Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[N+:6]([C:9]1[C:10]([N:15]2CCC(=O)[CH2:17][CH2:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:4]=[C:3]1[CH2:17][CH2:16][N:15]([C:10]2[C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:1][CH2:2]1
Reactant: O=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium in hexanes (2.5 M, 4.93 mL, 12.3 mmol) was added dropwise over 10 min. into a suspension of 98% methyltriphenylphosphonium bromide (4.65 g, 12.8 mmol) in 40 mL of THF stirred at −70° C. After 0.5 h, a solution of 1-(3-nitro-2-pyridyl)-4-oxopiperidine (2 g, 8.5 mmol) in 16 mL of THF was added and the reaction mixture was allowed to warm up to r.t. After overnight resting, the mixture was quenched with an aqueous saturated solution of NH4Cl, extracted with EtOAc, dried over Na2SO4, evaporated to dryness in vacuo. The crude product was purified by automated flash chromatography (SP1®TM-Biotage) eluting with a Petroleum Ether-EtOAc gradient from 1:0 to 9:1 yielding 1.23 g of the title compound as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:15][C:14](=[CH2:16])[CH2:13][CH:12]2[NH2:17])=[O:10])=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[C:26]([N:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]2=[O:34])[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:15][C:14](=[CH2:16])[CH2:13][CH:12]2[NH:17][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:26]([N:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]3=[O:34])=[CH:27][C:19]=2[F:18])=[O:10])=[CH:4][CH:3]=1
Reactant: C=C1CC(N)C(C(=O)Nc2ccc(Cl)cc2)C1
Reactant: O=C(O)c1ccc(-n2ccccc2=O)cc1F
Product: C=C1CC(NC(=O)c2ccc(-n3ccccc3=O)cc2F)C(C(=O)Nc2ccc(Cl)cc2)C1
Yield: 69 %

Procedure:
Starting from 35d and 35e, the title compound was prepared in 69% yield according to the procedure for example 1 and 2, step 2. MS: 466.3 (M+H)+.
Reaction SMILES: [OH-].[Na+:2].C([O:5][C:6](=[O:49])[CH2:7][CH2:8][CH2:9][NH:10][C@H:11]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:12][N:13]1[C:18](=[O:19])[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:21]=2[Cl:28])=[C:16]([CH3:29])[N:15]([CH2:30][C:31]2[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:32]=2[F:41])[C:14]1=[O:42])C.O>CCO>[Na+:2].[Cl:28][C:21]1[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[C:18](=[O:19])[N:13]([CH2:12][C@H:11]([NH:10][CH2:9][CH2:8][CH2:7][C:6]([O-:49])=[O:5])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:14](=[O:42])[N:15]([CH2:30][C:31]2[C:36]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:34]=[CH:33][C:32]=2[F:41])[C:16]=1[CH3:29]
Reactant: CCOC(=O)CCCN[C@@H](Cn1c(=O)c(-c2cccc(OC)c2Cl)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](NCCCC(=O)[O-])c3ccccc3)c2=O)c1Cl
Reaction time: 2 h

Procedure:
NaOH (338 mL, 169 mmol, 0.5 M aq.) was added to a solution of 7d (103.9 g, 153.68 mol) in EtOH (472 mL) and the mixture was stirred for 2 hours. The EtOH was distilled off and water added to a total volume of 1080 mL (10.5 mL/g). This mixture was passed through a filter and washed with MIBK (600 mL×2). MIBK (700 mL) was added followed by NaOH (289 mL, 50% w/w) and extracted. The organic layer was separated and the aqueous extracted with MIBK (250 mL) and the combined organic layers washed with brine (500 mL), dried (NaSO4) and concentrated in vacuo to give a foam. This was lyophilized from 300 mL water to give 4-((R)-2-[5-(2-chloro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid sodium salt 7-1 as an off white powder (92 g).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.[OH:25][CH2:26][P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])=[CH:6][C:7]=1[O:25][CH2:26][P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])([O-:13])=[O:12]
Reactant: CCOP(=O)(CO)OCC
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOP(=O)(COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OCC

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (500 mg, 1.38 mmol), diethyl hydroxymethylphosphonate (295 mg, 1.66 mmol) and potassium carbonate (285 mg, 2.07 mmol) in 2-butanone (5 ml) is heated under reflux for 6 hours. After cooling, the reaction mixture is filtered, and the filtrate is concentrated to dryness. The crude product is purified by preparative thin layer chromatography (prep. TLC) (silica gel, developed with 50% ethyl acetate/hexane) to give diethyl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethyl-phosphonate.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[C:18]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:18]([C:22]1[N:23]=[C:24]([NH:27][C:13]2[N:12]=[C:11]([C:7]3[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=3)[CH:16]=[N:15][CH:14]=2)[S:25][CH:26]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Reactant: CC(C)(C)c1csc(N)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3nc(C(C)(C)C)cs3)n2)c1
Yield: 21 %

Procedure:
Following Method L, 2-(3-acetamidophenyl)-6-chloropyrazine (4a) (60 mg, 0.24 mmol), 4-(tert-butyl)-1,3-thiazol-2-amine (54.7 mg, 0.35 mmol), Pd(0)2 dba3 (9 mg, 0.01 mmol), BINAP (50 mg, 0.04 mmol), sodium tert-butoxide (33 mg, 0.34 mmol) and toluene (5 mL) were reacted at 85° C. for 16 hours. The same workup as is Method L produced a solid that was washed with 50 mL dichloromethane and filtered. The dichloromethane slowly evaporated to produce white crystals that were removed by filtration and washing with dichloromethane (10 mL). The dichloromethane was then evaporated and the resulting crude was chromatographed in silica gel using ethyl acetate: dichloromethane, 2:1, as eluent to furnish 18.5 mg of title compound. Yield: 21.0%. 1 H NMR (250 MHz, DMSO-d6) δ 1.30 (s, 9H), 2.10 (s, 3 H), 6.69 (s, 1 H), 7.47 (t, 1 H, 7.9 Hz), 7.69 (d, 1 H, 8.0 Hz), 7.89 (d, 1 H, 7.8 Hz), 8.38 (s, 1 H), 8.45 (bs, 1 H), 8.58 (s, 1 H), 10.11 (s, 1 H), 11.78 (bs, 1 H);
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[O:8]1)=[O:6])[CH3:3].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[OH:8][CH:7]([CH:9]([O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)[C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6]
Reactant: CC(C)NC(=O)C1OC1c1ccc(Cl)cc1
Reactant: Oc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)NC(=O)C(O)C(Oc1ccccc1)c1ccc(Cl)cc1

Procedure:
This compound was prepared from N-(1-methylethyl)-3-(4-chlorophenyl)-2-oxiranecarboxamide (7.2 g.), phenol (3.0 g.), sodium hydride (50% oil dispersion, 1.6 g.), 18-crown-6 (0.9 g.), and acetonitrile (250 ml.) as described in Example 12. The crude product was recrystallized from ethanol, giving 2.3 g. of the compound, m.p. 175°-177°. Another recrystallization from ethanol gave analytical sample, m.p. 176°-178°.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][C:9]([OH:11])=O)=[C:6]([CH3:12])[O:5][N:4]=1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[CH2:34]([O:33][CH2:32][C@H:14]([NH:13][C:9](=[O:11])[CH2:8][C:7]1[C:3]([CH3:2])=[N:4][O:5][C:6]=1[CH3:12])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: Cc1noc(C)c1CC(=O)O
Agent: Cl
Product: Cc1noc(C)c1CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 72 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3,5-dimethylisoxazol-4-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 150, (S)-3-(benzyloxy)-2-(2-(3,5-dimethylisoxazol-4-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (48 mg, 72%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (br s, 1H), 8.52-8.50 (d, 1H), 7.63-7.60 (d, 2H), 7.33-7.27 (m, 5H), 7.23-7.19 (t, 2H), 7.03-6.98 (m, 4H), 4.73-4.68 (m, 1H), 4.53 (s, 2H), 3.70-3.63 (m, 1H), 3.31 (s, 2H), 2.28 (s, 3H), 2.11 (s, 3H). MS (EI) for C29H28FN3O5. found 518.0 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][C:7]([CH3:13])=[CH:6][CH:5]=2.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[C:10]2[CH:11]=[O:12]
Reactant: Cc1ccc2c(c1)c(C=O)c(Cl)n2-c1ccccc1
Reactant: C1CNCCN1
Product: Cc1ccc2c(c1)c(C=O)c(N1CCNCC1)n2-c1ccccc1
Yield: 63 %

Procedure:
2-Chloro-5-methyl-1-phenyl-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Example 2 to give 5-methyl-1-phenyl-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde as a pale yellow solid (63% yield).
Reaction SMILES: C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][C:28](OC)=[O:29])[CH:23]=[CH:24][CH:25]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCCCCC.C(OCC)(=O)C.CO>[F:18][C:19]([F:32])([F:33])[C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH:28]=[O:29])[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCc1cccc(C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCCCCC
Product: O=CCCc1cccc(C(F)(F)F)c1
Temperature: -77.5 °C

Procedure:
Methyl 3-[3-(trifluoromethyl)phenyl]propanoate (5 gm) as obtained in example 2 was added to toluene (50 ml) and then cooled to −75 to −80° C. To the solution was added a solution of diisobutylaluminium hydride (4.59 gm) in n-hexane (33 ml) slowly for 1 hour 30 minutes at −75 to −80° C. The reaction mass was maintained for 1 hour at −75 to −80° C. and then added methanol (5 ml) at −75 to −80° C. The temperature of the reaction mass was raised to 0° C. and the reaction mass was poured to the chilled water (150 ml). To the reaction mass was added ethyl acetate (50 ml) and then added sodium sulfate solution (20%, 25 ml). The reaction mass was maintained for 1 hour 30 minutes at room temperature and then filtered through celite bed. The layers were separated and the aqueous layer was extracted with toluene. The combined organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure to obtain 4.2 gm of 3-[3-(trifluoromethyl)phenyl]propionaldehyde.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].O=[C:15]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C([BH3-])#N.[Na+]>C(O)C>[CH2:19]([O:18][C:16]([C@@H:15]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(CCc1ccccc1)C(=O)OCc1ccccc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
A solution of L-alanyl-L-proline (167 mg) and benzyl 2-oxo-4-phenylbutyrate (1.20 g) in 5 ml of ethanol is stirred at room temperature with 3 g of powdered molecular sieves, type 4A. Sodium cyanoborohydride (75 mg) is then added in portions over the course of three hours. The product is purified by absorption on strong cation exchange resin and elution with 2% pyridine in water. After passage through a gel filtration (LH-20) column 220 mg of N-(1-benzyloxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline is obtained as a mixture of isomers. Thin layer chromatography on silica gel eluted with 1 EtOAc, 1 n-butanol, 1 H2O, 1 HOAc shows one main post, Rf 0.71. Isomers are separated using reverse phase HPLC to yield N-(1(S)-benzyloxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:39])[NH:25][C@H:26]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=3)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][F:65])(=O)=O)=CC=1.C1(C)C=CC=CC=1>CN(C=O)C>[F:65][CH2:64][CH2:63][O:62][CH2:61][CH2:60][O:59][CH2:58][CH2:57][O:38][C:34]1[CH:33]=[C:32]([C@@H:26]([NH:25][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)[CH2:19]2)=[O:39])[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:37]=[CH:36][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCF)cc1
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cccc(OCCOCCOCCF)c1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
To tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(3-hydroxyphenyl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (26 mg, 50 μmol) in DMF (6.6 mL) was added cesium carbonate (38.8 mg, 120 μmol) and 2-[2-(2-fluoroethoxy)ethoxy]ethyl 4-methylbenzenesulfonate (22 mg, 70 μmol) while stirring at room temperature. After 5 hours toluene was added and the mixture was concentrated in vacuum. The DMF free residue was purified by preparative thin layer chromatography on silica gel (dichloromethane in ethyl acetate 30%) to yield 21 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-1-(3-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}phenyl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[OH:19].[OH-].[Na+].Cl>[Cl-].C([N+](CC)(CC)CC)C.O>[OH:19][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: CO
Agent: CC[N+](CC)(CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1O

Procedure:
27 g of 2-chloro-3-nitro-5-trifluoromethyl-benzoic acid and 1 g of tetraethylammonium chloride are initially introduced into 200 ml of methanol, and 70 g of 50% strength sodium hydroxide solution are added dropwise, whilst stirring. The mixture is subsequently stirred at 65° C. for 5 hours, diluted with 300 ml of H2O and then rendered acid with hydrochloric acid. The solid product is filtered off and recrystallised from water. 16 g of 2-hydroxy-3-nitro-5-trifluoromethylbenzoic acid with the melting point: 166° to 168° C. are obtained.
Reaction SMILES: Br.[OH:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([NH:15][CH3:16])[C:8]2=O.[ClH:17]>[Pd].O>[ClH:17].[OH:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([NH:15][CH3:16])[CH2:8]2
Reactant: CNC1CCc2c(ccc(O)c2O)C1=O
Agent: [Pd]
Agent: Br
Agent: Cl
Solvent: O
Product: CNC1CCc2c(ccc(O)c2O)C1
Temperature: 0 °C

Procedure:
A mixture of 10.0 g of 5,6-dihydroxy-2-methylamino-1-tetralone hydrobromide, 2.0 g of Pd/C 5%, 90 ml of water and 10 ml of 37% HCl is hydrogenated in an autoclave (Hastelloy) (20 atm, 80° C.) for 8-9 hours, then is filtered washing with hot water. The aqueous solution is concentrated under vacuum and the resulting solid is warm triturated with 100 ml of 37% hydrochloric acid, then cooled to 0° C. and filtered. The resulting solid is recrystallized from acetone and dried under vacuum at 60° C. Yield: 7.4 g.
Reaction SMILES: [CH3:1][C:2]1([C:15]([O:17]C)=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[OH-].[Na+]>O1CCOCC1>[CH3:1][C:2]1([C:15]([OH:17])=[O:16])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COC(=O)C1(C)c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C(=O)O)c2ccccc2-c2ccccc21

Procedure:
12.6 g (0.053 mol) of methyl 9-methylfluorene-9-carboxylate and 53 mL of 2 molar, aqueous sodium hydroxide solution are stirred in 120 mL of 1,4-dioxane for 24 hours at ambient temperature. The dioxane is distilled off, made up to a total volume of 300 mL with water, and extracted with diethyl ether. The aqueous phase is acidified with 3 molar aqueous HCl, crystallized, and filtered. Yield: 11.25 g of white crystals (95% of theoretical yield); melting point: 168° C.-169° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:16]=1)=[N:13][O:14][N:15]=2.[Br-:17].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>ClCCl>[Br:17][C:5]1[CH:4]=[C:3]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]([CH:16]=2)=[N:13][O:14][N:15]=3)[C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: Oc1ccccc1-c1ccc2nonc2c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Br)cc1-c1ccc2nonc2c1
Temperature: 18 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 5-(2-hydroxyphenyl)benzofurazan (11.2 g, 52.8 mmol), and tetrabutylammonium tribromide (25.5 g, 52.8 mmol) in dichoromethane (530 mL) is stirred at 18° C. for 18 h. The solvent is evaporated off under reduced pressure to yield a residue which is treated with water (300 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts are washed (saturated NaCl), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from ethyl acetate-hexane to give 5-(3-bromo-6-hydroxyphenyl)benzofurazan as a pale-yellow crystalline solid, m.p. 179-181° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO.[Fe]>[NH2:12][C:7]1[C:6]2[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1cccc2c(F)cccc12
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc2c(F)cccc12
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A solution of compound 208A (62 mg, 0.32 mmol) in 1 mL EtOH containing 0.1 mL 12 N HCl was heated to reflux. Iron powder (62 mg, 1.11 mmol) was added in small portions and heating was continued for 2 h. The mixture was cooled, neutralized with 1 N NaOH solution and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried over MgSO4 and concentrated in vacuo to leave a residue which was purified by flash chromatography on silica gel eluting with 40 to 80% EtOAc in hexanes to give 42 mg (0.26 mmol, 80%) of compound 208B as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[O:11][CH:12]([CH2:24][CH2:25][O:26]CC2C=CC(OC)=CC=2)[CH2:13][O:14]CC2C=CC(OC)=CC=2)=[C:4](Cl)[N:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C([O-])=O.[NH4+].O>ClCCl.CO.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[O:11][CH:12]([CH2:24][CH2:25][OH:26])[CH2:13][OH:14])=[CH:4][N:3]=1
Reactant: COc1ccc(COCCC(COCc2ccc(OC)cc2)On2cnc3c(Cl)nc(N)nc32)cc1
Agent: [Pd]
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C[O-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Nc1ncc2ncn(OC(CO)CCO)c2n1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 36 %

Procedure:
To a solution of 2-amino-9-[1,4-bis(4-methoxybenzyloxy)but-2-oxy]-6-chloropurine (0.94 g, 1.8 mmol) in dichloromethane (7.2 ml) and methanol (0.8 ml) was added 2,3-dichloro-5,6-dicyanobenzoquinone (0.91 g, 4.0 mmol) and the solution was stirred at room temperature for 80 minutes. The solution was diluted with dichloromethane (8 ml) and extracted with water (3×8 ml). The aqueous layers were combined, filtered and the solvent removed. The residue was purified by reverse-phase column chromatography on Spherisorb C18 300 silica eluting with 10% methanol in water followed by column chromatography on silica gel eluting with chloroform-methanol (12:1). The product was suspended in a solution of ammonium formate (208 mg, 3.3 mmol) in methanol (8 ml), 10% palladium-on-charcoal was added (25 mg) and the mixture was heated under reflux. After 30 minutes further 10% palladium-on-charcoal (10 mg) was added and the mixture was heated under reflux for a further 1 hour. The mixture was allowed to cool and water (2 ml) was added. The solution was filtered and the solvent was removed. The residue was purified by reverse-phase column chromatography on Spherisorb C18 300 silica eluting with water and 10% methanol to afford 2-amino-9-(1,4-dihydroxybut-2-oxy)purine (155 mg, 36%), m.p. 178°-179° C.; UV: λmax (H2O) 222 (ε24,100) and 304 (ε7,020)nm; IR: υmax (KBr) 3330, 3210, 3070, 1655, 1640, 1580, 1510, 1480 and 1435 cm-1 ; 1H NMR: δH [(CD3)2SO] 1.84 (2H, q, J=6.4 Hz, 3'-H), 3.58 (4H, m, 1'-H and 4'-H), 4.42 (1H, m, 2'-H), 4.63 (1H, t, J=5.2 Hz, D2O exchangeable, OH), 4.98 (1H, t, J=5.9 Hz, D2O exchangeable, OH), 6.70 (2H, s, D2O exchangeable, 2-NH2), 8.23 (1H, s, 8-H) and 8.59 (1H, s, 6-H). Found: C, 45.13; H, 5.47; N, 29.30%. C9H13N5O3 requires C, 45.18; H, 5.48; N, 29.27%.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([NH:8][C:9]2[C:14]([C:15]3[N:16]=[C:17]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:18]4=[N:19][CH:20]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:2]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[CH3:29][Si:28]([CH3:31])([CH3:30])[CH2:27][CH2:26][O:25][CH2:24][N:21]1[C:18]2=[N:19][CH:20]=[C:15]([C:14]3[C:9]([NH:8][CH:3]4[CH2:4][CH2:5][CH2:6][CH2:7][N:1]([C:32](=[O:34])[CH3:33])[CH2:2]4)=[N:10][CH:11]=[CH:12][CH:13]=3)[N:16]=[C:17]2[CH:23]=[CH:22]1
Reactant: CC(=O)OC(C)=O
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3NC3CCCCNC3)cnc21
Product: CC(=O)N1CCCCC(Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
1-(3-{3-[5-(2-Trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-ylamino}-azepan-1-yl)-ethanone was prepared from azepan-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and acetic anhydride, following the general synthetic procedures described in the above Examples.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[C:6]1([CH2:11][CH2:10][N:9](C(OCC)=O)[CH2:8][CH2:7]1)[CH2:5]2.Cl>>[F:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[C:6]1([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:5]2
Reactant: CCOC(=O)N1CCC2(CC1)Cc1cc(F)ccc1C2=O
Agent: Cl
Product: O=C1c2ccc(F)cc2CC12CCNCC2
Yield: 113.1 %

Procedure:
To a stirred solution of ethyl 5-fluoro-1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate (188 mg, 0.645 mmol) in HCl (19.61 μL, 0.645 mmol) was heated at 100° C. over night. The reaction mixture was concentrated to dryness without any further purification to give the title compound (160 mg, 97% yield). MS calculated for C13H15FNO 220.3. found (ESI) m/z 220.0 (M+H)+, retention time 0.51 min.