Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:39]([C:35]2[CH:34]=[C:33]3[C:38](=[CH:37][CH:36]=2)[N:30]([CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:18]4[C:17]([C:15]([OH:16])=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:28][CH:27]=2)[C:31]([CH3:43])=[C:32]3[CH3:42])=[O:40])=[CH:4][CH:3]=1
Reactant: NCc1ccc(N)cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc(N)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-aminobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: C([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([S:15]([Cl:18])(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=O)C.Cl.[CH3:22][NH2:23]>>[ClH:18].[CH3:20][O:19][C:12]1[C:13]([S:15](=[O:17])(=[O:16])[NH:23][CH3:22])=[CH:14][C:7]2[CH2:6][CH2:5][NH:4][CH2:10][CH2:9][C:8]=2[CH:11]=1
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)CCN(C(C)=O)CC2
Reactant: CN
Agent: Cl
Product: CNS(=O)(=O)c1cc2c(cc1OC)CCNCC2

Procedure:
3-Acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (2 g) was stirred with 10 ml of 40% aqueous methylamine, then was treated with hydrochloric acid and concentrated in vacuo to give 8-methoxy-7-(N-methylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. This 8-methoxy-7-(N-methylsulfamoyl) compound was treated with boron tribromide in methylene chloride and then with methanol to give 8-hydroxy-7-(N-methylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 130°-135° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].O1CCOCC1.[I-:33].[Na+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.C(OCC)(=O)C.O>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([I:33])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Oc2cncc(Br)c2)SC[C@H]1OC(C)=O
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(I)c1
Temperature: 130 °C
Yield: 85 %

Procedure:
1.34 g (3 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-α-D-xylo-pyranoside, 10 ml of dioxane, 0.057 g (0.3 mM) of copper(I) iodide, 0.899 g (6 mM) of sodium iodide and 0.085 g (0.6 mM) of (1R,2R)—N,N′-dimethyl-1,2-cyclohexanediamine are mixed under an argon atmosphere in a reactor adapted for microwaves and the mixture is heated for 3 h 30 min at 130° C. 100 ml of water are added to the cooled reaction mixture and extraction is then carried out with ethyl acetate. The organic phase is washed with 1 N sodium thiosulfate solution and with water, dried over sodium sulfate and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using a toluene/acetone mixture (1/1; v/v) as the eluent to give the expected product in the form of a white solid with a yield of 85%.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:19](=O)([O:23]CC)[O:20][CH2:21][CH3:22]>>[CH3:18][CH2:17][O:16][C:14]([CH:13]([C:19]([O:20][CH2:21][CH3:22])=[O:23])[C:7]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=1[Cl:5])=[O:15]
Reactant: CCOC(=O)Cc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Cl)cc1Cl
Yield: 85 %

Procedure:
Sodium (1.86 g, 0.081M) was added in portions to absolute ethanol (150 ml) with stirring. After all the sodium had dissolved a solution of ethyl 2,4-dichlorophenylacetate (20 g) in diethyl carbonate (50 ml) was added dropwise. The reaction mixture was heated until EtOH distilled over. The rate of addition was controlled such that it equalled the rate of distillation. After the completion of addition the reaction mixture was heated and distilled for further 4 hours. The cooled reaction mixture was partitioned between water (300 ml) and EtOAc (300 ml) and the organic layer dried and evaporated in vacuo to give a yellow oil (21 g, 85%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[S:20][C:21]([S:24][CH2:25][C:26]2[O:27][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:29][N:30]=2)=[CH:22][N:23]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(Cl)Cl.O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15]([NH:18][C:19]2[S:20][C:21]([S:24][CH2:25][C:26]3[O:27][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:29][N:30]=3)=[CH:22][N:23]=2)=[O:17])[CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)O)CC1
Reactant: CC(C)(C)c1cnc(CSc2cnc(N)s2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(C(=O)Nc2ncc(SCc3ncc(C(C)(C)C)o3)s2)CC1
Reaction time: 8 h

Procedure:
To a solution of 5 g of crude 4-(t-butoxycarbonylamino)cyclohexane carboxylic acid and 3.50 g (13 mmol) of 2-amino-5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]thiazole in 13 mL of N,N-dimethylformamide and 36 mL of methylene chloride was added 5.0 g (26 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at room temperature. The reaction mixture was stirred overnight and diluted with 100 mL of water. The aqueous layer was separated and extracted with two-150 mL portions of ethyl acetate. The combined organic phases were dried (sodium sulfate) then filtered through a pad of silica gel. The filtrate was concentrated in vacuo to afford an orange solid. The crude material was recrystallized (95% ethanol) to give 4-(t-butoxycarbonylamino)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide as a yellow solid. The mother liquors were also concentrated in vacuo to give additional 4-(t-butoxycarbonylamino)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide as a brown solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:5](COC)[C:4]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>Cl>[OH:1][CH2:2][C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[NH:5][C:4]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1
Reactant: COCn1c(-c2ccncc2)c(C)c(CO)c1-c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(-c2ccncc2)[nH]c(-c2ccncc2)c1CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.1 %

Procedure:
3-Hydroxymethyl-1-methoxymethyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole (150 mg, 0.49 mmol) was dissolved in 10% aqueous HCl solution (20 mL) and the mixture was stirred for 1 day at room temperature then heated at reflux temperature for 1 hour. After cooling, the mixture was neutralized with saturated aqueous sodium bicarbonate solution. Volatiles were removed by evaporation, and the residue was suspended in EtOH. After removal of insolubles by filtration, the filtrate was concentrated in vacto. The crude product was purified by flash chromatography eluting with CH2Cl2—EtOH (5:1), followed by recrystallization from EtOH to give the title compound (30 mg, 23% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:30][C:31]([C:33]1[N:34]=[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:36][C:37]=1[CH3:38])=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([C:33]2[N:34]=[C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[O:36][C:37]=2[CH3:38])=[O:32])=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)CBr
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: Cc1oc(-c2ccccc2)nc1C(=O)Cn1cc(C(=O)N2CCC3(CC2)OC(=O)c2cc(F)ccc23)c2ccc(Cl)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with 2-bromo-1-(5-methyl-2-phenyl-oxazol-4-yl)-ethanone (described in Journal of Medicinal Chemistry (1992), 35(14), 2617-26) gave the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Li])CCC.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1.CCCCCC>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([OH:30])([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1ccc2ccccc2n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A solution of 2-bromoquinoline (2.0 g, 9.61 mmol) in tetrahydrofuran (10 mL) was added dropwise to a mixture of n-butyllithium in hexane (4.2 mL of a 2.5 M solution) and tetrahydrofuran (10 mL) at −65° C. under N2, and the mixture was stirred at this temperature for 1 hour. A solution of t-butyl-4-oxo-1-piperidine carboxylate (1.92 g, 9.61 mmol) in tetrahydrofuran (10 niL) was added dropwise over 3 minutes., after the addition, the reaction was slowly warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with sat. ammonium chloride (15 mL); the resulting mixture was stirred at ambient temperature for 10 minutes. The organic layer was separated, washed with water (20 mL), brine (20 mL), dried over magnesium sulfate. Concentration yielded 4-hydroxy-4-quinolin-2-yl-piperidine-1-carboxylic acid tert-butyl ester (3.16 g, 98%) as a yellow oil which was used without further purification. 1H NMR CDCl3 δ 8.20 (d, J=9 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.73 (t, J=8 Hz, 1H), 7.55 (t, J=7 Hz, 1H), 7.42 (d, J=9 Hz, 1H), 5.94 (brd s, 1H), 4.23-4.00 (m, 2H), 3.70 (t, J=6 Hz, 1H), 3.40-3.22 (m, 2H), 2.42 (t, J=6 Hz, 1H), 2.13-1.98(m, 2H), 1.49 (s, 9H).
Reaction SMILES: O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[Cl:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][C:23]2[N:24]=[C:25]([O:34][CH2:35][CH2:36][CH3:37])[C:26]3[N:31]=[C:30](SC)[O:29][C:27]=3[N:28]=2)=[CH:20][CH:19]=1.[NH2:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1.O>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].S1C=CC=C1C([O-])=O.[Cu+].C(OCC)(=O)C>[Cl:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][C:23]2[N:24]=[C:25]([O:34][CH2:35][CH2:36][CH3:37])[C:26]3[N:31]=[C:30]([C:45]4[CH:46]=[C:41]([NH2:40])[CH:42]=[CH:43][CH:44]=4)[O:29][C:27]=3[N:28]=2)=[CH:20][CH:19]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(SC)nc12
Agent: [Cu+]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cccc(N)c3)nc12
Temperature: 80 °C
Yield: 31.2 %

Procedure:
Under argon atmosphere, 13.1 mg of tris(dibenzylideneacetone)dipalladium and 13.3 mg of tri(furan-2-yl)phosphine were added to a solution of 125 mg of 5-(4-chloro-benzyl)-2-methylsulfanyl-7-propoxy-oxazolo[5,4-d]pyrimidine, 81.7 mg of copper(I)thiophene-2-carboxylate and 58.7 mg of 3-amino-benzeneboronic acid in 3.5 ml of tetrahydrofuran. The mixture was heated to 80° C. for 2 h in a microwave reactor (CEM Discover). After cooling, 3 ml of water and 3 ml of ethyl acetate were added. The mixture was filtered through a ChemElut cartridge and the cartridge washed with ethyl acetate. The combined filtrates were evaporated in vacuo. Preparative HPLC (method HPLC1) of the residue yielded 44 mg of the title compound in the form of the 3-[5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-phenylamine trifluoroacetic acid salt.
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)[C:4]=1[C:17]1[C:18]([CH3:27])=[C:19]([C:23]([O:25]C)=[O:24])[O:20][C:21]=1[CH3:22])=[O:2].B(Br)(Br)Br>C(Cl)Cl>[CH:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:4]=1[C:17]1[C:18]([CH3:27])=[C:19]([C:23]([OH:25])=[O:24])[O:20][C:21]=1[CH3:22])=[O:2]
Reactant: COC(=O)c1oc(C)c(-c2c(-c3ccc(OC)cc3)nn(C)c2C=O)c1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1oc(C(=O)O)c(C)c1-c1c(-c2ccc(O)cc2)nn(C)c1C=O
Temperature: 25 °C
Yield: 88.1 %

Procedure:
methyl 4-(5-formyl-3-(4-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)-3,5-dimethylfuran-2-carboxylate (55 mg, 0.15 mmol) was dissolved in CH2Cl2 (7.5 mL) and BBr3 (1 M solution on DCM, 0.75 mL, 0.75 mmol) was added and stirred at room temperature over night. The reaction was quenched using water and extracted with CH2Cl2. Concentration and filtration trough a short plug of silica gave 4-(5-formyl-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazol-4-yl)-3,5-dimethylfuran-2-carboxylic acid (45 mg, 75%) which was used as such in the next step.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][O:7][C:8]1[CH:20]=[CH:19][C:11]2[NH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:10]=2[CH:9]=1.C([O-])(O)=O.[Na+]>CC(O)=O.CCOC(C)=O.O>[Cl:4][C:9]1[C:10]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[NH:12][C:11]=2[CH:19]=[CH:20][C:8]=1[O:7][CH3:6]
Reactant: COc1ccc2[nH]c(C(F)(F)F)nc2c1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2[nH]c(C(F)(F)F)nc2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
Sulfuryl chloride (0.39 mL, 4.86 mmol) was added dropwise to a 0° C. solution of 5-(methyloxy)-2-(trifluoromethyl)-1H-benzimidazole (1.0 g, 4.63 mmol) in HOAc (10 mL). The ice bath was removed and the mixture was allowed to stir at rt for 2 h. The concentrated reaction mixture was suspended in a mixture of EtOAc and H2O and the pH was adjusted to 7 with saturated aqueous NaHCO3. The reaction was partitioned and the aqueous portion was extracted with EtOAc. The combined organic fractions were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound (0.93 g): MS (ESI) m/z 251 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C>C1COCC1>[F:13][C:14]1[C:15]([B:27]([OH:32])[OH:28])=[CH:16][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)=[CH:18][N:19]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(CN2CCSCC2)cn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OB(O)c1cc(CN2CCSCC2)cnc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of diisopropylamine (0.767 mL, 5.43 mmol) in 2 mL of THF at −40° C. was treated with n-butyllithium (3.4 ml of 1.6 M solution in hexanes, 5.43 mmol) and stirred at this temperature for 30 min. The solution was cooled to −78° C. and treated dropwise via cannula with a solution of 4-((6-fluoropyridin-3-yl)methyl)thiomorpholine (922 mg, 4.34 mmol) in THF (2+2 mL) over 10 min. The brown mixture was stirred at −78° C. for 90 min and then treated dropwise via syringe with a solution of triisopropyl borate (1.49 mL, 6.51 mmol) in THF (1 mL). The mixture was stirred at −78° C. for 30 min. The cooling bath was removed, and the reaction mixture was allowed to warm up to RT. The mixture was quenched with 1.0 N NaOH (5 mL) and stirred for an additional 30 min. The mixture was transferred to a separatory funnel and extracted with 5 mL of ether. The ether layer was discarded, and the aqueous layer was carefully acidified with 2.5 N aqueous HCl until acidic (pH 4about5) and the resulting cloudy mixture was diluted with EtOAc (50 mL). The separated aqueous layer was extracted with EtOAc (2×15 mL) and the combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to give 2-fluoro-5-(thiomorpholinomethyl)pyridin-3-ylboronic acid (790 mg, 3.08 mmol, 71.0% yield) as an off-white crystalline solid. 1H NMR (400 MHz, d4-MeOH) δ 8.11 (1H, d, J=2.5 Hz); 8.00 (1H, dd, J=8.0, 2.5 Hz); 3.75 (2H, s.); 2.91 (4H, m); 2.73 (4H, br. s.). m/z (ESI, +ve ion) 257 (M+H)+.
Reaction SMILES: N(C[CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][N:12]=[C:13]=[O:14])[CH2:6]1)=C=O.[N-:15]=[C:16]=[O:17].[N-]=[C:19]=O.O=C1CC(C)(C)CC(C)=C1>>[N:12]([CH2:11][CH:7]1[CH2:6][CH2:5][CH:10]([CH2:19][N:15]=[C:16]=[O:17])[CH2:9][CH2:8]1)=[C:13]=[O:14]
Reactant: O=C=NCC1CCCC(CN=C=O)C1
Reactant: [N-]=C=O
Solvent: CC1=CC(=O)CC(C)(C)C1
Product: O=C=NCC1CCC(CN=C=O)CC1

Procedure:
1,3-bis-(isocyanato-methyl)-cyclohexane (H6XDI) isophorone-di-isocyanate
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[N:4][CH:5]=[C:6]([C:11]=1[O:12][CH3:13])[C:7](OC)=[O:8].[BH4-].[Na+].[Cl-].[NH4+]>CO>[Cl:1][C:2]1[C:11]([O:12][CH3:13])=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[CH3:14]
Reactant: COC(=O)c1cnc(C)c(Cl)c1OC
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COc1c(CO)cnc(C)c1Cl
Yield: 105.7 %

Procedure:
The above methyl 5-chloro-4-methoxy-6-methylnicotinate (1.0 g) was dissolved in 30 ml of methanol, and sodium borohydride (1.75 g) was then added to the solution. The resulting mixture was heated under reflux for 1 hour. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution under cooling on ice, followed by extraction with chloroform three times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away, so as to obtain the title compound (0.92 g) as an oily substance.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]1([C:12]2N(C(C)C)N=[CH:14][C:13]=2[CH:20]=[O:21])[CH2:11][CH2:10]1>>[CH:9]([C:12]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[CH:14][C:13]=1[CH:20]=[O:21])([CH3:11])[CH3:10]
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Reactant: NNc1ccccc1
Product: CC(C)c1c(C=O)cnn1-c1ccccc1

Procedure:
5-Isopropyl-1-phenyl-1H-pyrazole-4-carbaldehyde was prepared from ethyl 3-oxo-3-methyl-pentanoate and phenyl hydrazine in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: C([C@@H:4]1[CH2:7][C@H:6]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][C:17]=3[F:30])=[C:11]([CH2:31][CH2:32][CH3:33])[N:10]3[N:34]=[C:35]([CH3:37])[N:36]=[C:9]23)[CH2:5]1)(=O)C.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:43].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:30][C:17]1[CH:18]=[C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:21][C:16]=1[CH2:15][C:12]1[C:13](=[O:14])[N:8]([C@H:6]2[CH2:5][C@@H:4]([OH:43])[CH2:7]2)[C:9]2[N:10]([N:34]=[C:35]([CH3:37])[N:36]=2)[C:11]=1[CH2:31][CH2:32][CH3:33]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](C(C)=O)C2)c2nc(C)nn12
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: ClC(Cl)Cl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](O)C2)c2nc(C)nn12
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a mixture of 4′-{[4-(cis-3-acetylcyclobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (2.83 g), 30% aqueous hydrogen peroxide solution (28.5 mL) and chloroform (30 mL) was added trifluoroacetic acid anhydride (15.75 mL), and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in tetrahydrofuran (5 mL)-methanol (5 mL) was added 2 N aqueous sodium hydroxide solution (4 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was acidified with 1 N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel chromatography [eluent: hexane/ethyl acetate=60/40→35/65 (volume ratio)] to give the title compound as a colorless amorphous compound (1.70 g, 63%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([NH:7][C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cccc(NC(=O)CCl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of potassium carbonate (773 mg, 5.59 mmol) in dichloromethane (25 mL) was added m-toluidine (0.5 mL, 4.66 mmol) followed by dropwise addition of chloroacetyl chloride (0.44 mL, 5.59 mmol) and the mixture was stirred at ambient temperature overnight. The reaction was quenched by addition of water, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated under vacuum to provide 2-chloro-N-m-tolyl-acetamide. MS (DCI-NH3): m/z 201 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH:3]=1.[O:21]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)C>C(O)C>[O:21]([C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]3)[CH:3]=2)=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ncn2)C1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)C1
Temperature: 100 °C
Yield: 41.9 %

Procedure:
To a stirring solution of tert-butyl 3-(6-chloropyrimidin-4-ylamino)pyrrolidin-1-carboxylate (0.5 g, 1.6 mmol) and 4-phenoxy aniline (0.309 g, 1.6 mmol) in ethanol (4 mL) was added acetic acid (0.1 mL) and the reaction mixture was heated at 100° C. for 36 h. The reaction mixture was cooled, ethanol was removed under reduced pressure and the residue was taken in ethyl acetate (10 mL). It was washed with NaHCO3 solution (2 mL), brine (2 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was further purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to yield tert-butyl 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)pyrrolidine-1-carboxylate (0.3 g, 42.8%) as a white solid.