Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10])[C:3]#[CH:4].C[O:14][C:15]([CH3:17])=[CH2:16]>>[CH3:1][C:2]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10])=[CH:3][CH:4]=[CH:16][C:15](=[O:14])[CH3:17]
Reactant: C#CC(C)(O)CCC=C(C)CC
Reactant: C=C(C)OC
Product: CCC(C)=CCCC(C)=CC=CC(C)=O

Procedure:
The acid-catalysed reaction of 3,7-dimethyl-non-1-yn-6-en-3-ol with isopropenyl methyl ether and subsequent base-catalysed isomerisation of the resulting β-keto-allene [see G. Saucy, R. Marbet, Helv. 50, 1158 (1967)] yielded in good yield 6,10-dimethyl-dodeca-3,5,9-trien-2-one which was cyclised in a known manner [see H. Rouve, M. Stoll, Helv. 30, 2216 (1947)] with 85% phosphoric acid to give 12/13-methyl-α-ionone. Subsequent reduction with lithium aluminium hydride gave 12/13-methyl-α-ionol.
Reaction SMILES: Br[C:2]1[CH2:6][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C:16]3=[N:17][C:18]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)[N:20]=[C:15]3[CH2:14][CH2:13][CH2:12]2)[O:4][N:3]=1.[CH3:35][O-:36].[Na+]>CO>[C:24]1([CH3:27])[CH:25]=[CH:26][C:21]([C:19]2[N:20]=[C:15]3[CH2:14][CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH:5]4[O:4][N:3]=[C:2]([O:36][CH3:35])[CH2:6]4)[C:16]3=[N:17][C:18]=2[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[CH:22][CH:23]=1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCC2CC(Br)=NO2)CCC3)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC1=NOC(CCCCN2CCCc3nc(-c4ccc(C)cc4)c(-c4ccc(C)cc4)nc32)C1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-5-(4-(2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)butyl)-4,5-dihydroisoxazole (step 1) (5195 mg, 10 mmol) in MeOH (5 ml) was treated with NaOMe (10 ml of 30% solution by weight) and heated at reflux for 2 hours. After cooling to RT, the reaction was quenched with water (100 ml) and the aqueous portion was extracted with EtOAc. The combined organic extracts were washed with brine, dried by passing through a phase separator and were concentrated under reduced pressure. The crude product was purified by chromatography on silica eluting with 0-60% EtOAc in iso-hexane to afford the titled compound as an orange oil;
Reaction SMILES: [CH3:1][O:2][P:3]([O:6]C)[O:4][CH3:5].[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>Cl.C(OCC)(=O)C>[CH3:1][O:2][P:3]([CH2:14][C:13]1[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=1)(=[O:6])[O:4][CH3:5]
Reactant: CSc1ccc(CCl)cc1
Reactant: COP(OC)OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COP(=O)(Cc1ccc(SC)cc1)OC
Temperature: 140 °C
Reaction time: 18 h

Procedure:
To trimethylphosphite (8.6 g, 70 mmol) at 140° C. was added 4-methylthiobenzyl chloride (10 g, 58 mmol). The resulting mixture was stirred at 140° C. for 18 h, cooled at 21° C. then diluted with HCl 10% and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered, and concentrated. Purification by flash chromatography (eluting with ethyl acetate) provided the (4-methylsulfanyl-benzyl)-phosphonic acid dimethyl ester compound.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:35]([CH3:37])[CH3:36])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)[N:8]=1)=[O:6].C(OC1C(=O)N=C(CC2C=CC=C(Cl)C=2Cl)N2CCN(C(C)C)C(=O)C=12)C1C=CC=CC=1>>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)[N:8]2[CH2:2][CH2:3][N:4]([CH:35]([CH3:37])[CH3:36])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(Cc2ccccc2C2=CCCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)N1CCn2c(Cc3cccc(Cl)c3Cl)nc(=O)c(OCc3ccccc3)c2C1=O
Product: CC(C)N1CCn2c(Cc3ccccc3C3=CCCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Yield: 44.2 %

Procedure:
9-Benzyloxy-6-(2-cyclohex-1-enyl-benzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (156) (42.5 mg, 44.15%) as an off-white solid was synthesized from 5-benzyloxy-2-(2-cyclohex-1-enyl-benzyl)-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (155) (100 mg, 0.199 mmol) following the procedure as described for 9-benzyloxy-6-(2,3-dichlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (134).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:10][C@H:9]1[CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([N:13]([CH3:32])[C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])[CH2:10][C@H:9]1[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@@H](NC(=O)C(F)(F)F)CN2C(=O)OC(C)(C)C)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(OC[C@@H]2C[C@@H](N(C)C(=O)C(F)(F)F)CN2C(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
To a stirred solution of methyl 4-(trans-1-tert-butoxycarbonyl-4-trifluoroacetamido-(2S)-pyrrolidinyl)methoxybenzoate (520 mg, 1.17 mmol) in DMF (10.0 ml) was added K2CO3 (321 mg, 2.33 mmol) and MeI (330 mg, 2.33 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 18 hr. Water was added to the mixture and extracted with EtOAc. The organic layer was washed with water, then dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc-n-hexane (1:2, v/v) as eluent to give methyl 4-[trans-1-tert-butoxycarbonyl-4-(N-methyl-trifluoroacetamido)-(2S)-pyrrolidinyl]methoxybenzoate (390 mg, 73%) as a colorless oil. 1H-NMR (CDCl3) δ 1.46 (9H, s), 2.12–2.40 (m, 2H), 2.96 and 3.05 (each s, total 3H), 3.28–3.70 (m, 2H), 3.88 (s, 3H), 3.95–4.42 (m, 3H), 5.10–5.40 (m, 1H), 6.89–6.91 (m, 2H), 7.96–8.00 (m, 2H).
Reaction SMILES: [Cl:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][C@H:15]([CH3:29])[C@:16]2([O:24][C:25](=[O:28])[CH2:26][CH3:27])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:31])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:30])[CH:6]=[CH:5]1.[C:32](OC(=O)C)(=[O:34])[CH3:33].O.Cl>N1C=CC=CC=1>[C:32]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([O:24][C:25](=[O:28])[CH2:26][CH3:27])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([Cl:1])[CH2:22]2)[C@:4]2([CH3:31])[C:9](=[CH:8][C:7](=[O:30])[CH:6]=[CH:5]2)[CH2:10][CH2:11]3)[CH2:14][C@@H:15]1[CH3:29])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)O[C@]1(C(=O)COC(C)=O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C

Procedure:
A solution of 11β-chloro-21-hydroxy-16β-methyl-17-propionyloxypregna-1,4-diene-3,20-dione (75 mg) in pyridine (1 ml) was treated with acetic anhydride (0.2 ml) at room temperature. After 3 hours water (0.4 ml) was added and the solution was poured into dilute by hydrochloric acid. The precipitated solid was removed by filtration and after drying was recrystallized from methanol to give the title compound, m.p. 212°-213°(K), [α]D + 101.1° (c 0.6 chloroform). λmax 239 nm (ε 16,280) (Found: C, 65.7; H, 7.0; Cl, 6.8. C27H35ClO6 requires C, 66.0; H, 7.2, Cl, 7.2%).
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[CH:7][C:6]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:5][N:4]=1.Br.O>CO.[Pd].C(O)(=O)C>[OH:9][C:8]1[C:3](=[O:2])[NH:4][CH:5]=[C:6]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:7]=1
Reactant: COc1cc(C#Cc2ccccc2C)cnc1OC
Agent: [Pd]
Agent: Br
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1CCc1c[nH]c(=O)c(O)c1
Temperature: 180 °C
Yield: 17.6 %

Procedure:
2,3-Dimethoxy-5-[(2-methylphenyl)ethynyl]pyridine (Intermediate 33) (437 mg, 1.7 mmol) was hydrogenated in methanol using palladium on carbon as catalyst at 20 bar. The crude product was dissolved in acetic acid (5 ml) and 48% aqueous hydrobromic acid (5 ml) was added before the mixture was irradiated in the microwave with heating at 180° C. for 1 hour. The resulting mixture was then poured into water and the precipitated solid was filtered off and washed with water before being recrystallised from ethanol (twice) to afford 3-hydroxy-5-(2-methylphenethyl)pyridin-2(1H)-one (70 mg, 0.3 mmol, 18% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].S1C=CN=C1C1C=CC(CNS(C2C=NC=CC=2)(=O)=O)=CC=1.[CH3:56][O:57][C:58]1[CH:59]=[CH:60][C:61]2[CH:65]=[C:64]([CH2:66]O)[S:63][C:62]=2[CH:68]=1>>[C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:66][C:64]2[S:63][C:62]3[CH:68]=[C:58]([O:57][CH3:56])[CH:59]=[CH:60][C:61]=3[CH:65]=2)[NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:18])=[O:19])[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2cc(CO)sc2c1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CNS(=O)(=O)c2cccnc2)n1
Agent: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1
Product: COc1ccc2cc(CC(NS(=O)(=O)c3cccnc3)c3cccc(N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n3)sc2c1
Yield: 77.7 %

Procedure:
Reaction was carried out in the same manner as in Example 2-(a) except for using tert-butyl(tert-butoxycarbonyl{6-[(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetate (69.4 mg, 0.145 mmol) obtained in Reference Example 12-(d) in place of N-[4-(thiazol-2-yl)benzyl]pyridin-3-ylsulfonamide, and using (6-methoxybenzo[b]-thiophen-2-yl)methanol (see WO 2006/106711A, 33.9 mg, 0.175 mmol) in place of tert-butyl [tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetate. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extraction with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=3:1→1:1 (V/V)) and then to reversed phase column chromatography (column; Megabond Elut™ C18 (manufactured by Varian, Inc.), eluent; acetonitrile:water=1:1→1:0 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (73.8 mg) as a white foam. (Yield: 78%)
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([N:13]=[C:14]=[S:15])[C:10]([CH3:16])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)#[N:2].[CH2:17]([NH2:20])[CH2:18][NH2:19]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:12]=[C:11]([NH:13][C:14]([NH:19][CH2:18][CH2:17][NH2:20])=[S:15])[C:10]([CH3:16])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)#[N:2]
Reactant: NCCN
Reactant: Cc1c(N=C=S)cc(C#N)c2cccnc12
Solvent: Cc1ccccc1
Product: Cc1c(NC(=S)NCCN)cc(C#N)c2cccnc12
Reaction time: 0.17 h

Procedure:
A solution of 5-cyano-8-methyl-7-quinolinylisothiocyanate (0.85 g) in toluene (100 mL) is added dropwise to a solution of 1,2-ethylenediamine (1.94 g) in toluene (100 mL). A yellow-white precipitate is observed after the reaction stirs at room temperature for 10 minutes. The precipitate is filtered and dried in vacuo to afford N-(5-cyano-8-methyl-7-quinolinyl)-N'-2-aminoethylthiourea as a yellow-white solid.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:15][C@@H:14]3[CH2:16][C@H:11]2[CH2:12][N:13]3[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=O)=O)=CC=1.Br>C(O)(=O)C>[CH2:17]([N:13]1[CH2:12][C@@H:11]2[CH2:16][C@H:14]1[CH2:15][NH:10]2)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)N2C[C@@H]3C[C@H]2CN3Cc2ccccc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Temperature: 70 °C
Yield: 166.7 %

Procedure:
A mixture of (1S,4S)-2-(4-toluenesulfonyl)-5-phenylmethyl-2,5-diazabicyclo[2.2.1]heptane (54.9 g) in acetic acid (830 mL) containing hydrobromic acid (30% wt) was heated at 70° C. for 18 h. The reaction mixture was allowed to cool and concentrated under reduced pressure to a final volumen of ca. 300 mL. The precipitate that formed was filtered and washed with acetone to give (1S,4S)-N-benzyl-2,5-diazabicyclo[2.2.1]heptane (50.30 g 91.3%, m.p. 272-275° C.).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:7](/[CH:12]=[C:13](/[C:20]2[NH:24][N:23]=[N:22][N:21]=2)\[CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]>[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:7](/[CH:12]=[C:13](/[C:20]2[NH:24][N:23]=[N:22][N:21]=2)\[CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[C:8]([CH:10]=[O:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CO)c(/C=C(\Cc2cccs2)c2nnn[nH]2)n1Cc1ccccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Product: CCCCc1nc(C=O)c(/C=C(\Cc2cccs2)c2nnn[nH]2)n1Cc1ccccc1Cl

Procedure:
The title compound is prepared by manganese dioxide oxidation of the 4-hydroxymethyl-group of (E)-1-[2-n-butyl-1-{(2-chlorophenyl)methyl}-4-hydroxymethyl-1H-imidazol-5-yl]-2-(1H-tetrazol-5-yl]-3-(2-thienyl)-1-propene, prepared in Example 18.
Reaction SMILES: C[O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:21])[CH2:10][CH2:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1.[OH-].[Na+]>>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([CH2:11][CH2:10][C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[C:3]([OH:22])=[O:2])=[O:21])=[O:20])=[CH:14][CH:15]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CCC(=O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A mixture of 2.64 g. of 1-[3-(4-bromobenzoyl)propionyl]-L-proline methyl ester (Example 26) and 26 ml. of 1 N sodium hydroxide is stirred at room temperature. The solids are collected by decantation, dissolved in tetrahydrofuran and returned to the alkaline solution which is stirred further at room temperature. This alkaline solution is washed with ethyl acetate and poured into iced hydrochloric acid. This mixture is extracted with dichloromethane. The organic extract is dried over magnesium sulfate and evacuated to dryness in vacuo leaving a gum. This gum is triturated with ether giving white crystals which are recrystallized from acetone-hexane giving the desired product as 1.35 g. of white crystals, mp. 138°-139° C.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[NH:21][C:20](=[O:23])[CH2:19][CH2:18]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>>[C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[NH:21][C:20](=[O:23])[CH:19]=[CH:18]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2cccc(OCCCCSc3ccccc3)c2N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: O=c1ccc2cccc(OCCCCSc3ccccc3)c2[nH]1

Procedure:
Prepared analogous to Example 86 from 8-(4-phenylmercapto-butoxy)-3,4-dihydro-carbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:9]([OH:22])([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C.O>C(Cl)Cl.C(OCC)(=O)C>[CH3:23][S:24]([O:11][CH2:10][C@@:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=1)([OH:22])[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:19])([CH3:21])[CH3:20])([CH3:16])[CH3:17])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC[C@](O)(CO)c1ccc(F)c(Br)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC[C@](O)(COS(C)(=O)=O)c1ccc(F)c(Br)c1
Yield: 110.5 %

Procedure:
The compound (1.50 g, 3.80 mmol) obtained in Example 91d was dissolved in methylene chloride (60 mL), the mixture was stirred under ice cooling, methanesulfonyl chloride (0.35 mL, 4.56 mmol) and triethylamine (0.79 mL, 5.70 mmol) were added, and the mixture was stirred at the same temperature under a nitrogen atmosphere for 4 hours. After the reaction was completed, water was added to the reaction mixture under ice cooling, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude title compound (1.98 g) as a colorless oily substance.
Reaction SMILES: C([O:5][C:6]([C:8]1[NH:9][C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Br:30])=[N:11][C:12](=[O:22])[C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[Li+].[OH-].O>O1CCCC1>[CH2:15]([O:14][C:13]1[C:12](=[O:22])[N:11]=[C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Br:30])[NH:9][C:8]=1[C:6]([OH:7])=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1[nH]c(Cc2ccccc2Br)nc(=O)c1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1[nH]c(Cc2ccccc2Br)nc(=O)c1OCc1ccccc1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
5-(Benzyloxy)-2-(2-bromobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid tert-butyl ester (67) (2.69 g, 5.71 mmol, Eq: 1.00) and LiOH (683 mg, 28.5 mmol, Eq: 5) were stirred in tetrahydrofuran (18 ml)/water (9.00 ml) under reflux for 6 h, at room temperature overnight and again to reflux for 3 h. Then the solvent was mostly removed. The remaining oil was diluted with water and extracted with ethyl acetate. The aqueous layer was cooled in an ice bath and was acidified with HCl conc. Precipitate formed, was collected by filtration, washed with water and dried to afford 5-(benzyloxy)-2-(2-bromobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid (68) (2.14 g, 5.15 mmol, 90.3% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:38])[C@H:8]([CH2:33][C:34]([F:37])([CH3:36])[CH3:35])[NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:32])([CH3:31])[CH:28]([F:30])[F:29])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH2:5][CH2:4]1)#[N:2]>C(O)C>[C:1]([C:3]1([NH:6][C:7](=[O:38])[C@H:8]([CH2:33][C:34]([F:37])([CH3:35])[CH3:36])[NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C@:27]([OH:32])([CH3:31])[CH:28]([F:30])[F:29])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc(C(C)(O)C(F)F)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Solvent: CCO
Product: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc([C@@](C)(O)C(F)F)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1

Procedure:
The 1:1 diastereomeric mixture from step 2 in example 9 (80 mg) was dissolved in ethanol (2 mL). The mixture of compounds was resolved in ˜10 injections (10×200 μL) with a Chiralcel OD semi-preparative column (2 cm I.D.×25 cm) eluting with 32.5% 2-propanol in hexanes and a flow rate of 6 mL/min. The fast fractions eluted at 21-23 min were pooled and concentrated to give N1-(1-cyanocyclopropyl)-N2-((1S)-1-{4′-[(1R)-2,2-difluoro-1-hydroxy-1-methylethyl]biphenyl-4-yl}-2,2,2-trifluoroethyl)-4-fluoro-L-leucinamide as a white powder (98% d.e.). Stereochemistry is tentative.
Reaction SMILES: O.S.[Na].[N:4]([CH2:7][C:8]1[N:18]=[C:11]2[N:12]=[C:13]([CH3:17])[CH:14]=[C:15]([SH:16])[N:10]2[N:9]=1)=[N+]=[N-].[C:19]1([C:25]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[O:29][C:28]3[CH:30]=[CH:31][C:32]([C:34](ON4C5C=CC=CC=5N=N4)=[O:35])=[CH:33][C:27]=3[O:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[SH:16][C:15]1[N:10]2[N:9]=[C:8]([CH2:7][NH:4][C:34]([C:32]3[CH:31]=[CH:30][C:28]4[O:29][C:25]([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[O:26][C:27]=4[CH:33]=3)=[O:35])[N:18]=[C:11]2[N:12]=[C:13]([CH3:17])[CH:14]=1
Reactant: Cc1cc(S)n2nc(CN=[N+]=[N-])nc2n1
Reactant: O=C(On1nnc2ccccc21)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Agent: S
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(S)n2nc(CNC(=O)c3ccc4c(c3)OC(c3ccccc3)(c3ccccc3)O4)nc2n1
Yield: 86.2 %

Procedure:
A dried solution of 2.0 g of sodium hydrogen sulphide monohydrate (drying agent molecular sieve 4 Å) in 100 ml of dimethylformamide is treated with 2.2 g of 2-azidomethyl-5-methyl[1.2.4]triazolo[1,5-a]pyrimidine-7-thiol and stirred until the evolution of gas has finished (about 15 minutes). Thereupon, 4.35 g of 1H-benzotriazol-1-yl 2,2-diphenyl-1,3-benzodioxol-5-carboxylate are added and the reaction mixture is stirred at room temperature for 20 hours and at 45° C. for 24 hours. The solvent is evaporated in a high vacuum, the residue is taken up in 200 ml of ethyl acetate and 200 ml of water and stirred in an ice bath for 30 minutes. The resulting precipitate is filtered off under suction, washed with water and ethyl acetate and dried in a vacuum at 40° C. The yellow product is dissolved in 100 ml of methanol, a small amount of insoluble material is removed by filtration and the filtrate is concentrated to dryness. The residue in 100 ml of acetonitrile is heated at reflux on a steam bath for 1 hour. After cooling in an ice bath the product is filtered off under suction and dried. There are obtained 4.25 g of N-[(7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidin-2-yl)methyl]-2,2-diphenyl-1,3-benzodioxol-5-carboxamide as a yellow solid of melting point 267°-271° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)[CH:8]=2)[N:3]=1.[NH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24]>C1COCC1>[CH:16]1([CH2:15][O:14][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([NH:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])[C:11]([CH:12]=[O:13])=[CH:10]3)[CH2:18][CH2:17]1
Reactant: CC(=O)NCCN
Reactant: O=Cc1cc2cc(OCC3CC3)ccc2nc1Cl
Solvent: C1CCOC1
Product: CC(=O)NCCNc1nc2ccc(OCC3CC3)cc2cc1C=O
Temperature: 160 °C
Reaction time: 6 h
Yield: 38 %

Procedure:
To a stirred solution of 2-chloro-6-(cyclopropylmethoxy)quinoline-3-carbaldehyde SLA 47086 (770 mg, 2.94 mmol) in THF (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added N-(2-aminoethyl)acetamide (1.202 g, 11.8 mmol) and the reaction mixture was stirred for 6 h at 160° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up in a mixture of THF:1 N aq. HCl=1:1 (50 mL) and stirred for 20 min at RT. The volatiles were then removed at 40° C. under vacuum and the residue was then neutralised with a 10 N aqueous NaOH solution. THF was then evaporated before extraction with CH2Cl2 (100 mL). The separated organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum to give N-(2-(6-(cyclopropylmethoxy)-3-formylquinolin-2-ylamino)ethyl)acetamide SLA 47092 as a yellow solid (365 mg, 38% yield).