Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:30])=[N:6][C:7]([C:19](=[O:29])[NH:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)(=[O:3])[CH3:2].[BH4-].[Na+].C(Cl)(Cl)Cl>CO>[OH:3][CH:1]([C:4]1[C:5]([CH3:30])=[N:6][C:7]([C:19](=[O:29])[NH:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH3:2]
Reactant: CC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(C(=O)NCCN2CCOCC2)nc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nc(C(=O)NCCN2CCOCC2)cc(-c2cccc([N+](=O)[O-])c2)c1C(C)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
To a solution of 3-acetyl-2-methyl-6-(2-morpholinoethylcarbamoyl)-4-(3-nitrophenyl)pyridine (3 g) in methanol (30 ml) was added sodium borohydride (0.28 g) under ice-cooling. After stirring for 1 hour at same temperature, the solution was poured into a mixture of ice water (50 ml) and chloroform (50 ml). The organic layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent, the residue was recrystallized from a mixture of ethanol and ethyl acetate to give 3-(1-hydroxyethyl)-2-methyl-6-(2-morpholinoethylcarbamoyl)-4- (3-nitrophenyl)pyridine (1.53 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[CH:16](=O)[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:16]2[C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[OH:19])([O-:15])=[O:14]
Reactant: O=Cc1ccccc1O
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cnn2c1-c1ccccc1NC2c1ccccc1O
Yield: 76 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with salicylaldehyde as described in Example 11. 1-Nitro-5-(o-hydroxyphenyl)-5,6-dihydropyrazolo[1,5-c]quinazoline is obtained with a yield of 76%. M.p.: 235°-237° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:13])[C:8](OCC)=[O:9])[CH2:3][CH2:2]1.O.[NH2:15][NH2:16]>C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:13])[C:8]([NH:15][NH2:16])=[O:9])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)N1CCOCC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.3 %

Procedure:
Ethyl 2-morpholino-2-oxoacetate (1.0 g, 5.34 mmol) was dissolved in ethanol (7 mL) and hydrazine hydrate (0.267 g, 5.34 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure to give 0.9 g of the crude product, which was used without further purification in the following step. Crude yield 90%. 1H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 4.43-4.48 (m, 2H), 3.56-3.61 (m, 4H), 3.40-3.48 (m, 4H). LCMS m/z 174.16 [M+H]+, tR=2.031 min.
Reaction SMILES: [Br-].[C:2]12([CH2:12][NH:13][C:14]([C:16]3[C:17]([CH3:33])=[N+:18]([CH2:22][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=4)=[O:24])[CH:19]=[CH:20][CH:21]=3)=[O:15])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH3:34]OC(OC)N(C)C>CN(C=O)C>[C:2]12([CH2:12][NH:13][C:14]([C:16]3[C:17]4[N:18]([C:22]([C:23](=[O:24])[C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=5)=[CH:34][CH:33]=4)[CH:19]=[CH:20][CH:21]=3)=[O:15])[CH2:3][CH:4]3[CH2:10][CH:8]([CH2:7][CH:6]([CH2:5]3)[CH2:11]1)[CH2:9]2
Reactant: COC(OC)N(C)C
Reactant: Cc1c(C(=O)NCC23CC4CC(CC(C4)C2)C3)ccc[n+]1CC(=O)c1cccc(C#N)c1
Agent: [Br-]
Solvent: CN(C)C=O
Product: N#Cc1cccc(C(=O)c2ccc3c(C(=O)NCC45CC6CC(CC(C6)C4)C5)cccn23)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 3-[(adamantan-1-ylmethyl)carbamoyl]-1-[2-(3-cyanophenyl)-2-oxoethyl]-2-methylpyridinium bromide (400 mg, 0.81 mmol) and N,N-dimethylformamide dimethyl acetal (0.22 mL, 1.62 mmol) in DMF (2.0 mL) is stirred at 110° C. for 3 h. The mixture is concentrated in vacuo and purified by column chromatography (gradient from CH2Cl2 to 10% EtOAc/CH2Cl2) to give the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.91 (1H, d), 8.53 (1H, t), 8.15 (1H, m), 8.05 (2H, m), 7.74 (1H, t), 7.66 (1H, dd), 7.44 (1H, d), 7.22 (1H, t), 6.95 (1H, d), 3.01 (2H, d), 1.93 (3H, s), 1.63 (6H, m), 1.52 (6H, s). Mass spec. (438.19, M+H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C(O)(=O)C.[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)CCC>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]2[NH:22][N:3]=[N:2][N:1]=2)=[CH:23][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCO
Product: c1ccc(COc2ccc(-c3nnn[nH]3)cc2)cc1
Yield: 85 %

Procedure:
6.6×10-2 mol of sodium azide and 6.6×10-2 mol of acetic acid were added to a solution of 5×10-2 mol of 4-benzyloxy benzonitrile (VIII) in 20 ml butanol. The reaction medium was then reflux-heated for 4 hours. 1 g sodium azide, 2 g acetic acid and 10 ml butanol were added and the reaction medium was again reflux-heated for 2 days. After concentration by evaporation of the solvent, the residue was dissolved in 20 ml of 10% aqueous NaOH. After filtration, the aqueous phase was extracted with ether. The alkaline solution was acidified with 2N HCl to obtain the expected compound, which was isolated with an 85% yield (M.P.=228° C.).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[F:21])[NH2:17]>C(O)C>[F:13][C:14]1[CH:15]=[C:16]([N:17]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1ccc(F)c(F)c1
Solvent: CCO
Product: O=C(O)C1CCN(c2ccc(F)c(F)c2)C1=O
Yield: 49.2 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 3,4-difluoroaniline (0.442 mL; 4.36 mmol) in ethanol (3 mL). 1-(3,4-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid 0.172 g (70%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:12][CH:11]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH:10]3[CH2:9]2)[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:9][CH:10]3[CH:11]([CH2:13][NH:14][CH2:15]3)[CH2:12]2)[N:3]=1
Reactant: Cc1ncnc(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncnc(N2CC3CNCC3C2)n1

Procedure:
tert-Butyl 5-(4-methyl-1,3,5-triazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (43 mg, 0.142 mmol), DCM (1.4 mL) and TFA (0.71 mL) were stirred at room temperature for 2 h. The mixture was concentrated in vacuo and taken on to the next step without further purification.
Reaction SMILES: [CH2:1]1[O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4][O:3][CH2:2]1.FC(F)(F)[C:22](O)=[O:23]>>[CH2:1]1[O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][C:12]2[CH:11]=[C:10]([CH:22]=[O:23])[CH:9]=[CH:8][C:7]=2[O:6][CH2:5][CH2:4][O:3][CH2:2]1
Reactant: c1ccc2c(c1)OCCOCCOCCOCCO2
Reactant: O=C(O)C(F)(F)F
Product: O=Cc1ccc2c(c1)OCCOCCOCCOCCO2

Procedure:
A solution of hexamethylenetretramine (1.87 mmol, 0.27 g) in trifluoroacetic acid (1.4 cm3) was added to benzo 15-crown-5 ether (1.87 mmol, 0.5 g) under nitrogen; the mixture was heated to reflux for 12 hours.
Reaction SMILES: [F:1]N(C(C)(C)C)S(C1C=CC(C)=CC=1)(=O)=O.[C:17]1([O-:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.[K+]>O1CCCC1.CCOCC>[F:1][C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]=1[OH:27]
Reactant: Cc1ccc(S(=O)(=O)N(F)C(C)(C)C)cc1
Reactant: [O-]c1cccc2ccccc12
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Oc1c(F)ccc2ccccc12
Yield: 60 %

Procedure:
Potassium hydride (93.6 mg as a 35% oil dispersion, 0.82 mmol) was suspended in anhydrous tetrahydrofuran (2.5 mL) under nitrogen. 1-Naphthol (72 mg, 0.5 mmole) was added and the mixture was stirred until hydrogen evolution ceased (about 5 minutes) to produce potassium naphtholate. N-Fluoro-N-t-butyl-p-toluenesulfonamide (122 mg, 0.5 mmole) was dissolved in anhydrous tetrahydrofuran (2.5 mL) and the solution was added dropwise to the potassium naphtholate. After 20 minutes the reaction mixture was diluted with ether (100 mL), washed with aqueous 1N oxalic acid solution (30 mL), water (30 mL), and saturated aqueous sodium chloride solution (30 mL), and then dried over anhydrous magnesium sulfate. Filtration, removal of solvent under reduced pressure, and purification by flash column chromatography (silica, 25% methylene chloride in hexane) yielded 2-fluoro-1-naphthol (49 mg, 60% yield) as a white crystalline solid. This material, and an additional sample prepared by this procedure, were analyzed and provided the following results: 1H NMR (90 MHz, CDCl3) δ5.58 (b, 1H, OH), 7.00-8.30 (m, 6H, aromatic); 19F NMR (94.1 MHz, CDCl3) -146.78(m); HRMS calcd. for C10H7OF: 162.0480; found: 162.0439.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:25][N:26]([CH2:30][CH2:31]Cl)[CH2:27][CH2:28]Cl>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:28][CH2:27][N:26]([CH2:25][C:24]2[CH:33]=[CH:34][C:35]([Cl:36])=[C:22]([Cl:21])[CH:23]=2)[CH2:30][CH2:31]1)=[O:20])[CH3:2]
Reactant: ClCCN(CCCl)Cc1ccc(Cl)c(Cl)c1
Reactant: CCCCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83. Starting from (4-butoxy-benzenesulfonyl)acetic acid ethyl ester (13.2 g 44 mmol) (3,4-dichloro-benzyl)-bis-(2-chloro-ethyl)-amine (14.3 g, mmol). Yield 14.1 g (60%), white solid, MP 86° C.; MS: 527.9 (M+H)+
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.[F-].[K+]>O1CCCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:10][C:5]1[CH:4]=[C:3]([O:11][CH3:12])[C:2]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: OB(O)c1cccs1
Reactant: COc1cc(O)c(C=O)cc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(O)c(C=O)cc1-c1cccs1
Temperature: 60 °C
Yield: 95.9 %

Procedure:
Ex-13C: 5-Bromo-2-hydroxy-4-methoxybenzaldehyde (Ex-13B, 1.5 g, 6.5 mmol) and thiophene-2-boronic acid (0.91 g, 7.1 mmol) were dissolved in tetrahydrofuran (15 mL). Nitrogen was bubbled into the solution for 10 min followed by the sequential addition of potassium fluoride (0.80 g, 14 mmol, spray-dried) and bis(tri-t-butylphosphine)palladium (0) (0.033 g, 0.065 mmol). The solution was immediately heated to 60° C. and aged for 1.5 h. Upon completion, as determined by HPLC, the reaction was diluted with water (25 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over sodium sulfate and concentrated to a brown solid. Silica gel chromatography (ethyl acetate/hexanes, 1:3) gave 1.46 g (97%) of 2-hydroxy-4-methoxy-5-thien-2-ylbenzaldehyde as a yellow solid, mp 118–119° C. 1H-NMR (300 MHz, CDCl3) δ 11.48 (s, 1H), 9.79 (s, 1H), 7.72 (s, 1H), 7.37 (d, 1H, J=3.6 Hz), 7.31 (dd, 1H, J=5.1, 1.5 Hz), 7.08 (dd, 1H, J=5.1, 3.6 Hz), 6.54 (s, 1H), 3.98 (s, 3H). MS (ESI) m/z 235 ([M+H]+, 100%). Anal. Calcd. for C8H7O3S: C, 61.52; H, 4.30; S, 13.69; Found: C, 61.12; H, 4.34; S, 13.56.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH2:14][CH2:15][OH:16])[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].CCN(C(C)C)C(C)C.Cl[CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH2:14][CH2:15][O:16][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)c1cccc2c1ccn2CCO
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOCCn1ccc2c(C(=O)OC)cccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of -(2-Hydroxy-ethyl)-1H-indole-4-carboxylic acid methyl ester in DCM (3 ml) is added DIPEA (0.129 ml, 0.739 mmol) and 1-Chloromethoxy-2-methoxy-ethane (0.084 ml, 0.739 mmol). The solution is stirred at room temperature for 72 hours. The reaction is diluted with DCM (50 ml) and washed with 0.5 M HCl (20 ml), 1 M NaOH (20 ml) and 0.5 M HCl (20 ml). The organic layer is dried over MgSO4 and the solvent is removed in vacuo. Purification by chromatography (SiO2, DCM/MeOH) affords 1-[2-(2-Methoxy-ethoxymethoxy)-ethyl]-1H-indole-4-carboxylic acid methyl ester; [M+H]+ 308
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][N:8]([CH3:10])[CH3:9])[S:5][CH:6]=1.[CH:11]([O:14][B:15](OC(C)C)[O:16][CH:17]([CH3:19])[CH3:18])([CH3:13])[CH3:12].[Li]CCCC.CCCCCC>C1COCC1>[CH3:9][N:8]([CH2:7][C:4]1[S:5][CH:6]=[C:2]([B:15]([O:16][CH:17]([CH3:19])[CH3:18])[O:14][CH:11]([CH3:13])[CH3:12])[CH:3]=1)[CH3:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CN(C)Cc1cc(Br)cs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)OB(OC(C)C)c1csc(CN(C)C)c1
Temperature: -78 °C
Reaction time: 6.5 h

Procedure:
To a solution of 1-(4-bromo-2-thienyl)-N,N-dimethylmethanamine (2.8 g, 12.8 mmol) in THF (130 mL) at −78° C. under N2 was added tri-isopropylborate (4.4 mL, 19.2 mmol). The reaction mixture was stirred briefly before nBuLi (12 mL of a 1.6 M hexane solution) was added dropwise via syringe. The reaction mixture then stirred for 6.5 h at −78° C. before being concentrated by rotary evaporation. The resulting white solid was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:19][C:20]1([F:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:23]3[CH2:24][CH2:25][C:20]([F:26])([F:19])[CH2:21][CH2:22]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: FC1(F)CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1Cc2ccc(N3CCC(F)(F)CC3)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 4,4-difluoropiperidine hydrochloride. Yellow solid. MS (m/e): 339.1 ([M+H]+, 100%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1>>[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc(Br)cc2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Bromo-benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:9]([O:11][CH2:12][C@@:13]2([OH:24])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[OH:23])[CH2:14]2)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:9]([O:11][CH2:12][C@@:13]2([OH:24])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:23][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:14]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(OC[C@@]1(O)CCc2c(O)cccc2C1)N(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CC[C@](O)(COC(=O)N(c1ccc(F)cc1)c1ccc(F)cc1)C2
Reaction time: 16 h

Procedure:
To a mixture of (2R)-2-{[N,N-di(4-fluorophenyl)-carbamoyloxy]methyl}-2,5-dihydroxy-1,2,3,4-tetrahydro-naphthalene (0.18 g) and powder K2CO3 in dry DMF (1.8 ml) was added ethyl bromoacetate (0.047 ml) at room temperature. After stirring for 16 hours, the reaction mixture was partitioned between AcOEt and water. The organic layer was washed with water, brine, dried over MgSO4 and evaporated in vacuo. The residue was crystallized from n-hexane to give (2R)-2-{[N,N-di(4-flurophenyl)carbamoyloxy]methyl}-5-[(ethoxycarbonyl)methoxy]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (0.16 g) as white solid.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[Cl:24][C:25]1[CH:36]=[CH:35][C:28]([C:29](N(OC)C)=[O:30])=[CH:27][C:26]=1[S:37](=[O:40])(=[O:39])[NH2:38]>O1CCCC1>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][CH2:8][CH2:7][O:6][C:5]1[CH:17]=[CH:18][C:2]([C:29]([C:28]2[CH:35]=[CH:36][C:25]([Cl:24])=[C:26]([S:37]([NH2:38])(=[O:39])=[O:40])[CH:27]=2)=[O:30])=[CH:3][CH:4]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Temperature: -78 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
[2-(4-Bromo-phenoxy)-ethoxy]tert-butyl-dimethyl-silane (7.3 g, 22.12 mmol) is dissolved in tetrahydrofuran (120 mL) and cooled to −78° C. The solution is treated with a solution of n-butyllithium (1.6 M in hexanes, 13.8 mL, 22.12 mmol) and stirred 30 minutes after which a solution of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide (2.05 g, 7.37 mmol) in tetrahydrofuran (20 mL) is added. The reaction is allowed to stir for 18 hours while warming to ambient temperature. The reaction is quenched with a saturated solution of ammonium chloride and extracted twice with ether. The organic phase is separated and concentrated in vacuo. The residue is purified by column chromatography (gradient of ethyl acetate in hexanes 10-50%) affording 1.84 g (53% yield) of the title compound. MS (m/z): 470.2 (M+1).
Reaction SMILES: C(Br)C=C.[CH3:5][C:6]1[CH:11]=[C:10]2[O:12][C:7]=1[C:8]([CH3:13])=[CH:9]2>>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:13])[C:7]=1[OH:12]
Reactant: Cc1cc2cc(C)c1o2
Agent: *c1ccccc1*
Solvent: C=CCBr
Solvent: CCOCC
Product: Cc1cccc(C)c1O

Procedure:
Substantially the same reaction as in Examples 1 to 9 was conducted except that various alkenyl halides as shown in Table 5 were employed instead of allyl bromide. PPE-1 was used in Examples 17 and 18. Poly 2,6-dimethyl-1,4-phenylene ether [viscosity (ηsp/c): 0.59 (hereinafter referred to as PPE-4)] was used in Examples 19 to 21. A bifunctional polyphenylene ether obtained by oxidative polymerization of 2,6-dimethylphenol (hereinafter referred to as PPE-5) in the presence of bis (3,5-dimethyl-4-hydroxyphenyl) sulfone as a polyfunctional phenol compound was used in Example 22. Toluene/TMEDA (100 ml +2.5 ml) was used as a solvent instead of THF in Examples 19 and 22.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([C:15]([CH3:17])=[CH2:16])[N:3]=1.[H][H]>[Pd].C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: C=C(C)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)c1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-isopropenyl-pyrimidine-5-carbonitrile, hydrogen and palladium on charcoal in THF. ES-MS m/e (%): 229 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=2[CH:13]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[OH:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=3[CH:13]=2)=[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=1
Reactant: Oc1ccc(-c2cc3cc(O)ccc3o2)c(Br)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: Oc1ccc(-c2cc3cc(O)ccc3o2)c(-c2ccccc2)c1
Yield: 47.9 %

Procedure:
Compound 102 (0.2 g, 0.69 mmol) in a solution consisting of Tol/EtOH/2M Na2CO3 aq (5/1/5) was treated with phenylboronic acid (0.12 g, 1.0 mmol) and cat Pd(PPh3)4 and heated to reflux until TLC analysis indicated complete reaction. The reaction was worked up by acidifying with 2 N HCl aq and extracting with EtOAc. The organic layer was washed with saturated NaHCO3 aq, brine, and dried over MgSO4. After filtering and concentrating, the crude material was chromatographed on silica gel (1:9 EtOAc/hexanes to 4:6 EtOAc/hexanes) and then triturated with hexanes to yield 0.10 g of the desired material: Mp.=167–709° C.; 1H NMR (DMSO-d6) δ 9.98 (br s, 1 H), 9.07 (br s, 1 H), 7.68 (d, 1 H, J=8.5 Hz), 7.4–7.38 (m, 3 H), 7.26–7.22 (m, 2 H), 7.18 (d, 1 H, J=8.7 Hz), 6.90 (dd, 1 H, J=8.5 Hz, 2.5 Hz), 6.72 (d, 1 H, J=2.5 Hz), 6.67 (d, 1 H, J=2.3 Hz), 6.62 (dd, 1 H, J=8.7 Hz, 2.4 Hz), 5.81 (s, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([OH:31])=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([O:31][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21]
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N5CCCC5)sc34)ccc12

Procedure:
This material was prepared from the reaction of (7-chloro-thieno[3,2-b]pyridin-2-yl)-pyrrolidin-1-yl-methanone 28a with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 16e and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) □8.47 (1H, d, J=5.3 Hz), 7.82 (1H, s), 7.74 (1H, d, J=8.4 Hz), 7.14 (1H, d, J=1.7 Hz), 7.02 (1H, dd, J=1.7, 8.4 Hz), 6.55 (1H, d, J=5.3 Hz), 5.91 (1H, bs), 3.84 (2H, m), 3.70 (2H, m), 3.65 (3H, s), 3.05 (3H, d, J=4.5 Hz), 2.72 (3H, s), 2.02 (4H, m). LCMS (ESI+) [M+H]/z Calc'd 449, found 449.