Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[O:10])[CH:5]=[N:4][CH:3]=1.[CH2:24]1[C@@H:28]2[CH2:29][NH:30][CH2:31][C@@H:27]2[CH2:26][N:25]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>>[CH3:23][O:22][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([NH:11][C:9](=[O:10])[NH:8][C:6]3[N:7]=[C:2]([N:30]4[CH2:29][C@@H:28]5[CH2:24][N:25]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26][C@@H:27]5[CH2:31]4)[CH:3]=[N:4][CH:5]=3)=[CH:13][CH:14]=[N:15]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Reactant: COc1ccc2c(NC(=O)Nc3cncc(Br)n3)ccnc2c1
Product: COc1ccc2c(NC(=O)Nc3cncc(N4C[C@H]5CN(C(=O)OC(C)(C)C)C[C@H]5C4)n3)ccnc2c1
Yield: 65 %

Procedure:
The compound was prepared by the method described for Example 1 using 1-(6-bromopyrazin-2-yl)-3-(7-methoxyquinolin-4-yl)urea and (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate as starting compounds and was obtained as a white solid (96 mg, 65%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[C:10]1([CH:16]([CH3:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C(=S)=S>[CH:16]([C:10]1[CH:15]=[CH:14][C:13]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:12][CH:11]=1)([CH3:18])[CH3:17]
Reactant: CCC(=O)Cl
Reactant: CC(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: CCC(=O)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.1 %

Procedure:
Propionyl chloride (11.6 g, 125 mmol) was dropwise added to a suspension of aluminium chloride (16.7 g, 125 mmol) and cumene (18.0 g, 150 mmol) in carbon disulfide (30 mL) at −5° C., and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into water with ice, and the organic layer was separated, washed with an aqueous saturated sodium hydrogencarbonate and water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 1-(4-isopropylphenyl)propan-1-one (24.7 g). Sodium borohydride (1.29 g, 34.2 mmol) was added to a solution of the thus-obtained compound (13.0 g, 68.4 mmol) in ethanol (80 mL) with cooling with ice, and the mixture was stirred for 30 minutes at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (11.5 g, yield 79%). This was oily.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17](/[CH:26]=[CH:27]/[C:28]([O:30]C)=[O:29])[C:16]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N2C(C3C=CC(OCC4C=CC=CC=4)=CC=3)=CC(/C=C/C(O)=O)=N2)CCCCC1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])[C:16]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/c1nn(C2CCCCC2)c(-c2ccc(OCc3ccccc3)cc2)c1-c1ccccc1
Agent: O=C(O)/C=C/c1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Product: O=C(O)/C=C/c1nn(C2CCCCC2)c(-c2ccc(OCc3ccccc3)cc2)c1-c1ccccc1
Yield: 95 %

Procedure:
Acid 8.7 was prepared from ester 8.6 according to the procedure described above for the preparation acid 2.4. Thus, 8.6 (50 mg, 0.11 mmol) was saponified to yield 46 mg (95%) of 8.7. HRMS (ESI) calc'd for C31H31N2O3, 479.2335, found 479.2343 (MH+); 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=15.7, 1H), 7.46–7.21 (m, 8H), 7.12–7.08 (m, 4H), 6.97 (d, J=8.7, 2H), 6.60 (d, J=15.7, 1H), 5.06 (s, 2H), 4.04–3.97 (m, 1H), 2.10–1.85 (m, 5H), 1.65 (br s, 1H), 1.33–1.22 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[N:14]([O-])=O.[Na+]>O.Cl>[Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:7][C:5]([NH:6][NH2:14])=[C:4]([F:13])[CH:3]=1
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1cc(NN)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
A stirred solution of 11.0 g (0.054 mole) of 4-chloro-2-fluoro-5-(1-methylethoxy)aniline and 50 mL of concentrated hydrochloric acid was cooled to 0° C. and a solution of 3.7 g (0.054 mole) of sodium nitrite in 15 mL of water was added dropwise. The reaction mixture temperature was not allowed to rise above 6° C. during the addition. Upon completion of addition the reaction mixture stirred at 0° C. for 30 minutes and a solution of 26.8 g (0.12 mole) of stannous chloride in 30 mL of concentrated hydrochloric acid was added dropwise. Upon completion of addition the reaction mixture was stirred at 0° C. for one hour then was filtered to collect a solid precipitate. The solid was slurried in 100 mL of aqueous 25% sodium hydroxide and collected by filtration to give 11.0 g of 4-chloro-2-fluoro-5-(1-methylethoxy)phenylhydrazine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2Cl)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[NH:22]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.N12CCCN=C1CCCCC2.C(OCC)(=O)C>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[N:22]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(Cn2c(Cl)nc3ccccc32)o1
Reactant: C1CNCCNC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)o1
Reaction time: 48 h

Procedure:
Combine 1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-2-chloro-1H-benzimidazole (10 mmol), [1,4]diazepane (10 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.8 mL) in pyridine (20 mL). Heat to reflux. After 2 days, evaporate in vacuo to give a residue. Combine the residue and ethyl acetate. Extract with water and brine. Dry the the organic layer over Na2SO4, filter, and evaporate in vacuo to give 4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:34]([CH2:36][CH2:37][CH2:38][CH2:39][CH:40]([CH:52]=O)[CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=1)#[N:35].[Cl-].[NH4+]>CCCCCC.C1COCC1>[C:34]([CH2:36][CH2:37][CH2:38][CH2:39][CH:40](/[CH:52]=[CH:10]/[C:9]1[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=1[OH:7])[CH2:41][C:42]1[CH:43]=[CH:44][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:50][CH:51]=1)#[N:35]
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(CC(C=O)CCCCC#N)cc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCCCC#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.9 %

Procedure:
14.34 ml (35.85 mmol) of a 2.5 M solution of n-butyllithium in hexane are slowly added to a solution of 5.753 g (12.81 mmol) of (2-hydroxybenzyl)triphenylphosphonium bromide in 300 ml of anhydrous THF at 0° C. Then, at this temperature, 3.5 g (12:81 mmol) of methyl 4-(6-cyano-2-formylhexyl)benzoate from Example 118A are slowly metered in. After warming to room temperature, the reaction solution is stirred for 4 hours, then mixed with saturated ammonium chloride solution and concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). 2976 mg (64% yield) of a colorless solid are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[C:11]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]([CH3:17])=[CH:13][C:14]=2[CH3:16])[NH:9][CH2:8]1)=[O:4].I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH2:26]([N:9]1[C:10]2[C:15](=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=2[NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[CH:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:8]1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: COC(=O)CCC1CNc2c(NC(=O)C(C)(C)C)c(C)cc(C)c21
Reactant: CCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCN1CC(CCC(=O)OC)c2c(C)cc(C)c(NC(=O)C(C)(C)C)c21
Temperature: 40 °C
Reaction time: 10 h
Yield: 82.2 %

Procedure:
N-[3-(2-Methoxycarbonylethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide (1.0 g) was dissolved in DMF (10 ml) and 1-iodooctane (1.44 g) and K2CO3 (830 mg) were added, which was followed by stirring at 40° C. for 10 hr. AcOEt (100 ml) was added, and after washing with water, the mixture was dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt=20/1-5/1) to give 1.1 g of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH2:14][CH3:15])[CH:5]=2)[CH2:3][CH2:2]1.[I:16]I.S(=O)(=O)(O)O>CC(O)=O>[CH:1]1([C:4]2[C:13]([I:16])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH2:14][CH3:15])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CCc1cc(C2CC2)ccc1C(=O)OC
Reactant: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCc1cc(C2CC2)c(I)cc1C(=O)OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
To a round-bottom flask was added a solution of methyl 4-cyclopropyl-2-ethylbenzoate (compound 226.3, 5.00 g, 24.5 mmol, 1.00 equiv) in AcOH (40 mL). I2 (6.80 g, 26.8 mmol, 1.10 equiv), NaIO4 (2.60 g, 12.2 mmol, 0.50 equiv), and sulfuric acid (400 mg, 4.08 mmol, 0.15 equiv) were added to the reaction. The resulting solution was stirred for 2 h at 50° C. After cooling to ambient temperature, the reaction was carefully quenched with Na2S2O3 (aq., sat.). The mixture was extracted with 2×100 mL of ethyl acetate, and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with petroleum ether/ethyl acetate (20:1) as eluent to furnish 4.00 g (49%) of methyl 4-cyclopropyl-2-ethyl-5-iodobenzoate as a yellow oil.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: O=Cc1ccccc1O
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccccc1OCCCCCBr

Procedure:
A solution of salicylaldehyde (82 mmoles) in acetone (50 ml) was added dropwise to a refluxing solution of 1,5-dibromopentane (90.2 mmoles), potassium carbonate (90.2 mmoles) and potassium iodide (0.4 g) in acetone (200 ml). The mixture was refluxed for 18 hours, filtered and the filtrate concentrated. The residue was dissolved in ether and washed with cold 10% sodium hydroxide solution, water and brine. The organic layer was dried over magnesiun sulfate and concentrated. The product was purified by flash chromatography (4% ethyl acetate/hexane) to give 2-(5-bromopentoxy)benzaldehyde. A mixture of this compound (11.1 mmoles), 4-acetyl-3-hydroxy-2-propyl phenol (11.62 mmoles) and potassium carbonate (5.55 mmoles) in acetone (30 ml) was refluxed for 5 days, stirred at room temperature for 2 days and then refluxed for 24 hours. The suspension was cooled to room temperature, filtered and the filtrate concentrated. The residue was dissolved in ethyl acetate and then washed with ice-cold 5% sodium hydroxide solution, water and brine. The dried solution was concentrated and the product flash chromatographed to give the desired product.
Reaction SMILES: COC1C=C2C([C@H]3[C@@](O)(C2)COC2C=C(O)C=CC3=2)=CC=1OC.N#N.[CH3:26][O:27][C:28]([C:30]1[CH:34]=[C:33](Br)[O:32][C:31]=1[CH3:36])=[O:29].CC1(C)C(C)(C)OB([C:45]2[CH:50]=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=2)O1.C(=O)(O)[O-].[Na+]>COCCOC.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>[CH3:26][O:27][C:28]([C:30]1[CH:34]=[C:33]([C:45]2[CH:50]=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=2)[O:32][C:31]=1[CH3:36])=[O:29]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: COC(=O)c1cc(Br)oc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1cc2c(cc1OC)[C@@H]1c3ccc(O)cc3OC[C@]1(O)C2
Agent: N#N
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(N)cc2)oc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
DK002+003 (The following reaction is carried out in a N2 atmosphere.) Dissolve Pd(PPh3)4 (1.26 g, 1.09 mmol) and 5-Bromo-2-methyl-furan-3-carboxylic acid methyl ester (53) (4.77 g, 21.77 mmol) in DME (116 mL) and stir for 15 min at rt. Add 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (5.25 g, 23.96 mmol) followed by an aqu. 1M sodium bicarbonate solution (65.4 mL, 65.3 mmol). Degas the reaction mixture carefully, flush with N2 (5 times) and stir for 4 h at 95° C. (reflux). Cool reaction mixture to rt, remove organic solvent under reduced pressure and partition the residue between water and EtOAc. Extract the aqu. layer with EtOAc (3 times), wash the combined organic layer with water and brine and dry it with Na2SO4. Purify the obtained crude product by flash chromatography (silica gel, EtOAc/CyH 1+2) to obtain 5-(4-Amino-phenyl)-2-methyl-furan-3-carboxylic acid methyl ester (54) (2.35 g, 46%) as a yellow-brown solid. 1H NMR (400 MHz, CDCl3): 2.60 (s, 3H); 3.74 (br.s, 2H); 3.82 (s, 3H); 6.64 (s, 1H); 6.67 (dt, 1H, J1=8.6 Hz, J2=2.3 Hz); 7.42 (dt, 2H, J1=8.8 Hz, J2=2.3 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7](Br)[N:6]=1)=[O:4].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([CH3:27])[CH:19]=1>>[NH2:11][C:10]1[C:5]([C:3]([OH:2])=[O:4])=[N:6][C:7]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][C:20]=2[CH3:27])=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Product: Cc1cc(Cl)ccc1-c1nc(C(=O)O)c(N)cc1C(F)(F)F

Procedure:
This compound was prepared from 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) and 4-chloro-2-methylphenylboronic acid analogously to Intermediate H; LC-MS Rt=1.53 mins, [M+H]+ 331 (Method 2 min LC_v002).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18]O)[C:15]([CH3:20])=[N:14]1.[BrH:21].S(=O)(=O)(O)O>O>[Br:21][CH2:18][C:16]1[C:15]([CH3:20])=[N:14][N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=2[Cl:12])[N:17]=1
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1CO
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1CBr

Procedure:
A mixture of this product (38.5 g) and caesium carbonate (32.6 g) in tetrahydrofuran (1000 ml) was stirred at room temperature for 1 hour. The mixture was stirred at room temperature for 11/2 hours. The solvent was evaporated under reduced pressure and the residue taken up in ether. The extract was washed with water, dried and evaporated. The residue was triturated with light petroleum (bp 40°-60°) and filtered to give 2-(2,6-dichloro-4-trifluoro-methylphenyl)-2H-1,2,3-triazole-4-carboxaldehyde oxime. A mixture of 2-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-2H-1,2,3-triazol-4-ylmethanol (4.1 g). hydrobromic acid (10 ml of 48%) and concentrated sulphuric acid (1ml) was heated under reflux for 10 minutes. The mixture was added to water and extracted with ether. The extract was worked up to give 4-bromomethyl-2-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-2H-1,2,3-triazole, m.p. 98°-100°. Compound 6 (5 g), isopropanol (50 ml) and methanol (20 ml) was added sodium borohydride (0.67 g), portionwise. The mixture was stirred at room temperature overnight. Water was added and the mixture made acidic with hydrochloric acid. The mixture was extracted with ether and the extract washed with brine dried and evaporated to give [2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazol-4-yl]methanol, mp 87°-88°.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH2:29][CH2:28]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:38]([C:37]3[CH:36]=[CH:35][C:34]([CH2:33][N:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)=[CH:41][CH:40]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cscn3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: Brc1cnc2[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1N1CCN(Cc2cscn2)CC1
Temperature: 85 °C
Yield: 19.7 %

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-4-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.045 g, 0.11 mmol), EtOH (2.6 mL) and DMF (0.35 mL), 4-(morpholinomethyl)-benzaldehyde (0.025 g, 0.12 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.33 mL, 0.33 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a off-white solid (0.012 g, 20%); 1H-NMR (500 Mz, DMSO-d6): δ 2.33-2.43 (m, 4H), 2.65-2.73 (m, 4H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.64-3.72 (m, 4H), 3.77 (s, 2H, NCH2), 7.47 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.58 (d, J=2.0 Hz, 1H, thiazole 5-H), 8.14 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 9.07 (d, J=2.0 Hz, 1H, thiazole 2-H), 13.46 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 1.95 min—554/556 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 554.1338, calculated for C25H29N7OSBr (M+H)+: 554.1339.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=2[CH:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[CH:33]=3)[CH2:28]2)=O)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(OC1C=CC(CCNC2C=C(OC)C=CC=2C2CCC3C(=CC=C(OC)C=3)C2)=CC=1)C1C=CC=CC=1>>[CH3:26][O:25][C:23]1[CH:22]=[CH:21][C:20]([CH:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[CH:33]=3)[CH2:28]2)=[C:19]([NH:18][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH:24]=1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NC(=O)Cc1ccc(OCc3ccccc3)cc1)C2
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(OCc3ccccc3)cc1)C2
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(O)cc1)C2

Procedure:
Synthesized from 2-(4-benzyloxyphenyl)-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide according to an analogous synthetic method to Example 337, [2-(4-benzyloxyphenyl)ethyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (2.3 g) was used according to an analogous synthetic method to Example 22 to provide the title compound (1.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][CH3:14])[C:7]([CH:15]=[O:16])=[CH:6]2>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][CH3:14])[C:7]([CH2:15][OH:16])=[CH:6]2
Reactant: CNc1nc2ccc(OC)cc2cc1C=O
Solvent: C1CCOC1
Product: CNc1nc2ccc(OC)cc2cc1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
To a stirred solution of 6-methoxy-2-(methylamino) quinoline-3-carbaldehyde SLA 28150 (1.006 g, 4.65 mmol) in THF (80 mL) in a 250 mL round-bottomed flask equipped with a magnetic stirrer was added sodium borohydride NaBH4 (0.176 g, 4.65 mmol) and the mixture was stirred for 4 h at RT then cooled in an ice bath before quenching by addition of a 1 N aq. HCl solution (40 mL). After stirring for 15 min at RT, the mixture was basified to pH=9 with a 2 N aq. NaOH solution. THF was then removed at 40° C. under vacuum and the solution was extracted with CH2Cl2 (200 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give (6-methoxy-2-(methylamino)quinolin-3-yl)methanol SLA 28152 as an orange oil (0.907 g, 89% yield).
Reaction SMILES: C1([C:7]([N:9]2[CH:13]3[CH2:14][CH2:15][C:10]2([C:16]([O:18]C)=[O:17])[CH2:11][CH2:12]3)=[O:8])C=CC=CC=1>Cl>[CH2:16]([O:17][C:7]([N:9]1[CH:13]2[CH2:12][CH2:11][C:10]1([C:16]([OH:18])=[O:17])[CH2:15][CH2:14]2)=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C12CCC(CC1)N2C(=O)c1ccccc1
Agent: Cl
Product: O=C(OCc1ccccc1)N1C2CCC1(C(=O)O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A mixture of methyl 7-(phenylcarbonyl)-7-azabicyclo[2.2.1]heptane-1-carboxylate (8.0 g) produced above and concentrated hydrochloric acid (100 mL) was heated under reflux for 24 hr, and concentrated under reduced pressure. To the residue was added water (50 mL), and the mixture was washed twice with ethyl acetate. To the obtained aqueous layer was basified with sodium carbonate, a solution of sodium carbonate (9.80 g) and benzylchlorocarbonate (5.40 mL) in 1,4-dioxane (30 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was washed twice with ethyl acetate, and the aqueous layer was adjusted to pH3 with 2M hydrochloric acid. The organic product was extracted 3 times with ethyl acetate (150 mL), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (2.45 g) as a yellow solid.
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].[NH2:8][C:9]1[N:10]=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:12][C:13]=1[C:14]([NH2:16])=[O:15].[OH-].[Na+].Cl>C(O)C.C(O)(=O)C>[CH3:1][C:2]1[NH:8][C:9]2[N:10]=[C:11]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[S:12][C:13]=2[C:14](=[O:15])[N:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1sc(N2CCOCC2)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc(=O)c2sc(N3CCOCC3)nc2[nH]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
A mixture of acetic anhydride (4 ml, 42.4 mmol), Acetic Acid (2.00 ml) and 4-amino-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (200 mg, 0.876 mmol) was stirred at 60° C. for 3 h, then quenched with methanol and concentrated under reduced pressure. A mixture of the residue, Ethanol (2.000 ml) and 6N NaOH (2 ml, 12.00 mmol) was irradiated (uwave) at 120° C. for 30 min, then acidified with 6N HCl to pH ˜5. The precipitate was collected, rinsed with water, and dried under vacuum to furnish 5-methyl-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (175 mg, 79%). LC/MS: MS(ES+) m/e 253 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.31 (s, 3H) 3.54-3.59 (m, 4H) 3.69-3.75 (m, 4H) 12.34 (br. s., 1H).