Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH:5]=[CH2:6])=[O:3].C(N(CC)CC)C.[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[S:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>ClCCl>[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[S:24][CH:25]1[CH2:30][CH2:29][N:28]([C:2]([O:4][CH:5]=[CH2:6])=[O:3])[CH2:27][CH2:26]1
Reactant: C=COC(=O)Cl
Reactant: Brc1ccc2[nH]cc(SC3CCNCC3)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=COC(=O)N1CCC(Sc2c[nH]c3ccc(Br)cc23)CC1
Reaction time: 2 h

Procedure:
Vinyl chloroformate (0.75 ml) is added dropwise to a solution of triethylamine (1.2 ml) and 5-bromo-3-(piperidin-4-ylthio)-1H-indole (2.5 g, prepared in Example 49) in dichloromethane (25 ml) at 0° C. After 2 hours at room temperature, the solution is washed with water. The organic phase is dried over magnesium sulfate and concentrated. Vinyl 4-[(5-bromo-1H-indol-3-yl)thio]piperidine-1-carboxylate (1.8 g) is obtained after chromatography on silica gel (eluent: cyclohexane/AcOEt 70/30).
Reaction SMILES: [C:1]([O:4][CH:5]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:30](Cl)(=[O:32])[CH3:31]>O1CCCC1>[C:1]([O:4][CH:5]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:30](=[O:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)OC(CCCCCCCCO)c1coc([Si](C)(C)C)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCCCCCCCCC(OC(C)=O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-(1-acetoxy-9-hydroxynonyl)-2-trimethylsilylfuran (0.075 g, 0.221 mmol) and pyridine (0.056 g, 0.662 mmol) in tetrahydrofuran (2 ml) under argon at 0° was added dropwise acetyl chloride (0.052 g, 0.662 mmol). The mixture was warmed to room temperature, stirred for one hour, quenched with water and extracted into ethyl ether. The organic portion was washed with 10% hydrochloric acid, saturated sodium bicarbonate, aqueous 5% cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to an oil. Purification by flash chromatography (silica, 5 to 10% ethyl acetate/hexane) gave the desired product.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C:16]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])[N:14]=[CH:15][C:8]=12>>[Cl:3][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C:16]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])[N:14]=[CH:15][C:8]=12
Reactant: N#Cc1cccc(C#N)c1-n1ncc2c(O)ncnc21
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cccc(C#N)c1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
Phosphoryl trichloride (6842 μl, 71.40 mmol) was added to 2-(4-hydroxy-1H-pyrazolo[3,4-d]pyrimidin-1-yl)isophthalonitrile (Intermediate BK2) (1872 mg, 7.14 mmol). The resulting solution was stirred at 100° C. for 4 hours. The reaction mixture was evaporated and ice/water added to the residue. After stirring for 1 hour a precipitate formed that was filtered off and washed with water (3×5 mL) to give a yellow solid. This was dried under high vacuum for 20 hours to give the product (879 mg, 43.9%) which was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[C:14]([N:21]1[CH2:25][CH2:24][CH:23](Br)[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:12]([C:10]1[CH:9]=[CH:8][N:7]=[C:6]([C:4]2[N:3]=[CH:2][N:1]([CH:24]3[CH2:23][CH2:22][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:25]3)[CH:5]=2)[CH:11]=1)#[N:13]
Reactant: CC(C)(C)OC(=O)N1CCC(Br)C1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3cc(C#N)ccn3)c2)C1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 1-boc-3-bromopyrrolidine according to the procedure for the preparation of Example 43, part A (heating to 120°). [M+H] Calc'd for C18H21N5O2, 340. Found, 340.
Reaction SMILES: C(C1C=CC(CC(=O)C(O)=O)=CC=1)C(C)C.[OH-].[Na+:18].CI.Cl.[O:22]=[C:23]([CH:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:31][CH:30]=1)[CH3:28])[C:24]([OH:26])=[O:25]>CO>[O:22]=[C:23]([CH:27]([C:29]1[CH:30]=[CH:31][C:32]([CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:33][CH:34]=1)[CH3:28])[C:24]([O-:26])=[O:25].[Na+:18]
Reactant: CC(C)Cc1ccc(C(C)C(=O)C(=O)O)cc1
Agent: CC(C)Cc1ccc(CC(=O)C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CC(C)Cc1ccc(C(C)C(=O)C(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 76 %

Procedure:
Methanol (25 ml) was added to 2.20 g (10 mmoles) of p-isobutylphenylpyruvic acid to dissolve it completely. With ice cooling, a 3N aqueous solution of sodium hydroxide (7 ml; 21.0 mmoles) was added. Then, 2.0 ml of methyl iodide was added, and the mixture was stirred at room temperature for 13 hours. The reaction mixture was acidified by adding 1N hydrochloric acid and extracted with 90 ml of ether. The ether layer was dried over magnesium sulfate and the ether was evaporated under reduced pressure to give a pale red oil. The NMR spectral analysis of this product led to the determination that this product was nearly pure 2-oxo-3-(p-isobutylphenyl)butanoic acid. A 3N aqueous solution of sodium hydroxide (4.0 ml) was added to this product, and the mixture was concentrated under reduced pressure. Ether was added to the resulting pale yellowish white solid. By filtration, 1.87 g (yield 76 %) of sodium 2-oxo-3-(p-isobutylphenyl)butanoate was isolated.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:25]([CH2:27][CH2:28][NH:29][C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)=[O:31])#[N:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:36]4[CH:37]=[C:32]([CH:33]=[CH:34][CH:35]=4)[C:30]([NH:29][CH2:28][CH2:27][C:25]#[N:26])=[O:31])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: N#CCCNC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(C(=O)NCCC#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 8.2 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.05 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(2-cyanoethyl-carbamoyl)phenylboronic acid (22 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 mins. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N-(2-cyanoethyl)benzamide (1.96 mg, 8%). 1H-NMR (MeOD): 2.52 (m, 1H), 2.64 (m, 1H), 2.83 (t, 2H), 3.35 (s, 3H), 3.68 (t, 2H), 5.86 (d, 1H), 7.18 (d, 1H), 7.43 (m, 3H), 7.55 (m, 3H), 7.57 (d, 1H), 7.71 (d, 1H), 7.79 (m, 2H), 8.05 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]2[C:8]([CH3:20])=[N:9][C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][CH2:23]Cl.[NH2:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28]>>[CH2:27]([CH:26]([N:25]1[C:2]2[N:7]3[C:8]([CH3:20])=[N:9][C:10]([C:11]4[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=4[CH3:19])=[C:6]3[N:5]=[C:4]([CH3:21])[C:3]=2[CH2:22][CH2:23]1)[CH2:29][CH3:30])[CH3:28]
Reactant: Cc1cc(C)c(-c2nc(C)n3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Reactant: CCC(N)CC
Product: CCC(CC)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)nc(C)n3c21
Reaction time: 8 h

Procedure:
A solution of 4-chloro-3-(2-chloroethyl)-8-mesityl-2,6-dimethylimidazo[1,5-a]pyrimidine (139 mg, 0.38 mmol) in 3-aminopentane (10 mL) was heated under reflux for five days. After overnight, the residue was purified by dry pack silica gel column chromatogrpahy (25-40% ethyl acetate/hexane), to give the title compound (69 mg) as pale yellow crystals.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([S:9][CH3:10])[C:5]=2[C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][C:13]=2[CH3:22])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([S:9]([CH3:10])=[O:32])[C:5]=2[C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][C:13]=2[CH3:22])[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1noc(C2CC2)c1C(=O)c1ccc(S(C)(=O)=O)cc1C
Solvent: ClCCl
Product: Cc1cc(S(C)(=O)=O)ccc1C(=O)c1c(S(C)=O)noc1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a solution of 5-cyclopropyl-3-methylthio-4-(2-methyl-4-methylsulfonylbenzoyl)isoxazole (750 mg, 2.127 mmol) in dichloromethane (35 mL) was added 3-chloroperbenzoic acid (650 mg, 57-87%, Aldrich). The resulting mixture was stirred at r.t. for 2 hours, then diluted with dichloromethane, washed with aqueous sodium bicarbonate, brine, dried and evaporated to dryness. The crude product was purified by preparative thin-layer chromatography to give crystalline 5-cyclopropyl-3-methylsulfinyl-4-(2-methyl-4-methylsulfonylbenzoyl)isoxazole (436 mg), rp. 147° C. and 5-cyclopropyl-3-methylsulfonyl-4-(2-methyl-4-methylsulfonylbenzoyl)isoxazole (378 mg), m.p. 142° C.
Reaction SMILES: [CH:1]1([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].O1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])S1(=O)=O.Cl>CN(C)C=O>[CH2:13]([O:12][C:10](=[O:11])[C:4]([CH2:21][CH2:20][NH:19][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH:1]1[CH2:3][CH2:2]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:14]
Reactant: CCOC(=O)C(C(=O)OCC)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCNC(=O)OC(C)(C)C)(C(=O)OCC)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To a solution of diethyl cyclopropylmalonate (7.7 g) obtained in Step A of Example 388 in N,N-dimethylformamide (90 mL) was added sodium hydride (60% in mineral oil, 1.8 g), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (9.4 g) at the same temperature, and the mixture was stirred at 0° C. for 2 hr. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.7 g).
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH2:24]([O:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:35])[C:25]#[CH:26]>>[Cl:34][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:35])[C:28]=1[O:27][CH2:24][C:25]1[N:1]([CH:4]2[CH2:23][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:2]=[N:3][CH:26]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CCOc1c(Cl)cccc1Cl
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1COc1c(Cl)cccc1Cl)CC2

Procedure:
The title compound was prepared using analogous procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 2,6-dichlorophenyl prop-2-yn-1-yl ether. 1H NMR (400 MHz, DMSO-d6): δ 12.14 (s, 1 H), 7.91 (s, 1 H), 7.54 (d, 2 H), 7.49 (d, 1 H), 7.35 (d, 1 H), 7.25 (t, 1 H), 7.11-7.00 (m, 2 H), 5.48-5.32 (m, 3 H), 4.78 (dd, 1 H), 4.37 (t, 1 H), 3.62 (d, 2 H), 3.43-3.34 (m, 1 H), 3.24-3.09 (m, 1 H), 3.09-2.97 (m, 1 H). MS (+ESI) m/z: 471.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:28][CH:29]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:28][CH:29]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (523 mg), 1 N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 3 hours, diluted with 1 N hydrochloric acid (2.5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (456 mg, yield: 93%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 135–136° C.
Reaction SMILES: O1CCOCC1.[Cl:7][C:8]1[N:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[O:22][CH3:23])[N:9]=1.[S-2].[Na+].[Na+]>O>[Cl:7][C:8]1[N:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[O:22][CH3:23])[N:9]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(Cl)n1
Agent: [Na+]
Agent: [S-2]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(N)ccc1-n1cnc(Cl)n1
Temperature: 75 °C
Yield: 72.8 %

Procedure:
Step E (3): Water (8 mL) and dioxane (8 mL) were added to a mixture of 3-chloro-1-(2-methoxy-4-nitrophenyl)-1H-1,2,4-triazole (0.900 g, 3.53 mmol) and sodium sulfide (1.379 g, 17.67 mmol) in a 20 mL vial. The vial was capped and heated at 70-80° C. for 24 hours. The mixture was cooled to rt, poured into water (300 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyaniline (577 mg, 73%) as a brown solid. LC-MS (M+H)+ 225.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[C:31]([OH:36])(=[O:35])[CH:32]([CH3:34])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH:32]([C:31]([OH:36])=[O:35])[CH3:34])=[O:27])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: CC(O)C(=O)O
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(OC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1)C(=O)O

Procedure:
A flask containing 10.0 g. 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoic acid, 3.3 g. lactic acid, 500 mg. toluene sulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated 4A Linde molecular sieves. The solution is refluxed for 24 hours during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon 1-carboxyethyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]-benzoate separates as off-white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][OH:17])[CH3:13]>ClCCl.CO>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:17][CH2:16][CH2:15][N:14]([CH2:18][CH3:19])[CH2:12][CH3:13]
Reactant: CCN(CC)CCO
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1Br

Procedure:
Prepared analogously to Example 4.13.a. starting from 0.66 g (2.00 mmol) of 2-bromo-1-fluoro-4-nitrobenzene and 0.40 mL (3.00 mmol) of 2-diethylaminoethanol. Yield: 0.95 g (100% of theory); C12H17BrN2O3 (M=317.185); calc.: molecular ion peak (M+H)+: 317/319; found: molecular ion peak (M+H)+: 317/319; Rf value: 0.50 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[OH:8][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cccc(C(=O)c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cccc(C(O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 3-benzoylbenzoate (1.0197 g, 4.0 mmol, 1.0 equiv) in ethanol (10 mL) was added of NaBH4 (0.32 g, 2.1 equiv). The reaction mixture was stirred at rt for 1.5 h, quenched with 10% aq Na2CO3, extracted three times with CH2Cl2, and dried over Na2SO4. The crude product was used in the next step without further purification. LC-MS (3 min) tR=1.64 min, m/z 239 (M+—OH). 1H NMR (400 MHz, CDCl3) δ 8.09 (m, 1H), 7.93-7.96 (m, 1H), 7.56-7.59 (m, 1H), 7.26-7.43 (m, 6H), 5.89 (s, 1H), 4.36 (q, J=7.2 Hz, 2H), 2.38 (br s, 1H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][C:14]1[O:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=1.CC(C)([O-])C.[Na+].Cl[C:28]1[N:29]=[N:30][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)=[CH:32][CH:33]=1.C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][C:14]1[O:15][CH:16]=[C:17]([CH2:19][O:20][C:28]2[N:29]=[N:30][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]3[CH:42]=[CH:41][N:40]=[N:39]3)=[CH:32][CH:33]=2)[N:18]=1
Reactant: OCc1coc(C=Cc2ccc(C(F)(F)F)cc2F)n1
Reactant: Clc1ccc(CCCCn2ccnn2)nn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cc(C(F)(F)F)ccc1C=Cc1nc(COc2ccc(CCCCn3ccnn3)nn2)co1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{2-[2-(2-Fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-yl}-methanol (0.114 g, 0.40 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (3 ml) followed by the addition of sodium tert-butoxide (NaOtBu) (0.043 g, 0.43 mmol). After stirring for 15 min at r.t. 3-chloro-6-(4-[1,2,3]triazol-1-yl-butyl)-pyridazine (0.075 g, 0.32 mmol) is added slowly and stirred for further 4 h at 60° C. Ethyl acetate (20 ml) is added; the mixture is washed with saturated ammonium chloride (NH4Cl), dried over MgSO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate/methanol 98:2) 3-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-6-(4-[1,2,3]triazol-1-yl-butyl)-pyridazine is obtained as a colorless solid. Yield 0.115 g (75%).
Reaction SMILES: COC([C@@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C(=S)CC(=O)C)=O.COC([C@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C(=S)CC(=O)C)=O.Cl.Cl.C(NN)C1C=CC=CC=1.[CH3:68][O:69][C:70]([C@H:72]1[CH2:76][C@@H:75]([S:77]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][C:81]=2[C:86]([F:89])([F:88])[F:87])(=[O:79])=[O:78])[CH2:74][N:73]1[C:90]1[N:91]([CH2:96][C:97]2[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=2)[N:92]=[C:93]([CH3:95])[CH:94]=1)=[O:71]>>[CH3:68][O:69][C:70]([C@@H:72]1[CH2:76][C@@H:75]([S:77]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][C:81]=2[C:86]([F:87])([F:88])[F:89])(=[O:78])=[O:79])[CH2:74][N:73]1[C:90]1[N:91]([CH2:96][C:97]2[CH:98]=[CH:99][CH:100]=[CH:101][CH:102]=2)[N:92]=[C:93]([CH3:95])[CH:94]=1)=[O:71]
Reactant: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1Cc1ccccc1
Agent: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Agent: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1Cc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, a mixture of (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) and of (2R,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with benzylhydrazine dihydrochloride (CAS Reg. No. 20570-96-1) to give a mixture of the title compound and (2R,4R)-1-(2-benzyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as orange oil. MS (ESI): m/z=508.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:10](Br)[CH3:11])=[CH:5][CH:4]=1.C([Li])CCC.Cl[P:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:10]([P:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:11])=[CH:5][CH:4]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(=C(C)Br)c2ccc(OC)cc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(=C(C)P(c2ccccc2)c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: -65 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
Into a reactor were introduced 2.00 g (6.00 mmol) of the 1,1-bis(4-methoxyphenyl)-2-bromopropene and 30 mL of THF under a nitrogen atmosphere. The contents were cooled to −65° C., and 4.0 mL (6.0 mmol; 1.5 M hexane solution) of butyllithium was gradually added dropwise thereto. The resultant mixture was stirred for 30 minutes. Thereafter, 0.90 mL (5.0 mmol) of chlorodiphenylphosphine was added, and this mixture was stirred at that temperature for 1 hour and then at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture. The resultant mixture was extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol to obtain 1.45 g (66%) of the target compound as white crystals.