Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:15]([C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH2:3]1.Cl[C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[N:2]1[CH2:5][CH:4]([C:6]2[C:15]([C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH2:3]1
Reactant: Clc1ccc2ccccc2n1
Reactant: Cc1cccc(-c2nc3ccccc3nc2C2CNC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc3ccccc3nc2C2CN(c3ccc4ccccc4n3)C2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 2-azetidin-3-yl-3-m-tolyl-quinoxaline hydrochloride (311 mg, 1 mmol) and 2-chloro-quinoline (163 mg, 1.0 mmol) in DMF (6 mL) was added Cs2CO3 (650 mg, 2 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give 2-(1-quinolin-2-yl-azetidin-3-yl)-3-m-tolyl-quinoxaline (256 mg, 0.64 mmol yield 63.7%).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C@H:4]([N:8]([CH3:14])[CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.[ClH:25].[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH2:34][CH2:35][CH2:36][NH2:37])=[CH:29][CH:28]=1.C(OCC)C>CN(C=O)C>[ClH:25].[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)[CH2:34][CH2:35][CH2:36][NH:37][C:5](=[O:7])[C@@H:4]([N:8]([CH3:14])[CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:3][CH:2]([CH3:1])[CH3:15])=[CH:29][CH:28]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)CCN(C)[C@@H](CC(C)C)C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CCN(C)[C@@H](CC(C)C)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 66.8 %

Procedure:
(S)-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid (0.300 g, 1.39 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.728 mL, 4.18 mmol) and solid O-benzotriazol-1-yl-N,N,N″,N′-tetramethyluronium hexafluorophosphate (0.528 g, 1.39 mmol). The resulting reaction mixture was stirred at that temperature for 25 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.415 g, 1.39 mmol) was then added. After stirring for, sequentially, 20 minutes at 0° C. and 60 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (40% EtOAc in hexane) and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.460 g (65%) of the pure titled compound as a white foam: mp 37-46° C. APCI-MS m/z 459.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].Cl[C:11]1[S:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[O:8][C:11]1[S:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Oc1c(Cl)cncc1Cl
Product: COC(=O)c1cc([N+](=O)[O-])c(Oc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for step A of example 18 from 3,5-dichloropyridin-4-ol (370 mg, 2.26 mmol) and methyl 5-chloro-4-nitro-thiophene-2-carboxylate (500 mg, 2.26 mmol). The title compound was obtained as a solid (510 mg, 65% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.65 (2H, s), 8.26 (1H, s), 3.93 (3H, s). MS m/z: 348.00, 350.99 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)[Cl:36]>>[ClH:36].[ClH:36].[N:11]1([C:14]2[C:19]([C:20]3[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[CH:24][CH:25]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccc(CO)cc2)CC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: OCc1ccc(-c2nccnc2N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
Dissolve 3′-(4-hydroxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (2.76 g, 7.45 mmol) in DCM (25 mL) and add trifluoroacetic acid (5 mL) and allow the mixture to stir at room temperature for six hr. Evaporate the solution then dilute with DCM and wash with saturated sodium bicarbonate. Dry the organics over sodium sulfate then filter and evaporate. Chromatograph the residue over silica gel (eluting with 8:92 methanol (with 2 M ammonia):DCM), then dissolve the solid in methanol and add ammonium chloride then sonicate the mixture for 10 min. Evaporate the solution to give [4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl)-phenyl]-methanol dihydrochloride as a white solid (1.303 g, 65%). MS (ES): m/z=271 [M+H]+.
Reaction SMILES: [OH:1][C@:2]12[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:12]3[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]3=[O:14])[C@@:6]1([O:21][CH3:22])[O:5][CH2:4][CH2:3]2.[CH3:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([C:29](Cl)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[CH:27][CH:26]=1.C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.ClCCl>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([C:29]([O:11][CH2:10][C@H:9]2[O:8][C@@H:7]([N:12]3[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]3=[O:14])[C@:6]3([O:21][CH3:22])[C@@:2]2([OH:1])[CH2:3][CH2:4][O:5]3)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:28]2[CH:45]=[CH:46][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CO[C@]12OCC[C@@]1(O)[C@@H](CO)O[C@H]2n1cc(C)c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@@]3(OC)OCC[C@@]23O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.5 %

Procedure:
A mixture of compound 17 (0.95 g, 3.03 mmol) and 4,4′-dimethoxytrityl chloride (1.54 g, 4.77 mmol) was dissolved in anhydrous pyridine (20 cm3) and stirred for 4 h at room temperature. The reaction mixture was evaporated to give an oily residue which was co-evaporated with toluene (2×20 cm3). Dichloromethane (50 cm3) and a saturated aqueous solution of sodium hydrogencarbonate (50 cm3) were added, the organic phase was separated and evaporated, and the residue purified by silica gel HPLC (the residue was dissolved in the minimum amount of dichloromethane containing 0.5% triethylamine (v/v) and applied to the column equilibrated by the same solvent. The column was washed (ethylacetate:petroleum ether:triethylamine; 15:84.5:0.5 (v/v/v, 1000 cm3) and the product was eluted in a gradient of methanol (C-2%) in dichloromethane containing 0.5% of triethylamine (v/v/v) to give compound 18 (1.71 g, 92.8%) as white solid material. δH (CDCl3) 7.51-7.17 (10H, m, DMT, 6-H), 6.79-6.85 (4H, m, DMT), 6.04 (1H, s, 1′-H), 4.12-3.98 (3H, m, 5-Ha, 5′-Hb, 4′-H), 3.77 (6H, s, CH3-DMT), 3.49 (3H, s, CH3—O), 3.45-3.32 (2H, m, 2″-Ha, 2″-Hb), 2.11-2.01 (1H, m, 1″-Ha), 1.94-1.87 (1H, m, 1″-Hb), 1.93 (3H, s, CH3). δC (CDCl3) 164.2 (C-4), 158.6, 144.7, 135.7, 130.1, 128.2, 127.9, 126.8, 113.2 (DMT), 150.7 (C-2), 137.7 (C-6), 109.8, 109.7 (C-5, C-2′), 86.5, 85.3, 85.0, 81.4 (DMT, C-1′, C-3′, C-4′), 69.2, 62.4 (C-5′, C-2″), 55.2 (CH3-DMT), 51.7 (CH3—O), 35.5 (C-1″), 12.7 (CH3). FAB-MS m/z 617.26 [M+H]+, 639.23 [M+Na]+ (Found: C, 66.4; H, 6.1; N, 4.2; C34H36O9N2 requires C, 66.2; H, 5.9; N, 4.5%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1([CH2:11][NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].N12CCCN=C1CCCCC2>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1([CH2:11][N:12]2[C:13](=[O:21])[C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:20][C:23]2=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)CC1(CNC(=O)c2ccccc2N)CCCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CC1(Cn2c(=O)[nH]c3ccccc3c2=O)CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a solution of {1-[(2-amino-benzoylamino)-methyl]-cyclohexyl}-acetic acid methyl ester (620 mg, 2.04 mmol) and 1,1′-carbonyldiimidazole (660 mg, 4.07 mmol) in THF (25 mL) is added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL, 4.01 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with EtOAc (100 mL) and is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate, and is concentrated to afford the desired [1-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-cyclohexyl]-acetic acid methyl ester (670 mg, 99%).
Reaction SMILES: C([O:8][C:9]1[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[CH:31][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)(=[O:20])=[O:19])=[CH:14][C:13]=1[F:30])C1C=CC=CC=1.O1CCCC1>C(O)C>[CH2:35]([C:33]1[CH:32]=[CH:31][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][CH2:24][N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)(=[O:20])=[O:19])=[CH:14][C:13]=2[F:30])=[C:9]([OH:8])[CH:34]=1)[CH3:36]
Reactant: CCc1ccc(Oc2ccc(S(=O)(=O)NCCCn3ccnc3)cc2F)c(OCc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc(Oc2ccc(S(=O)(=O)NCCCn3ccnc3)cc2F)c(O)c1
Yield: 42.3 %

Procedure:
According to the procedure of example 20(b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for 4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-(3-imidazol-1-yl-propyl)-benzenesulfonamide (160 mg; 0.31 mmol) and tetrahydrofurane for ethanol (3 mL), the title compound (55 mg; 42%) was obtained as a clear oil, after purification via preparative TLC (dichloromethane/methanol/triethylamine)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7](Cl)=[CH:6][C:5]=1[NH:12]C(=O)C)([O-:3])=[O:2].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.[OH-].[K+].[K+].[Br-]>CS(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:6][C:5]=1[NH2:12])([O-:3])=[O:2]
Reactant: CC(=O)Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Reactant: C1CCNC1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(N2CCCC2)c(F)cc1[N+](=O)[O-]
Yield: 85.3 %

Procedure:
2-Nitro-4-fluoro-5-(pyrrolidin-1-yl)aniline (12.3 g, 85%) was prepared by an analogous procedure to that described in preparation 1 (step 3) using N-(2-nitro-4-fluoro-5-chlorophenyl)acetamide (15.0 g, 0.064 mol) (obtained in preparation 1, step 2), pyrrolidine (22.9 g, 0.32 mol), potassium hydroxide (5.4 g, 0.096 mol) and dimethyl sulfoxide (60 mL). mp 115-116° C.; IR (KBr) 3478, 1536 cm-1 ; 1H NMR (CDCl3) δd 1.98 (m, 4H, (CH2)2), 3.50 (m, 4H, N(CH2)2), 5.64 (d, J=7.8 Hz, 1H), 6.09 (brs, 2H, NH2), 7.72 (d, J=14.6 Hz, 1H); Mass (m/z) 225 (M+.).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH3:27][NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1>>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([S:16]([NH:15][C:10]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:28]([CH3:27])[C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:31][CH:30]=4)=[CH:4][CH:5]=3)=[N:14][CH:13]=[CH:12][N:11]=2)(=[O:17])=[O:18])=[CH:24][CH:23]=1)#[N:26]
Reactant: N#Cc1ccc(S(=O)(=O)Nc2nccnc2-c2ccc(CCl)cc2)cc1
Reactant: CNc1ccc(OC(F)(F)F)cc1
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccc(C#N)cc2)cc1)c1ccc(OC(F)(F)F)cc1
Yield: 70 %

Procedure:
Following the general method as outlined in Example 1 (Method D), N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-4-cyanobenzenesulfonamide, and N-methyl-4-(trifluoromethoxy)aniline, the title compounds were isolated as a yellow solid in 70% yield (92% purity by HPLC).
Reaction SMILES: [CH2:1]([C:3]1([CH3:11])[N:7]([CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][O:4]1)C.N(CCO)CCO.C(C(C)=O)C>CC(C)=O>[OH:10][CH2:9][CH2:8][N:7]1[CH2:6][CH2:5][O:4][C:3]1([CH3:11])[CH3:1]
Reactant: CCC1(C)OCCN1CCO
Solvent: OCCNCCO
Solvent: CC(C)=O
Solvent: CCC(C)=O
Product: CC1(C)OCCN1CCO

Procedure:
Part (A) of Example I is a process for making MEHEOX, i.e., 2-ethyl-3-(2-hydroxyethyl)-2-methyloxazolidine by reaction of diethanolamine with methyl ethyl ketone. Replacement of the latter ketone with acetone in molarly corresponding amount yields 3-(2-hydroxyethyl)-2,2-dimethyl-oxazolidine, herein referred to by the acronym DMHEOX, i.e., dimethyl-hydroxyethyloxazolidine. Replacement of the ketone with cyclopentanone or cyclohexanone yields 3-(2-hydroxyethyl)-2,2-tetramethylene- or 3-(2-hydroxyethyl)-2,2-pentamethylene-oxazolidine.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[O:11][CH2:10][C:9]([CH3:14])([CH3:13])[C:8]=2[CH:7]=[C:6]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]=1[CH3:24])([CH3:3])[CH3:2].[CH2:25]([Li])[CH2:26][CH2:27]C.IC(C)C>O1CCCC1>[CH:1]([C:4]1[C:12]2[O:11][CH2:10][C:9]([CH3:13])([CH3:14])[C:8]=2[CH:7]=[C:6]([N:15]([CH:26]([CH3:27])[CH3:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]=1[CH3:24])([CH3:3])[CH3:2]
Reactant: COc1ccc(Nc2cc3c(c(C(C)C)c2C)OCC3(C)C)cc1
Reactant: [Li]CCCC
Solvent: CC(C)I
Solvent: C1CCOC1
Product: COc1ccc(N(c2cc3c(c(C(C)C)c2C)OCC3(C)C)C(C)C)cc1
Yield: 7 %

Procedure:
Following general procedure L and using 7-isopropyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 52, 0.6 g, 2.7 mmol), 1.6M solution of n-butyllithium in hexanes (2.2 mL, 3.5 mmol) and 2-iodopropane (0.9 g, 5.4 mmol) in 10mL of anhydrous tetrahydrofuran, the title compound (0.077 g, 7%) was obtained as a brown oil after separation from recovered 7-isopropyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 52, 0.2 g) by preparative normal phase HPLC using 4% ethyl acetate in hexanes as the mobile phase. 1H NMR (300 MHz, CDCl3): δ 6.75 (d, 2H, J=9.2 Hz), 6.62 (s, 1H), 6.38 (d, 2H, J=9.2 Hz),4.25-4.11 (m, 3H), 3.73 (s, 3H), 3.19 (heptet, 1H, J=7.0 Hz), 2.06 (s, 3H), 1.33 (d, 6H, J=7.0 Hz), 1.27 (s, 6H), 1.11 (br m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:15]2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:15]2)[CH2:12][CH2:13]1)(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1C1CCN(C2CCN(C(=O)CNC(=O)c3ccc(Cl)c(Cl)c3)C2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1C1CCN(C2CCN(C(=O)CNC(=O)c3ccc(Cl)c(Cl)c3)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
To N-(2-(3-(4-(2-aminophenyl)piperidin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)-3,4-dichlorobenzamide (Example #4.149, 0.050 g, 0.10 mmol) in DCM (1 mL) was sequentially added triethylamine (0.044 mL, 0.32 mmol) and acetic anhydride (10.9 μL, 0.116 mmol). The reaction mixture was stirred at room temperature for about 16 h. The solvent was removed in vacuo and the residue purified by RP-HPLC (10% acetonitrile/0.05M aqueous ammonium acetate, buffered to pH 4.5 for 3 min., 5% to 60% acetonitrile/0.05M aqueous ammonium acetate over 6 min at 22.5 mL/min with 2.5 mL/min. acetonitrile at-column dilution; APCI positive mode detection; Xterra prep. MS C18. 19×50 mm column) to afford N-(2-(3-(4-(2-acetamidophenyl)piperidin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)-3,4-dichlorobenzamide (0.0075 g, 0.014 mmol). RP-HPLC (Table 1, Method a) Rt 1.92 min; nm/z: (M+H)+ 517.
Reaction SMILES: [C:1]([N:4]1[CH2:19][CH2:18][CH2:17][C:7]2=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]([CH3:16])=[C:6]2[CH2:5]1)(=[O:3])[CH3:2].[OH:20]O>C(O)(=O)C>[C:1]([N:4]1[CH2:19][CH2:18][CH2:17][C:7]2=[N+:8]([O-:20])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]([CH3:16])=[C:6]2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCc2nc3ccccc3c(C)c2C1
Reactant: OO
Solvent: CC(=O)O
Product: CC(=O)N1CCCc2c(c(C)c3ccccc3[n+]2[O-])C1

Procedure:
6 gm (23.8 millimols) of 2-acetyl-2,3,4,5-tetrahydro-11-methyl-1H-azepino[4,3-b]quinoline were dissolved in 7 ml of glacial acetic acid, and 4 ml of 30% hydrogen peroxide were added to the solution at room temperature. The mixture was subsequently heated at 60° to 80° C. for 2 hours. After distilling off the solvent, the mixture was dissolved in 2 N sodium hydroxide, the resulting solution was extracted with chloroform, the solvent was distilled out of the chloroform extract, and the residue was recrystallized from ethyl acetate.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](C2C=CC=CC=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([S:27]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)cc1
Reactant: O=[N+]([O-])c1ccccc1I
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1

Procedure:
2,4-Difluoro-1-((E)-2-{4-[(2-nitrophenyl)sulfonyl]phenyl}vinyl)benzene was prepared according to the method of Example 135 Step 2 using 2-iodonitrobenzene and Intermediate 2.
Reaction SMILES: [Cl:1][C:2]12[CH2:9][N:8](C(OCC)=O)[CH2:7][CH:6]1[N:5]([CH3:15])[CH:4]([CH3:16])[CH2:3]2>Cl>[Cl:1][C:2]12[CH2:9][NH:8][CH2:7][CH:6]1[N:5]([CH3:15])[CH:4]([CH3:16])[CH2:3]2
Reactant: CCOC(=O)N1CC2N(C)C(C)CC2(Cl)C1
Agent: Cl
Product: CC1CC2(Cl)CNCC2N1C

Procedure:
7.6 g (30.8 mmol) of ethyl 5-chloro-2,3-dimethyl -2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux overnight with 30 ml of concentrated hydrochloric acid. The mixture is concentrated, the residue is taken up in 30 ml of water, and the mixture is rendered alkaline with potassium carbonate, extracted five times with 50 ml of chloroform each time, dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[OH-:14].[Na+:15].[S:16]([O-:19])([OH:18])=[O:17].[Na+].Cl>O.[Cu]Cl>[C:7]([C:6]1[S:5][C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=2[C:2]=1[S:16]([O-:19])(=[O:18])=[O:17])([OH:14])=[O:8].[Na+:15]
Reactant: O=S([O-])O
Reactant: [OH-]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Agent: Cl[Cu]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1sc2ccccc2c1S(=O)(=O)[O-]
Yield: 48 %

Procedure:
74.0 gm (0.32 mol) of 3-chloro-benzo[b]thiophene-2-carboxylic acid chloride (m.p. 112°-113° C.) were stirred with a solution of 25.6 gm (0.64 mol) of sodium hydroxide in 250 cc of water for 12 hours while keeping the reaction temperature at 50° C. Thereafter 66.6 gm (0.64 mol) of solid sodium hydrogen sulfite were added to the neutral-reacting solution. The reaction mixture was made slightly alkaline by addition of a 40% sodium hydroxide solution and heated for 16 hours to 143° C. in an autoclave after addition of 3.0 gm (0.03 mol) of copper(I)-chloride. After cooling, the mixture was adjusted to pH 4 by adding hydrochloric acid, filtered and extracted once with 200 cc of ethyl acetate to remove the residual unreacted starting material. After further acidification to pH 1 and by addition of 60 gm of sodium chloride a colorless precipitate was obtained from the aqueous phase, which was suction-filtered off, washed with 30 cc of saturated aqueous sodium chloride solution and suction-filtered. The reaction product was dissolved in warm methanol and separated from the insoluble excess sodium chloride. The solvent was evaporated in vacuo, and the residue was dried by azeotropic distillation with 50 cc of toluene. 43 gm (48% of theory) of colorless crude sodium 2-carboxy-benzo[b]thiophene-3-sulfonate were obtained, which were further processed without further purification.
Reaction SMILES: CN(C)C1C=CC=CC=1.[NH2:10][C:11]1[C:12]([Cl:19])=[N:13][C:14]([CH3:18])=[CH:15][C:16]=1[Cl:17].O.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)(Cl)Cl>[Cl:19][C:12]1[C:11]([NH:10][C:26](=[O:27])[CH2:25][O:24][C:21](=[O:23])[CH3:22])=[C:16]([Cl:17])[CH:15]=[C:14]([CH3:18])[N:13]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1cc(Cl)c(N)c(Cl)n1
Solvent: CN(C)c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCC(=O)Nc1c(Cl)cc(C)nc1Cl
Temperature: 23 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
N,N-Dimethylaniline (142.4 g, 1,175 mmol) was added to a solution of 3-amino-2,4-dichloro-6-methylpyridine (130.0 g, 734 mmol) in chloroform (910 mL). Under cooling with water, a solution of acetyloxyacetyl chloride (150.4 g, 1,102 mmol) in chloroform (390 mL) was added dropwise thereto over 30 minutes while the temperature of the reaction mixture was maintained at 19 to 27° C., followed by stirring at room temperature overnight (18 hours). After HPLC was performed to confirm that starting materials had been completely consumed, water (650 mL) was added to the reaction mixture. The formed organic layer was collected, and the aqueous layer was extracted with chloroform (650 mL). The obtained organic layers were combined, followed by washing sequentially with water and saturated brine. The thus-washed organic layer was dried over sodium sulfate anhydrate, and the solvent was removed under reduced pressure. Subsequently, isopropyl alcohol (195 mL) and diisopropyl ether (390 mL) were added to the residue, and the resultant mixture was heated for dissolution. Diisopropyl ether (650 mL) was added dropwise thereto at an internal temperature of 62 to 66° C. The reaction mixture was cooled, followed by stirring for 3.5 hours under cooling with ice. The crystals that precipitated were collected through filtration, followed by washing with a cooled mixture of isopropyl alcohol (19.5 mL) and diisopropyl ether (104 mL). The obtained mixture was dried at room temperature under reduced pressure, to thereby yield N-[2,4-dichloro-6-methylpyrrolidin-3-yl]-2-acetyloxyacetamide as colorless crystals (171.7 g, 619.6 mmol, yield: 84.4%, HPLC: 99.20%).
Reaction SMILES: [F:1][C:2]([F:16])([C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[C:3](F)=[O:4].[F-:17].[K+].F[H-]F.[K+].[F:23][C:24]([F:31])([F:30])[C:25]([F:29])=[C:26]([F:28])[F:27]>COCCOCCOC>[F:23][C:24]([F:31])([F:30])[C:25]([F:29])([C:26]([F:17])([F:28])[F:27])[C:3](=[O:4])[C:2]([F:16])([F:1])[C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: [F-]
Reactant: O=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F[H-]F
Agent: [K+]
Solvent: COCCOCCOC
Product: O=C(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F
Temperature: 50 °C
Yield: 440.2 %

Procedure:
A mixture consisting of 775 g of perfluoropentanoyl fluoride, 800 g of anhydrous diglyme, 13.1 g of potassium fluoride, 17.8 g of anhydrous potassium bifluoride and 775 g of hexafluoropropylene was heated in a 3-liter stainless steel pressure vessel under autogeneous pressure at 50° C. for 16 hours. The product was fractionally distilled to give 413 g of 1,1,1,2,4,4,5,5,6,6,7,7,7-tridecafluoro-2-trifluoromethyl-heptan-3-one, having a boiling point of 97° C. and a 99.0% purity as determined by gas chromatography and mass spectroscopy.