Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])/[CH:5]=[CH:6]/[C:7]([OH:9])=O.Cl.[CH3:15][CH:16]1[CH2:22][NH:21][CH2:20][CH2:19][NH:18][C:17]1=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:6]/[C:7]([N:21]2[CH2:22][CH:16]([CH3:15])[C:17](=[O:23])[NH:18][CH2:19][CH2:20]2)=[O:9])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CC1CNCCNC1=O
Reactant: O=C(O)/C=C/c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CC1CN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCNC1=O

Procedure:
In analogy to the procedure described in intermediate 78C, (E)-3,4-dichlorocinnamic acid and 6-methyl-[1,4]diazepan-5-one hydrochloride gave the title compound as a colorless gum, MS: 327.1 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([CH:22]3[N:26]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=4)[CH:25]([C:37]4[CH:42]=[CH:41][C:40]([NH:43][C:44]([C@@H:46]5[CH2:50][CH2:49][CH2:48][N:47]5C(OC(C)(C)C)=O)=[O:45])=[CH:39][CH:38]=4)[CH2:24][CH2:23]3)=[CH:21][C:15]=2[N:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([N:26]2[C@@H:22]([C:20]3[CH:19]=[CH:18][C:16]4[NH:17][C:13]([C@@H:9]5[CH2:10][CH2:11][CH2:12][NH:8]5)=[N:14][C:15]=4[CH:21]=3)[CH2:23][CH2:24][C@@H:25]2[C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:44]([C@@H:46]3[CH2:50][CH2:49][CH2:48][NH:47]3)=[O:45])=[CH:41][CH:42]=2)=[CH:28][CH:29]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc(C2CCC(c3ccc4[nH]c([C@@H]5CCCN5C(=O)OC(C)(C)C)nc4c3)N2c2ccc(C(C)(C)C)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(N2[C@@H](c3ccc(NC(=O)[C@@H]4CCCN4)cc3)CC[C@@H]2c2ccc3[nH]c([C@@H]4CCCN4)nc3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37 %

Procedure:
To a solution of the product from Example 179H (0.302 g, 0.389 mmol) in CH2Cl2 (3 mL) was added TFA (2.5 mL), and the resulting mixture was stirred at rt for 1.5 h. The mixture was concentrated in vacuo, and the crude product was purified by reversed-phase HPLC (C18) using a solvent gradient of 10-100% acetonitrile in H2O (0.1% TFA). The trans-pyrrolidine isomer eluted before the cis-pyrrolidine isomer. Fractions containing the trans-isomer were concentrated in vacuo, and the residue was partitioned between CH2Cl2 and saturated aq. NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (83 mg, 37%).
Reaction SMILES: [CH2:1]([C:3]12[CH2:23][CH2:22][C:17]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:16][CH:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([CH3:15])=[CH:10][C:9]=12)[CH3:2].[C:24]([O-])(=[O:26])[CH3:25].[K+].C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([C@:3]12[CH2:23][CH2:22][C:17]3([O:18][CH2:19][CH2:20][O:21]3)[CH2:16][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([NH:14][C:24](=[O:26])[CH3:25])[C:11]([CH3:15])=[CH:10][C:9]=12)[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCC12CCC3(CC1CCCc1cc(N)c(C)cc12)OCCO3
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC[C@]12CCC3(C[C@H]1CCCc1cc(NC(C)=O)c(C)cc12)OCCO3
Yield: 62.1 %

Procedure:
rac-(4aR,11bS)-11b-ethyl-10-methyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-amine (24, R2=Ethyl) (0.178 g, 0.563 mmol) was dissolved in DCM (4 mL) then potassium acetate (0.138 g, 1.408 mmol) and acetic anhydride (0.115 g, 1.126 mmol) were added. After about 10 min sat. aq. NaHCO3 (3 mL) was added and the mixture was diluted with DCM (15 mL). The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-50% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-N-((4aR,11bS)-11b-ethyl-10-methyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-yl)acetamide (25, R2=Ethyl) (0.125 g, 62%); LC/MS, method 3, Rt=2.36 min, MS m/z 358 (M+H)+. 1H NMR (400 MHz, DMSO) δ 9.12 (s, 1H), 7.13 (s, 1H), 6.99 (s, 1H), 3.89-3.73 (m, 4H), 2.87-2.81 (m, 1H), 2.67-2.59 (m, 1H), 2.39-2.32 (m, 1H), 2.22-2.06 (m, 1H), 2.15 (s, 3H) 2.02 (s, 3H), 2.01-1.91 (m, 2H), 1.69-161 (m, 3H), 1.58-1.51 (m, 1H), 1.49-1.20 (m, 5H), 0.61 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C@H:19]([N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])[CH2:20]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C([O-])=O.[NH4+]>[Pd].CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C@H:19]([N:22]1[C:23](=[O:32])[C:24]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]2[C:26]1=[O:27])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@H](CI)Cc1c[nH]c2c(OCc3ccccc3)cccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: O=C[O-]
Solvent: CN(C)C=O
Product: C[C@H](Cc1c[nH]c2c(OCc3ccccc3)cccc12)N1C(=O)c2ccccc2C1=O
Temperature: 85 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
A 10% palladium on carbon catalyst (content 50%) 4.00 g was suspended in 200 ml of DMF, and 20.00 g of (S)-7-benzyloxy-3-(3-iodo-2-phthalimidopropyl)indole was added thereto. Added while stirring were 8.00 g of potassium carbonate and 6.00 g of ammonium formate, the suspension was heated in an oil bath of 85° C. For one hour. After cooling down, the catalyst was filtered off, and the filtrate was diluted with ethyl acetate. Then, water was added thereto, and the organic layer was separated. The organic layer was washed in order with a 10% sodium thiosulfate aqueous solution, a sodium hydroxide aqueous solution, hydrochloric acid and a saturated sodium chloride aqueous solution, and then it was dried, filtered and concentrated under reduced pressure, whereby 12.16 g of the title compound was obtained in the form of a yellow amorphous solid shaped substance.
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:8]1([Mg]Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[NH4+]>ClCCl.O=[Mn]=O>[C:8]1([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][N:2]2[OH:1])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: ON1CCCCC1
Agent: O=[Mn]=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: ON1CCCCC1c1ccccc1
Reaction time: 1 h
Yield: 37.6 %

Procedure:
Activated MnO2 (1.29 g, 14.8 mmol) was added to a solution of N-hydroxypiperidine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of phenylmagnesium chloride (2.0 M in tetrahydrofuran, 4.95 mL, 9.90 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (25 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 30% diethyl ether in hexanes to give the title compound (0.330 g, 38%) as a white crystalline solid.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C@H:3]([OH:14])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[N:6]1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCCl>[C:18](=[O:19])([O:14][C@H:3]([CH2:4][N:5]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[N:6]1)[C:2]([CH3:16])([CH3:15])[CH3:1])[O:20][C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[C@H](O)Cn1ccc(C(F)(F)F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)[C@@H](Cn1ccc(C(F)(F)F)n1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To 875.3 mg (3.71 mmol) of (2S)-3,3-dimethyl-1-[3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-butanol in 12 mL of 1,2-dichloroethane at room temperature was added 746.8 g (3.71 mmol) of 4-nitrophenyl chloroformate. Then, 359.6 μL (4.45 mmol) of pyridine was added and the solution was heated at reflux for 22 h. Upon cooling to room temperature, saturated aqueous sodium bicarbonate was added to the solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:4) to give 1.39 g (93%) of 4-nitrophenyl (1S)-2,2-dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propyl carbonate. Rf=0.29 (3:7 ethyl acetate:hexanes); 1H-NMR (300 MHz, DMSO-d6): δ 8.28 (d, J=9 Hz, 2H), 8.07 (s, 1H), 7.31 (d, J=9 Hz, 2H), 6.74 (s, 1H), 4.87 (d, J=8 Hz, 1H), 4.69 (d, J=14 Hz, 1H), 4.42 (dd, J=15 Hz, J=10 Hz, 1H), 1.03 (s, 9H); ES-LCMS m/z 424 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>CN(C)C=O>[N:10]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(Br)cn1
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2ccnc2)cn1
Temperature: 130 °C
Yield: 66.3 %

Procedure:
5-bromopicolinonitrile (2.0 g, 10.9 mmol), imidazole (818 mg, 12 mmol) potassium carbonate (1.66 g, 12 mmol) and dimethylformamide (40 mL) were combined and heated to 130° C. for 20 hours. The reaction solution was evaporated and the residue was partitioned between dichloromethane (150 mL) and water (100 mL). The phases were separated and the organic phase was washed with water (50 mL), dried over magnesium sulfate and evaporated to give a residue which was purified by flash chromatography eluting with 2-3% methanol in dichloromethane gradient to give 5-(1H-imidazol-1-yl)picolinonitrile (1.23 g, 66%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:25][CH2:26][CH2:27]P(OCC)(OCC)=O)(=[O:24])[CH3:23].CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[CH:23]/[C:22]([O:25][CH2:26][CH3:27])=[O:24])=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Reactant: O=Cc1cn(-c2ccccc2)nc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.7 %

Procedure:
To a mixture of 3-benzyloxy-1-phenyl-1H-pyrazole-4-carbaldehyde (3.00 g), diethylphosphonoethyl acetate (2.67 g) and N,N-dimethylformamide (50 ml) was added sodium hydride (60% in oil, 0.52 g) at 0° C. and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated brine, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration to give ethyl (E)-3-(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)propenoate (3.18 g, yield 85%), which was then recrystallized from ethyl acetate-hexane. melting point: 105–106° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[CH:15][N:16]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.[I:17]N1C(=O)CCC1=O.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14]([I:17])=[CH:15][N:16]=[C:10]3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2ccn3ccnc3c2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2ccn3c(I)cnc3c2)cc1
Reaction time: 2 h
Yield: 28.9 %

Procedure:
To a solution of 7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridine (13.0 g, 61.3 mmol) in N,N-dimethylformamide (100 mL) stirring under a nitrogen atmosphere at ambient was added N-iodosuccinimide (14.5 g, 64.4 mmol). The reaction mixture was stirred for 2 h and then poured into water (1 L) and stirred for a further 30 min. The solid obtained was collected by filtration, washed with water and air dried on the filter. The solid was triturated with ether, collected by filtration and dried under vacuum at 50° C. The solid obtained was partitioned between water and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The solid thus obtained was partitioned between aqueous sodium thiosulphate solution and EtOAc. The organic layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The product was triturated with EtOAc, collected by filtration and air-dried to afford 6.0 g (29%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.23 (1H, d), 7.91 (1H, s), 7.78 (1H, s), 7.67 (2H, dd), 7.28 (1H, d), 7.22 (2H, t). A further crop of product (11.0 g) containing minor impurities was obtained by evaporating the filtrates under reduced pressure, triturating with petrol/EtOAc and collection by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6]2.[H-].[Na+].Cl[CH2:21][C:22]1[N:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:21][C:22]1[N:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[CH:24][CH:23]=1)[C:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[CH:6]2
Reactant: COC(=O)c1cccc(CCl)n1
Reactant: COc1ccc2[nH]c(-c3ccccc3)cc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(-c3ccccc3)cc3cc(OC)ccc32)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 9.4 %

Procedure:
Under an argon atmosphere, to a solution of 5-methoxy-2-phenyl-1H-indole (582 mg) in N,N-dimethylformamide (13 mL) was added sodium hydride (dispersed in liquid paraffin, 55% or more, 171 mg) under ice-cooling. This mixture was stirred for 5 minutes under ice-cooling, and then stirred for 30 minutes at room temperature. Subsequently, methyl 6-chloromethylpyridine-2-carboxylate (483 mg) was added thereto, followed by stirring at 80° C. for 18 hours. The reaction mixture was poured into an ice-cooled saturated aqueous ammonium chloride solution, and then ethyl acetate was added to the mixture to separate the organic layer. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (91 mg). 1H-NMR (CDCl3) δ ppm: 3.87 (3H, s), 4.02 (3H, s), 5.58 (2H, s), 6.60-6.75 (2H, m), 6.81 (1H, dd, J=2.5, 8.8 Hz), 7.02 (1H, d, J=8.8 Hz), 7.15 (1H, d, J=2.5 Hz), 7.30-7.45 (5H, m), 7.60-7.70 (1H, m), 7.95-8.05 (1H, m).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:9]([OH:11])=O)=[C:6]([CH3:8])[N:7]=1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[CH3:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([CH3:46])=[C:24]([NH:23][C:9]([C:5]5[O:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=5[CH3:8])=[O:11])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: CCc1nc(C)c(C(=O)O)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CCc1nc(C)c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)o1
Yield: 70.6 %

Procedure:
In the same manner as in Example 259 and using 2-ethyl-4-methyl-1,3-oxazole-5-carboxylic acid (230 mg, 1.5 mmol), tetrahydrofuran (6 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (520 μL, 6.0 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (400 mg, 1.2 mmol) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (390 mg, 69%) was obtained as a white solid.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:9][CH:8]=1)(C)(C)C.[CH3:20][C:21]1[C:29]2[C:28]([N:30]3[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]3)=[N:27][CH:26]=[N:25][C:24]=2[S:23][C:22]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[OH:16][CH:15]([CH2:17][NH:36][CH:33]1[CH2:34][CH2:35][N:30]([C:28]2[C:29]3[C:21]([CH3:20])=[C:22]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[S:23][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:31][CH2:32]1)[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=1
Reactant: Cc1c(-c2ccccc2)sc2ncnc(N3CCC(N)CC3)c12
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Product: Cc1c(-c2ccccc2)sc2ncnc(N3CCC(NCC(O)COc4ccc(O)cc4)CC3)c12
Yield: 17 %

Procedure:
Synthesis followed SP6 (3 h), using 150 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(5-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) with 17% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) with 14% yield.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[S:18][C:17]([C:19]([N:21]2[CH2:25][CH:24]([C:26]([OH:28])=O)[O:23][CH2:22]2)=[O:20])=[CH:16][CH:15]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][C:37]2=[O:42])=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[O:42]=[C:37]1[CH2:38][O:39][CH2:40][CH2:41][N:36]1[C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:26]([CH:24]2[O:23][CH2:22][N:21]([C:19]([C:17]3[S:18][C:14]([Cl:13])=[CH:15][CH:16]=3)=[O:20])[CH2:25]2)=[O:28])=[CH:35][CH:34]=1
Reactant: O=C(O)C1CN(C(=O)c2ccc(Cl)s2)CO1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)C1CN(C(=O)c2ccc(Cl)s2)CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4.1 1.48 ml (19.9 mmol) of 37% aqueous formaldehyde solution are added to a solution of 2.00 g (19.0 mmol) of DL-isoserine in 10 ml of 1N aqueous sodium hydroxide solution. The resultant solution is left at 5° C. for 18 hours. A solution of 3.46 g (19.1 mmol) of 5-chlorothiophenecarbonyl chloride in 10 ml of acetone is added dropwise to this solution at an internal temperature of 0-5° C. During the dropwise addition, the pH is held at a value above 7 by addition of solid sodium hydrogencarbonate. When the addition is complete, the mixture is allowed to warm to room temperature, water is added, and the mixture is extracted with tert-butyl methyl ether. The aqueous phase is acidified using 1N HCl and extracted with tert-butyl methyl ether. This organic phase is dried over sodium sulfate and evaporated, giving 3-(5-chlorothiophene-2-carbonyl)oxazolidine-5-carboxylic acid as a colourless solid; ESI 262. 4.2 479 mg (2.50 mmol) of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (DAPECI) are added to a solution of 500 mg (1.91 mmol) of 3-(5-chlorothiophene-2-carbonyl)oxazolidine-5-carboxylic acid and 367 mg (1.91 mmol) of 4-(4-aminophenyl)morpholin-3-one in 5 ml of dimethylformamide (DMF), and the mixture is stirred at room temperature for 18 hours. The reaction mixture is added to saturated sodium hydrogencarbonate solution, and the precipitate formed is filtered off, giving N-[4-(3-oxomorpholin-4-yl)phenyl]-3-(5-chlorothiophene-2-carbonyl)oxazolidine-5-carboxamide (“A5”) as a colourless solid; ESI 436.
Reaction SMILES: [C:1]1([C:7]#[C:8][C@@H:9]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH:19]=2)(=[O:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC1C=CC=CC=1[S:43]([NH2:46])(=[O:45])=[O:44]>>[NH2:46][S:43]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:7]#[C:8][C@@H:9]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:19]=1)(=[O:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])(=[O:45])=[O:44]
Reactant: O=C(O)C[C@@H](C#Cc1ccccc1)NS(=O)(=O)c1cccc(OCCCCNc2ccccn2)c1
Reactant: NS(=O)(=O)c1ccccc1I
Product: NS(=O)(=O)c1ccccc1C#C[C@H](CC(=O)O)NS(=O)(=O)c1cccc(OCCCCNc2ccccn2)c1

Procedure:
The procedure for the preparation of the product of EXAMPLE 18 was repeated using 2-iodobenzene-1-sulfonamide (Maybridge) in the place of iodobenzene to provide the title product. 1H (CD3OD): δ 7.88 (2H, m); 7.81 (1H, d); 7.52 (1H, d); 7.44 (4H, m); 7.11 (1H, d); 7.05 (2H, m); 6.87 (1H, t); 4.68 (1H, t); 4.01 (2H, m); 3.37 (2H, m); 2.84 (2H, m); 1.82 (4H, m).
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]([CH3:24])[C:22]#[N:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]([CH3:24])[C:22]([NH2:2])=[NH:23])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [NH4+]
Reactant: CC(C#N)c1ccccc1OCc1ccccc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C(=N)N)c1ccccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 149.3 %

Procedure:
To a mixture of ammonium chloride (4.49 g) in toluene (25.5 ml) at 5° C. was added trimethylaluminium (2M solution in toluene, 42 ml. The mixture was stirred for 2 hours. 2-(2-benzyloxyphenyl)-propionitrile (10 g) in toluene (50 ml) was added and the mixture heated at 80° C. for 18 hours. The cooled mixture was poured into a slurry of silica gel in chloroform, stirred for 5 minutes and filtered. The silica gel was washed with methanol and the combined organic solutions evaporated to give 2-(2-benzyloxyphenyl)propionamidine (16 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]Cl)=[CH:7][CH:6]=[CH:5][C:4]=1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18].[I-].[Na+].[C-:21]#[N:22].[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[C:4]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:5][CH:6]=[CH:7][C:8]=1[CH2:9][C:21]#[N:22]
Reactant: COc1c(CCl)cccc1Sc1ccccc1Cl
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(CC#N)cccc1Sc1ccccc1Cl
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A mixture of 2-chlorophenyl 2-methoxy-3-chloromethylphenyl thioether (9.2 g) and sodium iodide (4.8 g) in dimethyl sulfoxide (50 ml) was stirred at room temperature. To the mixture was added powdered potassium cyanide (2.1 g) all at once, and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with water, dried and then evaporated to give oily 2-[2-methoxy-3-(2-chlorophenylthio)phenyl]acetonitrile (8.9 g). This product was purified by column chromatography (silica gel 150 g, benzene) to give purified oily product (4.1 g).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[O:10][CH2:9][O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:2].O.[CH3:18]O>S(=O)(=O)(O)O>[CH2:1]([C:3]1[C:11]2[O:10][CH2:9][O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:12][CH2:13][C:14]([O:16][CH3:18])=[O:15])[CH3:2]
Reactant: CCc1c(CCC(=O)O)ccc2c1OCO2
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1c(CCC(=O)OC)ccc2c1OCO2

Procedure:
A solution of the product from Stage (i) (20 g) in methanol (400 ml) and concentrated sulphuric acid (40 ml) was heated on a steam bath for 20 min, cooled and poured onto a mixture of ice and water. The mixture was extracted with ether and the extracts were dried and evaporated. The residue was purified by FCC using hexane/ether (7:3) as eluent to give the title compound (19.2 g), m.p. 44°-46°.