Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[NH:20][C:21](=[O:25])[N:22]=[CH:23][CH:24]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Cl.Cl[CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][N:22]([CH2:32][C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[C:21](=[O:25])[N:20]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:27])([F:29])[F:28]
Reactant: N#Cc1cc(COc2ccnc(=O)[nH]2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: ClCc1cccnc1
Agent: Cl
Product: N#Cc1cc(COc2ccn(Cc3cccnc3)c(=O)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-{[(2-oxo-2,3-dihydro-4-pyrimidinyl)oxy]methyl}benzonitrile and 3-(chloromethyl)pyridine hydrochloride. LC-MS (ESI): m/z 513 [M+H]+; 2.94 min (ret time).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([O:17][C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[C:20]([CH3:35])[CH:19]=2)[CH2:15][CH3:16])=[CH:12][CH:13]=1)=[O:8].[OH-].[Na+].Cl>CO>[CH3:24][C:22]1[CH:23]=[C:18]([O:17][CH:14]([C:11]2[S:10][C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[O:8])=[CH:13][CH:12]=2)[CH2:15][CH3:16])[CH:19]=[C:20]([CH3:35])[C:21]=1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=1
Reactant: CCC(Oc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(Oc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
A solution of 3-({5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxy)-propyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (chiral Isomer 1) (79.6 mg, 0.153 mmol) in methanol (1.54 mL) is treated with 5N NaOH (0.154 mL) and shaken at rt overnight. The reaction is neutralized with 1N HCl (0.158 mL), and extracted into ethyl acetate (2×). The combined organic layers are dried and concentrated, giving the title compound (76 mg). MS (ES): 506.4 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])C.[Li+].[I-]>N1C=CC=CC=1>[Cl:22][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1c(N2CCCC2=O)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)c1c(N2CCCC2=O)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 20 step D from 6-chloro-2-(2-oxo-pyrrolidin-1-yl)-4-phenyl-quinoline-3-carboxylic acid ethyl ester (50 mg, 0.13 mmol) and LiI in pyridine. Yellow solid (11 mg, 24%). LC-MS: 367 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[C:14](OC(=O)C)(=[O:16])[CH3:15]>[OH-].[Na+]>[C:14]([O:13][C:12]1[CH:11]=[CH:10][C:4]([CH:5]=[CH:6][C:7]([OH:9])=[O:8])=[CH:3][C:2]=1[Cl:1])(=[O:16])[CH3:15]
Reactant: O=C(O)C=Cc1ccc(O)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1ccc(C=CC(=O)O)cc1Cl
Temperature: 0 °C

Procedure:
104 g (0.525 mol) of 3-chloro-4-hydroxy-cinnamic acid are dissolved in 530 ml of 2 N sodium hydroxide solution, 800 g of ice are added and 107 g (1.05 mols) of acetic anhydride are introduced dropwise over the course of 15 minutes at 0°-5° C, whilst stirring. The crystals which have precipitated are then filtered off, suction-dried and recrystallised from alcohol-water. 4-Acetoxy-3-chloro-cinnamic acid of melting point 210°-213° C is obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[C:20]1(O)[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[C:28]([F:35])[C:27]=2[F:36])[CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[C:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[C:28]([F:35])[C:27]=2[F:36])[CH2:22][CH:21]=1
Reactant: CCCCCC1CCC(c2ccc(C3(O)CCC(c4ccc(OCC)c(F)c4F)CC3)c(F)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(c2ccc(C3=CCC(c4ccc(OCC)c(F)c4F)CC3)c(F)c2F)CC1
Temperature: 30 °C
Yield: 50.2 %

Procedure:
The compound (51) (9.7 g), p-toluenesulfonic acid (0.15 g) and toluene (200 ml) were mixed, and the mixture was heated under reflux for 2 hours while water being distilled was removed. The reaction mixture was cooled to 30° C., and then water (200 ml) and toluene (300 ml) were added thereto and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution obtained was purified with a fractional operation by means of column chromatography using a mixed solvent of heptane and toluene (heptane:toluene=2:3 by volume) as the eluent and silica gel as the stationary phase powder. The solvent was distilled off, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The product was further purified by means of recrystallization from a mixed solvent of Solmix A-11 and ethyl acetate (Solmix A-11:ethyl acetate=2:1 by volume) and dried, giving 4.7 g of 1-(4-(2,3-difluoro-4-(4-pentylcyclohexyl)phenyl)cyclohex-3-enyl)-4-ethoxy-2,3-difluorobenzene (No. 12). The yield based on the compound (10) was 49.8%.
Reaction SMILES: [NH:1]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[NH2:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30]3)[C:25](=[O:32])N(CCO)N=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH:28]=[CH:29][CH2:30]3)[C:25](=[O:32])[N:1]([C:3]3[S:4][C:5]4[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=4[N:7]=3)[N:2]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: NNc1nc2ccccc2s1
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(c3nc4ccccc4s3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 2-hydrazinobenzothiazole as described for compound 35. Crystallized from ethyl acetate/petroleum ether (60°-80° C). M.p. 176°-177° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[B:9]1[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:4][C:3]=1[B:9]1[O:10][C:11]([CH3:17])([CH3:16])[C:12]([CH3:15])([CH3:14])[O:13]1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CS(=O)(=O)Cl
Product: Cc1ccc(NS(C)(=O)=O)cc1B1OC(C)(C)C(C)(C)O1
Yield: 84.2 %

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 2.14 mmol) was treated with methanesulfonyl chloride (162 μl, 2.10 mmol) according to the method described in Preparation 15b to give 550 mg (83% yield) of the title compound. Purity 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[CH2:12]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc(F)cc1Cl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a solution of 2-chloro-4-fluorophenol (617, 7 g, 0.05 mol) in tetrahydrofuran (100 mL) was added sodium hydride (1.8 g, 95% dry powder, 0.071 mol) at room temperature over 15 minutes under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 30 minutes. Benzyl bromide (10 g, 0.060 mol) was added slowly to the reaction mixture, then stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with hydrochloric acid (10%), water, brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide compound as a white solid (618, 7.6 g, 60%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21][C:7]=3[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.[CH2:32]([N:40]1[CH2:45][CH2:44][NH:43][C:42](=[O:46])[CH2:41]1)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[O:46]=[C:42]1[CH2:41][N:40]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:45][CH2:44][N:43]1[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21][C:7]=3[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1
Reactant: O=C1CN(CCc2ccccc2)CCN1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CN(C(=O)OC(C)(C)C)CC3)cc1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(N5CCN(CCc6ccccc6)CC5=O)cc42)CN(C(=O)OC(C)(C)C)CC3)cc1
Yield: 60.1 %

Procedure:
tert-Butyl 7-bromo-5-tosyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (600 mg, 1.19 mmol) and 4-phenethylpiperazin-2-one (266 mg, 1.30 mmol) were reacted according to Example 2 (step f) to provide the title compound (450 mg, 60%) as a white powder: ESI MS m/z 629 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[S:22][C:6]2[NH:7][C:8](=[O:21])[N:9]([CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]=[C:40](C(Cl)(Cl)Cl)[O:39][N:38]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-:47].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:3]1[S:22][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:47])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:8](=[O:21])[N:9]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1cc2c(=O)n(CCCc3ccccc3)c(=O)[nH]c2s1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CCCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
A mixture of 6-ethyl-3-(3-phenylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.3 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.45 g), potassium carbonate (0.15 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and methanol (5 mL). 1N Aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.24 g, 45%).
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:31])([CH3:30])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[CH2:23][NH2:24])=[CH:17][CH:18]=2)[CH:13]=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:35][C:36](=O)[NH:37][C:38]1[N:39]([CH3:47])[N:40]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:42]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CCOCC>[Si:1]([O:8][C:9]([CH3:31])([CH3:30])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[CH2:23][NH:24][C:36]([NH:37][C:38]3[N:39]([CH3:47])[N:40]=[C:41]([C:43]([CH3:45])([CH3:44])[CH3:46])[CH:42]=3)=[O:35])=[CH:17][CH:18]=2)[CH:13]=[N:12]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Reactant: CC(C)(Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21)O[Si](C)(C)C(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: Cn1nc(C(C)(C)C)cc1NC(=O)NCc1cc(F)ccc1Oc1ccc2c(cnn2CC(C)(C)O[Si](C)(C)C(C)(C)C)c1
Temperature: 80 °C
Yield: 83.2 %

Procedure:
A mixture of 2-{1-[2-(tert-butyldimethylsilanyloxy)-2-methyl-propyl]-1H-indazol-5-yloxy}-5-fluorobenzylamine (0.072 g, 0.162 mmol), (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloroethyl ester (0.080 g, 0.24 mmol) and DIEA (0.06 mL, 0.324 mmol) in DMA (3 mL) was heated to 80° C. for 16 hours. The mixture was diluted with ether (60 mL) and washed with water (3×5 mL), brine, dried over MgSO4, and concentrated under reduced pressure. The residue was chromatographed on silica eluting with ethyl acetate/hexanes (3:1) to afford 0.084 g of product (83% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[CH2:12]([CH:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].O>[N+](C)([O-])=O>[CH2:12]([CH:14]([CH2:18][CH3:19])[C:15]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=2[C:7]=1[CH3:10])=[O:16])[CH3:13]
Reactant: Cc1coc2ccc(F)cc12
Reactant: CCC(CC)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CCC(CC)C(=O)c1oc2ccc(F)cc2c1C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of 5-fluoro-3-methyl-1-benzofuran (12.0 g) synthesized in Example A67(2), 2-ethylbutyrylchloride (9.58 g) in nitromethane (240 mL) was added aluminum chloride (anhydrous) (12.94 g) at 0° C., and the mixture was stirred for 1.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-90:10, v/v) to give the title compound (15.02 g, 93%) as a yellow oil.
Reaction SMILES: [C-]#N.[Na+].[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]=[O:13])=[CH:10][CH:11]=1.[CH2:14]([N:16](CC)CC)C.Cl>C(O)C>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:13])[C:14]#[N:16])=[CH:8][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CCN(CC)CC
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(O)C#N)cc1
Reaction time: 6 h

Procedure:
To 49 g (1 mole) of sodium cyanide and 136 g (1 mole) anisaldehyde in ethyl alcohol 800 ml), containing triethylamine (5 mol %, 5.1 g) is added HCl gas (1 mol, 36.5 g) over 30 minutes at 5°-10° C. The resulting slurry is stirred at that temperature for 6 hours. In situ sampling of the reaction mixture shows the reaction to be complete. Additional HCl (0.2 moles) is added to quench the reaction. tHE solution is filtered and used in the next step without further purification. Yield, ca. 80%.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.C1CCCCC1.[Br:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[C:40]([O:46][C:47]([F:50])([F:49])[F:48])[CH:39]=1>CCOCC>[Br:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][CH:2]=[O:3])=[C:40]([O:46][C:47]([F:50])([F:49])[F:48])[CH:39]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: O=CCc1ccc(Br)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.6 %

Procedure:
To a suspension of (methoxymethyl) triphenylphosphonium chloride (5.29 g, 14.9 mol) in Et2O (50 mL) was added 1.8 M phenyl lithium in 30% Et2O in cyclohexane (8.58 mL, 15.5 mmol). The mixture was stirred at ambient temperature for 10 min. To the reaction mixture was added 4-bromo-2-trifluoromethoxy-benzaldehyde (4 g, 14.9 mmol) in Et2O (18 mL). The mixture was stirred at ambient temperature for 4 hr, filtrated, and concentrated. To the above residue was added 10% H2SO4 in AcOH (40 mL). The mixture was stirred at ambient temperature for 90 min. The solution was poured into H2O, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was washed with saturated aqueous NaHCO3, washed with brine, dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel, 9% EtOAc in hexane) to give (4-bromo-2-trifluoromethoxy-phenyl)-acetaldehyde (1.25 g, 30%) as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]([CH3:21])[CH:17]=[N:18]2)=C(Cl)[N:13]=1>>[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]([CH3:21])[CH:17]=[N:18]2)=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: Cn1cnc2nc(Cl)nc(Cl)c21
Reactant: O=CNc1ccc(Cl)cc1
Product: Cn1cnc2nc(Cl)nc(Nc3ccc(Cl)cc3)c21

Procedure:
Was prepared according to Example 3 from N-(4-chloro-phenyl)-formamide and 2,6-dichloro-7-methyl-7H-purine.
Reaction SMILES: [C:1]([O:5][C:6](NC(COC(=O)NCCCCCCCCCCCCCCCCCC)CN)=O)(C)(C)C.ClCCCS([NH:42][CH2:43][CH:44](OC)[CH2:45][S:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])(=O)=O.C1(=O)NC(=O)C2=CC=CC=C12>>[CH2:47]([S:46][CH2:45][CH:44]([CH2:1][O:5][CH3:6])[CH2:43][NH2:42])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)NC(=O)OC(C)(C)C
Agent: O=C1NC(=O)c2ccccc21
Product: CCCCCCCCCCCCCCCCSCC(CN)COC

Procedure:
3-Hexadecylthio-2-methoxymethylpropanol IV k3 is allowed to react and worked up by the same procedure as described in (4). The phthalimide compound m.p. 45° C. The summary of the experimental condition and the physical data of the product are listed in Tables 5 and 6.
Reaction SMILES: ClCC#N.Cl([O-])(=O)(=O)=O.[Li+].[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:31])[C:27]([O:29]C)=[O:28])=[CH:22][CH:21]=1)([O-:13])=[O:12]>>[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:31])[C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1)([O-:13])=[O:12]
Reactant: COC(=O)C(C)c1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: N#CCCl
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CC(C(=O)O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1

Procedure:
The 2-(2'-nitro-4-biphenylyl)propionic acid is readily prepared in the following manner: 2-nitrobiphenyl is acylated with acetyl chloride, giving 4-acetyl-2'-nitrobiphenyl. This is converted with chloroacetonitrile under alkaline conditions to the intermediate isomeric 2-methyl-2-[4-(2'-nitrophenyl)]glycidonitriles which, when treated with lithium perchlorate and then base, is isomerized to methyl 2-(2'-nitro-4-biphenylyl)propionate. Saponificiation of the latter gives the desired 2-(2'-nitro-4-biphenylyl)-propionic acid. The esters are readily converted to the acid and the acid to the esters by conventional means.
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:59]1[CH:64]=[C:63](B(O)O)[CH:62]=[N:61][CH:60]=1>>[F:17][C:15]1[CH:16]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:26][CH2:27]4)=[CH:7][CH:8]=3)[C:3](=[O:32])[C:2]=2[C:63]2[CH:64]=[N:59][CH:60]=[N:61][CH:62]=2)[CH:12]=[C:13]([F:18])[CH:14]=1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Reactant: OB(O)c1cncnc1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2cncnc2)=C3c2cc(F)cc(F)c2)CC1
Yield: 34 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-[2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy]-1H-inden-1-one obtained in Step 1 of Example 50 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, and 5-pyrimidinylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (34%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.O.[NH2:14]N.O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([NH2:14])[C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: NN
Reactant: O=C1NC(=O)c2cc(Cl)ccc21
Solvent: CCO
Solvent: O
Product: NN1C(=O)c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 20.3 %

Procedure:
To a cooled mixture of 1.81 g (10 mmol) 4-chloro phthalimide in 20 mL ethanol (96%) was added 0.5 mL (10 mmol) hydrazine monohydrate. The reaction mixture was stirred for 2 min. at room temperature and 2 min. at reflux. By adding 50 mL cold water pale yellow crystals formed after 1 h. Resulting crystals was filtered and recrystallized from ethanol to give 0.4 g (20%)4-chloro-N-amino-phthalimide :top 172°-175° C.; 1H NMR (200 MHz, DMSO-d6) d 4.90 (s, 2H, NH2), 7.82-7.92 (m, 3H, C6H3); it solidifies after melting and melts again around 345° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:41])=[C:4]([CH:38]=[CH:39][CH:40]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:37])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26]CC3C=CC=CC=3)=[CH:23][CH:24]=2)[C:19]([C:34](=[O:36])[CH3:35])=[CH:18]1)=[O:8].C(O)(C(F)(F)F)=O.C1(SC)C=CC=CC=1>>[Cl:1][C:2]1[C:3]([F:41])=[C:4]([CH:38]=[CH:39][CH:40]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:37])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=2)[C:19]([C:34](=[O:36])[CH3:35])=[CH:18]1)=[O:8]
Reactant: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(OCc3ccccc3)cc12
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(O)cc12

Procedure:
The title compound was prepared in a similar manner as described above for Example 577 from (1R,3S,5R)-2-[2-(3-acetyl-5-benzyloxy-indol-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide (79.0 mg, 0.138 mmol), TFA (3 mL) and thioanisole (0.163 mL, 1.38 mmol). Solid. MS (LC/MS): 484 [M+H]+; tR (HPLC, conditions k): 3.18 min.