Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:9][C:10]([CH3:16])([CH3:15])[C:11](=[O:14])[N:12]([CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[N:24]=C=O.BrC1C2C(C3C=CC=CC=3Cl)=NC(C)(C)C(=O)N(C)C=2C=CC=1NC(NCCO)=O>CC(C)=O.CCOCC>[NH2:24][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH3:13])[C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:7]=2[C:2]=1[Br:1]
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2c1ccc(N=C=O)c2Br
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2c1ccc(NC(=O)NCCO)c2Br
Solvent: CCOCC
Solvent: CC(C)=O
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2c1ccc(N)c2Br

Procedure:
From 4.5 g (0.011 mol) of 7-amino-6-bromo-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details in Example 4, via [6-bromo-5-(o-chlorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate, 1-[6-bromo-5-(o-chlorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7yl]-3-(2-hydroxyethyl)urea of melting point 214°-218° (acetone/ether).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][N:15]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C@H:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:17])[CH2:12][O:11][CH2:10][C@@H:9]1[CH2:35][CH:36]=[CH2:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].C12BC(CCC1)CCC2.CO.B1([O-])O[O:50]1.O.O.O.O.[Na+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([CH2:35][CH2:36][CH2:37][OH:50])[CH2:10][O:11][CH2:12][C@H:13]1[CH2:14][N:15]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C@H:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [O-]B1OO1
Reactant: C=CC[C@H]1COC[C@@H](CN(C(=O)OCc2ccccc2)[C@@H](C)C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](C(=O)OC(C)(C)C)N(C[C@@H]1COC[C@H](CCCO)N1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80.7 %

Procedure:
To a solution of (3S,5R)-3-allyl-5-{[benzyloxycarbonyl-((S)-1-tert-butoxycarbonyl-ethyl)-amino]-methyl}-morpholine-4-carboxylic acid tert-butyl ester (4.50 g, 8.68 mmol) in tetrahydrofuran (90 mL) was added 9-borabicyclo[3.3.1]nonane solution (0.5 M in tetrahydrofuran, 36.4 mL, 18.2 mmol) at 0° C., then after 21/2 h another portion of 9-borabicyclo[3.3.1]nonane solution (0.5 M in tetrahydrofuran, 20.8 mL, 10.4 mmol) was added. The reaction mixture was stirred for another 45 min at 0° C., then methanol (80 mL), water (115 mL) and sodium perborate tetrahydrate (37.3 g, 242 mmol) were added. After 90 min the ice bath was removed, then after stirring for 16 h the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) afforded the title compound (3.76 g, 81%). Colourless gum, MS: 537.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:10](Cl)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[O:27]1CCOCC1>N1C=CC=CC=1>[C:10]([N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])(=[O:27])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCl
Reactant: C1COCCO1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)n1cc(F)c(=O)[nH]c1=O
Temperature: 80 °C
Yield: 54 %

Procedure:
2.6 g of 5-fluorouracil was suspended in 20 ml of absolute dioxane and 10 ml of absolute pyridine, and 15 g of palmityl chloride was added to the suspension followed by heating at 80° C for 1 hour while stirring. After completion of the reaction, the solvent was removed under reduced pressure (25 mm Hg), and the residual solid was washed with hot hexane (50° C). Any insoluble matter in the hot hexane was recrystallized from benzene to obtain 4.0 g of 1-N-palmitoyl-5-fluorouracil in a yield of 54%. Melting Point: 98° C.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:7]=3[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1>O1CCOCC1.[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:6]2[C:5]3[C:10](=[C:11]([F:12])[C:2]([F:1])=[CH:3][CH:4]=3)[O:9][C:8](=[O:13])[C:7]=2[CH:14]=1
Reactant: O=c1oc2c(F)c(F)ccc2c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc2c(c1)c(=O)oc1c(F)c(F)ccc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 73 %

Procedure:
3,4-Difluoro-8-nitrobenzo[c]chromen-6-one (Reference Compound No. 1-2-(3), g, 13.5 mmol) was dissolved in 1,4-dioxane (300 mL), then 5% palladium on charcoal (375 mg) was added thereto, and then the reaction mixture was stirred under hydrogen atmosphere (3 kgf/cm2) at room temperature for 4 days. After the mixture was filtered, the filtrate was removed under reduced pressure. 1,4-Dioxane was added to the obtained residue, and then filtered to give the titled reference compound (2.44 g) as an orange solid. (Yield 73%)
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH:23]([CH3:25])[CH3:24])[CH2:11][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:27]1(C)[CH:32]=CC(S(O)(=O)=O)=C[CH:28]=1.COC(C)=C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][CH2:9][C@H:10]([CH:23]([CH3:25])[CH3:24])[CH2:11][C@H:12]1[CH2:13][O:14][C:27]([CH3:32])([CH3:28])[N:15]1[C:16]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)[C@@H](COCc1ccccc1)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: C=C(C)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@@H](COCc1ccccc1)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The solution of 3.51 g of tert-butyl (3(S)-benzyloxymethyl-1(S)-hydroxymethyl-4-methyl-pentyl)carbamate in 20 ml of dichloromethane is cooled to 0° C. and admixed successively with 0.076 g of p-toluenesulphonic acid monohydrate and 2.6 ml of 2-methoxypropene. The reaction mixture is stirred at room temperature for another 16 hours and subsequently poured onto 1M sodium hydrogencarbonate solution, extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a yellowish oil. Rf=0.42 (1:4 EtOAc-heptane); Rt=6.20 (gradient I).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1>>[C:25]([N:24]([CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])[C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:2]=2[Cl:1])=[CH:19][CH:20]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)N(CCN(C)C)c1ccc(N)cc1
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Product: CC(=O)N(CCN(C)C)c1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
The product was prepared according to general working method I from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and N-(4-amino-phenyl)-N-(2-dimethylamino-ethyl)-acetamide (142b).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)(=[O:3])[CH3:2].[CH3:13][I:14]>CCOCC>[I-:14].[CH3:13][N+:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:12]=1
Reactant: CI
Reactant: CC(=O)NCCc1cnccn1
Solvent: CCOCC
Product: CC(=O)NCCc1c[n+](C)ccn1
Product: [I-]

Procedure:
3.0 g of 2-(2-acetamidoethyl)pyrazine, prepared by the method of G. M. Singerman, et. al., J. Org. Chem., 30, 4379 (1965), was dissolved in 10 ml of ether and 10 ml of methyl iodide added. The flask was stoppered and stored in the dark for 2 weeks. The resultant solid was filtered, washed with ether and dried in vacuo to give 3.4 g of a yellow solid product (3800). It was recrystallized from ethyl acetate/ethanol, m.p. 138°-9°. UV H2O max: 226 (4.17), 281 (3.85).
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[CH2:8]([SH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1CCCCC1>[CH2:8]([S:15][C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)=CC(=O)O
Reactant: SCc1ccccc1
Solvent: C1CCNCC1
Product: CC(C)(CC(=O)O)SCc1ccccc1
Yield: 921.3 %

Procedure:
A solution of 3,3-dimethylacrylic acid (7 g, 70 mmol) and benzyl mercaptan (8.9 mL, 7.5 mmol) in piperidine (70 mL) was heated to reflux for 2 days. Piperidine was then evaporated and the product was partitioned between EtOAc and an aqueous solution of 1N HCl. The organic phase was washed with brine and dried over MgSO4. After evaporation of the solvent the product was distilled with a Kugelrohr apparatus under high vacuum (1 mmHg) to give 15.5 g of the title compound (99% yield).
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].[O:5]1[C:9]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[O:8][CH2:7][CH2:6]1.CCN(CC)CC.C(OCC)(=O)C>C(#N)C>[Cl:4][CH2:3][CH2:2][N:12]1[CH2:13][CH2:14][C:9]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:10][CH2:11]1
Reactant: ClCCBr
Reactant: C1CC2(CCN1)OCCO2
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: ClCCN1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 48 h
Yield: 6348.2 %

Procedure:
Step 1): 1-Bromo-2-chloroethane (10.0 g, 0.07 mmol) was added by portions to a solution of 1,4-dioxa-8-azaspiro[4,5]decane (1.0 g, 7.0 mmol) and Et3N (0.7 g, 7.0 mmol) in acetonitrile (10 ml) at 0° C. The mixture was stirred at 0° C. for 48 hours, poured into ethyl acetate and washed with water. The organic layer was dried (MgSO4) and concentrated to give 8-(2-chloroetyl)-1,4-dioxa-8-azaspiro-[4,5]decane (0.914 g, 63.5%) as a solid product.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([NH:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]([CH2:25][CH:26]([O:27][CH3:28])[O:29][CH3:30])[C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(CNC(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(CN(C(=O)c1ccccc1)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C)OC
Yield: 54.1 %

Procedure:
A solution of 3-benzyl-7-chloro-2-[1-(2,2-dimethoxy-ethylamino)-2-methyl-propyl]-3H-quinazolin-4-one (505 mg, 1.17 mmol), benzoyl chloride (247 mg, 1.76 mmol), and triethylamine (179 mg, 1.76 mmol) in methylene chloride (10 mL) was stirred at room temperature for 18 h. The reaction was washed sequentially with 0.5 N HCl, water, 5% NaHCO3, water, and brine. The organic layer was dried (Na2SO4) and concentrated to yield the title compound as an orange oil (338 mg, 54%). MS(ES+) m/e 534 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[C:31]5[O:30][CH2:29][CH2:28][C:27]=5[CH:26]=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.[NH3:32]>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[C:31]5[O:30][CH2:29][CH2:28][C:27]=5[CH:26]=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH2:32])=[O:13])=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21
Solvent: C1CCOC1
Product: NC(=O)Cn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) ammonia in THF, gave the title compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:18][C:19]([CH3:33])([CH3:32])[CH2:20][CH2:21][NH:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[SH:30].CCCCCC.CC(=O)OCC>CC(C)=O>[CH3:18][C:19]([CH3:33])([CH3:32])[CH2:20][CH2:21][NH:22][C:23]([C:24]1[C:25]([S:30][CH2:8][C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:31]
Reactant: CC(C)(C)CCNC(=O)c1cccnc1S
Reactant: O=C(CCl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)CCNC(=O)c1cccnc1SCC(=O)Cc1ccccc1
Temperature: 50 °C
Yield: 55 %

Procedure:
840 mg (6.1 mmol) of K2CO3 and 340 mg (2.0 mmol) of 1-chloro-3-phenylpropan-2-one were added to a solution of 450 mg (2.0 mmol) of N-(3,3-dimethylbutyl)-2-mercapto-nicotinamide in acetone (10 ml), and the mixture was then heated for 1 h at 50° C. Dilution with water (20 ml) and extraction with EA (2×30 ml) were then carried out. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 4:1) of the residue yielded 420 mg (1.1 mmol, 56%) of N-(3,3-dimethyl-butyl)-2-[(2-oxo-3-phenyl-propyl)sulfanyl]-pyridine-3-carboxylic acid amide. MS: m/z 371.2 [M+H]+.
Reaction SMILES: Cl.[F:2][C@@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.CCN(C(C)C)C(C)C.Br[CH2:22][CH2:23][CH:24]=[CH2:25]>C(#N)C>[CH3:11][O:10][C:8]([C@@H:5]1[CH2:4][C@H:3]([F:2])[CH2:7][N:6]1[CH2:25][CH2:24][CH:23]=[CH2:22])=[O:9]
Reactant: COC(=O)[C@@H]1C[C@H](F)CN1
Reactant: C=CCCBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCN1C[C@@H](F)C[C@H]1C(=O)OC
Temperature: 70 °C
Reaction time: 48 h

Procedure:
In a 25 mL round-bottomed flask, (2S,4S)-methyl 4-fluoropyrrolidine-2-carboxylate hydrochloride (160 mg, 871 μmol, Eq: 1.00) was combined with acetonitrile (3 mL) to give a white suspension. Hunig's base (282 mg, 380 μL, 2.18 mmol, Eq: 2.50) and 4-bromobut-1-ene (144 mg, 108 μL, 1.05 mmol, Eq: 1.20) were added sequentially. The reaction mixture was stirred at 70° C. for 2 days. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into an aqueous 5% Na2CO3 solution and extracted with DCM (2×). The organic layers were combined, washed with brine (1×), the organic layers were dried over Na2SO4 and concentrated in vacuo to yield a yellow liquid (160 mg; 91%). m/z=202.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH:16]=[C:4]2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:31][NH2:32].[CH2:33](O)[CH3:34]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[CH:16]=[C:4]3[N:3]=[C:2]([NH:31][N:32]=[CH:22][C:17]4[CH:15]=[CH:16][CH:4]=[C:33]([CH3:34])[CH:18]=4)[CH:7]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:5]3[N:14]=2)=[CH:18][CH:19]=1
Reactant: CCO
Reactant: NN
Reactant: Clc1ccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccc(Cl)cc4)cc3n2)c1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
There was suspended, in ethanol (2 mL), 5-chloro-2-(4-chloro-phenyl)-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine (50.0 mg, 0.143 mM) and then potassium carbonate (21.7 mg, 0.157 mM) and hydrazine monohydrate (69.4 μL, 1.43 mM) were added to the suspension. This suspension was stirred at 150° C. for 20 minutes, while applying microwaves to the same. This reaction liquid was diluted with a saturated aqueous common salt solution and then extracted with ethyl acetate. The extracts thus obtained were combined together and then dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting residue was suspended in ethanol (2 mL), then acetic acid (5.0 μL, 0.087 mM) and 3-methyl-benzaldehyde (17.0 μL, 0.144 mM) were added to the suspension and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methylene chloride) to give the title compound (36.8 mg, overall yield of these two steps: 58%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[S:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:18])C=1.[BH4-].[Na+].Cl.[OH2:24]>C(Cl)Cl>[CH3:1][CH:2]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[S:4](=[O:18])(=[O:24])[NH:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nsc2sccc12
Reactant: O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1NS(=O)(=O)c2sccc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 25 %

Procedure:
To a solution of the product from Step A (4.23 g, 27.2 mmol) in methylene chloride (40 mL) which had been degassed under nitrogen and cooled to 0° C. was added m-chloroperbenzoic acid (5.9 g, 24.1 mmol). After stirring for six hours the reaction mixture was filtered and the solvent removed. The residue was dissolved in dry THF (50 mL), cooled in an ice bath, and NaBH4 (1.7 g, 41 mmol) was added followed by allowing the reaction mixture to warm to room temperature with continued stirring for 18 hr. Water (25 mL) was added to the reaction mixture and after the pH was adjusted to 6.0 with 2N HCl it was extracted with ethyl acetate (3×10 mL). The combined extracts were dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, hexane/ethyl acetate) to provide 1.31 g (25%) of product: mp 79°-81° C.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O[N:23]1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.C[CH2:46][O:47][C:48]([CH3:50])=[O:49]>>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([NH:23][CH2:50][C:48]([O:47][CH3:46])=[O:49])=[O:14])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: COC(=O)CNC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Dipeptide Boc-Ser(Bzl)-Gly-OH: A solution of Boc-Ser(Bzl)-OH (23.6 g) and N-hydroxysuccinimide (9.8 g) in EtOAc (400 mL) was cooled to 0° C. A solution of DCC (71.54 g) in EtOAc (100 mL) was added to the cooled solution. The mixture was stirred at 0° C. for 4 h and then filtered. The collected solid was washed with EtOAc. The filtrate was cooled to 0° C. HCl.H-Gly-OCH3 (10.67 g) and DIEA (42 mL) was added to the cooled solution. The mixture was stirred for 18 h while the temperature of the mixture gradually came to room temperature. The mixture was filtered. The filtrate was concentrated to ca 400 mL, washed serially with H2O, 5% aqueous NaHCO3, 1N HCl and H2O, dried (Na2SO4 /MgSO4), and concentrated to dryness. The residual oil was dissolved in Et2O (100 mL). A flocculent precipitate developed which was removed by filtration. The filtrate was concentrated to dryness and dried under reduced pressure to give Boc-Ser(Bzl)-Gly-OCH3 as a colorless oil (28.7 g). A solution of the latter compound (28.0 g) in dioxane (140 mL) and H2O (60 mL) was cooled to 0° C. A solution of NaOH (4.0 g) in H2O (80 mL) was added dropwise to preceding solution. The mixture was stirred at 0° C. during the addition and for 15 min thereafter. The mixture was diluted with H2O and washed with Et 2 O. The aqueous phase was separated and shaken with EtOAc. Solid citric acid was added to mixture (pH=3-4). The aqueous layer was separated from the EtOAc and extracted with fresh EtOAc. The combined organic extracts were washed with H2O, dried (Na2SO4) and concentrated. The glassy residue was dried under high vacuum to give the dipeptide Boc-Ser(Bzl)-Gly-OH (27.22 g).
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH:13]=[CH:14][C:15]2[C:23]3[O:22][C:21]([CH3:25])([CH3:24])[CH2:20][C:19]=3[CH:18]=[C:17]([F:26])[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[F:26][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:28][CH:27]=2)[C:23]2[O:22][C:21]([CH3:25])([CH3:24])[CH2:20][C:19]=2[CH:18]=1
Reactant: [H][H]
Reactant: CC1(C)Cc2cc(F)cc(C=Cc3ccc(OCc4ccccc4)cc3)c2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)Cc2cc(F)cc(CCc3ccc(O)cc3)c2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 7-(4-(benzyloxy)styryl)-5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran (649) (207.7 mg, 0.583 mmol) in ethanol (6 mL) was added Pd/C (20 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred overnight at room temperature, was filtered through a pad of celite and concentrated in vacuo to give 4-(2-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)phenol (650).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[CH:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([CH2:32][N:33]5[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]5)[CH:23]=4)=[O:20])=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][N:4]=1)#[N:2].OO.C(=O)([O-])[O-:43].[K+].[K+]>CS(C)=O>[CH3:39][N:36]1[CH2:35][CH2:34][N:33]([CH2:32][C:24]2[CH:23]=[C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]3[CH:16]=[CH:17][C:12]([N:11]4[C:7]5[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:43])[C:8]=5[N:9]=[CH:10]4)=[CH:13][CH:14]=3)[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=2)[CH2:38][CH2:37]1
Reactant: O=C([O-])[O-]
Reactant: CN1CCN(Cc2cc(NC(=O)Nc3ccc(-n4cnc5c(C#N)nccc54)cc3)cc(C(F)(F)F)c2)CC1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(Cc2cc(NC(=O)Nc3ccc(-n4cnc5c(C(N)=O)nccc54)cc3)cc(C(F)(F)F)c2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
In 1 mL of dimethyl sulfoxide, 40 mg (0.07 mmol) of 1-[4-(4-cyano-imidazo[4,5-c]pyridin-1-yl)phenyl]-3-[3-(4-methylpiperazin-1-ylmethyl)-5-(trifluoromethyl)phenyl]urea was dissolved, and 40 μL (0.35 mmol) of a 30% hydrogen peroxide aqueous solution and 21 mg (0.15 mmol) of potassium carbonate were added thereto and the mixture solution was stirred at 50° C. for one hour. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and a saturated sodium chloride solution in the order named and concentrated under reduced pressure. The crude product was purified by a silica gel column (dichloromethane:methanol=10:1) to obtain 19 mg (45%) of a target product as a white solid.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10]OC(OC)N(C)C.Cl[CH2:19][C:20](=[O:22])[CH3:21]>C(OCC)(=O)C>[C:2]1([C:1]2[S:8][C:19]([C:20](=[O:22])[CH3:21])=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: COC(OC)N(C)C
Reactant: NC(=S)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)c1cnc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.6 %

Procedure:
A mixture of 10.0 g (72.9 mmol) of thiobenzamide and 17.4 g (146 mmol) dimethylformamide dimethyl acetal was stirred at room temperature for 2 hours. The volatiles were evaporated under reduced pressure. The residue was dissolved in ethanol (40 ml). To this solution was added 1.0 g (109 mmol) of chloroacetone and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was diluted with ethyl acetate and washed twice with aqueous sodium bicarbonate, once with water, once with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 3:97 acetone:hexanes as eluant to give 3.5 g of the title compound (25%). 1H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H), 8.01 (d, 2H), 7.49 (m, 3H), 2.61 (s, 1H).