Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)=[CH:5][CH:4]=2)[CH2:26][CH2:25]1
Reactant: CC(=O)NC1(c2ccc(CCl)cc2)CC1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Product: CC(=O)NC1(c2ccc(CN3CCN(c4ncccn4)CC3)cc2)CC1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)cyclopropyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(2-pyrimidyl)piperazine dihydrochloride instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=145-146° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([C:26]4[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:16][C:17]=3[C@:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[C:9]([F:33])[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:41]1[N:46]=[CH:45][CH:44]=[CH:43][N:42]=1)CCC.[Cl-].[Li+]>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.[Cu]I.CN(C=O)C>[F:33][C:9]1[C:10]2[O:11][C:12]3[C:17](=[CH:16][C:15]([C:26]4[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:14][CH:13]=3)[C@@:18]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]=2[CH:20]=[C:7]([C:41]2[N:42]=[CH:43][CH:44]=[CH:45][N:46]=2)[CH:8]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(OS(=O)(=O)C(F)(F)F)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(-c3ncccn3)cc12
Temperature: 85 °C
Yield: 46.2 %

Procedure:
A microwave vial was charged with (S)-2-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (100 mg, 0.195 mmol), tetrakis(triphenylphosphine)palladium(0) (22.51 mg, 0.019 mmol), copper(i) iodide (3.71 mg, 0.019 mmol), 2-(tributylstannyl)pyrimidine (216 mg, 0.584 mmol) and DMF (974 μL). Lithium chloride (83 mg, 1.948 mmol) was added, the vial was flushed with argon, sealed and heated at 85° C. for 4 hrs. The mixture was cooled to the room temperature, diluted with water (1 ml) and ethyl acetate (3 ml). The organic layer was loaded onto 2 g SCX-2 column and washed with ethyl acetate and methanol. The material was released from the column using 2 M ammonia in MeOH solution. The filtrated was concentrated and purified by silica gel chromatography (10-80% CH2Cl2/MeOH/NH4OH in CH2Cl2) to afford (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(pyrimidin-2-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (40 mg, 0.090 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH3:17])[CH:12]([CH2:18][NH2:19])[CH2:11]2)=[CH:4][CH:3]=1.C1([O:26][C:27](=O)[NH:28][C:29]2[CH:34]=[C:33]([C:35]3[N:39]([CH3:40])[N:38]=[N:37][N:36]=3)[CH:32]=[C:31]([CH2:41][CH3:42])[CH:30]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH2:41]([C:31]1[CH:30]=[C:29]([NH:28][C:27]([NH:19][CH2:18][CH:12]2[CH:13]([CH2:16][CH3:17])[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:11]2)=[O:26])[CH:34]=[C:33]([C:35]2[N:39]([CH3:40])[N:38]=[N:37][N:36]=2)[CH:32]=1)[CH3:42]
Reactant: CCC1CCN(CCc2ccc(F)cc2)CC1CN
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(NC(=O)NCC2CN(CCc3ccc(F)cc3)CCC2CC)cc(-c2nnnn2C)c1
Reaction time: 18 h
Yield: 50.9 %

Procedure:
A solution of 1-[2-(4-fluorophenyl)ethyl]-4-ethyl-piperidin-3-ylmethylamine (52 mg, 199 μmol) and [3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (50 mg, 199 μmol) in N,N-dimethylformamide (1.0 mL) was treated with triethylamine (55 μL, 398 μmol). After 18 hours, the mixture was concentrated under vacuum. The residue was purified by flash chromatography, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonium hydroxide, provided an amorphous solid (50 mg, 51%). 1H NMR (300 MHz, CDCl3) δ8.37 (s, 1H), 7.74 (s, 1H), 7.56 (s, 1H), 7.11 (m, 2H), 7.03 (s, 1H), 6.92 (t, J=9 Hz, 2H), 6.11 (m, 1H), 4.12 (s, 3H), 3.53 (m, 1H), 3.18 (m, 2H), 3.00 (m, 1H), 2.80 (m, 2H), 2.63 (m, 4H), 2.2-2.0 (m, 2H), 1.82 (m, 1H), 1.66 (m, 2H), 1.40 (m, 1H), 1.3-1.1 (m, 2H), 1.20 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H). Mass spec (ES+) m/z 494.4 (M+H+, 100%).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:11]Br)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C(=O)([O-])O.[Na+]>CO>[CH2:4]([CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:11][NH:2][OH:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC(CBr)CCCCCC
Reactant: NO
Agent: Cl
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Solvent: CO
Product: CCCCCCCCC(CCCCCC)CNO

Procedure:
69 g of hydroxylamine hydrochloride, 30.5 g of 2-hexyldecylbromide, 0.5 g of EDTA and 500 ml of methanol were mixed and thereto 84 g of sodium hydrogencarbonate was added. The resulting mixture was heated under reflux for 3 hours. Then, the reaction mixture was concentrated, ethyl acetate and water were added thereto, the solution obtained was extracted by liquid separation, and the organic phase was dried over magnesium sulfate. The dried organic phase was concentrated and bis(2-hexyldecyl)hydroxylamine as a by-product was removed using silica gel column chromatography to produce the objective compound. The product was a colorless liquid. Yield: 10.5 g (40.9%).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([Br:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:14](=[O:25])/[CH:15]=[CH:16]/[C:17]1[S:21][C:20]([CH:22]([CH3:24])[CH3:23])=[N:19][CH:18]=1.CC#N.CC(O)=O.OP(O)(O)=O>[Cl-].[Cl-].[Zn+2].O>[Br:13][C:7]1[C:6]2[C:2]3[NH:1][CH:16]([C:17]4[S:21][C:20]([CH:22]([CH3:23])[CH3:24])=[N:19][CH:18]=4)[CH2:15][C:14](=[O:25])[C:3]=3[O:4][C:5]=2[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc2oc(C(=O)/C=C/c3cnc(C(C)C)s3)c(N)c2c1Br
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc2oc3c(c2c1Br)NC(c1cnc(C(C)C)s1)CC3=O
Temperature: 90 °C
Yield: 79.1 %

Procedure:
A mixture of 14A (1.4 g, 3.3 mmol), ZnCl2 (6 g), MeCN (10 mL), AcOH (2 mL) and H3PO4 (2 mL) was heated to 90° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water, extracted with ethyl acetate and concentrated to give 14B (1.1 g, 78% yield).
Reaction SMILES: [O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)[CH2:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14].C([O-])(=O)C.[NH4+:33].[OH-].[NH4+]>CO>[O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)/[CH:3]=[C:4](\[NH2:33])/[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14]
Reactant: [NH4+]
Reactant: O=C(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CO
Product: N/C(=C\C(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 5 L round-bottom flask was charged with methanol (100 mL), the ketoamide 2-3 (200 g), and ammonium acetate (110.4 g). Methanol (180 mL) and 28% aqueous ammonium hydroxide (58.6 mL) were then added keeping the temperature below 30° C. during the addition. Additional methanol (100 mL) was added to the reaction mixture. The mixture was heated at reflux temperature and aged for 2 h. The reaction was cooled to room temperature and then to about 5° C. in an ice-bath. After 30 min, the solid was filtered and dried to afford 2-4 as a solid; m.p. 271.2° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:29]2[CH:37]=[C:36]3[C:32]([CH2:33][C:34](=[O:38])[NH:35]3)=[CH:31][CH:30]=2)[CH:26]=[CH:27][CH:28]=1>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:33]1[C:32]2[C:36](=[CH:37][C:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)=[CH:30][CH:31]=2)[NH:35][C:34]1=[O:38])([OH:16])=[O:15]
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C(=O)O)c(C)c2CCC(=O)O)c1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 92.6 %

Procedure:
5-Formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (281 mg), 6-(3-methoxy-phenyl)-2-oxindole (287 mg), and piperidine (2 drops) in ethanol (5 mL) were stirred at 90° C. overnight. The precipitate was filtered and washed with ethanol. The yellow orange solid and potassium hydroxide (4 pellets) were stirred in ethanol (3 mL) at 90° C. for 2.5 hours. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 413 mg of 4-(2-Carboxyethyl)-5-[6-(3-methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Cl[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Si:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.6 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propionate (5 g, 27.7 mmol) and chlorotert-butyldimethylsilane (5 g, 33.3 mmol) in DMF was treated with triethylamine (4.6 ml). The mixture was stirred at room temperature for 20 hours. More chlorotert-butyldimethylsilane (0.8 g) and triethylamine (0.8 ml) were added, the resulting mixture was stirred at room temperature for another 2 hours, poured into saturated aqueous sodium bicarbonate (500 ml). The mixture was stirred at room temperature for 5 minutes and extracted with ether. The organic phase was washed with brine, dried over sodiun sulfate and concentrated in vacuo. Bulb-to-bulb distillation gave the title material (7.39 g, 91%) as a colorless oil (b.p. 104-105° C./0.025 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12])[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:3]=1.C(N(CC)CC)C.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:32]=1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH:12][S:37]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)(=[O:39])=[O:38])[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:3]=1
Reactant: CC(C)(CN)CNc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(CNc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1)CNS(=O)(=O)c1cccnc1
Reaction time: 4 h
Yield: 36.2 %

Procedure:
To a solution of Example 74 (55.0 mg, 0.167 mmol) in DMF (1 mL) was added triethylamine (0.070 mL, 0.50 mmol) and pyridine-3-sulfonyl chloride (35.5 mg, 0.200 mmol). After 4 hours, the reaction was quenched with 20% brine and extracted with EtOAc (2×). The organic layers were combined, concentrated, and purified by reverse-phase HPLC as described in Example 56 to give the title compound (28.5 mg) as trifluoroacetic acid salts. 1H NMR (500 MHz, DMSO-d6) ppm 0.89 (s, 6H), 2.68 (d, J=7.02 Hz, 2H), 3.13 (s, 2H), 6.80 (s, brd, 1H), 6.89 (d, J=1.22 Hz, 1H), 6.94 (s, 1H), 7.22 (dd, J=8.09, 4.73 Hz, 1H), 7.60 (dd, J=7.63, 4.58 Hz, 1H), 7.77 (t, J=6.87 Hz, 1H), 8.12-8.18 (m, 2H), 8.28-8.35 (m, 2H), 8.77 (d, J=6.41 Hz, 1H), 8.94 (d, J=2.14 Hz, 1H), 12.19 (s, 1H). MS (APCI+) m/z 471.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:6](Br)=[CH:5][S:4][CH:3]=1.[P:8]([O-])([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:9].C(N(C(C)C)CC)(C)C.P([O-])([O-])(O)=O.[Na+].[Na+].P([O-])(O)(O)=O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[Br:1][C:2]1[C:6]([P:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][S:4][CH:3]=1
Reactant: CCOP(=O)([O-])OCC
Reactant: Brc1cscc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])(O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(OCC)c1cscc1Br
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under nitrogen, 0.0968 g (0.4 mmols) of 3,4-dibromothiophene and 0.0131 g (0.016 mmols) of commercially available Pd(dppf)2Cl2 were added to DMF (4 ml) and were dissolved under stirring at room temperature for 5 minutes. To the thus obtained solution, 0.1326 g (0.96 mmols) of commercially available diethyl phosphate and 0.1241 g (0.96 mmols) of diisopropylethylamine were added at room temperature. Thereafter, the reaction mixture was heated to 110° C. and stirred for 4 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a disodium hydrogen phosphate/sodium dihydrogen phosphate buffer solution, adjusted to pH=7.0, was added, followed by extraction with ethyl acetate. The resulting organic phase was washed with a saturated saline and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a PTLC plate (developed with ethyl acetate:hexane=1:1) to obtain a specified substance 1 in the form of a brown solid and the specified substance 2 in the form of a yellow oil. The thus obtained substances were used for the reaction of Example 2(2) as they are. The yields of the compounds 1 and 2 are shown in Table 1.
Reaction SMILES: [Cl:1][C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.Cl.[CH3:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:19]=1>>[ClH:1].[CH3:9][C:10]1[CH:15]=[C:14]([NH:16][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:19]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(N)ccc1NC1=NCCCCC1
Agent: Cl
Product: CCOC(=O)Nc1ccc(NC2=NCCCCC2)c(C)c1

Procedure:
The title compound was prepared by the method of Example 16 using ethyl chloroformate and 1.0 g (3.1 mmole) of the product compound of Example 15. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6])#[N:2].B(Br)(Br)Br>C(Cl)Cl.O>[C:1]([C:3]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6])#[N:2]
Reactant: COc1ccc(C#N)c(C(N)=O)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(O)cc1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-cyano-5-methoxybenzamide (5.2 g, 0.027 mol) in methylene chloride is cooled to 0° C., treated dropwise with boron tribromide (54 mL of a 1M solution in methylene chloride), stirred at 0° C. for 30 minutes, stirred at room temperature for 1 hour, refluxed for 4 hours, cooled to 0° C., treated with additional boron tribromide (54 mL of a 1M solution in methylene chloride), refluxed for 17 hours, cooled to room temperature and diluted with water. The aqueous mixture is filtered to obtain a solid which is washed sequentially with water and ether and dried to give the title product as a beige solid, mp 268°-270° C.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[H-].[Na+].[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[C:17]([CH:20]=1)[C:18]#[N:19].O>CN(C)C=O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[C:17]([CH:20]=1)[C:18]#[N:19]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(Br)cc1C#N
Reaction time: 0.5 h
Yield: 105 %

Procedure:
Octanol (0.834 g) was dissolved in N,N-dimethylformamide (10 ml), and sodium hydride (60%, 0.256 g) was added. After stirring for 30 min, 5-bromo-2-fluorobenzonitrile (0.640 g) was added, and the mixture was further stirred at 40-50° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the object product (1.042 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]2[C:10]=1[CH2:9][NH:8][C:7]([NH2:11])=[N:6]2>CCO.[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH2:11])=[N:6]2
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)n2c1CNC(N)=N2
Agent: [Pd]
Solvent: CCO
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(N)ncc12
Temperature: 25 °C
Yield: 38.7 %

Procedure:
A mechanical mixture of 5-methyl-7-[3-(trifluoromethyl)phenyl]-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-amine (Intermediate 44) (1.30 g, 4.41 mmol) and Pd/C (0.50 g) in EtOH (250 mL) was heated at reflux for 7 days. The reaction mixture was then cooled to rt and filtered through celite. Concentration of the filtrate followed by purification of the residue by chromatography afforded 5-methyl-7-[3-(trifluoromethyl)phenyl]-imidazo[5,1-f][1,2,4]triazin-2-amine (0.50 g) as a pale yellow solid. 1H NMR (Acetone-d6): δ9.06 (s, 1H), 8.94 (s, 1H), 8.92-8.86 (m, 1H), 7.75-7.69 (m, 2H), 6.29 (bs, 2H), 2.55 (s, 3H). MS m/z 292 (M−1).
Reaction SMILES: C(OC(=O)[NH:7][C@@:8]12[CH2:15][C@@:12]([NH:16][C:17]([C:19]3[CH:24]=[N:23][CH:22]=[C:21]([CH3:25])[N:20]=3)=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10][CH2:9]2)(C)(C)C.[CH3:27][C:28]1[N:29]=[C:30]([C:33]([OH:35])=O)[S:31][CH:32]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.Cl.O1CCOCC1>[CH3:27][C:28]1[N:29]=[C:30]([C:33]([NH:7][C@@:8]23[CH2:15][C@@:12]([NH:16][C:17]([C:19]4[CH:24]=[N:23][CH:22]=[C:21]([CH3:25])[N:20]=4)=[O:18])([CH2:13][CH2:14]2)[CH2:11][CH2:10][CH2:9]3)=[O:35])[S:31][CH:32]=1
Reactant: Cc1csc(C(=O)O)n1
Reactant: Cc1cncc(C(=O)N[C@@]23CCC[C@@](NC(=O)OC(C)(C)C)(CC2)C3)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cncc(C(=O)N[C@@]23CCC[C@@](NC(=O)c4nc(C)cs4)(CC2)C3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a solution of {(1R,5S)-5-[(6-methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamic acid tert-butyl ester (intermediate 13, 0.050 g, 0.14 mmol) in 1 mL of methylene chloride, 4 M of hydrogen chloride in 1,4-dioxane (0.5 mL) was added. After stirring at rt overnight, the reaction mixture was concentrated under reduced pressure to dryness. The resulting residue was dissolved in methylene chloride (1.0 mL), 4-methyl-1,3-thiazole-2-carboxylic acid (19.8 mg, 0.14 mmol), triethylamine (7.73 μL, 0.56 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (61.4 mg, 0.14 mmol) were added. After stirring at rt for 1 hour, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified on the CombiFlash® system (hexane/ethyl acetate: 100/0 to 10/90 in 10 mins, then hexane/ethyl acetate: 10/90) to afford 31 mg (58%) of 6-methyl-pyrazine-2-carboxylic acid {(1S,5R)-5-[(4-methyl-thiazole-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide. Analytical data are listed in Table 3.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[CH:4][C:3]=1[OH:12]>C(OCC)(=O)C.[Ni]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:11])=[CH:4][C:3]=1[OH:12]
Reactant: Nc1c(O)cc(Br)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1cc(Br)cc(O)c1N
Reaction time: 2 h

Procedure:
As shown in step 6-iv of Scheme 6, to a solution of 2-amino-5-bromo-3-nitrophenol (7.5 g, 31.8 mmol) in ethyl acetate (60 mL) was added Raney Nickel™ (1.90 g, 214 μL, 32.4 mmol) and the reaction mixture was shaken for 2 hours under an atmosphere of H2 at 30 p.s.i. After filtering and drying over Na2SO4, the mixture was concentrated under reduced pressure to provide 2,3-diamino-5-bromophenol (compound 1016), which was used as is in subsequent reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8]C)=[C:4]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])[CH2:17][CH2:16]2)[CH:3]=1.Br.O.[OH-].[K+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])[CH2:17][CH2:16]2)[C:5](=[O:8])[NH:6][N:7]=1
Reactant: COc1ccccc1N1CCN(CCCCNc2cc(Cl)nnc2OC)CC1
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1N1CCN(CCCCNc2cc(Cl)n[nH]c2=O)CC1
Yield: 99.7 %

Procedure:
4.00 g (0.00985 mol) of 6-chloro-3-methoxy-4-((4-(4-(2-methoxyphenyl)-1-piperazinyl)butyl)amino)-pyridazine are dissolved in 40 ml of glacial acetic acid, and 40 ml of 63% strength HBr are added. The mixture is refluxed for 2 hours, 200 ml of water are added, 30% strength KOH is added to pH 6, and the precipitated substance is filtered off with suction and thoroughly washed with water. 3.85 g (99.7% of theory) of 6-chloro-4-((4-(4-(2-methoxyphenyl)-1-piperazinyl)butyl)amino)-3(2H)-pyridazinone are obtained, purified by recrystallization from ethanol with addition of charcoal, and immediately added to a solution of ethanolic hydrochloric acid, resulting in 3.26 g (68.7% of theory) of pure dihydrochloride, m.p. 247°-252° C.; C 47.2%, H 6.0%, Cl(tot) 21.9%, Cl- 14.6%, N 14.4%, O 10.0%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[CH3:12]O>OS(O)(=O)=O>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([OH:11])[CH:4]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)c(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)c(O)c1

Procedure:
To a solution of 4-bromo-3-hydroxy-benzoic acid (prepared according to J. Amer. Chem Soc. 1946, 68, 574) (5 g, 32.8 mmol) in MeOH (100 mL), conc. H2SO4 (1 mL) is added. The solution is refluxed for 14 h, then concentrated to about 30 mL and poured into a water. The aqueous layer is extracted with ether (50 mL×4) and the combined organic extracts are neutralized with a saturated aqueous solution of NaHCO3 (50 mL×2), washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give the title compound as a white powder. TLC, Rf (AcOEt)=0.9. 1H-NMR (CDCl3, 300 MHz): δ=5.8 (bs, 1H), 7.45 (d, 1H), 7.55 (d, 1H), 7.7 (s, 1H) ppm.