Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[CH2:6]([O:5][CH:4]([O:8][CH2:9][CH3:10])[CH2:3][CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([C:19]([C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=2)=[O:20])[CH2:22][CH2:23]1)[CH3:7]
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CCOC(CCCl)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CCOC(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)OCC
Yield: 53 %

Procedure:
A mixture of 4.5 parts of 1-chloro-3,3-diethoxypropane, 12.15 parts of (4-fluorophenyl)(4-piperidinyl)methanone hydrochloride, 10.6 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of methylbenzene and 2,2'-oxybispropane, yielding 9 parts (53%) of [1-(3,3-diethoxypropyl)-4-piperidinyl](4-fluorophenyl)methanone.
Reaction SMILES: [OH:1][CH:2]1[CH:6]=[CH:5][C:4](=O)[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]([O:16]CC)=[O:15].S(=O)(=O)(O)[OH:20].[Cl-].[Na+]>>[C:14]([CH2:13][S:12][CH2:11][CH2:10][CH2:9][CH2:8][C:3]1[C:2](=[O:1])[CH2:6][CH:5]([OH:20])[CH:4]=1)([OH:16])=[O:15]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)CSCCCCC1C(=O)C=CC1O
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)CSCCCCC1=CC(O)CC1=O

Procedure:
The solution, containing crude 3-hydroxy-2-[4-(carbethoxymethylthio)butyl]cyclopent-4-en-1-one, is cooled and treated during 10 minutes with 75 ml of sulfuric acid (d=1.84) with stirring. The stirred solution is refluxed for 16 hours, cooled, saturated with sodium chloride, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated. The residue is subjected to chromatography on silica gel with chloroform progressively enriched in ether, ether, and ether progressively enriched in acetone to afford the subject compound as an oil, pmr spectrum (CDCl3): δ3.24 (singlet, --S--CH2 --CO2C2H5), 5.0 (broad singlet --CHOH--).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([C:11](=O)/[CH:12]=[CH:13]/[N:14](C)C)[CH:8]=[CH:7][C:6]=1[S:18]([CH3:21])(=[O:20])=[O:19])(=O)C.[NH:22]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][N:31]=1)[C:27]#[N:28])N>CCO.CC(O)=O>[CH3:1][O:4][C:5]1[CH:10]=[C:9]([C:11]2[N:22]([C:24]3[CH:25]=[C:26]([C:27]#[N:28])[CH:29]=[CH:30][N:31]=3)[N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: N#Cc1ccnc(NN)c1
Reactant: CC(=O)Oc1cc(C(=O)/C=C/N(C)C)ccc1S(C)(=O)=O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(-c2ccnn2-c2cc(C#N)ccn2)ccc1S(C)(=O)=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
A mixture of 5-[(2E)-3-(dimethylamino)prop-2-enoyl]-2-(methylsulfonyl)phenyl acetate (1.5 g, 5.3 mmol) and 2-hydrazinylisonicotinonitrile (0.8 g, 6 mmol, PREPARATION 2) in EtOH (15 mL) and AcOH (3 mL) was stirred at 90° C. overnight. The reaction mixture was cooled, concentrated, and purified by prep-HPLC to afford the title compound (270 mg, 14%). 1H NMR (400 MHz, CDCl3): δ 3.26 (3H, s), 3.96 (3H, s), 6.58 (1H, d, J=1.6 Hz), 6.96 (1H, dd, J=8.4, 1.2 Hz), 7.05 (1H, d, J=1.2 Hz), 7.41 (1H, dd, J=4.8, 1.2 Hz), 7.81 (1H, d, J=2.0 Hz), 7.93 (1H, d, J=8.4 Hz), 8.18 (1H, s), 8.35 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H14N4O3S, 355. Found, 355.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[C:23](Br)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:33][O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[C:23]([C:39]4[CH:38]=[CH:37][CH:36]=[C:35]([O:34][CH3:33])[CH:40]=4)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnc(-c3cc(Br)cnc3N)o2)CC1
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: COc1cccc(-c2cnc(N)c(-c3nnc(C4CCN(C(=O)OC(C)(C)C)CC4)o3)c2)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[5-(2-amino-5-bromo-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.35 mmol) in dioxane (20 mL) and water (20 mL) were added K2CO3 (0.95 g, 7.05 mmol), 3-methoxyphenyl boronic acid (0.39 g, 2.59 mmol) in a sealed tube. The reaction mixture was degassed with argon for 20 min, then Pd(PPh3)4 (0.13 g, 0.11 mmol) was added to the reaction mixture. The reaction mixture was stirred for 18 h at 100° C. The reaction mixture was diluted with water (100 mL) extracted with ethyl acetate (2×150 mL) and organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude product. The crude compound was purified by column chromatography using 100-200 mesh silica gel and compound was eluted with 40% ethyl acetate in petroleum ether to afford 500 mg, which was further purified by washing with diethyl ether and hexane to afford the title compound as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][S:7][CH2:6][CH2:5]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:28][C:29]1[CH:48]=[CH:47][C:32]([NH:33][C:34]2[C:43]3[C:38](=[CH:39][C:40](O)=[C:41]([O:44][CH3:45])[CH:42]=3)[N:37]=[CH:36][N:35]=2)=[C:31]([F:49])[CH:30]=1.C(P(CCCC)CCCC)CCC>C(Cl)Cl.CCOCC>[Cl:28][C:29]1[CH:48]=[CH:47][C:32]([NH:33][C:34]2[C:43]3[C:38](=[CH:39][C:40]([O:1][CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][S:7][CH2:6][CH2:5]4)=[C:41]([O:44][CH3:45])[CH:42]=3)[N:37]=[CH:36][N:35]=2)=[C:31]([F:49])[CH:30]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: OCCN1CCSCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1CCSCC1
Reaction time: 3.5 h
Yield: 22.3 %

Procedure:
4-(2-Hydroxyethyl)thiomorpholine (114 mg, 0.78 mmol), (J. Am. Chem. Soc. 1934. 56, 1720), in methylene chloride (1 ml) followed by 1,1′-(azodicarbonyl)dipiperidine (525 mg. 2.08 mmol) were added to a stirred solution of 4-(4-chloro-2-fluoroanilino)7-hydroxy-6 methoxyquinazoline (225 mg, 0.70 mmol), (prepared as described for the starting material in Example 2), and tributylphosphine (0.51 ml, 2.08 mmol) in methylene chloride (10 ml) under nitrogen. The mixture was stirred for 3.5 hours and allowed to stand for a further 18 hours. Ether (8 ml) was added, the precipitate removed by filtration and the solvent removed from the filtrate by evaporation. The residue was dissolved in acetone and ethereal hydrogen chloride (2.5 m! of a 1M solution) added. The precipitated product was collected by filtration and purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (150/8/1). The purified product was triturated with ether to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-thiomorpholinoethoxy)quinazoline (70 mg, 22%) as a pale yellow solid.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:14]2[C:15]([F:33])=[N:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:21]=3)[CH:19]=2)[CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[C:6]([C:7]1[N:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:14]2[C:15]([F:33])=[N:16][CH:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:24][CH:25]=3)[CH:19]=2)[CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cc(-c2cc(-c3ccc(CN4CCCCC4)cc3)cnc2F)c(N)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1cc(-c2cc(-c3ccc(CN4CCCCC4)cc3)cnc2F)c(N)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6′-((trimethylsilyl)ethynyl)-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4′]bipyridinyl-3′-ylamine (90 mg, 0.2 mmol) and potassium carbonate (150 mg, 1.1 mmol) in methanol (2 mL) was stirred at ambient temperature for 1 h. The cooled reaction mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a brown residue that was taken to the next step without purification.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH:32]=[N:31][CH:30]=[N:29]1>>[N:29]1[N:28]([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:36][CH:35]=2)[CH:32]=[N:31][CH:30]=1
Reactant: Nc1ccc(Cn2cncn2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(Cn2cncn2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(1,2,4-triazol-1-yl-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C26H21N5O3
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[N:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH3:35])=[CH:28][N:27]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[N:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH3:35])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: CCCOc1cnc(Cl)nc1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: Cl
Solvent: CN1CCCC1=O
Product: CCCOc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-chloro-5-propoxy-pyrimidine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.49 min; Mass spectrum (ESI+): m/z=448 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.O>[CH2:16]([O:15][C@H:12]1[CH2:13][CH2:14][N:10]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.13 g, 53.41 mmol) was added portionwise to an ice-cooled solution of (S)-(−)-N-boc-3-pyrrolidinol (10 g, 53.41 mmol) in tetrahydrofuran (100 mL) and the mixture was stirred at 0° C. for 1 hour. Benzyl bromide (6.4 mL, 53.41 mmol) and tetrahydrofuran (50 mL) were added and the mixture was stirred for 6 hours allowing the temperature to rise to 25° C. The reaction mixture was then slowly diluted with water (50 mL), concentrated in vacuo and the aqueous residue was extracted with ethyl acetate (3×70 mL). The combined organic solution was washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo to give an orange oil. This oil was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 90:10:1. The appropriate fractions were evaporated under reduced pressure and the residue was further purified by column chromatography on silica gel, eluting with pentane:ethyl acetate, 66:33, to afford the title compound as a colourless oil in 74% yield, 10.93 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.[NH:22]1[CH:26]=[C:25]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:24]=[CH:23]1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:25]2[N:24]=[CH:23][N:22]([C:2]3[N:3]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[N:7]=3)[CH:26]=2)[CH:28]=1
Reactant: c1cncc(-c2c[nH]cn2)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4cccnc4)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.2) (0.16 g, 0.5 mmol) and commercially available 3-(1H-imidazol-4-yl)-pyridine [CAS-No. 51746-85-1] (0.073 g, 0.5 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.11 g, 49%). MS (ISP) 436.1 [(M)+]; mp 200.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H].[ClH:20]>[Pd]>[ClH:20].[ClH:20].[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1
Reactant: N=C(Nc1cccc([N+](=O)[O-])c1)N1CCCC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: N=C(Nc1cccc(N)c1)N1CCCC1

Procedure:
A sample of the product of step (a), 17 g, was dissolved in 200 ml of 1 M hydrochloric acid. The mixture was then hydrogenated with 1 g of 5% Pd/C. When hydrogen uptake had stopped the catalyst was filtered off. The solvent was evaporated in vacuum, and the residue dissolved in isopropanol, evaporated in vacuum again and the residue dissolved in 100 ml of methanol. To this mix was added 200 ml of toluene. This was then concentrated on a steam bath until the volume had decreased to approximately 175 ml. The crystals that precipitated were filtered to give N-(3-aminophenyl)-1-pyrrolidinecarboximidamide dihydrochloride, m.p. 250-251° C.
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([O:5][C:6](=[O:40])[CH2:7][CH2:8][C:9]1[N:10]([C:30]2[CH:35]=[CH:34][C:33]([C:36](=[O:38])[NH2:37])=[CH:32][C:31]=2[CH3:39])[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23]C3C=CC=CC=3)=O)=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH3:4].CS(C)=O>O>[CH2:3]([O:5][C:6](=[O:40])[CH2:7][CH2:8][C:9]1[N:10]([C:30]2[CH:35]=[CH:34][C:33]([C:36](=[O:38])[NH2:37])=[CH:32][C:31]=2[CH3:39])[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH2:2])=[O:23])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH3:4]
Reactant: [NH4+]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCc1ccc(-c2ccc(NC(N)=O)cc2)n1-c1ccc(C(N)=O)cc1C
Temperature: 85 °C
Yield: 35 %

Procedure:
Under a nitrogen atmosphere, ammonium hydroxide (2 mL) was slowly added to 3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-phenoxycarbonylaminophenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (13B) (66 mg, 0.13 mmol). Dimethylsulfoxide (1 mL) was slowly added. The reaction was then heated to 85° C. for 24 hrs. After cooling, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by preparative TLC plate (1500 microns, 10% IPA/CH2Cl2). The desired band (rf=0.2) was isolated and dried under high vacuum to yield 3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-ureidophenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (13C) (20 mg, 35%, light yellow powder).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13]([C:15]1[C:20]([O:21][CH2:22][CH3:23])=[C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:18]=[C:17]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[N:16]=1)=[O:14])[CH3:11]>C(Cl)(Cl)Cl>[CH2:10]([O:12][C:13]([C:15]1[C:20]([O:21][CH2:22][CH3:23])=[C:19]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:18]=[C:17]([C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[S:9])=[CH:34][CH:35]=2)[N:16]=1)=[O:14])[CH3:11]
Reactant: S=C=Nc1ccccc1
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)c1OCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccc(NC(=S)Nc3ccccc3)cc2)nc(N2CCOCC2)c1OCC
Yield: 60 %

Procedure:
Phenyl isothiocyanate (0.02 ml, 1.5 eq.) was added to a stirred solution of 2-(4-amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethyl ester (40 mg, 1 eq.) in CHCl3 (3 ml) and the mixture was reacted overnight at r.t. The reaction mixture was extracted with EA and washed with brine. The crude was purified by chromatography to give a product (32.6 mg, 60%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][NH2:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:13](OC)(=[O:18])[CH2:14][C:15]([CH3:17])=O>C1(C)C=CC=CC=1>[CH3:17][C:15]1[NH:12][N:11]([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=2)[C:13](=[O:18])[CH:14]=1
Reactant: COC(=O)CC(C)=O
Reactant: Cc1cc(NN)ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(=O)n(-c2ccc([N+](=O)[O-])c(C)c2)[nH]1
Temperature: 100 °C

Procedure:
The mixture of 500 mg of 3-methyl-4-nitrophenylhydrazine, 0.32 ml of methyl acetoacetate and 20 ml of toluene was heated to 100° C. for 8 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was stirred in t-butyl methyl ether. The solid was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH3:23])[CH2:5][C@@H:6]([CH3:22])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[CH3:24]I.O>CN(C)C=O>[CH3:24][O:3][C@@H:4]([CH3:23])[CH2:5][C@@H:6]([CH3:22])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: C[C@H](O)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@@H](C)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
0.13 g of 55% sodium hydride was mixed with 1 ml of dimethylformamide. A solution of 0.56 g of the (R,S)-4-[4'-(3"-hydroxy-1"-methylbutoxy)phenyl]benzonitrile prepared in the above Example 1 in 2 ml of dimethylformamide was added dropwise thereto under ice-cooling. The obtained mixture was then stirred at room temperature for one hour. Subsequently a solution of 0.36 g of methyl iodide in 2 ml of dimethylformamide was added thereto and the obtained mixture was stirred at room temperature for two hours. 10 ml of water was carefully added to the reaction mixture and the obtained mixture was extracted with diethyl ether. After thoroughly washing with water, drying and desolvating, the obtained residue was purified by silica gel column chromatography, similar to the case of Example 1, with the use of a mixture of n-hexane and ethyl acetate (4:1) as a developing solvent. Thus 0.36 g of the title compound, namely, (R,S)-4-[4'-(3"-methoxy-1"-methylbutoxy)phenyl] benzonitrile was obtained.
Reaction SMILES: [N:1]1[N:2]([C:6]23[CH2:13][N:10]([CH2:11][CH2:12]2)[CH2:9][CH2:8][CH2:7]3)[N:3]=[N:4][CH:5]=1.[Br:14]C1NN=NN=1>>[Br:14][C:5]1[N:4]=[N:3][N:2]([C:6]23[CH2:13][N:10]([CH2:11][CH2:12]2)[CH2:9][CH2:8][CH2:7]3)[N:1]=1
Reactant: Brc1nnn[nH]1
Reactant: c1nnn(C23CCCN(CC2)C3)n1
Product: Brc1nnn(C23CCCN(CC2)C3)n1
Yield: 56 %

Procedure:
5-(Tetrazol-2-yl)-1-azabicyclo[3.2.1]octane (the free base of E29) (0.2 g, 1.12 mmol) was converted to the 5-bromotetrazole according to the method of Example 40. Chromatography on silica using 4% methanol/chloroform afforded the title compound (E50) as a white crystalline solid (0.16 g, 56%) m.p. 108-110° C.
Reaction SMILES: [CH3:1][C:2]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6][N:5]([C:8](OC(C)(C)C)=O)[CH2:4][CH2:3]1.Cl.ClC1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>Cl.O1CCOCC1>[CH3:1][C:2]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3][CH2:4][N:5]([C:8]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:6][CH2:7]1
Reactant: Clc1ccncc1
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C1(C)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-tert-Butyl 4-ethyl 4-methylpiperidine-1,4-dicarboxylate (500 mg, 1.84 mmol) obtained in Step 1 was dissolved in 4N hydrochloric acid/1,4-dioxane (4 ml), and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethanol (18.4 ml). 4-Chloropyridine hydrochloride (276 mg, 1.84 mmol) and triethylamine (2.57 ml, 18.4 mmol) were added thereto, and the reaction mixture was stirred at 170° C. overnight in a sealed tube. The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate 95:5-10:90) to give the title compound.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][CH:6]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7]1>CS(C)=O.O>[C:1]([CH2:5][CH:6]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7]1)#[N:2]
Reactant: [C-]#N
Reactant: BrCC1COc2ccccc2O1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1COc2ccccc2O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Potassium cyanide (2.05 g, 31.5 mmol) was added to 2-bromomethyl-(2,3 dihydrobenzo[1,4]dioxine) (6.87 g, 30 mmol) in DMSO (90 mL) and stirred at ambient temperature for 20 h. The reaction mixture was then diluted with water (250 mL) and extracted twice with diethyl ether. The diethyl ether was washed with water, then washed twice with brine, dried (Na2SO4) and evaporated in vacuo to yield 2-cyanomethyl-(2,3 dihydrobenzo[1,4]dioxine) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:9]=2)[CH:5]=1)([O-])=O.[Cl-].[NH4+].[CH2:22](O)C.O>[Fe]>[N:15]1([CH2:14][CH2:13][N:8]2[CH:7]=[C:6]3[C:10]([CH:11]=[CH:12][C:4]([NH2:1])=[CH:5]3)=[N:9]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:22]1
Reactant: CCO
Reactant: O=[N+]([O-])c1ccc2nn(CCN3CCCC3)cc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Nc1ccc2nn(CCN3CCCCC3)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-Nitro-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole (0.325 g, 1.18 mmol), iron powder (0.659 g, 11.8 mmol) and ammonium chloride (0.0317 g, 0.592 mmol) was suspended in a 4:1 ethanol/H2O solution and heated to reflux for 3 hours. The mixture was cooled to room temperature, the solvent were removed in vacuo and the residue stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes. The mixture was filtered through a plug of silica gel, rinsed with triethylamine/ethyl acetate (1/4) and the filtrate was concentrated to afford the title product. 1H NMR (300 MHz, DMSO-d6) ppm 1.31–1.52 (m, 6H) 2.40 (m, 4H), 2.78 (m, 2H), 4.38 (t, 2H, J=6.78), 4.79 (s, 2H), 6.55 (m, 1H), 6.72 (m, 1H), 7.29 (s, 1H), 7.89 (s, 1H); MS (DCI/NH3) m/z 245 [M+H]+.