Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([OH:39])([CH3:38])[CH3:37])[CH:35]=1)[C:30](O)=[O:31])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([OH:39])([CH3:38])[CH3:37])[CH:35]=1)[C:30]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:31])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)O)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Product: Cc1ccc(NC(=O)c2cc(C(C)(C)C)cc(C(C)(C)O)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
40 mg (0.14 mmol) of the compound of Example 6A and 33 mg (0.14 mmol) of the compound of Example 28A were reacted and worked up analogously to the procedure of Example 33. This gave 31 mg (44% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:10][C:11]([F:19])([F:18])[CH2:12][O:13][CH2:14][C:15](N)=[NH:16].C(OCC)(=O)C>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:15]([CH2:14][O:13][CH2:12][C:11]([F:19])([F:18])[F:10])[N:16]=1
Reactant: N#Cc1nccnc1N
Reactant: N=C(N)COCC(F)(F)F
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nc(COCC(F)(F)F)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 7.2 g (0.060 mole) of 3-amino-2-pyrazinecarbonitrile and 14.2 g (0.091 mole) of 2-(2,2,2-trifluoroethoxy)acetamidine in 230 ml of absolute ethanol. Refluxing time: 7 hours. Yld: 6.5 g (42%), m p. 145°-147° C. (ethyl acetate).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[S:31](Cl)(=[O:33])=[O:32]>>[CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]2[N:8]([S:31]([C:23]3[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=3[O:21][CH3:20])(=[O:32])=[O:33])[C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2[nH]c(=O)n(-c3ccccn3)c2c1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Product: CCOc1ccc2c(c1)n(-c1ccccn1)c(=O)n2S(=O)(=O)c1ccc([N+](=O)[O-])cc1OC
Yield: 65.1 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 37 step A) starting from 1 g of 5- ethoxy-1,3-dihydro-3-(pyrid-2-yl)-2H-benzimidazol-2-one and 1.2 g of 2-methoxy-4-nitrobenzenesulfonyl chloride. 1.2 g of the expected product are obtained after crystallization from iso ether. M.p.=175° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:12]=O)[S:10][CH:11]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[C:7]1[CH:8]=[C:9](/[CH:12]=[CH:22]/[CH:23]=[O:24])[S:10][CH:11]=1
Reactant: O=Cc1cc(-c2ncccn2)cs1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1cc(-c2ncccn2)cs1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 4-(2-pyrimidinyl)-2-thiophenecarboxaldehyde (prepared as described in Reference Example 90) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 217 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17](=[O:25])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:19]1([NH:18][C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)=[O:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Nc1ccccc1)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccccc1)C1CCCNC1
Yield: 0.1 %

Procedure:
A solution of 3-(S)-Phenylcarbamoyl-piperidine-1-carboxylic acid benzyl ester (1.80 mol, 608 mg) and Pd-C 30% (100 mg) in CH3OH (10 mL) at 25° C. were added to a Paar hydrogenator low pressure reaction vessel. The mixture was reacted at 55 psi with vigorous shaking until hydrogen uptake subsided (2 h). The catalyst was filtered through a pad of celite. The filtrate was concentrated in vacuo which provided piperidine-3-carboxylic acid phenylamide (367 mg, 367 mg theoretical, 99%) as a white foam: LRMS m/z 205 (M++1, C12H16N2O requires 205).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:22]1[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:24]([CH3:35])[CH:23]=1)[CH2:4][CH2:5][C:6]1[S:7][C:8]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:9]=2[C:10]=1[CH:11]([CH3:13])[CH3:12].[H-].[Na+].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[Cl-].[NH4+]>C1COCC1>[CH2:38]([O:1][N:2]=[C:3]([C:22]1[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:24]([CH3:35])[CH:23]=1)[CH2:4][CH2:5][C:6]1[S:7][C:8]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:9]=2[C:10]=1[CH:11]([CH3:13])[CH3:12])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCOC(=O)COc1ccc(C(CCc2sc3cc(C(F)(F)F)ccc3c2C(C)C)=NO)cc1C
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(C(CCc2sc3cc(C(F)(F)F)ccc3c2C(C)C)=NOCc2ccccc2)cc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23.2 %

Procedure:
To an ice-cold solution of ethyl 4-[1-hydroxyimino-3-[3-isopropyl-6-(trifluoromethyl)benzothiophen-2-yl]propyl]-2-methylphenoxyacetate [Example 16 (1)] (90 mg, 0.18 mmol) in THF (1.8 mL) was added 55% sodium hydride (12 mg, 0.27 mmol). The mixture was stirred for 10 minutes, to which was added benzyl bromide (0.03 mL, 0.3 mmol). The mixture was stirred for 72 hours at room temperature, treated with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/1), to give the titled compound as a colorless oil (25 mg, yield 24%).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][NH:34][CH:35]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[NH:33]1[CH:32]=[C:31]([C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:3]=2)[CH:35]=[N:34]1
Reactant: Clc1nc(-c2ccc(N3CCOCC3)cc2)cc2nccn12
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: COCCOC
Product: c1cn2c(-c3cn[nH]c3)nc(-c3ccc(N4CCOCC4)cc3)cc2n1
Temperature: 100 °C
Yield: 36.2 %

Procedure:
4-(4-(5-Chloroimidazo[1,2-c]pyrimidin-7-yl)phenyl)morpholine (0.0400 g, 0.127 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.0370 g, 0.191 mmol) and potassium carbonate (0.0527 g, 0.381 mmol) were suspended in a mixture of DME (2 mL) and water (1 mL) and de-gassed with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.00734 g, 0.00635 mmol) was added and the reaction sealed and heated at 100° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The organics were washed with brine, dried, MgSO4 and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 0.5%-6% (9:1 MeOH:NH4OH)/DCM) to furnish 4-(4-(5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)phenyl)morpholine (0.0160 g, 0.046 mmol, 36.4% yield). MS (apci) m/z=347.1 (M+H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28](O)=[O:29])=[CH:20][C:19]=3[CH:31]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][S:48][C:49]2[N:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=2)[CH:42]=1>C1COCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:55][C:52]4[CH:53]=[N:54][C:49]([S:48][CH2:47][C:43]5[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=5)=[CH:50][CH:51]=4)=[O:29])=[CH:20][C:19]=3[CH:31]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCC)cc1
Reactant: Nc1ccc(SCc2cccnc2)nc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)nc2)CCN3CCC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
In THF (50 ml) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (2.5 g), and DMF (5 droplets) was added to the mixture, thionyl chloride (0.86 ml) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. The solution was added dropwise to a solution of 6-[(3-pyridinylmethyl)sulfanyl]-3-pyridinylamine (1.41 g) and triethylamine (12.3 ml) in THF (42.3 ml) under ice-cooling, and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[6-[(3-pyridinylmethyl)sulfanyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 273) (0.92 g).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:21]=[CH:20][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[Cl:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[S:46](Cl)(=[O:48])=[O:47].[N-]=C=O>C(Cl)Cl>[Cl:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[S:46]([N:5]([CH2:4][C:3]1[CH:20]=[CH:21][C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:23][C:2]=1[Cl:1])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:8][CH:7]=1)(=[O:48])=[O:47]
Reactant: Clc1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Cl)cc1Cl)N(Cc1ccc(OC2CCCCO2)cc1Cl)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 100 %

Procedure:
To a solution of [2-chloro-4-(tetrahydro-pyran-2-yloxy)-benzyl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.060 g, 0.15 mmol) in 0.4 mL methylene chloride was added triethylamine (0.06 mL, 0.45 mmol) and 2,4-dichlorobenzenesulfonyl chloride (0.074 g, 0.3 mmol). The reaction mixture was stirred at room temperature for 6 days. PS-isocyanate resin (0.050 g) and PStrisamine resin (0.050 g) were added and the reaction mixture was stirred for 2 hr. at room temperature. The resin was filtered off with the aid of methylene chloride. The filtrate was concentrated to afford the title compound of Step A (0.096 g). MS 639.3 (M+1)+
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[N:3]1.S(Cl)(Cl)=O.[CH2:27](Cl)Cl>>[CH3:1][C:2]1([CH3:22])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:27])=[O:20])=[CH:15][CH:14]=2)=[N:3]1
Reactant: CC1(C)COC(c2ccccc2-c2ccc(C(=O)O)cc2)=N1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(-c2ccccc2C2=NC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
10.0 g (33.8 mmol) of 4,4-dimethyl-2-(4'-carboxybiphenyl-2-yl)oxazoline was dissolved in methylene chloride (200 ml). 4.8 g (40.3 mmol) of thionyl chloride was added thereto, followed by stirring at room temperature for 2 hours. The reaction liquid was subjected to vacuum concentration. Methanol (100 ml) was added to the residue, followed by stirring for 3 hours. After distilling out the solvent under a reduced pressure, methylene chloride and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue and obtained mixture was caused liquid-liquid separation. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (an ethyl acetate/n-hexane system) to give 9.53 g of the title compound as an oil (yield 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:32][CH2:31][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4(O)[CH2:29][O:28][CH2:27]4)=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].CCN(S(F)(F)[F:39])CC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:32][CH2:31][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([F:39])[CH2:29][O:28][CH2:27]4)=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1N(c2ccc(C3(O)COC3)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Solvent: ClCCl
Product: O=C1N(c2ccc(C3(F)COC3)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Temperature: -78 °C
Reaction time: 3 h
Yield: 41.8 %

Procedure:
To a solution of 8-(2-chloro-benzenesulfonyl)-2-[4-(3-hydroxy-oxetan-3-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (described in example 229, 35 mg, 0.07 mmol) in DCM was added DAST (11 uL, 0.08 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 3 hr and then quenched with sat. NaHCO3. The reaction mixture was diluted with DCM and washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (1:1 AcOEt/heptane) to give 8-(2-chloro-benzenesulfonyl)-2-[4-(3-fluoro-oxetan-3-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (14 mg, 40%) as a white solid. MS (ESI): 479.1 (MH+).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:31])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=3)[CH:20]=2)[C:16]=1Cl)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:32][C:33]1([CH3:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.Cl.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN1C(=O)CCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:31])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=3)[CH:20]=2)[C:16]=1[N:36]1[CH2:37][CH2:38][C:33]([CH3:39])([CH3:32])[CH2:34][CH2:35]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Reactant: CC1(C)CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(-c3ccc4c(c3)CCCC4)nn2c(N2CCC(C)(C)CC2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Yield: 29.6 %

Procedure:
To a solution of (S)-methyl 2-(tert-butoxy)-2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (40 mg, 0.091 mmol) and 4,4-dimethylpiperidine.HCl (13.55 mg, 0.091 mmol) in NMP (1 mL) was added DIEA (0.047 mL, 0.272 mmol) and the mixture was heated at 50° C. for 2 h. Then, 1N NaOH (0.272 mL, 0.272 mmol) was added to the reaction mixture and the contents were heated at 50° C. for 2 h. The reaction mixture was then filtered and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (13.5 mg, 0.027 mmol, 29.6% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.77-7.71 (m, 2H), 7.19 (s, 1H), 6.95 (s, 1H), 5.80 (s, 1H), 2.91 (s, 2H), 2.84-2.76 (m, 4H), 1.83-1.75 (m, 4H), 1.65-1.58 (m, 2H), 1.56-1.45 (m, 2H), 1.20 (s, 9H), 1.11 (s., 6H). LCMS (M+H)=506.5.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([CH2:21][S:22]C(=O)C)[CH2:6][C:7]1[CH:8]=[N:9][C:10]([NH:13]C(OC(C)(C)C)=O)=[CH:11][CH:12]=1)C>Cl>[NH2:13][C:10]1[N:9]=[CH:8][C:7]([CH2:6][CH:5]([CH2:21][SH:22])[C:4]([OH:26])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(CSC(C)=O)Cc1ccc(NC(=O)OC(C)(C)C)nc1
Agent: Cl
Product: Nc1ccc(CC(CS)C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.1 %

Procedure:
2-Acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-propionic acid ethyl ester (38 mg, 0.096 mmol) was dissolved in conc. HCl (2.0 mL) under argon. The solution was stirred at room temperature for 1 h and then heated to reflux for 1 h. Concentration under reduced pressure gave the title compound (25.7 mg, 100%) as the hydrochloride salt.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10](S(C)(=O)=O)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][OH:26].[Cl-].[NH4+]>CN(C)C=O>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][O:26][C:10]1[CH:11]=[C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])[N:7]=[CH:8][N:9]=1
Reactant: OCc1c(F)cccc1F
Reactant: CC#CCOc1cc(S(C)(=O)=O)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(OCc2c(F)cccc2F)ncn1
Temperature: 50 °C
Reaction time: 7 h
Yield: 72.8 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.15 g of 4-(2-butynyloxy)-6-methanesulfonylpyrimidine, 0.14 g of potassium carbonate, and 0.16 g of 2,6-difluorobenzylalcohol, followed by stirring at 50° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.14 g of 4-(2,6-difluorobenzyloxy)-6-(2-butynyloxy)pyrimidine (the present compound (68)).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([N:19]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:20][CH:21]([O:24][C:25](=[O:27])[CH3:26])[CH2:22][CH3:23])=[O:18])[CH:8]=2)[N:3]=1.[H-].[Na+].[CH3:36]I.O>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:36])[C:17]([N:19]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[CH2:20][CH:21]([O:24][C:25](=[O:27])[CH3:26])[CH2:22][CH3:23])=[O:18])[CH:8]=2)[N:3]=1
Reactant: CI
Reactant: CCC(CN(C(=O)NCCCOc1ccc2nc(Cl)ccc2c1)C1CCCCC1)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CN(C(=O)N(C)CCCOc1ccc2nc(Cl)ccc2c1)C1CCCCC1)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-6-{3-[3-cyclohexyl-3-(2-acetyloxybutyl)ureido]propoxy}quinoline (5.6 g) in dimethylformamide (80 ml) is added sodium hydride (60% oily, 0.8 g), and the mixture is stirred at room temperature for one hour. To the reaction solution is added methyl iodide (1.1 ml), and the mixture is stirred for one hour. To the mixture is further added methyl iodide (2 ml), and the mixture is stirred at room temperature overnight. The reaction solution is poured into water, and extracted with ethyl acetate. The ethyl acetate layer is separated, washed with water, and dried over anhydrous magnesium sulfate. The resultant is concentrated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol=20:1) to give 2-chloro-6-{3-[1-methyl-3-cyclohexyl-3-(2-acetyloxybutyl)ureido]propoxy}quinoline (5.5 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:14]([NH2:24])[C:15]1[CH:23]=[CH:22][C:21]2[O:20][CH2:19][O:18][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[CH2:19]1[O:20][C:21]2[CH:22]=[CH:23][C:15]([CH2:14][NH:24][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:16][C:17]=2[O:18]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CSc1ccc2ncnc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CSc1ccc2ncnc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 83.4 %

Procedure:
4.12 g (0.0196 mol) of 4-chloro-6-methylthioquinazoline, 3.70 g (0.0245 mol) of piperonylamine and 3.50 g (0.0330 mol) of sodium carbonate were mixed with 100 ml of isopropyl alcohol. The obtained mixture was heated under reflux for 24 hours and distilled under a reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from chloroform/n-hexane to give 5.32 g of the title compound as a pale-yellow crystal.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[N:8]=1)=O.[C:22]1([NH:28]N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:9]1[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]2[N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:2]=[CH:3][CH:4]=2)=[N:8]1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccccc2F)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: O=c1ccn(-c2ccccc2F)nc1-c1ccnn1-c1ccccc1
Yield: 31 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(2-fluorophenyl)pyridazin-4(1H)-one (crude 776 mg, 2.70 mmol) in 20 mL of methanol was added phenylhydrazine (438 mg, 4.10 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(2-fluorophenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (278 mg, 31% for two steps) as a yellow solid.
Reaction SMILES: C([O:8][CH:9]([CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)[CH2:10][CH2:11][CH:12]1[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC2C=CC=CC=2)=[O:24])[C:15](=[O:33])[CH2:14][S:13]1(=[O:35])=[O:34])C1C=CC=CC=1.C(Cl)(Cl)Cl>C(O)C.C(OCC)(=O)C>[F:44][C:41]1[CH:40]=[CH:39][C:38]([O:37][CH2:36][CH:9]([OH:8])[CH2:10][CH2:11][CH:12]2[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:15](=[O:33])[CH2:14][S:13]2(=[O:34])=[O:35])=[CH:43][CH:42]=1
Reactant: O=C(CCCCCCN1C(=O)CS(=O)(=O)C1CCC(COc1ccc(F)cc1)OCc1ccccc1)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C(O)CCCCCCN1C(=O)CS(=O)(=O)C1CCC(O)COc1ccc(F)cc1

Procedure:
A solution of benzyl 7-{2-[3-benzyloxy-4-(4-fluorophenoxy)butyl]-1,1,4-trioxo-3-thiazolidinyl}heptanoate (1.1 g., 1.76 millimole) in absolute ethanol-ethyl acetate (100:2; v:v; 102 ml.) is magnetically stirred and hydrogenated at 25° C. and atmospheric pressure in the presence of 10% palladium/charcoal until hydrogen consumption ceases (~139 ml. of hydrogen is consumed). After removing the catalyst by filtration, the filtrate is concentrated in vacuo leaving an oily residue which is applied to a silica gel column (20 g.) with chloroform. Impurities are eluted with chloroform-acetic acid (25:1; v:v; 200 ml.); continued elution with the same eluant (375 ml.) affords the title compound as a tlc homogeneous, viscous oil (0.59 g., 75%); pmr (CDCl3) δ2.31 (2H, t), 2.73-3.37 (H, m), 3.60-4.30 (6H, m, containing singlets at 3.80 and 3.90), 4.61 (H, t), 6.67-7.60 (6H, m, containing a broad singlet at 7.30).