Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:17][C:18]1[C:23]([F:24])=[C:22]([N:25]([CH3:36])[C:26]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:21]([F:37])=[C:20](F)[N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][N:40]1[CH2:44][CH2:43][N:42]=[C:41]1[C:45]1[CH:46]=[C:47]([OH:51])[CH:48]=[CH:49][CH:50]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:17][C:18]1[C:23]([F:24])=[C:22]([N:25]([CH3:36])[C:26]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:21]([F:37])=[C:20]([O:51][C:47]2[CH:48]=[CH:49][CH:50]=[C:45]([C:41]3[N:40]([CH3:39])[CH2:44][CH2:43][N:42]=3)[CH:46]=2)[N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(N(C)c2c(F)c(F)nc(Oc3cc(C#N)ccc3OCc3ccccc3)c2F)CCCC1
Reactant: CN1CCN=C1c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(N(C)c2c(F)c(Oc3cccc(C4=NCCN4C)c3)nc(Oc3cc(C#N)ccc3OCc3ccccc3)c2F)CCCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 4-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile (0.87 g, 1.7 mmol) in DMSO (17 mL) was added 3-(1-methylimidazolin-2-yl)phenol (0.32 g, 1.8 mmol) and cesium carbonate (0.7 g, 2.1 mmol). The resultant mixture was stirred at 35° C. After 4 days, the mixture was cooled to ambient temperature and poured into 100 mL of water and 100 mL of ethyl acetate. The aqueous layer was separated and extracted with another 100 mL of ethyl acetate. The combined organic extracts were washed with 0.5 M aqueous KOH solution (100 mL), brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford 4-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile as a solid foam: NMR (CDCl3) 7.4-6.8 (m, 12), 5.0 (s, 2), 4.2 (q, 2), 3.9 (t, 2), 3.5 (t, 2), 3.2 (s, 3), 2.8 (s, 3), 2.4-1.7 (m, 8), 1.3 (t, 3) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[C@H:10]([CH2:12][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)=[CH:15][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[C:32](=[O:33])[CH2:31][CH2:30][C@H:29]1[C:34]([NH:36][C@H:37]([C:44]([NH:46][C@H:47]([C:58]([NH:60][C@H:61]([C:64](O)=[O:65])[CH2:62][OH:63])=[O:59])[CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)=[O:45])[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:35].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:27])[C@H:10]([CH2:12][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)=[CH:15][CH:14]=1)[NH:11][C:62](=[O:63])[C@H:61]([CH2:64][OH:65])[NH:60][C:58](=[O:59])[C@H:47]([CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)[NH:46][C:44](=[O:45])[C@H:37]([CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)[NH:36][C:34](=[O:35])[C@@H:29]1[CH2:30][CH2:31][C:32](=[O:33])[NH:28]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Reactant: O=C1CC[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)N[C@@H](CO)C(=O)O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CC[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
O-Benzyl-L-tyrosine benzyl ester (VIII) hydrochloride (0.397 g) and L-pyroglutamyl-L-histidyl-L-tryptophyl-L-serine (VII) (0.539 g) in dry dimethylformamide (50 ml) is treated with triethylamine (0.14 ml) and dicyclohexylcarbodiimide (0.227 g) in dry dimethylformamdie (5 ml) at 0° C. After stirring at room temperature for 24 hours, the reaction mixture is evaporated to dryness. The residue is triturated in methanol and the dicyclohexylurea is removed by filtration. The filtrate is concentrated to L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-O-benzyl-L-tyrosine benzyl ester (IX).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[CH2:19]O)[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[CH2:19][Cl:23])[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CO)c(OCc2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(CCl)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The product of step (iii) (9.5 g) was dissolved in DCM (200 ml), cooled to 0° C. and thionyl chloride (3.57 ml) was added and stirred at rt for 2 h. The solvents were evaporated and the residue taken up in DCM and washed with aq. NaHCO3. The combined organics were dried, filtered and evaporated to give the subtitle compound as a brown oil, 9.60 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](Cl)=[O:13])([CH3:4])([CH3:3])[CH3:2].[NH2:16][NH2:17].C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:13])[NH:16][NH2:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)NN
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
A solution of carbamoyl chloride 1 (1.00 g; from above) in dry THF (3.5 ml) was added over 10 minutes to an ice-cold solution of anhydrous hydrazine (0.269 g; 0.310 ml; 8.40 mmol) and triethylamine (0.708 g; 0.975 ml; 7.00 mmol) in dry THF (4 ml). Stirring was continued overnight at room temperature. The mixture was filtered and evaporated to a light yellow solid. Recrystallization from hexanes-ethyl/acetate gave pure carbazide 3 (0.533 g; 2.33 mmol; 52%) as a white solid, mp 83°-84° C. TLC (silica gel; CH2Cl2 --CH3OH, 10:1)Rf=0.25-0.35. MS m/e 173 (M+ -56). Analysis: Calculated for C10H19N3O3 : C, 52.39; H, 8.35; N, 18.33. Found: C, 52.08; H, 8.58; N, 18.01; NMR (CDCl3); δ1.43 (9H.S); 2.0-2.3 (4H,m); 3.1-3.4(2H,m); 3.8(2H,bs): 4.3-4.6(1H,m); 6.2(1H,bs); IR(CHCl3 ): 3500-3300, 1730, 1660, 1640 cm-1. [α]D =-46.5±0.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([N+:22]([O-:24])=[O:23])=[CH:17][CH:18]=2)[NH:13][C:12]1=O.P(Cl)(Cl)(Cl)(Cl)[Cl:27]>O=P(Cl)(Cl)Cl>[Cl:27][C:12]1[N:11]([CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([N+:22]([O-:24])=[O:23])=[CH:17][CH:18]=2)[N:13]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)n1CCc1ccc(Cl)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2ccc([N+](=O)[O-])cc2nc(Cl)n1CCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.8 %

Procedure:
3-[2-(2,4-Dichlorophenyl)ethyl]-7-nitro-2,4(1H, 3H)-quinazolinedione (2.0 g, 5.26 mmol) and PCl5 (1.2 g, 5.79 mmol) were added to a flask containing POCl3 (20 mL) and the resulting solution was refluxed with stirring for 6 hours. The reaction was allowed to cool to RT and stirred overnight at this temp. The POCl3 was removed under reduced pressure and CH2Cl2 was added to the residue. The unreacted starting material was removed via vacuum filtration and the product was purified by silica gel flash chromatography (100% CH2Cl2 eluent) to give the product (0.96 g, 46% yield) as a white solid. 1H NMR (DMSO-D6) 400 MHz δ ppm 8.35-8.25 (m, 3H), 7.58 (d, J=2.2 Hz, 1H), 7.41-7.34 (m, 2H), 4.41 (t, J=7.5 Hz, 2H), 3.15 (t, J=7.5 Hz, 2H) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[O:12][CH:11]=[CH:10][C:5]2=3)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: CN1CCC(O)c2ccoc2C1
Product: CN1CCC(Oc2ccc(Cl)c(Cl)c2)c2ccoc2C1

Procedure:
The same method as in Example 1 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)[CH3:5])(O)=[O:2].C(N1C=CN=C1)([N:24]1C=CN=C1)=O.[OH-].[NH4+]>>[NH2:24][C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)[CH3:5])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(Oc1ncn(-c2cccc(C(F)(F)F)c2)n1)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CC(Oc1ncn(-c2cccc(C(F)(F)F)c2)n1)C(N)=O
Yield: 56.2 %

Procedure:
The process was carried out as was Example 45, starting with 5 g of the compound of Example 24, 4 g of carbonyldiimidazole and 1.2 g of ammonium hydroxide. The yield was 2.8 g of the desired product, m.p. 147°-149°.
Reaction SMILES: C([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([C:26](O)=[O:27])=[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)C.[C:29](Cl)(=[O:33])[C:30](Cl)=O>ClCCl.CN(C=O)C>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[CH2:12][N:7]1[C:8]2[C:4](=[CH:3][CH:11]=[CH:10][CH:9]=2)[C:5]([C:26](=[O:27])[NH:7][CH2:6][CH:5]2[O:33][CH2:29][CH2:30][CH2:4]2)=[C:6]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1c(C(=O)O)c2c(CC)cccc2n1Cc1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c(C(=O)NCC2CCCO2)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 47 %

Procedure:
To a stirred solution of ethyl N-(3,4-dichlorobenzyl)-2-ethoxycarbonylindole-3-carboxylic acid (100 mg) in dichloromethane (4 ml) at ambient temperature, under argon, was added DMF (1 drop) and oxalyl chloride in dichloromethane (2M, 153 μl). The reaction was stirred at ambient temperature for 7 hours, then concentrated in vacuo and dissolved in dichloromethane (4 ml). Tetrahydrofurfurylamine (53 μl) was added, followed by triethylamine (71 μl) and the reaction stirred under argon for 16 hours. The reaction was diluted with dichloromethane (30 ml), washed with HCl (2M, 30 ml) and water (30 ml), dried (MgSO4) and concentrated in vacuo to give a crude residue which was purified by column chromatography, using ethyl acetate:iso-hexane as eluent (gradient 10/90-50/50), to give the product as an off-white solid (57 mg, 47%); M/z (+) 475.3 (MH+),
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[N:13][OH:14].[O-]CCCC.[K+]>C1COCC1.O.C(OCC)(=O)C>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]2[O:14][N:13]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:3]=2[CH:4]=1
Reactant: ON=C(Nc1ccncc1)c1cc(C(F)(F)F)ccc1F
Agent: CCCC[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccc2onc(Nc3ccncc3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
Synanti 2-fluoro-5-trifluoromethylphenyl-4-pyridinylamino methanone oxime (10.7 g, 35.8 mmol) was dissolved in THF (400 mL) and potassium butoxide (4.4 g, 1.1 eq) was added in one portion. The reaction was stirred for 6 hours at room temperature under nitrogen. The reaction was diluted with water and ethyl acetate. The organic layer was collected and washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. Trituration with ethyl acetate provided the title compound (7.0 g, 70%). The title compound is recrystallized from methanol, mp >280° C.
Reaction SMILES: [OH-].[Li+].O.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[C:9]([CH:22]=1)[C:10]([O:12]CC1C=CC(F)=CC=1F)=[O:11]>O1CCCC1>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[C:9]([CH:22]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(OCc1ccc(F)cc1F)c1cc(Br)ccc1OCc1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ccc1OCc1ccc(F)cc1F

Procedure:
Lithium hydroxide (0.83 g, 34.5 mmol) and water (50 ml) were added to a solution of (2,4-difluorophenyl)methyl 5-bromo-2-{[(2,4-difluorophenyl)methyl]oxy}benzoate (may be prepared by Description 102; 5.39 g, 11.49 mmol) in tetrahydrofuran (200 ml). The mixture was heated to reflux for 2 hrs. The tetrahydrofuran was then removed on a buchi and the aqueous mixture was acidified to pH=1 using 2M aqueous HCl. The solid formed was filtered off, washed with water (2×50 ml) and dried in air under vacuum. The solid was triturated with diethyl ether to give a white solid. 3.1 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25](O)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:61][NH:62][CH2:63][C:64]1[CH:65]=[N:66][CH:67]=[CH:68][CH:69]=1>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:62]([CH3:61])[CH2:63][C:64]4[CH:65]=[N:66][CH:67]=[CH:68][CH:69]=4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35]
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reactant: CNCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)N(C)Cc4cccnc4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a stirred solution of the 10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step E (0.17 g, 0.37 mmol) in N,N-dimethylformamide (15 mL), was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.092 g, 0.48 mmol) and 1-hydroxybenzotriazole monohydrate (0.065 g, 0.48 mmol). After the solution became homogeneous 3-(methylaminomethyl) pyridine (0.045 g, 0.37 mmol) was added, and the solution was stirred at room temperature overnight. The solution was then poured into water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried and concentrated to dryness. The residue was subjected to silica chromatography eluting with 10% methanol in chloroform. The pure fractions were concentrated and the residue azeotroped and triturated several times with hexane to provide the title product (0.150 g) as an amorphous white solid, 150–153° C. (dec.)
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=1.CI>C1COCC1.C([Li])CCC.[Cl-].[NH4+]>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)([CH3:1])[C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=1
Reactant: COC(=O)C(c1ccc(Cl)cc1)C1CCCC1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(c1ccc(Cl)cc1)C1CCCC1
Temperature: -35 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (0.15 ml) in THF (2 ml), n-butyl lithium (1.5 M hexane solution, 0.6 ml) was added at −78° C., stirred for 10 minutes and another solution of methyl 2-(4-chlorophenyl)-2-cyclopentylacetate (200 mg) in THF (1.5 ml) was added dropwise. After 15 minutes' stirring, the system temperature was raised to −35° C., and methyl iodide (0.15 ml) was added. The reaction liquid temperature was raised to 0° C., and the liquid was stirred for 1.5 hours, diluted with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and condensed under reduced pressure. The resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate 60/1) to provide methyl 2-(4-chlorophenyl)-2-cyclopentylpropionate (180 mg) as yellow oily substance.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br-].[F:12][C:13]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:14]=1[CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:42](=O)[CH3:43].O>O1CCOCC1>[F:12][C:13]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:14]=1[CH:15]=[CH:42][CH3:43]
Reactant: CC=O
Reactant: O=[N+]([O-])c1ccc(F)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC=Cc1cc([N+](=O)[O-])ccc1F
Reaction time: 1 h

Procedure:
At 10° C., 5.99 g (32.7 mmol) of sodium bis(trimethylsilyl)amide are added dropwise to a solution of 13.5 g (27.3 mmol) of the compound from example 35A in 145 ml of dioxane. The mixture is stirred at this temperature for 1 h. Then a solution of 2.40 g (54.5 mmol) of acetaldehyde in 5 ml of dioxane is added and the mixture is stirred at RT for 1 h, then admixed with 400 ml of water and extracted three times with dichloromethane, and the combined organic phases are washed twice with saturated aqueous sodium chloride solution. After drying over sodium sulfate and subsequent filtration, the solvent is removed under reduced pressure. It is purified by means of chromatography on silica gel (eluent: cyclohexane/ethyl acetate=40:1). This affords 5.2 g (100% of theory) of the desired product as an E/Z isomer mixture.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([C:22](O)=[O:23])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].Cl.[NH:30]([CH2:32][C:33]([OH:35])=[O:34])[CH3:31].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:15][CH2:16][C:17]([C:22]([N:30]([CH2:32][C:33]([OH:35])=[O:34])[CH3:31])=[O:23])([CH2:18][CH2:19]3)[CH2:20][CH2:21]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: CNCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)N(C)CC(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
To a stirred mixture of 0.100 g (0.257 mmol) of 4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid (Example 13), 0.039 g (0.257 mmol) of sarcosine hydrochloride, 0.143 ml (1.03 mmol) of NEt3, and 2 ml anhydrous acetonitrile was added 0.103 g (0.270 mmol) of HATU. The reaction solution was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo and combined with 10 ml EtOAc and 10 ml of 10% citric acid. The aqueous layer was separated and washed twice with 10-ml portions of EtOAc. The combined organic fractions were washed with 10-ml portions of sat'd NaHCO3 and brine and conc'd in vacuo. The resultant solid was dissolved in a mixture of 5 ml of MeOH and 5 ml of 1 N NaOH and stirred for 16 h. The reaction solution was conc'd in vacuo, taken up in 10 ml of water, and washed twice with 10-ml portions of CH2Cl2. The aqueous layer was acidified with conc'd HCl and the resultant precipitate collected by suction filtration to give 0.094 g (77% yield) of an off-white solid. (MH+=460.18)
Reaction SMILES: [NH2:1][C@H:2]([CH3:20])[CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:1]([CH2:3][C:4]1[CH:19]=[CH:18][CH:7]=[CH:6][CH:5]=1)[C@H:2]([CH3:20])[CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@@H](N)Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Reactant: BrCc1ccccc1
Product: C[C@H](Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
Using a method similar to example 2, using (R)-6-[4-(2-amino-propyl)-phenoxy]-nicotinamide and benzyl bromide gives the title product: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 8.04 minutes, Purity: 99.8%; mass spectrum (ion spray): m/z=452.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:23]=[CH:22][NH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16](C)[N:15]=3)[N:13]=2)[CH:5]=[N:6][CH:7]=1.IC1C2C=CNC=2N=C(C2C=CC=C(C)N=2)N=1.IC1C2C=CNC=2N=C(C2C=CC=CN=2)N=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:23]=[CH:22][NH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:13]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1cccc(-c2nc(-c3cncc(Br)c3)c3cc[nH]c3n2)n1
Agent: Cc1cccc(-c2nc(I)c3cc[nH]c3n2)n1
Agent: Ic1nc(-c2ccccn2)nc2[nH]ccc12
Product: Brc1cncc(-c2nc(-c3ccccn3)nc3[nH]ccc23)c1

Procedure:
4-(5-Bromo-pyridin-3-yl)-2-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidine is prepared by an analogous method to that for 4-(5-bromo-pyridin-3-yl)-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (Example 16) by replacing 4-iodo-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 3) with 4-iodo-2-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 4).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[C:22](=[O:23])[C:21]3[C:24]([CH3:32])=[C:25]([O:28][CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17]2)=[C:13]([CH3:33])[CH:12]=[C:11]([CH3:34])[N:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:33][C:13]1[CH:12]=[C:11]([CH3:34])[NH:10][C:9](=[O:8])[C:14]=1[CH2:15][N:16]1[C:22](=[O:23])[C:21]2[C:24]([CH3:32])=[C:25]([O:28][CH:29]([CH3:30])[CH3:31])[N:26]=[CH:27][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: Cc1cc(C)c(CN2CCOc3cnc(OC(C)C)c(C)c3C2=O)c(OCc2ccccc2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(CN2CCOc3cnc(OC(C)C)c(C)c3C2=O)c(=O)[nH]1
Reaction time: 3 h
Yield: 98.7 %

Procedure:
A mixture of 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-6-methyl-7-(propan-2-yloxy)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one (131 g, 140 mg, 0.30 mmol) and 10% Pd/C (80 mg) in MeOH (15 mL) was stirred under an H2 balloon for 3 hours. The reaction mixture was filtered through a pad of CELITE® and the filtrate was concentrated under vacuum to give the title compound (Example 131, 110 mg, 98%) as a white solid. 1H NMR (400 MHz, chloroform-d): δ 11.45 (s, 1H), 7.72 (s, 1H), 5.97 (s, 1H), 5.26-5.21 (m, 1H), 4.87 (s, 2H), 4.00-3.97 (t, 2H), 3.56-3.53 (t, 2H), 2.36 (s, 3H), 2.28-2.26 (d, 6H), 1.35-1.33 (d, 6H); MS 372.2 [M+H].
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:10]([OH:21])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[OH:21])=[CH:19][CH:18]=1
Reactant: Cc1ccc(C2CCN(Cc3ccccc3)CC2O)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(C2CCNCC2O)cc1
Yield: 67.6 %

Procedure:
A solution of 2.5 g (8.9 mmol) of (3RS,4RS)-1-benzyl-4-(p-tolyl)-piperidin-3-ol in 100 ml of methanol was hydrogenated at 5 bar at room temperature for 18 hours using a palladium (10%)-carbon catalyst. For the working up, the catalyst was filtered off, washed with methanol and the solution obtained was evaporated under reduced pressure. For purification, the residue was chromatographed on silica gel using a 5:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There were obtained 1.15 g (68% of theory) of (3RS,4RS)-4-(p-tolyl)-piperidin-3-ol as a colourless solid; MS: 191 (M)+.