Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:13]12([NH2:23])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.C(N(C(C)C)CC)(C)C>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:23][C:13]23[CH2:14][CH:15]4[CH2:21][CH:19]([CH2:18][CH:17]([CH2:16]4)[CH2:22]2)[CH2:20]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1S(=O)(=O)Cl
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Br)cccc1S(=O)(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Bromo-2-methylbenzene-1-sulfonyl chloride (300 mg) and 1-adamantanamine (185 mg) were dissolved in dichloromethane (4 mL). Diisopropylethylamine (432 mg) was added, and the solution was stirred at room temperature for 16 hours. The solution was diluted with 70% ethyl acetate (hexanes), washed three times with 1 M aqueous HCl, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed to yield the product.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[O:4][N:3]=1.C1N=CN([C:13](N2C=NC=C2)=[O:14])C=1.C[O:21][C:22](=[O:73])[C@@H:23]([NH:40][C:41]([C@@H:43]1[CH2:52][C:51]2[CH:50]=[C:49]3[O:53][CH2:54][C@H:55]([C:57]4[CH:62]=[CH:61][C:60]([O:63][CH2:64][C:65]5[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=5)=[CH:59][CH:58]=4)[O:56][C:48]3=[CH:47][C:46]=2[CH2:45][NH:44]1)=[O:42])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=2[CH3:39])=[CH:27][CH:26]=1>CN(C1C=CN=CC=1)C.ClCCCl>[Cl:72][C:67]1[CH:66]=[C:65]([CH:70]=[CH:69][C:68]=1[Cl:71])[CH2:64][O:63][C:60]1[CH:61]=[CH:62][C:57]([C@H:55]2[CH2:54][O:53][C:49]3=[CH:50][C:51]4[CH2:52][C@@H:43]([C:41]([NH:40][C@@H:23]([CH2:24][C:25]5[CH:26]=[CH:27][C:28]([O:31][C:32]6[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=6[CH3:39])=[CH:29][CH:30]=5)[C:22]([OH:21])=[O:73])=[O:42])[N:44]([C:13](=[O:14])[NH:7][C:5]5[O:4][N:3]=[C:2]([CH3:1])[CH:6]=5)[CH2:45][C:46]=4[CH:47]=[C:48]3[O:56]2)=[CH:58][CH:59]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(N)on1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: Cc1cc(NC(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(Oc3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)on1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
3-Methyl-isoxazol-5-ylamine was stirred at 60° C. with 1 eq CDI and a catalytic amount of DMAP in DCE for 1 hour, then cooled. A solution of (S)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (1 eq) in DCE was added and stirred at 60° C. for 1 hour. The reaction mixture was cooled, then directly purified by flash chromatography. The resulting compound was hydrolyzed according to General Procedure B to give the title compound (4 mg). LCMS (m/z) 879.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1I.C(N(CC)CC)C.[C:16]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]#[CH:29])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:16]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]1[O:1][C:2]2=[CH:3][N:4]=[CH:5][CH:6]=[C:7]2[CH:29]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: Oc1cnccc1I
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ccncc2o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 829 mg (3.7 mmol) sample of 3-hydroxy-4-iodopyridine, from step 9b above, 130 mg (0.18 mmol) of (Ph3P)2PdCl2, 170 mg (0.74 mmol) of CuI, and 0.6 mL of triethylamine were combined in 10 mL of DMF at ambient temperature and stirred for 3 hours. To this mixture was added a solution of 1-BOC-2-(S)-ethynylpyrrolidine (1.5 g, 7.7 mmol, from Example 1c above) in 5 mL of DMF, and the reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with ether. The ether layer was filtered, washed with 10% NaOH then 50% brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel, eluting with 100:0 to 50:50 hexane:EtOAc to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:20])=[CH:5][C:6]([OH:19])=[C:7]([C:9](=[O:18])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:8]=1)[CH3:2].Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl.O1C2C(=CC=CC=2)C=CC1C([O-])=O>N1C=CC=CC=1.CCCCCC.CCOC(C)=O>[CH2:26]([O:25][C:23](=[O:24])[C:22](=[O:28])[CH:10]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:9]([C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]([OH:20])=[CH:5][C:6]=1[OH:19])=[O:18])[CH3:27]
Reactant: CCc1cc(C(=O)Cc2ccc(F)cc2)c(O)cc1O
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Agent: O=C([O-])C1C=Cc2ccccc2O1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(=O)C(C(=O)c1cc(CC)c(O)cc1O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(5-Ethyl-2,4-dihydroxy-phenyl)-2-(4-fluoro-phenyl)-ethanone (10.3 g, 37.6 mmol) in dried pyridine (100 ml) at 0° C., ethyl chlorooxoacetate (15.4 g, 112.8 mmol) was added. The solution was stirred at 0° C. for 4 hours and at room temperature for 16 hours. The aq. layer was neutralised with 1M HCl and extracted with DCM (2×100 ml). The combined DCM layers were then washed with 2M HCl (2×80 ml), sat. NaHCO3 (1×100 ml), brine (1×100 ml) and dried with Na2SO4. After filtration and evaporation of the solvent, dark brown oil was obtained (11.4 g). Rf=0.22 (EtOAc:n-hexane/1:2). LCMS shows it is a mixture of desired product [(M−1)−=373.1, RT=7.27) and the cyclised chromene carboxylate [(M−1)−=355.4, RT=7.83) in a ratio of ca. 6:1. A small amount of sample was purified by prep. TLC for spectroscopic analysis. 1H NMR (d6-acetone) δ=7.75 (1H, s); 7.30 (2H, m); 7.00 (1H, m); 6.45 (1H, s); 4.65 (1H, s); 4.25 (2H, q); 2.55 (2H, q) and 1.10 (6H, t)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Brc1ccncc1
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: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccncc2)cc1
Yield: 111.4 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 9, 4-bromo pyridine (2 g, 8.44 mmol) was coupled with (4-bromophenyl) boronic acid (1 g, 9.2 mmol) in sodium carbonate (3.57 g, 33.7 mmol), Pd(PPh3)4 (487 mg, 0.422 mmol) and toluene/ethanol/water (50/50/20 ml) to afford 2.2 g of the crude product which was taken as such for next reaction. LCMS: 235.9 m/z=(M+2).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:9]=1[C:10]([OH:12])=[O:11]>C(Cl)(Cl)Cl>[Cl:4][C:16]1[C:8]([O:7][CH3:6])=[C:9]([C:13]([O:17][CH3:18])=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11]
Reactant: COc1cccc(OC)c1C(=O)O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cl)c(OC)c1C(=O)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 16.2 ml (0.2 mol) of sulphuryl chloride in 100 ml of chloroform is added dropwise while stirring to a solution of 36.4 g (0.2 mol) of 2,6-dimethoxybenzoic acid in 300 ml of chloroform. The mixture is heated for 0.5 h at 50° C. and left overnight at room temperature. The solvent is evaporated and the residue recrystallized from isopropyl ether--light petroleum. Yield: 35.4 g, m.p. 132°-33° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:12](/[N:16]=[CH:4]/[C:3]1[C:6]([F:11])=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[Cl:1])[CH2:13][CH2:14][CH3:15]
Reactant: O=Cc1c(F)ccc(Cl)c1Cl
Reactant: CCCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCC/N=C/c1c(F)ccc(Cl)c1Cl

Procedure:
Butyl-[1-(2,3-dichloro-6-fluoro-phenyl)-meth-(E)-ylidene]-amine was prepared from 2,3-dichloro-6-fluorobenzaldehyde, N-butylamine and p-toluenesulphonic acid in analogy to Example 191a): brown oil; 1H-NMR (CDCl3): 0.96 (3H, t, CH3), 1.39 (2H, sextet, CH2), 1.73 (2H, quintet, CH2), 3.71 (2H, q, CH2), 7.02 (1H, dd, ArH), 7.44 (1H, dd, ArH), 8.44 (1H, s, CH═N).
Reaction SMILES: C([Li])CCC.C[CH2:7][O:8]CC.[C:11]([Si:15]([O:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:22][CH2:21][CH2:20]1)([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([Si:15]([CH3:17])([CH3:16])[O:18][CH:19]1[C:28]2[C:23](=[C:24]([CH:7]=[O:8])[CH:25]=[CH:26][CH:27]=2)[O:22][CH2:21][CH2:20]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OC1CCOc2ccccc21
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCOc2c(C=O)cccc21
Temperature: 3 °C
Reaction time: 15 h

Procedure:
Butyllithium was added to an Et2O (80 mL) solution of tert-butyl-(chroman-4-yloxy)-dimethyl-silane (6.21 g, 23.5 mmol) at −80° C. After stirring the mixture at 3° C. for 15 h, DMF (10 mL) was added at 0° C. Following a 30 min stirring at RT, the reaction was quenched with saturated NH4Cl solution. The reaction was diluted with Et2O (200 mL) and washed with brine. The organic phase was dried over MgSO41 filtered, and concentrated in vacuo to provide the crude compound (40% conversion by 1H NMR) which was purified by column chromatography (silica, 0 to 10% ether in hexane) to provide the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5]([Cl:14])=[N:6][C:7]2[N:8]([N:11]=[CH:12][CH:13]=2)[C:9]=1Cl.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C)C=O>[C:15]([N:19]1[C:9]2[N:8]3[N:11]=[CH:12][CH:13]=[C:7]3[N:6]=[C:5]([Cl:14])[C:4]=2[CH2:3][CH2:2]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: ClCCc1c(Cl)nc2ccnn2c1Cl
Reactant: CC(C)(C)N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)N1CCc2c(Cl)nc3ccnn3c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.6 %

Procedure:
In 70 ml of dimethylformamide were dissolved 12.50 g of 6-(2-chloroethyl)-5,7-dichloropyrazolo[1,5-a]pyrimidine, and 9.55 g of tert-butylamine and 11.47 g of triethylamine were added to the solution. The mixture was stirred for 2 days at room temperature. Excess amines and the solvent were distilled off under reduced pressure, and the residue was dissolved in chloroform. After the chloroform layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was treated with a chloroform-ether system to deposit crystals. The crystals were collected by filtration and recrystallized from ethanol to obtain 11.34 g (yield: 90.6%) of the intended product. White crystals.
Reaction SMILES: [NH2:1][C:2]([CH3:38])([CH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:35](=[CH:36][CH:37]=1)[C:16]1=[N:17][O:18][C:19]([C:20]3[C:24]([C:25]([F:28])([F:27])[F:26])=[C:23]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:22][N:21]=3)=[C:15]1[CH2:14][CH2:13]2)[C:3]([O:5]CC)=[O:4].[OH-:39].[Na+].[OH2:41]>CO>[NH2:1][C:2]([CH3:38])([CH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:35](=[CH:36][CH:37]=1)[C:16]1=[N:17][O:18][C:19]([C:20]3[C:24]([C:25]([F:26])([F:28])[F:27])=[C:23]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:22][N:21]=3)=[C:15]1[CH2:14][CH2:13]2)[C:3]([OH:5])=[O:4].[C:24]([OH:41])([C:25]([F:28])([F:27])[F:26])=[O:39]
Reactant: CCOC(=O)C(C)(N)CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CC(N)(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)C(=O)O
Product: O=C(O)C(F)(F)F
Temperature: 66 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
A mixture of ethyl 2-amino-2-methyl-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (Preparation 94A, isomer 1, 8 mg, 0.015 mmol), 2 M aqueous solution of sodium hydroxide (0.015 mL, 0.030 mmol), water (0.1 mL) and methanol (0.2 mL) was stirred at 66° C. under nitrogen for 30 min. Purification using reverse phase HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration and lyophilization gave 2-amino-2-methyl-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoic acid, TFA (6 mg, 9.42 μmol, 61.9% yield) as a white solid. The compound had an HPLC retention time=3.45 min. (condition C); LC/MS M+1=498.5.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(#[N:14])C>>[O:9]1[CH2:10][CH2:11][N:6]([NH:14][S:1]([Cl:5])(=[O:3])=[O:2])[CH2:7][CH2:8]1
Reactant: O=S(=O)(Cl)Cl
Reactant: C1COCCN1
Reactant: CC#N
Product: O=S(=O)(Cl)NN1CCOCC1
Temperature: 25 °C

Procedure:
To a solution of sulphuryl chloride (27.7 ml, 3mol equiv) in acetonitrile (25 ml) under nitrogen was added a solution of morpholine (10 g, 114 mmol) in acetonitrile (25 ml). The reaction was heated under reflux for 15 hours, then cooled to room temperature and concentrated in vacuo to give the title compound (20.45 g).
Reaction SMILES: C1(C(C2C=CC=CC=2)=C)C=CC=CC=1.C1COCC1.[Li:20]CCCC.[C:25]1([CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][Li])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCCCCC.CO>[C:25]1([C:31]([Li:20])([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: [Li]CCCC
Reactant: [Li]CCCCCC(c1ccccc1)c1ccccc1
Agent: C=C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CO
Product: [Li]C(CCCCC)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Into a flask equipped with a mechanical stirrer and under a constant flow of argon was injected 0.8 ml (0.0044 mole) of 1,1-diphenylethylene followed by 100 ml of THF and 0.0038 mole of 1.6 M n-BuLi in hexane. The blood red color of diphenylhexyllithium developed immediately and the solution was stirred at room temperature for five minutes. It was then cooled to -74° C. and 3.2 ml (0.024 mole) of GMA was added dropwise from a hypodermic syringe. The red color discharged to a faint yellow after about 0.5 ml had been added, and the temperature rose to -70° C. until addition was complete (about 5 minutes). The temperature then returned to -74° C. and 10 ml (0.09 mole) of MMA was added dropwise at such a rate that the temperature did not exceed -69° C. (about 15 minutes). Following that, another 3.2 ml of GMA was added, the solution was stirred at -72° C. for 10 min, 1 ml of methanol was injected and the solution was poured into 1 liter of hexane. The stringy white polymer was collected and dried; yield, 15.0 g (97%).
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>O1CCCC1>[C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([NH:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ncoc1-c1ccccc1
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
3.6 g (19.1 mmol) of 5-phenyl-4-oxazolecarboxylic acid were added portionwise to a suspension of 3.1 g (19.1 mmol) of 1,1'-carbonyldiimidazole in 20 ml of dry tetrahydro- furan, whereby a brown solution formed with the evolution of gas. After a reaction period of 15 minutes at 20° 3.05 g (19.0 mmol) of t-butyl (2-aminoethyl)carbamate in 10 ml of dry tetrahydrofuran were added dropwise (slight warming) and the reaction mixture was stirred for a further 30 minutes. Thereafter, the reaction mixture was evaporated under reduced pressure and the residue was partitioned between methylene chloride and 0.1N hydrochloric acid. After washing neutral with saturated sodium chloride solution the organic phase was dried over magnesium sulfate and evaporated, whereby there were obtained 5.8 g (92%) of t-butyl [2-(5-phenyl-4-oxazole-carboxamido)ethyl]-carbamate which were stirred at 20° for 20 minutes in 20 ml of trifluoroacetic acid. Thereafter, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in 5 mo of methanol and treated with 10 ml of 5.5N hydrogen chloride in methanol. Filtration of the separated crystals yielded 2.4 g (51%) of N-(2-aminoethyl)-5-phenyl-4-oxazole-carboxamide hydrochloride as white crystals, melting point 257° (dec.). The 5-phenyl-4-oxazolecarboxylic acid used as the starting material was prepared as follows:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1>>[CH3:29][C:27]1[NH:26][N:25]=[C:24]([NH:23][C:13]2[N:12]=[C:11]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:20]3[C:15]([CH:14]=2)=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[CH:28]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OCCN1CCOCC1
Product: COc1ccc2c(OCCN3CCOCC3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-morpholin-4-yl-ethanol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-[1-(2-morpholin-4-yl-ethoxy)-6-methoxy-isoquinolin-3-yl]-amine. LC-MS m/e 384(MH+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][C:16]([N+:19]([O-])=O)=[CH:17][CH:18]=[C:11]3[C:10]2=[O:22])[CH2:4]1)[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[NH2:19][C:16]1[CH:15]=[C:12]2[C:13](=[O:14])[N:9]([CH:5]3[CH2:6][CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4]3)[C:10](=[O:22])[C:11]2=[CH:18][CH:17]=1
Reactant: CCN1CCCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCN1CCCC(N2C(=O)c3ccc(N)cc3C2=O)C1

Procedure:
2.8 Grams of 1-ethyl-3-(4-nitrophthalimido)piperidine were dissolved in 50 milliliters of hot glacial acetic acid and were hydrogenated at 50° C. and 50 p.s.i. in the presence of 0.1 grams of 5% palladium-on-charcoal catalyst until the theoretical amount of hydrogen was taken up. The hot solution was filtered and the mixture cooled and the solid formed was filtered and dried to give 1.06 grams of the title compound in the form of the monohydrochloride.
Reaction SMILES: O=P(Cl)(Cl)Cl.C[N:7]([CH:9]=O)C.[CH3:11][C:12](=O)[C:13]([CH3:16])([CH3:15])[CH3:14].NO.[ClH:20]>>[Cl:20][C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][C:9]#[N:7]
Reactant: CN(C)C=O
Reactant: Cl
Reactant: CC(=O)C(C)(C)C
Agent: NO
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)C(Cl)=CC#N
Temperature: 40 °C
Yield: 91.9 %

Procedure:
3-Chloro-4,4dimethyl-2-pentenenitrile was prepared following a literature procedure (Hatcher et al. J. Heterocycl. Chem. 1989, 26, 1575). POCl3 (22.4 mL), 0.24 mol, 2.4 equiv) was slowly added to a 0° C. solution of DMF (20.2 mL, 0.26 mol, 2.6 equiv) keeping the temp. under 20° C. The resulting pink solid was heated to 40° C., pinacolone (12.5 mL, 0.10 mol) was added to the resulting red solution, and this mixture was heated to 55° C. for 2 h and 75° C. for 2 h. NH2OH.HCl (16.7 g, 0.24 mol, 2.4 equiv) was added to the 75° C. mixture slowly (<100 mg portions; CAUTION gas evolution and foaming). The resulting solution was heated to 85° C. for 2 h, then allowed to cool to room temp. overnight. The resulting yellow gel was separated between H2O (500 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layers were washed with a saturated NaCl solution, dried (Na2SO4) and concentrated under reduced pressure to give 3-chloro-4,4-dimethyl-2-pentenenitrile as a brown oil (13.2 g, 93%): 1H NMR (CDCl3) δ1.23 (s, 9H), 5.56 (s, 1H); GC-LRMS m/z (rel abundance) 143 (28%), 145 (11%). This material was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[O:11].[CH:12]([N:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1)([CH3:14])[CH3:13]>C(#N)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]([N:17]1[CH2:18][CH2:19][CH2:20][N:15]([CH:12]([CH3:14])[CH3:13])[CH2:16]1)=[O:11]
Reactant: Cc1cccc(C)c1N=C=O
Reactant: CC(C)N1CCCNC1
Solvent: CC#N
Product: Cc1cccc(C)c1NC(=O)N1CCCN(C(C)C)C1

Procedure:
2,6-Dimethylphenylisocyanate (1.5 g) was added dropwise to a solution of N-isopropylhexahydropyrimidine (1.3 g) in acetonitrile (5 ml) (exothermic). After cooling the title compound was isolated by filtration and recrystallised from acetonitrile (2,5 g, 89%), mp 138°-139° C.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH3:2].[CH2:18](Br)[CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[CH2:20]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:5](=[N:4][O:3][CH2:1][CH3:2])[CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:12][CH:13]=1)[CH:19]=[CH2:18]
Reactant: CCON=C(CC(=O)OC)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(CC(=O)OC)=NOCC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of crude methyl 3-(ethoxyimino)-3-(4-hydroxyphenyl)propanoate obtained from Step A at 0° C. was added allyl bromide (0.65 mL) and potassium carbonate (781 mg) in DMF (5 mL), and the resulting suspension was stirred at 0° C. for 2 h. Ethyl acetate and water were added, the aqueous layer was extracted with ethyl acetate (×3), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give the title compound as an oil. The crude product was used in Step C without purification. HPLC retention time: 1.88 min (method A). MS (ESI) (M+H)+ 278.14.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Br[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:17][C:18]4[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(CSc2nnc(-c3ccc4c(c3)CCO4)o2)cc1
Yield: 36 %

Procedure:
In the same manner as in Example 1 and using 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and methyl 4-(bromomethyl)benzoate instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 36%) was obtained as colorless crystals.