Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[CH:24])[CH2:18][C@@H:17]1[C:25]([O:27][CH3:28])=[O:26].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1I.C(N(CC)CC)C>C(#N)C.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>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[C:24][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[F:29])[CH2:18][C@@H:17]1[C:25]([O:27][CH3:28])=[O:26]
Reactant: C#CCN1CC[C@@H](CCCc2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Reactant: Fc1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(CC#Cc2ccccc2F)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 20 h

Procedure:
0.041 g of tetrakis(triphenylphosphine)palladium and 0.070 g of cuprous iodide were added, at a temperature in the region of 20° C. and under an inert atmosphere, to a stirred solution of 0.7 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylate in 14 cm3 of acetonitrile. 0.32 cm3 of 1-fluoro-2-iodobenzene and 0.51 cm3 of triethylamine were subsequently added. The mixture was stirred at a temperature in the region of 20° C. for 20 hours. The reaction mixture was filtered and the cake was washed with 3 times 10 cm3 of acetonitrile. The combined filtrates were taken up with stirring in a mixture of 100 cm3 of dichloromethane and 100 cm3 of water. The organic phase was separated by settling, washed with 3 times 50 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, and then, after filtration, concentrated under reduced pressure (2 kPa) at a temperature in the region of 35° C. The residue obtained was purified by chromatography under argon pressure (50 kPa) on a column of silica gel (particle size 40-63 μm; diameter 4 cm; height 14 cm), elution was carried out with ethyl acetate, and 2-cm3 fractions were collected. Fractions 33 to 160 were combined and then evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.56 g of methyl (3R,4R)-4-(3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2-fluorophenyl)prop-2-ynyl]piperidine-3-carboxylate was obtained in the form of an oil with a light brown color.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]\[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:40][CH2:41][C:42]([NH:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:43]>C1COCC1.CCOCC>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]\[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:15])([F:17])[F:16])[CH:8]=[CH:7][C:3]=1[C:4]([NH:40][CH2:41][C:42](=[O:43])[NH:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:6]
Reactant: NCC(=O)NCC(F)(F)F
Reactant: O=C(O)c1ccc(/C=C\C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CNC(=O)c1ccc(/C=C\C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br)NCC(F)(F)F
Temperature: 50 °C

Procedure:
To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added carbonyldiimidazole (82 mg, 0.51 mmol). The mixture was heated in a 50° C. oil bath for 1.5 h, treated with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (109 mg, 0.057 mmol) and the resulting mixture heated to reflux for 8 h. After cooling to ambient temperature, the mixture was taken up in Et2O and washed twice with aqueous 5% sodium bisulfate (NaHSO4) (2×) and once with saturated NaCl (1×). After dying over MgSO4, concentration in vacuo and purification by medium pressure chromatography on silica with EtOAc/Hexanes as the eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61° C.: 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=7.9 Hz, 1H), 7.44-7.29 (m, 3H), 7.14 (dd, J=7.9, 1.6 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 6.59 (br s, 1H), 6.21-6.04 (m, 1H), 4.23 (d, J=5.5 Hz, 1H), 3.98 (qd, J=9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −69.31, −72.3; EIMS m/z 626.9 ([M+1]+).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]([CH:10]=[N:11][C@@H:12]([CH3:16])[C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C@@H:12]([CH3:16])[C:13]([NH2:15])=[O:14])=[CH:17][CH:18]=1
Reactant: C[C@H](N=Cc1ccc(OCc2ccccc2F)cc1)C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](NCc1ccc(OCc2ccccc2F)cc1)C(N)=O
Temperature: 3.5 °C
Yield: 95 %

Procedure:
A mixture of (S)-2-[4-(2-fluorobenzyloxy)benzylideneamino]propanamide (IIIb) prepared as described above (30 g) and methanol (180 mL) is cooled under stirring to 2-5° C. Sodium borohydride (3.8 g) is added in eighteen small portions in 90 min to the previously prepared cold mixture keeping the temperature below 5° C. The mixture is then stirred for additional 10 min at 5° C. The reaction mixture is concentrated under vacuum and worked up as described in Example 2 to provide 28.75 g (95% yield) of (S)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (ralfinamide, Ib) with a HPLC purity of 99.5 (area %) determined according to the method of Example 25A and a C,O-dialkylated (5)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide content less than 0.005% by weight determined by HPLC, according to the method of Example 25B.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCCCCCOCCc1ccccn1
Reactant: NCc1ccccc1
Product: c1ccc(CNCCCCCCOCCc2ccccn2)cc1

Procedure:
2-[2-[(6-Bromohexyl)oxy]ethyl]pyridine (6.3 g) was added to benzylamine (20 ml) at 140° under nitrogen. After 1 h at 140° the reaction mixture was cooled and partitioned between 2M sodium hydroxide (100 ml) and ether (100 ml). The organic layer was washed with water and brine, dried and concentrated to a yellow oil. The excess benzylamine was removed by distillation under reduced pressure to leave the title compound as a yellow oil (6.8 g) t.l.c. (System A 80:20:2) Rf 0.44.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH2:16]2)=[CH:11][CH:10]=1.Br[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:22]([Cl:35])[CH:21]=1>C1(C)C=CC=CC=1>[Cl:35][C:22]1[CH:21]=[C:20]([N:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][C:9]([F:8])=[CH:10][CH:11]=3)[CH2:16]2)[CH:25]=[C:24]([CH3:26])[C:23]=1[NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:32])([CH3:31])[CH3:33]
Reactant: Cc1cc(Br)cc(Cl)c1NC(=O)CC(C)(C)C
Reactant: Fc1ccc2c(c1)CNCC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3ccc(F)cc3C2)cc(Cl)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol), 7-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (121 mg, 0.65 mmol) and N-(4-bromo-2-chloro-6-methylphenyl)-3,3-dimethylbutanamide (200 mg, 0.63 mmol) were then added and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid.
Reaction SMILES: [O:1]1CCNCC[O:3][B:2]1[C@@H:9]([NH:14][C:15](=[O:33])[C@@H:16]([NH:24][C:25]([C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][CH:11]([CH3:13])[CH3:12].Cl>CO>[B:2]([OH:3])([OH:1])[C@@H:9]([NH:14][C:15]([C@@H:16]([NH:24][C:25]([C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)=[O:26])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:33])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OCCNCCO1
Agent: Cl
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B(O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
A 100 ml three neck round bottom flask was equipped with a stir bar, thermocouple and nitrogen inlet/outlet then charged with 5.0 g (10.4 mmol) of (2S)—N-[(1R)-1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl]-3-phenyl-2-(pyrazin-2-ylformamido)propan-amide (i.e., boronic ester of Formula XI), 50 ml of methanol and 10.4 ml of 2N aqueous hydrochloric acid. The reaction was stirred at room temperature overnight before removing the solvent in vacuo at 40° C. The resulting residue was dissolved in 50 ml of ethyl acetate and washed with saturated sodium bicarbonate (1×50 mL) before once again concentrating the organic to dryness in vacuo. The residue was then triturated overnight at room temperature with 50 mL of pentane under nitrogen. The resulting free flowing solids were collected by vacuum filtration, washed with pentane (1×20 ml) then dried in a vacuum oven at 30° C. overnight to provide 3.29 g (8.56 mmol, 82.3%) of the title compound as a white solid. HPLC analysis indicated chemical purity >99.8 A % and a 93.5:6.5 ratio of diastereomers (i.e., 87% de).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[ClH:19].Cl.[NH2:21][CH2:22][CH2:23][O:24][NH2:25].N1C=CC=CC=1>C(O)C>[ClH:1].[ClH:19].[NH2:21][CH2:22][CH2:23][O:24][N:25]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=C(CCCn1ccnc1)c1ccc(Cl)c(Cl)c1
Reactant: NCCON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NCCON=C(CCCn1ccnc1)c1ccc(Cl)c(Cl)c1
Reaction time: 3 h
Yield: 65.7 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)-4-(1-(1H)-imidazolyl)-1-butanone (2.29 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.45 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for three hrs. The reaction mixture was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and evaporated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 1.1 g (33%) of product, mp 205°-208° C. (dec).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[ClH:22]>CO>[ClH:22].[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:3]([N:2]([CH3:21])[CH3:1])=[O:20]
Reactant: CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-tert-butyloxycarbonyl-(S)-phenylalanine dimethylamide (Preparation 7, 24.8 g, 84 mmol) in methanol (50 mL) was added a solution of hydrochloric acid (4N, in dioxane, 40 mL) and the mixture stirred at rt for 3 h. The resulting solution was concentrated in vacuo then dissolved in water (300 mL). The aqueous solution was washed with ethyl acetate (3×100 mL) and concentrated again. Successive recrystallisations with methanol (200 mL) and a mixture of methanol and toluene (1:1, 200 mL) gave the title compound as colourless crystals. δH (D2O) 2.75, 2.90 (6H, 2×s), 3.18 (2H, m), 4.72 (1H, t), 7.28–7.45 (5H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:29]([O-])=O)=[C:14]([CH2:16][CH2:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:27]([O:26][C:24]([CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:16][C:14]1[CH:15]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:11]=[CH:12][C:13]=1[NH2:29])=[O:25])[CH3:28]
Reactant: CCOC(=O)C(CCc1cc(CNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-])C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCc1cc(CNC(=O)OC(C)(C)C)ccc1N)C(=O)OCC
Yield: 93.9 %

Procedure:
A solution of ethyl 4-(5-tert-butoxycarbonylaminomethyl-2-nitrophenyl)-2-ethoxycarbonylbutanoate (3.2 g, 7.3 mmol) in ethyl acetate (30 mL) was hydrogenated over palladium/charcoal (500 mg) under atmospheric pressure of hydrogen at room temperature for 2.5 h. The mixture was passed through celite and the filtrate was concentrated to give 2.8 g of the title compound (94%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[N:3]=[CH:2]1.N1C=CC(=O)N=C1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[S:28])[N:3]=[CH:2]1
Reactant: O=c1nc[nH]c2ccccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=c1cc[nH]cn1
Product: S=c1nc[nH]c2ccccc12

Procedure:
In the next step the carbonyl function of the 1H-quinazolin-4-one derivative, or the 1H-pyrimidin-4-one derivative with a condensed 5-membered heterocyclic ring structure is reacted further e.g. with phosphorous pentasulfide or Lawesson's reagent to yield the 1H-quinazolin-4-thion derivatives, or the 1H-pyrimidin-4-thion one derivatives with a condensed 5-membered heterocyclic ring structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.[BH4-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:15]([O:17][CH3:18])=[O:16])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1
Reactant: COC(=O)C(=Cc1ccc(OC)cc1[N+](=O)[O-])C(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Cc1ccc(OC)cc1[N+](=O)[O-])C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a solution of dimethyl (4-methoxy-2-nitrophenyl)methylidenemalonate (25 g) in methanol (200 ml) was added sodium borohydride (3.36 g) in an ice bath. After stirring at room temperature for 1 hr, the reaction mixture was neutralized by adding 1 N aqueous hydrochloric acid. The reaction mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried and concentrated. The residue was purified by silica gel column chromatography (eluent:ethyl acetate:hexane=1:4) to obtain the titled compound (19 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]2[S:19][C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:17][C:16]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([S:36]([C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=3[F:46])(=[O:38])=[O:37])[CH2:33][O:34][CH3:35])[C:27]=2[F:47])[CH:12]=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:49](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:48])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]2[S:19][C:18]([CH:20]3[CH2:25][CH2:24][N:23]([CH3:49])[CH2:22][CH2:21]3)=[N:17][C:16]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([S:36]([C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=3[F:46])(=[O:37])=[O:38])[CH2:33][O:34][CH3:35])[C:27]=2[F:47])[CH:12]=[CH:11][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCN(c1cccc(-c2nc(C3CCNCC3)sc2-c2ccnc(CNC(=O)OC(C)(C)C)c2)c1F)S(=O)(=O)c1cc(F)ccc1F
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COCN(c1cccc(-c2nc(C3CCN(C)CC3)sc2-c2ccnc(CNC(=O)OC(C)(C)C)c2)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
Tert-butyl-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-2-(piperidin-4-yl)-1,3-thiazol-5-yl]pyridin-2-yl}methylcarbamate (65 mg, 0.09 mmol) was dissolved in MeOH (5 mL) and glacial acetic acid (15 μL, 0.26 mmol). 37% aqueous formaldehyde (6.5 μL, 0.13 mmol) and sodium cyanoborohydride (8.5 mg, 0.17 mmol) were then added to the mixture, that was stirred at r.t. for 1 h. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and 15% aqueous ammonia. The organic phase was dried over Na2SO4 and evaporated to dryness, to give 34 mg of tert-butyl-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-2-(1-methylpiperidin-4-yl)-1,3-thiazol-5-yl]pyridin-2-yl}methylcarbamate that were employed for the next step without any further purification.
Reaction SMILES: [N:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][C:9]2[C:10]([CH2:20][CH3:21])=[N:11][N:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[CH2:28][CH3:29])[CH3:25]>C(#N)C.CCOC(C)=O.[Cu]I>[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[C:28]1[N:3]=[N:2][N:1]([C:4]2[CH:23]=[CH:22][C:7]([CH2:8][C:9]3[C:10]([CH2:20][CH3:21])=[N:11][N:12]4[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=34)=[CH:6][CH:5]=2)[CH:29]=1)[CH3:25]
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(CC)OCC
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(OCC)c1cn(-c2ccc(Cc3c(CC)nn4c(C)cc(C)nc34)cc2)nn1

Procedure:
A solution of 3-(4-azido-benzyl)-2-ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidine (20) (2 g, 6.53 mmol), propionaldehyde diethylacetal (1.294 g, 9.79 mmol) and copper(I) iodide (1.492 g, 7.83 mmol) in 33 ml of acetonitrile was stirred at r.t. for 24 h. The reaction was diluted in EtOAc and washed with sat aq Na2 CO3, water and brine. The organic layer was dried over anhydrous Na2 SO4, filtered and concentrated under HV. The crude product was purified by flash chromatography (silica gel, EtOAc/DCM 0% to 50%) to give a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:9]2=[O:27])=[C:4]([OH:28])[CH:3]=1.[C:29]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:29][O:28][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][C:18]1[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)[C:9]3=[O:27]
Reactant: O=C1C(c2ccc(Br)cc2O)c2ccccc2N1Cc1ccc(C(F)(F)F)o1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C12COc1cc(Br)ccc12

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(4-bromo-2-hydroxyphenyl)-1-((5-(trifluoromethyl)furan-2-yl)methyl)indolin-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6-bromo-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-2H-spiro[benzofuran-3,3′-indolin]-2′-one was obtained (78%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.30 (ddd, J=7.9, 7.9, 1.5 Hz, 1H), 7.16-7.03 (m, 3H), 6.69 (d, J=7.9 Hz, 1H), 6.93 (dd, J=8.2, 1.8 Hz, 1H), 6.77-6.71 (m, 1H), 6.53 (d, J=8.2 Hz, 1H), 6.42-6.37 (m, 1H), 5.06 (d, J=16.1 Hz, 1H), 4.97 (d, J=9.4 Hz, 1H), 4.86 (d, J=16.1 Hz, 1H), 4.71 (d, J=9.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ176.5, 161.5, 151.8, 141.4, 131.6, 129.3, 128.0, 124.5 (d), 124.0, 114.2, 112.6 (d), 109.2 (d), 80.1, 57.5, 36.9; MS (ES+) m/z 463.9 (M+1), 465.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]=O)[CH:3]=1.[NH2:11][OH:12].Cl.C([O-])(=O)C.C(O)(=O)C.[Na+]>C(O)C.O>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]=[N:11][OH:12])[CH:3]=1
Reactant: NO
Reactant: Cc1nc(Br)cc(C=O)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(Br)cc(C=NO)n1
Temperature: 90 °C
Yield: 33.8 %

Procedure:
To a stirred solution of 6-bromo-2-methylpyrimidine-4-carbaldehyde (11 g, 54.7 mmol, Preparation #17 step 1) and NH2OH.HCl (7.61 g, 109 mmol, Sisco Research Labs) in ethanol (75 mL) and water (25 mL) was added sodium acetate acetate (13.47 g, 164 mmol). The reaction mixture was heated to reflux at about 90° C. for about 1 h. The mixture was cooled to RT and diluted with water (200 mL). The separated product (solid) was collected by filtration, washed with water and dried under vacuum to afford 6-bromo-2-methylpyrimidine-4-carbaldehyde oxime 4.0 g (33.8%), 1H NMR (400 MHz, DMSO) δ: 12.43 (s, 1H), 8.01 (s, 1H), 7.78 (s, 1H), 2.61 (s, 3H), MS m/z: 216 (negative mode).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][NH:20][C:21]3[N:30]=[C:29]([N:31]([CH3:33])[CH3:32])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([O:34][C:35]([F:38])([F:37])[F:36])[CH:3]=1.[H-].[Na+].I[CH3:42]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][NH:20][C:21]3[N:30]=[C:29]([N:31]([CH3:33])[CH3:32])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH2:15][CH2:14]2)[CH3:42])(=[O:10])=[O:9])=[C:4]([O:34][C:35]([F:36])([F:37])[F:38])[CH:3]=1
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CNS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1nc(NC[C@H]2CC[C@H](CN(C)S(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
To a solution of trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide obtained in step H of example 1 (380 mg, 0.61 mmol) in DMF (2 mL) was added 60% sodium hydride in oil (24.6 mg, 0.61 mmol). The reaction mixture was stirred at ambient temperature for 80 min. The reaction mixture was cooled at 0° C. and iodomethane (38.3 μL, 0.61 mmol) was added and stirred at ambient temperature for 3 hr. The reaction was quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 25% EtOAc in hexane, and silica gel, 5% MeOH in CHCl3) to give trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-N-methyl-2-trifluoromethoxy-benzenesulfonamide (268 mg, 69%) as a pale yellow solid.