Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([OH:33])=[O:32])[CH2:24][CH:23]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:43].O1CCOCC1.Cl>>[ClH:43].[C:11]1([C@H:9]([NH:8][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=3)[C:31]([OH:33])=[O:32])[CH2:24][CH:23]2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2cccc(C(=O)O)c2)CC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CCN(c2cccc(C(=O)O)c2)CC1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 99 mg of 3-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]benzoic acid was added 2.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution of hydrochloric acid. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, and to the obtained residue were added THF and isopropanol, followed by solidification to obtain 76 mg of 3-[4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]benzoic acid hydrochloride as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([CH3:25])[C:13]=1[CH3:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([CH3:25])[C:13]=1[CH3:26]
Reactant: CC(C)OC(=O)CBr
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(O)c2C)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of 4-fluoro-3-[[5-(3-fluorophenyl)-2,3-dimethyl-phenyl]methylamino]-2-methyl-phenol (230 mg, 0.65 mmol, 1.0 eq) in DMF (5 mL) was added Cs2CO3 (420 mg, 1.3 mmol, 2.0 eq) and isopropyl 2-bromoacetate (140 mg, 0.78 mmol, 1.2 eq). The reaction was stirred at room temperature for 1 h then water and EtOAc were added. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 400:1 to 40:7) to give the title compound as a colorless oil (180 mg, 62%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:21]=[C:20]([CH2:22][N:23]([CH3:42])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[CH:19]=[CH:18][CH:17]=3)=[O:15])=[C:9]([C:43](=[O:60])[NH:44][C:45]3[CH:49]=[CH:48][N:47]([C:50]4[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=4)[N:46]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH3:42][N:23]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([C:14](=[O:15])[NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:8][C:9]=2[C:43](=[O:60])[NH:44][C:45]2[CH:49]=[CH:48][N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:57])([F:58])[F:59])[CH:51]=3)[N:46]=2)[N:21]=1
Reactant: CN(CCOCCOCCOCCC(=O)OC(C)(C)C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCOCCOCCOCCC(=O)O)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.8 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(2-(2-(2-(((6-((4-(piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)carbamoyl)-phenyl)carbamoyl)pyridin-2-yl)methyl)(methyl)amino)ethoxy)ethoxy)ethoxy)propanoate (210 mg, 0.25 mmol, 1.00 equiv) in dichloromethane (4 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 2 h at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 32.9 mg (13%) of a brown solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.81-8.78 (d, J=9.3 Hz, 1H), 8.48-8.47 (d, J=2.7 Hz, 1H), 8.33-8.31 (d, J=7.5 Hz, 1H), 8.21-8.16 (d, J=7.5 Hz, 2H), 7.87-7.86 (d, J=2.4 Hz, 1H), 7.79-7.72 (m, 2H), 7.64-7.62 (d, J=6.9 Hz, 2H), 6.98-6.97 (d, J=2.4 Hz, 1H), 4.75 (s, 2H), 3.80-3.77 (t, J=4.5 Hz, 2H), 3.66-3.47 (m, 16H), 3.11-3.09 (d, J=6.3 Hz, 3H), 2.49-2.45 (d, J=6 Hz, 2H), 1.94-1.75 (m, 6H). MS (ES, m/z): 782 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:17][CH:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](O)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:19][CH:18]([F:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C(F)c1ccccc1
Reactant: O=S(=O)(c1ccc(Br)cc1)C1CCNCC1
Product: O=S(=O)(c1ccc(Br)cc1)C1CCN(CC(F)c2ccccc2)CC1

Procedure:
4-(4-Bromophenylsulphonyl)piperidine (0.7 g, 2.3 mmol) was reacted with α-fluorophenylacetic acid (0.53 g, 3.45 mmol) in a similar manner as described for Example 13, Steps a and b, to give the required product as a colourless solid, 0.56 g (58%), m.p. 126-127° C. (EtOAc-pet. ether 60-80°). δH (400 MHz, CDCl3) 1.70-1.77 (2H, m), 2.00-2.03 (2H, m), 2.13-2.20 (2H, m), 2.57-2.69 (1H, m), 2.83-2.93 (2H, s), 3.04-3.18 (2H, m), 5.51-5.65 (1H, m), 7.28-7.39 (5H, m), 7.70-7.75 (4H, m).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[N:10]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:9]=2)[CH2:4][CH2:3]1.C(O)(=O)C>C(O)C.[Zn]>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[N:10]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:21])=[O:22])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc(N)cc23)CC1
Yield: 54 %

Procedure:
Zinc (3.28 g, 50.46 mmol) was added to a solution of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1-(phenylsulfonyl)-1H-indole (2 g, 5.04 mmol) in ethanol (500 mL). Acetic acid (30 mL) was then added dropwise with stirring while the reaction was cooled in a ice water bath. The resulting solution was stirred for 2 hours at room and then filtered. The filtrate cake was washed with ethanol, and the collected filtrate was concentrated in vacuo. The residue was purified by column chromatography using a 10:1 methanol/ammonia solvent system to afford 1 g (54%) of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indol-5-amine as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][C:8](=[O:31])[NH:9][CH:10]([C:24](=[O:30])[NH:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:11][S:12][CH2:13][C:14](=O)[C:15](=[O:22])[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]([OH:5])=[O:4].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33].[NH2:39][OH:40].Cl.C(#N)C>O>[NH2:1][CH:2]([CH2:6][CH2:7][C:8](=[O:31])[NH:9][CH:10]([C:24](=[O:30])[NH:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:11][S:12][CH2:13][C:14](=[N:39][OH:40])[C:15](=[O:22])[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]([OH:5])=[O:4].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]
Reactant: NO
Reactant: NC(CCC(=O)NC(CSCC(=O)C(=O)N1CCCCC1)C(=O)NCC(=O)O)C(=O)O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: NC(CCC(=O)NC(CSCC(=NO)C(=O)N1CCCCC1)C(=O)NCC(=O)O)C(=O)O
Reaction time: 8 h

Procedure:
2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2,3-dioxo-3-piperidin-1-yl-propylsulfanyl)-ethylcarbamoyl]-butyric acid as its TFA salt (400 mg, 0.696 mol) was dissolved in 8 mL of water to which was added 1.3 eq. of solid NH2OH.HCl at 0° C. and the homogeneous solution was left standing over-night. LC/MS indicated that the reaction was incomplete. An additional 1 eq. of NH2OH.HCl was added at room temperature and the homogeneous solution was left standing overnight. LC/MS indicated complete conversion of the starting amide to the corresponding oxime. The aqueous mixture was then passed through reversed-phase C18 column using water and acetonitrile mixture as gradient eluent. The pure fractions were pooled, concentrated under vacuum at room temperature to one fourth of the volume and finally freeze-dried to obtain 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-hydroxyimino-3-oxo-3-piperidin-1-yl-propylsulfanyl)-ethylcarbamoyl]-butyric acid as its TFA salt (390 mg, 95.1%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[CH:15][S:16][CH:17]=1)[C:10]([OH:12])=O.[NH2:18][CH:19]1[C:39](=[O:40])[N:21]2[C:22]([C:36]([OH:38])=[O:37])=[C:23]([CH2:26][S:27][C:28]3[N:32]([CH2:33][CH:34]=[CH2:35])[N:31]=[N:30][N:29]=3)[CH2:24][S:25][C@H:20]12.C[Si](CC(N)=O)(C)C.[Cl-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.CN(C)C=O>[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[CH:15][S:16][CH:17]=1)[C:10]([NH:18][CH:19]1[C:39](=[O:40])[N:21]2[C:22]([C:36]([OH:38])=[O:37])=[C:23]([CH2:26][S:27][C:28]3[N:32]([CH2:33][CH:34]=[CH2:35])[N:31]=[N:30][N:29]=3)[CH2:24][S:25][C@H:20]12)=[O:12]
Reactant: CON=C(C(=O)O)c1cscn1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3cscn3)[C@H]2SC1
Temperature: -25 °C

Procedure:
To dimethylformamide (0.2 g) was added dropwise phosphorus oxychloride (0.4 g) under stirring and ice-cooling, and the mixture was stirred for 30 minutes at 40° C. and then suspended in ethyl acetate (10 ml). To the suspension was added 2-methoxyimino-2-(4-thiazolyl)acetic acid (syn isomer) (0.4 g) under stirring and ice-cooling and then stirred for 30 minutes under ice-cooling. Thus obtained solution was added to a solution, which was prepared by stirring a mixture of 7-amino-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (0.76 L g) and trimethylsilylacetamide (2.3 g) in ethyl acetate (20 ml), under cooling to -25° C. The mixture was stirred for 1 hour at -20° C. to -10° C., and a saturated aqueous solution of sodium chloride (100 ml) was added thereto. Thus obtained mixture was adjusted to pH 7.5 with 20% aqueous solution of sodium carbonate, and the aqueous layer was separated. To the aqueous layer was added ethyl acetate, and adjusted to pH 2 with 10% hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated. The residue was pulverized in diethyl ether, collected by filtration and then dried to give 7-[2-methoxyimino-2-(4-thiazolyl)-acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.01 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:35])[C:15](=[O:34])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[NH:23][C:24](=[O:33])[C:25]4[C:30]([CH:31]=3)=[C:29]([CH3:32])[CH:28]=[CH:27][CH:26]=4)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[CH3:35][N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[NH:23][C:24](=[O:33])[C:25]3[C:30]([CH:31]=2)=[C:29]([CH3:32])[CH:28]=[CH:27][CH:26]=3)=[CH:18][CH:17]=1
Reactant: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)N(C)C4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)N(C)C4CCNCC4)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
To 4-{methyl-[4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzoyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (21 mg, 0.044 mmol) was added 2:1 CH2Cl2/TFA (1 mL) and the reaction mixture stirred at RT for 1 h. The solvent was removed in vacuo, re-dissolved in MeOH and passed through an SCX-2 cartridge (1 g). The column was washed with MeOH (4× column volumes), the desired product eluted from the cartridge with 0.5M NH3/MeOH (4× column volumes) and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC-MS to obtain N-methyl-4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-N-piperidin-4-yl-benzamide as a white solid (2.4 mg, 14%).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12]C)(=[O:10])[CH2:4][C:5]([O:7][CH2:8]C)=[O:6].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1Br)[C:18]#[N:19].Cl>O1CCOCC1.[Cu]Br.O>[CH3:8][O:7][C:5](=[O:6])[CH:4]([C:22]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[Cl:14])[C:3]([O:11][CH3:12])=[O:10]
Reactant: N#Cc1ccc(Br)c(Cl)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cu]Br
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C(C(=O)OC)c1ccc(C#N)cc1Cl
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
7.6 g (0.191 mol) of 60% strength sodium hydride in paraffin oil were initially charged in 300 ml of dioxane. At from 55° C. to 60° C., 22.9 g (0.173 mol) of diethyl malonate were added dropwise, and the mixture was stirred at 50° C. for 1-2 hours. 9.9-g (0.069 mol) of copper(1) bromide were added. At 80° C., 15 g (0.069 mol) of 3-chloro-4-bromobenzonitrile were then added dropwise, and the mixture was subsequently stirred at 100° C. for 14 hours. The reaction mixture was then cooled and acidified by dropwise addition of concentrated hydrochloric acid at from 15° C. to 20° C. Water was added, the mixture was extracted with dichloromethane, the organic phase was dried over sodium sulphate and the solvent was removed. The residue was distilled at 1 mbar, giving 17.5 g of dimethyl(2-chloro-4-cyanophenyl)malonate.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[CH:3]1.[H-].[Na+].Br[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]>C1COCC1>[C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[N:14]1[N:15]=[C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[N:12]=[N:13]1)(=[O:21])[CH3:19]
Reactant: O=C(CBr)N1CCCCC1
Reactant: Cn1cc(-c2nnn[nH]2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CCCCC1n1nnc(-c2cn(C)c3ccccc23)n1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
5-(1-Methyl-1H-indol-3-yl)tetrazole (0.080 g, 0.402 mmol) was dissolved in dry THF (5 ml) and treated with sodium hydride (80%) (0.014 g, 0.441 mmol). When effervescence had ceased, 1-(bromoacetyl)piperidine (Bull. Soc. Chim. France 1964 5, 1063) (0.093 g, 0.422 mmol) in dry THF (2 ml) was added. After 1 h, a further amound of 1-(bromoacetyl)piperidine (0.047 g, 0.211 mmol) in dry THF (1 ml) was added. After a further 2 h, the reaction mixture was evaporated under reduced pressure to give a brown solid which was partitioned between CHCl3 and water. The organic layer was washed with NaHCO3 solution, and the combined aqueous layers were extracted with CHCl3. The combined organic layers were then dried (Na2SO4) and evaporated to give an off white foam which was dried in vacuo and then purified by silica-gel chromatography (pentane: EtOAc 1:1 as eluant) to give the title compound (D3 ) as a white solid (0.080 g, 61%)
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]([NH2:9])=[NH:8].C(=O)([O-])[O-].[Na+].[Na+].[CH3:16][C:17](=O)[CH2:18][C:19](=O)[CH3:20]>O>[NH2:8][C:7]1[N:9]=[C:19]([CH3:20])[CH:18]=[C:17]([CH3:16])[N:6]=1
Reactant: CC(=O)CC(C)=O
Reactant: N=C(N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)nc(N)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a stirred solution containing 4.00 g (37.0 mmol) of guanidine sulfate and 8.40 g (79.3 mmol) of sodium carbonate in 25 mL of water were added 6.00 mL (58.1 mmol) of 2,4-pentanedione. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was poured into 150 mL of water and then extracted with two 150-mL portions of dichloromethane. The combined organic phase was washed with 150 mL of brine, dried (MgSO4) and then concentrated under diminished pressure to afford the expected product as a colorless solid: yield 4.31 g (95%); mp 152-153° C.; silica gel TLC Rf 0.50 (9:1 dichloromethane-methanol); 1H NMR (CDCl3) δ 2.24 (s, 6H), 5.39 (br s, 2H) and 6.33 (s, 1H); 13C NMR (CDCl3) δ 23.7, 23.7, 110.5, 162.9, 162.9 and 167.7; mass spectrum (APCI), m/z 124.0869 (M+H)1 (C6H10N3 requires 124.0875).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:14][CH:13]([NH:15][C:16]3[C:21](Cl)=[C:20]([NH2:23])[N:19]=[CH:18][N:17]=3)[CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.O.C(=O)([O-])[O-].[Cs+].[Cs+].[O:37]([C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:23][C:20]1[N:19]=[CH:18][N:17]=[C:16]([NH:15][CH:13]2[CH2:14][C:10]3([CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]3)[CH2:12]2)[C:21]=1[C:47]1[CH:48]=[CH:49][C:44]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:45][CH:46]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CC2(CC(Nc3ncnc(N)c3Cl)C2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2(CC(Nc3ncnc(N)c3-c3ccc(Oc4ccccc4)cc3)C2)C1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
In a microwave vial containing 6-(6-Amino-5-chloro-pyrimidin-4-ylamino)-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (828.00 mg; 2.44 mmol; 1.00 eq.) in dioxane (4.00 ml; 46.94 mmol; 19.27 eq.) and water (0.40 ml; 22.20 mmol; 9.11 eq.) was added cesium carbonate (1190.86 mg; 3.65 mmol; 1.50 eq.), palladium(II) acetate (27.35 mg; 0.12 mmol; 0.05 eq.), 4-phenoxyphenylboronic acid (651.87 mg; 3.05 mmol; 1.25 eq.) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (100.03 mg; 0.24 mmol; 0.10 eq.). The reaction mixture was stirred at 140° C. for 16 h before it was concentrated and separated on a 50 g silica gel column with gradient EtOAc/Hexane (0-100%). The fractions were concentrated and carried to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:18]2[C:13](=[C:14]([O:19]C)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[CH3:21].B(Br)(Br)Br.C(Cl)Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:18]2[C:13](=[C:14]([OH:19])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[CH3:21]
Reactant: COc1cccc2c1cc(C)n2Cc1c(Cl)cccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(O)cccc2n1Cc1c(Cl)cccc1Cl
Yield: 83.3 %

Procedure:
By the method used in Example 1, Part D, 1.08 g (3.38 mmol) of 1-[(2,6 dichlorophenyl)methyl]-4-methoxy-2-methyl-1H-indole was O-demethylated by treating it with 13.5 mL of 1M BBr3/CH2Cl2 to give 862 mg (83% yield) of 1-[(2,6-dichlorophenyl)methyl]-4-hydroxy-2-methyl-1H-indole, after chromatography on silica gel (eluted with 20% EtOAc/hexane).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:6]1[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[N:36]([C:37]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:8]([C:17]#[N:18])=[C:9]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[N:10]=1)[CH2:4][CH3:5]>C(O)C.O1CCCC1>[OH:16][CH:11]([C:9]1[N:10]=[C:6]([CH2:3][CH2:4][CH3:5])[N:7]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[N:36]([C:37]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[N:35]=[N:34][N:33]=3)=[CH:24][CH:25]=2)[C:8]=1[C:17]#[N:18])[C:12]([CH3:15])([CH3:13])[CH3:14]
Reactant: CCCc1nc(C(=O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.2 %

Procedure:
A solution of 108 mg of sodium borohydride in 20 ml of ethanol was added to a solution of 2.00 g of 2-propyl-4-pivaloyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (a) above] in 40 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 2.5 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The syrupy residue was crystallized in a 1:4 by volume mixture of ethyl acetate and hexane, to give 1.93 g of the title compound as crystals, melting at 115°-117° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:29](=[O:32])[CH2:30][CH3:31])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN)cc3)nc12
Product: CCC(=O)NCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yi)-4-aminomethyl-benzamide and propionyl chloride, the title compound was prepared as off-white crystals (34% yield). MS: m/e=455(M+H+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]1[CH2:26][CH:25]([CH2:27][CH3:28])[O:24][C:22]1=[O:23].[Br:29][CH2:30]Br>CN(C)P(N(C)C)(N(C)C)=O.O1CCCC1>[Br:29][CH2:30][C:21]1([C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[Cl:13])[CH2:26][CH:25]([CH2:27][CH3:28])[O:24][C:22]1=[O:23]
Reactant: BrCBr
Reactant: CCC1CC(c2ccc(Cl)cc2Cl)C(=O)O1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC1CC(CBr)(c2ccc(Cl)cc2Cl)C(=O)O1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
To a solution of 14.8 g. (0.23 m) diisopropylamine in 100 ml. of dry tetrahydrofuran is added 14.8 g. (023 m) n-butyllithium at -60° C. under nitrogen. Stirring is continued for 15 minutes when a solution of 50 g. (0.19 m) 2-(2,4-dichlorophenyl)-4-ethyl-gamma-butyrolactone in 75 ml. of tetrahydrofuran is added dropwise in one hour. The resulting mixture is further stirred for an addition 1/2 hour when the temperature is raised to -40° C. and a solution of 40.3 g. (0.23 m) dibromomethane and 41.5 g. (0.23 m) hexamethylphosphoramide is added dropwise in 45 minutes. The reaction mixture is stirred at room temperature overnight. It is then poured into 500 ml. of saturated ammonium chloride solution and extracted with ether. The combined ether extracts are dried over sodium sulfate and filtered. The solvent is removed under vacuum and the residue is further purified by vacuum distillation (158° C./0.1 mm) to give 47 g. of a yellow oil.