Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:28][CH2:29][C:30]2[O:31][C:32]([CH3:36])([CH3:35])[O:33][CH:34]=2)=[CH:6][C:7]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[C:14]=3[CH2:22][CH:23]=[CH2:24])=[CH:10][C:9](=[O:25])[C:8]=2[C:26]=1[OH:27])[CH:2]=[CH2:3]>CN(C)C=O>[OH:27][C:26]1[C:8]2[C:9](=[O:25])[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[C:14]=3[CH2:22][CH2:23][CH3:24])[O:12][C:7]=2[CH:6]=[C:5]([O:28][CH2:29][C:30]2[O:31][C:32]([CH3:36])([CH3:35])[O:33][CH:34]=2)[C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: C=CCc1c(-c2cc(=O)c3c(O)c(CC=C)c(OCC4=COC(C)(C)O4)cc3o2)ccc(OC)c1O
Solvent: CN(C)C=O
Product: CCCc1c(-c2cc(=O)c3c(O)c(CCC)c(OCC4=COC(C)(C)O4)cc3o2)ccc(OC)c1O
Yield: 99.2 %

Procedure:
2.4 g of the compound of Example 27 are hydrogenated in 40 ml of dimethylformamide with 100 mg of catalyst (5% palladium-on-carbon) under a hydrogen pressure of 6300 hPa. After absorption of the theoretical amount of hydrogen, the mixture is filtered over Millipore and the filtrate is distilled under reduced pressure. The residue yields 2.4 g of the expected product which is used as it is. An analytical sample was prepared by recrystallisation from isopropanol, m.p. 148° C.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([CH2:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:16][CH:17]=1)([OH:10])=[O:9].ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.CN(C)CCCN=C=NCC.Cl>ClCCl>[CH:1]1([NH:7][C:19]([CH2:18][C:14]2[CH:13]=[C:12]([CH2:11][C:8]([OH:10])=[O:9])[CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Reactant: NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)Cc1cccc(CC(=O)NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.2 %

Procedure:
Cyclohexylamine (510 mg), (3-carboxymethyl-phenyl)-acetic acid (1.0 g), 1-hydroxybenzotriazole (700 mg) and Hunigs base (0.9 mL) were added to a round bottomed flask and dissolved in dichloromethane (40 mL) at room temperature. The mixture was stirred at room temperature for 5 minutes then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (990 mg) was added. The reaction was stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane (40 mL) and washed with 2M hydrochloric acid (2×40 mL). The organic layer was isolated and extracted with 2M sodium hydroxide (2×40 mL). The basic extract was isolated, acidified with 2M hydrochloric acid and extracted with dichloromethane (2×40 mL). The dichloromethane extracts were combined, dried over anhydrous sodium sulphate, filtered and concentrated to give 626 mg of the sub-titled product as a white solid.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:6][CH:5]([OH:7])[CH2:4]1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15](=O)[O:16]C1C=CC=CN=1>C1COCC1.CCOC(C)=O>[C:15](=[O:16])([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=1)[O:7][CH:5]1[CH2:6][O:3][CH2:4]1
Reactant: OC1COC1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Oc1ccccn1)OC1COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (0.594 g, 14.85 mmol) in THF (50 mL) was added oxetan-3-ol (1 g, 13.50 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (2.92 g, 13.50 mmol) in THF (50 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to give a residue that was purified by Biotage eluting with 20-50% EtOAc in hexanes to afford the desired product oxetan-3-yl pyridin-2-yl carbonate (452 mg, 17.16% yield) as an oil. 500 mg sm recovered. 1H NMR (400 MHz, CHLOROFORM-d) d 8.42 (dd, J=4.6, 1.6 Hz, 1H), 7.89-7.77 (m, 1H), 7.33-7.27 (m, 1H), 7.14 (d, J=8.3 Hz, 1H), 5.62-5.52 (m, 1H), 4.96-4.91 (m, 2H), 4.83-4.78 (m, 2H).
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH3:22])[CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.[ClH:23]>CO>[ClH:23].[ClH:23].[ClH:23].[NH2:8][CH2:9][C@H:10]([N:15]1[CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH2:20]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCN1CCN([C@@H](CNC(=O)OC(C)(C)C)C(=O)OC)CC1
Agent: Cl
Solvent: CO
Product: CCN1CCN([C@@H](CN)C(=O)OC)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
2.5 g (7.9 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-(4-ethylpiperazin-1-yl)propanoate are placed in 20 ml of methanol and 10 ml of isopropanolic hydrochloric acid having a concentration of 5-6N. The reaction medium is heated at 40° C. for 3 h and then evaporated to dryness. The residue is taken up in 50 ml of ethanol, stirred for 1 h at ambient temperature and then filtered. 1.4 g (54%) of methyl (S)-3-amino-2-(4-ethylpiperazin-1-yl)propanoate trihydrochloride are obtained in the form of a beige solid.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].CON(C)[C:16](=[O:33])[CH:17]=[CH:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1>>[F:5][C:3]([F:6])([C:2]([F:8])([F:7])[F:1])[C:16](=[O:33])[CH:17]=[CH:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:26]=[CH:27][C:28]([S:31][CH3:32])=[CH:29][CH:30]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: CON(C)C(=O)C=Cc1cccc(-c2ccc(SC)cc2)c1
Reactant: FC(F)(F)C(F)(F)I
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: CSc1ccc(-c2cccc(C=CC(=O)C(F)(F)C(F)(F)F)c2)cc1
Reaction time: 0.33 h
Yield: 78.2 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (200.9 mL, 168.8 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (112.5 mL, 168.8 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of N-methoxy-N-methyl-3-(4′-methylsulfanyl-biphenyl-3-yl)-acrylamide (17.6 g, 56.3 mmol, in tetrahydrofuran 20.0 mL) prepared in Step 2 was slowly added thereto at −78° C. The reaction mixture was stirred at room temperature, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with diethyl ether three times. The combined extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30) to give 16.4 g of the titled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=3)[S:18][C:11]=12.[C:25]1([CH2:31][C:32]([N:34]=[C:35]=[S:36])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[S:36])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=3)[S:18][C:11]=12
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Cn1cnc(-c2cc3nccc(Nc4ccc(N)cc4F)c3s2)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1cnc(-c2cc3nccc(Nc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a stirred solution of 418 (200 mg, 0.59 mmol) in a mixture of anhydrous toluene/ethanol (15mL/15mL) was slowly added a solution of 2-phenylacetyl isothiocyanate (522 mg, 2.95 mmol) in a mixture of anhydrous toluene/ethanol (5mL/5mL). The reaction mixture was stirred at room temperature for 4 hrs under nitrogen, concentrated, and adsorbed on silica gel. The crude material was purified by flash column chromatography (eluents 2% of NH4OH in methanol/CH2Cl2 from 5/95 to 10/90) followed by trituration with AcOEt (with traces of acetone)/hexanes, to afford title compound 415 (183 mg, 60% yield) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.51 (s, 1H), 11.81 (s, 1H), 8.82 (bs, 1H), 8.22 (d, J=5.5 Hz, 1H), 7.91 (dd, J=12.4, 2.3 Hz, 1H), 7.79 (d, J=1.1 Hz, 1H), 7.69 (d, J=0.8 Hz, 1H), 7.53 (s, 1H), 7.44 (dd, J=8.6, 2.2 Hz, 1H), 7.40-7.24 (m, 6H), 6.42 (dd, J=5.55, 2.22 Hz, 1H), 3.83 (s, 2H), 3.71 (s, 3H). LCMS: 517.0 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]([C:39](=[O:48])[CH2:40][C:41]([NH:44][C:45](=[O:47])[CH3:46])([CH3:43])[CH3:42])[CH:36]2[CH2:38][CH2:37]2)[CH2:9]1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>ClCCCl.[Zn+2].[Br-].[Br-]>[C:45]([NH:44][C:41]([CH3:42])([CH3:43])[CH2:40][C:39]([N:35]([CH2:34][C@@H:10]1[CH2:9][NH:8][CH2:12][C@H:11]1[CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)[CH:36]1[CH2:38][CH2:37]1)=[O:48])(=[O:47])[CH3:46]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)CC(C)(C)NC(C)=O)C2CC2)C(C)C)ccc1OC
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CN(C(=O)CC(C)(C)NC(C)=O)C2CC2)C(C)C)ccc1OC
Temperature: 55 °C
Reaction time: 16 h

Procedure:
ZnBr2 (110 mg, 0.49 mmol) is added to a solution of (3R,4R)-3-{[(3-acetylamino-3-methyl-butyryl)-cyclopropyl-amino]-methyl}-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.22 mmol) in 1,2-dichloroethane (5 mL) and the resulting suspension is stirred at 55° C. for 16 h. In order to drive the reaction to completion another portion of ZnBr2 (50 mg, 0.22 mmol) is added and heating is continued for another 24 h. For workup a sat. solution of NaHCO3 is added and the mixture is extracted with CH2Cl2. Drying (Na2SO4) of the combined extracts, filtration and evaporation of the solvent affords the desired product as free base. The free base is dissolved in dioxane (2 mL) and fumaric acid (11 mg, 0.11 mmol) is added. Lyophilization yields the title compound as hemifumarate salt. MS (LC-MS): 575.0 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 4.90 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[Cl:10])[C:5]#[N:6].[Br:14][CH2:15][C:16](Br)=[O:17]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:14][CH2:15][C:16]([NH:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[Cl:10])=[O:17]
Reactant: O=C(Br)CBr
Reactant: N#Cc1cc(N)c(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cc(NC(=O)CBr)c(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 103.4 %

Procedure:
To the solution of 3-amino-4-chloro-5-nitrobenzonitrile (300 mg, 1.518 mmol) in DCM (10 mL) at 0° C. was added TEA (0.317 mL, 2.278 mmol) and then 2-bromoacetyl bromide (0.145 mL, 1.670 mmol) was added drop wise. The reaction mixture was stirred at 0° C. for 3 h. LC-MS indicated a new peak. Then it was diluted with DCM and saturated aqueous sodium bicarbonate solution was added. After separating the layers, the aqueous layer was further extracted with DCM. The combined organic extracts were washed with water, brine, dried over MgSO4, filtered and concentrated. The crude was used in the next step without purification. To a solution of above obtained crude 2-bromo-N-(2-chloro-5-cyano-3-nitrophenyl)acetamide (500 mg, 1.570 mmol) in DCM (4 mL) was added TEA (0.438 mL, 3.14 mmol) then a solution of 2-(methylamino)ethanol (118 mg, 1.570 mmol) in THF (4 mL) was added slowly. After stirring at room temperature for 1 h, LC-MS indicated completion. After concentration purification via flash chromatography (0-5% MeOH in DCM, 12 g) gave N-(2-chloro-5-cyano-3-nitrophenyl)-2-((2-hydroxyethyl)(methyl)amino)acetamide (170 mg) as a yellow oil, MS (ESI+) m/z 313.0
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(N(CC)C(C)C)(C)C.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.O>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[N:15]([CH2:31][C:30]2[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Reactant: COc1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cn2ccnc2C(C)c2cccc(C)c2C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the compound of Example 1 (100 mg, 0.5 mmol) and N,N-diisopropylethylamine (77 mg, 0.6 mmol) in dichloromethane, under nitrogen, was added 4-methoxybenzyl bromide (151 mg, 0.75 mmol). The reaction mixture was stirred at room temperature for 90 min and water (10 ml) was added. The layers were separated, and the aqueous layer washed with dichloromethane (15 ml). The combined organics were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]([O:8][C:9]([C@@H:11]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:12][C@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](Cl)=[O:15])=[O:10])[CH3:7]>C(Cl)Cl>[CH2:6]([O:8][C:9]([C@@H:11]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:12][C@H:13]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:14]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:15])=[O:10])[CH3:7]
Reactant: NCCCO
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCCO
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the solution of 0.52 g of 3-amino-1-propanol in 10 ml of methylene chloride is added 0.5 g of 4-ethoxycarbonyl-2,4-(R*,R*)-dibenzylbutyryl chloride in 10 ml of methylene chloride. The mixture is stirred 10 minutes at room temperature. The reaction mixture is concentrated and diluted with ethyl acetate. The organic portions are washed with 1N hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated to give N-[4-ethoxycarbonyl-2,4-(R*,R*)-dibenzylbutyryl]-3-amino-1-propanol as a colorless oil; NMR (CDCl3) δ7.31 and 7.28 (s, 10H, Ar--H), 5.82 (t, 1H, J=7 Hz, NH), 4.02 (q, 2H, J=8 Hz, OCH2), 3.3-1.25 (m, 15H), 1.10 (t, 3H, J=8 Hz, CH3).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[F:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](O)=[O:35]>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[C:31]([F:30])[CH:32]=3)[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: O=C(O)c1cccc(F)c1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3cccc(F)c3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
83 mg (75% pure, 0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 23 mg (0.17 mmol, 1.1 eq.) of 3-fluorobenzoic acid were reacted according to General Method 1. Yield: 41 mg (65% of theory)
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]([CH3:16])([CH3:15])[CH2:12][CH:13]=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:13]/[CH2:12][C:11]([CH3:16])([CH3:15])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)(C)CC=O
Solvent: ClCCl
Product: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
A mixture of glycine tert-butyl ester (Alfa) (2.71 g, 20.0 mmol) and 3,3-dimethyl-butyraldehyde (Alfa) (2.21 g, 21.0 mmol) in CH2Cl2 (50 mL) was stirred at rt overnight. The reaction mixture was concentrated and the residue was dried in vacuo to give [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (4.29 g, 100%) as colorless oil which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:12]=[C:11]([C:13]3[N:14]=[CH:15][O:16][CH:17]=3)[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:9]=2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(O)CO.O1CCOCC1.[Cl-].[Na+].O.[Cu-]=O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:10]1[C:11]([C:13]2[N:14]=[CH:15][O:16][CH:17]=2)=[N:12][C:8]([C:4]2[CH:3]=[C:2]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:7]=[CH:6][N:5]=2)=[N:9]1
Reactant: C1COCCN1
Reactant: Fc1ccccc1Cn1nc(-c2cc(Br)ccn2)nc1-c1cocn1
Agent: O=[Cu-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Solvent: C1COCCO1
Product: Fc1ccccc1Cn1nc(-c2cc(N3CCOCC3)ccn2)nc1-c1cocn1
Temperature: 100 °C
Yield: 10.3 %

Procedure:
To a stirring suspension of 4-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)oxazole (I-54, 1 eq) and copper(I) oxide (1 eq) in ethylene glycol-dioxane (approx. 4:1) in a sealed tube was added morpholine (30 eq). The resultant reaction mixture was heated at 100° C. for 12 hr and then cooled to room temperature, treated with brine and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated and purified using SiO2 chromatography (methylene chloride/acetonitrile/methanol) to afford 4-(2-(1-(2-fluorobenzyl)-5-(oxazol-4-yl)-1H-1,2,4-triazol-3-yl)pyridin-4-yl)morpholine in 10.3% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([C:16]([O:18][CH3:19])=[O:17])#[C:11][C:12]([O:14][CH3:15])=[O:13]>C(O)(C)(C)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1]/[C:11](=[CH:10]\[C:16]([O:18][CH3:19])=[O:17])/[C:12]([O:14][CH3:15])=[O:13])#[N:5]
Reactant: N#Cc1ccccc1N
Reactant: COC(=O)C#CC(=O)OC
Solvent: CC(C)(C)O
Product: COC(=O)/C=C(\Nc1ccccc1C#N)C(=O)OC
Temperature: 25 °C
Yield: 44.3 %

Procedure:
A solution of 2-aminobenzonitrile (5.00 g, 42.3 mM) and dimethyl acetylenedicarboxylate (6.42 g, 45.2 mM) in t-butanol (70.5 mL) was refluxed under a nitrogen atmosphere for 12 hr. After cooling the reaction mixture to room temperature, a precipitate formed and was collected by filtration. The material was washed with cold methanol and air dried to give a yellow solid (4.88 g). Recrystallization of this solid from methanol provided the title compound (4.39 g, 39.9%) as yellow crystals, mp 116.5°-117.5° C.; MS(CI): 261 (M+H).
Reaction SMILES: [CH3:1][NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[N:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[CH:48][N:47]=[C:46]2[C:50]([O:52]C)=O)=[CH:31][CH:30]=1.CN>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[N:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[CH:48][N:47]=[C:46]2[C:50]([NH:2][CH3:1])=[O:52])=[CH:31][CH:30]=1
Reactant: COC(=O)c1nccn1Cc1c(-c2ccc(Cl)cc2)nc2cccnn12
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: CN
Product: CNC(=O)c1nccn1Cc1c(-c2ccc(Cl)cc2)nc2cccnn12

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1H-imidazole-2-carboxylate and methylamine 1H-NMR (CDCl3, 400 MHz, δ) 8.54 (d, J=4.4 Hz, 1H), 8.09 (d, J=9.3 Hz, 1H), 7.87 (s, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.51 (s, 1H), 7.47 (d, J=7.9 Hz, 2H), 7.37 (dd, J=4.5, 9.2 Hz, 1H), 6.93 (s, 1H), 6.90 (s, 1H), 6.31 (s, 2H), 2.91 (s, 3H) ppm; m/e 367 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[Br:22][CH2:23]/[CH:24]=[CH:25]/[CH2:26]Br>O1CCOCC1.O>[Br:22][CH2:23]/[CH:24]=[CH:25]/[CH2:26][NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6]
Reactant: BrC/C=C/CBr
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NC/C=C/CBr)c1Oc1ccccc1

Procedure:
A solution of 3-amino-4-phenoxy-5-sulfamylbenzoic acid (2 g) and 1,4-trans-dibromo-2-butene (3.2 g) in dioxane (35 ml) was heated to reflux overnight. The solvent was removed under reduced pressure and the dark, gummy residue was chromatographed on a silica gel column using chloroform/benzene/acetic acid/methanol (80:10:10:2.5) as the eluting solvent. The fractions containing the product were combined and concentrated leaving an acetic acid solution of it. This was diluted with water to give a cream colored powder which was filtered, dried and washed with pet. ether to remove unreacted dibromobutene. The resulting 3-(4-bromo-trans-2-butenylamino)-4-phenoxy-5-sulfamylbenzoic acid was an off-white solid 0.75 g (26%) with m.p. 191°-194°; ir (Nujol) 3350, 3200, 2600 (broad), 1690, 1605, 1585, and 1530 cm-1 ; nmr (CDCl3 /d6 -DMSO) 3.7-4.5 (m, 5H incl. NH), 5.73 (t, 2H, vinyl), 6.27 (s, SO2NH2), 6.8-7.4 (m, C6H5), 7.57 (d, J=2, CH), and 8.03 ppm (d, CH); mass spectrum is of decomposition products.
Reaction SMILES: Cl.C([O:9][C:10]1[C:15](=[O:16])[CH:14]=[CH:13][N:12]([CH2:17][CH2:18][OH:19])[C:11]=1[CH:20]([OH:28])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)C1C=CC=CC=1.[OH-].[Na+]>C(OCC)(=O)C>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH:20]([OH:28])[C:11]2[N:12]([CH2:17][CH2:18][OH:19])[CH:13]=[CH:14][C:15](=[O:16])[C:10]=2[OH:9])=[CH:26][CH:25]=1
Reactant: O=c1ccn(CCO)c(C(O)c2ccc(Cl)cc2)c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=c1ccn(CCO)c(C(O)c2ccc(Cl)cc2)c1O
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
26 ml of 37% conc. HCl are poured over 2.65 g of 3-benzyloxy-1-(2-hydroxy-ethyl)-2-[hydroxy-(4-chloro-phenyl)-methyl]-1H-pyridin-4-one and the reaction mixture is heated with stirring at 110° C. for 10 minutes. After cooling, 100 g of ice are added. With stirring and cooling in an ice-bath, the reaction mixture is neutralised with approximately 22 ml of conc. sodium hydroxide solution to a pH of 6.5. 50 ml of ethyl acetate are added and stirring is carried out at room temperature for 4 hours. The resulting product is filtered off and washed with water and ethyl acetate, yielding 2-[(4-chloro-phenyl)-hydroxy-methyl]-3-hydroxy-1-(2-hydroxy-ethyl)-1H-pyridin-4-one. M.p.: 184°-186° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:20])[S:13]([CH2:16][CH2:17][CH2:18][Cl:19])(=[O:15])=[O:14])=[CH:8][C:6]=2[N:7]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]1B(O)O>>[NH:27]1[C:35]2[C:30](=[C:31]([C:2]3[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]4[S:10][C:9]([CH2:11][N:12]([CH3:20])[S:13]([CH2:16][CH2:17][CH2:18][Cl:19])(=[O:14])=[O:15])=[CH:8][C:6]=4[N:7]=3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1
Reactant: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)S(=O)(=O)CCCCl
Reactant: OB(O)c1cc2ccccc2[nH]1
Product: CN(Cc1cc2nc(-c3cccc4[nH]ccc34)nc(N3CCOCC3)c2s1)S(=O)(=O)CCCCl

Procedure:
3-Chloro-propane-1-sulfonic acid (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amide was reacted with indole boronic acid in general procedure A. Purification on silica yielded 3-chloro-propane-1-sulfonic acid [2-(1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-methyl-amide.