Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([Cl:17])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1)=O.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl.O>C(O)C>[Cl:1][CH:2]([Cl:17])[C:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=2)[N:24]([C:23]2[CH:18]=[CH:19][C:20]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:21][CH:22]=2)[N:25]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(C(=O)CC(=O)C(Cl)Cl)cc1F
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc(C(Cl)Cl)nn2-c2ccc(S(N)(=O)=O)cc2)cc1F
Yield: 63 %

Procedure:
4,4-Dichloro-1-(3-fluoro-4-methoxyphenyl)-butane-1,3-dione from Step (2 (2.8 g, 10 mmol) was dissolved in ethanol (100 mL). To the stirred mixture was added 4-sulfonamidophenylhydrazine hydrochloride (2.46 g, 11 mmol) and heated to reflux for 16 hours. The mixture was cooled and water was added until crystals slowly appeared. Filtration yielded a light tan solid (2.7 g, 63%): mp 190-193°C.; 1HNMR (DMSO-d6) 7.84 (d, J=8.4 Hz, 2H), 7.53 (s, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.47 (brs, 2H), 7.3-7.0 (m, 3H), 6.95 (s, 1H), 3.85 (s, 3H). Anal. Calc'd for C17H14N3SO3FCl2: C, 47.45; H, 3.28; N, 9.76. Found: C, 47.68; H, 3.42; N, 10.04.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][NH:10][C:9](=O)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C=O.S(Cl)([Cl:21])=O>ClC1C=CC=CC=1>[Cl:21][C:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=2[S:11][N:10]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]sc2c([N+](=O)[O-])cccc12
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1cccc2c(Cl)nsc12
Reaction time: 1 h
Yield: 86 %

Procedure:
A 1 L four-neck flask equipped with a stirrer, a thermometer and a condenser tube was charged with 98.1 g (0.5 mol) of 7-nitro-1,2-benzisothiazol-3-one, 146.2 g (2 mol) of N,N-dimethylformamide and 500.0 g of chlorobenzene. While stirring, 119.0 g (1.0 mol) of thionyl chloride was added dropwise thereto at 80° to 90° C. over 1 hour, and the mixture was reacted at the same temperature for 3 hours. After terminating the reaction, the liquid reaction mixture was concentrated, and a crude product obtained was recrystallized from toluene to give 91.2 g (0.43 mol) of 3-chloro-7-nitro-1,2-benzisothiazole. The yield based on 7-nitro-1,2-benzisothiazol-3-one was 85%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([OH:14])[C@H:5]([OH:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O[C@H:17]([C@@H:22](O)[CH2:23][C:24]1C=CC=CC=1)[C:18](OC)=O>>[CH3:1][O:2][C:3]([C@@H:4]1[C@@H:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:13][C:22]([CH2:23][CH3:24])([CH2:17][CH3:18])[O:14]1)=[O:15]
Reactant: COC(=O)[C@@H](O)[C@H](O)Cc1ccccc1
Reactant: COC(=O)[C@H](O)[C@@H](O)Cc1ccccc1
Product: CCC1(CC)O[C@H](C(=O)OC)[C@@H](Cc2ccccc2)O1
Yield: 50 %

Procedure:
The substantially same method as described in Example 263 was conducted, except that (2S,3R)-methyl-2,3-dihydroxy-4-phenylbutanoate (Preparation example 269) was used instead of (2,3-dihydroxy-4-phenylbutanoate (Preparation example 260), to obtain the title compound (1.5 g, 50˜75%)
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:16][CH2:17][OH:18])[CH2:3][CH2:4][C:5]12[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:9](=[O:15])[NH:8][C:6]2=[O:7].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][C:2]([CH3:19])([CH2:16][CH2:17][O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:3][CH2:4][C:5]12[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:9](=[O:15])[NH:8][C:6]2=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CCO)CCC12C=CC=CC1C(=O)NC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCOS(C)(=O)=O)CCC12C=CC=CC1C(=O)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.57 g (6.0 mmol) of 1-(3,3-dimethyl-5-hydroxypentyl)phthalimide and 0.92 ml (6.6. mmol) of triethylamine in 30 ml of dichloromethane was added, at 0° C., 0.51 ml (6.6 mmol) of methanesulfonyl chloride. The mixture was stirred for 30 minutes at room temperature, to which was added a saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with dichloromethane. The extract was dried, followed by distilling off the solvent to give 1-(3,3-dimethyl-5-methanesulfonyloxypentyl)phthalimide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].Cl[CH2:19][CH:20]([OH:29])[CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>O>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][CH2:21][CH:20]([OH:29])[CH2:19][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][CH:10]=[CH:11][N:12]=3)=[CH:6][CH:7]=2)[CH:24]=1
Reactant: OC(CCl)CCc1cccnc1
Reactant: Oc1ccc(-c2nccs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC(CCc1cccnc1)COc1ccc(-c2nccs2)cc1

Procedure:
Prepared according to the method as described in Example 24b) from 2-(4-hydroxyphenyl)thiazole (1 g), ethanol (20 ml), sodium hydroxide (0.255 g), water (5 ml) and (±)-α-(chloromethyl)-3-pyridinepropanol (1 g, from Example 24a)) to give the title compound after purification as a white solid (0.42 g).
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[CH:3]/[CH2:4]Cl.[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C1C=CC=CC=1.[OH-].[K+]>O>[CH:2]([CH:3]1[CH2:4][C:8]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([O:15][CH2:16][CH3:17])=[O:14])=[CH2:1]
Reactant: ClC/C=C/CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: C=CC1CC1(C(=O)OCC)C(=O)OCC
Temperature: 60 °C
Yield: 65.7 %

Procedure:
To illustrate yet another variation of the present process a reaction vessel fitted with a suitable stirrer, Dean-Stark trap, and condenser was charged with 866 g (6.9 mol) trans 1,4-dichlorobutene-2, 640 g (4.0 mol) diethyl malonate, 1.2 g (0.08 mol percent based on malonate) tricaprylylmethylammonium chloride and 1.8 liters benzene. The reactor and its contents were heated to 60° C. with stirring and incremental additions of flaked solid (85%) potassium hydroxide made over a 4.75-hour period while azeotropically removing water of reaction. A total of 528 grams solid KOH were charged. After 5.5 hours the theoretical amount of water was removed and the reaction mixture was cooled, filtered to remove potassium salts and the benzene solution concentrated. The crude brown oil, upon distillation at reduced pressure, yielded the desired diethyl 2-vinylcyclopropane-1,1-dicarboxylate (65.7% yield).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.[OH-].[Na+]>O>[CH3:15][C:12]1([CH3:16])[CH2:11][CH2:10][N:9]([C:6]2[CH:7]=[N:8][C:3]([OH:2])=[CH:4][CH:5]=2)[CH2:14][CH2:13]1
Reactant: COc1ccc(N2CCC(C)(C)CC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)CCN(c2ccc(O)nc2)CC1
Temperature: 200 °C
Yield: 71.8 %

Procedure:
A mixture of 6′-methoxy-4,4-dimethyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl (1.28 g, 5.81 mmol) and pyridine hydrochloride (5.00 g, 43.3 mmol) was heated in a kugelrohr oven at 200° C. for 15 minutes. After cooling to room temperature water was added and the solution was made slightly basic with aqueous 1N sodium hydroxide. The solution was extracted three times with dichloromethane and the combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo, yielding the title compound (0.86 g, 72% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13].[H-].[Na+].Cl[S:19]([C:22]1[S:26][C:25]2[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:24]=2[C:23]=1[CH3:32])(=[O:21])=[O:20]>C1COCC1>[CH3:31][C:29]1[CH:28]=[CH:27][C:25]2[S:26][C:22]([S:19]([NH:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[S:12]([CH3:15])(=[O:14])=[O:13])(=[O:21])=[O:20])=[C:23]([CH3:32])[C:24]=2[CH:30]=1
Reactant: Cc1ccc2sc(S(=O)(=O)Cl)c(C)c2c1
Reactant: COC(=O)c1ccc(N)c(S(C)(=O)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(C)cc3c2C)c(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
Into 8.0 mL of THF was dissolved 183 mg of methyl 4-amino-3-methanesulfonylbenzoate, followed by addition of 96 mg of sodium hydride (oily, 60%) at 0° C. After 20 minutes of stirring at the same temperature, 250 mg of 2-chlorosulfonyl-5-methyl-3-methylbenzo[b]thiophene was added at 0° C., followed by 6 hours of stirring at room temperature. After confirmation of disappearance of the starting material, the reaction was terminated by adding 1 mol/L hydrochloric acid at 0° C., followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation and then the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1 to 1/1) to obtain 181 mg of the title compound as colorless powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6]([CH3:9])([CH3:8])[CH2:5][NH:4][CH2:3]1.[CH2:11]([O:18][CH2:19][CH:20]=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[CH2:11]([O:18][CH2:19][CH2:20][N:4]1[CH2:5][C:6]([CH3:9])([CH3:8])[O:7][C:2]([CH3:10])([CH3:1])[CH2:3]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)CNCC(C)(C)O1
Reactant: O=CCOCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CC1(C)CN(CCOCc2ccccc2)CC(C)(C)O1
Yield: 63.3 %

Procedure:
Dissolve 500 mg (2.79 mmol) of 2,2,6,6-tetramethyl-morpholine (500 mg, 2.79 mmol) in dichloroethane (10 mL). Add benzyloxy-acetaldehyde (470 μl, 3.35 mmol) and stir at room temperature for 20 min. Add sodium triacetoxyborohydride (770 mg, 3.63 mmol) and continue stirring at room temperature for 20 h. Pour the reaction mixture into 100 mL of 1N NaOH (100 mL) and extract with CH2Cl2 (2×100 mL). Wash the combined organic layers with brine (100 mL). Purify using silica gel chromatography, using a gradient of 0% to 10% (2N NH3 in MeOH)/CHCl3 as eluent, to give 490 mg (63%) of the desired product. MS (ES+) 278.3 (M+1)+.
Reaction SMILES: C1CO[C:3]([C@@H:5]2[C@:22]3([CH3:23])[C@H:8]([C@H:9]4[C@H:19]([C:20](=[O:24])[CH2:21]3)[C@:17]3([CH3:18])[C@H:12]([CH2:13][C@H:14]([OH:25])[CH2:15][CH2:16]3)[CH2:11][CH2:10]4)[CH2:7][CH2:6]2)([CH3:4])[O:2]1.C(O)(=O)C>C(Cl)(Cl)Cl>[OH:25][C@@H:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C@@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[C@H:20]([OH:24])[CH2:21][C@@:22]2([CH3:23])[C@H:8]3[CH2:7][CH2:6][C@@H:5]2[C:3](=[O:2])[CH3:4])[CH2:13]1
Reactant: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)CC[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@H](O)C[C@]12C
Reaction time: 18 h
Yield: 51.5 %

Procedure:
A solution of 20,20-ethylenedioxy-3α-hydroxy-5α-pregnan-11-one (350 mg.) in mthanol (20 ml.) was treated with 25% aqueous acetic acid (2 ml.) at room temperature. After 18 hr. more 25 % aqueous acetic acid (2 ml.) was added and after a further 27 hr. the mixture was diluted with chloroform, washed with water, dried (Na2SO4) and evaporated to leave a white foam (300 mg.). Crystallisation from acetone and petroleum ether (b.p. 60°-80°) gave the title compound (160 mg.) as off-white rods; m.p. 152°-154°; [α]D + 79°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[C:12]12[C:29](=O)[O:28][C:26](=[O:27])[C:24]3=[C:25]1[C:16](=[CH:17][C:18]1[C:23]3=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:15]=[CH:14][CH:13]=2>C(O)C>[O:27]=[C:26]1[C:24]2[C:25]3[C:16](=[CH:15][CH:14]=[CH:13][C:12]=3[C:29](=[O:28])[N:11]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2][NH2:1])[CH:17]=[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:23]1=2
Reactant: NCCNCCCNCCN
Reactant: O=C1OC(=O)c2c3ccccc3cc3cccc1c23
Solvent: CCO
Product: NCCNCCCNCCN1C(=O)c2cccc3cc4ccccc4c(c23)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.3 %

Procedure:
A solution of 5.0 g (31 mmol) of N,N'-bis(2-aminoethyl)-1,3-propanediamine in 200 ml of ethanol 99% is treated with 1,5 g (6 mmol) of anthracene-1,9-dicarboxylic acid anhydride in 100 ml of ethanol and stirred for 24 hours at room temperature. The solid is collected on a filter, washed with ethanol and crystallized from ethanol to give 0.5 g (20%) of N-[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-N'-(2-aminoethyl)-1,3-propanediamine. M.p. 150° C.
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH2:24]([CH2:26][NH2:27])[OH:25]>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:27][CH2:26][CH2:24][OH:25])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: NCCO
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Product: CCOC(=O)C(=CNCCO)C(=O)c1c(C)c(F)c(F)c(F)c1F

Procedure:
Employing ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-ethoxyacrylate (7.0 g) and ethanol amine (1.33 ml), the procedure of Reference Example 21 is repeated to give ethyl 2-(2-methyl-3,4,5,6-tetraflurobenzoyl)-3-(2-hydroxyethyl)aminoacrylate. To the product are added pyridine (70 ml) and acetic anhydride (2.57 ml) and the mixture is stirred at room temperature over-night. After concentration, the resultant is diluted with water, subjected to extraction with dichloromethane, and the extract is washed with water and then with a saturated saline solution and dried to give ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-(2-acetyloxyethyl)aminoacrylate, which is then treated with 60% sodium hydride (1.09 g) as in Reference Example 22 to give ethyl 1-(2-acetyloxyethyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (6.15 g), as colorless prisms (recrystallized from ethyl acetate), m.p. 192°-193° C.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4](=[CH2:25])[CH2:5][O:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[C:10]([C:22](=[O:24])[CH3:23])=[CH:9][CH:8]=1.[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:28]=1[CH:29]=O>C(O)C.O>[CH3:25][C:4](=[CH2:3])[CH2:5][O:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[C:10]([C:22](=[O:24])[CH:23]=[CH:29][C:28]2[C:27]([Cl:26])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:35])=[CH:9][CH:8]=1
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: C=C(C)COc1ccc(C(C)=O)c2oc3ccccc3c(=O)c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=C(C)COc1ccc(C(=O)C=Cc2c(Cl)cccc2Cl)c2oc3ccccc3c(=O)c12
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 3-(2-methylallyloxy -4acetyl-xanthen-9-one (2.31 g, 0.0075 mol) and 2,6dichloro-benzaldehyde (1.31 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.1 g of product m.p. 135-137° C., 1H-NMR (CDCl3)δ:4.74 (m, 2H), 5.4 (m, 2H), 5.95 (m, 1H), 7.06-8.5 (m, 11 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:27]N1CCCC1=O.[H-].[Na+].IC>O>[CH3:8][O:7][C:5](=[O:6])[C:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:10]=1)([CH3:27])[C:3]([O:2][CH3:1])=[O:26]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reactant: CN1CCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC(=O)C(C)(C(=O)OC)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of dimethyl-(3-benzyloxy-4-nitrophenyl)malonate(2.3 g), N-methylpyrrolidinone(15 mL) and a 60% dispersion of sodium hydride in mineral oil(0.31 g) was stirred under an argon atmosphere at 0° C. for 0.5 h. The mixture was treated with iodomethane(0.8 mL) and stirred at ambient temperature for 4 h then treated with water (50 mL). The precipitate was collected and washed with water and hexane to give dimethyl-2-(3-benzyloxy-4-nitrophenyl)-2-methylmalonate(2.19 g). [m/e374(MH+)].
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:30]5[CH:31]=[CH:32][C:27]([Br:26])=[CH:28][CH:29]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Reactant: OB(O)c1ccc(Br)cc1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccc(Br)cc4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 4-bromophenyl boronic acid. Mass spectrum (ESI) 472.2 (M+1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:24])[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([C:18]2[CH:19]=[CH:20][C:15]([CH3:24])=[CH:16][CH:17]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccc(C(=O)OC(C)(C)C)cc2)cc1
Yield: 79.5 %

Procedure:
To a mixture of tert-butyl-4-bromobenzoate (40 g, 0.15 mol), 4-tolylboronic acid (23.3 g, 0.17 mol) and sodium carbonate (150 g) in toluene (350 mL) and water (350 mL) was added tetrakis(triphenylphosphine)palladium(0) (8.7 g, 0.007 mol) and the reaction mixture was refluxed for 10 h under nitrogen atmosphere. The organic layer was separated, washed with water, dried and concentrated to give tert-butyl-4-(4-tolyl)benzoate (32 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:28])[C:13]3[S:17][C:16]([NH:18][C:19](=[O:27])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:26])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][C:7](=O)[C:6]=2[CH:30]=1.CO.[CH3:33][NH2:34].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:28])[C:13]3[S:17][C:16]([NH:18][C:19](=[O:27])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:26])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([NH:34][CH3:33])[C:6]=2[CH:30]=1
Reactant: CN
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)s2)c2ccc(Cl)cc21
Reaction time: 8 h

Procedure:
To a suspension of 7-chloro-5-oxo-1-[5-(2-methylbenzoylamino)thenoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1g) in methanol (40 ml) are added molecular sieve 4A (2 g) and 40% methylamine methanol solution (10 ml), and the mixture is refluxed for 6 hours, and cooled. To the mixture is added with stirring sodium borohydride (0.13 g) at room temperature, and the mixture is stirred at the same temperature overnight. The reaction solution is filtered on Celite, and to the filtrate is added water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-5-methylamino-1-[5-(2-methylbenzoylamino)thenoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.93 g) as white powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].[C:9](=N)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.O>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[N:6]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](C)N=C(c1ccccc1)c1ccccc1
Reaction time: 15 h

Procedure:
To a solution of alanine methyl ester hydrochloride (10.0 g, 71.6 mmol) in 100 mL CH2Cl2 was added benzophenone imine (12.0 mL, 71.6 mmol). A white ppt gradually came out of solution as the reaction was allowed to proceed at rt for 15 h. The reaction was diluted with H2O and CH2Cl2, and the layers were separate, the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to afford methyl-N-(diphenylmethylene)alaninate as a viscous oil which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.62 (m, 2H), 7.47-7.29 (m, 6H), 7.19-7.16 (m, 2H), 4.16 (q, J =6.8 Hz, 1H), 3.7 (s, 3H, 1.40 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].C([O-])([O-])=O.[K+].[K+].[CH2:19](Cl)[C:20]#[CH:21].O>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[O:12][CH2:21][C:20]#[CH:19]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: C#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C#CCOc1cc([N+](=O)[O-])ccc1OC
Temperature: 65 °C
Yield: 88 %

Procedure:
2-methoxy-5-nitrophenol (6.0 g, 35 mmol) and K2CO3 (6.5 g, 43 mmol) were stirred in acetone (200 mL) for 30 min and then propargyl chloride (6 mL, excess) was added to the suspension and heated at 65° C. overnight. After cooled to room temperature, water was added and the reaction mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with water and brine and dried over Na2SO4. Recrystallization of the crude product in MeOH/EtOAc gave the title product as a white solid (6.4 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:30])=[C:13]([NH:15][C:16](=[O:29])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4([C:26]#[N:27])[CH2:25][CH2:24]4)[C:18]=3[Cl:28])[CH:14]=2)=[N:6][CH:7]=1.[S-:31][C:32]#[N:33].[K+].BrBr>C(O)(=O)C>[NH2:33][C:32]1[S:31][C:7]2[C:2]([N:1]=1)=[CH:3][CH:4]=[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([F:30])=[C:13]([NH:15][C:16](=[O:29])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4([C:26]#[N:27])[CH2:24][CH2:25]4)[C:18]=3[Cl:28])[CH:14]=1)[N:6]=2
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc(N)cn4)ccc3F)c2Cl)CC1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(N)sc5n4)ccc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.2 %

Procedure:
To a solution (50 mL) of N-{5-[(5-aminopyridin-2-yl)oxy]-2-fluorophenyl}-2-chloro-3-(1-cyanocyclopropyl)benzamide (4.23 g, 10 mmol) and potassium thiocyanate (3.89 g, 40 mmol) in acetic acid was added dropwise bromine (2.40 g, 15 mmol) at 15° C., and the mixture was stirred at room temperature for 6 hr. The yellow suspension was filtered through celite, and the yellow insoluble material was thoroughly washed with acetic acid (50 mL). The filtrate and washing solution were combined, and the mixture was concentrated under reduced pressure. The residue was suspended in 0.1N aqueous sodium hydroxide solution (100 mL), and the suspension was extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=100/0→0/100). The obtained residue was crystallized from diethyl ether to give the title compound (3.32 g, 69%) as a pale-yellow powder.