Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:17])[N:8]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:27])[Cl:26])=[O:22]>CCOC(C)=O>[Cl:26][C:25]([Cl:28])([Cl:27])[CH2:24][O:23][C:21](=[O:22])[NH:17][C:7]1[N:8]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a mixture of 5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylamine (for reference procedure see for example WO2003/072569, which is incorporated herein by reference in its entirety; 833 mg, 3.62 mmol) in NaOH (1M in water, 5.4 mL, 4.4 mmol) and EtOAc (5 mL) was added 2,2,2-trichloroethyl chloroformate (548 μL, 3.98 mmol) and the reaction mixture was stirred at RT for 1 h. Additional NaOH (1M in water, 5.4 mL) and 2,2,2-trichloroethyl chloroformate (548 μL) were added and stirring at RT was continued for 1 h. Additional NaOH (1M in water, 5.4 mL) and 2,2,2-trichloroethyl chloroformate (548 μL) were added and stirring at RT was continued for 2 h. Additional NaOH (1M in water, 10.8 mL) and 2,2,2-trichloroethyl chloroformate (1.10 mL) were added and stirring at RT was continued for 24 h. The aqueous layer was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 10-50% EtOAc in cyclohexane, to afford the title compound (550 mg, 37%) as a white foam. LCMS (Method 3): Rt 3.87 min, m/z 405 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].Br[CH2:15][C:16]([CH3:24])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC>[CH3:12][C:4]1[C:3]([CH3:13])=[C:2]([O:1][CH2:15][C:16]([CH3:24])=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][CH:10]=[O:11]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: CC(=Cc1ccccc1)CBr
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=Cc1ccccc1)COc1cc(C)c(NC=O)c(C)c1C
Yield: 41 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and 1-(3-bromo-2-methyl-1-propenyl)benzene, the title compound was synthesized according to Reference Example 17b. Yield: 41%. Melting point: 152-154° C. (Ethyl acetate-hexane)
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[C:19]3[CH:22]=[N:23][N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]=3[N:17]=[C:16]2[C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:20](=[O:21])[C:19]3[CH:22]=[N:23][N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]=3[N:17]=[C:16]2[C:31]2[CH:32]=[CH:33][C:34]([C:2]3[N:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:35][CH:36]=2)=[CH:13][CH:14]=1
Reactant: Clc1cccnn1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(-c3cccnn3)cc2)n1-c1ccc(Cl)cc1

Procedure:
5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyridazin-3-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one is prepared from 3-chloropyridazine and 5-(4-chloro-phenyl)-1-phenyl-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one by using the same method described in example 338. The crude product is purified by flash column chromatography (silica gel, 0˜70% EtOAc/hexane). 1H NMR (CDCl3) δ (ppm) 9.19 (b, 1H), 8.34(s, 1H), 8.15(d, 2H), 8.02(d, 2H), 7.84(d, 1H), 7.51(m, 5H), 7.33 (m, 3H), 7.15(d, 2H). HPLC-MS calculated C27H17ClN6O (M+1+): 477.1. Found: 477.1.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(CCCCCO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
Ethyl N-piperazinecarboxylate (25.50 g, 161.39 mmol), 5-bromo-1-pentanol (26.96 g, 161.39 mmol), potassium carbonate (55.68 g, 403.48 mmol) and anhydrous acetonitrile (200 mL) were placed in a 500 mL round-bottomed flask and heated under reflux with stirring overnight; the reaction system was cooled down to room temperature, filtered, concentrated and separated by column chromatography (eluent: dichloromethane/methanol/triethylamine system, v/v/v 100:1:0.5), to obtain a pale yellow oil 20.48 g, yield 52.0% (which was directly used in the next step reaction).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=1.NC(N)=[S:27].[OH-].[Na+].Cl>C(O)C>[SH:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCBr)cc1
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NCCCCCCCCCCCS)cc1

Procedure:
A solution of 10 g. of ethyl 4-[(11-bromoundecyl)amino]benzoate and 2.0 g. of thiourea in 80% of 95% ethanol is stirred under reflux for 3 hours, allowed to cool, treated with 12 ml. of 10 N aqueous sodium hydroxide solution and again stirred under reflux for 2 hours. The mixture is acidified with dilute hydrochloric acid and filtered. The solid is recrystallized from ethanol-water to yield the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([O:17]CC)=[O:16].[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cc2ccccc2n1Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccccc2n1Cc1cccc(Cl)c1
Reaction time: 16 h
Yield: 81.8 %

Procedure:
Ethyl N-(3-chlorobenzyl)indole-2-carboxylate (0.47 g) was dissolved in THF/MeOH (1:1) and sodium hydroxide (2M, 4.5 ml) was added and the reaction stirred for 16 hours. The reaction was then concentrated in vacuo to dryness and the residue dissolved in water. The solution was acidified to pH 3 by dropwise addition of acetic acid, resulting in the precipitation of a white solid which was filtered off, washed with water and dried in vacuo to give the desired end product (0.35 g, 82%), mp 188-189°; NMR δ (CD3SOCD3) 5.85 (s, 2H), 6.90 (d, 1H), 7.1 (m, 2H), 7.3 (m, 4H), 7.55 (d, 1H), 7.70 (d, 1H); M/z (−) 284 (M−H+).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[F:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[CH:34]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH3:35]>>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH:22]=[CH:21][C:20]=1[CH:34]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH3:35]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)c(F)c1
Yield: 39.7 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (800 mg, 2.6 mmoL) was reacted with tert-butyl 1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethylcarbamate (1.4 g, 3.9 mmol) to afford the desired product (480 mg, 40%) as a brown solid: ESI MS m/z 469 [C25H2FN2O4S+H]+.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].CO.[CH2:14](Cl)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])[CH2:15][CH2:16][CH3:17]
Reactant: O=C1CCCCCN1
Reactant: CCCCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCN1CCCCCC1=O
Temperature: 150 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
113.2 g of fresh caprolactam (1.0 mol) is dissolved in 250 g of crude distillate containing 3.4% of caprolactam (8.5 g of caprolactam prepared as in a), and the resulting mixture is heated to 150° C. 202 g of a 30.16 wt. % strength sodium methoxide-methanol solution (1.13 mol) is metered in at 140° C. over a period of one hour while distilling methanol. All the methanol is distilled by briefly applying vacuum. 104.5 g of n-butyl chloride (1.13 mol) is then metered in at 140° C. over a period of one hour. After allowing the mixture to continue reacting for 4 hours, the reaction mixture is subjected to an initial cooling, and all the NBC is distilled from the sodium chloride in vacuo; boiling point of NBC: 90° C./0.5 mbar. Weight: 406 g. GC Purity: 96.3% of NBC, 2.7% of caprolactam. Yield: 83.0% of theory or 91.2% if caprolactam is recycled. NBC can be redistilled through a column to give a product having a purity of about 99%.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O>ClCl>[CH2:1]([NH:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=[CH:7][C:6]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCNC(=O)c1ccccc1[Si](C)(C)C
Agent: ClCl
Agent: O=S(=O)(O)O
Product: CCNC(=O)c1cc([N+](=O)[O-])ccc1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of the amide of example 49 (1.10 g, 5 mmol) in CH2 Cl2 (50 mL) at 0° C. was added dropwise over 2 min, a cold mixture of 70% nitric acid (0.95 mL, 15 mmol) and concentrated sulfuric acid (5 mL) dropwise. The mixture was stirred at 0° C. for 10 min and was poured onto ice. The mixture was extracted with ethyl acetate, the combined organic layers washed with brine, sat NaHCO3, brine, dried (MgSo4) and concentrated to a solid (2.68 g, 101%) consisting of a 2:1 ratio of 5-nitro and 3-nitro isomers. The title compound was obtained by RC (ethyl acetate/hexanes) in 60% yield as a white solid. m.p. 100°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[NH2:25][C@H:26]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([NH:25][C@H:26]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:21])[C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cc1cccc(C)c1N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyric acid and ethyl L-phenylalaninate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]-L-phenylalaninate (oil), saponification of which and processing of the reaction product yields N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl-L-phenylalanine (M.P. 153° to 155°).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][N:30]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f26) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.C[O:21][C:22](=[O:31])[C:23]([CH3:30])([CH3:29])[CH2:24][C:25](=O)[CH2:26][CH3:27]>C(O)(C)(C)C>[Br:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:26]([CH3:27])=[C:25]2[CH2:24][C:23]([CH3:30])([CH3:29])[C:22]([OH:31])=[O:21])=[CH:5][CH:4]=1
Reactant: CCC(=O)CC(C)(C)C(=O)OC
Reactant: COc1ccc(N(N)Cc2ccc(Br)cc2)cc1
Agent: Cl
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)c(C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Br)cc1

Procedure:
Following the method of Example 2, but using 1-[4-bromobenzyl]-1-(4-methoxy phenyl) hydrazine hydrochloride and methyl-2,2-dimethyl-4-oxohexanoate as the starting materials, using t-butanol as the solvent, the title compound was prepared.
Reaction SMILES: [H-].[Na+].[C:3]1(/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)=[CH:21][N:20]=1.O>CN(C)C=O>[N:28]1([CH2:27][CH2:26][CH2:25][C:22]2[CH:23]=[CH:24][C:19]([O:17][CH2:16][C:14]3[N:15]=[C:11](/[CH:10]=[CH:9]/[C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[O:12][CH:13]=3)=[N:20][CH:21]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: OCc1coc(/C=C/c2ccccc2)n1
Reactant: Clc1ccc(CCCn2ccnc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C(=C/c1nc(COc2ccc(CCCn3ccnc3)cn2)co1)\c1ccccc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
Sodium hydride (oily, 60%, 660 mg) was added to a solution of 2-[(E)-2-phenylethenyl]-4-oxazolylmethanol (3.02 g) in N,N-dimethylformamide (30 ml) and stirred at 90° C. for 30 minutes, to which was added a solution of 2-chloro-5-[3-(1-imidazolyl)propyl]pyridine (1.10 g) in N,N-dimethylformamide (10 ml). The resultant was stirred at 90° C. for 14 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane-methanol (10:1:0.5, v/v), crystals of 5-[3-(1-imidazolyl)propyl]-2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]pyridine (900 mg, 47%) was obtained. Recrystallization ethyl acetate-hexane gave pale brown prisms, mp 120-121° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>CN1C(=O)CCC1>[CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CSc1nc2ccc(O)cc2s1
Reactant: Clc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CSc1nc2ccc(Oc3ccnc4ccccc34)cc2s1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 79.7 %

Procedure:
To the reaction mixture of 2-(methylthio)benzo[d]thiazol-6-ol (750 mg, 3.79 mmol) in 10 ml of NMP was added Cesium Carbonate (3.2 g, 9.5 mmol) and stirred at RT for 3 minutes. To this mixture was added 4-chloroquinoline (682 mg, 4.17 mmol). The reaction mixture was stirred at 110° C. for 24 hours. The reaction was worked up by adding 250 ml ethyl acetate and washed with 75 ml of saturated NaHCO3, 2×60 ml water, 1×50 ml saturated NaCl, dried with sodium sulfate, filtered and concentrated in vacuo. The resulting solid residue was purified by silica gel column chromatography, eluted with (40% EtOAc:60% Hexanes) and concentrated in vaccuo to give 2-(methylthio)-6-(quinolin-4-yloxy)benzo[d]thiazole as solid (980 mg). ES/MS m/z 325.1 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:7]=1)=[O:4].C(N(C(C)C)C(C)C)C.Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>CC#N>[O:4]=[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:7]=1)[C@@H:2]([NH:1][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)Nc1cccc(-c2ccncc2)c1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cccc(-c2ccncc2)c1
Yield: 15.1 %

Procedure:
To a flask with (S)-2-amino-3-(4-fluorophenyl)-N-(3-(pyridin-4-yl)phenyl)propanamide (200 mg, 0.6 mmol) was added CH3CN as solvent, N-ethyl-N-isopropylpropan-2-amine (0.15 mL, 0.89 mmol) and tert-butyl 2-bromoacetate (0.097 mL, 0.66 mmol) and was heated at 55 degree for 5 hours. Reverse phase purification on HPLC followed by silica gel purification afforded 39 mg (15%) 34.4. 1H NMR (400 MHz, MeOH) δ ppm 8.50-8.68 (m, 2H) 7.88-7.99 (m, 1H) 7.61-7.75 (m, 2H) 7.55-7.60 (m, 1H) 7.42-7.52 (m, 2H) 7.23-7.31 (m, 2H) 6.97-7.04 (m, 2H) 3.53 (t, J=6.85 Hz, 1H) 3.29 (s, 2H) 3.05-3.12 (m, 1H) 2.95-3.03 (m, 1H) 1.43 (s, 9H)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[CH:37]=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(=O)(O)[O-].[Na+]>ClCCl>[Br:21][C:20]([Br:24])=[CH:37][C@@H:33]1[CH2:34][CH2:35][CH2:36][N:32]1[C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCCC1C=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=C(Br)Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of triphenylphosphine (21.1 g, 80.3 mmol) and carbon tetrabromide (13.32 g, 40.16 mmol) in dichloromethane (300 mL) at 0° C. was treated with a solution of 2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (4.0 g, 20.08 mmol) in dichloromethane (10 mL) dropwise via syringe. The solution was stirred for 1 hour at room temperature, poured into a saturated sodium bicarbonate solution and separated. The organic phase was dried (MgSO4), filtered and concentrated. The concentrate was purified by flash chromatography on silica gel using 0–1% methanol/dichloromethane to give 6.13 g (86% yield) of the desired product. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.47 (s, 9H), 1.81 (m, 3H), 2.16 (m, 1H), 3.39 (m, 2H), 4.37 (s, 1H), 6.38 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11]Cl)[CH3:2].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][N:18]1[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]2[C:14]1=[O:24])[CH3:2]
Reactant: CCOC(=O)COCCOCCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)COCCOCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
A solution of 10.5 g (50 mmol) of 2-[2-(chloroethoxy)-ethoxy]-acetic acid ethyl ester (Chemical Abstracts-Registry No. 82227-25-6) in 100 ml of DMF is reacted with 9.25 g (50 mmol) of potassium phthalimide (Fluka, Buchs, Switzerland) and 50 mg of 18-crown-6 ether (1,4,7,10,13,16-hexaoxacyclooctadecane, Fluka, Buchs, Switzerland) and the mixture is stirred for 2.5 h at 100° C. The reaction mixture is cooled and then concentrated under reduced pressure. The residue is taken up in ether and washed twice in each case with water and brine. After drying and concentrating, the title compound is obtained by column chromatography (SiO2, ethyl acetate/hexane: 1/1); TLC Rf (ethyl acetate/hexane: 4/1)=0.45;
Reaction SMILES: [CH2:1]([P:3]([CH2:10][CH2:11][OH:12])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].CC(C)=[O:15].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH2:1]([P:3]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH2:10][C:11]([OH:15])=[O:12])=[O:9])[CH3:2]
Reactant: CC(C)=O
Reactant: CCCCOP(=O)(CC)CCO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCCCOP(=O)(CC)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.1 %

Procedure:
19.4 g (0.1 mol) of butyl ethyl(2-hydroxyethyl)phosphinate (prepared as in Example 6) in 500 ml of acetone were admixed with 0.11 mol of Jones reagent (12.7 g of chromium trioxide in 36.7 ml of water and 11.0 ml of concentrated sulfuric acid) at 0° C. by dropwise addition. The reaction mixture was subsequently stirred for 3½ hours with ice cooling and for 1 hour at room temperature. Following addition of 12 ml of isopropanol, the mixture is poured onto ice-water. Volatile constituents are then distilled off in vacuo. The residue was taken up in tetrahydrofuran and extracted. Insoluble salts were filtered off. The solvent of the filtrate was removed in vacuo and the residue was recrystallized from acetone to obtain 1.68 g (81% of theory) of 2-(ethylbutoxyphosphinyl)acetic acid as colorless solid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2I)[O:9][C:8]1=[O:24].[CH:34]([C:37]1[CH:38]=[CH:39][C:40]([O:46][CH3:47])=[C:41](B(O)O)[CH:42]=1)([CH3:36])[CH3:35]>>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[C:41]2[CH:42]=[C:37]([CH:34]([CH3:36])[CH3:35])[CH:38]=[CH:39][C:40]=2[O:46][CH3:47])[O:9][C:8]1=[O:24]
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: C[C@@H]1[C@@H](c2cc(C(F)(F)F)ccc2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1[C@H]1OC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
Following the procedure described in EXAMPLE 81, 41 mg of (4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]4-methyl-1,3-oxazolidin-2-one and 17 mg of (5-isopropyl-2-methoxyphenyl)boronic acid gave title compound. Mass spectrum (ESI) 620.4 (M+1). 1H NMR signals are doubled because of atropoisomerism. 1H NMR (500 MHz, CDCl3): δ 7.53-7.80 (m, 5H), 7.33 (d, J=8 Hz, 1H), 7.21-7.29 (m, 1H), 7.00, 6.76 (d, J=2.5 Hz, 1H), 6.91, 6.86 (d, J=8.5 Hz, 0.4H), 5.15, 5.10 (d, J=4.5 Hz, 1H), 4.80, 4.74 (d, J=16 Hz, 1H), 4.25, 4.21 (d, 16 Hz, 1H), 3.76 (s, 2H), 3.49 (s, 1H), 3.43 (m, 0.4H), 3.18 (m, 0.5H), 2.77-2.98 (m, 1H), 1.24 (m, 3H), 1.16 (m, 3H), 0.78, 0.61 (d, J=6.5 Hz, 3 Hz).