Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:17](=[O:20])(=[O:19])[NH2:18])[C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:5]([OH:7])=[O:6].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:29](O)[CH3:30]>>[CH2:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:17](=[O:19])(=[O:20])[NH2:18])[C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:5]([O:7][CH2:29][CH3:30])=[O:6])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1N1CCCCC1
Reactant: CCO
Product: CCOC(=O)c1cc(NCc2ccccc2)c(N2CCCCC2)c(S(N)(=O)=O)c1

Procedure:
A mixture of 3-amino-4-piperidino-5-sulphamyl-benzoic acid (2.5 g), benzyl bromide (1.4 g), and dry ethanol (30 ml) was refluxed for 3 days. The reaction mixture was evaporated in vacuo, and the residue was washed with petroleum ether. The crude ethyl 3-benzylamino-4-piperidino-5-sulphamyl-benzoate obtained was saponified by addition of 1N sodium hydroxide and heated on a steam bath for 1 hour. After cooling and adjusting the pH to 4 by means of a 4N hydrochloric acid, 3-benzylamino-4-piperidino-5-sulphamyl-benzoic acid precipitated. After collecting and recrystallizing from aqueous ethanol, the compound was obtained as a hemi-hydrate with a melting point of 195° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:12]([OH:22])[CH:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Br:30].C(=O)([O-])[O-].[K+].[K+].O.[C:38]1(C)C=CC(S(O)(=O)=O)=C[CH:39]=1>CC(=O)CC>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:38][CH3:39])=[O:20])=[C:12]([O:22][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Br:30])[CH:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: BrCCCCCBr
Reactant: CCOC(=O)CCc1ccc2c(CCC(=O)O)c(O)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)CCc1ccc2c(CCC(=O)OCC)c(OCCCCCBr)ccc2n1
Temperature: 90 °C
Reaction time: 37 h
Yield: 83 %

Procedure:
A mixture of 0.866 g (2.51 mmol) of 6-hydroxy-2,5-quinolinedipropanoic acid ethyl ester from the preceding example, 2.33 g (10.1 mmol) of 1,5-dibromopentane, 1.75 g (12.7 mmol) of anhydrous granular potassium carbonate and 25 mL of 2-butanone was stirred at 90° C. for 8.25 hr and at room temperature for another 37 hr. The mixture was filtered through anhydrous magnesium sulfate and the solids were washed with ethyl acetate. The filtrate and washes were combined and concentrated under reduced pressure. The residue was dissolved in 200 mL of ethanol, 1.21 g (6.36 mmol) of p-toluenesulfonic acid monohydrate was added and the resulting solution was stirred at room temperature for 22 hr. Most of the ethanol was removed under reduced pressure. The residue was treated with saturated aqueous sodium bicarbonate and worked-up with ethyl acetate in the usual manner. The crude product was partially purified by flash chromatography on 110 g of silica gel, eluting with hexane-ethyl acetate (3:1 and 2:1) giving 1.03 g of the title compound.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([S:42]([CH3:41])(=[O:44])=[O:43])[N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)Nc2c(C)cc3cn(S(C)(=O)=O)nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropylamide (0.800 g, 1.71 mmol) in dichloromethane (5.0 mL) was added triethylamine (0.476 mL, 3.42 mmol), followed by methanesulphonyl chloride (0.265 mL, 3.42 mmol). The dark colored homogeneous reaction mixture was stirred for 1 h at 20° C. The reaction mixture was then concentrated in vacuo and the residue was purified by flash-chromatography (SiO2, CH2Cl2/ethyl acetate 4:1) yielding a brown solid that was recrystallized from ethyl acetate to afford the title compound as colourless crystals with a melting range of 135-175° C. (with decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]4[CH2:28][CH2:27][N:26]([C:29](=[O:32])[CH2:30][Cl:31])[CH2:25][C:20]=4[N:21]3[CH3:24])=[CH:17][CH:16]=2)[C:11](=[O:33])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[ClH:31].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]4[CH2:28][CH2:27][N:26]([C:29](=[O:32])[CH2:30][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:25][C:20]=4[N:21]3[CH3:24])=[CH:17][CH:16]=2)[C:11](=[O:33])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCN(C(=O)CCl)C2
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cl
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCN(C(=O)CN1CCCC1)C2
Temperature: 80 °C
Yield: 89.7 %

Procedure:
4-(Benzyloxy)-1-(2-(2-chloroacetyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one (120 mg. 0.23 mmol), pyrrolidine (85 mg, 1.2 mmol) and K2CO3 (331 mg, 2.39 mmol) were combined in DMF (3 mL) and heated to 80° C. for 1 h. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried over Na2SO4 and concentrated. The residue was converted to the hydrochloride salt as of Example 30 (step g) to provide the title compound (110 mg, 60%) as a yellow solid: mp 190-200° C.; 1H NMR (500 MHz, CD3OD) δ 7.86 (d, J=7.5 Hz, 1H), 7.62 (dd, J=8.2, 2.7 Hz, 1H), 7.51-7.50 (m, 3H), 7.46-7.43 (m, 2H), 7.41-7.40 (m, 1H), 7.08-7.06 (m, 1H), 6.63 (dd, J=7.8, 2.6 Hz, 1H), 6.40 (d, J=1.4 Hz, 1H), 5.31 (s, 2H), 4.93 (s, 1.3H), 4.77 (s, 0.7H), 4.56-4.55 (m, 2H), 4.04-4.02 (m, 0.6H), 3.81-3.78 (m, 3.4H), 3.76 (s, 3H), 3.24-3.19 (m, 2H), 2.79-2.97 (m, 1.3H), 2.92-2.85 (m, 0.7H), 2.22-2.19 (m, 2H), 2.11-2.19 (m, 2H); ESI MS m/z 497 [M+H]+; HPLC (Method B)>99% (AUC), tR=13.7 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH2:9][CH:8]2[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH:24]=[CH:23]3)[CH2:16][CH2:15]1.[C:29]([OH:34])(=[O:33])[C:30]([NH2:32])=[O:31]>>[C:29]([OH:34])(=[O:33])[C:30]([OH:2])=[O:31].[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([N:17]3[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH:8]4[C:7]5[C:11](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=5)[N:10]([C:29](=[O:33])[C:30]([NH2:32])=[O:31])[CH2:9]4)[CH2:19][CH2:18]3)=[CH:28][CH:27]=2)[CH:23]=[CH:24]1
Reactant: NC(=O)C(=O)O
Reactant: COc1cccc2c1NCC2CCN1CCN(c2ccc3[nH]ccc3c2)CC1
Product: COc1cccc2c1N(C(=O)C(N)=O)CC2CCN1CCN(c2ccc3[nH]ccc3c2)CC1
Product: O=C(O)C(=O)O

Procedure:
from 5-{4-[2-((RS)-7-methoxy-2,3-dihydro-1H-indol-3-yl)-ethyl]-piperazin-1-yl}-1H-indole and oxalamic acid.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C@H:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([F:19])=[CH:13][C:14]=3[F:18])[CH2:9]2)[C:6](=[S:20])[NH:5][CH:4]=1.[CH:21]([O-:23])=O.[NH4+:24]>O>[F:18][C:14]1[CH:13]=[C:12]([F:19])[CH:11]=[C:10]2[C:15]=1[CH2:16][CH2:17][C@H:8]([N:7]1[C:3]([CH2:2][NH:24][CH:21]=[O:23])=[CH:4][NH:5][C:6]1=[S:20])[CH2:9]2
Reactant: O=C[O-]
Reactant: OCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Reactant: [NH4+]
Solvent: O
Product: O=CNCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Temperature: 125 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A mixture of (S)-5-hydroxymethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (1.0 g, 3.5 mmol), prepared as in Example 18, and ammonium formate (10 g, 158.6 mmol) was stirred at approximately 125° C. for 1 hour. The mixture was then heated to approximately 138° C. and stirred for an additional 35 minutes. The mixture was diluted with 25 mL of water and allowed to cool to room temperature. The mixture was aged for approximately 18 hours giving a crystalline material. The material was isolated by filtration and the filter residue was washed with water. Drying to constant weight gave (S)-N-[3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl]formamide (0.92 g, 2.96 mmol).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.N1CCCC1.BrC[C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=C[C:18]=1[F:26].CCOC(C)=O>C1COCC1>[F:26][C:18]1[CH:17]=[CH:22][C:21]([N+:23]([O-:25])=[O:24])=[CH:20][C:9]=1[CH2:7][N:3]1[CH2:2][CH2:1][CH2:6][CH2:4]1
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.9 %

Procedure:
A −20° C. mixture of DIEA (552 mg, 4.27 mmol) and pyrrolidine (152 mg, 2.137 mmol) in THF (5 mL) was treated drop-wise with a solution of 2-(bromomethyl)-1-fluoro-4-nitrobenzene (500 mg, 2.137 mmol) in THF (5 mL), allowed to warm to RT and stirred for 6 h. The mixture was treated with EtOAc, washed with water, then brine, dried over Na2SO4 and concentrated to dryness to afford 1-(2-fluoro-5-nitrobenzyl)pyrrolidine (450 mg, 94% yield). MS (ESI) m/z: 225.1 [M+H]+.
Reaction SMILES: [Br:1][CH:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH2:15][C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:19]=[CH:18][N:17]=1>>[BrH:1].[BrH:1].[CH2:2]([N:17]1[CH:18]=[CH:19][C:20]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)=[CH:21][C:16]1=[NH:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:17]1[CH:18]=[CH:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[CH:21][C:16]1=[NH:15]
Reactant: Cc1ccc(-c2ccnc(N)c2)cc1
Reactant: CCCCCCCCCCCC(Br)Br
Product: Br
Product: Cc1ccc(-c2ccn(CCCCCCCCCCCCn3ccc(-c4ccc(C)cc4)cc3=N)c(=N)c2)cc1

Procedure:
The procedure is as above, with dibromododecane and 2-amino-4-para-tolylpyridine, which is synthesized according to Chambron J.Cl. Strasbourg Tetrah. 1987 43 (5) 895/905. The product obtained is purified in the base state on a silica column with a benzene/ethyl acetate mixture. It is reconverted to the hydrobromide with a mixture of ether and an isopropanol solution of hydrogen bromide. It can then be recrystallized.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(=O)CC>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCc1cccc(O)c1)OCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cccc(CCNC(=O)OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A suspension of 12.79 g. (47.1 mMol) 3-[2-(benzyloxycarbonylamino)-ethyl]-phenol, 120 ml. butan-2-one and 19.5 g. pulverised potassium carbonate is maintained at reflux temperature for 1 hour, then cooled, 200 mg. pulverised potassium iodide and 9.12 g. (51.9 mMol) ethyl bromoacetate added thereto and the reaction mixture stirred for 18 hours at 90° C. Subsequently, it is filtered off with suction and the filter cake is washed with hot butan-2-one. The combined butanone phases are evaporated, the oily residue is taken up in diethyl ether and the ethereal phase is extracted twice with ice-cold 2N aqueous sodium hydroxide solution, and thereafter with ice water. After drying with anhydrous sodium sulphate, it is evaporated in a vacuum. There are obtained 15.62 g. (93% of theory) of the desired product in the form of a colourless oil.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH:19]([CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23]1)([CH3:21])[CH3:20].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH:19]([CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1)([CH3:21])[CH3:20]
Reactant: CC(C)C1Cc2ccccc2N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)C1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 62 %

Procedure:
The product is prepared by following the procedure described in example 1c using 0.30 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 0.17 g of (−)-2-isopropylindoline and 0.27 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.26 ml of pyridine and 4.4 ml of N,N-dimethylformamide. 0.25 g of (−)-2-[2-(2-isopropyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (reference example 11c) is thus obtained in the form of a very pale pink solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]([S:25]([CH3:28])(=[O:27])=[O:26])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([B:16]2[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]2)=[CH:12][CH:11]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Li+].BrC1C=CC(CCC(C)(S(C)(=O)=O)C(O)=O)=CC=1>>[CH3:1][C:2]([S:25]([CH3:28])(=[O:26])=[O:27])([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([B:16]2[O:20][C:19]([CH3:21])([CH3:22])[C:18]([CH3:23])([CH3:24])[O:17]2)=[CH:14][CH:15]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)S(C)(=O)=O
Agent: CC(CCc1ccc(Br)cc1)(C(=O)O)S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Product: CC1(C)OB(c2ccc(CCC(C)(C(=O)O)S(C)(=O)=O)cc2)OC1(C)C
Yield: 112.7 %

Procedure:
The title compound (5.47 g, 100%) was prepared from (+/−)-ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoate (5.2 g, 12.7 mmol) and lithium hydroxide (2.13 g, 50.8 mmol) by a procedure analogous to that described for (+/−)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoic acid (II/Step 3-Preparation Number 2). LCMS m/z 381.6 (M−1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 12H) 1.75 (s, 3H) 2.19-2.30 (m, 1H) 2.44-2.55 (m, 1H) 2.56-2.67 (m, 1H) 2.76-2.87 (m, 1H) 3.09 (s, 3H) 7.23 (d, J=8.01 Hz, 2H) 7.76 (d, J=8.20 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[OH:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1)[CH2:15][NH2:16].[BH4-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:16][CH2:15][CH:14]([OH:13])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=2)[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(CC(C)NCC(O)c2cccc(Br)c2)cc1

Procedure:
1-(4-Methoxyphenyl)propan-2-one (3.10 g) and 2-hydroxy-2-(3-bromophenyl)ethanamine (4.08 g) were condensed and subsequently reduced with sodium borohydride (3.8 g) by an analogous procedure to that described in Example 1. The crude product was recrystallised from diethyl ether-hexane to give N-[2-(4-methoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-bromophenyl)ethanamine, mp 79°-83° C., as a 47:53 mixture of diastereoisomers.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([OH:10])=O.C(Cl)[Cl:12]>C(Cl)(=O)C(Cl)=O.CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([Cl:12])=[O:10]
Reactant: ClCCl
Reactant: O=C(O)CCc1cccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1cccs1

Procedure:
To a solution of 5.0 g (0.032 mol) of 3-(2-thienyl)propionic acid in 2 ml of methylene chloride and 25 ml of oxalyl chloride was added three drops of N,N-dimethylformamide slowly. Following evolution of the gas the reaction mixture was concentrated under vacuum and 20 ml of hexane was added to the residue. The resulting mixture was filtered and the filtrate was concentrated under vacuum. The resulting compound, 3-(2-thienyl)propionyl chloride, was used directly in the following reaction.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15]N(C=O)C.CI>O>[CH3:15][O:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Oc1cccc2c1oc1ccccc12
Solvent: CI
Solvent: O
Product: COc1cccc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of 4-hydroxydibenzo[b,d]furan (2 g, 0.0109 mol) in DMF (5 mL) potassium carbonate (3.2 g, 0.0232 mol) and methyl iodide (1.35 mL, 0.0217 mol) was added. The reaction slurry was stirred at room temperature for 3 h. Subsequently the reaction mixture was poured into the cold water (100 mL) and extracted with hexane (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated at reduced pressure to, give the desired product in 66% yield, Rf 0.74 (Ethyl acetate:Hexane (3:7); MS m/z: 199.1 (M+1).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]1[CH2:8][CH:7]2[O:9][CH:6]2[CH2:5][CH2:4]1.[C:10]([OH:21])(=[O:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].C(N([CH2:27][CH3:28])CC)C>C1(C)C=CC=CC=1>[OH:9][CH:7]1[CH2:8][CH2:3][CH:4]([CH:27]=[CH2:28])[CH2:5][CH:6]1[O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([O:21][CH:7]1[CH2:8][CH:3]([CH:2]=[CH2:1])[CH2:4][CH2:5][CH:6]1[OH:9])=[O:20]
Reactant: C=CC1CCC2OC2C1
Reactant: O=C(O)CCCCCCC(=O)O
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC1CCC(O)C(OC(=O)CCCCCCC(=O)OC2CC(C=C)CCC2O)C1
Temperature: 90 °C
Yield: 22 %

Procedure:
As shown in scheme 1, the reagents, 4-vinyl-1-cyclohexene-1,2-epoxide (12.4 g, 0.1 moles), suberic acid (13.7 g, 0.07 moles), triethylamine (15.9 g, 0.016 moles) and toluene (60 mL) were combined in a reaction flask equipped with a stir bar, water condenser and drying tube. Cuprous chloride and 2,5-diphenylbenzoquinone (200-500 ppm) were added to inhibit polymerization. The temperature of the reaction flask was controlled with a thermal heating unit. The reaction mixture was heated to 90° C., and the progress of the reaction monitored by gas chromatography (GC). After about 5 hours the epoxide could not be detected by GC analysis. The reaction mixture was washed twice with 2N HCl and twice with 2N NaOH (100 ml each washing). The organic layer was then dried with magnesium sulfate and the toluene removed by flash evaporation. Methanol was used to remove the last traces of toluene by azetropic distillation. A vacuum was applied to the distilled product (pressure less than one mm for several hours with gentle heating at 50° C. A brown viscous oil, 6.4 g (22% yield) was obtained. The product was analyzed by electo-spray time of flight mass spectroscopy (M+H and M+Na fragments).
Reaction SMILES: C([CH:3](CC)[C:4]([CH3:9])([CH3:8])[C:5](=[NH:7])[NH2:6])C.[CH2:12]([O:14][CH:15]=[C:16]([C:20]([O-])=O)[C:17]([O-])=[O:18])[CH3:13].[O-:23]CC.[Na+].C(O)C>C(O)C>[C:4]([C:5]1[NH:6][C:17](=[O:18])[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:23])=[CH:20][N:7]=1)([CH3:3])([CH3:8])[CH3:9]
Reactant: CCC(CC)C(C)(C)C(=N)N
Reactant: CC[O-]
Reactant: CCOC=C(C(=O)[O-])C(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(C(C)(C)C)[nH]c1=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
To a solution of diethyl 2,2-dimethylpropanimidamide m hydrochloride (1.36 g) and (ethoxymethylene)malonate (2.16 g) in ethanol (100 ml) was added 20% sodium ethoxide-ethanol solution (6.8 g) under ice-cooling, and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid (10 ml) was added under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, hexane was added to the residue, and the precipitate was collected by filtration to give the object product(1.65 g) as a powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]=[C:25]=[O:26])[CH:19]=1>C(Cl)Cl>[F:17][C:18]1[CH:19]=[C:20]([NH:24][C:25]([NH:13][C:12]2[CH:14]=[CH:15][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(F)c3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 g, 4.43 mmol) in CH2Cl2(30 ml) under argon was treated with 1-fluoro-3-isocyanatobenzene (0.515 ml, 4.43 mmol), added dropwise. The reaction was stirred at room temperature for 18 hours, and was concentrated to a solid. Methylene chloride and hexane were added to precipitate the product, which was collected and dried in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 4-methyl-3-nitrobenzoyl chloride (2.0 g) in dichloromethane (20 ml), a solution of triethylamine (0.7 ml) and 3-chloro-4-fluoroaniline (0.7 g) in dichloromethane (15 ml) was added dropwise in an ice-bath with the temperature no more than 5° C. After addition, the reaction was carried out for 30 min in an ice-bath, and then at room temperature overnight. The completion of reaction was indicated by TLC. Then potassium carbonate solution (10%) was added to precipitate a solid. The mixture was left to stand, and filtered. The filter cake was washed with water, and dried to give a pale yellow powdered solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([NH:15][OH:16])=[NH:14].[O-2].[Mg+2].[C:19]1([S:25][CH2:26][C:27](Cl)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[C:19]1([S:25][CH2:26][C:27]2[O:16][N:15]=[C:13]([CH2:12][N:3]3[C:2](=[O:1])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:4]3=[O:11])[N:14]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)CSc1ccccc1
Reactant: N=C(CN1C(=O)c2ccccc2C1=O)NO
Agent: [Mg+2]
Agent: [O-2]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1noc(CSc2ccccc2)n1
Temperature: 105 °C
Reaction time: 0.25 h
Yield: 53.8 %

Procedure:
To 10 g (0.046 mol) of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-hydroxy-acetamidine dissolved in 500 mL of DMF, 1.84 g (0.046 mol, 1 eq) of magnesium oxide were added. After 15 min, 8.5 g (0.046 mol, 1 eq) of phenylsulfanyl-acetyl chloride were added, and the temperature was raised to 105° C. and the solution was stirred overnight. The reaction mixture was partitioned between aqueous NH4Cl and EtOAc, dried over Na2SO4. Column chromatography on silica gel with EtOAc/Heptane 1:1 yielded 8.7 g (55%) of 2-(5-phenylsulfanylmethyl-[1,2,4]oxadiazol-3-ylmethyl)-isoindole-1,3-dione as a light yellow solid, MS: 352 (MH+).