Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([Cl:13])(Cl)=[O:11].[CH2:14]([NH:20][CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(OCC)C>[CH2:14]([N:20]([CH3:21])[C:10]([Cl:13])=[O:11])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCNC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCCCCCN(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 0.35 ml of (i-Pr)2NEt in 10 ml of diethyl ether at 0° C. was added phosgene (1.06 ml, 1.93 M solution in toluene) and N-hexylmethylamine (0.31 ml, 2.05 mm). The reaction mixture was allowed to warm up to 25° C., and further stirred at 25° C. for 14 h. The mixture was filtered, and the solvent was removed under vacuum. The product was used for the next step reaction without further purification. 1H NMR (CDCl3): δ3.42 (m, 2H), 3.07 (s, 3H), 1.59 (m, 2H), 1.31 (m, 6H), 0.90 (m, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.[NH2:10][C@H:11]([CH2:13][OH:14])[CH3:12].C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[CH3:12][C@H:11]([NH:10][C:7]([C@@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9])[CH2:13][OH:14]
Reactant: C[C@H](N)CO
Reactant: O=C1N[C@H](C(=O)O)CS1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](CO)NC(=O)[C@@H]1CSC(=O)N1
Yield: 66.3 %

Procedure:
In 20 ml of dry tetrahydrofuran were dissolved 1.0 g of (4R)-2-oxothiazolidine-4-carboxylic acid and 0.56 g of L-alaninol, 2.8 ml of triethylamine and 1.8 ml of diphenylphosphoryl azide were added thereto with stirring under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Then, the solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography employing ethyl acetate as an eluent and further purified by silica gel column chromatography employing dichloromethane-methanol (95:5) as an eluent to obtain 0.92 g of the desired compound as colorless crystals.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:37]=[CH:36][C:19]([C:20]([NH:22][C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:21])=[CH:18][C:17]=2[NH:38][C:39]2[C:40]3[CH:48]=[CH:47][C:46]([CH:49]([CH3:51])[CH3:50])=[N:45][C:41]=3[N:42]=[CH:43][N:44]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:37]=[CH:36][C:19]([C:20]([NH:22][C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:21])=[CH:18][C:17]=2[NH:38][C:39]2[C:40]3[CH:48]=[CH:47][C:46]([CH:49]([CH3:50])[CH3:51])=[N:45][C:41]=3[N:42]=[CH:43][N:44]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(C)(NC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)(NC(=O)c1ccc(Sc2ccc(N)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
The product of Example 444A (93 mg.) was reacted with trifluoroacetic acid [TFA] (0.60 mL) in dichloromethane (0.60 mL) added dropwise at room temperature then stirred at room temperature for 1 hour. The reaction mixture was concentrated and partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was chromatographed on a C-18 HPLC column with a gradient elution of acetonitrile in 0.1% TFA water (0-100%). The desired fractions were combined, concentrated, dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 then brine, dried over MgSO4 and concentrated to give a pale yellow amorphous solid (67 mg, 84%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.07 (t, J=6.99 Hz, 3 H) 1.34 (d, J=6.62 Hz, 6 H) 1.84 (s, 3 H) 3.15-3.29 (m, 1 H) 4.03 (q, J=7.35 Hz, 2 H) 5.59 (s, 2 H) 6.62 (d, J=8.46 Hz, 2 H) 6.84 (d, J=8.46 Hz, 1 H) 7.12 (d, J=8.46 Hz, 2 H) 7.24-7.41 (m, 4 H) 7.52 (d, J=7.35 Hz, 2 H) 7.63 (d, J=8.46 Hz, 1 H) 7.73 (dd, J=8.46, 1.84 Hz, 1 H) 7.90 (d, J=1.84 Hz, 1 H) 8.57 (s, 1 H) 8.83 (s, 1 H) 8.86 (d, J=8.46 Hz, 2 H) 10.13 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C@@H:4]([C:5]#[C:6][C:7]([O:9][C:10]([CH2:13][CH3:14])([CH3:12])[CH3:11])=[O:8])[C@H:3]1[C:15]([O:17][C@H:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16].N1C2C(=CC=CC=2)C=CC=1>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[CH3:34][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][C:10]([CH2:13][CH3:14])([CH3:11])[CH3:12])=[O:8])[C@H:3]1[C:15]([O:17][C@H:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:20]=1)=[O:16]
Reactant: CCC(C)(C)OC(=O)C#C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CCC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A mixture of 1.34 g of the product of Step A, 220 mg of 10% palladium hydroxide on barium sulfate, 20 ml of ethyl acetate and 0.25 ml of quinoline was hydrogenated for 30 minutes and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 9:1 cyclohexane-ethyl acetate mixture yielded 1.05 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-(tert.-amyloxycarbonyl)-ethenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+63.5°±2.5° (c=0.7% in chloroform).
Reaction SMILES: CC([NH:5][S:6]([C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7])(C)C.C(C(O)=[O:21])(F)(F)F>>[CH3:15][C:14]1[CH:13]=[CH:12][CH:11]=[N+:10]([O-:21])[C:9]=1[S:6]([NH2:5])(=[O:8])=[O:7]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cccnc1S(=O)(=O)NC(C)(C)C
Product: Cc1ccc[n+]([O-])c1S(N)(=O)=O
Reaction time: 6 h

Procedure:
A mixture of the N-oxide of N-(1,1-dimethylethyl)-3-methyl-2-pyridinesulfonamide (2.5 g, 8.2 mmol) and 50 mL of CF3CO2H were stirred for 6 hours. The CF3CO2H was removed under vacuum and the resulting solids were washed with butyl chloride to afford 1 g of the desired product, m.p. 233°-235° C., (M+ =188, expected, 188).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[C:8]([C:18](=[O:21])[CH2:19]Br)[CH:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][CH3:15])[C:11]=1[OH:12])([CH3:5])[CH2:3][CH3:4].[I-:22].[Na+].CCCCCC>COCCOC>[CH3:1][C:2]([C:6]1[CH:7]=[C:8]([C:18](=[O:21])[CH2:19][I:22])[CH:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][CH3:15])[C:11]=1[OH:12])([CH3:5])[CH2:3][CH3:4]
Reactant: CCC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)CC)c1O
Reactant: [I-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Product: CCC(C)(C)c1cc(C(=O)CI)cc(C(C)(C)CC)c1O
Reaction time: 16 h
Yield: 53.4 %

Procedure:
To a solution of 3.56 g (10 mmol) of 1-(3,5-bis(1,1-dimethylpropyl)-4-hydroxyphenyl)-2-bromo-ethanone in 15 ml of 1,2-dimethoxyethane, a solution of 1.65 g (11 mmol) of sodium iodide in 10 ml of 1,2-dimethoxyethane is added dropwise at room temperature. After the addition, stirring is continued for 16 hours at room temperature. Then 5 ml of hexane is added and, after stirring for additional 15 minutes, the precipitated salts are removed by filtration. The obtained solution is evaporated and the resulting residue is purified by recrystallization from hexane to give 2.15 g (53%) of compound 204, m.p. 76-77° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>>[C:1]([NH:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc(C(=O)O)ccc1C
Product: CC(=O)Nc1c(C)ccc(C(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
3-Acetamido-4-methylbenzoic acid (205 g, 1061 mmol) was added portionwise over 45 min to stirred fuming nitric acid (1 L) at −5° C., maintaining a reaction temperature below 0° C. The mixture was stirred for an additional 1 h and then crushed ice (2.5 kg) was added. The mixture was stirred for a further 30 min. The precipite that formed was filtered off and thouroughly washed with water. The resulting cake was air dried and suspended in 1 L of acetic acid at 65° C. The suspension was sitrred for 1 hour, allowed to cool down to RT and then filtered. The filtrate was washed with acetic acid and ether to give 3-acetamido-4-methyl-2-nitrobenzoic acid (160 g, 63%) as a white solid. MS (M+H)+ 239.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([C:12]3([OH:19])[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]=2[O:5][C:4]1=[O:20])[CH3:2].[NH:21]1[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[O:27])[CH2:22]1>>[CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([C:12]3([OH:19])[CH2:17][CH2:16][CH:15]([N:21]4[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=5)=[O:27])[CH2:22]4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]=2[O:5][C:4]1=[O:20])[CH3:2]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CCn1c(=O)oc2ccc(C3(O)CCC(=O)CC3)cc21
Product: CCn1c(=O)oc2ccc(C3(O)CCC(N4CC(NC(=O)CNC(=O)c5cccc(C(F)(F)F)c5)C4)CC3)cc21

Procedure:
The title compound was prepared as a white solid by reductive amination of 3-ethyl-5-(1-hydroxy-4-oxo-cyclohexyl)-3H-benzooxazol-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C(O)(=O)C>O>[OH:6][CH2:5][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[N:1]1[C:14](=[O:15])[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]1=[O:16]
Reactant: Nc1ccccc1CCO
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1ccccc1CCO
Temperature: 100 °C
Yield: 39.6 %

Procedure:
A flask containing 2-aminophenethyl alcohol (565 mg, 4.12 mmol), phthalic anhydride (641 mg, 4.32 mmol) and acetic acid (4 mL) was heated at 100° C. for 1 h. The reaction mixture was poured into water (30 mL) and the solid was filtered off and the solids were washed with water. The crude was purified by flash column chromatography to afford the desired product as white solid (435 mg, 1.63 mmol, 40%). 1H NMR: 1.79 (br s, 1H), 2.78 (t, 2H, J=6.4 Hz), 3.81 (t, 2H, J=6.4 Hz), 7.20 (d, 1H, J=8 Hz), 7.36-7.41 (m, 1H), 7.46 (d, 2H, J=4 Hz), 7.79-7.83 (m, 2H), 7.94-7.97 (m, 21-1).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:17])[CH2:12][C:13]([CH2:15]Br)=O)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[NH2:21][C:22]([NH2:24])=[S:23].C(=O)(O)[O-].[Na+]>O>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([CH2:12][C:13]2[N:21]=[C:22]([NH2:24])[S:23][CH:15]=2)=[O:17])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nnc(NC(=O)CC(=O)CBr)s1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1nnc(NC(=O)Cc2csc(N)n2)s1
Yield: 96.1 %

Procedure:
A reaction mixture comprising 11.2 g (0.035 mole) of N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-4-bromoacetoacetamide, 200 ml of ethanol and 2.8 g (0.037 mole) of thiourea was refluxed for three hours. The reaction solution was cooled and added to 300 ml of water. With stirring, there was slowly added an excess of saturated aqueous sodium bicarbonate. The product was collected and dried. There was obtained 10 g (96.2%) of white solid, m.p. 226° (dec.). N.M.R. (dimethyl-d6 sulfoxide) ∂ 1.4 [C(CH3)3 ], 3.6 (CH2), 6.3 (hetero-aromatic), 6.9 (NH).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:19]=[O:20])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:14]([CH:19]=[O:20])[CH:13]=1
Reactant: CCOC(=O)CCCCBr
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1ccc(Br)cc1C=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Ethyl 5-bromopentanoate (28.6 g) was added to a suspension of 4-bromo-2-formylphenol (25.0 g) and potassium carbonate (18.9 g) in DMF (100 ml), and the resulting solution was stirred at 50° C. overnight under a nitrogen atmosphere. The solution was allowed to cool. Water was added and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain yellow oil of ethyl 5-(4-bromo-2-formylphenoxy)pentanoate (40.9 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl.CN.[CH2:16]([N:18](CC)CC)C.O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([S:9]([NH:18][CH3:16])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CNS(=O)(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.8 %

Procedure:
Commercially available 3,4-difluorophenylsulfonylchloride (117 μL, 0.87 mmol) was dissolved in dichloromethane (5 mL), and methylamine hydrochloride (49 mg, 0.73 mmol) and triethylamine (203 μL, 1.45 mmol) were added, followed by stirring at room temperature for 2 hours. To the reaction solution, water (15 mL) was added, extraction was carried out twice with dichloromethane (15 mL), and washing was carried out with saturated brine (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, followed by vacuum drying, to afford the desired compound (44.7 mg, yield 30%) as a colorless oil.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[CH2:30]([OH:32])[CH3:31].C([O:37]C)(C)(C)C>C(O)(=O)C>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([O-:37])(=[O:32])[CH3:31]
Reactant: COC(C)(C)C
Reactant: CCO
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CC(=O)O
Product: CC(=O)[O-]
Temperature: 50 °C

Procedure:
Sunitinib base (3 g) was dissolved in acetic acid (6 ml) and absolute ethanol (6 ml) by stirring for 10 min at 20° C. and the solution was heated to 50° C. Then methyl tert-butyl ether (60 ml) was added within 300 min with stirring, the mixture was cooled to −10° C. After 16 h at −10° C. the solid was filtered, washed with 2×20 ml of MTBE, dried on filter for one hour obtaining a red solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:15]=[C:16](I)[C:3]=12.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:15]=[C:16]([C:31]3[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=3)[C:3]=12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN1CCN(CCn2nc(I)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(CCn2nc(-c3cnn(C)c3)c3c(Cl)c(-c4ccccc4)nnc32)CC1

Procedure:
Nitrogen was bubbled through a suspension of 4-chloro-3-iodo-1-(2-(4-methylpiperazin-1-yl)ethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (75 mg, 0.16 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (37 mg, 0.18 mmol) and K3PO4 (99 mg, 0.47 mmol) in DMF (1.2 mL) and water (0.4 mL) for 20 min. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (13 mg, 0.016 mmol) was added and the tube sealed and heated using microwave irradiation to 60° C. for 30 min. The crude reaction mixture was filtered and purified by preparative HPLC to provide Compound Ic (42 mg).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].CC(C)=O.[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:26](Cl)=[O:27])=[CH:20][CH:19]=1>O>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:26](=[O:27])[O:25][CH2:24][C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)N(CCO)CCO
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
A suspension of 2,2′-azanediyldiethanol (7.3 ml, 76.09 mmol), sodium carbonate (18.33 g, 172.94 mmol), acetone (125 ml), and water (125 ml) at 0° C. was treated dropwise over a 15 minute period with Cbz-Cl (10.25 ml, 69.17 mmol). The suspension was stirred an additional 3 hours at 0° C. The suspension was diluted with water (500 ml) and extracted with CHCl3 (2×250 ml). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, eluting with MeOH/DCM, 0→10% over 40 minutes) to give the title compound (12.5 g, yield: 76%).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=C(C2C=CC(C)=CC=2)O[C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[F:28][C:29]([F:39])([F:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1>>[I:1][CH2:2][C:3]1[N:4]=[C:34]([C:33]2[CH:36]=[CH:37][C:30]([C:29]([F:38])([F:39])[F:28])=[CH:31][CH:32]=2)[O:35][C:7]=1[CH3:8]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CC(=O)/C(C)=N/O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime and 4-trifluoromethylbenzaldehyde gave 4-iodomethyl-5-methyl-2-(4-trifluoromethylphenyl)oxazole.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([NH:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5].Cl[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26].Cl>C(=O)([O-])O.[Na+].O1CCCC1>[CH2:28]([O:27][C:25]([S:1][CH2:2][CH:3]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([NH:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5])=[O:26])[CH:29]([CH3:31])[CH3:30]
Reactant: Cc1c(NC(=O)C(CS)Cc2ccccc2)cccc1C(=O)O
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)C(CSC(=O)OCC(C)C)Cc2ccccc2)cccc1C(=O)O
Yield: 36 %

Procedure:
3-[(2-Mercaptomethyl-3-phenylpropionyl)amino]-2-methylbenzoic acid (compound of Example 7) (0.66 g) is dissolved in a mixture of saturated aqueous sodium hydrogen carbonate solution and tetrahydrofuran (1 ml), and to the mixture is added a solution of isobutyl chloroformate (0.33 g) in tetrahydrofuran (5 ml) with stirring under ice cooling, and the mixture is stirred under ice cooling for 30 minutes and further at room temperature for one hour. The reaction mixture is acidified with 4N hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated under reduced pressure, and the precipitates are separated by filtration to give the title compound (0.31 g).
Reaction SMILES: BrC1C=CC(OC2N=C[C:10]([CH:13]=O)=[CH:9]C=2)=CC=1.[F:17][C:18]([F:38])([F:37])[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1OS(C(F)(F)F)(=O)=O>>[CH:13]1([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][C:19]=2[C:18]([F:38])([F:37])[F:17])[C:23]([O:25][CH3:26])=[O:24])[CH2:10][CH2:9]1
Reactant: COC(=O)c1ccc(C(F)(F)F)c(OS(=O)(=O)C(F)(F)F)c1
Reactant: O=Cc1ccc(Oc2ccc(Br)cc2)nc1
Product: COC(=O)c1ccc(C(F)(F)F)c(C2CC2)c1

Procedure:
Instead of 6-(4-bromophenoxy)pyridine-3-carbaldehyde, methyl 4-(trifluoromethyl)-3-{[(trifluoromethyl)sulfonyl]oxy}benzoate (see WO 2007/129745) (2.21 g) was used and treated by the same technique as in Reference Example 13-37(2) to give methyl 3-cyclopropyl-4-(trifluoromethyl)benzoate as a colorless oil (1.42 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1(=O)[CH2:18][CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH:15]1([N:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCCN(C2CCC2)CC1
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a stirred solution of [1,4]diazepane-1-carboxylic acid tert-butyl ester (5 g, 24.97 mmol) in DCE (70 ml) at 20 to 25° C. was added cyclobutanone (1.75 g, 24.97 mmol) followed by acetic acid (1.5 g, 24.97 mmol) dropwise. The resulting mixture was stirred at 20 to 25° C. for ca. 2 h. Sodium triacetoxyborohydride (7.94 g, 37.46 mmol) was added in 9 portions, keeping the temperature in the range of 20 to 25° C. The resulting suspension was stirred at 20 to 25° C. overnight. Saturated NaHCO3 (80 ml) was added in four portions and the biphasic mixture stirred at 20 to 25° C. for ca. ½ h. The organic layer was separated, washed with water (20 ml) and the aqueous phase back extracted at pH 9 with DCM (20 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound as yellow oil (6.1 g, 96%).
Reaction SMILES: S(O[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.BrCC1CCCCO1.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]2([C:54]3[C:45](=[CH:46][C:47]4[O:52][CH2:51][CH2:50][O:49][C:48]=4[CH:53]=3)[O:44][CH2:43]2)[C:35]1=[O:55]>>[O:55]=[C:35]1[C:36]2([C:54]3[C:45](=[CH:46][C:47]4[O:52][CH2:51][CH2:50][O:49][C:48]=4[CH:53]=3)[O:44][CH2:43]2)[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:34]1[CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: BrCC1CCCCO1
Product: CC(C)(C)OC(=O)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)CC1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, tert-butyl 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate was obtained (99%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.34-7.26 (m, 1H), 7.14-7.19 (m, 1H), 7.08-7.01 (m, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.19 (s, 1H), 4.87 (d, J=9.0 Hz, 1H), 4.62 (d, J=9.0 Hz, 1H), 4.23-4.06 (m, 6H), 3.80-3.44 (m, 2H), 2.76-2.59 (m, 2H), 2.11-1.93 (m, 1H), 1.74-1.60 (m, 2H), 1.45 (s, 9H), 1.37-1.20 (m, 2H).