Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([C@H:23]5[C@@H:27]([F:28])[CH2:26][NH:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH:36](=O)[CH3:37]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([C@H:23]5[C@@H:27]([F:28])[CH2:26][N:25]([CH2:36][CH3:37])[CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:34])([F:35])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CNC[C@@H]1F
Reactant: CC=O
Product: CCN1C[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(cis)-1-ethyl-4-fluoropyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(cis)-4-fluoropyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione (Example 322) and acetaldehyde (in place of formaldehyde) following General Procedure R2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([F:34])[CH:33]=1>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:30]2[CH:29]=[C:28]([F:27])[CH:33]=[C:32]([F:34])[CH:31]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cc(F)cc(F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 15 %

Procedure:
The title compound was prepared in 15% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example 15, step (f)) and 3,5-difluorobenzeneboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[CH2:8][C:9](=O)[C:10]([F:13])([F:12])[F:11].C(C1C=CC=CN=1)(=O)C.[NH2:25][C:26]1[C:30]([C:31]#[N:32])=[CH:29][NH:28][N:27]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[N:27]2[N:28]=[CH:29][C:30]([C:31]#[N:32])=[C:26]2[N:25]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccn1
Agent: CC(=O)c1ccccn1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccccn3)nc12
Yield: 46.7 %

Procedure:
Reaction of 1-pyridin-2-yl-4,4,4-trifluoro-butane-1,3-dione (217 mg, 1.0 mmol), prepared from commercially available 2-acetylpyridine according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light brown solid (135 mg, 47%). MS (ISP) 289.9 [(M+H)+]; mp 208° C.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:6][CH2:5][S:4][C:3]1=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=1.O.[OH-].[Li+]>C(O)C.O>[F:21][C:2]1([F:1])[CH2:6][CH2:5][S:4][C:3]1=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(C)c1ccc(C=C2SCCC2(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(C=C2SCCC2(F)F)cc1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 85.1 %

Procedure:
Ethyl 2-[4-(3,3-difluorothiolan-2-ylidenemethyl)phenyl]propionate (43 mg) obtained in Example 24 was dissolved in a solution of ethanol/water (1/1, 1.0 ml), and to the solution was added lithium hydroxide monohydrate (20 mg), and the reaction mixture was stirred at room temperature for 16.5 hours. After completion of the reaction, to the reaction mixture was added 2.0 M aqueous hydrochloric acid, phase separation was performed with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give the title compound (33.3 mg, 85.1%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([O:17][CH3:23])=[O:16])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(Oc2ccccc2)cc1

Procedure:
To a solution of 4-phenoxyphenylacetic acid (1.0 g, 4.38 mmoles) in methanol (5.0 ml) was added concentrated sulfuric acid (0.05 ml, 0.88 mmoles) and the mixture was heated to reflux for about 5 hours. The mixture was cooled and concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate (20.0 ml) and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and evaporated to dryness to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].C(N(CC)CC)C.[CH:25]([NH:28][C:29]([CH:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH3:32])=[O:30])([CH3:27])[CH3:26]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:36]1[CH2:35][CH2:34][N:33]([CH:31]([C:29]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:30])[CH3:32])[CH2:38][CH2:37]1)=[O:9]
Reactant: CC(C)NC(=O)C(C)N1CCNCC1
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(C=CC(=O)N2CCN(C(C)C(=O)NC(C)C)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15.15 g of 3,4,5-trimethoxycinnamoyl chloride and 8.92 ml of triethylamine are added with ice cooling and stirring to a solution of 9.80 g of 1-[1-(isopropylaminocarbonyl)ethyl]piperazine in 200 ml of chloroform, and the resulting solution is stirred at room temperature for 1 hour.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([O:19]CC)=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Temperature: 80 °C
Yield: 98 %

Procedure:
1500 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 128.4 g of water, and 4500 g of acetic acid were introduced and 53 g of sulfuric acid were added. The mixture was heated at reflux for 4 hours. 2020 ml of distillate were then distilled off until a bottom temperature of 109° C. was reached. The suspension was then cooled to 80° C. and 2204 g of 4% strength by weight sodium acetate solution were added dropwise. The pH was then in the range 3 to 4. The mixture was then cooled to 20° C. and the solid was filtered off with suction. The solid was washed with 2000 ml of water and dried in vacuo at 50° C. 1329 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid were isolated, which corresponds to a yield of 98%.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[C:15]([O:23][C@H:24]1[C@@H:28]([O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:27]([CH2:38][O:39][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:26][C@H:25]1[N:48]1[CH:55]=[CH:54][C:52](=O)[NH:51][C:49]1=[O:50])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([O:23][C@H:24]1[C@@H:28]([O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:27]([CH2:38][O:39][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:26][C@H:25]1[N:48]1[CH:55]=[CH:54][C:52](=[S:2])[NH:51][C:49]1=[O:50])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(OC[C@@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Product: O=C(OC[C@@H]1O[C@@H](n2ccc(=S)[nH]c2=O)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 95.5 %

Procedure:
Phosphorus pentasulfide (5.99 g, 26.95 mmol) was added to a solution of compound 18 (3.75 g, 6.73 mmol) inpyridine (70 ml) and was refluxed for four hours. After cooling, the solvent was evaporated and the residue dissolved in CHCl3, washed with water and brine. After drying over anhydrous Na2SO 4, evaporation of the solvent gave the crude product which was purified on a silica gel column using 30% EtOAc/petroleum ether as solvent to give compound 19 (3.68 g, 95%) as golden yellow foam.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:17][CH3:18])[C:5]2[CH:10]=[CH:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.O1CCOC[CH2:20]1>>[CH3:1][C:2]1[N:3]([CH3:20])[C:4](=[N:17][CH3:18])[C:5]2[CH:10]=[CH:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CNc1nc(C)nc2c1ccn2-c1ccccc1
Reactant: C1COCCO1
Product: CN=c1c2ccn(-c3ccccc3)c2nc(C)n1C

Procedure:
A mixture of 2-methyl-4-methylamino-7-phenyl-7H-pyrrolo-[2,3-d] pyrimidine (0.5g, 2.1mM) and dioxan (15ml) was heated under reflux for 18 hours. The mixture was cooled and then the solvent was removed by evaporation. The residue was purified by flash chromatography on ICN neutral alumina (32-63) using methylene chloride which contained an increasing amount of methanol (up to a maximum of 5%) as eluant to give a solid. This solid was recrystallised from hexane to give 2,3-dimethyl-4-methylimino-7-phenyl-3H,7H-pyrrolo[2,3-d] pyrimidine as a white solid (126mg), m p. 160-161° C; microanalysis, found: C, 71 2; H,5 9; N,22.0%; C14H14N4 requires C,71.4; H, 6.3; N, 22.2%; NMR: 2.48(3H,s,C-CH3), 3.48 (3H,s,N-CH3), 3.56(3H,s,N-CH3), 6.90(1H,d,CH), 6.97(1H,d,CH), 7.34(1H, complex, aromatic), 7.47(2H, complex, aromatic), 7.60(1H, complex, aromatic).
Reaction SMILES: Br[CH:2]([C:4]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)[CH3:3].Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH2:29][NH2:30])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:13]1[C:4]2[CH:2]([CH3:3])[N:30]([CH2:29][C:19]3[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[C:17]([CH3:16])[CH:18]=3)[C:6](=[O:8])[C:5]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(CN)ccc1OCC(F)(F)F
Reactant: COC(=O)c1ccnc(Cl)c1C(C)Br
Agent: Cl
Product: Cc1cc(CN2C(=O)c3ccnc(Cl)c3C2C)ccc1OCC(F)(F)F
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield (137 mg, brown oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-6, racemate) and (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride (200 mg, 0.79 mmol, Amine-34) in a similar manner to Intermediate-2.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1Br.CC1(C)COB([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)OC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:3]([OH:12])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[C:20]1[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: COC(=O)c1sc(Br)c(Br)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1sc(-c2ccnn2C)c(Br)c1O
Reaction time: 12 h
Yield: 14.9 %

Procedure:
Methyl 4,5-dibromo-3-hydroxy-2-thiophenecarboxylate (500 mg, 1.59 mmol), 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (339 mg, 1.75 mmol), Pd(PPh3)4 (92 mg, 79.4 μmol) and K2CO3 (876 mg, 6.35 mmol) in dioxane (6.6 mL) and H2O (1.3 mL) were combined in a sealed tube. After 12 h at 80° C., the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 0.5% MeOH in DCM) affording the title compound (75 mg, 15%) as a brown residue: LCMS (ES) m/z=318 (M+H)+.
Reaction SMILES: NC1N=C2[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:11][N:5]2C(=O)C=1N=O.C(OC)(=[O:22])C(C)C.C(N)CN>>[C:14]([NH:13][CH2:12][CH2:11][NH2:5])(=[O:22])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CN1CCn2c1nc(N)c(N=O)c2=O
Reactant: COC(=O)C(C)C
Solvent: NCCN
Product: CC(C)C(=O)NCCN

Procedure:
7-AMINO-2,3-DIHYDRO-1-(2-METHYLPROPYL)-6-NITROSOIMIDAZO[1,2-a]PYRIMIDIN-5(1H)-ONE.-- Methyl isobutyrate and ethylenediamine in a molar ratio of 1:3 were heated in a closed pressure vessel at 100° for 62 hrs. The mixture was cooled, clarified by filtration, and the excess ethylenediamine removed from the filtrate by distillation in vacuo. The residue was distilled, boiling point 115°-117°/0.9 mm Hg to yield N-isobutyrylethylenediamine whose identity was confirmed by examination of the NMR and IR spectra. The latter, 15 g., was suspended in 200 ml. of dry THF and a solution of 20 g. (ca. 0.5 mole) of lithium aluminum hydride in 200 ml. of dry THF was added dropwise. The mixture was refluxed for 23 hrs., the excess lithium aluminum hydride destroyed by hydrolysis. The insoluble material was removed by filtration, and the filtrate concentrated in vacuo to yield N-(2-methylpropyl)ethylenediamine as an oil, yield 37 g. The identity of the product was confirmed by examination of the NMR spectrum, and 5.8 g. (0.05 mole) thereof was then dissolved in 20 ml. of MeOH and a solution of 5.8 g. (0.055 mole) of cyanogen bromide in MeOH was added in dropwise fashion with cooling. The mixture was stirred for 1/2 hr. and then concentrated in vacuo to an oil. The latter was dissolved in methylene chloride and again concentrated in vacuo to aid in removal of last traces of MeOH. The NMR spectrum of the residue, an oil, confirmed the structure 1-(2-methylpropyl)-1H-imidazo-2-amine hydrobromide. This material was then condensed with ethyl oximinocyanatoacetate substantially according to the method described in Procedure 1. The product was recovered by distillation of the solvent from the reaction mixture in vacuo. The residue was dissolved in water and acidified with acetic acid. The precipitate that formed was collected and air dried. The damp solid was recrystallized from methanol/ethanol, m.p. 242.5-243.5° d.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:25]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:25])=[O:2])=[CH:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1
Yield: 80 %

Procedure:
The title compound is prepared in analogy to example 3 from N-[4-(4-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield: 80%. Colorless solid. MS: m/e=303.2 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[CH3:12])[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:22][NH:23][O:24][CH3:25]>>[CH3:25][O:24][N:23]([CH3:22])[C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:13][CH3:14])[C:11]([CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CNOC
Reactant: COc1cc(C(=O)O)cc(OC)c1C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Product: COc1cc(C(=O)N(C)OC)cc(OC)c1C

Procedure:
3,5-Dimethoxy-4-methylbenzoic acid was allowed to react with oxalyl chloride, and the resulting acid chloride was allowed to react with N,O-dimethylhydroxyamine hydrochloride to obtain N,3,5-trimethoxy-N,4-dimethylbenzamide. The resulting compound was allowed to react with 4-phenylbutylmagnesium chloride to obtain 1-(3,5-dimethoxy-4-methylphenyl)-5-phenylpentan-1-one. The resulting compound was allowed to react with lithium diisopropylaminez and methyl[4-(bromomethyl)phenyl]acetate in the presence of N,N,N′,N″,N″-pentamethyldiethylenetriamine to obtain methyl{4-[2-(3,5-dimethoxy-4-methylbenzolyl)-5-phenylpentyl]phenyl}acetate. Using the obtained compound, the procedure similar to Example 2 were carried out to give the title compound having the following physical properties.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:3]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O:54][C:55](=O)[C@H:56]([O:58][C:59]1[CH:64]=[C:63](Cl)[N:62]=[C:61]([S:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[C:69]=2[F:75])[N:60]=1)[CH3:57])C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:75][C:69]1[C:70]([F:74])=[CH:71][CH:72]=[CH:73][C:68]=1[CH2:67][S:66][C:61]1[N:62]=[C:63]([NH:11][S:8]([N:4]2[CH2:5][CH2:6][NH:7][C@@H:2]([CH3:1])[CH2:3]2)(=[O:10])=[O:9])[CH:64]=[C:59]([O:58][C@H:56]([CH3:57])[CH2:55][OH:54])[N:60]=1
Reactant: C[C@H]1CN(S(N)(=O)=O)CCN1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)N2CCN[C@@H](C)C2)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
To a solution of (2S)-2-methylpiperazine (0.914 g) in dioxane (10 ml) was added sulfamide (0.746 g) and the reaction mixture was then heated at reflux in dioxane for 3 d. The reaction mixture was partitioned between EtOAc (150 ml) and H2O (150 ml) and the aqueous re-extracted with EtOAc (2×150 ml). Organics were collected dried and reduced in vacuo to yield (3S)-3-methylpiperazine-1-sulfonamide as a white solid (0.27 g). A mixture of (3S)-3-methylpiperazine-1-sulfonamide (0.27 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.628 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester ((the product of example 5 step i), 0.50 g) in dioxane (20 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 30 mins. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield: 0.940 g
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:15]=[C:14]3[C:9]([CH:10]=[CH:11][N:12]=[CH:13]3)=[CH:8][CH:7]=2)=[CH:2]1.Cl.[H][H]>ClCCl.C(O)C.[Pt]=O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:15]=[C:14]3[C:9]([CH2:10][CH2:11][NH:12][CH2:13]3)=[CH:8][CH:7]=2)=[CH:2]1
Reactant: c1cc2ccc(-c3ccsc3)cc2cn1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: c1cc(-c2ccc3c(c2)CNCC3)cs1
Yield: 63.5 %

Procedure:
A solution of 7-(3-thienyl)isoquinoline (0.15 g, 3 mmol) in dichloromethane was treated with an excess of HCl gas. The mixture was evaporated under reduced pressure to give a colourless solid. The solid was dissolved in ethanol, platinum oxide (100 mg) added, the reaction mixture hydrogenated at 50 psi on a Parr apparatus until uptake of hydrogen ceased. The catalyst was collected by filtration and the filtrate was hydrogenated again using fresh catalyst until the starting material had been consumed. The filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml), washed with sodium carbonate solution (100 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give crude 7-(3-thienyl)-1,2,3,4-tetrahydroisoquinoline as an oil (0.41 g, 62%). A mixture of this oil (0.40 g, 1.85 mmol) and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.325 g, 1.85 mmol) in toluene (3 ml) was heated at reflux under nitrogen for 6 h. The mixture was allowed to cool and the crystallised product collected. Recrystallisation from toluene afforded the title compound (0.17 g, 28%), m.p. 228°-230° C.; (Found: C, 72.82; H, 5.46; N, 12.05. C21H19N3S requires C, 73.01; H, 5.54; N, 12.16%); δH (DMSO-d6) 2.72 (2H, t, J 5.4 Hz, CH2), 2.80 (2H, t, J 5 Hz, CH2), 3.59 (2H, s, CH2), 3.82 (2H, s, CH2), 7.02 (1H, dd, J 7.7, 4.7 Hz, 5-H), 7.11 (1H, d, J 8.0 Hz, ArH), 7.35 (1H, s, ArH), 7.42-7.50 (3H, m, ArH), 7.57 (1H, dd, J 5.1, 3 Hz, ArH), 7.76 (1H, s, ArH), 8.04 (1H, dd, J 7.7, 1 Hz, 4-H), 8.20 (1H, dd, J 4.6, 1 Hz, 6-H), and 11.49 (1H, br s, NH); m/z (CI+, NH3) 345 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:17])[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28].O>ClCCl>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([N:8]2[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[N:1]=[C:26]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10][C:11]=1[F:17])#[N:14]
Reactant: CCOC(=O)C(=O)Cl
Reactant: N#Cc1ccc(Nc2ncccc2N)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1nc2cccnc2n1-c1ccc(C#N)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of 4-[(3-aminopyridin-2-yl)amino]-2-fluorobenzonitrile (C15) (300 mg, 1.31 mmol) and triethylamine (270 mg, 2.67 mmol) in dichloromethane (20 mL) was added ethyl chloro(oxo)acetate (220 mg, 1.61 mmol), and the solution was stirred at 0° C. for 2 hours. After addition of water (20 mL), the mixture was extracted with dichloromethane (3×20 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by preparative thin layer chromatography on silica gel (Eluent: 10:1 dichloromethane/methanol) to afford the product as a yellow solid. Yield: 40 mg, 0.13 mmol, 10%. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 8.55 (d, J=5 Hz, 1H), 4.46 (q, J=7 Hz, 2H), 1.43 (t, J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH2:15])=[CH:4][CH:3]=1.[C:23]([NH:25][C:26](=[N:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH:40]=1)OC1C=CC=CC=1)#[N:24]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][NH:15][C:26]([NH:25][C:23]#[N:24])=[N:34][CH2:35][CH2:36][CH2:37][O:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)[CH:40]=2)[CH3:16])=[CH:4][CH:3]=1
Reactant: CN(CCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Solvent: CCOC(C)=O
Product: CN(CCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.5 g (1.57 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,3-propanediamine and 0.6 g (1.5 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography (eluant: ethyl acetate) analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=616 ([M+H]+, 1), 230 (100).