Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:13]=1[NH2:14].C(OCC)(=O)C.CCCCCCC>O>[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:13]=1[NH:14][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: COc1ccc(OC)c(N)c1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: O
Product: COc1ccc(OC)c(NC(=O)C2CCCCC2)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 80.5 %

Procedure:
1 ml (7.62 mmol, 1.1 eq.) of cyclohexanoic acid chloride is added to a solution of 1.05 g (6.89 mmol) of 2,5-dimethoxyaniline in 10 ml of a mixture toluene/methanol (1/1). The reaction mixture is maintained under stirring at 70° C. for 1.5 hour, and, after returning to ambient temperature, is poured into 50 ml of water. The expected product is extracted twice with 50 ml of toluene, then washed twice with 50 ml of water. The organic phases are combined, dried over magnesium sulphate and the solvent evaporated off under reduced pressure. 1.46 g (yield=67%) of N-(2,5-dimethoxyphenyl)cyclohexanecarboxamide is obtained and used without other purification in the following stage.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[Cl:31][C:32]1[N:33]=[CH:34][C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][S:2](=[O:1])(=[O:30])[CH2:3][CH2:4]2)=[O:9])=[CH:36][CH:37]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: OB(O)c1ccc(Cl)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccc(Cl)nc2)CC1
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 2-chloropyridine-5-boronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a light brown solid (19%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:17][CH:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[C:7]([F:16])=[C:8]([CH:10]([O:14][CH3:15])[C:11]([OH:13])=O)[CH:9]=1)[CH3:2].[NH2:25][CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1>>[C:26]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:11](=[O:13])[CH:10]([C:8]2[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[C:6]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[C:7]=2[F:16])[O:14][CH3:15])=[CH:29][CH:28]=1)#[N:25]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCOc1cc(OC2CCN(C)CC2)c(F)c(C(OC)C(=O)O)c1
Product: CCOc1cc(OC2CCN(C)CC2)c(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2)c1

Procedure:
(RS)-[5-Ethoxy-2-fluoro-3-(1-methyl-piperidin-4-yloxy)-phenyl]-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-[5-ethoxy-2-fluoro-3-(1-methyl-piperidin-4-yloxy)-phenyl]-2-methoxy-acetamide. Colorless foam. MS 456.5 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:11][O:12][C:13](=[O:32])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22](Cl)[C:23]3[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1>>[CH3:11][O:12][C:13](=[O:32])[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:23]3[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:24]=3[N:25]=2)=[CH:18][CH:19]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCc1cc2c(Cl)nc(-c3ccc(C(=O)OC)cc3)nc2s1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccc(C(=O)OC)cc3)nc2s1

Procedure:
The reaction procedure as above wherein 3,4-dichlorobenzylamine is reacted with 4-(4-chloro-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dichlorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([OH:12])(=O)[CH2:8][CH2:9][CH3:10]>[Pd]>[CH2:7]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])[CH2:8][CH2:9][CH3:10].[CH3:2][CH2:3][O:12][CH2:7][CH3:8]
Reactant: CCCC(=O)O
Reactant: OCC(O)CO
Agent: [Pd]
Product: CCCCOCC(O)CO
Product: CCOCC
Temperature: 120 °C
Yield: 68 %

Procedure:
A stirred autoclave was charged, at room temperature, with 65.60 g (712 mmol) of glycerol, 1.58 g (17.9 mmol) of butyric acid, 0.16 g (10 wt %) of AMBERLYST® (a polymer based catalyst) 35 resin and 0.39 g (1.0 mol %) of Pd/C at 5%. The autoclave was then pressurized at 50 bar of dihydrogen gas H2, and then was heated at 120° C. for 16 h, under vigorous stirring. After 16 h of reaction, the reaction mixture was cooled down to room temperature. The catalyst was filtered through a MILLIPORE® filter (a membrane filter) (0.45 μm) and was rinsed with absolute ethanol. The solvents were evaporated and the organic products were extracted from the glycerol phase using CH2Cl2 (3×50 ml). The organic phases were combined and then was washed with water (2×30 ml) and CH2Cl2 was evaporated under reduced pressure. The crude reaction product was purified on a flash silica column (eluent: cyclohexane/ethyl acetate=4:1˜1:1). 1-O-butyl-glycerol ether was obtained with an isolated yield of 68%.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.Cl.[C:24]([S:43][CH2:44][CH2:45][NH2:46])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O.C(N(CC)CC)C>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH:46][CH2:45][CH2:44][S:43][C:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:13])=[CH:8]2
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.31 g), 2-(tritylthio)ethylamine hydrochloride (0.33 g), 1H-1,2,3-benzotriazol-1-ol (0.15 g), triethylamine (0.15 mL) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.21 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.54 g, yield 92%) was obtained as colorless crystals from a fraction eluted with ethyl acetate. melting point>188° C. (decomposition).
Reaction SMILES: [I-].[CH2:2]([N+:6]1[N:10]=[C:9]([CH3:11])[S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].C1CCN2C(=NCCC2)CC1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([N:31]=[C:32]=[O:33])[CH:30]=1>O>[CH2:2]([N:6]1[N:10]=[C:9]([CH3:11])[S:8]/[C:7]/1=[CH:12]\[C:32]([NH:31][C:29]1[CH:30]=[C:25]([Cl:24])[CH:26]=[CH:27][C:28]=1[O:34][CH3:35])=[O:33])[CH2:3][CH2:4][CH3:5]
Reactant: COc1ccc(Cl)cc1N=C=O
Reactant: CCCC[n+]1nc(C)sc1C
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCCCN1N=C(C)S/C1=C\C(=O)Nc1cc(Cl)ccc1OC

Procedure:
A solution of the product from Example 47A (149 mg, 0.5 mmol), DBU (105 μL, 0.75 mmol) and 5-chloro-2-methoxy phenyl isocyanate (91 mg, 0.5 mmol) was stirred overnight. The solution was diluted with water (10 mL), extracted with dichloromethane (3×5 mL). The organic layers were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo. The residue was purified by the HPLC procedure specified in Example 47B to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.5 Hz, 3 H), 1.27-1.39 (m, 2 H), 1.64-1.75 (m, 2 H), 2.36 (s, 3 H), 3.82-3.91 (m, 5 H), 5.81 (s, 1 H), 6.92-7.01 (m, 2 H), 8.36 (d, J=2.4 Hz, 1 H), 8.68 (s, 1 H); MS (ESI) m/z 354 (M+H)+. Anal. Calcd for C16H20ClN3O2S.0.5 C2HF3O2: C, 48.92; H, 4.92; N, 9.99. Found: C, 49.28; H, 5.09; N, 10.07.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH3:10].[O:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([NH:26][NH2:27])=[O:25])(=[O:20])=[O:19])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[C:9](=[N:27]/[NH:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][CH:30]=[C:21]([S:18]([N:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)(=[O:19])=[O:20])[CH:22]=1)/[CH3:10]
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1Cl
Temperature: 120 °C

Procedure:
1-(2,5-Dichlorophenyl)ethanone (20 mg, 0.106 mmol) and 3-(morpholinosulfonyl)benzohydrazide (30.2 mg, 0.106 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography affording the title compound in a 10 mg yield. 1H NMR (400 MHz, CDCl3): δ 8.29 (m, 1H), 8.09 (m, 1H), 7.81 (m, 1H), 7.57 (m, 1H), 7.40 (m, 1H), 7.26 (m, 2H), 3.52 (m, 4H), 2.91 (m, 4H), 2.28 (s, 3H). ESI-MS: 456.1 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5]NC(=N)N.N[CH2:14]C(N)=O>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH:4]([CH3:14])[CH3:5]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: NCC(N)=O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
Arg.Pro.Gly-NH2 (nafarelin, as its acetate; RS-94991-298).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([C:27]#[N:28])[N:18]=1>CN1C(=O)CCC1.O>[C:27]([C:19]1[N:18]=[C:17]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][CH:25]=2)#[N:28]
Reactant: N#Cc1cc2ccccc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccccc23)C1
Temperature: 160 °C
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
To (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.906 g, 10.18 mmol) in NMP (10 mL) at 0° C. was added NaH (0.339 g, 8.48 mmol). The mixture was stirred for 5 minutes and then 1-chloroisoquinoline-3-carbonitrile (1.6 g, 8.48 mmol) was added. The reaction mixture was heated at 160° C. for 30 minutes in a microwave reactor and was subsequently diluted with water and extracted with EtOAc (2×). The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by silica column chromatography eluting with a gradient of 0-75% EtOAc in hexane to give the title compound as a yellow solid (1.61 g, 55.9%). ESI-MS m/z [M+H-tert-butyl]+ 284.2.
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:6]([O:7][CH2:8][C:9]#[N:10])=[CH:5][C:4]=1[CH3:14])=[O:2].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[CH3:14][C:4]1[CH:5]=[C:6]([O:7][CH2:8][C:9]2[NH:17][N:16]=[N:15][N:10]=2)[CH:11]=[C:12]([CH3:13])[C:3]=1[CH:1]=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(OCC#N)cc(C)c1C=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2nnn[nH]2)cc(C)c1C=O
Temperature: 100 °C

Procedure:
To a solution of (4-formyl-3,5-dimethyl-phenoxy)-acetonitrile (120 mg) in DMF (3 mL) were added sodium azide (62 mg) and ammonium chloride (51 mg). The reaction mixture was heated at 100° C. for 1 h. The mixture was then diluted by water and the whole was loaded onto a cartridge that contained C18 silica gel (reverse phase). Wash-to-waste (10 mL water) was followed by elute-to-collect (10 mL, acetonitrile) and, after evaporation of volatiles, 2,6-dimethyl-4-(1H-tetrazol-5-yl-methoxy)-benzaldehyde was obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:9][CH:8]=[C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[C:3]1[C:4]#N.S(=O)(=O)(O)O.[OH-:21].[OH2:22]>>[O:1]=[C:2]1[NH:9][CH:8]=[C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[C:3]1[C:4]([OH:22])=[O:21]
Reactant: [OH-]
Reactant: O
Reactant: N#Cc1cc(-c2cccnc2)c[nH]c1=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(-c2cccnc2)c[nH]c1=O

Procedure:
A mixture containing 41 g. of 1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinonitrile and 410 ml. of 50% aqueous sulfuric acid was refluxed for two hours and then poured into 1.5 kg. of a mixture of ice and water. The acidic mixture was neutralized with 35% aqueous hydroxide solution and the mixture cooled. The separated solid was collected, washed with water and dried in vacuo at 80° C. to yield 47 g. of 1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinic acid which was used directly without further purification in the next step described below as Example C-2.
Reaction SMILES: COC1C=CC(C[N:8]2[C:13](=[O:14])[CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)[CH2:10][C:9]2=[O:24])=CC=1>CC#N.O>[N+:21]([C:18]1[CH:17]=[CH:16][C:15]([CH:11]2[CH2:10][C:9](=[O:24])[NH:8][C:13](=[O:14])[CH2:12]2)=[CH:20][CH:19]=1)([O-:23])=[O:22]
Reactant: COc1ccc(CN2C(=O)CC(c3ccc([N+](=O)[O-])cc3)CC2=O)cc1
Solvent: CC#N
Solvent: O
Product: O=C1CC(c2ccc([N+](=O)[O-])cc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 22.8 g (64.2 mmol) of 1-(4-methoxy-benzyl)-4-(4-nitro-phenyl)-piperidine-2,6-dione (as prepared in the previous step) in CH3CN (150 mL) was treated with 70.4 g (128 mmol) of ceric ammonium nitrate (CAN) as a solution in water (100 mL). The mixture was stirred at RT for 5 h, diluted with water (100 mL), and extracted with EtOAc (2×150 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (1×100 mL) and water (1×100 mL). The combined aqueous layers were extracted with EtOAc (1×100 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The solid residue was triturated with a minimum amount of CH3CN, filtered, and air-dried. The filtrate was concentrated and triturated again with a minimum amount of CH3CN, filtered, and air-dried as a second batch. The two batches were combined to afford 7.00 g (47%) as an off-white solid: 1H-NMR (CDCl3; 400 MHz): δ 8.26 (d, 2H, J=8.8 Hz), 7.97 (br s, 1H), 7.42 (d, 2H, J=8.8 Hz), 3.62-3.52 (m, 1H), 3.02-2.93 (m, 2H), 2.84-2.74 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[C:17]([NH2:18])=[N:16][C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([N:23]=[C:24]=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[NH2:15][C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:17]([NH:18][C:24]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[N:16][C:10]=2[N:11]=1
Reactant: Nc1ncc2cc(-c3ccccc3)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1ccccc1

Procedure:
Following the procedure of Example 2, 0.246 g of 6-phenyl-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 81 was reacted with 0.128 mL of tert-butyl isocyanate. The product is purified by medium pressure chromatography using silica gel and eluting with a gradient of 1:1 CHCl3 :EtOAc to EtOAc to afford the title compound; mp >250° C., CIMS (1% ammonia in methane): m/z (relative intensity) 337 (MH+ +1, 64), 338 (MH+ +2, 11), 236 (100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])=[O:22])[C:16]=1[CH3:34].C(N(CC)CC)C.ClC(OCC)=O.[NH2:48][OH:49]>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:48][OH:49])=[O:32])=[O:22])[C:16]=1[CH3:34]
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCCCC(=O)O
Reactant: NO
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCCCC(=O)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
8-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-octanoic acid (469 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (237 mg, 49%) as a red solid. LC-MS (m/z) 485 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][OH:8])[CH:4]=[N:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][O:8][S:17]([CH3:16])(=[O:19])=[O:18])[CH:4]=[N:3]1
Reactant: Cn1cc(CO)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(COS(C)(=O)=O)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a partial suspension of (1-methyl-1H-pyrazol-4-yl)methanol (75 mg, 0.67 mmol) in CH2Cl2 (4 mL) at 0° C. was added triethylamine (0.19 mL, 1.34 mmol) followed by methanesulfonyl chloride (57 μL, 0.74 mmol). The cloudy reaction mixture was stirred at 0° C. for 1 h then quenched with water and extracted with CH2Cl2. The organics were dried over MgSO4 and concentrated to give 110 mg of methanesulfonic acid 1-methyl-1H-pyrazol-4-ylmethyl ester a colorless oil which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:38]([NH:37][CH2:35][CH3:36])=[O:39])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
7-[[4-[(1-t-Butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile obtained in Reference Example 2 (150 mg) was dissolved in 2 ml of dichloromethane, 35 mg of ethyl isocyanate was added, and the mixture was stirred at room temperature for 15 hours. Then, 117 mg of ethyl isocyanate was added, the mixture was stirred at room temperature for 6 hours, and then the reaction solution was evaporated. The resulting residue was purified by silica gel column chromatography using hexane:ethyl acetate (65:35) as the eluent to give 154 mg of 1-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-1-[(7-cyano-2-naphthyl)methyl]-3-ethylurea.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]#[C:7][C:8]([NH:10][C:11]1[S:15][N:14]=[C:13]([CH3:16])[CH:12]=1)=[O:9])[CH3:2].ClC1C=CC=CC=1.[N:27]([CH:30]([C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][C:36]([O:42][CH2:43][CH2:44][O:45][CH3:46])=[CH:35]2)[CH3:31])=[N+:28]=[N-:29]>>[CH2:18]([O:17][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]1[N:29]=[N:28][N:27]([CH:30]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]=[CH:37][C:36]([O:42][CH2:43][CH2:44][O:45][CH3:46])=[CH:35]3)[CH3:31])[C:7]=1[C:8]([NH:10][C:11]1[S:15][N:14]=[C:13]([CH3:16])[CH:12]=1)=[O:9])[CH3:19]
Reactant: COCCOc1cnc2ccc(C(C)N=[N+]=[N-])cc2c1
Reactant: CCOC(CC#CC(=O)Nc1cc(C)ns1)OCC
Solvent: Clc1ccccc1
Product: CCOC(Cc1nnn(C(C)c2ccc3ncc(OCCOC)cc3c2)c1C(=O)Nc1cc(C)ns1)OCC
Temperature: 100 °C

Procedure:
5,5-diethoxy-N-(3-methylisothiazol-5-yl)pent-2-ynamide (0.700 g, 2.5 mmol) was dissolved in chlorobenzene (2.5 mL, 2.5 mmol), and to the solution was added 6-(1-azidoethyl)-3-(2-methoxyethoxy)quinoline (0.68 g, 2.5 mmol). The mixture was heated to 100° C. overnight and then increased to 110° C. for 5.5 h. The reaction was concentrated in vacuo. The compound was purified via MPLC (eluting with 0-40% EtOAc in hexanes) to yield 5-(2,2-diethoxyethyl)-3-(1-(3-(2-methoxyethoxy)quinolin-6-yl)ethyl)-N-(3-methylisothiazol-5-yl)-3H-1,2,3-triazole-4-carboxamide.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]([OH:22])=[CH:18][CH:19]=[CH:20][CH:21]=1.C[O:30][C:31](=[O:40])[CH:32](Br)[CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[C:16]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:7]1[CH:6]=[N:5][N:4]([CH:32]([CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:31]([OH:30])=[O:40])[C:3](=[O:15])[CH:2]=1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: Oc1ccccc1-c1ccccc1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2-c2ccccc2)cc1=O
Yield: 75 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and biphenyl-2-ol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 2-[4-(biphenyl-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentylpropionic acid (15.4 g, 75%) as a solid; HPLC (0.17% trifluoroacetic acid in acetonitrile/water, 50%-100% acetonitrile, gradient, 1 mL/min, Venusil MP-C18, C18-15 cm×4.6 mm-5 μm), purity>96% (214 nm). 1H-NMR (CDCl3, 300 MHz) δ0.97-1.10 (m, 2H), 1.45-1.69 (m, 7H), 2.00-2.07 (m, 1H), 2.17-2.22 (m, 1H), 5.39 (dd, J=10.5, 1H), 5.83 (s, 1H), 7.17 (d, J=7.5, 1H), 7.24-7.48 (m, 8H), 7.65 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:1][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:6][CH:7]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13]1
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3ccccn3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 53 (c)] with 2-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{4-[2-(pyridin-2-ylmethoxy)-ethoxy]-phenyl}-piperidine-1-carboxylate as a colourless oil.