Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1B1OC(C)(C)C(C)(C)O1.[Br:30][C:31]1[CH:32]=[C:33]2[C:41](I)=[CH:40][N:39]([CH3:43])[C:34]2=[C:35]([O:37][CH3:38])[N:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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]>[Br:30][C:31]1[CH:32]=[C:33]2[C:41]([C:6]3[CH:7]=[C:8]([CH2:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=3[F:1])=[CH:40][N:39]([CH3:43])[C:34]2=[C:35]([O:37][CH3:38])[N:36]=1
Reactant: COc1nc(Br)cc2c(I)cn(C)c12
Reactant: CC1(C)OB(c2cc(CS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)OC1(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: COc1nc(Br)cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
The product from Example 91D (0.058 g, 0.136 mmol), the product from Example 91C (0.05 g, 0.136 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.74 mg, 4.09 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (3.98 mg, 0.014 mmol) and potassium phosphate (0.087 g, 0.409 mmol) were combined and sparged with argon for 15 minutes. Meanwhile a solution of 4:1 dioxane/water (2 mL) was sparged with nitrogen for 15 minutes and transferred by syringe into the reaction vessel under argon. The mixture was stirred for 2 hours at ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), treated with 3-mercaptopropyl functionalized silica gel, filtered, and concentrated. Purification by chromatography (silica gel, 10-50% ethyl acetate in heptanes) afforded the title compound (0.064 g, 87%).
Reaction SMILES: [I:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.Br[CH2:23][CH2:24][CH2:25][NH:26][C:27]([CH:29]1[CH2:31][CH2:30]1)=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:21][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[C:12]([S:11][C:3]1[C:2]([I:1])=[CH:10][C:6]3[CH2:7][CH2:8][O:9][C:5]=3[CH:4]=1)[N:13]2[CH2:23][CH2:24][CH2:25][NH:26][C:27]([CH:29]1[CH2:31][CH2:30]1)=[O:28]
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3I)CCO4)nc12
Reactant: O=C(NCCCBr)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1I)CCO3)n2CCCNC(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a solution of 8-((5-iodo-2,3-dihydrobenzofuran-6-yl)thio)-9H-purin-6-amine (26 mg, 0.06 mmol) in DMF (1.5 mL) was added N-(3-bromopropyl)cyclopropanecarboxamide (39 mg, 0.18 mmol) and Cs2CO3 (41 mg, 0.12 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2Cl2:NH3-MeOH (7N), 20:1) to yield WS61 as a white solid (12 mg, 35%). 1H NMR (600 MHz, CDCl3): δ 8.30 (s, 1H), 7.57 (s, 1H), 7.16 (m, 1H), 6.55 (s, 1H), 5.67 (br s, 2H), 4.50 (t, J=8.8 Hz, 2H), 4.22 (t, J=6.3 Hz, 2H), 3.13 (t, J=8.6 Hz, 2H), 3.01-3.07 (m, 2H), 1.80-1.86 (m, 2H), 1.38-1.44 (m, 1H), 0.87-0.93 (m, 2H), 0.67-0.72 (m, 2H); HRMS (ESI) m/z [M+H]+ calcd. for C20H22IN6O2S, 537.0570. found 537.0567.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:31])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=4[O:29][CH3:30])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:32][NH2:33]>>[F:31][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])[C:15]2[O:14][CH:13]([CH2:12][NH:33][CH3:32])[CH2:17][C:16]=2[CH:18]=1
Reactant: COc1ccc(C)cc1-c1cc(F)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(F)cc(-c3cc(C)ccc3OC)c2O1

Procedure:
The title compound was prepared (0.77 g, 48%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-(2-methoxy-5-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.45 mmol) and methylamine (0.139 g, 4.5 mmol). mp 197-199° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([NH:22][C:23]([N:25]3[CH2:34][CH2:33][C:32]4[CH:31]=[N:30][C:29]([NH:35][CH:36]([CH3:38])[CH3:37])=[N:28][C:27]=4[CH2:26]3)=[O:24])[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.O1CCOCC1.Cl>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([NH:22][C:23]([N:25]3[CH2:34][CH2:33][C:32]4[CH:31]=[N:30][C:29]([NH:35][CH:36]([CH3:38])[CH3:37])=[N:28][C:27]=4[CH2:26]3)=[O:24])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)NC1(c3ccc(Cl)c(Cl)c3)CCN(C(=O)OC(C)(C)C)CC1)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: CC(C)Nc1ncc2c(n1)CN(C(=O)NC1(c3ccc(Cl)c(Cl)c3)CCNCC1)CC2

Procedure:
To a stirred solution of 362 (102 mg, 0.1810 mmol) in DCM (1.8 mL) at RT in a capped flask was added MeOH (180 μL) followed by 4M HCl dioxane solution (452.5 μL, 1.810 mmol). After 2 h the reaction was diluted with Et2O (5 mL) which produced a coarse yellow precipitate. The solid was filtered off and washed with generous amounts of ether to afford 80 mg (80%) of I-93 as a pale yellow solid which was dried under high vacuum: MS m/z (APCI-pos) M+1=463.4.
Reaction SMILES: [NH:1]([C:8]([N:10]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=3)=[N:22][CH:23]=2)[CH2:13][CH2:12]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:50])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[NH:1]([C:8]([N:10]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:11]1[CH2:12][CH2:13][N+:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])=[CH:27][CH:26]=3)=[N:22][CH:23]=2)([O-:50])[CH2:15][CH2:16]1)=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc(CN3CCC(N(C(=O)Nc4ccccc4)c4ccccc4)CC3)cn2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1ccc(Oc2ccc(C[N+]3([O-])CCC(N(C(=O)Nc4ccccc4)c4ccccc4)CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the compound prepared in Example 8(10) (361 mg) in chloroform (6.1 ml) was added m-chloroperbenzoic acid (116 mg) on ice bath. The reaction mixture was stirred for 4 hours at room temperature. To reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was washed with chloroform and methanol, dried to give the compound of the present invention (194 mg) having the following physical data.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[C:14](=[O:24])[CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:17][CH:18]=1>C(Cl)Cl.O>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[C:14](=[O:24])[CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:17][CH:18]=1
Reactant: CCOC(=O)c1cc(=O)c(-c2ccccc2OC)co1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc(=O)c(-c2ccccc2O)co1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boron tribromide (3.0 ml) was added dropwise to a stirred solution of ethyl 5-(2-methoxyphenyl)-4-oxo-4H-pyran-2-carboxylate (3.2 g) in methylene chloride (100 ml) at 5°-10° C. The mixture was stirred for 2 hours at room temperature, then cooled to 5° C. and carefully diluted with water (50 ml). The solid title product was recrystallised from ethanol (mp 187°-189° C.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH2:17][CH2:18][OH:19])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH3:37][S:38]([O:19][CH2:18][CH2:17][CH:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH2:8][CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)(=[O:40])=[O:39]
Reactant: COc1ccc(C(CCO)c2ccccc2OCCN2CCOCC2)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(CCOS(C)(=O)=O)c2ccccc2OCCN2CCOCC2)cc1OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
To a solution of (S)-1-(3-(2-morpholinoethoxyphenyl)-3-(3,4-dimethoxyphenyl)propan-1-ol (0.4 g, 1.0 mmol) in dichloromethane (5.0 mL) under N2 was added triethylamine (0.4 g, 4.0 mmol). The solution was then cooled to 0° C., methanesulfonyl chloride (0.28 g, 2.5 mmol) was added, and the reaction was stirred at 0° C. for 1.5 h. Ice cold water (5.0 mL) was added to the reaction mixture and it was extracted with dichloromethane. The combined organic extract was washed with a cold solution of ammonium chloride, brine, then dried over anhydrous MgSO4. Evaporation of the solvent afforded (S)-1-(3-(2-morpholinoethoxyphenyl)-3-(3,4-dimethoxyphenyl)propyl methanesulfonate (0.42 g, 88% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]([O:15]C2C=CC=CC=2)=O)[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:23]=1>>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([NH:31][C:13]([NH:12][C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[O:15])(=[O:30])=[O:29])[CH:23]=1
Reactant: NS(=O)(=O)c1cccnc1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1cccnc1

Procedure:
As the starting substances, methyl 4-chloro-2-phenoxycarbonylaminobenzoate and pyridine-3-sulfonamide were used and the same method was applied as in Example 36 to obtain N-(3-pyridine sulfonyl)-N'-(2-methoxycarbonyl-5-chlorophenyl)urea and further to obtain from 1.3 g (3.66 mmol) of N-(3-pyridine sulfonyl)-N'-(2-carboxyl-5-chlorophenyl)urea 1.1 g of the above-identified compound (yield 88.3%). Properties: colorless crystal, Melting point: >226° C. (decomposition), PMR (δppm, DMSO-d6):7.10 (1H,s), 7.24 (1H,d), 7.73 (1H,t), 7.85 (1H,d), 8.50 (1H,d), 7.93 (1H,d), 9.23 (1H,s), 11.68 (1H,s).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:13]1[CH:18]=[N:17][CH:16]=[CH:15][N:14]=1>CCOC(C)=O>[N:14]1[CH:15]=[CH:16][N:17]=[CH:18][C:13]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Clc1cnccn1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Nc2cnccn2)cc1
Temperature: 150 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
Into a 250 mL roundbottom flask, was placed methyl 4-aminobenzoate (vii) (10 g, 66.23 mmol) followed by the addition of 2-chloropyrazine (75.9 g, 665.79 mmol). The resulting solution was stirred at 150° C. for 4 hours. The reaction progress was monitored by TLC (EtOAc/PE=1:2). After completion, the reaction was cooled to room temperature and the undissolved material was filtered off. The filtration was dissolved in 400 mL of water and the pH was adjustmented to 9 by the addition of Na2CO3. The resulting solution was extracted four times with 800 mL of EtOAc and the organic layers were combined and dried over Na2SO4. Removal of the solvent and volatile components from the organic layer under reduced pressure provided the crude product methyl 4-(pyrazin-2-ylamino)benzoate (viii) (13.6 g, 90% yield) as a yellow solid which was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1)=[O:4].CN(C=O)C>CCOC(C)=O>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([OH:16])[CH2:8][CH2:7]1)=[O:4]
Reactant: O=C1CC[C@@H](NC(=O)C(F)(F)F)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CC[C@@H](O)c2ccccc21)C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
(R)-2,2,2-Trifluoro-N-(4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (0.5 g), RuCl[(R,R)-Tsdpen(p-cymene)] and DMF (25 mL) were added to a flask that was purged with argon (catalyst prepared using procedure from Org Syn, Vol 82, pg 10-17, note 5). Triethylamine and HCOOH were added and the reaction mixture was stirred at 50° C. overnight. Further addition of catalyst (0.06 g), TEA (0.4 mL) and HCOOH (0.12 mL) were required to drive the reaction to completion after continued heating at 50° C. for an additional 6-8 hr. The reaction mixture was cooled to room temp, diluted with 150 mL EtOAc, and washed with 20 mL distilled water. The organic phase was dried over MgSO4 and concentrated in vacuo, and purified by column chromatography (eluting with 1% MeOH/DCM), to give 0.417 g (83%) of the titled compound. 1H-NMR (300 MHz, CDCl3) □ 7.5 (d, 1H), 7.3 (m, 2H), 7.2 (d, 1H), 6.4 (broad s, 1H), 5.3 (q, 1H), 4.8 (d, 1H), 2.4 (m, 1H), 2.2 (m 1H), 1.8 (m, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH2:15]([C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1)[CH:16]=[CH2:17].[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[CH2:15]([C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:26])[O:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])=[CH:7][CH:8]=2)[CH:21]=[CH:22][CH:23]=1)[CH:16]=[CH2:17]
Reactant: COC(COc1ccc(O)cc1)OC
Reactant: C=CCc1cccc(N=C=O)c1
Agent: [N-]=C=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCc1cccc(NC(=O)Oc2ccc(OCC(OC)OC)cc2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-(2,2-Dimethoxyethoxy)phenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. 3-Allylphenyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is stripped of solvent and unreacted isocyanate to yield the desired product O-[4-(2,2-dimethoxyethoxy)phenyl] N-3-allylphenylcarbamate as the residue.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH:13]=O)[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].Cl>CC(O)=O.CO>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH2:13][N:27]1[CH2:26][CH2:25][N:24]([CH:23]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:20]2[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=2)[CH2:29][CH2:28]1)[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)C[C@@H](CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
(S)-(1-Formyl-3-methyl-butyl)-carbamic acid tert-butyl ester (0.39 mg, 1.8 mmol) and 1-bis(4-fluorophenyl)methyl piperazine (0.50 g, 1.7 mmol) were dissolved in 1% HOAc in methanol (8 mL) under nitrogen atmosphere at ambient temperature. After stirring at that temperature for 1 hour, a solution of sodium cyanoborohydride (250 mg, 3.6 mmol) in methanol was added. The resulting reaction mixture was stirred at ambient temperature for 24 hours at which time TLC showed no starting aldehyde. 3N aqueous HCl was added in 5 mL portions until bubbling subsided; pH was adjusted to 8 with saturated aqueous NaHCO3 solution. The resulting mixture was extracted with EtOAc (3×25 mL), the combined organic solution was washed with brine (50 mL) and dried over MgSO4. The solution was concentrated in vacuo affording an amber oil. The crude product was further purified by flash chromatography (20%-30% EtOAc in hexanes) affording 342 mg (41%) of the pure titled compound as a clear oil. APCI-MS m/z 488.3 (MH+).
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][C:7]([NH2:9])=[O:8])#[N:5].[Cl:10][C:11]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:12]=1[C:13]([C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[N+:21]=[N-:22])=[CH:17][CH:16]=1)=[O:14].C(O)(=O)C>C(O)C>[NH2:5][C:4]1[N:20]([CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:13](=[O:14])[C:12]3[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:11]=3[Cl:10])=[CH:24][CH:23]=2)[N:21]=[N:22][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: [N-]=[N+]=NCc1ccc(C(=O)c2c(Cl)cccc2Cl)cc1
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=O)c1nnn(Cc2ccc(C(=O)c3c(Cl)cccc3Cl)cc2)c1N
Reaction time: 0.17 h
Yield: 4.9 %

Procedure:
A stirred, 65° C. mixture of sodium methoxide (330 mg, 6.11 mmol) in absolute ethanol (20 ml) was treated with 2-cyanoacetamide (527 mg, 6.27 mmol) and kept 10 minutes. The resulting suspension was treated with 4-(2,6-dichlorobenzoyl)benzyl azide (1.6 g, 5.2 mmol), refluxed 2 hours, cooled, treated with glacial acetic acid (600 μl, 629 mg, 10.5 mmol), and evaporated to dryness under vacuum. The residue was chromatographed on a column of silica gel (100 g) eluted with 19:1 (v/v) dichloromethane-methanol to provide 100 mg (5%) 5-amino-1-(4-[2,6-dichlorobenzoyl]benzyl)-1,2,3-triazole-4-carboxamide, m.p. 165°-167° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:7][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][OH:10])([CH3:6])[C:4]#[N:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>COC(C)(C)C>[NH2:5][CH2:4][C:3]([NH:7][CH:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][OH:10])([CH3:6])[C:2]([F:17])([F:18])[F:1]
Reactant: CC(C#N)(NC(CO)c1ccccc1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Product: CC(CN)(NC(CO)c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
31 g (120.0 mmol) of 3,3,3-trifluoro-2-[(2-hydroxy-1-phenylethyl)amino]-2-methylpropanonitrile from Example 48A were initially charged in tert-butyl methyl ether (3.1 l) and cooled to 0° C., 18.25 g (480.2 mmol) of lithium aluminium hydride were added and the reaction mixture was stirred at RT for 16 h. Subsequently, the mixture was cooled to 0° C., first quenched with 24 ml of water, then admixed with 24 ml of 15% aqueous potassium hydroxide solution and 48 ml of water. The resulting mixture was filtered through silica gel and washed with tert-butyl methyl ether. The organic phase was separated off, dried over sodium sulphate, filtered and concentrated. This gave 29.2 g (83% of theory, purity 89%) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH3:13])[CH:6]=[CH:5]2.C1C(=O)N([Br:21])C(=O)C1>C1COCC1>[Br:21][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[O:12][CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2cc(Br)ccc2c1
Solvent: C1CCOC1
Product: COc1ccc2cc(Br)ccc2c1Br

Procedure:
6-Bromo-2-methoxynaphthalene (5.9 g, 24.81 mmol, 1 eq) and NBS (4.41, 24.81 mmol, 1 eq) are boiled in 50 ml of THF under reflux for 2 h. After washing with 1 N HCl, the organic phase is dried over magnesium sulfate, filtered and concentrated in vacuum on a rotary evaporator. The compound is obtained in quantitative yield (7.8 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[N:11]1[S:12][N:13]=[C:14]2[C:19]([CH:20]=O)=[CH:18][CH:17]=[CH:16][C:15]=12>>[N:11]1[S:12][N:13]=[C:14]2[C:19]([CH2:20][NH:7][C@@H:5]([CH3:6])[CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])=[CH:18][CH:17]=[CH:16][C:15]=12
Reactant: O=Cc1cccc2nsnc12
Reactant: CCOC(OCC)[C@H](C)N
Product: CCOC(OCC)[C@H](C)NCc1cccc2nsnc12
Yield: 93.6 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-2, (S)-1,1-diethoxypropan-2-amine (Compound XIX-1) 883 mg (6.0 mmol) was reacted with benzo[c][1,2,5]thiadiazole-4-carbaldehyde 837 mg (5.1 mmol) to obtain the title compound 1.41 g (95%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[OH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([O:13][CH2:2][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])=[CH:15][CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(O)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(COc2ccc(C#N)cc2)c1
Temperature: 20 °C

Procedure:
10.00 kg (43.6 mol) of methyl 3-(bromomethyl)benzoate and 5.21 kg (43.74 mol) of 4-hydroxybenzonitrile are dissolved in 100 litres of acetone and stirred with 8.4 kg (60.7 mol) of potassium carbonate in the presence of 0.1 kg of sodium iodide for about 4 h under reflux conditions. Then 35 litres of acetone are distilled off and 100 litres of water are added at reflux conditions. The reaction mixture is cooled to 20° C. and the crystallisation is completed by the addition of another 30 litres of water. The crystals formed are separated off, washed with 50 litres of water and dried in vacuo.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[C:6]=2[CH:7]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:17][O:16][C:8]1[C:6]2[CH:7]=[C:3]([CH2:2][N:18]3[CH2:23][CH2:22][N:21]([CH2:2][C:3]4[S:4][C:5]5[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[C:6]=5[CH:7]=4)[CH2:20][CH2:19]3)[S:4][C:5]=2[CH:11]=[C:10]([O:12][CH3:13])[C:9]=1[O:14][CH3:15]
Reactant: COc1cc2sc(CCl)cc2c(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc2sc(CN3CCN(Cc4cc5c(OC)c(OC)c(OC)cc5s4)CC3)cc2c(OC)c1OC

Procedure:
2-Hydroxymethyl-4,5,6-trimethoxbenzothiophene (374 mg) was treated in the same manner as in Preparation Example 4, and 2-chloromethyl-4,5,6-trimethoxy-benzothiophene thus obtained was immediately reacted with piperazine (63 mg) in the same manner as in Example 1 without isolating it to obtain the title compound as a free base.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]([NH2:19])=[O:18])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[N:6]=1.[CH3:20][O:21][CH:22]([O:33][CH3:34])[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25](F)[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:34][O:33][CH:22]([O:21][CH3:20])[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([NH:1][C:2]2[S:3][C:4]([C:17]([NH2:19])=[O:18])=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:13]([F:16])([F:14])[F:15])[N:6]=2)[CH:24]=1
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NC(=O)c1sc(N)nc1-c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(OC)c1ccc([N+](=O)[O-])c(Nc2nc(-c3ccccc3C(F)(F)F)c(C(N)=O)s2)c1
Temperature: 0 °C
Yield: 68.1 %

Procedure:
A mixture of 0.20 g (0.70 mmole) of 2-amino-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (V.17), 0.18 g (0.84 mmole) of 4-dimethoxymethyl-2-fluoro-1-nitro-benzene (IV.2a) and 1.14 g (3.5 mmole) of cesium carbonate in 12 mL of dimethylformamide was heated to 60 degrees for 3 hours, then cooled. The mixture was poured into ice water, extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (gradient 100:0-50:50) gave 0.23 g of 2-(5-dimethoxymethyl-2-nitro-phenylamino)-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.17a) as a yellow solid.