Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([CH3:20])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>>[CH3:1][N:2]([CH3:3])[C:5]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([CH3:20])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CNC
Reactant: CCOC(=O)c1c(C)cc(C(F)(F)F)nc1Cl
Product: CCOC(=O)c1c(C)cc(C(F)(F)F)nc1N(C)C
Reaction time: 24 h

Procedure:
A solution of dimethylamine (5 mL of 2M in THF) was added to ethyl 2-chloro-4-methyl-6-(trifluoromethyl)nicotinate (500 mg, 1.9 mmol) and stirred in a sealed tube for 24 hours. The mixture was partitioned between ethyl acetate (30 mL) and water (30 mL). The organic phase was dried over magnesium sulphate, filtered and evaporated to give ethyl 2-(dimethylamino)-4-methyl-6-(trifluoromethyl)nicotinate as a colourless oil (450 mg): 1H NMR (500 MHz, CDCl3): δ 6.79 (1H, s), 4.39 (2H, q, J 7.1), 3.05 (6H, s), 2.32 (3H, s), 1.39 (3H, t, J 7.1).
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.[Cl-].[C:15](Cl)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:15]([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC(=O)Cl
Reactant: CC(N)C(=O)O
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)NC(C)C(=O)O

Procedure:
The preparation is carried out analogously to the procedure of example 1A using 16.5 g (0.185 mol) of D,L-alanine, 41.23 g (0.407 mol) of triethylamine, 44.27 g (0.407 mol) of trimethylsilyl)l chloride and 30.12 g (0.185 mol) of octanoyl chloride. The product crystallizes from toluene/n-hexane.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C@@H:6]1[C@H:11]([CH2:12][CH2:13][CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9][N:8]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:7]1.O>CS(C)=O>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:10][CH2:9][N:8]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:7][C@@H:6]1[CH2:5][C:1]#[N:2]
Reactant: [C-]#N
Reactant: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4ccccc4)C[C@@H]3CCl)c2c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4ccccc4)C[C@@H]3CC#N)c2c1
Temperature: 60 °C
Yield: 26.7 %

Procedure:
0.565 g of sodium cyanide was added to a stirred solution of 1.3 g of (3R,4R)-3-chloromethyl-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine in 50 cm3 of dimethyl sulfoxide and then the mixture was heated at a temperature in the region of 60° C. for 20 hours. After cooling, the reaction mixture was poured onto 500 cm3 of water and then extracted with 2 times 200 cm3 of diethyl ether. The combined extracts were dried over magnesium sulfate, filtered, and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μm, diameter 2 cm; 32 g), elution was carried out with ethyl acetate, and 15-cm3 fractions were collected. Fractions 12 to 19 were combined and then evaporated (5 kPa) at a temperature in the region of 40° C. 0.34 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[3-phenylpropyl]piperidine-3-acetonitrile was obtained in the form of an oil with a yellow color.
Reaction SMILES: [OH:1][NH:2][CH:3]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[C:27](OC(=O)C)(=[O:29])C>C1COCC1.C(O)=O>[CH:27]([N:2]([CH:3]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:6])=[O:7])[OH:1])=[O:29]
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(CC(NO)c1ccccc1)N1CCN(c2ccc(F)cc2)CC1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CN(O)C(CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 1-[2-(hydroxyamino)-2-phenylethanesulfonyl]-4-(4-fluorophenyl)piperazine (338 mg, 0.89 mmol) in THF (5 ml) and formic acid (2 ml) was added a preformed mixture of formic acid (2 ml) and acetic anhydride (0.5 ml). The mixture was stirred at room temperature for one hour. The mixture was evaporated in vacuo and toluene (2×5 ml) was added and evaporated in vacuo. The residue was taken in CH2Cl2-methanol (6 ml, 9:1) and silica (1 g) was added. The mixture was stirred for 18 hours. The silica was filtered off and rinsed with CH2Cl2-methanol (9:1). The residue was purified on silica gel (eluant:CH2Cl2—MeOH 4%) to give the title compound as a light orange solid (220 mg, 61%).
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[CH3:13][C:12]1[C:11]2[C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:15][CH:16]=[CH:17][C:10]=2[O:9][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(N3CCOCC3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)O)oc2cccc(N3CCOCC3)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.8 %

Procedure:
To 140 mg 3-methyl-4-morpholin-4-yl-benzofuran-2-carboxylic acid tert-butyl ester was added 4 mL of TFA/dichloromethane (1:1). The solution was stirred at room temperature for 5 h. The solvents were removed under vacuum and the residue was triturated with ether. Filtration gave 107 mg of 3-methyl-4-morpholin-4-yl-benzofuran-2-carboxylic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([Cl:21])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C2(C(=O)O)CCCCC2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C2(C(=O)Cl)CCCCC2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
To a solution of 1-(4-methoxyphenyl)-cyclohexanecarboxylic acid (E3) (0.075 g, 0.32 mmol) in dry dichloromethane (2 ml) under argon atmosphere at ice bath temperature oxalyl chloride (0.327 g, 2.57 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at room temperature for 15 minutes and at 40° C. for one hour, then concentrated under reduced pressure to give crude title product (0.082 g, ca. 100%). The crude product was immediately utilized in the next step of the synthesis without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].F.C(F)([F:18])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([F:18])=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(F)F
Agent: F
Product: O=C(F)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 24 °C
Reaction time: 96 h

Procedure:
4-Chloro-3-(trifluoromethyl)phenyl carbamic fluoride was prepared in situ by the reaction of 221 parts of 4-chloro-3-(trifluoromethyl)isocyanatobenzene and 450 parts of hydrogen fluoride added over a period of 15-20 minutes at about 4° C. The reaction mixture was then sealed in a polytetrafluoroethylene reactor, heated to about 24° C. and maintained thereat, with agitation, for about 96 hours. The reactor was then opened to atmospheric pressure and most of the hydrogen fluoride and carbonyl fluoride gases removed. Analysis of the remaining organic product by gas chromatographic techniques, using n-heptadecane as an internal standard indicated a yield of 77 parts of 4-chloro-3-(trifluoromethyl)benzenamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[N:11]=[C:10]([C:21]([O:23]CC)=[O:22])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[N:11]=[C:10]([C:21]([OH:23])=[O:22])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(F)c2)n(-c2cccc(OC)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-n2nc(C(=O)O)cc2-c2cccc(F)c2)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
34.0 g (99.9 mmol) of the compound of Example 30A are provided in 150 ml of 1,4-dioxane, 150 ml (300 mmol) of a 2N solution of lithium hydroxide in water are added, and the mixture is stirred at 70° C. for 1 h. The mixture is concentrated, a conc. aqueous hydrogen chloride solution is subsequently added to the residue until the pH is acidic, the mixture is extracted with dichloromethane, and the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is recrystallized from diethyl ether. 26.1 g (84% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:14]([N:17]([CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])[C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH2:31][CH3:32])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:16])=[O:15])[CH:5]=[C:6]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:14]([N:17]([CH2:33][C:34]([OH:36])=[O:35])[C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH2:31][CH3:32])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:15])=[O:16])[CH:5]=[C:6]([C:8]#[C:9][Si:10]([CH3:13])([CH3:11])[CH3:12])[CH:7]=1
Reactant: CCn1c2ccccc2c2cc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3cc(Cl)cc(C#C[Si](C)(C)C)c3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c2ccccc2c2cc(N(CC(=O)O)S(=O)(=O)c3cc(Cl)cc(C#C[Si](C)(C)C)c3)ccc21

Procedure:
180 mg tert-butyl [(3-chloro-5-trimethylsilylethynyl-phenylsulphonyl)-(9-ethyl-9H-carbazol-3-yl)-amino]-acetate are dissolved in 5 ml dichloromethane. 1 ml of trifluoroacetic acid is added with stirring. The mixture is stirred overnight at ambient temperature and then the solvents are eliminated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 100:0 to 95:5).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:8])[C:6]=1[CH3:7].[C:9]([Cu])#[N:10].CCOCC>CN(C=O)C>[Br:8][C:5]1[C:6]([CH3:7])=[C:2]([C:9]#[N:10])[S:3][CH:4]=1
Reactant: N#C[Cu]
Reactant: Cc1c(Br)csc1Br
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1c(Br)csc1C#N

Procedure:
A mixture of 2,4-dibromo-3-methylthiophene (20.0 g, 78.1 mmol) and CuCN (6.30 g, 70.3 mmol) in 150 mL of DMF was stirred at reflux for 4 hours before cooling down. The reaction mixture was poured into 1 L of ether with stirring and the precipitate was removed by filtration. The filtrate was washed with water (100 mL×3), brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography (petrol ether:EtOAc=50:1) to afford 4-bromo-3-methylthiophene-2-carbonitrile.
Reaction SMILES: C([N:8]1[C@H:13]([CH3:14])[CH2:12][CH:11]([N:15]([CH2:37][CH3:38])[C:16]2[C:17]([CH3:36])=[C:18]([CH:32]=[C:33]([F:35])[CH:34]=2)[C:19]([NH:21][CH2:22][C:23]2[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=2[CH3:29])=[O:20])[CH2:10][C@H:9]1[CH3:39])C1C=CC=CC=1>CO.[Pd]>[CH3:29][C:28]1[CH:27]=[C:26]([CH3:30])[NH:25][C:24](=[O:31])[C:23]=1[CH2:22][NH:21][C:19](=[O:20])[C:18]1[CH:32]=[C:33]([F:35])[CH:34]=[C:16]([N:15]([CH:11]2[CH2:10][C@@H:9]([CH3:39])[NH:8][C@H:13]([CH3:14])[CH2:12]2)[CH2:37][CH3:38])[C:17]=1[CH3:36]
Reactant: CCN(c1cc(F)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1C[C@@H](C)N(Cc2ccccc2)[C@H](C)C1
Agent: [Pd]
Solvent: CO
Product: CCN(c1cc(F)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1C[C@@H](C)N[C@H](C)C1
Temperature: 23 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a stirred solution of 3-{[(2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl](ethyl)amino}-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-fluoro-2-methylbenzamide (378 mg, 0.709 mmol) in MeOH (7 mL) was added Pd/C (150 mg). The reaction mixture was stirred at 23° C. for 1 hour under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (1. NAM-300H silica gel produced by Nagara Science Co., Ltd., ethylacetate/MeOH=4/1 to ethylacetate/MeOH/triethylamine=1/1/0.01, 2. NH—SiO2, heptane/ethylacetate=30/1 to 8/1) to give title compound as a white solid (235 mg, 75% yield). 1HNMR (400 MHz, CDCl3) δppm; 7.08 (t, J=6.2 Hz, 1H), 6.82 (dd, J=10.7, 2.5 Hz, 1H), 6.75 (dd, J=8.2, 2.7 Hz, 1H), 5.93 (s, 1H), 4.51 (d, J=6.2 Hz, 2H), 3.40-3.48 (m, 1H), 2.95-3.09 (m, 3H), 2.83-2.92 (m, 1H), 2.39 (s, 3H), 2.22 (s×2, 6H), 1.63-1.78 (m, 4H), 1.13 (d, J=7.0 Hz, 3H), 1.02 (d, J=6.2 Hz, 3H), 0.84 (t, J=7.0 Hz, 3H); MS (ES) [M+H] 443.1, [M+Na] 465.2; HPLC; 99.3% purity.
Reaction SMILES: C(OC(=O)[C:5]([CH2:24][CH2:25][CH2:26][CH3:27])([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=2)[N:14]=[CH:13][C:12]=1[C:22]#[N:23])C(OCC)=O)C.[Cl-].[Li+].O>CS(C)=O>[I:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:22]#[N:23])=[C:11]2[CH2:5][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCC(C(=O)OCC)(C(=O)OCC)c1c(C#N)cnc2ccc(I)cc12
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 71b was used, starting from 2-butyl-2-(3-cyano-6-iodo-quinolin-4-yl)-malonic acid diethyl ester (example 72a), lithium chloride, water, and dimethylsulfoxide to give 6-iodo-4-pentyl-quinoline-3-carbonitrile. LC-MS m/e 351 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.O>CN(C=O)C>[Si:18]([O:1][CH2:2][C:3]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][CH2:11][CH2:12]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: OCc1cc(Br)ccc1OCCN1CCCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 76 %

Procedure:
To a solution of (500 mg, 1.67 mmol) 1-[2-(2-hydroxymethyl-4-bromophenoxy)ethyl]pyrrolidine (Part A) in 5.5 mL of anhydrous DMF was added 377 mg of t-butyldimethylsilyl chloride followed by addition of 113 mg of imidazole. The reaction mixture was stirred at room temperature for 30 h. To the reaction was added 6 mL of water. The mixture was extracted with EtOAc (3×60 mL). The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was azeotroped with xylenes to remove any DMF present. Purification by flash chromatography (silica gel, 3% to 4% [10% conc NH4OH in MeOH]/CH2Cl2) afforded 528 mg (1.27 mmol, 77%) of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH:9](=O)[CH2:10][CH3:11]>>[CH2:10]([C:11]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[CH3:9]
Reactant: Nc1ccccc1S
Reactant: CCC=O
Product: CCc1nc2ccccc2s1

Procedure:
The procedure of Example 1 was repeated, except that the reactants consisted of 37.5 g. of 2-aminothiophenol and 17.5 g. of propionaldehyde. The residue which remained after the removal of solvent was distilled in vacuo, chromatographed on a silica gel column with toluene as eluant, and redistilled at 94°-104°/0.3 mm. to give 2-ethylbenzothiazoline. The following elemental micro-analysis was obtained:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([OH:26])=[N:18][CH:17]=1>>[OH:14][C@H:3]1[C@H:4]([O:26][C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]=[CH:17][N:18]=2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11][C:2]1([CH3:15])[CH3:1]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Reactant: Oc1ncnc2ccccc12
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Oc2ncnc3ccccc23)[C@@H]1O

Procedure:
Following the procedure in Example 1, using (S,S)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and quinazolin-4-ol as starting material, the title compound was prepared as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=1)=[O:4].C(N(CC)C(C)C)(C)C.Cl[C:27]1[N:32]=[C:31]([N:33]2[CH:38]=[C:37]([CH:39]3[C:45]4[CH:46]=[CH:47][C:48]([CH3:50])=[CH:49][C:44]=4[CH:43]=[CH:42][C:41]4[CH:51]=[C:52]([CH3:55])[CH:53]=[CH:54][C:40]3=4)[C:36](=[O:56])[NH:35][C:34]2=[O:57])[CH:30]=[CH:29][N:28]=1>CN1CCCC1=O>[CH3:50][C:48]1[CH:47]=[CH:46][C:45]2[CH:39]([C:37]3[C:36](=[O:56])[NH:35][C:34](=[O:57])[N:33]([C:31]4[CH:30]=[CH:29][N:28]=[C:27]([NH:1][CH2:2][C:3]([NH:5][C:6]5[S:7][CH:8]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=5)=[O:4])[N:32]=4)[CH:38]=3)[C:40]3[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][C:41]=3[CH:42]=[CH:43][C:44]=2[CH:49]=1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O
Reactant: CCOC(=O)Cc1csc(NC(=O)CN)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cc1csc(NC(=O)CNc2nccc(-n3cc(C4c5ccc(C)cc5C=Cc5cc(C)ccc54)c(=O)[nH]c3=O)n2)n1

Procedure:
A mixture of the product from step (i) (0.194 g), N,N-diisopropylethylamine (0.35 ml) and the product from example 8 step (ii) (0.25 g) in 1-methyl-2-pyrrolidinone (5 ml) was heated at 90° C. for 10 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. Purification was by chromatography eluting with 70% ethyl acetate in isohexane. Yield 0.175 g.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][C:18](OCC)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][CH2:18][OH:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=C[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: FB(F)F
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Reaction time: 3 h
Yield: 52.6 %

Procedure:
To a stirred solution of (R)-ethyl 3-(N-benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate (574 g) in tetrahydrofuran (5.7 L) at about -78° C. was added boron trifluoride etherate (295.4 g) and then diisobutylaluminum hydride (1.5M in toluene, 3.91 L, 3.1 eq) added (over two hours) maintaining the temperature below -62° C. The resulting solution was stirred (between -78° and -62° C.) for three hours and then quenched into aqueous citric acid solution (2 kg citric acid in 5 L water plus 4 L ice) over about 40 minutes. The phases were separated and the aqueous phase extracted with ethyl acetate (2×2.1 L). The combined organic solution was dried (over magnesium sulphate) and evaporated, then the residual oil purified by chromatography through silica gel, eluting with mixed ethyl acetate/hexane (9:1 to 4:1) to give the-title compound as an oil (260 g), as produced in Example 12A (as an alternative, the residual oil can be purified by chromatography through silica gel eluting with ethyl acetate:hexane (1:1)).
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[NH:21]([CH3:45])[C@H:22]([C:26]([NH:28][C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24].O>C1COCC1>[NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([N:21]([CH3:45])[C@H:22]([C:26]([NH:28][C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:39])([CH3:41])[CH3:40])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1
Reactant: CN[C@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of Boc-Phe(4-F)-OH (890 mg, 3.14 mmol), N-Me-Val-Tyr(3-tBu)-NH2 (1 g, 2.86 mmol) and CMPI (804 mg, 3.15 mmol) in THF (20 ml), TEA (1.2 ml, 7.16 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: acetone:n-hexane=1:2), giving Boc-Phe(4-F)-N-Me-Val-Tyr(3-tBu)-NH2 (1.5 g, 85%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([O:16][CH3:17])[N:13]([CH3:18])[N:12]=2)=[CH:7][C:6]=1[CH3:19])([CH3:3])[CH3:2].[Cl:20]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>O>[Cl:20][C:15]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH3:19])[CH:7]=2)=[N:12][N:13]([CH3:18])[C:14]=1[O:16][CH3:17]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(-c2ccc(OC(C)C)c(C)c2)nn1C
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1c(Cl)c(-c2ccc(OC(C)C)c(C)c2)nn1C
Reaction time: 14 h
Yield: 85.3 %

Procedure:
At room temperature, a mixture of 3-(4-isopropoxy-3-methyl-phenyl)-5-methoxy-1-methyl-1H-pyrazole (described in Reference Preparation example 110) 5.8 g, N-chlorosuccinimide 3.3 g and chloroform 70 ml was stirred for 14 hours. Thereto was added water 50 ml and the resulting mixture was extracted with chloroform. The organic layer was washed with water, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 4-Chloro-3-(4-isopropoxy-3-methyl-phenyl)-5-methoxy-1-methyl-1H-pyrazole 5.6 g.
Reaction SMILES: O.C([O:4]CC)C.[C:7]([O:12][CH2:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])Cl)(=[O:11])[C:8]([CH3:10])=[CH2:9]>C1COCC1>[C:7]([O:12][CH2:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[OH:4])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: CCOCC
Reactant: C=C(C)C(=O)OCCC[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C(=O)OCCC[Si](C)(C)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Deionized water (100 mL) and diethyl ether (200 mL) were added to a single-neck 500 mL round-bottom flask fitted with a magnetic stirrer. The flask was cooled in an ice bath to 0° C. The flask was fitted with a dropping funnel and a mixture of (10 g, 0.045 mol) of 3-methacryloxypropyl dimethylchlorosilane and 50 mL of anhydrous THF was added to the flask. The reaction was stirred for one hour at 0° C. The organic layer was separated and dried over anhydrous sodium sulfate and filtered. The solvent was evaporated on a rotovap to give 3-methacryloxypropyl dimethylhydroxysilane in 9.0 g quantity, 99% yield as a clear, colorless oil.