Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CO[C:5]([C:7]1[C:16]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[C:9]([O:31][CH3:32])[C:8]=1[CH2:33][C:34](=[O:44])[NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[O:6]>CN(C=O)C.C(OCC)C>[CH:18]([O:17][C:16]1[C:7]2[C:5](=[O:6])[N:35]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:34](=[O:44])[CH2:33][C:8]=2[C:9]([O:31][CH3:32])=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1c(CC(=O)NCc2ccc(F)cc2)c(OC)c2cccnc2c1OC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C(=O)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
A 60% sodium hydride (NaH) mineral oil dispersion (0.002 g, 0.06 mmol was added to a solution of 8-benzhydryloxy-6-[(4-fluoro-benzylcarbamoyl)-methyl]-5-methoxy-quinoline-7-carboxylic acid methyl ester (0.020 g, 0.04 mmol) in 1 mL of anhydrous DMF. The resulting indigo-tinted solution was stirred at rt for a period of 30 min, and then diluted with diethyl ether (50 ml) and washed with sat. aq. NH4Cl (25 mL). The organic layer was dried over Na2SO4 and solvent was removed by rotary evaporation. The residue was purified by silica gel chromatography (1/1 hexanes/diethyl ether and then 100% MeOH to elute product fractions) to give 9-benzhydryloxy-7-(4-fluoro-benzyl)-10-methoxy-5H-1,7-diaza-anthracene-6,8-dione 295 (9 mg, 48%).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:21][O:22][C:23]1[C:24](=[O:51])[C:25]([CH3:50])=[C:26]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:42][CH2:43][C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[C:37]([CH:41]=2)[C:38](O)=[O:39])[C:27](=[O:31])[C:28]=1[O:29][CH3:30]>C(Cl)Cl>[CH:1]1([NH:4][C:38](=[O:39])[C:37]2[CH:41]=[C:33]([CH2:32][C:26]3[C:27](=[O:31])[C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[C:24](=[O:51])[C:25]=3[CH3:50])[CH:34]=[CH:35][C:36]=2[O:42][CH2:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)NC3CC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 12.5 %

Procedure:
Cyclopropylamine (0.0857 g, 1.500 mmol), triethylamine (0.152 g, 1.500 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.254 g, 1.500 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.2115 g, 0.500 mmol) and the resulting solution was stirred at room temperature for 13 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.029 g, 0.0627 mmol, 13%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[NH:7][CH:6]=1.[CH3:17]C(C)([O-])C.[K+]>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[CH2:17])[CH:12]=2)[NH:7][CH:6]=1
Reactant: CC(C)(C)[O-]
Reactant: CN(C)CCc1c[nH]c2ccc(C=O)cc12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc2[nH]cc(CCN(C)C)c2c1
Yield: 88.7 %

Procedure:
To a solution of 3-(2-dimethylamino-ethyl)-1H-indole-5-carbaldehyde (Example 13) (0.216 g, 1 mmol) in THF (5 mL), methyl triphenyl phosphonium bromide (0.393 g, 1.1 mmol) is added. To the obtained slurry, under an argon atmosphere potassium tert-butoxide (0.118 g, 1.05 mmol) is added in three portions at ambient temperature. When thin layer chromatography (TLC) indicates complete conversion of the aldehyde, the mixture is poured on ice and extracted with ethyl acetate. Removal of the solvent gives a residue which is chromatographed on silica (25 g, CHCl3, MeOH, NEt3 19:1:0.5 v:v:v) to give the title product as pale yellow oil (0.190 g, 88%). 1H-NMR (CDCl3, 300 MHz) δ 2.37 (s, 6H, N(CH3)2); 2.64-2.70 (m, 2H, CH2NMe2); 2.92-2.99 (m, 2H, CH2); 5.13 (d, 1H, J=10.9 Hz, cis H2C═CH); 5.69 (d, 1H, J=17.6 Hz, trans H2C═CH); 6.84 (dd, 1H, H2C═CH); 6.94 (br s, 1H, H-2); 7.24 (d, 1H, J=8.2 Hz, H-7); 7.31 (dd, J=1.8 Hz, H-6); 7.58 (d, 1H, H-4); 8.66 (br s, 1H, NH). 13C-NMR (CDCl3, 75 MHz) δ 24.00 (CH2); 45.73 (N(CH3)2); 60.62 (CH2NMe2); 110.93 (H2C═CH); 111.50 (C-7); 114.66 (C-3); 117.41 (C-4); 120.20 (C-6); 122.42 (C-2); 127.83 (C-5); 129.34 (C-9); 136.45 (C-8); 138.22 (H2C═CH).
Reaction SMILES: [C:1]([C:6]1[S:7][C:8]([C:13]([O:15]CC)=[O:14])=[C:9]([OH:12])[C:10]=1[OH:11])([O:3]CC)=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:24]1OC2C(=CSC=2)O[CH2:25]1.BrCCBr.BrCC(Br)CCCCCCCCCCCCCC.BrCC(Br)CCCC.C(C1SC(C(OCC)=O)=C2OCCOC=12)(OCC)=O.[OH-].[Na+]>O.CN(C=O)C>[C:13]([C:8]1[S:7][C:6]([C:1]([OH:3])=[O:2])=[C:10]2[O:11][CH2:25][CH2:24][O:12][C:9]=12)([OH:15])=[O:14]
Reactant: c1scc2c1OCCO2
Reactant: CCOC(=O)c1sc(C(=O)OCC)c(O)c1O
Agent: CCCCC(Br)CBr
Agent: CCCCCCCCCCCCCCC(Br)CBr
Agent: CCOC(=O)c1sc(C(=O)OCC)c2c1OCCO2
Solvent: BrCCBr
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1sc(C(=O)O)c2c1OCCO2

Procedure:
The salt either 5 or 6 is dissolved in water and acidified with 1 Molar HCI added slowly dropwise with constant stirring until the solution becomes acidic. Immediately following, thick white precipitate falls out. After filtration, the precipitate is washed with water and air-dried to give 2,5-dicarbethoxy-3,4-dihydroxythiophene (7). The salt either (5, 2.5 grams) or 6 can be alkylated directly or the dihydrothiophene derivative (7) can be suspended in the appropriate 1,2-dihaloalkane or substituted 1,2-dihaloalkane and refluxed for 24 hours in the presence of anhydrous K2CO3 in anhydrous DMF. To prepare EDOT, either 1,2-dicholorethane (commercially available from Aldrich) or 1,2-dibromoethane (commercially from Aldrich) is used. To prepare the various substituted EDOT derivatives the appropriate 1,2-dibromoalkane is used, such as 1-dibromodecane, 1,2-dibromohexadecane (prepared from 1-hexadecene and bromine), 1,2-dibromohexane, other reported 1,2-dibromoalkane derivatives, and the like. The resulting 2,5-dicarbethoxy-3,4-ethylenedioxythiophene or 2,5-dicarbethoxy-3,4-alkylenedioxythiophene is refluxed in base, for example 10 percent aqueous sodium hydroxide solution for 1 to 2 hours, and the resulting insoluble material is collected by filtration. This material is acidified with 1 Normal HCl and recrystallized from methanol to produce either 2,5-dicarboxy-3,4-ethylenedioxythiophene or the corresponding 2,5-dicarboxy-3,4-alkylenedioxythiophene. The final step to reduce the carboxylic acid functional groups to hydrogen to produce the desired monomer is given in the references above.
Reaction SMILES: [OH2:1].NN.[C:4]1(=O)[N:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:7](=O)[C:6]2=CC=CC=[C:5]12>C(O)C>[NH2:8][CH2:7][CH2:6][CH2:5][O:1][C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[CH:11][CH:10]=[C:9]2[N:8]2[CH2:4][CH2:5][CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cccc2ccccc12
Reactant: O
Agent: NN
Solvent: CCO
Product: NCCCOc1ccc2cccc(N3CCCC3)c2c1

Procedure:
85% hydrazine hydrate (9.6 ml) is added to a stirred solution of the phthalimido naphthalene prepared as described in the previous step (about 50 g) in absolute ethanol (about 500 ml). The reaction mixture is heated at reflux for about 3 hours and allowed to cool. The resulting precipitate is removed by filtration and washed with absolute ethanol. The filtrate is evaporated in vacuo and the residue triturated with 5% aqueous hydrochloric acid. The aqueous suspension is filtered and the solid washed with 5% hydrochloric acid. The filtrate is made strongly alkaline with 50% sodium hydroxide solution, resulting in an oily precipitate which is extracted into diethyl ether. The ether extract is washed with saturated sodium chloride solution, dried, filtered and the filtrate evaporated in vacuo, yielding the desired amine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:3]=1[O:4][Si:5]([CH:12]([CH3:14])[CH3:13])([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7].CN(CCN(CCN(C)C)C)C.C([Li])CCC.[CH:38](N1CCOCC1)=[O:39].Cl>C1COCC1>[F:1][C:2]1[C:3]([O:4][Si:5]([CH:6]([CH3:7])[CH3:8])([CH:12]([CH3:13])[CH3:14])[CH:9]([CH3:11])[CH3:10])=[CH:15][C:16]([O:19][CH3:20])=[CH:17][C:18]=1[CH:38]=[O:39]
Reactant: COc1ccc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: O=CN1CCOCC1
Agent: CN(C)CCN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)c(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: -60 °C
Reaction time: 3 h

Procedure:
To a 240 ml THF solution containing 113 g of (2-fluoro-5-methoxyphenoxy)triisopropylsilane and 70 g of N,N,N′,N′,N″-pentamethyldiethylenetriamine there was added dropwise 150 ml of n-butyllithium (2.66 M, hexane solution) over a period of 50 minutes, at −74° C. After stirring for 3 hours at −60° C., 70 ml of N-formylmorpholine was added. The temperature of the reaction mixture was slowly raised to 6° C. Next, 1N hydrochloric acid was added to the reaction mixture while cooling on ice, and then the mixture was extracted with a mixture of hexane and t-butylmethyl ether and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (t-butyl methyl ether-heptane) to give the title compound (113.26 g) as an oil.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[N:11]([Na])=[N+:12]=[N-:13]>CN(C=O)C.[Cl-].[Li+]>[C:2]1([C:1]2[NH:13][N:12]=[N:11][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Reactant: [N-]=[N+]=N[Na]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nnn[nH]2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A solution of benzonitrile (60.0 g, 581.9 mmol, 1.0 equiv) in DMF (anhydrous) (600 mL) was placed in a flask that had been purged and maintained with an inert atmosphere of nitrogen. Ammonium chloride (40.5 g, 757.2 mmol, 1.3 equiv) was added, followed by the addition of lithium chloride (2.0 g, 47.2 mmol, 0.1 equiv). To the mixture was added azidosodium (49.4 g, 756.8 mmol, 1.3 equiv). The resulting solution was stirred overnight, while maintaining the temperature at 100° C. The solids were filtered out and washed with EtOAc. The filtrates were combined and concentrated in vacuo. The residue was dissolved in a 10% NaOH aqueous solution (350 ml). The resulting solution was extracted with EtOAc (100 mL) and the aqueous layers were combined. The pH value of the solution was adjusted to 2 with concentrated HCl. The solids were filtered out and dried over reduced pressure to yield 5-phenyl-1H-tetrazole (78.0 g) as a white solid. ES m/z: [M+H]+ calcd for C7H6N4, 147.1. found 147.1.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:34]1[N:35]=[C:36]([NH:39]C=O)[S:37][CH:38]=1)[C:12]([NH:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:34]1[N:35]=[C:36]([NH2:39])[S:37][CH:38]=1)[C:12]([NH:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 50 %

Procedure:
A mixture of 7-[2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.3 g.), conc. hydrochloric acid (3.74 g.) and methanol (35 ml.) was stirred for 2 hours and 40 minutes at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a 10% aqueous solution of sodium hydroxide (pH 7~8). The aqueous solution was adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling and stirring and stirred for 30 minutes. Precipitates were collected by filtration, washed with water and dried to give 7-[2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.1 g.).
Reaction SMILES: [OH-].[Na+].FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CN([CH2:15][C:16]1[C:17]([N:23]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH2:24][CH:25]2[CH2:27][CH2:26]2)=[N:18][C:19]([F:22])=[CH:20][CH:21]=1)C1NN=NN=1.S(OC)(OC)(=O)=[O:42]>O.ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:25]1([CH2:24][N:23]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:17]2[C:16]([CH:15]=[O:42])=[CH:21][CH:20]=[C:19]([F:22])[N:18]=2)[CH2:27][CH2:26]1
Reactant: COS(=O)(=O)OC
Reactant: Fc1ccc(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn[nH]2)c(N(CC2CC2)CC2CC2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(F)nc1N(CC1CC1)CC1CC1
Reaction time: 0.25 h
Yield: 125.5 %

Procedure:
To sodium hydroxide (33.6 mg, 0.8 mmol) stirred in water (2 mL) was added (3-{[(3,5-bis-trifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-methyl}-6-fluoro-pyridine-2-yl)-bis-cyclopropylmethyl-amine (222 mg, 0.4 mmol) in dichloromethane (5 mL). After stirring for 15 minutes, dimethyl sulfate (0.05 mL, 0.44 mmol) and tetrabutylammonium bromide (7.5 mg, 0.0176 mmol) was added and the solution was left to stir at room temperature for 1 hour. The solution was extracted with dichloromethane (2×15 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give an orange oily product. Purification by silica gel chromatography and eluting with 30% ethyl acetate in hexanes afforded the title compound as an orange oil (124.6 mg, yield: 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].C(N(CC)CC)C.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:36])=[O:35])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccccc2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added triethylamine (100 mg) and benzenesulfonyl chloride (60.2 mg, 0.35 mmol) at ice-bath. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give N-[2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide LC/MS m/e obsd. (ESI+) [(M+H)+] 427.20.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH3:17][N:18]1[C:22]([CH2:23][C:24]#[N:25])=[N:21][CH:20]=[N:19]1.C(N(C(C)C)CC)(C)C.Cl>CO>[N+:1]([C:4]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([CH:23]([C:22]1[N:18]([CH3:17])[N:19]=[CH:20][N:21]=1)[C:24]#[N:25])=[O:7])([O-:3])=[O:2]
Reactant: Cn1ncnc1CC#N
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncnc1C(C#N)C(=O)c1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
263 mg (1.0 mmol) of 2-nitro-4-(methylsulfonyl)benzoyl chloride are added at 0° C. to 122 mg (1.0 mmol) of 2-(1-methyl-1,2,4-triazol-5-yl)acetonitrile and 258 mg (2 mmol) of diisopropylethylamine. The mixture is then stirred at room temperature for 16 h. 1 ml of methanol is then added and, after 15 min, 2N HCl is added. The mixture is extracted with dichloromethane, dried over Na2SO4, evaporated and purified by means of RP-HPLC (acetonitrile/water). Yield 156 mg (45%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a stirring solution of 4.48 g (20 mmol) of 2-chloro-5-trifluoromethyl-benzoic acid suspended in 40 mL of conc. H2SO4 at −20° C. was added dropwise a cold solution of 1.05 eq of potassium nitrate dissolved in 12 mL of sulfuric acid. The reaction mixture was stirred −20° C. for 15 min then warmed up to r.t. overnight. The mixture was poured into a beaker containing ice. The resulting solid was collected, washed with cold water and dried to give 4.8 g (90%) of 2-chloro-3-nitro-5-trifluoromethyl-benzoic acid as a solid. LCMS: 270 (M+1)+.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][C@H:13]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[N:12]([CH2:23][C:24]([N:26]2[C:34]3[C:29](=[N:30][CH:31]=[C:32]([C:35]([F:40])([F:39])[CH2:36][CH2:37][CH3:38])[CH:33]=3)[C:28]([CH3:42])([CH3:41])[CH2:27]2)=[O:25])[CH2:11][C@H:10]1[CH3:43])=O)(C)(C)C>O1CCOCC1.CCOC(C)=O>[ClH:1].[ClH:1].[F:39][C:35]([C:32]1[CH:33]=[C:34]2[N:26]([C:24](=[O:25])[CH2:23][N:12]3[CH2:11][C@@H:10]([CH3:43])[NH:9][CH2:14][C@@H:13]3[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[CH2:27][C:28]([CH3:42])([CH3:41])[C:29]2=[N:30][CH:31]=1)([F:40])[CH2:36][CH2:37][CH3:38]
Reactant: CCCC(F)(F)c1cnc2c(c1)N(C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1CN1CCOC[C@H]1C)CC2(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCC(F)(F)c1cnc2c(c1)N(C(=O)CN1C[C@@H](C)NC[C@@H]1CN1CCOC[C@H]1C)CC2(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4N HCl in dioxane (35 mL) was added to a solution of (2R,5S)-4-{2-[6-(1,1-difluoro-butyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (2.1 g) in EtOAc (10 mL). The resulting suspension was stirred for 1 h at room temperature. The solvent was then removed in vacuo. The solid was triturated in Et2O, collected by filtration, washed with Et2O and dried in vacuo to give the title compound (1.7 g) as a yellow solid. 1H NMR (Me-d3-OD): 8.77 (1H, s), 8.52 (1H, s), 4.36-3.91 (9H, m), 3.91-3.41 (8H, m), 3.18-2.99 (1H, m), 2.34-2.15 (2H, m), 1.67-1.36 (15H, m), 1.00 (3H, t). MS: [M+H]+=494.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:6]=2[CH:22]=1.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:25][CH2:24][C:23]([O:27][CH2:28][CH3:29])=[O:26])[CH2:18][CH2:17]3)[C:6]=2[CH:22]=1
Reactant: Clc1ccc2c(c1)C(N1CCNCC1)=Nc1ccccc1S2
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCN1CCN(C2=Nc3ccccc3Sc3ccc(Cl)cc32)CC1
Yield: 93.9 %

Procedure:
A mixture of 3.30 g of 2-chloro-11-(1-piperazinyl)dibenzo[b,f][1,4]thiazepine and 1.20 g of ethyl acrylate in 17 ml of ethanol was refluxed for 3 hrs. The reaction mixture was concentrated and the residue was chromatographed on silica gel using a mixture of n-hexane and ethyl acetate (1:1) as an eluent to give 4.04 g of yellow crystals, which were recrystallized from isopropyl ether to give colorless needles, mp 79°-80° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH2:15][CH2:14][CH2:13][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(OCCCc2ccccc2)cc1
Yield: 90.1 %

Procedure:
Using the general method of Compound 80 Part A, methyl 4-hydroxybenzoate (3.0 g, 19.7 mmole)was reacted with 1-bromo-3-phenylpropane (3.1 mL, 20.4 mmole) to provide 4.8 g of methyl 4-(3-phenylpropyloxy)benzoate as a white crystalline solid, m.p. 61.0°-61.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[Br:23]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:23][C:16]1[CH:17]=[CH:18][C:9]([NH:8][C:6]2[C:5]([C:19]([F:22])([F:20])[F:21])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[C:10]([CH:15]=1)[C:11]([NH:13][CH3:14])=[O:12]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Br)ccc1Nc1nc(Cl)ncc1C(F)(F)F
Reaction time: 1 h
Yield: 42.2 %

Procedure:
2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (WO 2010141406, 4.6 g, 13.9 mmol) and N-bromosuccinimide (2.46 g, 13.9 mmol) were taken up in DMF (8 mL) and stirred for 1 hr. The reaction mixture was poured into water and the resulting precipitate was collected via filtration, air dried and purified by column chromatography (SiO2, 1% methanol in dichloromethane) to give 2.4 g (42%) of the title compound. 1H NMR (600 MHz, DMSO-d6) δ: 11.88 (s, 1H), 8.93 (brs, 1H), 8.67 (s, 1H), 8.28 (d, J=9 Hz, 1H), 7.95 (s, 1H), 7.76 (d, J=9 Hz, 1H), 2.75 (d, J=4.2 Hz, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:16](=[O:17])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([S:6]([CH3:5])(=[O:8])=[O:7])=[CH:10][CH:11]=2)=[CH:22][CH:21]=1
Reactant: Fc1ccccc1
Reactant: CS(=O)(=O)c1ccc(CC(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
Thereafter 102 g (0.765 mole) of anhydrous aluminum chloride was suspended in 200 ml of fluorobenzene. To the suspension was added dropwise a suspension of 120 g of the 4-methylsulfonylphenylacetyl chloride obtained above in 200 ml of fluorobenzene at a temperature of 0° to 3° C. The reaction vessel used was rinsed with 30 ml of fluorobenzene and the mixture was stirred at 20° C. for 4 hours. The reaction mixture was gradually poured into a mixture of ice water and hydrochloric acid and left to stand overnight, giving gummy solids. The solids were collected by filtration. The organic layer was separated from the filtrate and subjected to distillation under reduced pressure to recover 200 ml (52%) of fluorobenzene. The gummy solids were dissolved in dichloromethane, washed sequentially with water, a 5% aqueous solution of sodium bicarbonate and a saturated saline solution and dried over magnesium sulfate. The dichloromethane was distilled off and the resulting crystals were washed with diethyl ether, giving 77 g (51%) of 1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone as pale yellow solids.