Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:17])[C:13]([O:15]C)=[O:14])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].CO.Cl>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:17])[C:13]([OH:15])=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=O)Nc1ccccc1C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccccc1NC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 3-L, 3-necked round-bottomed flask, equipped with a mechanic stirrer and a thermal probe (under nitrogen) was charged with Methyl 2-(2-tert-Butylphenylamino)-2-oxoacetate (154 g, 655 mmoles) and MeOH (1000 mL). The resulting mixture was stirred at a moderate speed at room temperature. A solution of 1N NaOH/MeOH (800 mL) was added dropwise to the reaction mixture via addition funnel. After 1 hour, agitation was stopped, and the suspension transferred to a filtration funnel and filtered to afford a white solid. This solid was then taken up in water (1200 mL) and the pH adjusted to 1.5–2 with addition of conc. HCl with stirring. After mixing for 1 hour, filtration and drying yielded the title compound as a white crystalline mass (127 g, 574 mmoles, 87.6%). TLC (silica F254, 3/1 v/v dichloromethane/MeOH, detection 254 nm) showed one spot and HPLC confirmed that. MP 110.9–112.6° C.; IR (KBr) 3405, 2973, 1688, 1548, 1300, 757 cm−1; 1H NMR (300 MHz, CDCl3): δ (ppm): 9.37 (br, 1H), 7.91 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.44 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.25 (m, 2H), 1.46 (s, 9H); 13C (300 MHz, CDCl3): δ (ppm): 160.87, 155.24, 141.18, 133.19, 126.92, 126.69, 126.63, 124.24, 34.21, 30.49.
Reaction SMILES: [CH:1]1([C:7]([N:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[O:25][CH3:26])[CH2:14][CH2:13]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[CH:1]1([C:7]([N:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:37](=[O:39])[CH3:38])=[CH:20][C:19]=3[O:25][CH3:26])[CH2:14][CH2:13]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(N)ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccn2)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc(NC(C)=O)ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
A mixture consisting of 0.35 g of compound of Example 6, 5 mL of chloroform and 0.063 mL of acetyl chloride was stirred for 2.5 h at room temperature, followed by dilution with 50 mL of dichloromethane. The obtained organic phase was then washed with a saturated sodium carbonate solution, and twice with water, followed by drying over anhydrous sodium sulphate and evaporation of the solvents to dryness. The obtained crude product was then purified by flash chromatography (ethyl acetate—3 N solution of ammonia, in methanol; 95:5), and the recovered fraction was evaporated to dryness, affording 0.300 g of the title compound (yield 78%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([CH:22]([CH2:26][CH3:27])[C:23]([OH:25])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O[N:29]1[C:33](=[O:34])[CH2:32][CH2:31][C:30]1=[O:35]>O1CCOCC1>[C:16]1([CH:22]([CH2:26][CH3:27])[C:23]([O:25][CH:31]2[CH2:32][C:33](=[O:34])[NH:29][C:30]2=[O:35])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: CCC(C(=O)OC1CC(=O)NC1=O)c1ccccc1
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of dicyclohexylcarbodiimide (6.91 g, 0.033 mol) in 33 mL of dry dioxane was added to a solution of 2-phenylbutyric acid (5.00 g, 0.030 mol) and N-hydroxysuccinimide (3.86 g, 0.034 mol) and the resulting mixture was allowed to stir overnight. The precipitated dicyclohexylurea by-product was filtered off and the filtrate concentrated under vacuum. The residue was dissolved in 5 mL of methylene chloride and filtered to remove a small amount of additional urea by-product. The solution was evaporated to give a white solid which was recrystallized from methanol to give 5.17 g (65%) of the product as white crystals; mp 96.5°-97.5° C.; 1H NMR (CDCl3) δ 0.99 (t, 3 H, J=7.4 Hz), 1.85-2.00 (m, 1 H), 2.13-2.28 (m, 1 H), 2.72 (br s, 4 H), 3.78 (t, 1 H, J=7.6 Hz), 7.35 (s, 5 H); 13C NMR (CDCl3) δ 11.49, 25.30, 26.89, 50.25, 127.95, 128.18, 128.92, 136.90, 169.24, 169.62; Anal. Calcd for C14H15NO4 : C, 64.36; H, 5.79; N, 5.36. Found: C, 64.63; H, 5.84; N, 5.34.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:44]([N:21]([CH2:22][C:23]([F:25])([F:26])[F:24])[C:19](=[O:20])[C:18]1[CH:27]=[CH:28][CH:29]=[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:15][CH2:14]2)[CH:17]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(NCC(F)(F)F)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1)N(Cc1ccccc1)CC(F)(F)F
Temperature: 60 °C
Reaction time: 3 h
Yield: 35.1 %

Procedure:
The compound (0.048 g) prepared in step (a) was dissolved in toluene (5 ml), and sodium hydroxide (0.014 g), potassium carbonate (0.028 g), tetrabutylammoniumhydrogen sulfate (0.003 g), and benzyl bromide (0.019 g) were added to the solution. The mixture was stirred at 60° C. for 3 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate=1:2) to give 0.020 g (21.0%) of the title compound.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].[CH3:12][CH:13]([Si:15](Cl)([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH3:14].N1C=CN=C1>CCOC(C)=O>[CH3:8][O:7][C:6]1[C:4]([O:5][Si:15]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:14])[CH3:12])=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH:2]=[O:1]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1cccc(C=O)c1O
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: COc1cccc(C=O)c1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 100 °C

Procedure:
O-vanillin (26.3 mmol) is mixed with TIPSCl (39.6 mmol) and imidazole (78.7 mmol) in a microwave vessel. The mixture is heated in the microwave at 100° C. for 3 minutes. The oily mixture is diluted with EtOAc (100 mL) and washed with NaHSO4 (1 M) (2×50 mL) and brine (50 mL). After drying with MgSO4, the filtrate is concentrated. The resultant crude mixture is purified by silica flash chromatography (2% EtOAc/hexane) to yield 3-methoxy-2-triisopropylsilanyloxy-benzaldehyde as an oil: 1H NMR (400 MHz, CDCl3) δ 10.6 (s, 1H), 7.38 (dd, J1=1.6 Hz, J2=8 Hz, 1H), 7.04 (dd, J1=1.6 Hz, J2=8 Hz, 1H), 6.93 (td, J1=8 Hz, J2=0.8 Hz, 1H), 3.82 (s, 3H), 1.34-1.25 (m, 3H), 1.1 (s, 18H); LC/MS (ES+): 309 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]OCC2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[O:50]1[CH2:55][CH2:54]CCN1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:54][CH2:55][O:50]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCONC1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCCCO2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and [1,2]oxazinane and isolated as light-yellow gum (13.6 mg, 75%). MS (m/e): 387.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[F:28])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4ccccc4F)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 2-fluorobenzoyl chloride gave the title compound.
Reaction SMILES: CC(O)(C(C)=C)C.Cl[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14]O)=[O:13].S([O-])([O-])=O.[Na+].[Na+].O>C(Cl)(Cl)Cl>[C:12]([OH:14])(=[O:13])[C:11]1[CH:16]=[CH:17][CH:18]=[CH:9][CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C=C(C)C(C)(C)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 46.7 g of 2,3-dimethyl-3-buten-2-ol in 602 ml of chloroform was cooled to 0°-5° in a dry ice-acetone bath. To this was added dropwise, during 4 hours, a solution of 96.5 g of m-chloroperoxybenzoic acid (113.5 g of 85%) in 966 ml of chloroform. The reaction mixture temperature was maintained at 0°-5° throughout the addition. Upon complete addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for 18 hours. To the reaction mixture was slowly added a solution of 11.8 g of sodium sulfite in a minimum amount of water. The reaction mixture was tested for peroxides using wet acidic sodium iodide-starch paper; there were no peroxides present. Concentration of the reaction mixture to below one-half the original volume resulted in precipitation of benzoic acid from the reaction mixture. The benzoic acid was removed by filtration. The concentration, precipitation, and filtration was repeated several time until at the last concentration only a small amount of precipitated benzoic acid was collected. There remained 16.6 g of residual yellow liquid, from which on standing a white solid crystallized. The liquid portion was decanted off and the solid was washed with diethyl ether. The ether wash was added to the liquid portion. The white solid had a melting point of 116°-118° and decomposed explosively at 170°-180°. The liquid portion was distilled using a Vigreux column, to give 9.32 g of 2-[(1-hydroxy-1- methyl)ethyl]-2-methyloxirane bp 35°-65°/15-20 mm. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([C:23](=[O:32])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:21]([NH:33][CH2:34][CH:35]3[CH2:42][CH2:41][C:38]4([CH2:40][CH2:39]4)[CH2:37][CH2:36]3)[N:20]=[C:19]([C:43]#[N:44])[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:25]([NH:24][C:23]([C:22]1[C:17]([O:16][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:18][C:19]([C:43]#[N:44])=[N:20][C:21]=1[NH:33][CH2:34][CH:35]1[CH2:36][CH2:37][C:38]2([CH2:39][CH2:40]2)[CH2:41][CH2:42]1)=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(NCC3CCC4(CC3)CC4)c2C(=O)NCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nc(NCC2CCC3(CC2)CC3)c(C(=O)NCc2ccccc2)c(OCCC2CCNCC2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-{5-benzylcarbamoyl-2-cyano-6-[(spiro[2.5]oct-6-ylmethyl)amino]-pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester (0.68 mmol) in CH2Cl2 (10 mL) is added TFA (2 mL) at 0° C. After stirring for 2 h at 0° C. under N2 atmosphere, the mixture is concentrated and dried in vacuo to give 2-cyano-4-(2-piperidin-4-yl-ethoxy)-6-[(spiro[2.5]oct-6-ylmethyl)amino]pyrimidine-5-carboxylic acid benzyl amide as a yellow solid. 1H-NMR (CDCl3), δ 0.17-0.30 (4H, m), 0.89-0.93 (2H, m), 1.00-1.11 (2H, m), 1.14-1.24 (2H, m), 1.29-1.38 (1H, m), 1.51-1.81 (9H, m), 2.41-2.48 (2H, m), 2.99-3.02 (2H, m), 3.42 (2H, t), 4.45 (2H, t), 4.56 (2H, d), 7.29-7.39 (5H, m), 8.17 (1H, t), 10.16 (1H, t).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:7](=[O:20])[C@@H:6]3[CH2:21][O:22][CH2:23][CH2:24][N:5]3[C:4]=2[N:3]=1.B1([C:34]2[NH:38][N:37]=[CH:36][CH:35]=2)OC(C)(C)C(C)(C)O1.O1CCOCC1.C([O-])(O)=O.[Na+]>[Pd].Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CN(C=O)C>[C:14]1([C@@H:12]([N:8]2[C:7](=[O:20])[CH:6]3[CH2:21][O:22][CH2:23][CH2:24][N:5]3[C:4]3[N:3]=[C:2]([C:36]4[CH:35]=[CH:34][NH:38][N:37]=4)[N:11]=[CH:10][C:9]2=3)[CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(c1ccccc1)N1C(=O)[C@@H]2COCCN2c2nc(Cl)ncc21
Reactant: CC1(C)OB(c2ccn[nH]2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: C[C@@H](c1ccccc1)N1C(=O)C2COCCN2c2nc(-c3cc[nH]n3)ncc21
Temperature: 120 °C
Yield: 17.9 %

Procedure:
To a 2 mL microwave vial were added (S)-2-chloro-5-(1-phenylethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x47, 36 mg, 0.104 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxabolone)-pyrrazole (40.5 mg, 0.209 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (4.29 mg, 5.22 μmol). After the vial was sealed, dioxane (0.6 mL) and aqueous saturated NaHCO3 (0.15 mL) were added, and the mixture was degassed by bubbling nitrogen through a syringe needle for 10 minutes. The mixture was then heated in a microwave to 120° C. for 60 minutes. Another 2 equivalents of boronic ester and 0.05 equivalents of palladium catalyst were added, and the mixture was heated in the microwave for another 60 minutes. DMF (1 mL) was added and the mixture was filtered by syringe filter. The crude product was purified by preparatory HPLC, eluting with a gradient of 25-30% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). Lyophilization of the collected fractions gave a diastereomeric mixture of the title compound (TFA salt) as a white solid (7 mg, 14%). 1H NMR (400 MHz, DMSO-d6) δ 1.68 (d, J=7.1 Hz, 3H), 1.75 (d, J=7.3 Hz, 4H), 2.26 (t, J=1.8 Hz, 1H), 2.60, (t, J=1.8 Hz, 1H), 2.94 (br s, 3H), 3.46-3.73 (m, 11H), 3.90-3.99 (m, 4H), 4.18 (dt, J=11.4, 3.6 Hz, 4H), 4.40-4.66 (m, 7H), 6.13 (d, J=6.8 Hz, 1H), 6.24 (d, J=7.1 Hz, 1H), 6.72 (br s, 3H), 7.17-7.38 (m, 14H), 7.40 (br s, 1H), 7.55 (d, J=18.4 Hz, 4H). ESI-MS m/z [M+H]+ calc'd for C20H20N6O2, 377.16; found 377.4.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O=[CH:26][C:27]1[CH:35]=[CH:34][C:32]([OH:33])=[C:29]([O:30][CH3:31])[CH:28]=1>C1(C)C=CC=CC=1>[OH:33][C:32]1[CH:34]=[CH:35][C:27](/[CH:26]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(O)c(OC)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
6.5 g (19.5 mmol, 3 eq) of methyl triphenylphosphoranylideneacetate are added to a solution of 1.0 g (6.5 mmol, 1 eq) of vanillin in 15 ml of toluene. The reaction mixture is stirred for 1 hour at 90° C. The solvent is evaporated off and the residual oil is then chromatographed on silica gel (8/2 heptane/ethyl acetate). 1.12 g of methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate are obtained in oil form. Yield=83%
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[K+].[K+].[CH2:21](I)[CH3:22].Cl>CN(C=O)C>[CH2:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:12]([O:14][CH2:21][CH3:22])=[O:13]
Reactant: CCI
Reactant: C=C1CCCC2(CCCC2)C1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C1CCCC2(CCCC2)C1C(=O)OCC
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
At 5° C., a solution of the previously obtained 7-methylenespiro[4.5]decane-6-carboxylic acid (1.2 g, 6.2 mmol) in DMF (30 ml) was treated with K2CO3 (0.94 g, 6.8 mmol). The resulting mixture was stirred for 30 min., treated with ethyl iodide (0.75 ml, 9.3 mmol), stirred at 20° C. for 2 h, poured into cold 2N aqueous HCl (20 ml), and extracted twice with hexane (50 ml). The combined organic phases were washed with water (50 ml), with a saturated aqueous solution of NaCl (50 ml), dried (MgSO4), and concentrated. FC (90 g SiO2, hexane/MTBE 98:2) of the crude product (1.23 g) gave ethyl 7-methylenespiro[4.5]decane-6-carboxylate (0.69 g, 50%). Boiling point: 90° C. (0.08 mbar).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:34]([N:38]=[C:39]=[O:40])([CH3:37])([CH3:36])[CH3:35]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:39]([NH:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[S:3][C:4]=2[CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][P:26]([O:28][CH2:29][CH3:30])([O:31][CH2:32][CH3:33])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[CH:12][CH:11]=1
Reactant: CC(C)(C)N=C=O
Reactant: CCOP(=O)(Cc1ccc(NC(=O)CCc2sc(N)nc2-c2ccc(Cl)cc2)cc1)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2sc(NC(=O)NC(C)(C)C)nc2-c2ccc(Cl)cc2)cc1)OCC
Reaction time: 20 h

Procedure:
A mixture of 3-[2-amino-4-(4-chlorophenyl)-5-thiazolyl)-N-[4-(diethylphosphonomethyl)phenyl]propionamide (400 mg), tert-butyl isocyanate (780 mg) and toluene (10 ml) was stirred at 70–80° C. for 20 hrs. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography and 3-(4-(4-chlorophenyl)-2-([(tert-butylamino)carbonyl]amino}-5-thiazolyl)-N-[4-(diethylphosphonomethyl)phenyl]propionamide was obtained as crystals (395 mg, yield: 83%) from a fraction eluted with 3% methanol-ethyl acetate. Recrystallization from ethyl acetate gave colorless prism crystals. melting point: 180–181° C.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([CH2:7][OH:8])[C@@H:5]([CH3:9])[N:4]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C@H:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH:26]([C:29]1[CH:30]=[CH:31][C:32]([O:37][CH3:38])=[C:33]([CH:36]=1)[CH:34]=O)([CH3:28])[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH2:13]([O:12][C:10]([N:4]1[C@H:5]([CH3:9])[C@H:6]([CH2:7][OH:8])[C@H:2]([NH:1][CH2:34][C:33]2[CH:36]=[C:29]([CH:26]([CH3:28])[CH3:27])[CH:30]=[CH:31][C:32]=2[O:37][CH3:38])[C@@H:3]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[C@@H]1[C@@H](CO)[C@H](N)[C@H](c2ccccc2)N1C(=O)OCc1ccccc1
Reactant: COc1ccc(C(C)C)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1CN[C@H]1[C@@H](CO)[C@@H](C)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Yield: 148.9 %

Procedure:
To a stirred solution of (2S*,3S*,4S*,5R*)-3-amino-1-benzyloxycarbonyl-4-hydroxymethyl-5-methyl-2-phenylpyrrolidine (0.61 g, 1.79 mmol) in dry CH2Cl2 (14 ml) was added a solution of 5-isopropyl-2-methoxybenzaldehyde (0.40 g, 2.24 mmol) in dry CH2Cl2 (2 ml) at room temperature. To this was then added NaBH(OAc)3 (0.57 g, 2.69 mmol) portionwise at room temperature. The added NaBH(OAc)3 dissolved gradually with stirring at room temperature. After stirring for 3 hours at room temperature, the reaction mixture was basified to pH 10-11 with 10% NaOH aq. solution. The mixture was separated, and the aqueous layer was extracted with CH2Cl2 (×3). The combined CH2Cl2 solution was washed with sat. NaCl aq. solution (×1), dried (K2CO3), and concentrated in vacuo to give a yellow oil (1.34 g). This was chromatographed over SiO2 (Merck Kieselgel 60, 20 g). Elution with n-hexane-AcOEt (30:1) followed by CH2Cl2 --MeOH (400:1→200:1) gave title compound (0.70 g, 78%) as a viscous pale yellow oil: IRmax (film): 3330(s), 1700(s), 1610(m), 1500(s), 1250(s), 1110(s), 1030(s), 815(s), 770(s), 738(s), 700(s) cm- ; 1H-NMR δ: 7.45-7.16(m, 9H), 7.05(dd, J=8.4, 1.8 Hz, 1H), 7.02(br.s, 1H), 6.88(d, J=1.8 Hz, 1H), 6.71(d, J=8.4 Hz, 1H), 5.33-4.93(m, 3H), 3.97-3.65(m, 3H), 3.81(d, J=12.1 Hz, 1H), 3.72(d,J=12.1 Hz, 1H), 3.67(s, 3H), 3.53-3.35(m, 1H), 3.38(dd,J=11.5, 7.9 Hz), 2.79 (sep, J=7.0 Hz, 1H), 2.17-1.98(m, 1H), 1.56(br.s, 4H), 1.18(d, J=7.0 Hz, 6H) ppm.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[CH:10][C:11]=1[Cl:12].[Sn](Cl)Cl>O.Cl.[OH-].[Na+]>[ClH:12].[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([OH:13])=[CH:7][C:6]=1[NH:5][NH2:1]
Reactant: Nc1cc(O)ccc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(O)ccc1Cl
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 44.4 %

Procedure:
A solution of sodium nitrite (2.07 g, 30.0 mmol) in water (6.0 mL) was added dropwise to an ice cold slurry of 3-amino-4-chlorophenol (4.30 g, 30.0 mmol) and hydrochloric acid (37% aqueous, 9.0 mL) and the mixture stirred for 45 min. Tin (II) chloride (15.4 g, 81.0 mmol) in water (18.0 mL) and hydrochloric acid (37% aqueous, 18.0 mL) was added dropwise and the reaction stirred overnight. The mixture was cooled in an ice/water bath, diluted with water and neutralised by addition of NaOH (1M aq). The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was passed through an acidic ion-exchange cartridge (SCX-2), washing with methanol and eluting with 2M ammonia in methanol. The basic fraction was evaporated in vacuo then purified by FCC, using 3-10% [2M NH3 in MeOH] in DCM, to give the title compound (1.30 g, 27%). 1H NMR (300 MHz, d6-DMSO): 4.12 (2H, br s), 6.03 (1H, dd, J=8.5, 2.9 Hz), 6.26 (1H, s), 6.63 (1H, d, J=2.7 Hz), 6.93 (1H, d, J=8.5 Hz), 9.22 (1H, s).