Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.[CH3:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:47](=[O:52])[C:48]([NH:50][CH3:51])=[O:49].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.P([O-])([O-])([O-])=O>C(OCC)(=O)C>[CH3:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH:47]([OH:52])[C:48]([NH:50][CH3:51])=[O:49]
Reactant: CNC(=O)C(=O)c1ccccc1C
Agent: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Solvent: CCOC(C)=O
Product: CNC(=O)C(O)c1ccccc1C

Procedure:
Using the plasmid pTrcGSRxc, E. coli HB101 was transformed. The resulting transformant was inoculated in a sterilized LB medium (100 ml) containing 0.1 mM of IPTG and 50 μg/ml of ampicillin, and was shaking-cultured (37° C., 15 hours). The resulting culture was centrifuged to obtain 0.1 g of wet bacterial cells. To a reaction tube were added 1.5 mg of 2-(2-methyl-phenyl)-N-methyl-2-oxo-acetamide, 0.1 g of the wet bacterial cells, 10 mg of NADPH, and 1.5 ml of a 100 mM phosphate buffer solution (pH 7), and these were reacted at a stirring rate of 1000 rpm at 30° C. for 20 hours. After the completion of the reaction, 5 ml of ethyl acetate was added to the reaction solution, and this was centrifuged (1000×g, 5 minutes) to recover an organic layer. The organic layer was distilled off to obtain oily 2-(2-methyl-phenyl)-N-methyl-2-hydroxy-acetamide. Content analysis by liquid chromatography under the following condition showed that the conversion rate was 87.2%. 1H-NMR analysis result of the resulting 2-(2-methyl-phenyl)-N-methyl-2-hydroxy-acetamide is shown below.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[C:9]([CH:16]([CH3:18])[CH3:17])[C:8]=1[O:19][CH2:20][CH2:21][CH3:22].[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.Cl>C1COCC1>[CH2:20]([O:19][C:8]1[C:9]([CH:16]([CH3:18])[CH3:17])=[CH:10][C:11]([CH:13]([CH3:15])[CH3:14])=[CH:12][C:7]=1[B:23]([OH:28])[OH:24])[CH2:21][CH3:22]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCOc1c(Br)cc(C(C)C)cc1C(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 23.2 %

Procedure:
To a solution of n-BuLi (1.6 M in hexane, 40 mL, 64.2 mmol) in THF (150 mL) at −78° C. was added 1-bromo-3,5-diisopropyl-2-propoxy-benzene (Intermediate 3,16.0 g, 53.5 mmol) in THF (50 mL and 10 mL rinse) slowly. Thereafter 0.5 h triisopropyl borate (24.7 mL, 107 mmol) in THF (40 mL) was added slowly and the reaction was stirred at −78° C. for 1 h and at room temperature for 2 h. The reaction was then treated with 3M HCl (200 mL) at room temperature for 1.5 h, and extracted with EtOAc (×2). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was washed with hexane to give 3.28 g of the title compound as a white solid. The hexane solution was filtered through a pad of SiO2 to give additional 11.0 g of the title compound as a yellow slurry containing minor impurities. This crude material was used in the next step without flirter purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][N:10]([CH3:17])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CC(C)([O-])C.[Na+].N#N.[OH-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][CH:11]([N:10]([CH3:17])[CH3:9])[CH2:12][CH2:13]2)=[N:3][CH:4]=1
Reactant: CN(C)C1CCNCC1
Reactant: Brc1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CN(C)C1CCN(c2ccc(Br)cn2)CC1
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 83.6 %

Procedure:
To a 100 mL single-necked round-bottom flask were placed 2,5-dibromopyridine (2 g, 8 mmol), 4-(dimethylamino)piperidine (1 ml, 8 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.07 g, 0.08 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.1 g, 0.2 mmol), and sodium t-butoxide (1 g, 12 mmol). The flask was subjected to 3 cycles of evacuation and back-filling with N2 before toluene (40 mL) was introduced under N2. The resulting mixture was stirred at a preheated oil bath at 100° C. for 40 min. The crude mixture was poured into ice and 4 N NaOH aqueous solution and extracted with ethyl acetate (2×). The combine organics were dried over sodium sulfate and concentrated in vacuo to give 2.7 g crude product. Trituration with ethyl acetate/hexanes gave highly pure 1-(5-bromopyridin-2-yl)-N,N-dimethylpiperidin-4-amine (91) (1.9 g, 95%) 1H NMR (400 MHz, CDCl3) δ 8.18 (1 H, d, J=2.3 Hz), 7.52 (1 H, dd, J=9.0, 2.7 Hz), 6.58 (1 H, d, J=9.0 Hz), 4.30 (2 H, d, J=12.9 Hz), 2.79-2.91 (2 H, m), 2.49 (1 H, br. s.), 2.37 (6 H, s), 1.97 (2 H, d, J=12.5 Hz), 1.45-1.60 (2 H, m) ppm.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25]C(OC(C)C)=O)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].C(N(CC)CC)C.C(Cl)Cl>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:25])[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The same reaction was done in parallel, using of ethyl 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (for a preparation see Intermediate 15) (0.89 g 2.030 mmol), aluminium chloride (1.03 g, 7.72 mmol), triethylamine (3.4 mL, 24.53 mmol), DCM (16 mL) and MeOH (1.3 mL). The products of both reactions were combined at this stage and the resulting mixture was stirred at room temperature for approximately 10 min (total volume: approximately 1 L). The mixture was filtered through Celite™, the insoluble residue was washed with EtOAc and a saturated NaHCO3 aqueous solution and the layers were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried (hydrophobic frit) and concentrated in vacuo to give ethyl 4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (6.6 g, 84%—allowing for the addition of the parallel experiment) as a cream solid. LCMS (formate, 2 min), Retention time 0.73 min, [M-NH2]+=336
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:19]1[CH:20]=[C:21]([F:32])[C:22]([C:25]2[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=2)=[N:23][CH:24]=1>>[NH2:31][C:28]1[N:27]=[CH:26][C:25]([C:22]2[N:23]=[CH:24][C:19]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])=[CH:20][C:21]=2[F:32])=[CH:30][N:29]=1
Reactant: Nc1ncc(-c2ncc(Cl)cc2F)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1cnc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid and 5-(5-chloro-3-fluoropyridin-2-yl)pyrimidin-2-amine. MS (ESI): mass calcd. for C19H20FN5O2S, 401.13; m/z found, 402.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.97 (d, J=1.1, 2H), 8.50-8.44 (m, 1H), 8.17 (dd, J=8.0, 1.3, 1H), 7.79 (dd, J=12.0, 1.8, 1H), 7.70 (m, 1H), 7.63 (m, 1H), 7.43 (dd, J=7.5, 1.5, 1H), 1.09 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]CC)=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17]1.[OH-].[Na+]>O.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:20][CH2:19][S:18](=[O:21])(=[O:22])[CH2:17]1
Reactant: CCOC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Temperature: 85 °C
Yield: 91.2 %

Procedure:
Ethyl 5-bromo-3-(1,1-dioxidotetrahydro-3-thienyl)-1H-indole-7-carboxylate (0.596 g, 1.54 mmol) was dissolved in water (8.2 mL) and methanol (13.8 mL). A 6M NaOH solution (2.55 mL) was added and heated to 85° C. for 1.5 hours. The methanol was then concentrated and the solution was acidified with 6M HCl. The resulting white solid was filtered and dried to give 0.503 g (91%) of product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:14]2[C:19]([O:20][CH2:21][O:22][CH3:23])=[CH:18][CH:17]=[CH:16][C:15]=2[O:24][CH3:25])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:14]2[C:19]([O:20][CH2:21][O:22][CH3:23])=[CH:18][CH:17]=[CH:16][C:15]=2[O:24][CH3:25])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COCOc1cccc(OC)c1-c1ccc([N+](=O)[O-])cc1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COCOc1cccc(OC)c1-c1ccc(N)cc1C(=O)OC

Procedure:
A solution of Example 32A (10.0 g) and 10% Pd/C (1.0 g) in methanol (200 mL) at room temperature was hydrogenated at 4 atm for 1 hour, filtered through diatomaceous earth (Celite®), and concentrated to provide the desired product. MS (ESI(−)QIMS) m/z 316 (M−H)−.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=1.[OH-].[Na+]>C1COCC1.Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1
Reactant: CCOC(=O)Cc1ccc(Nc2nc3ccccc3o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(Nc2nc3ccccc3o2)cc1
Reaction time: 24 h
Yield: 98.2 %

Procedure:
In THF (70 mL) was dissolved ethyl 4-(2-benzoxazolylamino)phenylacetate (2.08 g, 7.02 mmol), followed by the addition of 0.25N NaOH (42.0 mL, 10.5 mmol) at room temperature. After stirring for 24 hours, the reaction mixture was poured in 1N HCl (50 ml) at 0° C. The crystals thus precipitated were collected by filtration, whereby 4-(2-benzoxazolylamino)phenylacetic acid (1.85 g, 98%) was obtained as a solid.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd]>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2=NNC(c3ccccc3)C2)cc1
Agent: [Pd]
Product: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Yield: 76.4 %

Procedure:
The procedure of Example 18 is followed except that 2 parts of 5% palladium on barium sulfate are used in lieu of the palladium on alumina Example 18. Following a 2 1/2 hour of reflux, unreacted 3,5-diphenyl-2-pyrazoline is found to amount to 2.4%, and a 76.4% yield of 3,5-diphenylpyrazole, melting at 198° - 201°C. is obtained.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:15][CH2:16][CH2:17][NH3+:18].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]=O>>[Cl:2][C:3]1[C:4]([O:15][CH2:16][CH2:17][NH:18][CH2:24][C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[CH:10][C:9]([C:13]#[N:14])=[CH:8]2
Reactant: O=Cc1cccs1
Reactant: N#Cc1ccc2c(Cl)c(OCC[NH3+])ccc2c1
Agent: [Cl-]
Product: N#Cc1ccc2c(Cl)c(OCCNCc3cccs3)ccc2c1
Yield: 35 %

Procedure:
Prepared from 2-[(1-chloro-6-cyanonaphthalen-2-yl)oxy]ethanaminium chloride and thiophen-2-carbaldehyde in 35% yield as a whitish solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:33])[C@@H:13]([NH:22]C(OCC2C=CC=CC=2)=O)[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CC(=O)OCC.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:33])[C@@H:13]([NH2:22])[CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CC(=O)OC(C)(C)C)CC1
Yield: 98.5 %

Procedure:
4-((S)-2-benzyloxycarbonylamino-3-tert-butoxycarbonyl-propionyl)-piperazine-1-carboxylic acid ethyl ester (3.27 g) was hydrogenated in EA (25 ml) with Pd/C (10%, 327 mg) overnight. The mixture was filtered through celite and evaporated off. HV drying afforded 2.29 g of the desired compound.
Reaction SMILES: [CH2:1]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]/[C@H:21]([C:35](N2[C@@H](C(C)C)C(C3C=CC=CC=3)(C3C=CC=CC=3)OC2=S)=[O:36])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[O:12][CH2:11][CH2:10][O:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH2:58][C@@H:59]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([O:71][CH2:72][CH2:73][CH2:74][CH3:75])=[CH:67][CH:66]=1)[C:60]([NH:62][CH3:63])=[O:61]>ClCCl>[CH2:72]([O:71][C:68]1[CH:67]=[CH:66][C:65]([CH2:64][C@H:59]([NH:58][C:35]([C@@H:21](/[CH:20]=[CH:19]/[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:8]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[O:9][CH2:10][CH2:11][O:12]2)[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:36])[C:60](=[O:61])[NH:62][CH3:63])=[CH:70][CH:69]=1)[CH2:73][CH2:74][CH3:75]
Reactant: CCCCCCCC1(CCCCCC/C=C/[C@H](C(=O)N2C(=S)OC(c3ccccc3)(c3ccccc3)[C@@H]2C(C)C)[C@@](O)(CCOC)C(=O)OC(C)(C)C)OCCO1
Reactant: CCCCOc1ccc(C[C@H](N)C(=O)NC)cc1
Solvent: ClCCl
Product: CCCCCCCC1(CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc2ccc(OCCCC)cc2)C(=O)NC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)OCCO1
Yield: 52.6 %

Procedure:
No. 6801291, tert-butyl (E)-(2S,3S)-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-3-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidine-3-carbonyl)-2-(2-methoxy-ethyl)-undec-4-enoate (62 mg, 0.0824 mmol) and (S)-2-amino-3-(4-butoxy-phenyl)-N-methyl-propionamide (23 mg, 0.0989 mmol) were dissolved in dichloromethane. The solvent was distilled off under reduced pressure. The resulting residue was reacted at 45° C. for 4 days. After confirming the consumption of the starting materials by LCMS, the reaction mixture was purified with SP1 to obtain No. 6801292, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methylcarbamoyl-ethylcarbamoyl]-11-(2-hept yl-[1,3]dioxolan-2-yl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate (33 mg, 54% yield, ESI (LC/MS positive mode) m/z 762 (M+H); Rt 3.02 min.). To the obtained No. 6801292 (40 mg, 0.0526 mmol) were added dichloromethane (3.0 mL) and trifluoroacetic acid (1.0 mL), and the mixture was stirred at room temperature. After confirming the consumption of the starting materials by LCMS, the solvent was distilled off under reduced pressure. The residue was purified by preparative HPLC. The purified fraction was freeze-dried to obtain the title compound (27 mg, 78% yield, white powder).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>CO>[CH:11]1([NH:14][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH2:13][CH2:12]1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NC1CC1
Solvent: CO
Product: c1nc(NC2CC2)c2nc[nH]c2n1
Yield: 153.1 %

Procedure:
A solution of 6-chloropurine (Aldrich Chemical Company, 4.23 g, 27 mmoles) and cyclopropylamine (Aldrich Chemical Company, 12.5 g, 22 mmoles) in MeOH (100 ml) was heated at 50° C. for 48 hours. The solvent was removed, and the crude product was purified on a silica gel column eluting with CHCl3 : 5% MeOH to obtain 5.90 g of a cream solid. This was recrystallized from MeOH to give two crops, 2.69 g and 1.16 g (81.4% total yield); mp. 237-240.
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>Cl[Ni]Cl>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]
Reactant: CCOP(OCC)OCC
Reactant: BrC1=Cc2ccccc2C1
Agent: Cl[Ni]Cl
Product: CCOP(=O)(OCC)C1=Cc2ccccc2C1

Procedure:
To 91.0 g (0.467 mol) of 2-bromo-1H-indene and 3.02 g (0.023 mol) of NiCl2 in 250 ml flask equipped with a distillation head, 85.0 ml (82.4 g, 0.496 mol) of (EtO)3P were added. This black mixture was heated in the oil bath at 185–190° C. for 3 hours. During this procedure, argon gas was bubbled through the mixture to eliminate ethyl bromide formed. The crude product was distilled in vacuum (171–175° C./1 mm). Yield 102.4 g (87%) of colorless oil of diethyl 1H-inden-2-ylphosphonate, 9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]CS([O-])(=O)=O)[CH:5]=[CH:4][N:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:27][CH:24]2[CH2:23][CH2:22][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:26][CH2:25]2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)([O-])CCc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccnc(Cl)c2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-42 using (2-chloropyridin-4-yl)methylmethanesulfonate (Intermediate-4) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.215 g, 29%); MS: 327.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH:10]([CH:11]=[CH:12]2)[O:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(#N)C.O.[BH4-].[Na+]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo].C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:13]1[CH2:14][CH:10]([OH:9])[CH:11]=[CH:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1OC2C=CC1C2
Agent: [Mo]
Agent: [BH4-]
Agent: [C-]#[O+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1C=CC(O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.1 %

Procedure:
Molybdenum hexacarbonyl (1.46 g, 5.53 mmol) was added to a solution of the bicycle 2 (0.70 g, 3.55 mmol) in a 7:1 mature of acetonitrile and water (24 cm3). The suspension was stirred for 10 minutes at room temperature, then sodium borohydride (0.07 g, 1.85 mmol) was added and the suspension was heated under reflux for 3 hours. Upon completion of reaction, the mixture was allowed to cool to room temperature, filtered through a celite plug, and evaporated to dryness to give a dark oil. Flash chromatography (SiO2, 50% ethyl acetate in petrol) gave the alcohol 3 (0.46 g, 2.31 mmol, 65%) as a colourless oil; δH (200 MHz, CDCl3) 5.97 (1H, m, CH═CH), 5.85 (1H, dt, J 5.8 & 1.8 Hz, CH═CH), 4.80 (1H, m), 4.69 (1H, m), 4.42 (1H, m), 2.74 (2H, dt, J 14.3 & 7.1 Hz, CH2), 1.55 (1H, m, OH), 1.44 (9H, s, CO2C(CH3)3); m/z (CI) Found [MH]+ 200.1285 ([MH]+ C10H18NO3 requires 200.1287).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C@@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>Br>[CH3:12][C@H:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][NH:4]1
Reactant: C[C@H](NCCO)c1ccccc1
Agent: Br
Product: C[C@@H]1NCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
22.1 g(133.16 mmole) of (S)-(-)-N-(2-hydroxyethyl)-α-methylbezylamine produced in Example 11(1) above was suspended in 105 ml of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at 126° C. for 30 minutes under refluxing. Then, the reaction solution was distilled for 2 hours under normal pressure at constant temperature and 95 ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 112 ml of acetone, and 100 ml of ethyl acetate and 150 ml of ether were added thereto. The reaction solution was stirred for 30 minutes, cooled to 0° C. and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 70 ml of ethyl acetate and then dried to obtain 20 g of the first crop of the title compound. The filtrate was then concentrated. The residue was dissolved in 130 ml of ethanol and then concentrated under reduced pressure. The residue was dissolved in 104 ml of acetone, diluted with 143 ml of ether, and then allowed to stand at 0° C. for 12 hours. The resulting solid product was filtered, collected and washed with 75 ml of ethyl acetate to obtain 6.7 g of the second crop of the title compound.
Reaction SMILES: [C:1]([C:5]1[C:6]2[CH:7]=[C:8]([CH3:29])[C:9]([NH:17][C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=3)=[CH:10][C:11]=2[C:12]([CH3:16])([CH3:15])[CH2:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH:30](=O)[CH3:31]>>[CH2:30]([N:17]([C:9]1[C:8]([CH3:29])=[CH:7][C:6]2[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=2[CH:10]=1)[C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=1)[CH3:31]
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C(C)(C)C)=CCC3(C)C)cc1
Reactant: CC=O
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C(C)(C)C)=CCC3(C)C)cc1
Yield: 62 %

Procedure:
Following General Procedure D, ethyl 4-[(5-tert-butyl-3,8,8-trimethyl-7,8-dihydronaphthalen-2-yl)amino]benzoate (Compound 56, 0.019 g, 0.05 mmol) was reacted with acetaldehyde (0.030 mL, 0.5 mmol) to give 0.013 g (62%) of the title compound as a clear oil.
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].C(N(CC)CC)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1.CO>ClCCl>[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH:12][C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)=[O:29])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(=O)N1CCN(N)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(NC(=O)Nc2ccc(F)cc2)CC1
Yield: 71.4 %

Procedure:
To a solution of 1-acetyl-4-aminopiperazine dihydrochloride (540 mg) in dichloromethane (5 ml) was added dropwise triethylamine (0.8 ml) followed by addition a solution of 4-fluorophenylisocyanate (377 mg) in dichloromethane (2.5 ml) with stirring in an ice bath. After stirring for 100 minutes at the same temperature, a mixture of dichloromethane (15 ml) and methanol (3 ml) was added to the reaction mixture. The mixture was washed with brine, dried, and concentrated in vacuo. The residue was crystallized from ethanol to yield N-(4-acetyl-1-piperazinyl)-N'-(4-fluoroph-enyl)urea (500 mg).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:24])[N:4]=[C:5]2[C:10](=[O:11])[NH:9][C:8]([C:12]3[C:13]([O:21][CH2:22][CH3:23])=[N:14][CH:15]=[C:16]([N+:18]([O-])=O)[CH:17]=3)=[N:7][C:6]=12.C(OCC)(=O)C>Cl.C(O)(=O)C.[Cl-].[Cl-].[Cl-].[Ti+3]>[Br:1][C:2]1[N:3]([CH3:24])[N:4]=[C:5]2[C:10](=[O:11])[NH:9][C:8]([C:12]3[C:13]([O:21][CH2:22][CH3:23])=[N:14][CH:15]=[C:16]([NH2:18])[CH:17]=3)=[N:7][C:6]=12
Reactant: CCOc1ncc([N+](=O)[O-])cc1-c1nc2c(Br)n(C)nc2c(=O)[nH]1
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOc1ncc(N)cc1-c1nc2c(Br)n(C)nc2c(=O)[nH]1
Yield: 42.3 %

Procedure:
Titanium trichloride (20.93 g, 140 mL of a 15% solution in hydrochloric acid) was added to a solution of 3-bromo-5-(2-ethoxy-5-nitropyridin-3-yl)-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Example 53) (7.66 g, 19.4 mmol) in acetic acid (100 mL). After 2 h the acetic acid was evaporated and azeotroped with toluene. The residue was partitioned between sodium bicarbonate solution and dichloromethane and the titanium salts filtered to aid separation of the aqueous and organic phases. The aqueous layer was saturated with sodium chloride and re-extracted with dichloromethane. The organics were dried (MgSO4) and concentrated to give a solid. Trituration with ethyl acetate gave 3 g of pure product.