Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([NH:37]C(=O)OC(C)(C)C)[CH2:14][C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23]4[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:26]5[CH:33]=[CH:34][CH:35]=[CH:36][C:25]=5[N:24]=4)[CH2:18]3)=[O:16])=[CH:8][CH:7]=2)=[CH:2]1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>>[NH2:37][C@H:13]([CH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[CH:11][CH:10]=1)[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:26]3[CH:33]=[CH:34][CH:35]=[CH:36][C:25]=3[N:24]=2)[CH2:18]1)=[O:16].[C:47]([OH:49])([C:46]([F:51])([F:50])[F:45])=[O:48]
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(-c4ccoc4)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc(-c4ccoc4)cc3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl(R)-1-(4-(furan-3-yl)phenyl)-4-((R)-3-(1-(3-methoxypropyl)-1,1-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (54A) was dissolved in 25% trifluoroacetic acid and stirred at room temperature for 3 hrs. Solvent was removed under vacuum and purified by preparatory LC/MS (20-50% CH3CN in H2O) to give product (R)-3-amino-4-(4-(furan-3-yl)phenyl)-1-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)butan-1-one (145) as a TFA salt (32 mg, 64% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (br. s., 1H) 1.72-2.22 (m, 5H) 2.57-3.51 (m, 1H) 3.71 (br. s., 1H) 3.77-4.73 (m, 5H) 6.96 (br. s., 1H) 7.30 (m, 2H) 7.37-7.50 (m, 2H) 7.59 (m, 2H) 7.75 (br. s., 3H) 8.17 (s, 1H). ESI-MS:mlz 501.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br.O>ClS(O)(=O)=O.[S]>[Br:12][C:8]1[C:9]([Cl:11])=[CH:10][C:2]([Cl:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)Cl
Agent: [S]
Solvent: O
Product: O=C(O)c1cc(Br)c(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 187.5 %

Procedure:
To a solution of 2,4-dichlorobenzoic acid (compound 80, 25.0 g, 131 mmol) in chlorosulfonic acid (100 mL) was added bromine (3.4 mL, 65 mmol) and sulfur (0.20 g, 6.6 mmol). The reaction mixture was stirred at 70° C. overnight and then cooled to ambient temperature. The reaction mixture was poured into iced water. The resulting solid was isolated by filtration and dried in vacuo to yield title compound (32.9 g, 93%) as pale brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][N:2]1[CH:6]2[CH2:5][CH2:4][CH:3]1[CH2:9][CH:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:7]2
Reactant: CN1C2CCC1CC(O)C2
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C2CCC1CC(OS(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tropine (10.0 g, 70.8 mmol), 4-dimethylaminopyridine (80 mg, 0.60 mmol), and triethylamine (11.0 mL, 78.9 mmol) in DCM (125 mL) was cooled to 0° C., charged with methanesulfonyl chloride (5.50 mL, 71.0 mmol), slowly allowed to warm to rt, and stirred for an additional 16 h at rt. The reaction mixture was partitioned between CHCl3 and sat. NaHCO3, and the layers were separated. The aqueous layer was extracted with CHCl3 (3×) and the combined organic fractions were washed with sat. NaHCO3 (2×), brine (2×), dried over Na2SO4, filtered, and concentrated in vacuo resulting in the title compound as a pale brown solid. This material was taken on to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=1.94-2.09 (m, 6H), 2.20 (dt, J=15.4, 4.2 Hz, 2H), 2.28 (s, 3H), 2.99 (s, 3H), 3.10-3.17 (m, 2H), 4.94 (t, J=5.1 Hz, 1H).
Reaction SMILES: [Br:1]C(Br)C.[Mg].[Br:6][C:7]1[C:8]([O:27][CH2:28][CH:29]2[CH2:31][O:30]2)=[CH:9][CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])[N:13]=[CH:12]2>C1COCC1>[Br:1][CH2:31][CH:29]([OH:30])[CH2:28][O:27][C:8]1[C:7]([Br:6])=[C:15]2[C:11]([CH:12]=[N:13][N:14]2[CH2:16][CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])=[CH:10][CH:9]=1
Reactant: CC(Cn1ncc2ccc(OCC3CO3)c(Br)c21)O[Si](C)(C)C(C)(C)C
Reactant: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(Cn1ncc2ccc(OCC(O)CBr)c(Br)c21)O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
Dibromoethane (1.09 mL, 12.6 mmol) was added dropwise to a suspension of magnesium powder (0.81 g, 33.5 mmol) in anhydrous THF (150 mL) under nitrogen. During this period the mixture was heated at about 50° C. until gas evolution was observed and then allowed to cool to 40° C. Additional dibromoethane (0.05 mL) was added and the mixture was heated at reflux for 20 min and placed in an ice bath. To the cooled mixture was added a solution of the product from Step D (3.70 g, 8.38 mmol) in THF (50 mL). After stirring for 20 min at ambient temperature, the reaction was quenched with a saturated aqueous solution of ammonium chloride (200 mL) and the mixture was extracted with EtOAc (2×150 mL). Evaporation of the extracts gave a crude oil (3.78 g, 86%): LC/MS (+APCI) m/z 521, 523, 525 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([C:16]#[N:17])=[C:5]2[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.[CH:25]([CH:27]=[CH2:28])=[O:26].C(N(CC)CC)C.CN(C)C=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:12]([C:7]1[C:6]([C:16]#[N:17])=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2](/[CH:28]=[CH:27]/[CH:25]=[O:26])[CH:3]=2)[N:8]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(Br)cc23)cc1
Reactant: C=CC=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(/C=C/C=O)cc23)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
A mixture of 6-bromo-2-isobutyl-4-(4-methylphenyl)quinoline-3-carbonitrile (5.00 g, 13.2 mmol), acrolein (2.22 g, 39.6 mmol), benzyltriethylammonium chloride (3.00 g, 13.2 mmol), triethylamine (5.5 ml, 39.6 mmol), palladium acetate (150 mg, 0.66 mmol) and N,N-dimethylformamide (40 ml) was stirred under an argon atmosphere at 70° C. After 3 hrs., palladium acetate (150 mg, 0.66 mmol) and acrolein (2.22 g, 39.6 mmol) were added to the reaction mixture and the mixture was stirred at the same temperature for 17 hrs. The reaction mixture was diluted with ethyl acetate, washed 4 times with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 2-isobutyl-4-(4-methylphenyl)-6-[(1E)-3-oxoprop-1-en-1-yl]quinoline-3-carbonitrile (3.26 g, yield 70%) as white crystals.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.O.ON1C2C=CC=CC=2N=N1.[ClH:30].CN(CCCN=C=NCC)C.Cl>CN(C)C=O.ClCCl.C(O)C>[ClH:30].[NH2:8][CH2:9][C:10]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:11]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: NCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (100 ml), N-tert-butoxycarbonylglycine (2.00 g), morpholine (1.00 ml), 1-hydroxybenzotriazole monohydrate (1.74 g) and 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.84 g) were dissolved, followed by stirring overnight at room temperature. After concentration under reduced pressure, the residue was diluted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane:methanol=100:1), whereby a colorless foam was obtained. The substance was dissolved in dichloromethane (2 ml), followed by the addition of saturated solution of hydrochloride in ethanol (10 ml). The resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated to dryness under reduced pressure, whereby the title compound (1.80 g, quant.) was obtained as a pale yellow foam was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]N1C(=O)CCC1=O.O[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([S:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:30]=1.O>O1CCOCC1>[Br:20][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([S:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:30]=1
Reactant: CCOC(=O)CSc1nccc(O)n1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CSc1nccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 52.5 g (0.20 mol) of triphenylphosphine are initially charged in 600 ml of dioxane, and 35.6 g (0.20 mol) of N-bromosuccinimide are added a little at a time, with cooling. The mixture is stirred at RT for 30 min. 8.6 g (0.04 mol) of ethyl [(4-hydroxy-2-pyrimidinyl)thio]acetate are then added and the mixture is heated at reflux for 45 min. A total of 2 l of water are added to the mixture, which is then extracted 3× with in each case 300 ml of methyl tert-butyl ketone. The organic phase is washed 2× with water and 1× with concentrated NaCl solution, dried over magnesium sulphate and concentrated. The residue is stirred in 60 ml of methyl tert-butyl ketone and filtered off. The mother liquor is concentrated and the residue is purified by silica gel chromatography (dichloromethane).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].I[CH:18]([CH3:20])[CH3:19]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH:18]([CH3:20])[CH3:19])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(O)ccc1Br
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)Oc1ccc(Br)c(C#N)c1
Temperature: 60 °C
Yield: 78.4 %

Procedure:
2-Bromo-5-hydroxy-benzonitrile (20.0 g, 10.1 mmol) and K2CO3 (5.60 g, 40.4 mmol) were taken-up in dry DMF (12.5 mL). 2-Iodopropane (2.00 mL, 20.2 mmol) was added and the reaction mixture was heated at 60° C. for 2 h. The mixture was diluted with ether (100 mL), filtered over celite and the filtrate was washed with water (3×50 mL) and brine (50 mL), dried over MgSO4, evaporated and purified by column chromatography (5-45% EtOAc/hexanes) to give 1.9 g (81%) of 2-bromo-5-isopropoxybenzonitrile as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=9.0 Hz, 1H), 7.15 (d, J=2.9 Hz, 1H), 6.99 (dd, J=9.0, 3.0 Hz, 1H), 4.58-4.49 (m, 1H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 239.0, found 240.1 (M+1)+. Retention time: 1.81 minutes (3 min run).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]2=[O:16])[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[C:24]([F:25])=[CH:23][C:22]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:34][CH3:35])=[O:33])=[CH:28][CH:27]=2)=[C:21]([CH3:36])[CH:20]=1.C(O)(C(F)(F)F)=O>CC(O)C>[Cl:17][C:5]1[C:6]([NH:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]2=[O:16])=[N:7][C:2]([NH:18][C:19]2[C:24]([F:25])=[CH:23][C:22]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH3:35])=[O:33])=[CH:30][CH:31]=3)=[C:21]([CH3:36])[CH:20]=2)=[N:3][CH:4]=1
Reactant: O=C1NCCCCC1Nc1nc(Cl)ncc1Cl
Reactant: CNC(=O)c1ccc(-c2cc(F)c(N)cc2C)cc1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1ccc(-c2cc(F)c(Nc3ncc(Cl)c(NC4CCCCNC4=O)n3)cc2C)cc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of 3-(2,5-dichloropyrimidin-4-ylamino)azepan-2-one (Intermediate 16, 28 mg, 0.10 mmol), 4′-Amino-5′-fluoro-N,2′-dimethylbiphenyl-4-carboxamide (Intermediate 17, 31 mg, 0.12 mmol, 1.2 equiv.) and TFA (37 μL, 57 mg, 0.50 mmol, 5 equiv.) in 2-propanol (3 mL) is stirred in a sealed tube at 100° C. for 48 h. The resulting solution is concentrated and then purified by preparative RP-HPLC to afford (±)-4′-(5-chloro-4-(2-oxoazepan-3-ylamino)pyrimidin-2-ylamino)-5′-fluoro-N,2′-dimethylbiphenyl-4-carboxamide; ESMS m/z 497.2 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]1[C:24]([N:26]([CH2:28][C:29]([C:32](=O)[NH2:33])([CH3:31])[CH3:30])[CH3:27])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.Cl.C(Cl)Cl>N1C=CC=CC=1>[CH2:1]([N:8]1[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]1[C:24]([N:26]([CH2:28][C:29]([C:32]#[N:33])([CH3:30])[CH3:31])[CH3:27])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CC(C)(C)C(N)=O)C(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Agent: Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CC(C)(C)C#N)C(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a stirred solution of SC-174 (235 mg, 0.478 mmol) in pyridine (4.83 mL) was added at 0° C. TFAA (0.153 mL, 1.099 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 min. Aqueous 1 M HCl (20 mL) and DCM (10 mL) were added and the aqueous layer was set to pH 2 with aqueous 5 M HCl (10 mL). The layers were separated and extracted twice with DCM (10 mL). The combined organic layers were concentrated in vacuo. Purification was performed with flash chromatography (silica, gradient heptane/EtOAc, 1:0→0:1). The appropriate fractions were combined and solvents removed in vacuo to give SC-187 (187 mg, 82%) as a yellow foam.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([N:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[N:12]=[C:11]([O:21][CH2:22][CH3:23])[C:7]=3[NH:8][C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.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.O>[CH2:22]([O:21][C:11]1[C:7]2[NH:8][C:9]3[CH:10]=[C:2]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[CH:3]=[CH:4][C:5]=3[C:6]=2[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:12]=1)[CH3:23]
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CCOc1nc(N2CCNCC2)nc2c1[nH]c1cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1nc(N2CCNCC2)nc2c1[nH]c1cc(-c3ccncc3)ccc12

Procedure:
150 mg (0.4 mmol) 7-bromo-4-ethoxy-2-(piperazin-1-yl)-5H-pyrimido[5,4-b]indole (Example 4), 123 mg (0.6 mmol) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 276 mg (1.2 mmol) K3PO4×H2O, 6.6 mg (16 mmol) S-Phos and 9.2 mg (8 mmol) Pd(PPh3)4 in 6 ml THF were heated in a microwave oven to 120° C. for 2 h. Then, the solvent was removed and following LC (CH2Cl2/MeOH, O-20%) 93 mg (62%) of the title substance was obtained ESI-MS [m/z]: 375 [M+H]+
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]c(COCc2ccccc2)n1
Reactant: Clc1ncccn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ncccn2)c(COCc2ccccc2)n1
Yield: 41 %

Procedure:
As described for Example 63, 4-(2-benzyloxymethyl-1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (60 mg, 0.17 mmol) using 2-chloropyrimidine instead of 4-fluoroacetophenone was converted to the title compound (30 mg, 41%) which was obtained as an off-white solid. MS: m/e=424.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:31])[N:17]=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]3([CH2:15][CH2:14][CH2:13]3)[S:11](=[O:27])(=[O:26])[C@@H:10]2[CH2:28][CH2:29][OH:30])[C:5](F)=[N:6][CH:7]=1.[H-].[Na+]>C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[O:30][CH2:29][CH2:28][C@H:10]3[C@@:9]([CH3:31])([C:4]=2[CH:3]=1)[N:17]=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]1([CH2:15][CH2:14][CH2:13]1)[S:11]3(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cnc2F)[C@@H](CCO)S(=O)(=O)C12CCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(Br)cnc3OCC[C@@H]2S(=O)(=O)C12CCC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
A solution of tert-butyl ((6R,7R)-7-(5-bromo-2-fluoropyridin-3-yl)-6-(2-hydroxyethyl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-9-yl)carbamate (1.04 g, 1.998 mmol) in THF/DMF (20/2 mL) was brought to 0° C. followed by the addition of sodium hydride, 60% dispersion in mineral oil (0.200 g, 5.00 mmol) in one portion. After one min stirring at 0° C. the ice bath was removed. The reaction became yellow. More sodium hydride, 60% dispersion in mineral oil (0.200 g, 5.00 mmol) was added at rt and stirred for 20 min more. The reaction went to completion (3:1 mixture of epimers). The mixture was brought to 0° C. and carefully quenched with saturated NH4Cl and water was added. The reaction mixture was extracted with EtOAc and the combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-30% EtOAc/hexanes to afford each isomer as a white solid tert-butyl ((4a′S,11b′R)-10′-bromo-11b′-methyl-4′,4′-dioxido-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazin]-2′-yl)carbamate (0.46 g, 0.919 mmol, 46.0% yield). LC/MS (ESI+) m/z=521.8 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH2:18]([B-](F)(F)F)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[K+].C([O-])([O-])=O.[Cs+].[Cs+].Cl>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:9]=2)=[O:4]
Reactant: F[B-](F)(F)Cc1ccccc1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(O)c2ccc(Cc3ccccc3)cc2sc1=O
Yield: 43.3 %

Procedure:
To a mixture of 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) (220 mg, 0.70 mmol) in THF (8 mL) was added potassium benzyltrifluoroborate (138 mg, 0.70 mmol), Cs2CO3 (682 mg, 2.09 mmol), PdCl2(PPh3)2 (49 mg, 0.07 mmol) and then water (2 mL). The resulting mixture was refluxed overnight (18 h). After cooling, the reaction mixture was diluted with water (75 mL) and acidified using 1 N HCl to pH 4. The precipitate was collected, rinsed with water and the solid dissolved in CH2Cl2. The CH2Cl2 solution was dried over MgSO4, filtered, concentrated and the crude product purified by silica gel chromatography (5%-100% EtOAc/CH2Cl2) to provide 7-benzyl-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (99 mg). 1H NMR (200 MHz, CDCl3): 6 (ppm)=15.2 (s, 1H), 8.25 (d, J=8.2 Hz, 1H), 7.36-7.16 (m, 7H), 4.04 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: [C:1]([N:9]1[CH2:16][C@@H:15]([OH:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(C)=O>[C:1]([N:9]1[CH2:16][C@@H:15]([OH:17])[CH2:14][C@H:10]1[C:11]([O:13][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of (cis)-1-benzoyl-4-hydroxy-L-proline (7.074 gm, 30.1 mmole) in acetone was treated dropwise with 1,8-diazabicyclo[5.4.0]- undec-7-ene (5.4 ml, 36.1 mmole) while cooling with a water bath. After stirring under argon for 10 minutes, benzyl bromide (4.3 ml, 36.1 mmole) was added dropwise. After stirring for 3 hours at room temperature, an additional aliquot (0.25 ml) of benzyl bromide was added. The reaction was stirred overnight and the acetone removed in vacuo. The residue was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with additional HCl, sodium bicarbonate solution, brine, and dried (sodium sulfate). Filtration, followed by concentration in vacuo afforded a solid which was recrystallized from ethyl acetate. The yield of the title compound was 8.77 gm (90%).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]=[O:15])[CH:8]=[CH:7]2.O>C(O)(=O)C>[Br:1][C:5]1[C:4]([OH:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH:14]=[O:15])=[CH:10]2
Reactant: BrBr
Reactant: O=Cc1ccc2cc(O)ccc2c1
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccc2c(Br)c(O)ccc2c1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Step b) Bromine (7.45 mL, 145.3 mmol) was added dropwise to a cold (0° C.) solution of 6-hydroxy-2-naphthaldehyde (25.0 g, 145.3 mmol) in acetic acid (300 mL). After stirring for 30 minutes the mixture was poured into water (21), and the precipitated solid filtered and dried to yield a brown solid (34.5 g, 94% yield, m.p. 189-190).
Reaction SMILES: C.[NH2:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=[CH:5][N:4]=1.O.NN>CO>[NH2:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:12]2[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)=[CH:5][N:4]=1
Reactant: Nc1ncc(-c2ccc(Br)cc2)cc1[N+](=O)[O-]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1cc(-c2ccc(Br)cc2)cnc1N
Reaction time: 24 h
Yield: 51.1 %

Procedure:
0.145 g of ferric chloride and 0.12 g of activated charcoal are added to a suspension of 0.98 g of 2-amino-5-(4-bromphenyl)-3-nitropyridine (starting material H2) in 30 ml of methanol and the mixture is heated under reflux. 0.725 ml of hydrazine hydrate are added slowly and reflux is continued for 24 hours. After cooling the mixture is filtered and the filtrate is evaporated. The residue is partitioned between sodium-EDTA-solution (0.25M; pH 9–10) and dichloromethane. The organic phase is evaporated to give 0.45 g of the title compound as a yellowish solid of m.p. 187–188° C. The mass spectrum shows the molecular peak MH+ at 264.2 Da.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([NH2:27])[CH:14]=1)=[O:12]>C1(C)C=CC=CC=1>[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:15]([N:27]=[C:1]=[O:2])[CH:14]=1)=[O:12]
Reactant: Nc1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1

Procedure:
A stirred solution of 40 g (0.41 mol) of phosgene in 150 ml of toluene is held at 25° C while a mixture of (52.5 mmol) of 3-amino-4-benzyloxyphenyl 2-pyridyl ketone and 300 ml of toluene is added slowly. The mixture is refluxed for 30 minutes and then is concentrated to give 4-benzyloxy-3-isocyanatophenyl 2-pyridyl ketone.