Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]([CH3:18])[CH:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]([CH3:18])[CH:8]([O:17][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](Oc1ccc(Br)cc1)C(O)CCc1cccnc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@H](Oc1ccc(Br)cc1)C(CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a solution of (3RS,4S)-4-(4-Bromophenoxy)-1-pyridin-3-yl-pentan-3-ol (2.0 g, Example 4d)) in dry dichloromethane (50 ml) was added tert-butyldimethylsilyl chloride (1.17 g) and imidazole (1.08 g) and the resulting solution stirred for 24 hours, concentrated and the residue purified by chromatography on silica gel eluting with ethyl acetate:hexane (1:4 to 1:1) to afford the sub-title compound as an oil (2.52 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([C:23]#[N:24])(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>[I-].[Zn+2].[I-].O1CCCC1>[NH2:24][CH2:23][CH:12]([C:11]1[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[OH:13]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: COc1ccc(C(O)CN)cc1OCc1ccccc1
Yield: 30 %

Procedure:
50 mmol of 3-benzyloxy-4-methoxybenzaldehyde and 55 mmol of trimethylsilyl cyanide are heated together with 0.567 mmol of anhydrous zinc iodide for 4 hours under nitrogen and exclusion of moisture to 90°. The mixture is then taken up in 15 ml. of absolute tetrahydrofuran, and this solution is added dropwise to a suspension of 60 mmol of lithium aluminum hydride in 35 ml. of tetrahydrofuran. After heating the mixture for one hour to 60°, it is worked up as described in Example 1. Recrystallization from ethyl acetate produces 2-amino-1-(3-benzyloxy-4-methoxyphenyl)-ethanol, m.p. 100°-102°, in a 30% yield.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl.S(Cl)(Cl)(=O)=O.C(Cl)Cl.[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][NH2:38])[CH3:34]>O>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:38][CH2:37][CH2:36][N:35]([CH2:39][CH3:40])[CH2:33][CH3:34])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Reactant: CCN(CC)CCN
Agent: Cl
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Product: CCN(CC)CCNS(=O)(=O)c1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
4-(7-Chloro-4-quinazolinylamino)benzenesulphonyl chloride hydrochloride (36.0 g obtainable from the title compound of Example 1) and methylene chloride (180 ml) were cooled under nitrogen to 5° C. N,N-Diethylethylenediamine (35.4 g) was then added at 5°-10° C. over 20 minutes to give a light yellow solution. The solution was stirred for 2 hours under nitrogen at 5° to 15° C. and then water (200 ml) was added. A white solid precipitated. The mixture was cooled to 10° C. and the solid was filtered off, washed with water (2×40 ml) and with chloroform (2×40 ml) and dried in an oven to give 279 g of title compound.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.[N:13]1([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[CH:22]3)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C:10]([N:16]1[CH2:17][CH2:18][N:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[CH:22]3)[CH2:14][CH2:15]1)=[O:12]
Reactant: c1cc2cc(N3CCNCC3)ccc2[nH]1
Reactant: O=C(O)C1Cc2ccccc2C1
Product: O=C(C1Cc2ccccc2C1)N1CCN(c2ccc3[nH]ccc3c2)CC1

Procedure:
Prepared from 9a and 5-(piperazinyl)-1H-indole.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH2:49][O:50][CH3:51])[CH2:46][N:45]3[C:52](OC(C)(C)C)=[O:53])=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[CH3:59][O:60][C@H:61]([CH3:71])[C@H:62]([NH:66][C:67]([O:69][CH3:70])=[O:68])C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>Cl.CCO.CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@@H:6]([CH:7]([CH3:9])[CH3:8])[C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH2:49][O:50][CH3:51])[CH2:46][N:45]3[C:52](=[O:53])[C@@H:62]([NH:66][C:67]([O:69][CH3:70])=[O:68])[C@@H:61]([O:60][CH3:59])[CH3:71])=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11]
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCO
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)[C@H](C)OC)C1
Reaction time: 3 h
Yield: 58.6 %

Procedure:
Tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (119 mg, 0.15 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C. for 3 h and then concentrated under reduced pressure. The crude residue was treated with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (43 mg, 0.23 mmol), HATU (63 mg, 0.17 mmol) and DMF (2 mL), then N-methylmorpholine (0.050 mL, 0.45 mmol) was added dropwise. After 3 hr, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2S,3S)-3-methoxy-2-[(methoxycarbonyl)amino]butanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (76 mg, 59%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5](O)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:4]([CH2:5][OH:6])[CH:3]=1
Reactant: O=C(O)c1cc(O)cc(Br)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc(O)cc(Br)c1
Temperature: 25 °C
Yield: 35.8 %

Procedure:
To a solution of 3-bromo-5-hydroxy-benzoic acid (5.0 g, 23.4 mmol) in 40 mL of THF was added a solution of 1M LiAlH4 (30 mL), and the resulting solution was heated to reflux for 2 h. After cooling to room temperature, the reaction mixture was poured on ice and acidified with 10% aq. HCl. The solution was then filtered under vacuum and the filtrate was extracted with EtOAc. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (Isco™ 120 g) using 50% ethyl acetate/hexanes as eluting solvents to afford the title compound as a white solid (1.7 g, 36% yield). HR-ES(−) calcd for C7H7O2Br [M−H]− 200.9556, observed 200.9557.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C:5]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]2([CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:7][CH:6]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][N:2]([CH3:27])[C:3]([C:5]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7][CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)C1=CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)C1=CCC2(CCNCC2)c2ccccc21
Yield: 118.6 %

Procedure:
A solution of the dimethylamide (B2) (156 mg) in dichloromethane (5 ml) was treated with TFA (1 ml) for 1 h. After concentration and co-evaporation with acetonitrile, the residue was dissolved in dichloromethane, washed with a mixture of brine and 1 ml 6N NaOH, dried (Na2SO4), and concentrated to give N,N-dimethyl-2H-spiro[naphthalene-1,4′-piperidine]-4-carboxamide (B3) (135 mg). LC-MS: m/e=271.0 (M+H). Rt=1.30 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[O:13].[CH3:20][N:21]=[C:22]=[O:23]>CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH:15][C:22]([NH:21][CH3:20])=[O:23])=[O:13]
Reactant: CN=C=O
Reactant: NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Solvent: CO
Product: CNC(=O)NNC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
To a suspension of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinohydrazide (200 mg; 0.54 mmol) in methanol (10 mL) was added (methylimino)(oxo)methane (61 mg; 1.07 mmol) (methyl Isocyanate). After few minutes the reaction mixture became homogeneous, and then an yellow colored solid, 2-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}-N-methylhydrazinecarboxamide (50 mg) was separated out. The filtrate upon concentration gave 158 mg which was also pure. (208 mg, 90%) MS m/z: 429 M+1
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5](=[O:22])[CH2:6][C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[O:20][CH3:21])[CH2:12][CH2:11]CCC1)[CH3:2].[F:24][C:25]([Si](C)(C)C)([F:27])[F:26].[F-].C[N+](C)(C)C.Cl>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:23])[C:5]([OH:22])([C:25]([F:27])([F:26])[F:24])[CH2:6][C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[O:20][CH3:21])[CH2:12][CH2:11]1)[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC1(c2cccc(F)c2OC)CCCCC1
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(O)(CC1(c2cccc(F)c2OC)CC1)C(F)(F)F
Temperature: -25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
1.05 g (3.3 mmol) of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclohexyl]-2-oxopropionate and 0.74 ml (5 mmol) of (trifluoromethyl)-trimethylsilane in 7 ml of THF are mixed with 62 mg of tetramethylammonium fluoride at −40° C. It is stirred for 2 hours at −25° C., and then another 0.35 ml (2.4 mmol) of (trifluoromethyl)-trimethylsilane and 62 mg of tetramethylammonium fluoride are added. After another 2 hours, 1 ml of 2N hydrochloric acid is added, and the reaction mixture is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-40%), 800 mg of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)-propionate is obtained as a yellow oil. This oil is mixed in 40 ml of diethyl ether at 0° C. with 150 g (4 mmol) of lithium aluminum hydride and stirred for 2.5 more hours at room temperature. 20 ml of saturated ammonium chloride solution is carefully added to the batch at 0° C., and it is stirred vigorously for 15 minutes. It is extracted several times with diethyl ether, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-15%), 630 g of 3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-(trifluoromethyl)-propane-1,2-diol is obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=CC=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[NH:11][C:12](=[S:15])[NH:13][N:14]=1.Br.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:9][C:4]1[CH:3]=[C:2]([C:10]2[NH:14][N:13]=[C:12]([S:15][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:11]=2)[O:1][C:5]=1[CH3:6]
Reactant: S=c1[nH]nc(-c2cc3ccccc3o2)[nH]1
Reactant: BrCc1ccccn1
Agent: Br
Product: Cc1cc(-c2nc(SCc3ccccn3)n[nH]2)oc1C
Yield: 59 %

Procedure:
Prepared in a similar manner to example 1 using 5-(benzofuran-2-yl)-2H-1,2,4-triazole-3(4H)-thione (example 6a) and 2-(bromomethyl)pyridine hydrobromide. Yield 59%. 1H NMR (500 MHz, CDCl3): δ 4.37 (s, 2H), 7.26-7.34 (m, 5H), 7.4-7.42 (d, 1H), 7.55-7.57 (d, 1H), 7.65-7.67 (d, 1H), 7.75 (t, 1H), 8.62 (s, 1H). MS (M+H, 309).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:26][CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)=[O:29]>CN(C)C=O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([NH:26][CH2:27][C:28]([NH:30][C:31]1[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=1)=[O:29])=[O:10]
Reactant: NCC(=O)Nc1ccncc1
Reactant: O=C(O)CN1CCCC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(CN1CCCC1=O)NCC(=O)Nc1ccncc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
40.9 g of (2-oxo-1-pyrrolidinyl)acetic acid was dissolved in 300 ml of dimethylformamide and the solution was cooled to 0° C. Then, a solution of 78.7 g of dicylohexylcarbodiimide dissolved in 80 ml of dimethylformamide was added thereto while maintaining the temperature at -2° C. to +1° C. After stirring for 5 minutes, 28.8 g of 4-(glycylamino)pyridine dissolved in 50 ml of dimethylformamide was added while maintaining the temperature at 0° to 3° C. and then the reaction liquid was allowed to stand so as to rise its temperature to room temperature over 2 hours. The liquid was cooled with ice and 200 ml of ice water was added dropwise thereto. The precipitated dicyclohexylurea was filtered off and the solvent was distilled off under reduced pressure. 200 ml of ethanol was added to the residue and stirred and the insoluble matter was filtered off. This insoluble matter was dissolved in 130 ml of water and 50 ml of methanol with warming and then the solution was concentraterd to about 60 ml. After 300 ml of ethanol was added, again the solution was concentrated to about 100 ml and allowed to stand overnight to form the precipitate, which was filtered off to obtain the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:23]([O:26][CH2:27][C:28]1[C:29]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[N:30][CH:31]=[CH:32][C:33]=1B1OC(C)(C)C(C)(C)O1)(=[O:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O1CCCC1>[C:23]([O:26][CH2:27][C:28]1[C:29]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[N:30][CH:31]=[CH:32][C:33]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:25])[CH3:24]
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCNCC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCNCC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 25 °C
Yield: 58.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with magnetic stirrer and reflux condenser was charged with 5-bromo-1-methyl-3-(5-(piperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one 101j (200 mg, 0.55 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (210 mg, 0.55 mmol), Pd(dppf)Cl2 (45 mg, 0.055 mmol), K3PO4 (284 mg, 1.65 mmol), and tetrahydrofuran (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 5 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (33:1) to afford 127a as a brown solid (200 mg, 58.3%). MS: [M+H]+ 623.7.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][C:11]([C:21]1[CH:26]=[CH:25][N:24]2[C:27]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([C:36](O)([CH3:38])[CH3:37])[N:31]=3)=[CH:28][N:29]=[C:23]2[N:22]=1)([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:12].O.C([O-])(O)=O.[Na+]>ClCCCl>[F:7][C:36]([C:32]1[N:31]=[C:30]([C:27]2[N:24]3[CH:25]=[CH:26][C:21]([C:11]([CH3:12])([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:10])=[N:22][C:23]3=[N:29][CH:28]=2)[CH:35]=[CH:34][N:33]=1)([CH3:38])[CH3:37]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(C(C)(C)O)n3)cnc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(C(C)(C)F)n3)cnc2n1
Reaction time: 8 h
Yield: 29.7 %

Procedure:
(Diethylamino)sulphur trifluoride (150 mg, 0.95 mmol) was added to a stirred solution of 2-{4-[7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}propan-2-ol (Example 115, Step 1) (200 mg, 0.47 mmol) in 1,2-dichloroethane (5 ml) at room temperature under N2 and the reaction was stirred overnight. Water (20 ml) was added followed by NaHCO3 solution (20 ml) and then the organics were extracted with CH2Cl2 (3×50 ml) and concentrated under reduced pressure. The residue was purified by column chromatography on silica using 7% EtOH/EtOAc to yield 3-[2-(1-fluoro-1-methylethyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (60 mg, 30%): 1H NMR (400 MHz, CDCl3) δ 10.25 (1H, d, J 7.3), 8.71 (1H, d, J 5.5), 8.48 (1H, s), 7.60 (1H, d, J 7.2), 7.55 (1H, d, J 5.5), 1.87 (6H, d, J 21.6), 0.99 (9H, t, J 8.0), 0.68 (6H, q, J 8.0); m/z (ES+) 430 (M+H+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[C:13](C(OCC)=O)[C:12]2=[O:25])=[CH:2]1>CN(C)C(=O)C.O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:25])[CH:13]=[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(NC(C)C)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)NC1=CC(=O)C(=Cc2c[nH]c3ncccc23)O1
Temperature: 25 °C
Yield: 13 %

Procedure:
A solution of the compound (0.15 g, 0.43 mmol) of Example 56 in N,N-dimethylacetamide (1.5 mL) was refluxed for 12 h. Cooled to ambient temperature, the reaction mixture was diluted with water and the precipitate was collected by filtration. The solid was washed with diethyl ether then dried to afford the titled compound as solid (0.015 g, y. 12%).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16]#[N:17])=[N:13][N:12]=2)[CH2:7][CH2:6]1.Cl.[NH2:24][OH:25]>>[Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[S:15][C:14]([C:16](=[N:24][OH:25])[NH2:17])=[N:13][N:12]=2)[CH2:9][CH2:10]1
Reactant: N#Cc1nnc(N2CCC(Oc3cc(F)ccc3Br)CC2)s1
Reactant: NO
Agent: Cl
Product: NC(=NO)c1nnc(N2CCC(Oc3cc(F)ccc3Br)CC2)s1

Procedure:
The title compound was prepared in a similar manner as described for Example 7, step 2 from 5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazole-2-carbonitrile and hydroxylamine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]2[CH:31]=[C:30]([F:32])[C:29]([S:33](=[O:52])(=[O:51])[N:34](CC3C=CC(OC)=CC=3OC)[C:35]3[S:39][N:38]=[CH:37][N:36]=3)=[CH:28][C:27]=2[F:53])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]=3[CH:24]=2)[CH:7]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].Cl>ClCCl>[S:39]1[C:35]([NH:34][S:33]([C:29]2[C:30]([F:32])=[CH:31][C:26]([O:25][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=3[C:8]3[CH:9]=[CH:10][C:11]4[O:15][N:14]=[C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:12]=4[CH:24]=3)=[C:27]([F:53])[CH:28]=2)(=[O:51])=[O:52])=[N:36][CH:37]=[N:38]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(NC(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)Nc1noc2ccc(-c3cc(Cl)ccc3Oc3cc(F)c(S(=O)(=O)Nc4ncns4)cc3F)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
To a solution of tert-butyl (5-(5-chloro-2-(4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)phenyl)benzo[d]isoxazol-3-yl)carbamate (0.150 g, 0.19 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.1 mL) at 0° C. The reaction mixture was stirred for 20 minutes at 0° C. and saturated aqueous sodium bicarbonate (5 mL) was added. The mixture was allowed to warm to ambient temperature, diluted with dichloromethane (50 mL), and acidified to pH 5 with 1 N hydrochloric acid. The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a 0-100% ethyl acetate in hexanes, followed by a 0-10% gradient of methanol in ethyl acetate, to afford tert-butyl (5-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)-5-chlorophenyl)benzo[d]isoxazol-3-yl)carbamate in 59% yield (0.071 g) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ10.52 (s, 1H), 8.27 (s, 1H), 8.24 (d, J=1.5 Hz, 1H), 7.77 (dd, J=8.8, 1.6 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.67 (dd, J=6.8, 3.3 Hz, 1H), 7.63 (d, J=2.5 Hz, 1H), 7.48 (dd, J=8.8, 2.6 Hz, 1H), 7.22 (d, J=8.9 Hz, 1H), 7.22-7.16 (m, 1H), 1.44 (s, 9H), (NH not observed); MS (ES+) m/z 657.6 (M+23), 659.5 (M+23).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26]O)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:26][CH:23]2[CH2:22][CH2:21][N:20]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:2]1
Reactant: OCC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1c[nH]c2ccccc12
Product: O=C(OCC1CCN(Cc2ccccc2)CC1)c1c[nH]c2ccccc12
Yield: 88 %

Procedure:
Indole-3-carboxylic acid was converted to its acid chloride and then reacted with 1-benzyl-4-piperidinemethanol (D7) using the method given in Example 1a. The resulting orange oil was chromatographed on silica gel eluting with chloroform/ethanol (9:1) to afford (1-benzyl-4-piperidyl)methyl indole-3-carboxylate as a yellow oil (88%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5](=[O:8])[NH:6][CH:7]=1.[CH2:12]([OH:14])[CH3:13]>[Pd].C(O)(=O)C>[C:12]([NH:9][C:4]1[C:5](=[O:8])[NH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:14])[C:13]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:7]=1
Reactant: CCO
Reactant: O=c1[nH]cc(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(Nc1cc(Cl)c[nH]c1=O)c1ccccc1
Temperature: 25 °C

Procedure:
5-Chloro-3-nitro-2-pyridone (5.3 g.) was hydrogenated in 225 ml. of ethanol and 6 ml. of acetic acid in the presence of 0.6 g. of 5% palladium-on-carbon. The catalyst was removed by filtration and the filtrate was concentrated to dryness. The residue was dissolved in 75 ml. of pyridine, cooled in ice and treated over 15 minutes with 4.8 g. of benzoyl chloride. The ice bath and reaction mixture were allowed to warm to room temperature spontaneously. The mixture was poured onto 200 g. of ice. On dilution with 500 ml. of water an oil separated which on washing with water solidified (4 g.). The crude 3-benzoylamino-5-chloro-2-pyridone was used directly in the next step.