Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([OH:37])=O)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:43][C:44](=[O:48])[CH2:45][CH2:46][NH2:47])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][C:35]([NH:47][CH2:46][CH2:45][C:44]([OH:48])=[O:43])=[O:37])=[CH:31][CH:32]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)NCCC(=O)O)cc2)cc1

Procedure:
The product from Example 104A and β-alanine ethyl ester hydrochloride were processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 7.90 (t, 1 H), 7.14-7.34 (m, 8 H), 7.01 (m, 4 H), 6.87 (d, 4 H), 4.06 (s, 2 H), 4.02 (s, 2 H), 7.71 (br s, 1H), 3.22 (dd, 2 H), 2.91 (s, 3 H), 2.77 (t, 2 H), 2.34 (m, 7 H); MS (APCI) m/z 616 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[C:11]([O:12][CH2:13][CH:14]([NH2:16])[CH3:15])=[C:10]([CH3:17])[CH:9]=[CH:8][CH:7]=1.Cl.C(OCC)(=O)C.[OH-].[Na+]>O>[CH3:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:17])[C:11]=1[O:12][CH2:13][CH:14]([NH:16][C:1](=[O:3])[CH3:2])[CH3:15]
Reactant: Cc1cccc(C)c1OCC(C)N
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)COc1c(C)cccc1C
Temperature: 17.5 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
Acetyl chloride (99 ml, 1.39 mol, 1.5 eq) was added to a stirred suspension of mexiletine hydrochloride (200 g, 0.927 mol), ethyl acetate (750 ml), and 5N sodium hydroxide (750 ml) over a period of 35 minutes while keeping the temperature at ≤10° C. After the addition was complete, the reaction was allowed to stir for 45 minutes at 15-20° C. The mixture was then added to water (1 1) and the ethyl acetate layer separated. The aqueous layer was washed with ethyl acetate (2×300 ml) and the combined ethyl acetate layers were washed with saturated aqueous sodium bicarbonate until the washings were no longer acidic. The ethyl acetate solution was then washed with brine, dried over MgSO4, and concentrated to give N-[2-(2,6-dimethylphenoxy)-1-methylethyl]-acetamide (197 g, 96% yield, mp 85-85.8° C.).
Reaction SMILES: [C:1](=[S:3])=S.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.O(C(C)C)C(C)C>N1C=CC=CC=1>[N:24]([C:21]1[CH:20]=[CH:19][C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][CH:8]=3)[CH2:13][CH2:14]2)=[CH:23][CH:22]=1)=[C:1]=[S:3]
Reactant: S=C=S
Reactant: COc1ccc(N2CCN(c3ccc(N)cc3)CC2)cc1
Solvent: CC(C)OC(C)C
Solvent: c1ccncc1
Product: COc1ccc(N2CCN(c3ccc(N=C=S)cc3)CC2)cc1

Procedure:
To a stirred and cooled (ice-bath) mixture of 5 parts of N,N'-methanetetraylbis[cyclohexanamine], 25.2 parts of carbon disulfide and 40 parts of pyridine are added 6 parts of 4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine and the whole is stirred first for 1 hour in an ice-bath and further for 2 hours at room temperature. 35 Parts of 2,2'-oxybispropane are added and the whole is stirred for 30 minutes. The precipitated product is filtered off and crystallized from 4-methyl-2-pentanone. The product is filtered off again and recrystallized from 1,4-dioxane, yielding 2.45 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine; mp. 180.6° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:20]1([CH2:30][NH2:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH2:30][NH:31][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1cccc2ccccc12
Product: c1ccc2c(CNc3nccc(-n4cnc5ccccc54)n3)cccc2c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 1-naphthalenemethylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 352.0 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.60 (s, 1H); 8.44 (br s, 1H); 8.12 (m, 1H); 7.94 (m, 1H); 7.85 (m, 2H); 7.59 (m, 2H); 7.48 (m, 1H); 7.32 (br s, 1H); 6.86 (br s, 1H); 5.20 (d, J=5.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([N+:17]([O-])=O)=[CH:4][N:3]=1.C(O)(=O)C>[Zn].CO>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([NH2:17])=[CH:4][N:3]=1
Reactant: COc1ccc(Oc2nc(Cl)ncc2[N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(Oc2nc(Cl)ncc2N)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
To a stirred solution of Compound 1b (7.72 g; 27.4 mmol) in a mixture of glacial acetic acid (60 mL) and MeOH (120 mL) was added zinc dust (5.38 g; 82.2 mol) in portions at ambient temperature. The reaction mixture was stirred at room temperature for 20 h. The resultant mixture was filtered through a microglass filter and the filtrate was neutralized to pH 7 with 2 N KOH(aq). The mixture was partitioned between CH2Cl2 and H2O. The organic phase was washed sequentially with H2O and brine, and dried over Na2SO4. The mixture was filtered and the solvent was removed under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 1c (5.52 g; 80% yield) as an orange-red solid. 1H-NMR (400 MHz, CDCl3): δ 7.94 (s, 1H), 7.12-7.14 (m, 2H), 6.95-6.97 (m, 2H), 3.85 (s, 3H); MS: m/z 252.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][CH2:31][N:32]([CH3:34])[CH3:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: CN(C)CCCl
Product: CN(C)CCn1cc(C(=O)N2CCC3(CC2)OC(=O)c2cc(F)ccc23)c2ccc(Cl)cc21

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (the preparation of which have been described in example 19) with commercially available (2-chloro-ethyl)-dimethyl-amine as electrophile, the title compound was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]1[NH:23][C:24](=[O:27])[CH2:25]Cl)=[O:12])=[CH:5]2.[I-:28].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]1[NH:23][C:24](=[O:27])[CH2:25][I:28])=[O:12])=[CH:5]2
Reactant: [I-]
Reactant: O=C(CCl)NC1c2ccccc2CC1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CI)NC1c2ccccc2CC1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Yield: 93.2 %

Procedure:
5-Chloro-N-{1-[(chloroacetyl)amino]-2,3-dihydro-1H-inden-2-yl}-1H-indole-2-carboxamide (Method 7; 2.0 g, 5.0 mmol) and potassium iodide (2.0 g, 12.0 mmol) in acetone (50 mL) was heated at reflux for 6 hours and then cooled and the volatiles removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (50 mL) washed with IM aqueous sodium thiosulphate (2×25 mL), water (25 mL), brine (25 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure to give the title compound (2.3 g, 92%) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1([F:20])[C:15]([F:17])([F:16])[C:14]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([Br:19])=[CH:6][CH:7]=2.[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[F:17][C:15]1([F:16])[C:2]([F:20])([F:1])[C:3]2[CH:4]=[C:5]([Br:19])[CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][C:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:11][CH:10]=2
Reactant: FC1(F)c2cc(Br)ccc2-c2ccc(Br)cc2C1(F)F
Reactant: CCCCCCCC[Mg]Br
Product: CCCCCCCCc1ccc2c(c1)C(F)(F)C(F)(F)c1cc(Br)ccc1-2
Yield: 54.1 %

Procedure:
In analogy to Example 1, from 4.1 g of 9,9,10,10-tetrafluoro-2,7-dibromo-phenanthrene and 10 mmol of octylmagnesium bromide. The catalyst used is 0.2 mmol of 1,3-bis(diphenylphosphine)butanenickel(ll) chloride. Chromatography gives 2.4 g of 9,9,10,10-tetrafluoro-2-bromo-7-octyl-9,10-dihydrophenanthrene.
Reaction SMILES: [CH2:1]1[CH2:9][CH2:8][CH2:7][C:6]2[N:5]3[CH:10]=[CH:11][CH:12]=[CH:13][C:4]3=[CH:3][C:2]1=2.[CH2:14]([NH2:16])[CH3:15]>>[CH2:1]1[CH2:9][CH2:8][CH2:7][C:6]2[N:5]3[CH:10]=[CH:11][CH:12]=[CH:13][C:4]3=[C:3]([CH2:15][CH2:14][NH2:16])[C:2]1=2
Reactant: c1ccn2c3c(cc2c1)CCCC3
Reactant: CCN
Product: NCCc1c2c(n3ccccc13)CCCC2

Procedure:
2-Pyridylacetate (25 g, 150 mmol) and 2-chlorocyclohexanone were heated under reflux in dry benzene for 42 h. under a Dean Stark trap to remove water. Evaporation of the volatiles under reduced pressure gave a very thick red-brown oily residue. The residue was treated with toluene and filtered. The toluene filtrate was evaporated to give an orange-brown oil. The oil was purified on alumina eluting with 10% petroleum ether in toluene to give 2.7 g of 1,2,3,4-tetrahydropyrido[1,2-a]indol-10-carboxylic acid ethyl ester [modification of L. K. Dalton; T. Teitei Aust. J. Chem. 1969 22, 1525-1530]. The ethyl ester (1 g, 4 mmol) was dissolved in ethanol (40 mL) with warming. To the solution was added 2.5 N NaOH (30 mL). The reaction mixture was heated under reflux for 2 h, then allowed to cool and stir at room temperature for 2 days. The solution was acidified with 2N HCl and extracted into methylene chloride. Removal of the volatiles under reduced pressure gave a residue, which was purified by column chromatography on silica gel eluting with 5-15% ethyl acetate in hexane. The corresponding carboxylic acid was obtained. The carboxylic acid (210 mg, 0.98 mmol ) was dissolved in bromobenzene and heated at 170° C. for 15 min. The solvent was removed under reduced pressure to give a residue, which was purified on silica gel eluting with 100% hexane to remove bromobenzene followed by 5% ethyl acetate in hexane to isolate the product. Evaporation of the volatiles gave 1,2,3,4,-tetrahydropyrido[1,2-a]indole (140 mg), mp: 55-57° C. [M+H]+ 172 m/z. 1,2,3,4,-tetrahydropyrido[1,2-a]indole was formylated, converted to the nitroolefin and reduced to the corresponding ethylamine as described in Example 9 to give the title compound. The title compound was dissolved in ethanol and treated with an ethanolic solution of fumaric acid. After standing in a freezer overnight crystals formed. The solution was decanted from the crystals which were rinsed with ethyl ether and dried under reduced pressure to give the fumaric acid salt of the title compound, mp: 166-172° C. The filtrate was diluted with ethyl ether and a second crop of crystals was recovered, mp: 169-172° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:15](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: C#Cc1ccc(Br)cc1
Agent: [Na]
Product: Clc1ccc(C(/C=C\c2ccc(Br)cc2)SC(/C=C\c2ccc(Br)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A solution of 4-bromophenylacetylene (0.02 mol) and 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to Procedure 2 to form (Z)-4-bromostyryl 4-chlorobenzylsulfide. The title compound was obtained in 87% yield following oxidation. 1HNMR (CDC13) δ4.58 (2H, s), 6.72 (1H, d, JH,H=12.08), 7.15-7.68 (8H aromatic+1H ethylenic).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13]Br)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[H-].[Na+].O.Cl>O1CCCC1>[CH:10]1[C:5]2[O:4][N:3]=[C:2]3[N:1]=[CH:13][CH2:12][O:11][C:7]([C:6]=23)=[CH:8][CH:9]=1
Reactant: Nc1noc2cccc(OCCBr)c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C1=Nc2noc3cccc(c23)OC1
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
3-Amino-4-[(2-bromoethyl)oxy]1,2-benzisoxazole of Example 7(a) (10.86 g, 0.0428 mole) was dissolved in 200 ml of tetrahydrofuran (THF) and 5.0 g of NaH (50% oil dispersion, 0.10 mole) was added. The reaction mixture was brought to reflux. After 30 minutes the reaction mixture was allowed to cool, an additional 1.0 g of NaH dispersion was added, and reflux was continued for 30 minutes. At the end of this time the reaction mixture was poured into H2O, acidified with concentrated hydrochloric acid, and the product extracted into ether. The organic phase was separated, dried, and concentrated, after which the residue was purified by flash chromatography (10% ethyl acetate -CH2Cl2). The material obtained in this manner retained a little yellow color, which was removed by dissolving the compound in CH2Cl2 and passing the solution over a short column of alumina. The product obtained in this manner after concentration of the solvent was recrystallized from CH2Cl2 -pentane to give 2.20 g (29%) of 4,5-dihydroisoxazolo[3,4,5-ef][1,4]benzoxazepine, mp 165°-166° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[O:7][C@@H:8]([C:11]([OH:13])=O)[CH2:9][O:10][C:5]=2[CH:4]=1.[N:18]1[CH:23]=[C:22]([NH2:24])[CH:21]=[C:20]2[CH2:25][O:26][CH2:27][CH2:28][C:19]=12>>[N:18]1[CH:23]=[C:22]([NH:24][C:11]([C@@H:8]2[O:7][C:6]3[CH:14]=[CH:15][C:3]([C:2]([F:1])([F:17])[F:16])=[CH:4][C:5]=3[O:10][CH2:9]2)=[O:13])[CH:21]=[C:20]2[CH2:25][O:26][CH2:27][CH2:28][C:19]=12
Reactant: O=C(O)[C@H]1COc2cc(C(F)(F)F)ccc2O1
Reactant: Nc1cnc2c(c1)COCC2
Product: O=C(Nc1cnc2c(c1)COCC2)[C@H]1COc2cc(C(F)(F)F)ccc2O1
Yield: 91.2 %

Procedure:
The compound is prepared in a similar manner as Compound 18 by condensing (R)-6-(trifluoromethyl)-2,3-dihydrobenzo[1,4]dioxine-2-carboxylic acid (38 mg, 0.15 mmol) with 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-ylamine (42 mg, 0.28 mmol) for 16 hours and purified by semi-preparative HPLC (55-75 gradient) to give the titled amide (52 mg, 89%). m/z=381.1 (M+1)4. HPLC: 9.62 min. 1H NMR (400 MHz; d6-DMSO) δ 10.38 (m, 1H), 8.52 (d, 1H, J=2.3 Hz), 7.77 (d, 1H, J=2.3 Hz), 7.36 (d, 1H, J=2.0 Hz), 7.26-7.22 (m, 2H), 7.09 (d, 1H, J=7.7 Hz), 5.17-5.14 (m, 1H), 4.52-4.49 (m, 2H), 3.95 (t, 2H, J=5.7 Hz), 2.82 (t, 211, J=5.7 Hz).
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1F>CN(C=O)C.C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][C:18]=1[N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: c1c[nH]cn1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Br)c(-n2ccnc2)c1
Temperature: 150 °C
Yield: 60 %

Procedure:
A microwave vial charged with a solution of potassium tert-butoxide (0.462 g, 4.12 mmol), imidazole (0.280 g, 4.12 mmol), and 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (1.000 g, 4.12 mmol) in 2 mL DMF was heated to 150° C. in an oil bath overnight. The reaction mixture was diluted with DCM, filtered through a syringe filter, and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave 1-(2-bromo-5-(trifluoromethyl)phenyl)-1H-imidazole (0.720 g, 2.474 mmol). [M+H]+=291.0
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:11])=[C:8]([OH:10])[CH:9]=1)[CH3:2].[C:12]([Si:16]([CH3:19])([CH3:18])Cl)([CH3:15])([CH3:14])[CH3:13].N1C=CN=C1.O>CC(N(C)C)=O>[C:12]([Si:16]([O:10][C:8]1[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[CH:6][C:7]=1[F:11])([CH3:19])[CH3:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOc1ccc(F)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
To a solution of 75.5 g 5-ethoxy-2-fluoro-phenol described in example 1.1 in 250 ml DMA were added 80.2 g t-butyl dimethylchlorsilane and 36.2 g imidazole at 0° C. The reaction mixture was warmed to r.t. After 4 hrs, 400 ml water were added. The mixture was extracted with hexane. The organic layer was washed with water, 10% Na2CO3 solution, water and brine, dried over MgSO4, filtrated and concentrated to give 127.0 g tert-butyl-(5-ethoxy-2-fluoro-phenoxy)-dimethyl-silane as light brown liquid which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].C(=O)(O)[O-].[Na+].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:32][CH2:31]1>C(#N)C>[CH2:1]([N:3]([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:32][CH2:31]1)[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: BrCCCCC1CC1
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCCCC1CC1)CCCC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
According to Procedure B (Example 17, Step IV), a stirred mixture of N-[4-[4-(ethylamino)-1-hydroxybutyl]phenyl]methanesulfonamide Example 7, Step II) and sodium bicarbonate in acetonitrile was allowed to react with 1-bromo-4-cyclopropylbutane (Step IV) to give the titled product, a compound of Formula I'. The high resolution mass spectrum had M+ at m/z 382. Theory for C20H34N2O3S: 382.2290; measured: 382.2298.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2].[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32]>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[NH:30][C:31]([O:21][CH2:20][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:4]=1[O:3][CH2:1][CH3:2])[CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[O:32]
Reactant: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1CO
Reactant: O=C=Nc1ccc(F)cc1F
Product: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1COC(=O)Nc1ccc(F)cc1F

Procedure:
Using dimethyl 2-[4-ethoxy-3-(hydroxymethyl)benzyl]-malonate and 2,4-difluorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b)
Reaction SMILES: C1([C:7]2O[N:10]=[C:9]([NH2:12])[N:8]=2)C=CC=CC=1.[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>>[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[N:16]1[CH:7]=[N:8][C:9]([NH2:12])=[N:10]1
Reactant: Nc1noc(-c2ccccc2)n1
Reactant: Nc1ccccc1Cl
Product: Nc1ncn(-c2ccccc2Cl)n1

Procedure:
Prepared in analogy to example 18a), starting with 5-phenyl-[1,2,4]oxadiazol-3-ylamine and 2-chloroaniline. The title compound was obtained as brownish solid (Yield=61%). MS ISP (m/e): 195.1 (100) [(M+H)+].
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[N:16]=[C:15]([N:20]2[CH2:25][CH:24]=[CH:23][CH2:22][CH2:21]2)[N:14]=1>C(COC)OC>[NH2:19][C:17]1[N+:18]([O-:9])=[C:13]([NH2:12])[N:14]=[C:15]([N:20]2[CH2:21][CH:22]=[CH:23][CH2:24][CH2:25]2)[N:16]=1
Reactant: Nc1nc(N)nc(N2CC=CCC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: COCCOC
Product: Nc1nc(N2CC=CCC2)nc(N)[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
191 g. of m-chloroperbenzoic acid are dissolved in 800 ml. of dimethoxyethane and cooled to -5° C. 103 g. of 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]-s-triazine are then added in solid form within 2.5 hours. The mixture is left to warm to room temperature and then stirred overnight. The solvent is then concentrated at 20° C. under reduced pressure and 200 ml. of water are added. The pH value is then adjusted to 10 with sodium hydroxide and the solution is continuously extracted with chloroform for 20 hours. The solvent is then evaporated off and the crude product is chromatographed over silica gel, there being obtained pure 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]-s-triazine-3-oxide having a melting point of 261°-265° C.(decomposition).
Reaction SMILES: [C:1]([N:5]([C:22](=[O:31])[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)[NH:6][C:7]([C:9]1[CH:20]=[CH:19][C:12]2[O:13][CH2:14][CH:15]([CH:17]=O)[O:16][C:11]=2[C:10]=1[CH3:21])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[NH2:40][OH:41]>CO>[C:1]([N:5]([C:22](=[O:31])[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)[NH:6][C:7]([C:9]1[CH:20]=[CH:19][C:12]2[O:13][CH2:14][CH:15]([CH:17]=[N:40][OH:41])[O:16][C:11]=2[C:10]=1[CH3:21])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2C)OC(C=O)CO3)C(C)(C)C)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2C)OC(C=NO)CO3)C(C)(C)C)c1
Yield: 82.1 %

Procedure:
To a 100 mL round bottom flask, containing 100 mg (0.24 mm) of 3,5-dimethyl-benzoic acid N-tert-butyl-N′-(3-formyl-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-hydrazide, added 0.50 g of triethylamine, 70 mg (1 mm) of hydroxylamine hydrochloride and 25 mL of methanol. The reaction mixture was refluxed for 1 hour. The methanol was removed on a rotary evaporator and the residue was dissolved with chloroform and dilute HCl and transferred to a separatory funnel. The chloroform extract was dried and evaporated to dryness. The residue was chromatographed on silica and the product eluted with 40% ethyl acetate in hexane. Evaporation of solvent yielded 85 mg of 3,5-dimethyl-benzoic acid N-tert-butyl-N′-[3-(hydroxyimino-methyl)-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl]-hydrazide. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.7 (s, 1H), 7.4 (d, 1H), 7.05 (s, 2H), 6.95 (s, 1H), 6.55 (d, 1H), 6.15 (m, 1H), 4.8 (m, 1H), 4.0–4.4 (m, 4H), 2.248 (s, 6H), 1.915 (s, 3H), 1.574 (s, 9H); TLC: Rf=0.40 (1:1 ethyl acetate:hexane).
Reaction SMILES: [CH3:1][C@@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C(OCC)(=[O:20])C>O>[CH3:1][C@@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][C:4](=[O:20])[N:3]1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: COC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@]1(C)CCC(=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a vigorously stirred solution of (S)-1-tert-butyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate 106B (1 g, 4.11 mmol) in ethyl acetate (40 ml) was added a solution of NaIO4 (3.52 g, 16.46 mmol) and RuCl3 (10 mg, 0.04 mmol) in water (40 ml). The reaction mixture was stirred at room temperature overnight and quenched with isopropanol. The reaction mixture was stirred at room temperature for 20 min and concentrated. The residue was dissolved in ethyl acetate, washed with water and brine, and dried over Na2SO4. The crude product was purified by flash chromatography (20-50% EtOAc/hexane) to give (S)-1-tert-butyl 2-methyl 2-methyl-5-oxopyrrolidine-1,2-dicarboxylate 106C (1.02 g, 100%) as an oil. 1H NMR (CDCl3, 400 MHz) δ 3.74 (s, 3H), 2.51-2.64 (m, 2H), 2.16-2.21 (m, 1H), 1.97-2.02 (m, 3H), 1.65 (s, 3H), 1.46 (s, 9H).