Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:18]([C:19](=[O:35])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)=[C:17]([C:36]3[CH:41]=[CH:40][C:39]([O:42]C(=O)C4C=CC=CC=4)=[CH:38][CH:37]=3)[S:16][C:15]=2[CH:51]=1)(=O)C1C=CC=CC=1.C(O)C.CS(O)(=O)=O>O>[OH:10][C:11]1[CH:12]=[CH:13][C:14]2[C:18]([C:19](=[O:35])[C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)=[CH:24][CH:25]=3)=[C:17]([C:36]3[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=3)[S:16][C:15]=2[CH:51]=1
Reactant: O=C(Oc1ccc(-c2sc3cc(OC(=O)c4ccccc4)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1)c1ccccc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 20 °C
Reaction time: 72 h

Procedure:
The crude product of Example 2 above, 6-benzoyloxy-2-(4-benzoyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride, was combined with 400 ml. of ethanol, 400 ml. of water and 55 ml. of methanesulfonic acid. The mixture was stirred on the steam bath for 72 hours, and was then evaporated down to an oil which was diluted to about 6 liters with water. The aqueous solution was washed twice with 1 liter portions of diethyl ether, and was then thoroughly degassed under vacuum, cooled to about 20° C., and made basic with aqueous ammonia to pH 8.4. The product which precipitated was collected by filtration and vacuum dried, and was then recrystallized from about 80 ml. of acetone. The product was vacuum dried at 40° C. to obtain 18.1 g. of crystals which was found by nmr, mass spectrum, infrared and ultraviolet analysis to be substantially identical to the product of Example 3.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][C:9](=[O:16])[C:8]2([CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:23][CH2:22]1)SC.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:40]Cl.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH2:40][C:39]1[CH:42]=[CH:43][C:44]([O:45][CH3:46])=[C:37]([O:36][CH3:35])[CH:38]=1)[C:9](=[O:16])[CH:8]2[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:23][CH2:22]1
Reactant: COc1cc2c(cc1OC)C(CCN1CCN(c3ccccc3OC)CC1)(SC)C(=O)N2
Reactant: COc1ccc(CCl)cc1OC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)C(CCN3CCN(c4ccccc4OC)CC3)c3cc(OC)c(OC)cc32)cc1OC
Yield: 57.5 %

Procedure:
In dimethylformamide was suspended 38 mg of sodium hydride. To the suspension were added 285 mg of 5,6-dimethoxy-3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-3-methylthio-1,3-dihydro-2(2H)-indolone and 140 mg of 3,4-dimethoxybenzyl chloride. A sodium hydrogencarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was dissolved in ethanol. Separately, an acetone solution containing 2.0 g of Raney nickel was refluxed, and the solvent was removed by decantation. To the residue was added the above prepared ethanol solution, followed by refluxing for 15 minutes. A precipitate was removed by filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2 to 0:1) to obtain 201 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH:35]([CH3:37])[CH3:36]>C(OCC)(=O)C.CCCCCC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][CH:35]([CH3:37])[CH3:36])=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C=C2Oc3cc(OC(C)C)ccc3C2=O)cc1OC
Reaction time: 4 h
Yield: 109.1 %

Procedure:
To a solution of 2-[(3,4-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g, potassium carbonate 0.58 g and dimethylformamide 5 ml, 2-bromopropane 0.306 g was added. After the mixture was refluxed for 2.5 hours, water 50 ml was added. The resulting compound was extracted with ethyl acetate 30 ml twice. The ethyl acetate solution was washed with a saturated sodium chloride solution 50 ml twice, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dissolved in ethyl acetate 2 ml and hexane 5 ml, and the solution was allowed to stand at room temperature for four hours. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 622.7 mg.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([C:11]([CH2:13][CH3:14])=[O:12])[CH3:10]>>[C:2]1([CH:1]([OH:8])[CH:9]([CH3:10])[C:11](=[O:12])[CH2:13][CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCC(=O)CC
Product: CCC(=O)C(C)C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 0 h
Yield: 72 %

Procedure:
50 mmol (5.1 ml) of benzaldehyde are added at -78° C. to the manganous enolate of diethyl ketone, prepared by the procedure described above. After stirring for 10 seconds at -78° C., the reaction medium is hydroIyzed by the dropwise addition of a saturated solution of (NH4)2SO4. After decantation, filtration on hyflo-supercel and evaporation of the solvents under vacuum, 5-phenyl-5-hydroxy-4-methylpentan-3-one is isolated by low pressure liquid chromatography on 15 μm silica gel using cyclohexane/ethyl acetate (90/10) as the eluent. Yield=72%. Erythro/threo=61/39.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:11]=1.[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([CH2:25][C:26]2[C:27](=[O:34])[NH:28][C:29](SC)=[N:30][CH:31]=2)=[CH:23][CH:22]=1.C(Cl)(Cl)Cl.CO.N.C(O)(=O)/C=C\C(O)=O>CC(C)=O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][C:26]2[C:27](=[O:34])[NH:28][C:29]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][C:10]3[N:11]=[C:7]([NH:6][C:5]([NH2:17])=[N:4][CH2:3][C:2]([F:1])([F:18])[F:19])[S:8][CH:9]=3)=[N:30][CH:31]=2)=[CH:35][CH:36]=1
Reactant: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Agent: N
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: NC(=NCC(F)(F)F)Nc1nc(CCCCNc2ncc(Cc3ccc(Cl)cc3)c(=O)[nH]2)cs1

Procedure:
An intimate mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.39 g.) and 5-(4-chlorobenzyl)-2-methylthiopyrimid-4-one (0.39 g.) was heated at 150°-160° for 20 min. during which time effervescence occurred. The residue obtained on cooling was subjected to preparative thin layer chromatography using chloroform/methanol/ammonia 90:10:0.5 v/v/v for development. The appropriate zone of the chromatogram was isolated and extracted with hot ethanol/chloroform (50:50 v/v; 200 ml.). Evaporation of the eluate gave a glass which was dissolved in acetone (0.3 ml.) and treated with an excess of a saturated solution of maleic acid in acetone to give a maleate salt of 5-(4-chlorobenzyl)-2-{4-[2-(2,2,2-trifluoroethyl)guanidinothiazol-4-yl]butylamino}-pyrimid-4-one as a white powder (0.1 g.) which contained 1.5 moles of maleic acid and 1.5 moles of water of crystallisation. The n.m.r. spectrum in d6 dimethylsulphoxide using tetramethylsilane (δ=0) as internal standard included the following resonances (δ): 3.45 (2H, singlet); 4.1 (2H, multiplet); 7.1 (3H, singlet-maleic acid); 7.45 (1H, singlet) and 8.2 (4H, singlet).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN1CCOCC1.ClC(OCC)=O.[NH2:29][C@H:30]([C:33]([NH2:35])=[O:34])[CH2:31][OH:32]>O1CCCC1.CN(C)C=O.CO>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:29][C@H:30]([C:33]([NH2:35])=[O:34])[CH2:31][OH:32])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NC(=O)[C@@H](N)CO
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(N)=O
Reaction time: 0.03 h

Procedure:
To a solution of 1.00 g (4.65 mmoles) Boc-Pro-OH in 10 ml anhydrous tetrahydrofuran, 0.52 ml (4.65 mmoles) N-methylmorpholine, and 0.45 ml (4.65 mmoles) ethyl chloroformate are successively added at a temperature of -12° C. After stirring at this temperature for 2 minutes, a cold solution of 0.48 g (4.65 mmoles) H-Ser-NH2 (R. W. Hanson and H. N. Rydon, J. Chem. Soc., 836, 1964) in 10 ml dimethylformamide is added. The reaction mixture is stirred at -10° C. for 3 hours and at 20° C. for 1 hour, then filtered from salts and evaporated in vacuo. The residue is taken up with tetrahydrofuran, filtered, and the solution evaporated again in vacuo. By crystallization from methanol-diethylether 1.1 g of compound (1) are obtained: m.p. 138° C. [α]D25 -58.9° (c=1, MeOH); RfA =0.15; RfB =0.33.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.Cl.[CH2:16]([C:18]1[CH:19]=[C:20]([CH3:30])[C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:22][CH:23]=1)[CH3:17]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:27]2[CH2:28][CH2:29][N:24]([C:21]3[C:20]([CH3:30])=[CH:19][C:18]([CH2:16][CH3:17])=[CH:23][N:22]=3)[CH2:25][CH2:26]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Agent: Cl
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 99.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-2-(methanesulfonyl)benzoic acid (2.8 g) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine hydrochloride (2.4 g) described in Preparation Example 99, the title compound (4.6 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][S:8][C:7]([CH:10]([NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH2:11][CH3:12])=[N:6]1)=[O:4].C1CCN2C(=NCCC2)CC1.BrC(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH:10]([NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH2:11][CH3:12])[S:8][CH:9]=1)=[O:4]
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1=N[C@H](C(=O)OC)CS1
Solvent: ClC(Cl)(Cl)Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1nc(C(=O)OC)cs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a chilled (0° C.) solution of (R)-2-(1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-4,5-dihydro-thiazole-4-carboxylic acid methyl ester (0.296 g, 0.670 mmol) and DBU (200 μL, 1.34 mmol) in CH2Cl2 (8.0 mL) was added BrCCl3 (69.0 μL, 0.700 mmol). The mixture was then warm to room temperature. After 18 hours, the reaction mixture was diluted with CH2Cl2 (20 mL) and washed with saturated aqueous ammonium chloride (3×10 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The mixture was purified by silica gel chromatography eluting with a gradient of 0-80% ethyl acetate in heptane to afford the title compound. MS m/z 440.77 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([OH:17])[C:10]3[N:11]=[CH:12][CH:13]=[N:14][C:15]=3[CH:16]=2)[CH2:3][CH2:2]1.CS(O[C@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30]2[N:35]=[CH:34][C:33]([Br:36])=[CH:32][N:31]=2)[CH2:25][CH2:24]1)(=O)=O>O1CCOCC1.CCOC(C)=O>[Br:36][C:33]1[CH:34]=[N:35][C:30]([NH:29][C@H:26]2[CH2:27][CH2:28][C@@H:23]([O:17][C:9]3[CH:8]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH:16]=[C:15]4[C:10]=3[N:11]=[CH:12][CH:13]=[N:14]4)[CH2:24][CH2:25]2)=[N:31][CH:32]=1
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](Nc2ncc(Br)cn2)CC1
Reactant: Oc1cc(N2CCOCC2)cc2nccnc12
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Brc1cnc(N[C@H]2CC[C@@H](Oc3cc(N4CCOCC4)cc4nccnc34)CC2)nc1
Yield: 52.5 %

Procedure:
As shown in step 6-viii of Scheme 6, a solution of 7-morpholinoquinoxalin-5-ol (100 mg, 0.432 mmol), (trans)-4-((5-bromopyrimidin-2-yl)amino)cyclohexyl methanesulfonate (compound 1014, 303 mg, 0.865 mmol), and CsCO3 (282 mg, 0.865 mmol) in dioxane (1.0 mL was stirred for 16 hours at 105° C. After cooling, the reaction mixture was diluted with EtOAc, filtered through diatomaceous earth, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0 to 5% MeOH/DCM gradient) to produce 5-bromo-N-((cis)-4-((7-morpholinoquinoxalin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine (compound 1020, 110 mg) as a yellow foam: 1H-NMR (400 MHz, CDCl3) δ 8.70 (d, J=2.0 Hz, 1H), 8.64 (d, J=1.9 Hz, 1H), 8.29 (s, 2H), 6.98 (d, J=2.5 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 5.29 (d, J=8.3 Hz, 1H), 4.81 (s, 1H), 4.04-3.84 (m, 4H), 3.42-3.31 (m, 4H), 2.22 (s, 2H), 1.92 (d, J=4.9 Hz, 6H).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:27]=[C:26]([CH3:28])[N:25]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:24]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1>C1COCC1>[CH3:34][N:35]1[CH2:36][CH2:37][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH:47][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[CH:27]=[C:26]([CH3:28])[N:25]([C:29]([CH3:32])([CH3:30])[CH3:31])[N:24]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:33])=[CH:43][CH:42]=2)[CH2:39][CH2:40]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)nn1C(C)(C)C
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)nn1C(C)(C)C
Temperature: 65 °C
Reaction time: 24 h
Yield: 38 %

Procedure:
A small screw cap test tube was charged with 1-tert-Butyl-5-methyl-1H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 179 mg, 0.4027 mmol) and THF (4 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (77.2 mg, 0.404 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was redissolved in EtOAc (5 mL) and Hexane (˜40 mL) was added to the solution. The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (10 mL) to afford the title compound in 38% yield (0.0945 g, 0.153 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[CH2:9][CH2:8][N:7]=1)=[O:5])[CH3:2].[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:20][O:19][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][C:13]=1[N+:16]([O-:18])=[O:17])[CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:7][CH2:8][CH2:9]2
Reactant: CCOC(=O)C1=NCCc2cc(OC)c([N+](=O)[O-])cc21
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1NCCc2cc(OC)c([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 34 g of 6-methoxy-7-nitro-3,4-dihydroisoquinoline-1-carboxylic acid ethyl ester in 300 ml of acetic acid was treated with 25 g NaCNBH3 (added in several portions). The mixture was stirred for 2 h. The reaction mixture was poured onto 300 g of solid NaHCO3 and 2 l of ice-water was carefully added with vigorous stirring. The product was extracted into dichloromethane. The organic layer was washed twice with water, dried and concentrated, to give 32g of essentially pure 6-methoxy-7-nitro-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid ethyl ester 1f. The compound is used as intermediate in the synthesis described in examples 1 and 2.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=O.[C:16]([CH2:18][C:19]([NH2:21])=[O:20])#[N:17].C[O-].[Na+].O>CN(C)C=O.C(O)(=O)C>[C:16]([C:18]1[C:19](=[O:20])[NH:21][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])=[CH:4][CH:3]=1)#[N:17]
Reactant: COc1ccccc1C(=O)C=CN(C)C
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1-c1ccc(C#N)c(=O)[nH]1

Procedure:
A stirred mixture of 3-dimethylamino-1-(2-methoxyphenyl)-2-propene-1-one (5.74 g), cyanoacetamide (2.48 g) and sodium methoxide (from sodium hydride (50%, 4.32 g) and methanol (3.5 ml)) in dry dimethylformamide was heated under reflux for 10 hours. The reaction mixture was poured into water, acidified to pH4 with glacial acetic acid and extracted with ethyl acetate. The ethyl acetate extract was evaporated under reduced pressure to low volume and water was added to cause precipitation of a crude product (3.67 g) which was collected and recrystallised twice from dimethylformamide to yield the title compound, 1.68 g, m.p. 236°-238° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Product: COc1ccc(Nc2ccc(Cl)cc2C(=O)O)cc1

Procedure:
5-Chloro-2-(4-methoxyphenylamino)benzoic acid [X; R=5-Cl, OR°=4-OCH3, R"=H] was prepared from 2,5-dichlorobenzoic acid and p-methoxyaniline according to the procedure of Example 1A, part (a), and obtained as a light green solid, m.p. 188°-189° C.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH2:9][C:10]1([CH3:30])[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[C:18]([CH:26]=[C:27](Cl)[N:28]=2)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][CH2:11]1>>[NH2:9][C:10]1([CH3:30])[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[C:18]([CH:26]=[CH:27][N:28]=2)[C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:12][CH2:11]1
Reactant: CC1(N)CCN(c2cc(C(=O)OC(C)(C)C)cc(Cl)n2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC1(N)CCN(c2cc(C(=O)OC(C)(C)C)ccn2)CC1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a Parr hydrogenation vessel under a nitrogen atmosphere was charged 5% Pd/Al2O3 (1.02 g, 10 wt % load) and K3PO4 (6.92 g, 1.05 equiv) followed by the 1-methyl-2-pyrrolidinone solution from Example 13 (31.4 g of a 31 wt % solution, 29.9 mmol). The vessel was sealed and sparged with hydrogen and then warmed to 40° C. with shaking. After 4 hours, the vessel was sparged with nitrogen, cooled to ambient temperature and filtered. The catalyst and solids were rinsed with 1-methyl-2-pyrrolidinone (2×10 g). The crude solution was used in the next step.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][CH2:13][N:14]=2)=[CH:6][CH:5]=1>O.CO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:14]2)=[CH:8][CH:9]=1
Reactant: Brc1ccc(C2=NCCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Brc1ccc(C2CCCN2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
NaBH4 (1.52 g, 40 mmol) was added to a solution of 5-(4-bromophenyl)-3,4-dihydro-2H-pyrrole (4.48 g, 20 mmol) in H2O/MeOH (30 mL, v/v 1:4) at −41° C. After stirred for 4 hrs, the solution was allowed to warm to room temperature. Once the reaction was deemed complete by TLC, the unreacted NaBH4 was quenched by the addition of 2 N HCl. The solution was then diluted with water and ether, and separated two layers. The aqueous layer was washed with an additional portion of ether, basified with 4 M NaOH (pH 12-13) and washed with ethyl acetate. The combined organic extracts were washed with brine, and then dried over Na2SO4. Evaporation of the solvent afforded the title crude product as a yellow oil (3.8 g, yield 84%), which was used directly in the next step. LC-MS (ESI) m/z: 226 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:14])([F:13])[CH2:11][OH:12].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:12][CH2:11][C:10]([F:14])([F:13])[F:9])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OCC(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)COc1cc(Cl)ncn1
Reaction time: 60 h

Procedure:
4,6-dichloropyrimidine (20 g) potassium carbonate (37 g) and 2,2,2-trifluoroethanol (10.3 cm3) were stirred together at ambient temperature in dry dimethyl formamide (DMF) (130 cm3) for seven hours. The mixture was stored at ambient temperature for 60 hours before being poured into water. The product was extracted with diethyl ether and the organic layer was washed with saturated brine and dried over magnesium sulfate. Evaporation under reduced pressure afforded 4-chloro-6-(2,2,2-trifluoroethoxy)-pyrimidine as a 1:1.5 mixture with residual DMF. 1H NMR (CDCl3): δ4.79-4.89(2H,q); 6.93(1H, s); 8.61(1H,s). This was used directly in step 2.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=S)[NH:8]C3C=CC=CC=3S[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[C:22]([NH2:27])[CH:21]=1.FC1C=CC=CC=1C#N>CN(C=O)C>[F:29][C:19]([F:18])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([S:26][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=2[C:7]#[N:8])=[C:22]([NH2:27])[CH:21]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: S=C1Nc2ccccc2Sc2ccccc21
Agent: Cl
Agent: N#Cc1ccccc1F
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Sc1ccc(C(F)(F)F)cc1N

Procedure:
Using a procedure analagous to that of Example 3(a) and (b), 4-trifluoromethyl-2-aminothiophenol hydrochloride (11.48 g, 50 mmol) was combined with 2-fluorobenzonitrile in DMF solvent (100 ml) to give crude 2-(4-trifluoromethyl-2-aminophenylthio) benzonitrile (6.84 g). Hydrolysis and subsequent condensation gave the title compound as off-white crystals from ethanol (1.1 g, m.p. 233°-235° C., Rf 0.21, CH2Cl2 /MeOH 50:1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.[Li+].CCC[CH2-].CON(C)[C:16](=[O:18])[CH3:17]>O1CCCC1>[CH3:7][N:5]1[CH:6]=[C:2]([C:16](=[O:18])[CH3:17])[CH:3]=[N:4]1
Reactant: Cn1cc(Br)cn1
Reactant: CON(C)C(C)=O
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)c1cnn(C)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
4-Bromo-1-methyl-1H-pyrazole (41.3 mL, 400 mmol), was dissolved in tetrahydrofuran (750 mL) and cooled to −78° C. N-Butyllithium (2.5 M solution in hexanes, 160 mL, 400 mmol) was added drop-wise over 30 minutes, and the resulting mixture was stirred for 1 hour at −78° C. After drop-wise addition of a solution of N-methoxy-N-methylacetamide (40.9 mL, 400 mmol) in tetrahydrofuran (100 mL) to the −78° C. reaction mixture, the cooling bath was allowed to warm to 0° C. over 4 hours. The reaction was then quenched with saturated aqueous sodium chloride solution (50 mL), and volatiles were removed in vacuo. The residue was diluted with ethyl acetate (1000 mL), treated with magnesium sulfate, and stirred for 30 minutes before being filtered and concentrated in vacuo. Purification was carried out via silica gel chromatography (material was loaded in a minimum amount of dichloromethane; Gradient: 5% to 100% ethyl acetate in heptane) to provide a pale yellow oil that solidified on standing. Yield: 28.5 g, 230 mmol, 57%. 1H NMR (500 MHz, CDCl3) δ 2.37 (s, 3H), 3.90 (s, 3H), 7.83 (s, 1H), 7.84 (s, 1H).