Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:32]1[CH:33]=[N:34][C:35](Cl)=[CH:36][CH:37]=1)[C@H:10]1[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[N:11]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(=O)C.[K+]>[Pd].C(O)C>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C@H:12]2[CH2:13][CH2:14][C@H:10]([C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[N:11]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc([N+](=O)[O-])cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(Cl)nc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To 0.020 g (0.024 mmol) of 10% palladium on carbon was added a solution of 0.14 g (0.24 mmol) of tert-butyl (2R,5R)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(6-chloropyridin-3-yl)methyl]-5-(4-nitrobenzyl)pyrrolidine-1-carboxylate from Step A in 4 mL of anhydrous ethanol followed by 0.024 g (0.24 mmol) of potassium acetate. The resulting suspension was agitated under an atmosphere of hydrogen at 50 psi for 8 h. then filtered through a plug of Celite®. The plug was washed with ethanol (10 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 40% ethyl acetate in hexanes to afford the title compound as a colorless solid (0.065 g, 54%). LC-MS: m/z (ES) 498.4 (MH)+.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([C:21]5[CH:22]=[C:23]([NH:28][C:29](=[O:49])[C:30]6[CH:35]=[C:34]([S:36]([F:41])([F:40])([F:39])([F:38])[F:37])[CH:33]=[C:32]([N:42]7[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]7)[CH:31]=6)[CH:24]=[CH:25][C:26]=5[CH3:27])[CH:19]=[CH:18][N:16]4[N:17]=3)[CH:10]=[N:9]2)=CC=1>FC(F)(F)C(O)=O>[CH3:48][N:45]1[CH2:46][CH2:47][N:42]([C:32]2[CH:31]=[C:30]([CH:35]=[C:34]([S:36]([F:41])([F:38])([F:37])([F:39])[F:40])[CH:33]=2)[C:29]([NH:28][C:23]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:21]([N:20]3[C:15]4[N:16]([N:17]=[C:13]([C:11]5[CH:10]=[N:9][NH:8][CH:12]=5)[CH:14]=4)[CH:18]=[CH:19]3)[CH:22]=2)=[O:49])[CH2:43][CH2:44]1
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(NC(=O)c6cc(N7CCN(C)CC7)cc(S(F)(F)(F)(F)F)c6)ccc5C)ccn4n3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cc(N3CCN(C)CC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cn[nH]c3)cc12

Procedure:
At 80° C., 90 mg (0.12 mmol) of the compound of Example 48A were stirred in 0.61 ml of trifluoroacetic acid for 3 h. The reaction was then concentrated and the residue was purified by preparative HPLC (Method 18). The product fractions were concentrated, and the residue was dissolved in ethyl acetate and washed successively with saturated potassium carbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Drying of the residue under high vacuum gave 40 mg (53% of theory) of the title compound.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](/[C:18](/[CH3:25])=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=2)=[CH:8][CH:7]=1)\[CH3:5].[CH2:26]([O:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:27]>>[CH2:26]([O:28][C@H:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:1][CH2:2]/[CH:3]=[C:4](/[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14](/[C:18](/[CH3:25])=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=3)=[CH:8][CH:7]=2)\[CH3:5])=[CH:38][CH:37]=1)[CH3:27]
Reactant: CCOC(=O)/C=C(\C)c1cccc(-c2ccc(/C(C)=C/CO)cc2)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)/C=C(\C)c1cccc(-c2ccc(/C(C)=C/COc3ccc(C[C@H](OCC)C(=O)OCC)cc3)cc2)c1
Yield: 59 %

Procedure:
The title compound (230 mg, 58%) was prepared from (E,E)-ethyl 3-[4′-(3-hydroxy-1-methyl-propenyl)-biphenyl-3-yl]-but-2-enoate (235 mg, 0.70 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (175 mg, 0.73 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1)[NH2:3].Cl[C:15]1[C:20]([Cl:21])=[C:19]([CH2:22][CH3:23])[N:18]=[CH:17][N:16]=1.C(N(CC)CC)C.CCOCC>C1(C)C=CC=CC=1.O>[Cl:21][C:20]1[C:15]([NH:3][CH:2]([C:4]2[CH:9]=[CH:8][C:7]([Si:10]([CH3:12])([CH3:11])[CH3:13])=[CH:6][CH:5]=2)[CH3:1])=[N:16][CH:17]=[N:18][C:19]=1[CH2:22][CH3:23]
Reactant: CC(N)c1ccc([Si](C)(C)C)cc1
Reactant: CCc1ncnc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: CCc1ncnc(NC(C)c2ccc([Si](C)(C)C)cc2)c1Cl
Yield: 0.1 %

Procedure:
The product of Step D (17 g, 86 mole), 4,5-dichloro-6-ethylpyrimidine (15 g, 86 mole) and triethylamine (24 mL, 170 mole) were dissolved in toluene (65 mL). The reaction mixture was heated to reflux overnight and then cooled. Ether and water were added and the mixture was partitioned. The aqueous phase was extracted two times with ether and the combined organic phases were dried (MgSO4) and concentrated. The resultant solid was recrystallized from acetonitrile to give the title compound as a white solid (17 g, 60% yield), mp 79°-80° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=2)[CH2:3]1.[C:16](Cl)(=[O:27])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[C:16](=[O:27])([O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11](=[O:12])[NH2:13])=[CH:9][N:8]=2)[CH2:3]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccc(N2CCC(O)C2)nc1
Solvent: ClCCl
Product: NC(=O)c1ccc(N2CCC(OC(=O)Oc3ccc([N+](=O)[O-])cc3)C2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.5 %

Procedure:
To a solution of 6-(3-hydroxypyrrolidin-1-yl)nicotinamide (0.27 g, 1 mmol) in DCM (5 ml) was added 4-nitrophenyl carbonochloridate (0.20 g, 1 mmol). The resulting solution was stirred under N2 at room temperature for 24 h. The reaction mixture was then filtered and the filter cake was washed with DCM. The combined filtrates were concentrated to afford the title compound (0.11 g, 30%) as a yellow liquid. [LCMS RtA=1.71 min, [M+H]+=373.1].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(CCO)[CH2:9][CH2:10]O>>[NH:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=[CH:9]1
Reactant: OCCNCCO
Reactant: Nc1ccccc1
Product: c1ccc2[nH]ccc2c1
Yield: 24.5 %

Procedure:
Reaction was carried out in the same manner as described in Example 1 except that granular activated carbon was used in place of the Pd-C catalyst, 6.1 g (0.1 mole) of monoethanolamine or 9.3 g (0.1 mole) of diethanolamine was used as the ethanolamine, and the reaction temperature was raised to 400° C. When monoethanolamine was used, 2.7 g of indole was obtained in a 23.5% yield based on the aniline. Similarly, when diethanolamine was used, 2.9 g of indole was obtained in a 24.5% yield based on the aniline.
Reaction SMILES: C(OC1C=CC(C(C2C=CC=CC=2)=O)=CC=1)C=C.[CH3:19][SiH:20]([CH3:25])[O:21][SiH:22]([CH3:24])[CH3:23].C(OC1C=CC(C(C2C=CC=CC=2)=O)=CC=1)C=C.C1COCC1>C1COCC1>[CH3:19][SiH:20]([CH3:25])[O:21][Si:22]([CH3:24])([CH3:23])[O:21][SiH:20]([CH3:25])[CH3:19]
Reactant: C[SiH](C)O[SiH](C)C
Agent: C=CCOc1ccc(C(=O)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[SiH](C)O[Si](C)(C)O[SiH](C)C
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Allyloxybenzophenone 1 (200 g, 840 mmol) was dissolved with warming in THF (150 mL, EM Science) and charged to an addition funnel placed on a 2 L four-necked flask equipped with a mechanical stirrer, reflux condenser and internal temperature probe under a dry air purge. To the reaction vessel was added 1,1,3,3-tetramethyldisiloxane (740 mL, 4.18 mol, Hanse Chemie) and THF (100 mL). The internal pot temperature was raised to 50° C., at which point chlorotris(triphenylphosphine) rhodium (“Wilkinson's catalyst”, 22 mg, 11 ppm based on mass of allyloxybenzophenone 1, Aldrich Chemcial) was added to the pot along with a portion (5 mL) of the 4-allyloxybenzophenone/THF solution. The internal reaction temperature was raised to 60° C., at which point the 4-allyloxybenzophenone solution was added to the reactor pot over the course of 45 min. The internal temperature of the reaction was held between 60-65° C. during the course of the addition, which is exothermic. After the addition was complete, the reaction was stirred at 60° C. for an additional 15 min., at which point no starting material was present by GC analysis. The reaction was allowed to cool to 35° C., and activated carbon (3 lab scoops, Aldrich Chemical) was added. The resulting slurry was stirred for 30 min., then filtered to yield a pale yellow solution. Solvent was removed from the product in vacuo to yield a yellow oil (329 g, 104% due to presence of ˜10 mol % 1,1,3,3,5,5-hexamethyltrisiloxane in the commercial grade 1,1,3,3-tetramethyldisiloxne starting material; i.e. the reaction is essentially quantitative). The product exhibited acceptable 1H, 13C and 29Si NMR, UV-Vis and FT-IR spectral characteristics.
Reaction SMILES: [H-].[Na+].N1C=CN=[CH:4]1.[CH2:8]([NH:15][C:16](=[O:40])[C@@H:17]([CH2:38][OH:39])[NH:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CI>O1CCCC1.O>[CH2:8]([NH:15][C:16](=[O:40])[C@@H:17]([CH2:38][O:39][CH3:4])[NH:18][C:19]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: O=C(NCc1ccccc1)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCc1ccccc1
Temperature: -15 °C
Reaction time: 0.75 h

Procedure:
To a mixture of sodium hydride (6.59 g), imidazole (1.564 g) and tetrahydrofuran (150 ml), a solution of Example 5 product (i.e. N-benzyl-N2-trityl-D-serinamide, 50 g) in tetrahydrofuran (500 ml) was slowly added at −15° C. and the mixture was stirred for 45 minutes at −15° C. Methyl iodide (24.38 g) was slowly added to the mixture for 15 minutes at −15° C. to −5° C. and the formed reaction mixture was stirred at −5° C. for 3 hours. The reaction mixture was cooled to 0° C., water was added to it and then the tetrahydrofuran was recovered completely under vacuum at 40° C. Hexane (250 ml) was added to it and stirred for 15 minutes. The layers were separated and the aqueous layer was neutralized with acetic acid till pH=6.0. Dichloromethane (2×150 ml) was added to the aqueous layer and layers were separated. Oily product was recovered under vacuum at 35° C. to 40° C. from the organic layer. Hexane (100 ml) was added to the oily product and the solution formed was stirred for 15 minutes, filtered and dried to get the titled product of Formula Va.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[NH:11][C:10]2[CH:20]=[CH:21][CH:22]=[N:23][C:9]1=2)=[O:7].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C(O)C>[N:24]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[NH:11][C:10]3[CH:20]=[CH:21][CH:22]=[N:23][C:9]2=3)=[O:7])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCCCl)c2ccccc21
Reactant: C1CCNC1
Solvent: CCO
Product: O=C1Nc2cccnc2N(C(=O)CCCCN2CCCC2)c2ccccc21

Procedure:
4.5 gm of 11-(5-chlorovaleryl)-5,11-dihydro-6H-pyrido [2,3-b][1,4]-benzodiazepin-6-one and 10 ml of pyrrolidine were refluxed in 100 ml of ethanol for 12 hours. The alcohol was then distilled off, the residue was dissolved in chloroform/water, the organic phase was evaporated in vacuo to dryness, and the residue was recrystallized from ethyl acetate.
Reaction SMILES: C(NNC(=O)C1C=CC=CC=1)(=O)C.[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([NH:22][NH2:23])=[O:21])=[CH:18][CH:17]=1.[N:26]([C:29](Cl)=[O:30])([CH3:28])[CH3:27]>>[CH3:27][N:26]([CH3:28])[C:29]([NH:23][NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:25][CH:24]=1)=[O:30]
Reactant: COc1ccc(C(=O)NN)cc1
Reactant: CN(C)C(=O)Cl
Agent: CC(=O)NNC(=O)c1ccccc1
Product: COc1ccc(C(=O)NNC(=O)N(C)C)cc1

Procedure:
Synthesis and isolation were same as for 1-acetyl-2-benzoylhydrazine, using 1.8 g (10.8 mmol) of 4-methoxybenzoylhydrazine, 1.2 g (11.1 mmol) of (CH3)2NCOCl, and 1.1 g of TEA. Yield was 1.5 g (59%). MS (EI, m/e) calcd for C11H15N3O3 237, found 237 (M+, 8.3); mp 218-220° C.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:25]=[C:24](N)[CH:23]=2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:36][S:37]SC>C(Cl)(Cl)Cl>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:25]=[C:24]([S:37][CH3:36])[CH:23]=2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CSSC
Reactant: COc1ccc(-n2nc(N)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-n2nc(SC)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of t-butyl nitrite (1.14 ml) in CHCl3 (3 ml) was added dropwise to a solution of 5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-3-amino-1H-pyrazole (1.5 g) and dimethyldisulfide (1.15 ml) in CHCl3 (10 ml). After all of t-butyl nitrite solution was added, the temperature of reaction mixture began to rise and reached to reflux. After the reflux ceased, the mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=25% to give 5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-3-(methylthio)-1-H-pyrazole (635.2 mg) as an oil.
Reaction SMILES: [CH2:1]([C:3]1([C:28]#[N:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2].C(=O)=O.CO.C(#N)C>>[CH2:1]([C@@:3]1([C:28]#[N:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2]
Reactant: CCC1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Agent: O=C=O
Solvent: CO
Solvent: CC#N
Product: CC[C@@]1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Yield: 23.5 %

Procedure:
3-Ethyl-1-(2-((4-(morpholin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-oxopyrrolidine-3-carbonitrile (200 mg) obtained in Example 2 was resolved by SFC (column: CHIRALCEL OJH, 20 mmID×250 mmL, manufactured by Daicel Chemical Industries, mobile phase: carbon dioxide/methanol/acetonitrile=660/170/170), and the compound having a shorter retention time was recrystallized (hexane/ethyl acetate) to give the title compound (47 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][NH2:6])[CH3:2].Cl.CCN(CC)CC.[CH2:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH3:19]>C(Cl)Cl>[CH2:16]([NH:20][C:21]([NH:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:7])=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN=C=O
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCNC(=O)NCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Glycine ethyl ester·HCl (5.58 g, 40 mmol) was suspended in distilled CH2Cl2 (20 ml). After cooling in an ice bath, distilled Et3N (6.13 ml, 44 mmol) was added. Distilled n-butyl isocyanate (4.95 ml, 44 mmol) was added. The cooling bath was removed and the mixture was left stirring overnight at room temperature. Additional Et3N (3.05 ml) was added and the mixture was stirred 3 more hours. After diluting with more CH2Cl2, the solution was washed with water (50 ml), 1N HCl (50 ml), saturated NaHCO3 solution (50 ml) and water (50 ml). After drying (MgSO4), the solvent was removed in vacuo leaving the title compound (7.641 g, 94%) which slowly crystallized. This was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:28]([F:31])([F:30])[F:29])[CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:14]=[C:15]([C:28]([F:31])([F:30])[F:29])[CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: COc1ccc(Oc2ccc(C(F)(F)F)cc2N)cc1
Product: COc1ccc(Oc2ccc(C(F)(F)F)cc2NC(=O)c2cc(Cl)ccc2O)cc1
Yield: 88.1 %

Procedure:
Using 5-chlorosalicylic acid and 3-amino-4-(4-methoxyphenoxy)-benzotrifluoride as the raw materials, the same operation as the Example 1(1) gave the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][C:8]([C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=2)[CH3:2].[OH-].[Na+].Cl.O>C(O)C>[CH2:1]([C:3]1[N:4]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][C:8]([C:13]([OH:15])=[O:14])=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)c(C)c(CC)n2Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1c(C)c2cc(C(=O)O)ccc2n1Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A 587 mg portion of ethyl 2-ethyl-1-(4-fluorobenzyl)-3-methyl-1H-indole-5-carboxylate was dissolved in 10.5 ml of ethanol, and 3.5 ml of a 1 M sodium hydroxide aqueous solution was added, followed by overnight stirring at 80° C. Under ice-cooling, 1 M hydrochloric acid and water were added thereto, followed by stirring at pH 1 for 1 hour. Then, the resulting solid was collected by filtration to obtain 498 mg of 2-ethyl-1-(4-fluorobenzyl)-3-methyl-1H-indole-5-carboxylic acid as a pale pink solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[N:1]1([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccccc1Br
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1-n1ccc2ccccc21
Reaction time: 3.5 h
Yield: 47 %

Procedure:
A mixture of indole (4.16 g; 35.53 mmol), methyl 2-bromobenzoate (2.64 g; 35.53 mmol), potassium carbonate (5.50 g) and CuO (2.0 g) in 40 mL of DMF was refiuxed uncler an argon atmosphere for 3.5 hrs. The crude material obtained upon extraction into ethyl acetate and removal of the solvent was purified on a silica gel column (10% ethyl acetate/hexane) to obtain 4.20 g (47%) of methyl 2-(1-indolyl)benzoate, 1H NMR (CDCl3): δ 3.45 (s, 3H); 6.43 (d, 1H); 6.99-7.20 (m, 4H); 7.35-7.42 (m, 2H); 7.60 (m, 2H); 7.88 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[S:15][C:16]=1[CH2:17][OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:31][C:32]1[CH:39]=[C:38](F)[CH:37]=[CH:36][C:33]=1[C:34]#[N:35]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[S:15][C:16]=1[CH2:17][O:18][C:38]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([Cl:31])[CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1sc(-c2ccc(C(F)(F)F)nc2)nc1CCCOCc1ccccc1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)nc3)nc2CCCOCc2ccccc2)cc1Cl
Temperature: 25 °C
Yield: 33.4 %

Procedure:
1.44 g [4-(3-Benzyloxy-propyl)-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-methanol were dissolved in 15 ml dimethylformamide. 231 mg sodium hydride (95%) were added and the reaction mixture stirred at room temperature. After thirty minutes 549 mg 2-chloro-4-fluorobenzonitrile were added and the reaction mixture stirred at room temperature for one hour. Then the reaction was quenched by the addition of 20 ml water and extracted three times with portions of 50 ml methyltertbutylether. The combined organic phases were dried over MgSO4. The solvent was removed in vacuo. The resulting residue was purified by reversed phase HPLC to obtain 641 mg 4-[4-(3-Benzyloxy-propyl)-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-ylmethoxy]-2-chloro-benzonitrile as yellow lyophilisate.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH:7]([C:21]#[N:22])[CH2:6]1)[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH:7]([CH2:21][NH2:22])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(c2ccc(OC)c(OC)c2)C(C#N)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCN1CCN(c2ccc(OC)c(OC)c2)C(CN)C1

Procedure:
In a manner similar to preparation 2, react 4-butyl-1-(3,4-dimethoxyphenyl)-2-piperazinecarbonitrile with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[O:9][C:8]([C@@H:10]([NH:13][S@@](C(C)(C)C)=O)[CH2:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[ClH:20].O1CCOCC1>CO>[ClH:20].[CH3:1][S:2]([C:5]1[O:9][C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC[C@H](N[S@](=O)C(C)(C)C)c1ccc(S(C)(=O)=O)o1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@H](N)c1ccc(S(C)(=O)=O)o1
Reaction time: 1 h

Procedure:
To a solution of (R)-2-methyl-propane-2-sulfinic acid [(S)-1-(5-methanesulfonyl-furan-2-yl)-propyl]amide (0.530 g, 1.72 mmol) in methanol (5 mL) was added 4 N HCl in dioxane (2 mL, 8 mmol). After 1 hour, the mixture was concentrated in vacuo to afford (S)-1-(5-methanesulfonyl-furan-2-yl)-propylamine hydrochloride.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].[CH3:11]O>Cl>[CH3:11][N:4]([C:1](=[O:3])[CH3:2])[C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: CO
Agent: Cl
Product: CC(=O)N(C)[C@@H](CS)C(=O)O

Procedure:
A solution of N-acetyl-L-cysteine (3.26 g) (commercially available) in methanol (10 ml) with concentrated hydrochloric acid (four drops) was refluxed for 16 hours under a nitrogen atomosphere.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](=O)[CH2:21]Br)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[O:3][CH:21]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Product: COC(=O)c1ccc(-c2nc(-c3ccc(OC)cc3)co2)cc1
Yield: 18 %

Procedure:
In the same manner as in Example 1, methyl 4-carbamoylbenzoate was reacted with 4-methoxyphenacyl bromide to obtain methyl 4-[4-(4-methoxyphenyl)-2-oxazolyl]benzoate. The product was recrystallized from ethanol. Yield: 18%. Pale yellow prisms. Melting Point: 200 to 202° C.