Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[CH:29]=[C:28]([F:30])[C:27]([N:31]3[CH:35]=[N:34][C:33]([CH3:36])=[N:32]3)=[C:26]([F:37])[CH:25]=2)[N:19]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>CC(C)=O>[F:37][C:26]1[CH:25]=[C:24]([NH:23][C:20]2[N:19]=[C:18]3[CH:6]([C:7]4[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=4)[CH2:5][CH2:4][CH2:3][CH2:2][N:22]3[N:21]=2)[CH:29]=[C:28]([F:30])[C:27]=1[N:31]1[CH:35]=[N:34][C:33]([CH3:36])=[N:32]1
Reactant: Cc1ncn(-c2c(F)cc(Nc3n[nH]c(C(CCCCCl)c4ccc(OC(F)(F)F)cc4)n3)cc2F)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncn(-c2c(F)cc(Nc3nc4n(n3)CCCCC4c3ccc(OC(F)(F)F)cc3)cc2F)n1
Yield: 34.4 %

Procedure:
A solution of 5-(5-chloro-1-(4-(trifluoromethoxy)phenyl)pentyl)-N-(3,5-difluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (1.24 g, 2.30 mmol), sodium iodide (1.72 g, 11.5 mmol), and diisopropylethylamine (2.00 mL, 11.5 mmol) in acetone (50 mL) was heated in a sealed vessel at 100° C. for 6 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (70% EtOAc/chloroform) to afford 400 mg of the titled compound. The solid was recrystallized from EtOAc/Hex to afford 230 mg (19% yield) of the titled compound as a crystalline white solid. LC-MS (M+H)+ 506.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.11 (1H, s), 7.13-7.23 (6H, m), 6.92 (1 H, s), 4.22-4.33 (3 H, m), 2.49 (3 H, s), 2.15-2.27 (1 H, m), 2.05-2.13 (1H, m), 1.92-2.01 (2 H, m, J=14.8, 9.8, 7.2, 7.2 Hz), 1.82-1.90 (2 H, m).
Reaction SMILES: [CH2:1]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].P(Cl)(Cl)(Cl)(Cl)Cl.[Br:27]Br>C(Cl)(Cl)Cl>[Br:27][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:14]1=[O:20]
Reactant: BrBr
Reactant: CCCCCCCCCCCCN1CCCCCC1=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCN1CCCCC(Br)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold solution of 107 g (0.38 mol) of 1-dodecylazacycloheptan-2-one, in CHCl3 was added 159.7 g (0.77 mol) of PCl5, keeping the temperature between 1°-4° C. After 2 hours, a solution of 123.3 g (0.77 mol) of bromine in CHCl3 was added, and the mixture was stirred for 18 hours at room temperature. After removing the solvent and excess bromine by vacuum distillation, the residue was dissolved in CH2Cl2, washed with sat. Na2S2O5, dried over MgSO4, and concentrated in vacuo to give a crude oil. Purification by flash chromatography (silica gel; 1:1 ether/petroleum ether V/V) gave pure product.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7].C[N+]1([O-])CC[O:22]CC1.Cl>C(#N)C>[CH:2]([C:3]1[C:4]([CH3:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7])=[O:22]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1C
Reactant: C[N+]1([O-])CCOCC1
Agent: Cl
Solvent: CC#N
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1C
Temperature: 25 °C
Yield: 76.9 %

Procedure:
18.90 g of methyl 3-bromomethyl-4-methylsulfonyl-2-methylbenzoate was dissolved in 180 ml of acetonitrile, and 20.67 g of N-methylmorpholine oxide was added over 10 minutes at room temperature. The resulting solution was stirred at room temperature for an hour, poured into ice water, acidified with concentrated hydrochloric acid, and extracted with benzene. The organic layer was washed with water, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure to give 11.59 g of the title compound as white crystals. The crude product was washed with ethanol to give white crystals of the title compound. m.p. 108~110° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si](C)(C)[C:9]#[C:10][C:11]([C:13]1[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[N:15](C(OC(C)(C)C)=O)[CH:14]=1)=O.C(=O)(O)O.[C:35]1([NH:41][C:42]([NH2:44])=[NH:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>COCCO>[C:35]1([NH:41][C:42]2[N:44]=[C:11]([C:13]3[C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:16]=4[NH:15][CH:14]=3)[CH:10]=[CH:9][N:43]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)n1cc(C(=O)C#C[Si](C)(C)C)c2cnccc21
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCO
Solvent: O
Product: c1ccc(Nc2nccc(-c3c[nH]c4ccncc34)n2)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1.2 104 mg (0.75 mmol) of potassium carbonate are added to a solution of 103 mg (0.30 mmol of tert-butyl 3-(3-trimethylsilylpropynoyl)pyrrolo-[3,2-c]pyridine-1-carboxylate and 148 mg (0.75 mmol) of phenylguanidine carbonate in 1.5 ml of ethylene glycol monomethyl ether, and the mixture is heated at the boil for 68 hours. After cooling, 10 ml of water are added, and the mixture is stirred at 40° C. for 1 h. The precipitate formed is filtered off with suction, washed with water and dried in vacuo, giving phenyl-[4-(1H-pyrrolo[3,2-c]pyridin-3-yl)pyrimidin-2-yl]amine (“A1”) as pale-brown solid; ESI 287;
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][CH:14]1[CH2:19][CH2:18][O:17][C:15]1=[O:16].[CH3:20][S:21]SC>O1CCCC1>[CH3:13][C:14]1([S:21][CH3:20])[CH2:19][CH2:18][O:17][C:15]1=[O:16]
Reactant: CSSC
Reactant: CC1CCOC1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSC1(C)CCOC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
Under an argon atmosphere, n-butyllithium (1.7 M in hexane, 1800 ml, 3.06 mole) was added slowly to a stirred solution of diisopropylamine (309.4 g, 3.06 mole) in tetrahydrofuran (1800 ml) at -78° C. Upon completion of addition, the reaction mixture was allowed to stir for 30 minutes at which time alpha-methyl-gamma-butyrolactone (278.0 g, 2.78 mole) was added dropwise, also at -78° C. The reaction mixture was stirred 30 minutes then dimethyl disulfide (392.8 g, 4.17 mole) was added dropwise. After stirring for 30 minutes at -78° C., the reaction mixture was warmed to ambient temperature during a one hour period. The reaction mixture was quenched with 5% aqueous hydrochloric acid (1500 ml) and then diluted with ethyl acetate (2000 ml). The layers were separated, and the organic layer was washed with aqueous 10% hydrochloric acid (1×200 ml) and then saturated aqueous sodium bicarbonate (1×100 ml). The organic layer was dried and concentrated under reduced pressure. The residue was distilled to yield 234.6 g of alpha-methyl-alpha-methylthio-gamma-butyrolactone as a colorless oil, b.p. 104°-105° C./8 mm Hg. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12].[Li]CCCC.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CCOCC>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH2:10][O:11][CH3:12])=[C:2]([C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=1
Reactant: COCOc1ccc(Br)cc1Br
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1cc(Br)ccc1OCOC
Reaction time: 0.75 h
Yield: 112.8 %

Procedure:
A flask was charged with 2,4-dibromophenol (50.4 g, 200 mmol), potassium carbonate (69.1 g, 500 mmol) and acetone (500 mL). The suspension was stirred at RT for 30 minutes and then treated dropwise with chloromethyl ethyl ether (19 mL, 213 mmol). After 3 h at RT the mixture was filtered and the filtrate was partitioned between EtOAc and water. The organic phase was separated, washed with water, aqueous saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford 54.2 g 2,4-dibromo-1-(methoxymethoxy)benzene, which was used in the next step without further purification. Step 2: A solution of 2,4-dibromo-1-(methoxymethoxy)benzene (40.5 g, 137 mmol) in Et2O (140 mL) was cooled to −78° C. and treated with n-BuLi (2.5M in hexanes; 60.2 mL, 151 mmol) under nitrogen atmosphere. After 30 minutes a solution of diethyl oxalate (27.9 mL, 205 mmol) in Et2O (20 mL) was added dropwise. The reaction mixture was stirred for 45 minutes at that temperature then quenched cold with saturated ammonium chloride solution. The mixture was partitioned between Et2O and water. The organic phase was separated, washed with water, brine, then dried over MgSO4. The solvent was removed under reduced pressure to afford 49 g of ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-oxoacetate, which was used in the next step without further purification. Step 3: A flask was charged with (S)-2-methylpropane-2-sulfinamide (0.764 g, 6.31 mmol) and neopentylzinc(II) iodide (0.5 M in THF, 10.0 mL, 5.00 mmol) was added under nitrogen atmosphere. The mixture was stirred at RT for 15 minutes and ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-oxoacetate (1.00 g, 3.15 mmol) was added in one portion. The reaction mixture was quenched with saturated aqueous ammonium chloride after 8 h. The reaction was partitioned between EtOAc and water. The organic phase was separated, washed with NH4Cl, water and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography (10-30% EtOAc/hexane) to provide 0.675 g (S)-ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-(tert-butylsulfinylimino)acetate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:33][CH2:34][CH2:35][OH:36])[C:23]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:18](O)=[O:19])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:37]1[O:46][C:45]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][C:39]=2[O:38]1>>[O:46]1[C:45]2[CH:44]=[CH:43][C:41]([NH:42][C:18](=[O:19])[C:17]3[CH:21]=[C:22]([O:33][CH2:34][CH2:35][OH:36])[C:23]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)=[C:15]([NH:14][S:11]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][CH:7]=4)(=[O:12])=[O:13])[CH:16]=3)=[CH:40][C:39]=2[O:38][CH2:37]1
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)O)cc2OCCO)c1
Reactant: Nc1ccc2c(c1)OCO2
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)Nc3ccc4c(c3)OCO4)cc2OCCO)c1

Procedure:
Analogously to Example 74, by condensing 3-(4-tert-butyl-benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzoic acid with 3,4-methylenedioxyaniline there was obtained N-benzo-[1,3]dioxol-5-yl-3-(4-tert-butylbenzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzamide.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O=[C:15]([CH3:22])[CH2:16][C:17](OCC)=[O:18].C(=O)([O-])[O-].[K+].[K+]>O>[N:1]1([CH2:6][C:7]2[CH:12]=[C:11]3[C:10](=[CH:9][CH:8]=2)[NH:13][C:15]([CH3:22])=[CH:16][C:17]3=[O:18])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(Cn2ccnc2)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(=O)c2cc(Cn3ccnc3)ccc2[nH]1
Yield: 14.4 %

Procedure:
To a stirred and heated (100° C.) solution of 10 parts of 4-(1H-imidazol-1-ylmethyl)benzenamine in 50 parts of poly phosphoric acid were added 15 parts of ethyl 3-oxobutanoate. The whole was stirred for 4 hours at 140° C. 100 Parts of water were added to the mixture and the whole was neutralized with potassium carbonate. The product was extracted with a mixture of ethyl acetate and methanol. The extract was dried, filtered and concentrated. The concentrate was crystallized from a mixture of 2-propanone and methanol. The product was filtered off and dried, yielding 2 parts (14.4%) of 6-(1H-imidazol-1-ylmethyl)-2-methyl-4(1H)quinolinone; mp. 245.5° C. (decomp.) (compound 77).
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1.C(=O)(O)[O-].[Na+].Cl[CH:16]([CH:22]=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(COC)OC.ClCCl>[I:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][N:9]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Cc1cnc(N)cc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CCOC(=O)c1cnc2cc(I)c(C)cn12
Temperature: 100 °C

Procedure:
To a suspension of 4-iodo-5-methylpyridin-2-amine (I-28A) (1.55 g. 6.6 mmol), sodium bicarbonate (0.67 g, 7.9 mmol) in dry dimethoxyethane (10 mL) at room temperature, ethyl 2-chloro-3-oxopropanoate (1 g, 6.41 mmol) in dimethoxyethane (1 mL) was added dropwise. The reaction mixture was heated to 100° C. for 1 h and then cooled to room temperature and diluted with dichloromethane (50 mL). The organic layer was washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The brown crude oil was purified by silica gel chromatography with a gradient of 0-15% ethyl acetate/hexanes to yield ethyl 7-iodo-6-methylimidazo[1,2-a]pyridine-3-carboxylate (I-28B) as light tan solid. 1H-NMR (400 MHz, DMSO) δ 9.11 (s, 1H), 8.41 (s, 1H), 8.22 (s, 1H), 4.36 (q, J=7.2 Hz, 2H), 2.42 (s, 3H), 1.37 (t, J=7.2 Hz, 3H). MS m/z 331.0 (M+1).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=3[F:34])[C:13]([NH:19][S:20]([CH:23]3[CH2:25][CH2:24]3)(=[O:22])=[O:21])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:28]1[CH:29]=[C:30]([I:33])[CH:31]=[CH:32][C:27]=1[NH:26][C:12]1[C:13]([NH:19][S:20]([CH:23]2[CH2:24][CH2:25]2)(=[O:22])=[O:21])=[C:14]([O:17][CH3:18])[CH:15]=[C:16]2[C:11]=1[CH:10]=[N:9][NH:8]2
Reactant: COc1cc2c(cnn2C(=O)OC(C)(C)C)c(Nc2ccc(I)cc2F)c1NS(=O)(=O)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2[nH]ncc2c(Nc2ccc(I)cc2F)c1NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
A solution of 5-cyclopropanesulfonylamino-4-(2-fluoro-4-iodo-phenylamino)-6-methoxy-indazole-1-carboxylic acid tert-butyl ester (217 mg, 0.36 mmol) in DCM (5 mL) was treated with TFA (2 mL) and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue triturated with diethyl ether to give the title compound as an off-white solid (102 mg, 52%). LCMS (method A): RT=10.17 [M+H]+=503. 1H NMR (DMSO-d6, 400 MHz): 12.92 (1 H, s), 8.72 (1 H, s), 7.60-7.52 (2 H, m), 7.34-7.24 (2 H, m), 6.71 (1 H, s), 6.53 (1 H, t, J=8.80 Hz), 3.84 (3 H, s), 2.53-2.46 (1 H, m), 0.84-0.73 (2 H, m), 0.72-0.66 (2 H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:19]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCC1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 18 h

Procedure:
To a suspension of lithium aluminium hydride (1.41 g) in THF (15 mL) at 0° C. was added piperidine-1,3-dicarboxylic acid 1-tent-butyl ester 3-methyl ester as a solution in THF (10 mL) and the mixture stirred at room temperature for 3 h. The reaction was cooled to 0° C. and quenched by addition of aqueous ammonium chloride and the mixture filtered through celite. The filtrate was diluted with ethyl acetate, washed with water, separated and dried (MgSO4). The solvent was evaporated to give 3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.25 g). To a solution of this alcohol (422 mg) in THF (8 mL) was added sodium hydride (94 mg; 60% dispersion in mineral oil). After 15 min iodomethane (0.49 mL) was added and the reaction stirred for 18 h. The mixture was then diluted with ethyl acetate and washed sequentially with water, brine, separated and dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography to give 3-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester (414 mg). To a solution of 3-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester (204 mg) in DCM (3 mL) was added 2M hydrogen chloride in diethyl ether and the mixture stirred for 18 h. The solvent was evaporated to give the desired amine (168 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Cl>CS(C)=O>[C:10]([C:9]1([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)#[N:11]
Reactant: COc1ccc(CC#N)cc1
Reactant: ClCCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(C2(C#N)CCOCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
To a solution of 4-methoxyphenylacetonitrile (5 g, 34 mmol) and NaH (2.8 g, 71 mmol) in DMSO (50 ml) was added 2-chloroethyl ether (5.3 g, 37 mmol) with cooling. The mixture was stirred at room temperature for 3 h, quenched with water, and extracted with CH2Cl2. The combined extracts were dried (Na2SO4) and concentrated in vacuo to give an oil which was purified by a column chromatography to give Compound 88 (5.3 g, 24 mmol, 71%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3I)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([N:29]1[CH2:33][CH2:32][C@H:31]2[CH2:34][NH:35][CH2:36][C@@H:30]12)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]1[CH2:33][CH2:32][C@H:31]2[CH2:34][N:35]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[N:13]=[CH:12][C:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:20]4)[CH2:36][C@@H:30]12)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(CN2CC[C@H]3CNC[C@H]32)cc1
Reactant: O=S(=O)(c1cccc(F)c1)c1cnc2c(I)cccc2c1
Product: O=S(=O)(c1cccc(F)c1)c1cnc2c(N3C[C@@H]4CCN(Cc5ccccc5)[C@@H]4C3)cccc2c1

Procedure:
0.157 g of 8-((3aS,6aS)-1-benzylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-3-(3-fluorophenylsulfonyl)quinoline were prepared by analogy to the method of Example 27 by coupling of 3-(3-fluorophenylsulfonyl)-8-iodoquinoline with (3aS,6aS)-1-benzyloctahydropyrrolo[3,4-b]pyrrole
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNCCC
Reactant: O=C(O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCCN(CCC)C(=O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.98 g, 0.015 mole) and 1,1'-carbonyldiimidazole (2.59 g, 0.016 mole) in 120 ml of tetrahydrofruan was stirred at room temperature for 4 hrs. The di-n-propylamine (3.04 g, 0.03 mole) was added and the reaction mixture was heated at reflux for (65° C.) for 8-9 hrs. The reaction mixture was filtered and the filtrate was evaporated to an oil, which was placed under high vacuum for 3 hrs. The solid residue was treated with water, collected by filtration, washed with water, and dried under high vacuum. The solid was recrystallized from isopropyl alcohol-water, collected by filtration, washed with water, and dried under high vacuum to give 3.2 g (52%), mp 125°-27° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH:10]([CH3:11])[CH2:9][CH2:8][CH2:7][CH:6]1[CH3:12])=[O:4].[S-:13][C:14]#[N:15].[K+]>C(O)C>[S:13]([CH2:2][C:3]([N:5]1[CH:10]([CH3:11])[CH2:9][CH2:8][CH2:7][CH:6]1[CH3:12])=[O:4])[C:14]#[N:15]
Reactant: CC1CCCC(C)N1C(=O)CCl
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Product: CC1CCCC(C)N1C(=O)CSC#N
Reaction time: 3 h

Procedure:
1-(α-Chloroacetyl)-2,6-dimethylpiperidine (18.9 grams; 0.1 mol), potassium thiocyanate (18 grams; 0.2 mol) and ethanol (100 ml) were charged into a glass reaction flask equipped with a mechanical stirrier and reflux condenser. The reaction mixture was heated at reflux, with stirring, for a period of about 3 hours. After this time the reaction mixture was cooled and filtered. The ethanol was evaporated under reduced pressure to yield a dark solid. The solid was extracted with two 200 ml portions of hot benzene. The benzene extracts were combined, were filtered and treated with activated charcoal. The benzene solution was then evaporated under reduced pressure to yield a dark colored oil which solidified upon standing. The solidified product then crystallized, to yield 1-(α-thiocyanoacetyl)-2,6-dimethylpiperidine as a pale yellow solid having a melting point of 81° to 82° C. and leaving the following elemental analysis as calculated for C10H16N2OS.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([CH:12]=[O:13])[CH2:7][C:6]=2[N:5]=[CH:4][N:3]=1.[CH3:14][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([CH:12]([OH:13])[CH3:14])[CH2:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: O=CC1CCc2c(Cl)ncnc2C1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)C1CCc2c(Cl)ncnc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a cooled (0° C.) solution of 4-chloro-5,6,7,8-tetrahydroquinazoline-7-carbaldehyde (0.10 g, 0.51 mmol) in THF (5 mL) was added a solution of MeMgBr (3.0 M in ethyl ether, 0.40 mL, 1.2 mmol). The resulting mixture was stirred at ambient temperature for 30 minutes and then partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography provided 1-(4-chloro-5,6,7,8-tetrahydroquinazolin-7-yl)ethanol (0.09 g, 83% yield) as a waxy solid. MS (ES) for C10H13ClN2O: 213 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:29][C:30]1[C:31](Cl)=[N:32][CH:33]=[C:34]([CH:39]=1)[C:35]([O:37][CH3:38])=[O:36].C1N2CCN(CC2)C1>>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:39]=[C:30]([Cl:29])[C:31]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:32][CH:33]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Agent: C1CN2CCN1CC2
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)c(Cl)c1

Procedure:
In analogy to Example 62, step 1, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with methyl 5,6-dichloronicotinate and DABCO (17 h, r.t.) to give the title compound as a white solid. MS (m/e)=585.0 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:19]([O-:21])=[O:20])=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)COc1ccccc1CCCOC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1CCCOC
Reaction time: 0.5 h

Procedure:
4.00 g (15.9 mmol) of the above prepared [2-(3-methoxy-propyl)-phenoxy]-acetic acid ethyl ester was dissolved in 5.0 ml of TFAA and added slowly and carefully via dropping funnel to a mixture of 5 ml of TFAA and 4 ml of conc. HNO3 (65%) kept at −10° C.; the reaction was then allowed to proceed for additional 30 min. Careful quenching with ice, twofold extraction with EtOAc, washing with NaHCO3 and brine, drying over magnesium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiO2, hexane/EtOAc=75/25) to deliver finally 3.00 g of the title compound as light brown oil, contaminated according to NMR with roughly 35% of the ortho-isomer which was separated after the next step, MS: 298.3 (MH+)+.