Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:2]=1.[C:17]([O:21][C:22](ON=C(C1C=CC=CC=1)C#N)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1.O>[C:17]([O:21][C:22]([N:8]([CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: c1cncc(CNCCN2CCNCC2)c1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CCN1CCNCC1)Cc1cccnc1

Procedure:
1-(2-[3-pyridylmethylamino]-ethyl)-piperazine (2.20 g, 10 mmol) is dissolved in 20 mL of dioxane:water (1:1) mixture and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (2.46 g, 10 mmol) is added. The mixture is then stirred until no starting material is detected on thin layer chromatography. The obtained mixture is fractionally separated by silica gel chromatography, followed by RP-HPLC to obtain 1-(2-[N-tert-butoxycarbonyl-3-pyridylmethylamino]-ethyl)-piperazine. Following the procedure of Example 6, but replacing 1-benzylpiperazine with 1-(2-[N-tert-butoxycarbonyl-3-pyridylmethylamino]-ethyl)-piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1-(2-[N-tert-butoxycarbonyl-3-pyridylmethylamino]-ethyl)-piperazine (1.951 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5, followed by a carefully deprotection of N-tert-butoxycarbonyl group with 10% trifluoroacetic acid to obtain the pure title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2].C1C(=O)N([Cl:24])C(=O)C1.O>CN(C=O)C>[C:1]([O:4][C:5]1[C:6]([O:15][CH3:16])=[CH:7][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[C:9]([Cl:24])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(CC(=O)O)ccc1OC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)O)c(Cl)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of [4-(acetyloxy)-3-methoxyphenyl]acetic acid (650 mg, 2.90 mmol) in DMF (10 mL) was added a solution of NCS (428 mg, 3.192 mmol) in DMF (5 mL) dropwise at 0° C. The mixture was stirred at ambient temperature for 6 hrs, and then poured into water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were washed with 1 N HCl, brine, dried over Na2SO4 and then concentrated to obtain [4-(acetyloxy)-2-chloro-5-methoxyphenyl]acetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=O>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([O:10][CH3:11])[CH:6]=2)[N:1]=[C:14]([CH3:16])[C:13]=1[C:12]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: COc1ccc(N)c(C#N)c1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2ccc(OC)cc2c1N

Procedure:
Prepared as in Example 2a from 2-amino-5-methoxybenzonitrile (Campbell, J. B. et al. Synth. Commun. 1989, 19, 2255-2263.) and ethyl acetoacetate as an off-white solid (92%). 1H NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=6.8 Hz, 3H), 2.57 (s, 3H), 3.86 (s, 3H), 4.33 (q, J=6.8 Hz, 2H), 7.28 (dd, J=2.8, 9.2 Hz, 1H), 7.59 (d, J=9.2 Hz, 1H), 7.60 (bs, 2H), 7.63 (d, J=2.8 Hz, 1H). MS 261 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29].[CH:30]1([CH2:36][NH2:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:37][CH2:36][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29]
Reactant: NCC1CCCCC1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Solvent: ClCCl
Product: O=C1N(c2c(Cl)cccc2Cl)Cc2cnc(NCC3CCCCC3)nc2N1c1ccccc1
Yield: 94.2 %

Procedure:
A solution of 100 mg (0.22 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 285 μl (2.2 mmol) of cyclohexylmethylamine in 2 ml of dichloromethane was stirred at room temperature overnight. The mixture was diluted with 10 ml of dichloromethane, washed with 10 ml of 2M hydrochloric acid and with 10 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. 100 mg (94%) of 3-(2,6-dichlorophenyl)-7-(cyclohexylmethylamino)-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one were isolated as a white foam of melting point 229-233° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][O:32][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH:40]([Si:33]([CH:34]([CH3:36])[CH3:35])([CH:37]([CH3:39])[CH3:38])[O:32][CH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27]1)([CH3:41])[CH3:42]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](OCC1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.7 %

Procedure:
To a solution of Intermediate A (223 mg, 1.37 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 168 mg, 4.20 mmol) and the mixture stirred at RT for 15 min. A solution of Intermediate 54b (555 mg, 1.37 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 1.75 h. The cooled mixture was diluted with water and extracted with DCM (5×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-14% [2M NH3 in MeOH] in DCM, to give the title compound as a brown gum (344 mg, 46%). LCMS (Method 3): Rt 3.29 min, m/z 550 [MH+].
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([CH3:19])([CH3:18])[CH2:12][C:13](=[O:17])[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[CH2:25]([O:15][C:14](=[O:16])[C:13](=[O:17])[CH2:12][C:11]([C:5]1[C:6]2[O:10][CH2:9][O:8][C:7]=2[C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:19])[CH3:18])[CH3:26]
Reactant: CC(C)(CC(=O)C(=O)O)c1ccc(Br)c2c1OCO2
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)CC(C)(C)c1ccc(Br)c2c1OCO2

Procedure:
300 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valeric acid and 0.1 ml of sulfuric acid (96%) in 5 ml of ethanol are heated for 4 hours to 70° C. Then, the batch is concentrated by evaporation in a vacuum and added to water. It is extracted with ethyl acetate, washed with brine, dried and concentrated by evaporation in a vacuum. 272 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valeric acid-ethyl ester is obtained as a yellow oil. This ester and 0.32 ml of trifluoromethyl-trimethylsilane in 4 ml of THF are mixed with 0.14 ml of a tetrabutylammonium fluoride solution (1 M in THF) at −70° C. It is stirred for 1 hour at 70° C, for 1.5 hours at −10° C., for 1 hour at 0° C. and for 2 hours at room temperature. Another spatula-tip full of tetrabutylammonium fluoride is added, and after stirring is continued for 20 minutes, it is added to water. It is extracted with ethyl acetate, washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. 297 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid-ethyl ester is obtained as a yellow oil. This oil is mixed in 5 ml of ether at 0° C. with 29 mg of lithium aluminum hydride, and stirred for 1 hour at 0° C. and for another 10 hours at room temperature. The batch is added to dilute hydrochloric acid, extracted with ethyl acetate, washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. 164 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol is obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:24])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([O:17]C)=[O:16])[S:14][C:7]=12.[OH-].[Na+].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:24])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[S:14][C:7]=12
Reactant: COC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 7-(3-fluoro-4-(3-(2-fluoro-5-methylphenyl)ureido)phenoxy)thieno[3,2-b]pyridine-2-carboxylate (1.84 g, 3.92 mmol) was taken up in 100 mL THF followed by the dropwise addition of 1N sodium hydroxide (4.8 mL, 4.8 mmol). The solution was stirred at room temperature for 3 hours, at which time an additional 2.4 mL of 1N sodium hydroxide was added. The solution was stirred at room temperature for overnight and the resulting mixture was diluted with 75 mL of water and acidified using 1N HCl. The insoluble material was separated by filtration and the filter cake was suspended in ethyl acetate and stirred for several minutes before filtering. The filter cake was washed several times with ethyl acetate and dried under high vacuum to give 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid as an off white solid. Yield: 1.6 g (90%); MS [M+H]+ 456.1; 1HNMR (DMSO-d6) δ: 13.9 (bs, 1H), 9.2 (s, 1H), 9.0 (s, 1H), 8.6 (d, 1H), 8.3 (t, 1H), 8.1 (s, 1H), 8.0 (d, 1H), 7.5 (d, 1H), 7.2 (m, 2H), 6.8 (m, 2H), 2.1 (s, 3H) ppm.
Reaction SMILES: [C:1]([CH2:3][CH2:4][P:5]([C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:10])[O:6][CH:7]([CH3:9])[CH3:8])#[N:2].N>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][P:5]([C:11]([CH3:13])([CH3:12])[CH3:14])(=[O:10])[O:6][CH:7]([CH3:8])[CH3:9]
Reactant: CC(C)OP(=O)(CCC#N)C(C)(C)C
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)OP(=O)(CCCN)C(C)(C)C
Reaction time: 5 h

Procedure:
A mixture of 11.0 g of isopropyl 2-cyanoethyl(t-butyl)phosphinate, 17.0 g of ammonia and 1.7 g of Raney-Nickel in 110 ml of ethanol is hydrogenated during 5 hours. The catalyst is filtered off and the solvent removed by evaporation. The crude oil is purified by Kugelrohr-distillation to yield isopropyl 3-aminopropyl(t-butyl)phosphinate as an oil, b.p. 155°/1 Pa, nD20 =1.4600.
Reaction SMILES: F[C:2]1[C:3]([C:8]2[O:12][N:11]=[C:10]([C:13]3[N:18]=[C:17]([N:19]([CH3:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:16]=[C:15]([NH2:27])[N:14]=3)[N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:28]1([CH2:31][NH2:32])[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH:28]1([CH2:31][NH:32][C:2]2[C:3]([C:8]3[O:12][N:11]=[C:10]([C:13]4[N:18]=[C:17]([N:19]([CH3:26])[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[N:16]=[C:15]([NH2:27])[N:14]=4)[N:9]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:30][CH2:29]1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ncccc3F)n2)n1
Reactant: NCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ncccc3NCC3CC3)n2)n1
Reaction time: 3 h
Yield: 44 %

Procedure:
6-[5-(3-Fluoropyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-N-methyl-N-phenyl-[1,3,5]triazine-2,4-diamine (prepared in an analogous manner to Example 482, 50 mg, 0.137 mmol), 1-cyclopropylmethanamine (24 μL, 0.274 mmol) and potassium carbonate (57 mg, 0.411 mmol) were suspended in anhydrous DMF (2 mL) in a sealed tube at room temperature under nitrogen. The reaction mixture was stirred at 90 C for 3 h and then at 100 C for 18 h. The mixture was diluted with DCM (10 mL) and then washed with saturated aq. ammonium chloride (3×5 mL) and then brine (5 mL). The organic layer was dried over sodium sulfate and evaporated under vacuum. The crude residue was purified by flash chromatography (0-1% (7M ammonia in MeOH) in DCM) to afford the title compound (25 mg, 44%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=O)[CH3:18])[C:3]=1[O:20][CH3:21].[CH3:22][CH2:23][O:24][C:25]([CH:27](P(OCC)(OCC)=O)[F:28])=[O:26].C([Li])CCC>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:15])[CH3:16])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:18])=[C:27](/[F:28])\[C:25]([O:24][CH2:23][CH3:22])=[O:26])[C:3]=1[O:20][CH3:21]
Reactant: COc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Br)c1OC)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure F-1, 1-(4-bromo-8-isopropyl-3-methoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-103, 358 mg, 1.02 mmol) and triethyl 2-fluoro-2-phosphonoacetate (0.83 μL, 4.08 mmol) were reacted with n-butyllithium (1.6 M in hexanes, 2.55 mL, 4.08 mmol) in THF to produce the title compound after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14](O)=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.S(Cl)(Cl)=O.[CH3:36][S-:37].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14](=[O:15])[S:37][CH3:36])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1
Reactant: C[S-]
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccnc2)c1C(F)(F)F
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CSC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccnc2)c1C(F)(F)F
Yield: 9.4 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid (30 mg, 0.066 mmol) was treated with thionylchloride (1.5 mL) and stirred at reflux for 2 h. The mixture was concentrated under reduced pressure. The intermediate was treated with benzene (3×) and the benzene was evaporated to remove water. Then, the obtained mixture was dissolved in benzene (1.5 mL) and sodium methanethiolate (32.5 mg, 0.46 mmol) was added. The reaction mixture was stirred at reflux for 5 h. The mixture was diluted with dichloromethane and washed with water (3×), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product (example B-68) was purified by pTLC (1:1 EE/PE) to give 3 mg of a white solid (yield 9%). Result of LC/MS MH+: 482.76; 1H NMR (CDCl3): 2.33 (t, 3H), 7.19 (t, 1H), 7.33-7.55 (m, 6H), 8.23 (s, 1H)
Reaction SMILES: C[O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[CH:14]1[N:19]([CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)[C:18](=[O:31])[CH2:17][CH2:16][CH2:15]1.O>C(Cl)Cl>[OH:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[CH:14]1[N:19]([CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)[C:18](=[O:31])[CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1C1CCCC(=O)N1Cc1ccc2ccccc2n1
Solvent: O
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])c(O)c1C1CCCC(=O)N1Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 6-(2,6-dimethoxy-3-nitrophenyl)-1-(quinolin-2-ylmethyl)piperidin-2-one (403 mg; 0.95 mmol) in anh. DCM (9 ml) was treated dropwise at rt with a solution of boron tribromide BBr3 (1 M in DCM; 4.4 ml; 4.4 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 17 h. Water and ice were added, and the separated aq. layer was extracted with DCM. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by FC (DCM/MeOH=30/1) afforded 6-(2-hydroxy-6-methoxy-3-nitrophenyl)-1-(quinolin-2-ylmethyl)-piperidin-2-one as a yellow solid (340 mg; 87%). LC-MS (conditions A): tR=0.60 min.; [M+H]+: 407.82 g/mol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:9]=2[S:8][CH:7]=1)[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([NH:16][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:15][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)CC1=CSc2cc(N)ccc2N1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1=CSc2cc(NS(C)(=O)=O)ccc2N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A solution of (7-amino-4H-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (Example 8c, 2.38 g, 9.51 mmol) in dichloromethane (80 mL) was cooled to 0° C. and treated with triethylamine (3.1 g, 30.4 mmol) followed by dropwise addition of methanesulfonyl chloride (1.37 g, 9.51 mmol). The reaction mixture was stirred at 0° C. for 0.5 h and allowed to warm to 25° C. The reaction mixture was concentrated in vacuo and purified by flash chromatography (Merck silica gel 60, 40-63 μm, ethyl acetate/hexanes) to afford the desired product, (7-methanesulfonylamino-4H-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (2.2 g, 6.7 mmol, 71% yield) as a light tan solid. 1H NMR (400 MHz, CDCl3) δ 1.31 (t, 3H, J=7.0 Hz), 3.00 (s, 3H), 3.43 (s, 2H), 4.19 (quartet, 2H, J=7.1 Hz), 4.73 (s, 1H), 6.28 (s, 1H), 6.85 (d, 1H, J=8.5 Hz), 6.99 (dd, 1H, J1=8.5 Hz, J2=2.4 Hz), 7.12 (d, 1H, J=2.3 Hz), 10.64 (bs, 1H). LC-MS (ESI) calcd for C13H16N2O4S [M+H+] 329.06. found 329.10 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1[NH:4][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1C
Product: CS(=O)(=O)Nc1cc(Cl)c(Cl)cc1Cl

Procedure:
A mixture of 2,4,5-trichloroaniline (39.3 g.), methane sulfonyl chloride (22.9 g.) and 100 ml. of xylene were heated together under reflux conditions for 18 hours. The mixture was then allowed to cool, which formed a brown precipitate. The product was worked up in the same manner as set forth in Example 1 to yield 24.0 g. of product, m.p. 144°-145° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13].[I:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>CC(C)=O>[CH3:15][O:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][CH:18]=[C:9]([CH2:8][O:26][C:23]2[CH:24]=[CH:25][C:20]([I:19])=[CH:21][CH:22]=2)[CH:10]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Yield: 90.4 %

Procedure:
Freshly ground potassium carbonate (8.3 g, 60 mmol) was added to a solution of methyl 3-bromomethyl-benzoate (12.83 g, 56 mmol; available from Lancaster Synthesis Ltd., Lancashire, UK) and 4-iodophenol (13.2 g, 60 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.) in acetone (600 mL). The reaction mixture was heated at reflux overnight and then it was filtered and water was added. The resulting white solid was filtered off and dried in a vacuum oven overnight to give 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (18.63 g, 90%) as a white solid
Reaction SMILES: [CH:1](Br)=[CH2:2].[Mg].CN(C)[CH:7]=[CH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O1CCCC1.CCOCC>[CH2:1]=[CH:2][CH:7]=[CH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C=CBr
Reactant: CCCCCC(=O)C=CN(C)C
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC=CC(=O)CCCCC
Temperature: 25 °C

Procedure:
To a solution of Grignard reagent prepared from vinyl bromide (10.7 g), and magnesium (2.43 g) in dry tetrahydrofuran (40 ml) is added gradually a solution of 1-(dimethylamino)-1-octen-3-one (16.9 g), described in Example 37, in dry tetrahydrofuran (20 ml). The mixture is stirred and heated to reflux for 1 hr. The reaction mixture is cooled to room temperature, diluted with ether, washed with hydrochloric acid (10 ml), followed by saturated ammonium chloride solution. The ether extract is dried, and the solvent is removed. The residue is chromatographed to yield the title compound, λmaxEtOH 260 nm (ε=17,050), γmaxfilm 1686, 1668 cm-1.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11](O)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:12][N:13]([CH2:21][CH2:22][OH:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][CH2:10][C:11]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:23][CH2:22][CH2:21][N:13]([C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20])[CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O)(CCO[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC(CCO[Si](C)(C)C(C)(C)C)(c2ccccc2)C1
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 4-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-2-phenylbutyl(2-hydroxyethyl)carbamate (770 mg, 1.7 mmol) and triphenylphosphine (551 mg, 2.1 mmol) in 8 mL toluene was added diethyl azodicarboxylate (0.96 mL of a 40% solution in toluene, 2.1 mmol) and the reaction was stirred for 24 h. After evaporation, the residue was chromatographed (10% EtOAc/hex) to afford tert-butyl 2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-phenylmorpholine-4-carboxylate as an oil, which was used without further purification. ESI-MS 422 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.[CH2:19]([Li])CCC.IC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([CH3:19])=[CH:10][C:3]=12
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ccnc21
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2c(Cl)ccnc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.3 %

Procedure:
To a solution of 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.53 mmol) in THF (1 mL) at −78° C. under argon was added butyllithium (0.4 mL, 1.6 M in hexanes, 6.4 mmol) dropwise. The mixture was stirred at the same temperature for 5 min, and treated with iodomethane (0.1 mL). The mixture was warmed up to room temperature, quenched by the addition of saturated ammonium chloride solution, and extracted with ethyl acetate (3×10 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give the crude product (150 mg, 95%), which was used for the next reaction. 1H NMR (CDCl3) δ 8.19 (d, 1H, J=5.5 Hz), 7.14 (d, 1H, J=5.5 Hz), 6.42 (s, 1H), 5.74 (s, 2H), 3.60 (t, 2H, J=6.8 Hz), 2.61 (s, 3H), 0.96 (t, 2H, J=6.8 Hz), 0.07 (s, 9H); MS(ESI+) m/z 297 and 299 (M+H, 1 Cl)+.