClCCl>CS(C)=O>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]2[C:7]3=[N:8][C:9]([OH:20])=[C:10]([C:12]#[N:13])[N:11]=[C:6]3[C:5](=[O:19])[C:4]=2[CH:3]=1
Reactant: OO
Reactant: N#Cc1nc2c(nc1C#N)-c1ccc(Cl)cc1C2=O
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#Cc1nc2c(nc1O)-c1ccc(Cl)cc1C2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
To a suspension of 50 mg (0.19 mmol) 17g and 2.2 mg (5 Mol-%) Na2MoO4 in 2 ml DMSO was added dropwise 82 μl (0.95 mmol) of an aqueous solution of H2O2 (35%). The colour turned to red, and the mixture was stirred for 48 h at room temperature. After addition of 20 mL Dichloromethane, the resulting solution was washed with water and sat. brine (3×5 ml). After drying, filtration and evaporation, the crude product was purified by chromatography (DCM/MeOH 8/2) to yield 35 mg (70%) compound 42 as yellow-orange powder. 1H-NMR (d6-DMSO, 300 MHz): δ (ppm)=7.55 (s, 1H); 7.64 (m, 2H). ESI−MS: calcd for C12H4ClN3O2: 257.64; found: 255.9 (M-H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][NH:13][C:14]([NH:16][NH2:17])=[O:15].C(=O)(O)[O-].[Na+].C(=O)=O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][NH:13][C:14]([NH:16][NH:17][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NNC(=O)NN
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CCO
Product: O=C(NNS(=O)(=O)c1ccc(Cl)cc1)NNS(=O)(=O)c1ccc(Cl)cc1
Temperature: 20 °C

Procedure:
211 g (1.0 mole) p-chlorobenzenesulfonyl chloride was added to a suspension of 45 g (0.5 mole) carbohydrazide and 100 g sodium bicarbonate in 1000 ml ethanol in a 3 liter reaction flask. The mixture was stirred and heated gradually to gentle reflux (80° C) as carbon dioxide was evolved. Heating was continued until CO2 no longer evolved (3 hours). The mix was cooled to 20° C and filtered. The mixture of product and sodium chloride was dried at 60° C. Yield = 227 g. The solid mixture was suspended in 2000 ml water, stirred to dissolve the sodium chloride, and then the insoluble product was filtered, washed and dried. Yield = 129 g, m.p. 239°-240° C (dec.)
Reaction SMILES: C(OC([N:7]1[C@@H:11]([CH3:12])[CH:10]=[C:9]([C:13]2[N:14]=[C:15]([S:18][C:19]3[C@H:25]([CH3:26])[C@H:24]4[N:21]([C:22](=[O:30])[C@@H:23]4[C@H:27]([OH:29])[CH3:28])[C:20]=3[C:31]([O:33]CC=C)=[O:32])[S:16][CH:17]=2)[CH2:8]1)=O)C=C.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC.P([O-])([O-])([O-])=O>ClCCl>[OH:29][C@@H:27]([C@H:23]1[C:22](=[O:30])[N:21]2[C@@H:24]1[C@@H:25]([CH3:26])[C:19]([S:18][C:15]1[S:16][CH:17]=[C:13]([C:9]3[CH2:8][NH:7][C@@H:11]([CH3:12])[CH:10]=3)[N:14]=1)=[C:20]2[C:31]([OH:33])=[O:32])[CH3:28]
Reactant: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@H](C)N(C(=O)OCC=C)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H]1C=C(c2csc(SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)n2)CN1
Temperature: 0 °C
Yield: 50.8 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(4-{(5S)-1-[(allyloxy)carbonyl]-5-methyl-2,5-dihydro-1H-pyrrol-3-yl}-1,3-thiazol-2-yl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (70 mg, 0.13 mmol) in dichloromethane (2 ml) were added acetic acid (19 μl) and tributyltin hydride (0.32 ml, 1.2 mmol) and added at room temperature bis(triphenylphosphine)palladium chloride(II) (91 mg, 0.013 mmol). Ten minutes later the reaction mixture was poured into a mixture of ice (10 g) and phosphate buffer (pH7.0, 10 ml). After separation of the mixture with a separating funnel, the organic layer was extracted twice with water and the aqueous layer was washed twice with dichloromethane (3 ml). The organic solvent in the aqueous layer was evaporated under reduced pressure, and the residue was purified by polymer chromatography (CHP-20P). The fractions eluted with 1–3% aqueous THF solution were combined and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-({4-[(5S)-5-methyl-2,5-dihydro-1H-pyrrol-3-yl}-1,3-thiazol-2-yl)sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (26.9 mg) as a white amorphous.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:27][C:28]([N:30]1[C:34]2[N:35]=[CH:36][N:37]=[C:38](Cl)[C:33]=2[CH:32]=[CH:31]1)=[O:29].C(Cl)(=O)C.[OH:44][CH:45]([C:47]1[CH:48]=[C:49]([CH:51]=[CH:52][CH:53]=1)[NH2:50])[CH3:46]>C(O)CCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:27][C:28]([N:30]1[C:34]2[N:35]=[CH:36][N:37]=[C:38]([NH:50][C:49]3[CH:51]=[CH:52][CH:53]=[C:47]([CH:45]([OH:44])[CH3:46])[CH:48]=3)[C:33]=2[CH:32]=[CH:31]1)=[O:29]
Reactant: CC(O)c1cccc(N)c1
Reactant: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(NC(=O)n4ccc5c(Cl)ncnc54)c3)cc(C(F)(F)F)c2)cn1
Solvent: CC(=O)Cl
Solvent: CCCCO
Product: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(NC(=O)n4ccc5c(Nc6cccc(C(C)O)c6)ncnc54)c3)cc(C(F)(F)F)c2)cn1
Temperature: 80 °C
Reaction time: 24 h
Yield: 50.7 %

Procedure:
4-Chloro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide resin (50 mg, 0.05 mmol), prepared as in reference 3, in n-butanol (2 mL) is mixed with acetyl chloride (17.8 μL, 0.25 mmol) and 3-(1-hydroxyethyl)aniline (34 mg, 0.25 mmol) and shaken at 80° C. for 24 hours. The resulting mixture is filtered and the resin is treated with TFA/CH2Cl2/H2O (45/50/5) (600 μL) for 30 minutes before filtering and washing with CH2Cl2 (3×2 mL), MeOH (3×2 mL). The washes are then combined together with n-butanol and concentrated. The residue is purified by preparative HPLC-MS to give 4-[3-(1-hydroxy-ethyl)-phenylamino]-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide (16.6 mg, yield 51%); 1HNMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 10.68 (s, 1H), 9.85 (s, 1H), 9.62 (s, 1H), 8.62 (s, 1H), 8.57 (s, 1H), 8.54 (s, 1H), 8.47 (s, 1H), 8.43 (s, 1H), 8.17 (s, 1H), 7.85 (d, J=4.1 Hz, 2H), 7.70 (s, 1H), 7.61 (dd, J=6.5, 8.2 Hz, 1H), 7.35 (d, J=2.3 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 7.09 (s, 1H), 7.08 (d, J=6.8 Hz, 1H), 4.75 (q, J=6.4 Hz, 1H), 2.47 (s, 3H), 2.36 (s, 3H), 1.36 (d, J=6.4 Hz, 3H); ESIMS m/z 655.2 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=1.[H-].[Na+].Cl.[CH3:22][N:23]([CH2:25][CH2:26]Cl)[CH3:24].Cl>O1CCOCC1.C(O)C>[CH3:22][N:23]([CH2:25][CH2:26][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]=1)[CH3:24]
Reactant: CN(C)CCCl
Reactant: Oc1ccccc1-c1nc(-c2ccccc2)no1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CN(C)CCOc1ccccc1-c1nc(-c2ccccc2)no1
Temperature: 27.5 °C
Reaction time: 0.25 h

Procedure:
2.38 g of 5-(2-hydroxyphenyl)-3-phenyl-1,2,4-oxadiazole are dissolved in 100 ml of anhydrous dioxane and stirred with 0.3 g of 80% sodium hydride suspension in oil for 15 minutes at 25-30° C. To this solution is added 60 ml of anhydrous dioxane, the resulting mixture is combined with 2.88 g of 2-(N,N-dimethylamino)ethylchloride hydrochloride and 0.6 g of 80% sodium hydride suspension in oil. This solution is also stirred for 15 minutes at 25-30° C. The combined solutions are refluxed for 8 hours, left to stand overnight and evaporated down in vacuo. The residue is mixed with water and 20 ml of 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, the solvent evaporated in vacuo and the residue chromatographed on silica gel with ethyl acetate/isopropanol (70:30, mixed with 2.5% of a 25% ammonia solution). The base thus obtained is dissolved in anhydrous ethanol, acidified with ethereal HCl and precipitated with diethyl ether. The residue is recrystallised from anhydrous ethanol and diethylether. Yield: 2.2 g (64% of theory). m.p.: 186-187° C.
Reaction SMILES: P(O[CH2:10][CH3:11])(OCC)(OCC)=O.Br[CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C@H:20]2[CH2:25][CH2:24][Si@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1>C1COCC1.[Cu]I>[CH2:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:10][CH2:11][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C@H:20]3[CH2:25][CH2:24][Si@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[CH:15][CH:16]=1)[CH3:21]
Reactant: CCOP(=O)(OCC)OCC
Reactant: CCCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CBr)CC2)CC1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCCCc3ccc(CC)cc3)CC2)CC1

Procedure:
22.7 g (0.1 mol) of 4-(3-bromopropyl)-1-ethylbenzene was dropped in a mixture of 2.5 g (0.11 mols) of magnesium and 300 ml of THF to obtain a Grignard reagent. The resultant solution was further dropped in a solution, in 500 ml of THF, of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 34.5 g (0.1 mol) of trans-4-(trans-4-bromomethylcyclohexyl)-1-pentyl-1-silacyclohexane. The resultant product was subjected to ordinary aftertreatments to obtain trans-4-(trans-4-(4-(4-ethylphenyl)butyl)cyclohexyl)-1-pentyl-1-silacyclohexane. After ordinary aftertreatments, the product was purified through chromatography to obtain 32.6 g (yield: 79%) of the trans isomer product.
Reaction SMILES: Br.[Br:2][C:3]1[N:4]=[C:5]([CH3:11])[NH:6][C:7]=1[C:8](=O)[CH3:9].C(=O)(O)[O-].[Na+].CC(C)=O.[C:21]([NH:24][C:25]([NH2:27])=[S:26])(=[NH:23])[NH2:22]>O>[BrH:2].[NH:24]([C:25]1[S:26][CH:9]=[C:8]([C:7]2[N:6]=[C:5]([CH3:11])[NH:4][CH:3]=2)[N:27]=1)[C:21]([NH2:23])=[NH:22]
Reactant: N=C(N)NC(N)=S
Reactant: CC(=O)c1[nH]c(C)nc1Br
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nc(-c2csc(NC(=N)N)n2)c[nH]1
Yield: 79.3 %

Procedure:
2.8 g (9.86 mmol) of 4-bromo-acetyl-2-methylimidazole hydrobromide was dissolved in 10 ml water. Saturated sodium bicarbonate solution was added to pH 10 and the resultant solid was collected by filtration and washed with 15 ml water. The dried free base was heated at reflux in 50 ml acetone. To the refluxing clear acetone solution was added 1.2 g (9.86 mmol) of amidinothiourea. Solution occurred immediately and within a minute a solid began to form. After one hour reflux the slurry was cooled and the solid was collected by filtration and was washed with acetone followed by ether to give 2.37 g (79%) of the title compound, M.P. 158° (dec.); nmr (DMSO-d6) (delta): 7.71 (s shoulder on broad s, 1H); 7.56 (broad s, 4H); 4.32 (s, 1H); 2.51 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:30])/[C:5](/[CH3:29])=[CH:6]/[C@H:7]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Li+]>C(O)C>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:10][C:9]([CH2:8][C@@H:7]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])/[CH:6]=[C:5](\[CH3:29])/[C:4]([OH:30])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)/C(C)=C/[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: C/C(=C\[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
(E)-(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid ethyl ester (CAS#149709-59-1) is hydrolysed using lithium hydroxide in ethanol to yield (E)-(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid as a white solid. δH (400 MHz; DMSO) 1.31 (9H, s, (CH3)3), 1.59 (3H, s, 1-CH3), 2.68 (1H, dd, J 6.8, 13.2, 5-HA), 2.86 (1H, m, 5-HB), 4.44 (1H, m, 4-H), 6.51 (1H, d, J 9.2, 3-H), 7.16 (1H, d, J 8.0, NH), 7.26 (2H, d, J 8.0, Ar-ortho-H(Ph)), 7.31 (1H, t, J 7.6, Ar-(Ph)-para-H), 7.40 (2H, t, J 8.0, Ar-(Ph)-meta-H), 7.54 (2H, d, J 8.0, Ar-meta-H(Ph), 7.60 (2H, d, J 7.6, Ar-(Ph)-ortho-H), 12.26 (1H, s, CO2H); m/z (+ESI) 404 ([MNa]+, 17%), 382 ([MH]+, 2), 326 (10), 264 (100), 167 (13).
Reaction SMILES: C([O:5][C:6](=[O:15])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.[ClH:23].O1CCOCC1>>[ClH:23].[ClH:23].[CH3:14][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:15])=[O:5])[CH2:13][CH2:12]1
Reactant: CN1CCN(CC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CN1CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
tert-Butyl(4-methylpiperazin-1-yl)acetate (3.50 g, 16.3 mmol) was suspended in 4N hydrogen chloride/1,4-dioxane (35 mL) solution, trifluoroacetic acid (60 mL) was added to give a solution, and the solution was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, 4N hydrogen chloride/ethyl acetate (30 mL) was added to the obtained oily residue to give a suspension, and the suspension was stirred at room temperature for 2 hr. The obtained precipitate was collected by filtration, washed with ethyl acetate and diisopropyl ether on filter paper, and dried to give the title compound (3.33 g, 88%) as a colorless powder. The compound was used for the next reaction without further purification operation.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]1([NH:18][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CCOCC>[Cl:1][C:2]1[N:7]=[C:6]([N:18]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: COC(=O)[C@@H](C)NC1CCCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)[C@@H](C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (28.5 g, 146.9 mmol) in ether (200 mL) was added methyl N-cyclohexyl-D-alaninate (17.0 g, 91.8 mmol) at −10° C. To the resulting solution was then added aqueous potassium carbonate (19.0 g in 100 mL water) drop wise while maintaining the temperature below 0° C. Reaction mixture was then warmed to rt and stirred at rt for 16 h. The organic layer was separated and the aqueous layer was extracted with ether (3×75 mL). Combined ether solution was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel flash chromatography using ethyl acetate-hexane mixture (v:v=5:95) as eluent to give titled compound (yield, 41%). 1HNMR (300 MHz, CDCl3): δ 1.06-1.29 (m, 3H), 1.43-1.53 (m, 2H), 1.58 (s, 1H), 1.64 (d, J=6.9 Hz, 3H), 1.90-1.82 (m, 2H), 2.02-1.98 (m, 1H), 2.17-2.14 (m, 1H), 3.09-3.01 (m, 1H), 3.73 (s, 3H), 4.13 (q, J=6.9 Hz, 1H), 8.59 (s, 1H).
Reaction SMILES: N[C:2]1[S:3][C:4]([CH3:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.N(OC(C)(C)C)=O>O1CCCC1.O>[CH3:11][C:4]1[S:3][CH:2]=[N:6][C:5]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1nc(N)sc1C
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ncsc1C
Temperature: 50 °C
Yield: 59.5 %

Procedure:
To a solution of methyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate (2.15 g, 12.5 mmol) in tetrahydrofuran (60 mL) was slowly added tert-butyl nitrite (2.23 mL, 18.7 mmol) with stirring at 50° C., and the mixture was stirred at 60° C. for 2 hr. The mixture was diluted with water (100 mL), and extracted with ethyl acetate (100 mL×2). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→0/100) to give the title compound (1.17 g, yield 60%).