Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][C@@H:3]([OH:7])[CH2:2]1.CC(C)([O-])C.[K+].Br[CH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:18]=1[C:19]([O:21][CH3:22])=[O:20].O>ClC1C=CC=CC=1.CN1CCCN(C)C1=O>[OH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][C@H:1]([O:8][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:18]=2[C:19]([O:21][CH3:22])=[O:20])[CH2:2]1
Reactant: COC(=O)c1c(C)cccc1CBr
Reactant: O[C@@H]1CCC[C@H](O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: COC(=O)c1c(C)cccc1CO[C@H]1CCC[C@@H](O)C1
Yield: 13.7 %

Procedure:
5 g (42.8 mmol) of cis-1,3-cyclohexanediol were dissolved in 40 ml of chlorobenzene and 10 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, dimethylpropyleneurea), admixed at 20–23° C. with 3.36 g (30 mmol) of potassium tert-butoxide (KOtBu) and stirred. After 10–15 minutes, the mixture was cooled to 15–20° C. and 3.7 g (approx. 50%) of methyl 2-bromomethyl-6-methylbenzoate were added dropwise. The mixture was stirred at 20° C. for 1.5 h and then added to water. The organic phase was removed and concentrated under reduced pressure. The residue was taken up in NMP/water and, to remove impurities, washed twice with n-heptane. Subsequently, the product was isolated by extracting twice with MTBE. The combined MTBE phases were washed with water, dried (Na2SO4) and concentrated under reduced pressure. The residue (1.2 g) was chromatographed on silica gel (1:1 ethyl acetate/n-heptane). 580 mg of the desired compound were obtained as a slightly yellow oil; 1H-NMR (CDCl3), δ =1.27 (m, 1H), 1.45 (m, 1H), 1.55 (m, 1H), 1.74 (m, 1H), 1.83 (m, 1H), 2.05 (m, 1H), 2.34 (s, 3H), 3.47 (m, 1H), 3.72 (m, 1H), 3.91 (s, 3H), 4.58 (dd, 2H), 7.15 (d, 1H), 7.20 (d, 2H), 7.27 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: O[C@@H]1CCNC1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: O[C@@H]1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Yield: 17 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and (R)-3-pyrrolidinol to give the title compound in 17% yield; NMR Spectrum: 1.50-1.54 (m, 1H), 1.91-1.96 (m, 1H), 2.40 (dd, 1H), 2.55 (dd, 1H), 2.66 (dd, 1H), 2.80-2.89 (m, 3H), 4.16 (br s, 1H), 4.40 (t, 2H), 4.69 (br s, 1H), 5.28 (s, 2H), 7.24 (d, 1H), 7.37 (t, 1H), 7.55-7.58 (m, 2H), 7.87 (t, 1H), 7.92 (d, 1H), 8.29 (s, 1H), 8.45 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 482 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH:18]C(OC(C)(C)C)=O)[CH:15]=[CH:14][C:13]=2[CH3:26])=[CH:8][CH:7]=1)=[O:5])[CH3:2].Cl>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[CH3:26])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc(NC(=O)OC(C)(C)C)ccc2C)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Yield: 84.4 %

Procedure:
5′-tert-Butoxycarbonylamino-2′-methyl-biphenyl-4-carboxylic acid ethyl ester (6.6 g) was stirred in ethanol (120 ml) and 6M HCl (50 ml) at 20 C for 2 days. The ethanol was evaporated and the residue basified and then extracted with dichloromethane. The dried extracts were evaporated giving the title compound as a pale brown crystalline solid (4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1.C([O-])(=O)C.[Na+].[OH:17][C:18]1[C:19]([C:28](Cl)=[O:29])=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2.OC1C(C(O)=O)=CC2C(C=1)=CC=CC=2>ClC1C=CC=CC=1.CN(C=O)C>[OH:17][C:18]1[C:19]([C:28]([NH:1][C:2]2[CH:11]=[CH:10][C:5]3=[N:6][C:7](=[O:9])[N:8]=[C:4]3[CH:3]=2)=[O:29])=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Reactant: O=C(Cl)c1cc2ccccc2cc1O
Agent: CC(=O)[O-]
Agent: O=C(O)c1cc2ccccc2cc1O
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CN(C)C=O
Product: O=C1N=c2ccc(NC(=O)c3cc4ccccc4cc3O)cc2=N1
Temperature: 20 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
75.0 g (0.5 mol) of 5-aminobenzimidazolone and 41 g of anhydrous sodium acetate are initially introduced into 700 ml of N,N'-dimethylformamide and 776.8 g of 3-hydroxy-2-naphthoyl chloride (from 99.0 g (0.52 mol) of 3-hydroxy-2-naphthoic acid) in chlorobenzene are metered in at 5°-10° C. in the course of 30 min. After addition is complete, the mixture is subsequently stirred at 20° C. for 3 h, warmed to 50° C. and filtered. The filter cake does not filter off with suction very well (suction time: 14 h). For purification, the filter cake is taken up in 1 ml of methanol, the mixture is stirred and filtered off with suction, and the filter cake is washed with 250 ml of methanol and subsequently several times with a total of 1 l of boiling water. After drying, 130.3 g of 3-hydroxy-N-benzimidazolon-5-yl-2-naphthamide are obtained; this corresponds to 81.7% of theory.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=4)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: FC(F)(F)c1cccc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)c1
Temperature: 150 °C

Procedure:
Following the same procedure described for Example 401(c), the mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401 (b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), 3-(trifluoromethyl)phenylboronic acid (Aldrich Chemical Company) (47 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 m]L) gave, after heated in the Microwave Smith Synthesizer at 150° C. for 10 min and purification on a Biotage 40S column (4:1 hexane:EtOAc), the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 373 (M+1). Mp: 138.9-140.5° C.
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:34](=[O:50])[N:35]([CH2:39][CH2:40][CH2:41][O:42][Si](C(C)(C)C)(C)C)[CH2:36][CH2:37][CH3:38])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[CH2:10][C:11]([C:34](=[O:50])[N:35]([CH2:39][CH2:40][CH2:41][OH:42])[CH2:36][CH2:37][CH3:38])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28])=[CH:24][CH:25]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CCCCOC(=O)Cc1ccc(-c2ccc3c(c2)N=C(NC(=O)OC(C)(C)C)CC(C(=O)N(CCC)CCCO[Si](C)(C)C(C)(C)C)=C3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)Cc1ccc(-c2ccc3c(c2)N=C(N)CC(C(=O)N(CCC)CCCO)=C3)cc1
Reaction time: 1 h

Procedure:
Butyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate was dissolved in 2 mls of dichloromethane and 0.5 ml of TFA. After about one hour, the mixture was concentrated under reduced pressure and the resulting residue was then re-dissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2×), extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 10% MeOH/DCM/0.5% NH4OH) afforded butyl 2-(4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate. 1H NMR (400 MHz, CDCl3) δ 7.59-7.63 (m, 2H), 7.50-7.51 (m, 1H), 7.34-7.38 (m 2H), 7.32-7.34 (m, 2H), 6.88 (s, 2H), 4.09-4.14 (m, 2H), 3.58-3.68 (m, 6H), 3.45-3.51 (m, 2H), 2.87 (s, 2H), 1.79-1.88 (m, 2H), 1.57-1.76 (m, 4H), 1.30-1.42 (m, 2H), 0.89-0.96 (m, 6H); m/z (APCI-pos) M+1=492.2.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.O.[NH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([N:16]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]3)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Agent: Cl
Solvent: O
Product: O=C1CCN(S(=O)(=O)c2cccc3nsnc23)CC1

Procedure:
The title compound was prepared from benzo[1,2,5]thiadiazole-4-sulfonyl chloride and 4-piperidone monohydrate hydrochloride according to the procedure of Intermediate 22 as an off-white solid; 1H NMR (CDCl3) δ 2.57 (t, J=6.21 Hz, 2H), 3.77 (t, J=6.21 Hz, 2H), 7.60-7.84 (m, 1H), 8.25-8.32 (m, 1H), 8.40-8.46 (m, 1H); MS (ES) m/z 297.9 (MH+). C11H11N3O3S2
Reaction SMILES: [CH3:1][C:2]1[N+:7]([O-])=[CH:6][C:5]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[O:22][N:21]=3)=[CH:15][C:14]=2[CH3:29])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)[Cl:38]>>[Cl:38][CH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[O:22][N:21]=3)=[CH:15][C:14]=2[CH3:29])=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc(C)[n+]([O-])c1
Solvent: CCN(CC)CC
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc(CCl)nc1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a solution of 1.8 g (4.4 mmol) of 6-methyl-3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine-N-oxide in 18 ml of methylene chloride was added dropwise a solution of 0.41 ml (1.13 eq) POC13 in 4 ml of methylene chloride. After addition of 10% of POC13 solution, triethylamine (0.54 ml; 1.1 eq) in 4 ml of methylene chloride was added in portions. The exothermic mixture was stirred for 30 min, washed with saturated ammonium chloride solution, and the organic layer was separated and dried over sodium sulfate. The organic layer was concentrated in vacuo and purified by flash filtration through silica gel (hexane/ether, 2:1) to afford 0.59 g (31%) of 6-chloromethyl-3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethyl-phenoxy]-propyl]-pyridine (BIL-1991-187), as a pale yellow oil which solidified upon standing, m.p. 79°-81° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC>CN(C=O)C>[CH3:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([CH3:8])=[CH:7][C:2]=1[C:18](=[O:20])[CH3:19]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C)c([N+](=O)[O-])cc1C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-Bromo-2,5-dimethyl-4-nitrobenzene (1 g, 4.34 mmol) and tributyl(1-ethoxyvinyl)tin (1.88 g, 5.2 mmol) in DMF (20 mL), was added tetrakis(triphenylphospine) palladium (0) (250 mg, 5% mmol). The reaction tube was sealed, the mixture was purged with N2 for 3 min and then heated at 90° C. under N2 for overnight. The reaction was cooled to room temperature and poured into aqueous HCl (1N, 100 mL). The mixture was stirred for 1 hour, and then extracted with ethyl acetate (3×100 mL). The organic extracts were combined, washed with brine and concentrated. The crude product was purified with silica gel chromatography (20% ethyl acetate in hexanes) to afford 1-(2,5-dimethyl-4-nitrophenyl)ethanone as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:19])=[CH:10][N:11]2[CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl.C(Cl)Cl>CO.O>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:13]=2)[C:9]([CH3:19])=[CH:10]1
Reactant: COCCCn1cc(C)c2ccc(C(=O)OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COCCCn1cc(C)c2ccc(C(=O)O)cc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3-methoxy-propyl)-3-methyl-1H-indole-6-carboxylic acid methyl ester (1.56 g, 6.3 mmol) in MeOH (20 mL) and H2O (1 mL) is added NaOH (756 mg, 18.9 mmol) and the mixture is stirred at 50° C. overnight. Then neutralized by the addition of water and HCl 1.0 M (3 eq, 18.9 mmol). CH2Cl2 is added, the layers are separated, and the aqueous one is extracted twice with CH2Cl2. The combined organic layers are dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material is obtained in a pure form and is used in the next step without purification. MS (LC-MS): 248.0 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 4.93 min.
Reaction SMILES: [CH2:1](O)[C:2]#[CH:3].S(=O)(=O)(O)O.[CH3:10][C:11]1[C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:13]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][C:31]=2[CH3:32])[N:12]=1>>[CH3:10][C:11]1[C:15]([CH2:16][C:17]([O:19][CH2:3][C:2]#[CH:1])=[O:18])=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:13]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][C:31]=2[CH3:32])[N:12]=1
Reactant: Cc1ccncc1-n1nc(C)c(CC(=O)O)c1-c1ccccc1
Reactant: C#CCO
Agent: O=S(=O)(O)O
Product: C#CCOC(=O)Cc1c(C)nn(-c2cnccc2C)c1-c1ccccc1

Procedure:
0.445 g (6.345 mmol) of prop-2-yn-1-ol and a drop of concentrated sulfuric acid were added to 0.130 g (0.423 mmol) of [3-methyl-1-(4-methylpyridin-3-yl)-5-phenyl-1H-pyrazol-4-yl]acetic acid, and the mixture was stirred under reflux for 4 h. The solvent was removed under reduced pressure, a mixture of 10 ml of dichloromethane, 1.5 ml of diisopropylethylamine and 10 ml of water was added to the residue and the aqueous phase was extracted with 15 ml of dichloromethane. The combined organic phases were dried over sodium sulfate, and the solvent was removed under reduced pressure. Chromatography of the residue gave 0.083 g (57% of theory) of a light-beige solid of melting point 106° C.
Reaction SMILES: Cl.NO.[CH:4]1[C:16]2[N:15]([CH2:17][C:18]#[CH:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.C(N)C.Br[C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[Cl-].[Na+].Cl.[K+].[Br-]>O.CN(C)C=O>[CH:13]1[C:14]2[N:15]([CH2:17][C:18]#[C:19][C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:16]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CCCCCCCCCCCCC#CBr
Reactant: C#CCn1c2ccccc2c2ccccc21
Agent: CCN
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCC#CC#CCn1c2ccccc2c2ccccc21
Temperature: 37 °C
Yield: 96 %

Procedure:
A 250 ml, three-necked, round bottom flask was fitted with mechanical stirrer, addition funnel, reflux condenser, thermometer and means for providing nitrogen atmosphere. To the flask was added 0.5 g of hydroxylamine hydrochloride, 0.25 g of cuprous chloride, 15.0 g (0.073 mole) of 3-(N-carbazolyl) propyne (prepared as in Example 2A), 75 ml of dimethylformamide, 12 ml of water, and 12 ml of 70% ethylamine. The resulting mixture was stirred and heated to 37° C., and 21.9 g (0.080 mole) of 1-bromo-1-tetradecyne (from Example 17A) was added dropwise over a period of 30 min at a temperature of 37° to 52° C. After stirring and heating at 50° to 55° C. for an additional 75 min, the reaction mixture was cooled to room temperature and poured into an aqueous solution of 150 ml of sodium chloride containing 5 ml of concentrated HCl. The resulting mixture was extracted four times with 100 ml portions of ether. The combined ethereal layers were washed ten times with 50 ml portions of 0.6 N HCl, twice with 50 ml portions of sodium bicarbonate, dried and concentrated, resulting in 28.0 g (96% yield), of yellow powder, m.p. 53°-58° C. Recrystallization once from methanol gave colorless long needle crystals, m.p. 71°-72° C. I.R. (KBr Pellet) in cm-1 : 3060 (Ar--H), 2920+2850 (CH), 2260 (C≡C), 1620+1600 (C=C), 1480 (CH2), 1460+1330 (CN), 750+720 (Ar H). Anal: Calculated for C29H35N: C, 87.60%; H, 8.87%; N, 3.52%; found: C, 88.32%; H, 8.72%; N, 3.45%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[H-].[Na+].Br.Br[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C(OCC)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Reactant: BrCc1cccnc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A solution of 1 g (4.73 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate is added dropwise to a suspension of 0.38 g (9.45 mmol) of 60% sodium hydride in 10 ml of dimethylformamide, stirred at 0° C. under argon. The mixture is stirred for 30 minutes at 0° C. and then for 30 minutes at 20° C. The reaction mixture is cooled and 1.24 g (4.8 mmol) of 3-bromomethylpyridine hydrobromide are added portionwise. The mixture is stirred for 30 minutes at 0° C. and then for 30 minutes at 20° C. The reaction mixture is cooled again to 0° C. and a further 0.38 g (9.45 mmol) of 60% sodium hydride in 10 ml of dimethylformamide is added. After 30 minutes at 0° C., 1.24 g (4.8 mmol) of 3-bromomethylpyridine hydrobromide are added portionwise. The reaction mixture is stirred for 58 hours at 20° C. The mixture is then poured into a solution of 100 ml of ice-water and 100 ml of ethyl ether. The organic phase is separated out and the aqueous phase is re-extracted with 100 ml of ethyl ether. The organic phases are combined, washed with 50 ml of water and then dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue is purified by preparative chromatography (eluent: dichloromethane/acetone). 0.5 g of expected product is obtained in the form of a solid, which is used without further purification in the subsequent synthesis.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
(2-Chloro-6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure B to give, after purification by reverse HPLC, 10 mg of 221. MS (Q1) 491 (M+).
Reaction SMILES: [BH4-].[Na+].[C:3]([CH:6]([CH2:16][CH2:17][CH2:18][CH:19]([OH:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:5])[CH3:4].[OH-].[Na+].Cl>CCOCC.O>[OH:5][CH:3]([CH:6]([CH2:16][CH2:17][CH2:18][CH:19]([OH:29])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH3:4]
Reactant: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Reaction time: 19 h

Procedure:
Sodium borohydride (1.2 g., 0.03 mole) is added to a solution of 8-acetyl-12-hydroxy-13-(4-fluorophenoxy)-tridecanoic acid (15.4 g., 0.04 mole) and sodium hydroxide (2.0 g., 0.05 mole) in 70 ml. of water. The resulting solution is allowed to stand at room temperature for 19 hours, and is then acidified to Congo Red with concentrated hydrochloric acid. The oil product is taken up in ether, washed with water and dried over sodium sulfate. The ether is evaporated leaving 12.8 g. of the crude title compound as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([Br:10])[C:3]=1[NH2:4].[C:11]1(=O)[O:16][C:14](=[O:15])[CH:13]=[CH:12]1.[Sn](Cl)Cl>>[Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([Br:10])[C:3]=1[N:4]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16]
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1c(Br)cc(Br)cc1Br
Agent: Cl[Sn]Cl
Product: O=C1C=CC(=O)N1c1c(Br)cc(Br)cc1Br
Temperature: 142 °C
Reaction time: 1.9 h

Procedure:
A mixture of 2,4,6-tribromoaniline (1.20g, 3.64 mmol), maleic anhydride (0.83g, 8.5 mmol) and tin(II) chloride (0.064g, 0.34 mmol) is heated to 142° C. with mixing and held at this temperature for 1.9 hours. The reaction mixture is cooled, extracted with xylene, filtered and the resulting filtrate water washed. Solvent removal yielded N-(2,4,6-tribromophenyl)maleimide. Analysis by High Pressure Liquid Chromatography (HPLC) showed conversion of 2,4,6-tribromoaniline to be 99.9% and selectivity to N-(2,4,6-tribromophenyl)maleimide based on reacted 2,4,6-tribromoaniline of 75.0%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[CH2:21]1[O:23][CH:22]1[CH2:24][OH:25].CS(O)(=O)=O>CO>[OH:23][CH:22]([CH2:24][OH:25])[CH2:21][O:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CO1
Reactant: Cc1c(-c2cccc(O)c2)oc2ccccc12
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(-c2cccc(OCC(O)CO)c2)oc2ccccc12
Temperature: 200 °C

Procedure:
The ester which results from the condensation of 2'-hydroxyacetophenone and m-anisic acid is converted to 2-(3-methoxyphenyl)-3-methylbenzofuran by reductive cyclization in dioxane with a titanium tetrachloride/zinc metal catalyst according to the method of Banerji and Nayak, J. Chem. Soc., Chem. Comm., (1990), 150. The 2-(3-methoxyphenyl)-3-methylbenzofuran (47.6 gm, 0.198 mol) is treated with several volumes of pyridine hydrochloride at 200° C. for about 6 hours to cleave the methyl ether moiety to the free hydroxyl group. Three volumes of water are added to the cooled reaction mixture and the system is extracted twice with ether. The ether extracts are combined, washed once with water and then dried over sodium sulfate. Removal of solvent by rotary evaporation affords the desired product, 2-(3-hydroxyphenyl)-3-methylbenzofuran. 2-(3-hydroxyphenyl)-3-methylbenzofuran (22.4 gm 0.1 mol) is dissolved in 100 mL of methanol in a 250 ml round bottom flask under an atmosphere of argon. To this well stirred solution is added sodium methoxide (0.54 gm, 0.01 mol). Glycidol (Aldrich, 8.14 gm, 0.11 mol) is added and the system is gradually heated and held at reflux for 18 hours. The solution is neutralized with methanesulfonic acid. The solvent is removed by rotary evaporation. The resulting product is heated on a Kugelrohr apparatus at 200° C. under a vacuum of 1 mm Hg, to remove any 3-methoxy-1,2-propanediol by-product, affording 2-[3-(2,3-dihydroxypropoxy)phenyl]-3-methylbenzofuran having the structure: ##STR55##