Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>O>[CH2:3]1[O:4][C:5]2([CH2:10][CH2:9][N:8]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[CH2:7][CH2:6]2)[O:1][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
1,4-Dioxa-8-azaspiro[4,5]decane (7.88 g) was dissolved in N-methyl-2-pyrrolidine (50 mL), and diisopropylethylamine (9.5.8 mL) and 4-fluoronitrobenzene (7.06 g) were successively added. The mixture was stirred at room temperature for 2 hr. The reaction mixture was added to iced water, and the precipitated solid was collected by filtration to give N-(4-nitrophenyl)-4-piperidone ethylene ketal (10.6 g) as a yellow powder.
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:10])[O:7][CH2:8][CH3:9])C.[C:11]([C:14]1[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[C:16]([F:22])[CH:15]=1)(=[O:13])[CH3:12].C(O)(=O)C>CCOCC>[Cl:20][C:19]1[CH:18]=[C:17]([Cl:21])[C:16]([F:22])=[CH:15][C:14]=1[C:11]([CH2:12][C:6]([O:7][CH2:8][CH3:9])=[O:10])=[O:13]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cc(F)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)c1cc(F)c(Cl)cc1Cl
Yield: 45 %

Procedure:
To a suspension of prewashed sodium hydride (76.8 g) in ether was added 189 g of diethylcarbonate. The mixture was heated to reflux and a solution of 131.84 g of 6-acetyl-1,3-dichloro-4-fluorobenzene in 1500 ml of ether was added dropwise over 5 hours. The mixture was then refluxed 24 hours, cooled, poured onto a mixture of ice and acetic acid and extracted several times with ether. The ether extracts were combined, washed with water, dried and evaporated. The residue was purified by vacuum distillation giving 80 g of ethyl 2,4-dichloro-5-fluorobenzoylacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([NH2:12])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[N:13]([O-])=O.[Na+].Cl[Sn]Cl.O>Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([NH:12][NH2:13])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=N[O-]
Reactant: COc1ccc(N)c(C(=O)O)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NN)c(C(=O)O)c1
Reaction time: 1 h
Yield: 284 %

Procedure:
Part A: 5-(Furan-2-yl)-3-trifluoromethyl-1-(2-carboxyl-4-methoxyphenyl)-1H-pyrazole: 3-Methoxy-6-aminobenzoic acid (23 g, 138 mmol) in conc. HCl (300 mL) was cooled to 0° C. and NaNO2 (11.4 g, 165 mmol) in H2O (50 mL) was added dropwise while the temperature of the reaction was maintained below 10° C. The reaction was stirred at or below 10° C. for 1 h, then SnCl2.H2O (92.3 g, 413 mmol) in conc. HCl (125 mL) was added dropwise. The reaction was allowed to thaw to ambient temperature and stirred for 3 h. The precipitate was filtered and air-dried then heated in a vacuum oven for 18 h. There was obtained 71.4 g of 3-methoxy-6-hydrazinobenzoic acid entrained with tin (II) salts.
Reaction SMILES: [C:1]1([C:11]2([C:14](Cl)=[O:15])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][CH2:31][NH2:32])=[CH:28][C:27]=1[O:35][CH3:36])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][CH2:31][NH:32][C:14]([C:11]2([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:13][CH2:12]2)=[O:15])=[CH:28][C:27]=1[O:35][CH3:36])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Reactant: O=C(Cl)C1(c2cccc3ccccc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(CCNC(=O)C2(c3cccc4ccccc34)CC2)ccc1OCc1ccccc1
Reaction time: 64 h
Yield: 101.5 %

Procedure:
A solution of 1-(1-naphthyl)cyclopropane carbonyl chloride (7.1 g, prepared as described in Example CL32) in ethyl acetate (50 ml) was added to a stirred mixture of 4-benzyloxy-3-methoxyphenethylamine hydrochloride (9.29 g) in ethyl acetate (150 ml). Triethylamine (25 ml) was added and the mixture stirred for a further 64 hours. The organic layer was washed with dilute hydrochloric acid, dried over sodium sulphate and the solvent removed in vacuo to yield N-[2-(4-benzyloxy-3-methoxyphenyl)-ethyl]-1-(1-naphthyl)cyclopropane carboxamide (14.1 g).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]1[CH:16]=[CH:15][C:14]([N:17]([OH:32])[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1.[CH3:33][NH:34][CH2:35][CH2:36][OH:37]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18]([N:17]([OH:32])[C:14]2[CH:15]=[CH:16][C:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[N:34]([CH2:35][CH2:36][OH:37])[CH3:33])=[CH:12][CH:13]=2)=[O:19])=[CH:22][C:23]=1[C:28]([F:29])([F:31])[F:30]
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N(O)c1ccc(-n2cnc3c(Cl)ncnc32)cc1
Reactant: CNCCO
Product: CN(CCO)c1ncnc2c1ncn2-c1ccc(N(O)C(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-chloropurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)-1-hydroxyurea and 2-methylamino-ethanol by using the same techniques as in Example 53.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.Br[C:10]1[C:24]2=[C:25]3[C:13]([N:14]([Si](C(C)(C)C)(C)C)[CH2:15][CH:16]3[CH2:17][C@@H:18]3[C@@H:23]2[CH2:22][C@H:21]([NH:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:20][N:19]3[CH3:34])=[CH:12][CH:11]=1>>[CH2:29]([N:28]([CH2:31][CH3:32])[C:27]([NH:26][C@H:21]1[CH2:22][C@H:23]2[C@@H:18]([CH2:17][C:16]3[C:25]4[C:13](=[CH:12][C:11]([I:1])=[CH:10][C:24]2=4)[NH:14][CH:15]=3)[N:19]([CH3:34])[CH2:20]1)=[O:33])[CH3:30]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(Br)ccc4c3C(C[C@H]2N(C)C1)CN4[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1I
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(I)cc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
With N-iodosuccinimide and 3-(12-bromo-1-tert-butyldimethylsilyl-2,3-dihydro-6-methyl-8α-ergolinyl)-1,1diethylurea:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.O>CS(C)=O>[N:10]1([C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: N#Cc1cnccc1Cl
Reactant: c1nc[nH]n1
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cnccc1-n1cncn1
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 82.3 %

Procedure:
A mixture of known 4-chloro-nicotinonitrile (3.325 g, 24 mmol) (Tetrahedron Lett. 46:135-137, 2005), 1H-[1,2,4]triazole (1.99 g, 28.8 mmol), and CsCO3 (9.30 g, 28.5 mmol) in DMSO (5.0 mL) was stirred at 55° C. for 1.5 h. The resulting thin light brown slurry was shaken with water (50 mL) and extracted with DCM (1×50 mL, 2×25 mL). The organic layers were combined, dried (Na2SO4), and concentrated under vacuum at 90° C. to afford the title compound as a beige solid (3.38 g, 82%).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:18][CH2:19][C:20]1([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CN(C)C=O>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:16])[C:2]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:18][CH2:19][C:20]2([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12][CH2:11]1
Reactant: Cc1cc(C)c(NC2CCNCC2)c(C)c1
Reactant: COC(=O)CC1(CCBr)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)CC1(CCN2CCC(Nc3c(C)cc(C)cc3C)CC2)CCCCC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 52.7 %

Procedure:
A suspension of 4-(mesitylamino)piperidine (250 mg, 1.15 mmol), methyl [1-(2-bromoethyl)cyclohexyl]acetate (371 mg, 1.38 mmol) and potassium carbonate (318 mg, 2.3 mmol) in N,N-dimethylformamide (3 mL) was stirred at 80° C. for 10 hours. Chloroform (10 mL) was added to the reaction mixture, the insoluble portion was filtered out, and the filtrate was concentrated under reduced pressure. The residue was dissolved in xylene (10 mL) and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (10 g Merck Art 9385, hexane:ethyl acetate=7:3-chloroform:methanol=10:1) to obtain the title compound as a brown oil (243 mg) (53% yield).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH2:36][C:37]2[CH:46]=[CH:45][C:40]([C:41]([NH:43]O)=[NH:42])=[CH:39][CH:38]=2)[CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:29]2=[O:35])(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([C:41]3[N:42]=[C:1]([CH3:2])[O:4][N:43]=3)=[CH:45][CH:46]=2)[CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:29]2=[O:35])(=[O:25])=[O:26])=[CH:20][CH:19]=1
Reactant: N=C(NO)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(CN(C3CCCCNC3=O)S(=O)(=O)c3ccc(Cl)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.5 %

Procedure:
To a solution of acetic acid (63 μl, 1.10 mmol) in 5 ml dimethylformamide were added 1,1′-carbonyl-diimidazole (0.18 g, 1.10 mmol). The mixture was stirred at room temperature for 10 minutes, heated to 40° C. for a few minutes and cooled to room temperature. 4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-N-hydroxy-benzamidine (0.45 g, 1.00 mmol) was added and the mixture was stirred at 100° C. for 5 hours and then poured into water. Filtration and chromatography on silicagel with ethylacetate/heptane (1/1 to 4/1) yielded 0.43 g (91%) 4-chloro-N-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-N-(2-oxo-azepan-3-yl)-benzenesulfonamide as white solid, MS: m/e (%)=474.9 (MH+, 100).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3](=[O:26])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][C:21]3[N:22]=[CH:23][NH:24][CH:25]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.Cl[C:29]1[C:30]2[C:37]([CH3:38])=[CH:36][NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:27][N:2]([CH3:1])[C:3](=[O:26])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][C:21]3[N:22]=[CH:23][NH:24][CH:25]=3)[CH2:19][CH2:18][N:17]([C:29]3[C:30]4[C:37]([CH3:38])=[CH:36][NH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(Cc3c[nH]cn3)CCNCC2)c1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCC(Cc4c[nH]cn4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 100 °C
Yield: 42 %

Procedure:
3-(4-((1H-imidazol-4-yl)methyl)piperidine-4-carboxamido)phenyl dimethylcarbamate from step D (10 mg, 0.027 mmol), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (5 mg, 0.03 mmol), and N,N-diisopropylethylamine (23 μL, 0.135 mmol) were combined in isopropanol (0.5 mL). The resulting mixture was heated at 100° C. in a sealed pressure tube for 24 hours. The reaction mixture was cooled and concentrated under vacuum. The residue was purified by prep HPLC (10-95% MeOH:H2O with 0.1% HCOOH), then treated with AcOH in H2O and lyophilized to give the title compound (5.7 mg, 42%) as the acetate salt.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:19](=[C:20]([C:22]([NH2:24])=[O:23])[CH:21]=2)[NH:18][CH:17]=[C:16]3[CH:25]2[CH2:30][CH2:29][N:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH2:27][CH2:26]2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].Br[C:37]1[CH:42]=[CH:41]C(CCNC(=O)C)=[CH:39][CH:38]=1>>[CH:2]1([C:1]([NH:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]4[C:19](=[C:20]([C:22]([NH2:24])=[O:23])[CH:21]=3)[NH:18][CH:17]=[C:16]4[CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH2:34][CH3:35])(=[O:32])=[O:33])[CH2:27][CH2:26]3)=[CH:9][CH:8]=2)=[O:3])[CH2:41][CH2:42][CH2:37][CH2:38][CH2:39]1
Reactant: CC(=O)NCCc1ccc(Br)cc1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CCNC(C)=O)cc4)cc23)CC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CCNC(=O)C5CCCCC5)cc4)cc23)CC1
Yield: 52.5 %

Procedure:
The title compound was prepared according to the general procedure of 5-{4-[2-(acetylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, substituting N-[2-(4-bromophenyl)ethyl]cyclohexanecarboxamide (100 mg, 0.324 mmol) for N-[2-(4-bromophenyl)ethyl]acetamide. Purified by flash chromatography to afford 32 mg of the title compound (52.5%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.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>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[N:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cn2)CC1
Reactant: OB(O)c1cccc(F)c1
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: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cccc(F)c3)cn2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A 100 mL round-bottom flask was purged with and maintained an inert atmosphere of nitrogen then charged with tert-butyl 4-[(5-bromopyridin-2-yl)methyl]piperazine-1-carboxylate (1.00 g, 2.81 mmol, 1.00 equiv), (3-fluorophenyl)boronic acid (0.790 g, 5.65 mmol, 2.00 equiv), Tetrakis(triphenylphosphine)palladium (0.325 g, 0.280 mmol, 0.10 equiv), potassium carbonate (1.17 g, 8.47 mmol, 3.00 equiv), dioxane (24 mL), and water (4 mL). The resulting solution was stirred overnight at 80° C. and then diluted with water (10 mL) and extracted with ethyl acetate (3×5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1) to provide 0.955 g (92% yield) of tert-butyl 4-[[5-(3-fluorophenyl)pyridin-2-yl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 372 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[CH2:19][C:18]2[C:13](=[N:14][C:15](S(C)(=O)=O)=[N:16][CH:17]=2)[N:12]([CH3:24])[C:11]1=[O:25].[CH2:26]([N:28]([CH2:39][CH3:40])[CH2:29][CH2:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:27]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[CH2:19][C:18]2[C:13](=[N:14][C:15]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:28]([CH2:39][CH3:40])[CH2:26][CH3:27])=[CH:38][CH:37]=3)=[N:16][CH:17]=2)[N:12]([CH3:24])[C:11]1=[O:25]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CN1C(=O)N(c2c(Cl)cc(Cl)cc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2c(Cl)cc(Cl)cc2Cl)C3)cc1
Temperature: 180 °C
Yield: 17 %

Procedure:
A mixture of 200 mg (0.48 mmol) of 3-(2,4,6-trichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 300 mg (1.4 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 30 minutes. The mixture was cooled and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to afford 45 mg (17%) of 3-(2,4,6-trichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 142° C.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:16]O>C(O)(=O)C>[O:16]=[C:11]1[C:12]2[C:13](=[O:15])[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6][C:7]=2[CH:8]=[CH:9][CH2:10]1
Reactant: O=c1c2ccccc2sc2ccccc12
Reactant: OO
Solvent: CC(=O)O
Product: O=C1CC=Cc2sc3ccccc3c(=O)c21
Reaction time: 0.5 h

Procedure:
To a well stirred solution of 10.3 g of thioxanthen-9-one in 100 ml of glacial acetic acid at 80° C. 5 ml of hydrogen peroxide (35%) was added dropwise. The solution was stirred for 30 minutes, and then concentrated under reduced pressure and additional dichloromethane was added. The organic phase was washed with a solution of sodium hydroxide and then with water. After drying (Na2SO4) the solvent was removed under vacuum and 11 g of an oil were obtained. The oil was purified with a flash chromatography (SiO2) eluting with CH2Cl2 and CH2Cl2/Ethyl acetate 9:1; 8.44 g of a yellow solid were obtained in a yield of 72%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.[CH3:12][S:13][S:14][C:15]([CH3:19])([CH3:18])[CH:16]=O.[BH4-].[Na+]>C(O)C>[CH3:16][C:15]([S:14][S:13][CH3:12])([CH3:19])[CH2:18][NH:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: CSSC(C)(C)C=O
Reactant: Nc1cc(CO)cc(CO)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CSSC(C)(C)CNc1cc(CO)cc(CO)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
(5-amino-1,3-phenylene)dimethanol (2.5 g, 16.32 mmol) and 2-(methyldithio)isobutyraldehyde (2.347 ml, 16.32 mmol) were stirred at ambient temperature in absolute ethanol (82 ml) until completely dissolved (3 hours). The mixture was cooled to 0° C. in an ice bath and sodium borohydride (0.741 g, 19.59 mmol) was added. The reaction was stirred for 1 hour at 0° C., and was then quenched slowly with cold 5% HCl solution. The mixture was diluted with dichloromethane and the pH was adjusted to pH=8 with saturated sodium bicarbonate solution then extracted with dichloromethane and then washed with brine. The organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (MeOH/DCM) yielded (5-(2-methyl-2-(methyldisulfanyl)propylamino)-1,3-phenylene)dimethanol (3 g, 65%) as a white solid. 1H NMR (400 Hz, CDCl3): δ6.62 (s, 1H), 6.54 (s, 2H), 4.53 (s, 4H), 3.13 (s, 2H), 2.30 (s, 3H), 1.32 (s, 6H). See FIG. 47.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O.C(=O)(O)[O-].[Na+].O>[N:23]([CH2:21][CH:9]1[CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][N:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:24]=[N-:25]
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of 1,4-dibenzyl-2-chloromethyl-piperazine (8.8 g, 0.028 mol) in dimethylformamide (90 mL) under nitrogen was added sodium azide (5.5 g) and the reaction stirred at 50° C. for 18 h. The reaction was cooled and diluted with 10% aqueous sodium bicarbonate (100 mL) and water (250 mL) and the mixture extracted with ethyl acetate (2×200 mL). The organic extracts were washed with 10% sodium bicarbonate, brine, dried over sodium sulfate and concentrated to an oil.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[OH-].[Na+].Cl.C(OC)(=O)C>O1CCOCC1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:11]3[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[N:15][CH:14]=[N:13][C:12]=3[O:16][C:17]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[CH:20][CH:21]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3C)c(-c3ccc(OC)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: COC(C)=O
Product: COc1ccc(-c2c(-c3ccccc3C)oc3ncnc(NCCCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 65 mg (0.14 mmol) 6-{[5-(4-methoxyphenyl)-6-(2-methylphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester in 2.5 ml dioxan and add 0.50 ml 1 N sodium hydroxide solution. Stir for 16 h at RT, then add 0.50 ml 1 N hydrochloric acid and then 6 ml methyl acetate. Separate the organic phase, dry over sodium sulphate, filter, and concentrate by evaporation. 53 mg (82% of theor.) of the target compound is obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Si]([C:15]#[N:16])(C)(C)C.CN(C)C(Cl)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:15]#[N:16])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc[n+]([O-])cc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 139 mg (1.01 mmol) of 4-isopropylpyridine N-oxide in 10 mL of CH2Cl2 at r.t. was added 160 μL (1.20 mmol) of TMSCN. After 5 min., 100 μL (1.09 mmol) of dimethylcarbamyl chloride was added, and the solution was stirred at r.t. for 16 h. The solution was diluted with chloroform and washed with 20 mL of 10% aqueous K2CO3. The layers were separated, and the aqueous layer was extracted 3 times with CHCl3. The combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (30% EtOAc/hexanes) provided 4-isopropylpicolinonitrile with some impurity as a liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[NH:12][C:13](=[O:15])[NH:14][C:7]=23)[CH:3]=1)=[O:25]
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)Nc2cccc(Oc3ccnc4[nH]c(=O)[nH]c34)c2)c1
Yield: 40 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-methoxy-benzoyl chloride to afford the title compound as a brown solid (21 mg, 40%). 1H-NMR (δ, ppm, DMSO-d6): 3.83 (s, 3H, OMe), 6.49 (d, 1H, HPy,5, J=5.8 Hz), 6.90 (d, 1H, Harom, J=7.48 Hz), 7.16 (d, 1H, Harom, J=6.52 Hz), 7.39-7.49 (m, 3H, Harom), 7.52 (d, 1H, Harom, J=7.61 Hz), 7.62-7.68 (m, 2H, Harom), 7.81 (d, 1H, HPy,6, J=5.44 Hz), 10.31 (s, 1H, NHamide), 11.19 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2).