Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[O:27][C:28]([C:31]56OCC(C)(C[O:36]5)[CH2:33][O:32]6)=[CH:29][CH:30]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH3:33][O:32][C:31]([C:28]1[O:27][C:26]([C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][N:17]=[C:16]3[NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)=[CH:30][CH:29]=1)=[O:36]
Reactant: CC12COC(c3ccc(-c4ccc5ncnc(Nc6ccc(OCc7ccccc7)cc6)c5c4)o3)(OC1)OC2
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4-Benzyloxy-phenyl)-(6-(5-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)-furan-2-yl)-quinazolin-4-yl)-amine (0.680 g, 1.30 mmol) was dissolved in THF (10 ml) and 2N aqueous HCl (10 ml) was added. The mixture was stirred at room temperature for 2 hours. The THF was removed in vacuo and the residue diluted with water to preciptate the intermediate (partial hydrolysis) 5-(4-(4-benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carboxylic acid (3-methyloxetan-3-yl)-methyl ester which was collected by filtration and washed with water and acetone; δH [2H6]DMSO 12.10 (1H, s), 9.50 (1H, s), 8.87 (1H, s), 8.43 (1H, s), 8.00 (1H, s), 7.66 (2H, d), 7.58 (1H, d), 7.30-7.54 (6H, m), 7.13 (2H, d), 5.16 (2H, s), 4.14 (2H, s), 3.28-3.41 (4H, m), 0.88 (3H, s). This solid was suspended in a mixture of MeOH (15 ml) and NaOH (2N, 15 ml), and the mixture was stirred at room temperature for 2 hours. The reaction was diluted with water to give the title product as a yellow solid, which was collected by filtration (0.375 g, 0.831 mmol, 64%); δH [2H6]DMSO 10.06 (1H, s), 8.91 (1H, s), 8.48 (1H, s), 8.21 (1H, d), 7.80 (1H, d), 7.63 (2H, d), 7.25-7.52 (7H, m), 7.05 (2H, d), 5.10 (2H, s), 3.85 (3H, s); m/z (M+1+) 452.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[CH2:27]([NH2:29])[CH3:28]>>[CH2:27]([NH:29][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])[CH3:28]
Reactant: CCOC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nn1
Reactant: CCN
Product: CCNC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nn1
Yield: 61 %

Procedure:
As described for example 50, 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) was converted, using ethylamine instead of methylamine, to the title compound (87 mg, 61%) which was obtained as a white solid. MS: m/e=357.3 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH:11]1([C@H:14]([OH:16])[CH3:15])[CH2:13][CH2:12]1>C(Cl)Cl>[CH:11]1([C@H:14]([O:16][C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[CH3:15])[CH2:13][CH2:12]1
Reactant: O=C=Nc1ccc(I)cc1
Reactant: C[C@@H](O)C1CC1
Solvent: ClCCl
Product: C[C@@H](OC(=O)Nc1ccc(I)cc1)C1CC1
Yield: 90.6 %

Procedure:
To a suspension of 4-iodophenylisocyanate (0.84 g, 3.5 mmol) in CH2Cl2 (6 mL) was added (R)-1-cyclopropylethanol (0.67 mL, 6.9 mmol). The solution was then directly subjected to silica gel chromatography (CH2Cl2) to provide (R)-(4-iodo-phenyl)carbamic acid 1-cyclopropyl-ethyl ester (1.05 g, 93%).
Reaction SMILES: CC(=CC)C.P([O-])(O)(O)=O.[Na+].[CH3:12][C:13]1[N:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][C@@:22]2([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[C:29]([F:37])[CH:28]=3)[CH2:24][C@H:23]2[CH:25]=[O:26])=[CH:15][N:14]=1.Cl([O-])=[O:39].[Na+]>O.CC(C)=O.O>[CH3:12][C:13]1[N:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][C@@:22]2([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[C:29]([F:37])[CH:28]=3)[CH2:24][C@H:23]2[C:25]([OH:39])=[O:26])=[CH:15][N:14]=1
Reactant: [O-][Cl+][O-]
Reactant: COCOc1ccc([C@]2(COc3cnc(C)nc3C)C[C@H]2C=O)cc1F
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COCOc1ccc([C@]2(COc3cnc(C)nc3C)C[C@H]2C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.1 %

Procedure:
2-methyl-2-butene (11.5 ml) and sodium dihydrogen phosphate (3.89 g) were added to an acetone-water (100 ml-25 ml) solution of the compound 321-7 (7.8 g). The reaction solution was cooled on ice. Sodium chlorite (3.91 g) was added to the reaction solution, and the obtained mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1 to 0:1), so as to obtain the title compound (4.57 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:5][N:6]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:5][NH2:6]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)cc(Br)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cc(Cl)cc(Br)c1
Temperature: 25 °C

Procedure:
Step G4. A mixture of 2-(3-Bromo-5-chlorobenzyl)isoindoline-1,3-dione (5.1 g, 14.6 mmol) and hydrazine monohydrate (0.8 g, 16 mmol) in ethanol (150 mL) was refluxed for 4 hours. Upon cooling to room temperature, a white solid precipitated. The solid was filtered and washed with ethanol, then dried in vacuum. 1H NMR (DMSO-d6) showed that the white solid is a mixture of 3-bromo-5-chlorobenzylamine and 2,3-dihydrophthalazine-1,4-dione. This material was used in subsequent steps without further purification.
Reaction SMILES: Cl[Si](C)(C)C.C([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O)(=O)C1C=CC=CC=1>>[N:23]1[C:15]([NH2:14])=[C:16]2[C:20]([N:19]=[CH:18][NH:17]2)=[N:21][CH:22]=1
Reactant: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O)c1ccccc1
Agent: C[Si](C)(C)Cl
Product: Nc1ncnc2nc[nH]c12

Procedure:
N6 -Benzoyl-9-(2'-fluoro-b-D-ribofuranosyl)adenine was prepared from 9-b-D-arabinofuranosyladenine in a five-step synthesis using a modification of a procedure reported by M. Ikehara at al., Nucleosides and Nucleotides 2:373-385 (1983). Thus, the N6 -benzoyl derivative was obtained in good yield utilizing the method of transient protection with chlorotrimethylsilane. R. A. Jones, J. Am. Chem. Soc. 104:1316 (1982). Selective protection of the 3' and 5'-hydroxyl groups of N6 -Benzoyl-9-β-D-arabinofuranosyladenine with tetrahydro-pyranyl (THP) was accomplished by modification of a literature procedure G. Butke, et al., in Nucleic Acid Chemistry, Part 3:149-152, Townsend, L. B. and Tipson, R. S. eds., (J. Wiley and Sons, New York 1986) to yield N6 -Benzoyl-9-[3', 5'-di-O-tetrahydropyran-2-yl)-β-D-arabino furanosyl] adenine in good yield. Treatment of N6 -Benzoyl-9-[3', 5'-di-O-tetrahydro-pyran-2-yl)-β-D-arabinofuranosyl] adenine with trifluoromethanesulfonic anhydride in dichloromethane gave the 2'-tri-flate derivative N6 -Benzoyl-9-[2'-O-trifluoromethylsulfonyl-3', 5'-di-O-tetrahydropyran-2-yl)-β-D-arabino furanosyl] adenine which was not isolated due to its liability. Displacement of the 2'-triflate group was effected by reaction with tetra-butylammonium fluoride in tetrahydrofuran to obtain a moderate yield of the 2'-fluoro derivative N6 -Benzoyl-9-[2'- fluoro-3', 5'-di-O-tetrahydropyran-2-yl)-β-D-arabino furanosyl]-adenine. Deprotection of the THP groups of N6 -Benzoyl-9-[2'-fluoro-3', 5'-di-O-tetrahydropyran-2-yl)-β-D-arabino-furanosyl] adenine was accomplished by treatment with Dowex-50W in methanol to yield N6 -benzoyl-9-(2'-deoxy-2'-fluoro-β-D-ribofuranosyl)adenine in moderate yield. The 1H-NMR spectrum of 6 was in agreement with the literature values. M. Ikehara and H. Miki, Chem. Pharm. Bull. 26: 2449-2453 (1978). Standard methodologies were employed to obtain the 5'-dimeth-oxytrityl-3'-phosphoramidite intermediates N6 -Benzoyl-9-[2'-fluoro-5'-O-(4,4'-dimethoxytrityl)-β-D-ribofuranosyl] adenine and N6 -Benzoyl-[2'-deoxy-2'-fluoro-5'-O-(4,4'-dimethoxytrityl)] adenosine-3'-O-(N,N-diisopropyl-β-cyanoethylphosphoramidite. K. K. Ogilvie, Can J. Chem. 67:831-839 (1989).
Reaction SMILES: [NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[C:4]([CH3:20])[CH:3]=1.[C:21]1(=O)[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>C1(C)C=CC=CC=1>[O:25]=[C:24]1[C:23]2[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21](=[O:26])[N:1]1[C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:15])([CH3:16])[C:11]([O:13][CH3:14])=[O:12])=[C:4]([CH3:20])[CH:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COC(=O)C(C)(C)CCCOc1cc(C)c(N)cc1C
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(N2C(=O)c3ccccc3C2=O)cc1C
Yield: 68.4 %

Procedure:
A solution of 2.8 g (10 mmol) of 5-(4-amino-2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, methyl ester as the free base (Example 2) and 1.5 g (10 mmol) of phthalic anhydride in 100 mL of toluene is stirred at reflux beneath a phase separating head for 2 hours. The solvent is removed and on standing a red brown oil crystallizes. Recrystallization from isoctaneisopropyl ether with the addition of charcoal affords 2.8 g of the title compound as pale pink crystals; mp 109°-111° C.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=O)[CH2:3]2.[CH3:11][C:12]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[CH3:11][C:12]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:23]=[CH:22][C:20]([NH:21][CH:4]3[CH:5]4[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]4)[CH2:3]3)=[CH:19][CH:18]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(Oc2ccc(N)cc2)cc1
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Product: Cc1ccc(Oc2ccc(NC3CN4CCC3CC4)cc2)cc1

Procedure:
3-Quinuclidinone hydrochloride (Aldrich, 1.61 g, 10 mmol) was treated with 4-(4-methylphenoxy)aniline (0.99 g, 5.0 mmol) according to the procedure of Example 30A. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.10) as an oil (1.48 g, yield, 95%). 1H NMR (MeOH-d4, 300 MHz) δ 1.55–1.70 (m, 1H), 1.78–1.95 (m, 2H), 2.00–2.15 (m, 2H), 2.28 (s, 3H), 2.71 (ddd, J=12.9, 5.1, 2.2 Hz, 1H), 2.95–3.10 (m, 4H), 3.46 (ddd, J=12.9, 9.5, 2.4 Hz, 1H), 3.60–3.70 (m, 1H), 6.64 (dt, J=9.0, 2.7 Hz, 2H), 6.72–6.84 (m, 4H), 7.06 (dt, J=9.1, 2.8 Hz, 2H) ppm. MS (DCl/NH3) m/z 309 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[S:22][CH:21]=[CH:20][C:18]=2[N:19]=1>C1COCC1.O>[Cl:13][C:14]1[N:15]=[C:16]([O:12][C:5]2[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[CH3:3])[C:17]2[S:22][CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: Clc1nc(Cl)c2sccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(Oc2nc(Cl)nc3ccsc23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
A stirred suspension of NaH (7.8 mg, 0.19 mmol) in dry THF (1 mL) was added 2,4,6-trimethyl phenol (26.4 mg, 0.19 mmol) and stirred at room temperature for 30 min under Argon. The reaction mixture was added to a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (39.6 mg, 0.19 mmol) in dry THF (1 mL) at 0° C. and allow it to slowly warmed up to room temperature. After stirring the reaction for 4 h, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (9:1) to give the product as a white solid (32.4 mg, 56%):
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29].C(OCC)C>C(Cl)Cl>[ClH:29].[F:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[CH:14]=[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(F)cc3)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Fc1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1

Procedure:
4-[3-(4-Fluoro-phenoxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester (1.05 g, 2.74 mmol) (Step 2) was dissolved in CH2Cl2 (20 mL) and treated with HCl in diethyl ether (8.2 mL, 16.4 mmol). After 16 hours the solution was concentrated and the residue suspended in diethyl ether. The resulting solid was filtered to provide the title compound as the hydrochloride salt (774 mg).
Reaction SMILES: [I:1]I.[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH3:4]>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:7]1[CH:6]=[C:5]([CH2:3][CH3:4])[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: CCc1ccc(OC)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CCc1ccc(OC)c(I)c1
Temperature: 25 °C

Procedure:
A mixture of silver sulfate (1.15 g, 3.68 mmol) and iodine (0.93 g, 3.68 mmol) were stirred in methanol at room temperature. A solution of p-ethylanisole (0.50 g, 3.68 mmol) in methanol was added dropwise to the stirring mixture. The mixture was stirred at room temperature until completion of the reaction. It was filtered and the filtrate was concentrated. The residue was dissolved in methylene chloride, washed with 1 N sodium hydroxide, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was obtained without further purification. 1H NMR (CDCl3, 500 MHz) δ 7.64 (d, J=2.0 Hz, 1H), 7.15 (dd, J=8.5, 2.0 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 3.88 (s, 3H), 2.58 (q, J=15.5, 8.0 Hz, 2H), 1.23 (t, J=7.5 Hz, 3H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)(C)[C:13](O)=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Pb](=O)=O>C1(C)C=CC=CC=1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:19][CH:18]=3)=[CH2:13])=[CH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C(=O)O)(c1ccc(N2CCCC2)cc1)c1ccc(N2CCCC2)cc1
Agent: O=[Pb]=O
Solvent: Cc1ccccc1
Product: C=C(c1ccc(N2CCCC2)cc1)c1ccc(N2CCCC2)cc1
Reaction time: 1 h
Yield: 75.5 %

Procedure:
Into 500 ml of toluene was dissolved 5 g of 2,2-bis(4-pyrrolidinophenyl)propionic acid. Thereto was added 3.7 g of lead dioxide and the mixture was reacted at room temperature with stirring for one hour. The lead compound was removed by filtration and the toluene layer was washed with 100 ml of 5% aqueous solution of sodium hydroxide. Toluene was removed by distillation at a reduced pressure. The residue was recrystallized from ethanol to obtain 3.3 g (yield 76%) of 1,1-bis(4-pyrrolidinophenyl)ethylene, having a melting point of 220°~223° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].CS(O)(=O)=O.COC1C=CC(O)=CC=1>O.O.[Cu](Cl)Cl>[C:9]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:12])[CH:10]=[CH2:11]
Reactant: C=CC(=O)O
Reactant: C=CCCCCCC
Agent: Cl[Cu]Cl
Agent: COc1ccc(O)cc1
Agent: CS(=O)(=O)O
Solvent: O
Product: C=CC(=O)OCCCCCCCC
Temperature: 105 °C

Procedure:
A mixture of 15.0 g (134 mmoles, 3 eq) of 1-octene, 3.21 g (44.6 mmoles, 1 eq) of acrylic acid, 0.257 g (2.67 mmoles, 0.06 eq) of methanesulfonic acid, 0.0277 g of MEHQ and 0.0034 g of copper(II) chloride dihydrate was heated at 105° C. for 22 hours to give 2.5% conversion to octyl acrylate based on acrylic acid consumed.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.NC1C(C)=NN(C[CH2:31][OH:32])C=1>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH2:20][CH2:31][OH:32])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: Cc1nn(CCO)cc1N
Product: Cc1nn(CCO)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21

Procedure:
Alternatively, the title compound was synthesized in a similar manner as described for intermediate A starting from 2-(4-amino-3-methyl-pyrazol-1-yl)-ethanol (Stage 103.1.2).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]1([C:14]2[C:15]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH2:13][CH2:12]1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[C:14]([CH:11]4[CH2:13][CH2:12]4)=[CH:19][C:18]([CH3:20])=[CH:17][N:16]=3)[CH2:22][CH2:23]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C2CC2)c1
Yield: 46.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 27 and using 6-bromonicotinic acid (185 mg) and 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine (210 mg), the title compound (170 mg) was obtained.
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C[O-].[Na+].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO>[CH2:10]([S:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: Sc1nc[nH]n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CSc2nc[nH]n2)cc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A solution of 30 g (0.29 m) 3-mercapto-1,2,4-triazole in 300 ml of dry methanol containing 16.0 g (0.29 m) sodium methoxide is stirred under dry conditions, cooled to 5° C. and benzylchloride 41.3 g (0.32 m) is added dropwise. Stir the mixture at room temperature overnight, reflux 2 hours, cool and evaporate to dryness. The residue is stirred in water and the product is extracted with ethyl acetate. Dry the ethyl acetate layer and evaporate to dryness to give white product. Recrystallize from toluene-hexane, white crystals, 41.4 g (73%), m.p. 79°-80° C.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:16][CH2:17][CH:18]2[CH2:20][O:19]2)=[C:9]([CH:15]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:21]1([C:27]2[C:35]3[C:34]([N:36]4[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]4)=[N:33][CH:32]=[N:31][C:30]=3[S:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([O:16][CH2:17][CH:18]([OH:19])[CH2:20][NH:42][CH:39]2[CH2:40][CH2:41][N:36]([C:34]3[C:35]4[C:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:28][S:29][C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:37][CH2:38]2)=[C:9]([CH:15]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Reactant: CCOC(=O)c1cc(OCOC)ccc1OCC1CO1
Product: CCOC(=O)c1cc(O)ccc1OCC(O)CNC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Yield: 48 %

Procedure:
Synthesis followed SP6 (6 h), using 250 μmol ethyl 5-(methoxymethoxy)-2-(oxiran-2-ylmethoxy)benzoate and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give MOM intermediate upon purification by prep. TLC (2 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) with 48% yield. Product was obtained by MOM-removal according to SP8 with 32% yield upon purification by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 2:5:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:41])[CH2:9][CH2:10][N:11]([CH3:40])[C:12](=[O:39])[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=2)[C:16]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:15]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O.CO>[C:1]([O:5][C:6]([N:8]([CH3:41])[CH2:9][CH2:10][N:11]([CH3:40])[C:12](=[O:39])[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=2)[C:16]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:15]1[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3)n(CC(=O)N(C)CCN(C)C(=O)OC(C)(C)C)c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CN(CCN(C)C(=O)OC(C)(C)C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 4 h

Procedure:
The crude methyl 1-{2-[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]-2-oxoethyl}-3-cyclohexyl-2-phenyl-1H-indole-6-carboxylate in dioxane/H2O/MeOH solution (1:1:1; 0.06 M) was treated with an aqueous solution of KOH (5N) (3 eq). The solution was stirred at 60° C. for 4 h. The volume of the solution was reduced in vacuo, and the mixture acidified with HCl (1N) before extracting with EtOAc (2×). The combined organic fractions were washed with brine, before being dried over Na2SO4, filtered and concentrated in vacuo. The crude was then used in the next step without any further purification. (ES+) m/z 548 (M+H)+
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[Cl:14][CH2:15][Si:16]([CH3:19])([CH3:18])Cl.C(OCC)C>O1CCCC1>[Cl:14][CH2:15][Si:16]([CH3:19])([CH3:18])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C[Si](C)(Cl)CCl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Si](C)(CCl)c1ccc(F)cc1
Temperature: -70 °C

Procedure:
250 ml of n-butyl lithium (1.6M in hexane) are added to 39 ml of 4-bromo-fluoro-benzene in 400 ml of tetrahydrofuran within a period of 45 minutes with stirring at −70° C. The mixture is stirred for a further 30 minutes and then 53 ml of chloromethyl-dimethyl-chlorosilane dissolved in 50 ml of tetrahydrofuran are added dropwise. The mixture is stirred at −70° C. for a further 30 minutes and the temperature of the reaction mixture is then allowed to rise to 0° C. The reaction mixture is poured onto 200 ml of ice, and 300 ml of diethyl ether are added; the mixture is washed with water and saturated sodium chloride solution and dried over sodium sulfate; the solvent is evaporated off in vacuo. Distillation of the residue at 97-105° C. (21 mbar) yields the title product.
Reaction SMILES: CC1(C)[C@@H]2CC[C@]1(CS([O:14][C@@:15]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[F:38])([C@H:22]([C:24]1[C:29]([F:30])=[CH:28][N:27]=[CH:26][N:25]=1)[CH3:23])[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)(=O)=O)C(=O)C2.CCO.C([O-])(=O)C.[Na+]>O>[F:38][C:32]1[CH:33]=[C:34]([F:37])[CH:35]=[CH:36][C:31]=1[C@:15]([OH:14])([C@H:22]([C:24]1[C:29]([F:30])=[CH:28][N:27]=[CH:26][N:25]=1)[CH3:23])[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: C[C@@H](c1ncncc1F)[C@@](Cn1cncn1)(OS(=O)(=O)C[C@@]12CC[C@H](CC1=O)C2(C)C)c1ccc(F)cc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@@H](c1ncncc1F)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 32.5 °C
Reaction time: 13.5 h
Yield: 73.6 %

Procedure:
To (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol ((1R,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (2.125 g) was added EtOH (3.8 mL) and water (3.8 mL). The slurry was heated to 32.5° C. which resulted in an almost colourless solution. This solution was then added in small aliquots (1 mL) to a chilled (0° C.) solution of sodium acetate (0.30 g) in water (4.1 mL) over 45 minutes. To the resulting slurry was then added a solution of EtOH (0.45 mL) and water (0.45 mL). The mixture was then allowed to stir at 2° C. for 30 minutes before water (4.5 mL) was gradually added over 20 minutes. The slurry was then stirred at 2° C. for 13.5 hours before the solids were isolated and reslurried at 0-5° C. twice in water (6.4 mL). The isolated solid was then dried at 45° C. for ˜48 hours at reduced pressure to give (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol as a white solid (0.969 g, 76% yield).