Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH2:18][C:19]5[S:20][C:21]([C:24]6[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=6)=[CH:22][C:23]=5[C:16]=4[N:15](COCC[Si](C)(C)C)[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:39]>CO>[ClH:39].[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[C:17]4[CH2:18][C:19]5[S:20][C:21]([C:24]6[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=6)=[CH:22][C:23]=5[C:16]=4[NH:15][N:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(N3CCOCC3)cc2)c2c1-c1cc(-c3ccc(N)nc3)sc1C2
Agent: Cl
Solvent: CO
Product: Nc1ccc(-c2cc3c(s2)Cc2c(-c4ccc(N5CCOCC5)cc4)n[nH]c2-3)cn1
Temperature: 100 °C
Yield: 61.2 %

Procedure:
5-[6-(4-Morpholin-4-yl-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-ylamine (0.44 g, 0.8 mmol) was dissolved in MeOH and treated with concentrated HCl (0.25 mL, 8 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 5-[6-(4-Morpholin-4-yl-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-ylamine hydrochloride (0.24 g, 0.49 mmol) as yellow solid in 61% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH2:18])=[O:17])[CH:11]=1.[C:19]([CH:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)([CH3:22])([CH3:21])[CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:19]([C@@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][CH2:8][C:6]2[CH:5]=[CH:4][C:3]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH2:18])=[O:17])[CH:11]=3)=[C:2]([F:1])[CH:7]=2)[CH2:27][CH2:28]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: NC(=O)c1cccc(-c2ccc(C=O)cc2F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@@H](NCc2ccc(-c3cccc(C(N)=O)c3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 2′-fluoro-4′-formylbiphenyl-3-carboxylic acid amide (Preparation 9, 252 mg, 1.0 mmol) in DCM (100 mL) was added 4-tert-butylcyclohexylamine (500 μL, 3.2 mmol), acetic acid (200 μL, 3.5 mmol) and sodium triacetoxyborohydride (648 mg, 3.1 mmol). The mixture was stirred at rt for 16 h. EtOAc (100 mL) was added and the organics washed with aqueous NaHCO3 (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (17% EtOH: Toluene) to give cis-4′-[(4-tert-butylcyclohexylamino)methyl]-2′-fluorobiphenyl-3-carboxylic acid amide: RT=2.84 min; m/z (ES+)=383.0 [M+H]+, and trans-4′-[(4-tert-butylcyclohexylamino)methyl]-2′-fluorobiphenyl-3-carboxylic acid amide: RT=2.87 min; m/z (ES+)=383.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][C:3]=1[CH3:33].[CH3:34][C:35]([NH:38][S:39]([C:42]1[S:46][C:45](Br)=[CH:44][CH:43]=1)(=[O:41])=[O:40])([CH3:37])[CH3:36].CCCCCCC>C1(C)C=CC=CC=1>[C:35]([NH:38][S:39]([C:42]1[S:46][C:45]([C:18]2[N:17]=[CH:16][N:15]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:33])[CH:4]=4)[CH:13]=[C:12]([CH3:14])[N:11]=3)[CH:19]=2)=[CH:44][CH:43]=1)(=[O:40])=[O:41])([CH3:37])([CH3:34])[CH3:36]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)c(C)c3)n2)cn1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
A stirred mixture of 4-(4-chloro-3-methyl-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.8) (0.59 g, 1.03 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.34 g, 1.13 mmol), tetrakis(triphenyl-phosphine)palladium (0.071 g, 0.062 mmol) in toluene (8 ml) was heated under reflux conditions for 15 h, heptane (10 ml) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(4-chloro-3-methyl-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.54 g) as a white solid.
Reaction SMILES: [CH2:1]([Mg]Cl)C(C)C.C(Cl)C(C)C.[Mg].[F:13][C:14]([F:26])([F:25])[CH:15]([OH:24])[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CI>CCOCC.[CH-]1[C-]=[C-][C-]=[C-]1.[CH-]1[C-]=[C-][C-]=[C-]1.Cl[Ti]Cl>[F:13][C:14]([F:25])([F:26])[CH:15]([OH:24])/[CH:16]=[C:17](\[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)/[CH3:1]
Reactant: OC(C#Cc1ccccc1)C(F)(F)F
Reactant: CC(C)C[Mg]Cl
Agent: Cl[Ti]Cl
Agent: [Mg]
Agent: [c-]1[c-][c-][cH-][c-]1
Solvent: CI
Solvent: CCOCC
Solvent: CC(C)CCl
Product: C/C(=C/C(O)C(F)(F)F)c1ccccc1
Reaction time: 4 h
Yield: 63 %

Procedure:
In an isobutylmagnesium chloride solution that was prepared by reacting isobutyl chloride (3.74 g, 40 mmol) and magnesium (0.97 g, 40 mmol) in dry ether (40 ml) at 0° C., dichlorobis(π-cyclopentadienyl)titanium (0.22 g, 0.9 mmol) and 1,1,1-trifluoro-4-phenyl-3-butyne-2-ol (2 g, 10 mmol) were slowly added at 0° C. After 4 hour agitation of the mixture at room temperature, solvent was removed under heating for 30 min. Next, dry tetrahydrofuran (20 ml) was put into the reaction vessel and further methyl iodide (12.7 g, 90 mmol) was slowly added. After 12 hour agitation, the reaction mixture was treated by a method similar to the one in the above Examples to obtain (Z)-1,1,1-trifluoro-4-phenyl-3-pentene-2-ol (b.p.: 84°-86° C./2 mmHg) at a yield of 63%. The above product gave the following analytical data:
Reaction SMILES: [Na].[NH:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[C:11](=[O:23])[C:12]4[C:17]([S:18](=[O:22])(=[O:21])[C:19]=3[CH:20]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:5][N:4]=[N:3]1.Br[CH2:25][C:26]([O:28]CC)=[O:27]>C(O)C>[C:26]([CH2:25][N:4]1[N:3]=[N:2][C:6]([C:7]2[CH:8]=[CH:9][C:10]3[C:11](=[O:23])[C:12]4[C:17]([S:18](=[O:21])(=[O:22])[C:19]=3[CH:20]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:5]1)([OH:28])=[O:27]
Reactant: CCOC(=O)CBr
Reactant: O=C1c2ccccc2S(=O)(=O)c2cc(-c3nnn[nH]3)ccc21
Agent: [Na]
Solvent: CCO
Product: O=C(O)Cn1nnc(-c2ccc3c(c2)S(=O)(=O)c2ccccc2C3=O)n1
Reaction time: 2 h

Procedure:
Sodium (0.46 g) was dissolved in ethanol (20 ml) and 3-(5-tetrazolyl)thioxanthone-10,10-dioxide (6.24g) was added. Ethyl bromoacetate (3.34 g) was added to the mixture, which was boiled under reflux for 1.5 hr. The ester intermediate was deposited during this time, and after cooling was filtered off, washed with water and dried, m.p. 194°-195° C. The ester was boiled with concentrated hydrochloric acid (40 ml) and acetic acid (120 ml) for 2 hr. On cooling 3-(2-carboxymethyl-5-tetrazolyl)thioxanthone-10,10-dioxide crystallised out, and was filtered off, recrystallised from acetic acid, and dried, m.p. 252° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][N:8]([CH2:12][C:13]2[S:14][C:15]([CH:18]([OH:24])[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:17]=2)[S:7]1(=[O:26])=[O:25].C[N+]1([O-])CCOCC1>C1COCC1.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][N:8]([CH2:12][C:13]2[S:14][C:15]([C:18](=[O:24])[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:17]=2)[S:7]1(=[O:25])=[O:26]
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(C(O)CCC(C)C)s3)S2(=O)=O)c(OC)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)CCC(C)C)s3)S2(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title C compound, 2-(2,4-dimethoxy-benzyl)-5-[5-(1-hydroxy-4-methyl-pentyl)-thiophen-2-ylmethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (125 mg, 0.26 mmol) is dissolved in THF (10 mL) and 4-methylmorpholine N-oxide (152 mg, 1.3 mmol) is added. Tetrapropylammonium perruthenate (TPAP, 9 mg, 0.026 mmol) is added and the mixture is stirred at RT for 1 h. The mixture is filtered through Celite and diluted with EtOAc. The solution is washed with 1N aqueous HCl and the organic layer is dried over anhydrous MgSO4. The solvent is evaporated to afford 2-(2,4-dimethoxy-benzyl)-5-[5-(4-methyl-pentanoyl)-thiophen-2-ylmethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a clear oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([OH:18])=[CH:7][CH:8]=2)[O:3]1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>>[O:24]1[CH2:23][CH:22]1[CH2:20][O:18][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:2]([CH3:19])([CH3:1])[O:3]2)=[CH:8][CH:7]=1
Reactant: CC1(C)C=C(c2ccccc2)c2ccc(O)cc2O1
Reactant: ClCC1CO1
Product: CC1(C)C=C(c2ccccc2)c2ccc(OCC3CO3)cc2O1
Yield: 78 %

Procedure:
Reaction of 2,2-dimethyl-4-phenyl-2H-chromen-7-ol with epichlorohydrin, by an analogous process to that described in Example 1 gave 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-phenyl-2H-chromene (78%). Reaction of this epoxide with dimethylamine by an analogous process to that described in Example 2 gave 7-(2-hydroxy-3-dimethylaminopropoxy)-2,2-dimethyl-4-phenyl-2H-chromene isolated as its hydrochloride salt (48%), m.p. 208°-209°.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[S:17](Cl)(=[O:19])=[O:18].Cl.Cl.Cl.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:36][CH2:35][N:34]([C:37](=[O:47])[CH2:38][O:39][CH2:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][NH:42]3)[CH2:33][CH2:32]2)[CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:11]1([CH3:16])[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([CH3:8])[C:10]=1[S:17]([N:42]1[CH2:43][CH2:44][CH2:45][CH2:46][CH:41]1[CH2:40][O:39][CH2:38][C:37]([N:34]1[CH2:33][CH2:32][N:31]([CH:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)[CH2:36][CH2:35]1)=[O:47])(=[O:19])=[O:18]
Reactant: CN1CCC(N2CCN(C(=O)COCC3CCCCN3)CC2)CC1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCN(C3CCN(C)CC3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Triethylamine (0.221 ml, 1.608 mmol) and then 2,4,6-trimethylbenzenesulfonyl chloride (105 mg, 0.482 mmol) were added at 0° C. to a solution of 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-(piperidin-2-ylmethoxy)ethanone trihydrochloride (180 mg, 0.402 mmol) in tetrahydrofuran (10 ml). The reaction mixture was heated slowly to room temperature, stirred for 15 h at that temperature and then refluxed for 1 h. Saturated sodium hydrogen carbonate solution (5 ml) was then added to the mixture, and the aqueous phase was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried (Na2SO4) and concentrated in vacuo, and the crude product was then purified by column chromatography (silica gel) using ethyl acetate/methanol/ammonia solution (25% aq.) (300:100:5). Yield: 90 mg (43%), yellow oil; MS, m/z 520.3 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][CH2:16][S:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[OH:25]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][CH2:16][S:17](=[O:25])[C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1cc(F)ccc1SCC2
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1cc(F)ccc1S(=O)CC2
Temperature: 25 °C

Procedure:
To a solution of 1.8 g of 2-(4-chlorophenyl)-10-fluoro-5,6-dihydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)one, prepared in Example 22, in 20 ml of acetic acid is added 1.3 ml of 35% hydrogen peroxide with stirring at room temperature and furthermore stirred for 5 hours at the same temperature. To the resultant mixture is added water, and the precipitated crystals are collected by filtration and recrystallized from dimethylformamide-water to give 1.3 g of 2-(4-chlorophenyl)-10-fluoro-5,6-dihydro[1]benzothiepino[5,4-c]pyridazin-3(2H)-one 7-oxide, melting at 233°-235° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:9][N:10]([CH3:14])[C:11]=2[C:12]#[N:13])=[C:5]([CH3:22])[O:4][N:3]=1.[NH2:23][OH:24].CCOC(C)=O.O>CS(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:9][N:10]([CH3:14])[C:11]=2[C:12](=[N:23][OH:24])[NH2:13])=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: NO
Reactant: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)nn(C)c1C#N
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)nn(C)c1C(N)=NO
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a solution of 4-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbonitrile in DMSO (1.5 mL) was added neutral hydroxylamine solution (2 M in water, 1.27 mL, 2.55 mmol) and stirred at 130° C. for 10 min. EtOAc and water were added and the phases were separated. The crude product was purified on preparative HPLC to give E13 4-(3,5-dimethylisoxazol-4-yl)-N′-hydroxy-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carboximidamide (11.3 mg, 0.035 mmol, 34%) ES/MS m/z: 328.1 (M+H), 326.5 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.29 (m, 2H), 6.78 (m, 2H), 3.95 (s, 3H), 2.10 (s, 3H) and 1.88 (s, 3H), and E14 4-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carboxamide (12.7 mg, 0.041 mmol, 40%), ES/MS m/z: 313.1 (M+H), 311.5 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.25 (m, 2H), 6.79 (m, 2H), 4.11 (s, 3II), 2.11 (s, 3H) and 1.92 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[OH:19].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[O:19][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)c(Cl)c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1Cl

Procedure:
A mixture of 2,3-dichloro-4-(p-nitrophenoxy)phenol (11.5 g., 0.038 mole), ethyl bromoacetate (9.51 g., 0.057 mole) and pulverized potassium carbonate (7.9 g., 0.057 mole) in 100 ml. of 2-butanone was heated at reflux for 2 hours. The reaction mixture was then filtered and the filtrate concentrated under reduced pressure. The residue was taken into CH2Cl2 and the resulting solution was washed with aqueous NaCl and dried over MgSO4. Evaporation of the solvent was followed by trituration with hexane to furnish the solid product. Recrystallization from cyclohexane gave 12.5 g. of solid, m.p. 90°-91°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[C:8]([CH3:35])[C:7]=2[CH:36]=1)#[N:2].O1CCCC1.[OH-].[Li+]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[C:8]([CH3:35])[C:7]=2[CH:36]=1)#[N:2]
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(C#N)cc3c2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2ccc(C#N)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.4 %

Procedure:
To a mixture of ethyl 3-{[(4-{[(5-cyano-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl]amino}propanoate (195 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N lithium hydroxide aqueous solution (800 μL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (800 μL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (168 mg, 92%) as a white solid.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[C:17]2[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=2[CH:11]=[C:10]([CH:19]=[O:20])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[F:27][CH2:28][CH2:29]I>O>[F:27][CH2:28][CH2:29][N:13]1[C:12]2[CH:11]=[C:10]([CH:19]=[O:20])[CH:9]=[C:8]([O:7][CH3:6])[C:17]=2[O:16][CH2:15][C:14]1=[O:18]
Reactant: COc1cc(C=O)cc2c1OCC(=O)N2
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc2c1OCC(=O)N2CCF
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
To 3 ml of a DMF solution containing 233 mg of 8-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboaldehyde [CAS No. 711021-34-0], 312 mg of potassium carbonate and 236 mg of 1-fluoro-2-iodoethane were added. The resulting mixture was stirred at room temperature for one day, and water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give 4-(2-fluoroethyl)-8-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboaldehyde (151 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]([CH2:23][OH:24])[CH:12]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([C:9]1[CH:10]=[C:11]([CH:12]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[CH:23]=[O:24])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OCc1cc(CCc2ccccc2)cc(CCc2ccccc2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc(CCc2ccccc2)cc(CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
To a solution of (3,5-diphenethyl-phenyl)-methanol (2.0 g, 6.4 mmol) in dry dichloromethane (30 mL) was added pyridinium chlorochromate (1.4 g, 6.4 mmol) and the mixture was stirred at room temperature for 16 h. The product was purified by flash chromatography using dichloromethane as solvent to give 1.3 g 3,5-diphenethyl-benzaldehyde.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:15]1([CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: FC(F)(F)CNc1cnccc1I
Reactant: Cc1ccccc1B(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1NCC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2,2,2-trifluoro-ethyl)-amine and 2-methylphenylboronic acid (CAS RN 16419-60-6) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light brown solid (91%). MS (ESI): m/z=267.11 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15](S(C)(=O)=O)[N:14]=3)[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[N:9]2)=[CH:5][CH:4]=1.[CH2:34]([NH2:36])[CH3:35]>O1CCOCC1.O>[CH2:34]([NH:36][C:15]1[N:14]=[C:13]([C:11]2[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[N:9][N:8]([CH2:7][C:6]3[CH:32]=[CH:33][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:12]=2)[CH:18]=[CH:17][N:16]=1)[CH3:35]
Reactant: CCN
Reactant: COc1ccc(Cn2cc(-c3ccnc(S(C)(=O)=O)n3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCNc1nccc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc([N+](=O)[O-])c2)n1
Yield: 94 %

Procedure:
450 mg (0.97 mmol) of 4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-2-(methylsulfonyl)pyrimidine were dissolved in a mixture of 10 ml of dioxane and 5 ml of ethylamine 70% in water. The resulting solution was submitted to microwave irradiation in a sealed vial at 140° C. for 45 minutes. The solvent was then removed and the residue was partitioned between dichloromethane and aqueous sodium hydrogenocarbonate. The organic phase was then dried over sodium sulphate and evaporated to dryness. 391 mg (94%) of the title compound were obtained by trituration with diethylether.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.C(OCC)C>O1CCCC1>[CH3:1][N:2]1[CH2:6][CH2:7][O:8][C:17](=[O:19])[O:5][CH2:4][CH2:3]1
Reactant: CN(CCO)CCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CN1CCOC(=O)OCC1
Temperature: -20 °C
Reaction time: 2 h
Yield: 248.8 %

Procedure:
A round bottom flask was charged with N-methyl diethanolamine (10.0 g, 83.9 mmol), triethylamine (24.0 mL, 167.8 mmol), dry tetrahydrofuran (THF) (600 mL) and stirbar. The reaction flask was cooled to −20° C. under a nitrogen atmosphere. Separately, triphosgene (8.3 g, 28.8 mmol) was dissolved in dry THF (100 mL) and added slowly to the reaction mixture. A white precipitate formed instantly and stirring was continued for another 2 hours maintaining a reaction temperature less than 10° C. Diethyl ether (800 mL) was added to further precipitate any remaining HCl salts followed by filtration of the heterogeneous solution. The filtrate was concentrated yielding a yellow/brown oil product (10.4 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]2[S:11][CH:12]=[CH:13][CH:7]2[CH2:6]1.[Cl:18][CH2:19][C:20](Cl)=[O:21].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:18][CH2:19][C:20]([C:12]1[S:11][CH:8]2[CH:7]([CH2:6][N:5]([CH2:4][C:3]3[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=3[Cl:1])[CH2:10][CH2:9]2)[CH:13]=1)=[O:21]
Reactant: Clc1ccccc1CN1CCC2SC=CC2C1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)C1=CC2CN(Cc3ccccc3Cl)CCC2S1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To 10.0 g (33.3 mmol) 5-(2-chloro-benzyl)-3a,4,5,6,7,7a-hexahydro-thieno[3,2-c]pyridine is added 3.18 mL (40.0 mmol) chloro-acetyl chloride and then 8.88 g (66.6 mmol) aluminium(III)-chloride. The reaction mixture is stirred 1 h at 70° C. and then a water-ice mixture is added followed by DCM. The formed precipitate is collected and dried.