Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][CH:9]=[CH:10][CH:11]=[CH:12][CH3:13])=O)(C)(C)C.C[Si](C)(C)[N:16]1[C:20](=O)[CH:19]=[CH:18][C:17]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:13][CH:12]1[CH:19]2[CH:18]([CH2:17][NH:16][CH2:20]2)[CH:9]([NH:8][CH3:6])[CH:10]=[CH:11]1
Reactant: C[Si](C)(C)N1C(=O)C=CC1=O
Reactant: CC=CC=CNC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CNC1C=CC(C)C2CNCC12

Procedure:
Analogously to Example Z23, method I, 21.9 g (0.12 mol) of 1-(tert.-butyloxycarbonylamino)-1,3-pentadiene are reacted with 20.3 g (0.12 mol) of N-trimethylsilylmaleimide, and the product is subsequently reduced with 15.2 g (0.4 mol) of lithium aluminium hydride. The crude product is recrystallised from tetrahydrofuran.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Cl[C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[N:32]([CH:33]5[CH2:35][CH2:34]5)[CH:31]=[N:30][N:29]=4)[CH:23]=3)=[O:20])[CH:14]=2)=[CH:9][N:8]=1>CN1C=CC=CC1.O1CCCC1>[CH:33]1([N:32]2[CH:31]=[N:30][N:29]=[C:28]2[C:24]2[CH:23]=[C:22]([NH:21][C:19](=[O:20])[C:15]3[CH:14]=[C:13]([C:10]4[CH:9]=[N:8][C:7]([CH:1]5[CH2:3][CH2:2]5)=[N:12][CH:11]=4)[CH:18]=[CH:17][N:16]=3)[CH:27]=[CH:26][CH:25]=2)[CH2:35][CH2:34]1
Reactant: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(-c2cnc(Cl)nc2)ccn1
Reactant: Br[Mg]C1CC1
Agent: CN1C=CC=CC1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(-c2cnc(C3CC3)nc2)ccn1
Reaction time: 0.08 h
Yield: 45 %

Procedure:
Cyclopropyl magnesium bromide (0.5 M solution in tetrahydrofuran, 6.3 mL, 3 equiv) was added to a solution of 4-(2-chloropyrimidin-5-yl)-N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)picolinamide (440 mg, 1.06 mmol) and Fe(acac)3 (37 mg, 10 mol %) in N-methylpyridine (20 mL) and tetrahydrofuran (5 mL). After stirring for 5 minutes, the brown solution was quenched with 1 M hydrochloric acid (6 mL) and concentrated under reduced pressure at 70° C. The residue was purified by reverse-phase HPLC to give N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)-4-(2-cyclopropylpyrimidin-5-yl)picolinamide as a pale-yellow powder (200 mg, 45% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([CH:8]([CH3:21])[CH2:9][C:10]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:11](OCC)=[O:12])[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>C(OCC)C>[F:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([C@H:8]([CH3:21])[CH2:9][C@:10]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:11]=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)(CC(C)c1cccc(F)c1OC)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=O)C(F)(F)F
Reaction time: 1.5 h
Yield: 41.5 %

Procedure:
1.56 g (5.7 mmol) of 1,1′-bi-2-naphthol are admixed with 5.7 ml (2.85 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred for 2 hours at room temperature. 9.5 g (57.2 mmol) of 2-fluoro-6-(1-methyleneethyl)anisole and 12.5 ml (95 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 18 hours. After cooling it is immediately purified by column chromatography on silica gel (hexane/ethyl acetate 0-5%) to give 8.9 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate. 8.9 g (26.5 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate are dissolved in 200 ml of methanol and 2 ml of acetic acid, and 890 mg of palladium on carbon (10%) are added. The suspension is shaken for 1.5 hours under a hydrogen atmosphere under atmospheric pressure until the hydrogen uptake is 560 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 8.6 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanoate. 8.6 g (25.4 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanoate in 350 ml of diethyl ether are cooled to −30° C. and over 15 minutes 1.7 g (44.7 mmol) of lithium aluminum hydride in solid form are added in portions. The mixture is stirred for 1.5 hours, in the course of which the temperature climbs to −15° C., followed by dropwise addition in succession of ethyl acetate and water and by a further hour of stirring until a readily filterable precipitate has formed. The suspension is filtered through Celite, the filter bed being thoroughly rinsed with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Separation by column chromatography on silica gel (hexane/diisopropyl ether 0-15%) yields 3.1 g of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:7](=[O:14])[N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:4]=2[CH:3]=1.[O:23]=[S:24]1(=[O:40])[C:28]2[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:27]=2[C:26](=[O:34])[N:25]1[CH2:35][CH2:36][CH2:37][CH2:38]Br.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[O:40]=[S:24]1(=[O:23])[C:28]2[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:27]=2[C:26](=[O:34])[N:25]1[CH2:35][CH2:36][CH2:37][CH2:38][N:18]1[CH2:19][CH2:20][CH:15]([N:6]2[C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][C:4]=3[N:8]([CH2:9][C:10]([F:12])([F:13])[F:11])[C:7]2=[O:14])[CH2:16][CH2:17]1
Reactant: O=c1n(CC(F)(F)F)c2cc(F)ccc2n1C1CCNCC1
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCN1CCC(n2c(=O)n(CC(F)(F)F)c3cc(F)ccc32)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
The 4-(5-fluoro-3-(2,2,2-trifluoroethyl)-2-oxo-1-benzimidazolinyl)piperidine (~10 mmol.) above was dissolved in anhydrous DMF (25 mL) followed by the addition of 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one (3.54 g, 10 mmol.) and triethylamine (1.4 mL, 10 mmol.) and allowed to stir at 50° C. under an inert atmosphere for three hours or until reaction was complete. The cooled solution was diluted with EtOAc and washed with NaHCO3 /Na2CO3 solutions, water (3×), and the organic layer dried (Na2SO4), filtered and the solvent evaporated to give 1,1-dioxido-2-(4-(4-(5-fluoro-3-(2,2,2-trifluoroethyl)-2-oxo-1-benzimidazolinyl)piperidin-1-yl)butyl)-5-chloro-1,2-benzisothiazol-3(2H)-one as a viscous oil. This material was dissolved in EtOAc (50 mL) and excess HCl gas/EtOAc was added to give an immediate copious white precipitate which was gently digested in the warmed EtOAc to give the crystalline HCl salt of Compound A, mp: 255-257° C. Analysis calculated for C25H25ClF4N4O4S.HCl: C,48.00; H,4.19; N, 8.96; found: C,47.96; H, 4.17; N, 8.93. The NMR was consistent with structure.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.C(OP(OCC)(C(O[Si:21]([CH3:24])([CH3:23])[CH3:22])C)=O)C.[C:28]1([C:34]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1C[O:45][CH2:44][CH2:43]1>CCCCCC.O>[CH:28]1([C:34]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([O:35][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:44](=[O:45])[CH3:43])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(c1ccccc1)C1CCCCC1
Reactant: CCOP(=O)(OCC)C(C)O[Si](C)(C)C
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(=O)C(O[Si](C)(C)C)(c1ccccc1)C1CCCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a stirred solution of 35 ml (0.25 mole) of diisopropylamine in 800 ml of THF at -78° C. was added 100 ml of a 2.5M solution of n-BuLi in hexane. After the mixture was stirred at -78° C. for 1 hour, 52 g (0.205 mole) of 1-(diethoxyphosphinyl)-1-trimethylsilyloxyethane [prepared according to the procedure of G. H. Birum and G. A. Richardson, U.S. Pat. No. 3,113,139 (1963)] was added dropwise. The mixture was stirred for 1.5 hours at -78° C. and then 42.5 g (0.225 mole) of cyclohexyl phenyl ketone in 100 ml of THF was added dropwise at -78° C. The stirred solution was warmed to room temperature during 30 minutes and then it was poured into 2 L of water. Extraction of the mixture with ether, after washing with dilute hydrochloric acid, drying and concentrating gave 51 g (75%) of colorless liquid.
Reaction SMILES: C1(=O)OCCO1.[F-:7].[K+].Cl[C:10]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11].ClC([O-])=O>>[F:7][C:10]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11]
Reactant: [F-]
Reactant: CC(C)(C)COC(=O)Cl
Agent: O=C([O-])Cl
Agent: [K+]
Solvent: O=C1OCCO1
Product: CC(C)(C)COC(=O)F
Reaction time: 1 h
Yield: 92 %

Procedure:
The preparation was carried out as in Example 2 but using 120 g of ethylene carbonate, 45 g (0.77 mol) of potassium fluoride and 75.3 g (0.5 mol) of neopentyl chloroformate. After addition of the chloroformate, stirring of the reaction mixture was continued for 1 hour at 45° C. Evaporation under vacuum was carried out as in the preceding example. By distillation under reduced pressure, 61.7 g (92% yield) of neopentyl fluoroformate were recovered with a boiling point of 60° C. at 20 mm Hg.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](Cl)=[CH:4][C:5]([F:8])([F:7])[F:6].[OH-].[K+]>C(O)C.[Ni]>[F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)C=C(Cl)C(F)(F)F
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: FC(F)(F)CCC(F)(F)F
Yield: 46.7 %

Procedure:
40 g (0.2 mol) of 1,1,1,4,4,4-hexafluoro2-chloro-2-butene were hydrogenated in 300 ml of ethanol in the presence of 12 g of potassium hydroxide and 24 g of Raney nickel in the pressure range of from 20 to 40 bar and at a temperature from 20°to 100° C. The solid components were filtered off, the solvent was extracted with water, and the organic phase was separated and purified by distillation to give 15.5 g (47% of theory) of 1,1,1,4,4,4-hexafluorobutane. The boiling point was 25°to 27° C. at 1013 mbar.
Reaction SMILES: COC1C=CC(C[S:10][C:11]2[N:12]([CH2:31][CH:32]=[CH2:33])[CH:13]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:14]([C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:17])[N:16]=2)=CC=1.FC(F)(F)C(O)=O.C(S)C>ClCCl>[CH3:17][C:15]1[NH:16][C:11](=[S:10])[N:12]([CH2:31][CH:32]=[CH2:33])[CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:14]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: C=CCN1C(SCc2ccc(OC)cc2)=NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Solvent: CCS
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCN1C(=S)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
1,6-Dihydro-2-[[(4-methoxyphenyl)methyl]thio]-4-methyl-6-(3-nitrophenyl)-1-(2-propenyl)-5-pyrimidinecarboxylic acid, methyl ester (1.0 g, 2.14 mmol) in 15 ml of dichloromethane under argon at room temperature was treated with trifluoroacetic acid (0.6 ml, 0.85 g, 7.7 mmole) and ethanethiol (0.4 ml, 0.33 g, 5.4 mmole). No change (tlc) occurred within 2 hours. Heating at reflux temperature, however, effected complete reaction in several hours.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(#N)C>[C:26]([O:25][C:23]([N:17]1[CH2:22][CH2:21][N:20]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])[CH2:19][CH2:18]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)C(Br)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C(=O)OC)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.7 %

Procedure:
19.5 g (141 mmol) of potassium carbonate and then 19.5 ml (134 mmol) of dimethyl bromomalonate are added to a solution of 25 g (134 mmol) of tert-butyl piperazine-1-carboxylate in 300 ml of acetonitrile. The reaction medium is stirred at ambient temperature for 24 h and then filtered in order to remove the insoluble salts, and concentrated under vacuum. The crude residue obtained is purified by chromatography on silica gel, elution being carried out with a 70/30 heptane/ethyl acetate mixture. 41 g (97%) of dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate are obtained in the form of a light oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[Cl:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br>>[Cl:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: Clc1cccc(CBr)c1Cl
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Product: N#Cc1ccnc(-c2cn(Cc3cccc(Cl)c3Cl)cn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 4) and 2,3-dichlorobenzylbromide according to the procedure for the preparation of Example 43, part A using room temp. [M+H] Calc'd for C16H10Cl2N4, 330. Found, 330.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[C:18]([CH3:24])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[NH2:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1.C(N(CC)CC)C.[S:42](Cl)([CH3:45])(=[O:44])=[O:43]>CN1CCCC1=O>[NH2:23][C:20]1[N:19]=[C:18]([CH3:24])[C:17]([C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([N:32]4[CH2:33][CH2:34][CH:30]([NH:29][S:42]([CH3:45])(=[O:44])=[O:43])[CH2:31]4)[N:3]3[CH2:25][CH:26]3[CH2:28][CH2:27]3)=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:7]=2)=[CH:22][N:21]=1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Reactant: NC1CCNC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(N3CCC(NS(C)(=O)=O)C3)n(CC3CC3)c2n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
N-Methylpyrrolidone (1 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.25 mmol) and 3-aminopyrrolidine (130 mg, 1.5 mmol) and the resulting mixture was stirred at 120° C. for 1 hour. The reaction mixture was partitioned with chloroform and saturated brine and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, then triethylamine (100 μl, 0.75 mmol) and mesyl chloride (60 μl, 0.75 mmol) were added to the residue, and the resulting mixture was stirred for 1 hour. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (70 mg, 53%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([C:13](Cl)=[O:14])[CH:6]=1)(=[O:3])[CH3:2].[CH3:16][Si](C=[N+]=[N-])(C)C.[BrH:23]>C(Cl)Cl.CCCCCC.C(O)(=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:13](=[O:14])[CH2:16][Br:23])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1OC(C)=O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Br
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(C(=O)CBr)cc1OC(C)=O

Procedure:
Using the procedure in Example 85, step (b), the entire sample of 3-(chlorocarbonyl)-6-methoxyphenyl acetate (as prepared in the previous step) in 5 mL of anhyd CH2Cl2 was treated with 2.09 mL (4.18 mmol) of a 2 M solution of trimethylsilyldiazomethane in hexane and 456 μL (2.28 mmol) of 30 wt % HBr in acetic acid. Chromatography as in Example 85, step (b) followed by recrystallization from CH2Cl2-hexane afforded the title compound as a faintly yellow solid (366 mg, 67%). 1H-NMR (300 MHz, CDCl3) δ7.79 (dd, 1H, J=8.6, 2.2 Hz), 7.70 (d, 1H, 2.2 Hz), 7.03 (d, 1H, 8.6 Hz), 4.38 (s, 2H), 3.92 (s, 3H), and 2.34 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[O:4][C:5]([CH3:11])=[C:6]([C:8](=[O:10])[CH3:9])[N:7]=1.[BrH:14].BrBr>C(O)(=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[O:4][C:5]([CH3:11])=[C:6]([C:8](=[O:10])[CH2:9][Br:14])[N:7]=1
Reactant: Br
Reactant: CC(=O)c1nc(C(F)(F)F)oc1C
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1oc(C(F)(F)F)nc1C(=O)CBr
Temperature: 80 °C

Procedure:
3.8 g (0.02 mol) of 2-Trifluoromethyl-5-methyl-4-acetyl-oxazole are dissolved in 30 ml of glacial acetic acid, and 3 ml of a 33% strength solution of hydrogen bromide in glacial acetic acid are added. The mixture is heated to 80° C. and, over the course of 1 hour, a solution of 3.2 g (0.02 mol) of bromine in 10 ml of glacial acetic acid is added. After a further 30 minutes the glacial acetic acid is removed. The residue which remains is a dark oil which is reacted further as the crude product.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[C:18]([CH:19]=[O:20])=[CH:17][NH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:13][C:14]1[C:18]([CH:19]=[O:20])=[CH:17][N:16]([C:2]2[C:7]([CH:8]3[CH2:12][CH2:11][CH2:10][O:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)[N:15]=1
Reactant: Fc1ncccc1C1CCCO1
Reactant: Cc1n[nH]cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ncccc2C2CCCO2)cc1C=O
Temperature: 110 °C
Reaction time: 18 h
Yield: 60.9 %

Procedure:
To a screw-cap test tube containing 2-fluoro-3-(tetrahydrofuran-2-yl)pyridine (148 mg, 0.88 mmol) in dimethylformamide (2.2 mL) are added 3-methyl-1H-pyrazole-4-carbaldehyde (81 mg, 0.74 mmol) and potassium carbonate (152 mg, 1.1 mmol). The reaction tube is quickly sealed (caution: build-up of pressure possible; use a safety shield) and stirred in a preheated oil bath at 110° C. for 18 h with the aid of a magnetic stirrer. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is separated, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo. The resulting residue is purified by silica gel using normal phase Isco chromatography eluting with hexane: acetone (gradient from 5 to 20% in acetone) to give 116 mg of the title compound. MS (m/z): 258 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C@@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(Cl)(Cl)Cl>[CH:1]1[C:10]2[C@@H:11]3[CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[O:22])[CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=C(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCC3)c1ccc(F)cc1
Temperature: 100 °C
Yield: 58.1 %

Procedure:
To a solution of (7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.21 g, 1.0 mmol)) in 1,4-dioxane (7.0 mL) were added 4-chloro-4′-fluorobutyrophenone (0.40 g, 2.0 mmol), KI (catalytic amount) and K2CO3 (0.28 g, 2.0 mmol). The reaction mixture was heated at 100° C. for 48 h. The reaction mixture was cooled to 20° C. then diluted with CHCl3. The solution was filtered to remove excess K2CO3 and the filtrate was concentrated in vacuo and chromatographed (silica gel, CHCl3:MeOH 98:2) to give the title compound (0.22 g, 58%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 1.75-2.20 (m, 7H), 2.20-2.35 (m, 1H), 2.35-2.48 (m, 2H), 2.48-2.60 (m, 1H), 2.60-2.78 (m, 3H), 2.78-2.90 (m, 1H), 2.99 (t, J=7.2 Hz, 2H), 3.05-3.15 (m, 1H), 3.18-3.32 (m, 2H), 6.62 (t, J=7.3 Hz, 1H), 6.86 (d, J=7.3 Hz, 1H), 7.12 (t, J=8.6 Hz, 2H), 7.90-8.08 (m, 2H) ppm.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=[N:24]OCC)[CH:21]=4)[NH:16][N:15]=3)[CH:9]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.[NH2:28][NH:29][C:30](=O)[CH2:31][N:32]([CH3:34])[CH3:33].C[O-].[Na+]>CO>[CH3:33][N:32]([CH2:31][C:30]1[N:24]=[C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[C:10]2[CH:9]=[C:8]([C:6]([NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:13]=[CH:12][CH:11]=2)[NH:28][N:29]=1)[CH3:34]
Reactant: CN(C)CC(=O)NN
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(C(=O)NC4CCC4)c3)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cccc(C(=O)NC5CCC5)c4)c3c2)n1

Procedure:
The title compound was prepared according to the procedure of Example 367 C using N-cyclobutyl(3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl)carboxamide.2HCl (460 mg, 1.06 mmol), N-amino-2-(dimethylamino)acetamide (372 mg, 3.17 mmol) and sodium methoxide (608 μL of a 25% w/w in methanol) in anhydrous methanol (7.0 mL) with a reaction time of 44 h. Purification of the residue by flash chromatography on silica gel with 50% methanol in ethyl acetate gave the desired product as a pale yellow solid. The residue was dissolved in a minimum amount of anhydrous methanol and excess 1.0 N HCl in anhydrous ethyl ether was added dropwise to precipitate the desired product as the bis-hydrochloride salt. The product was collected and dried under vacuum to afford the title compound (27 mg, 5% yield) as a light yellow powder. 1H NMR (DMSO-d6) δ 10.6 (br s, 1H), 8.89 (d, 1H), 8.84 (s, 1H), 8.4 (s, 1H), 8.17 (d, 1H), 8.12 (d, 1H), 7.91 (d, 1H), 7.76 (d, 1H), 7.63 (t, 1H), 4.5–4.4 (m, 1H), 4.44 (s, 2H), 2.83 (s, 6H), 2.23–2.0 (m, 4H), 1.72–1.62 (m, 2H); ES-MS (m/z) 416 [M+H]+ (HCl salt not detected).
Reaction SMILES: [C:1]([NH:9][C:10](=[CH:15][N:16]([CH3:18])C)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1[S:21][CH:22]=[CH:23][N:24]=1.Cl.O>C(O)(C)C>[C:1]([NH:9][C:10](=[CH:15][NH:16][C:18]1[S:21][CH:22]=[CH:23][N:24]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nccs1
Reactant: COC(=O)C(=CN(C)C)NC(=O)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COC(=O)C(=CNc1nccs1)NC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
10g (39.5 mmol) of methyl 2-benzoylamino-3-dimethylaminoacrylate and 11.3 g (118 mmol) of 2-aminothiazole were dissolved at 40° C. in 200 ml of isopropanol. The solution was admixed with 3.96 ml (48 mmol) of concentrated hydrochloric acid within 5 minutes (min) and stirred for a further 60 min. 75 ml of deionized water were added, the suspension was cooled overnight and the crystallized product was filtered off. Yield: 8.6 g (70% of theory) 1H NMR: 3.62 (s, 3H); 7.08 (d, 1H); 7.32 (d, 1H); 7.45-7.60 (m, 3H); 8.02 (d, 2H); 8.22 (d, 1 H); 9.28 (s, 1 H); 10.45 (d, 1 H)
Reaction SMILES: [C:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=O)[CH:6]=1)([O:3][CH3:4])=[O:2].O=P(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[Cl:18][C:7]1[CH:6]=[C:5]([C:1]([O:3][CH3:4])=[O:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: COC(=O)c1cc(=O)[nH]c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)nc2ccccc12
Temperature: 25 °C

Procedure:
A stirred solution of 4-carbomethoxy quinolin-2-one (prepared as shown in Method D (1.76 g, 9 mmol), POCl3 (4.6 g, 30 mmol) in toluene (40 mL) was heated at reflux for 2 h then allowed to cool to room temperature and poured into ice water (50 mL). The mixture was extracted with ethyl acetate (3×50 mL). The organics were combined, washed with water, brine, dried (MgSO4) and concentrated in vacuo to afford the desired 2-chloro-4-carbomethoxyquinoline lv (1.50 mg). 1H NMR (DMSO-d6) δ 8.54 (d, J=8 Hz, 1H), 8.03-8.06 (m, 1H), 7.89-7.94 (m, 2H), 7.75-7.77 (m, 1H), 3.98 (s, 3H); ESI-MS m/z 222.1 (100, M+H+).