Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([C:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[N:19]1([C:17]([CH:12]2[C:11]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]([CH2:3][CH2:2][O:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:16]=3[CH2:15][CH2:14][CH2:13]2)=[O:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(C1CCCc2c1c1ccccc1n2CCO)N1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCn1c2c(c3ccccc31)C(C(=O)N1CCCCC1)CCC2
Temperature: 0 °C
Yield: 81.3 %

Procedure:
To a solution of [9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazol-4-yl]-piperidin-1-yl-methanone (23) (260 mg, 0.8 mmol) in dichloromethane (15 mL) was added pyridine (633 mg, 8.0 mmol, 0.65 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (458 mg, 4.0 mmol, 0.31 mL) was added. The reaction was allowed to warm to room temperature overnight. The mixture was washed with 2 N HCl (2×50 mL) and water (2×50 mL), dried and concentrated in vacuo. The crude material was triturated with diethyl ether to afford 263 mg (82%) of methanesulfonic acid 2-[4-(piperidine-1-carbonyl)-1,2,3,4-tetrahydro-carbazol-9-yl]-ethyl ester as a white solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 21.4, 21.8, 24.7, 25.9, 26.9, 27.4, 36.6, 36.8, 41.7, 43.3, 47.0, 67.9, 108.5, 109.5, 118.4, 119.7, 121.3, 126.9, 136.2, 172.7.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH2:33][CH2:32][CH2:31][C:30]2=[O:34])[CH2:25][CH2:24]1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:33][CH2:32][CH2:31][C:30]4=[O:34])[CH2:27][CH2:28]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: O=C1CCCN1C1CCNCC1
Agent: Cl
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(N2CCCC2=O)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-piperidin-4-yl-pyrrolidine-2-one, hydrochloride, praeparative HPLC (Method C) (55%, semi-crystaline oil). HPLC-MS m/z=450.1 (M+1), Rt: 3.81 min.
Reaction SMILES: CC([S@]([NH:7][C@:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[F:25])([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][F:10])=O)(C)C.Cl.O1CCOCC1>C(Cl)Cl.CO>[NH2:7][C@@:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[F:25])([CH2:9][F:10])[CH2:11][C@H:12]([OH:17])[C:13]([F:15])([F:16])[F:14]
Reactant: Cc1cccc([C@](CF)(C[C@H](O)C(F)(F)F)N[S@](=O)C(C)(C)C)c1F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cccc([C@](N)(CF)C[C@H](O)C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-2-methyl-N-((2S,4S)-1,5,5,5-tetrafluoro-2-(2-fluoro-3-methylphenyl)-4-hydroxypentan-2-yl)propane-2-sulfinamide (2.0 g, 5.16 mmol) in DCM (20 mL) and MeOH (10 mL) was added hydrogen chloride, 4.0m solution in 1,4-dioxane (12.91 ml, 51.6 mmol) and stirred at rt for 15 min. The reaction went to completion, concentrated, diluted with DCM and washed with 1N NaOH. The organic phase was separated, dried over Na2SO4, filtered and concentrated to afford (2S,4S)-4-amino-1,1,1,5-tetrafluoro-4-(2-fluoro-3-methylphenyl)pentan-2-ol. This amino-alcohol was dissolved in THF (12 mL) followed by the addition of benzoyl isothiocyanate (0.764 ml, 5.68 mmol) and the resulting mixture was stirred at rt for 40 min. The reaction went to completion then triethylamine (0.862 ml, 6.20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hcl (1.089 g, 5.68 mmol) were added and the resulting mixture was heated at 70° C. for 1 h. The reaction went to completion. The mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-20% EtOAc/hexanes to afford a white solid as N-((4S,6S)-4-(2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1.69 g, 4.10 mmol, 79% yield). MS m/z=412.9 [M+H]+. Calculated for C20H17F5N2O2S: 412.12.
Reaction SMILES: C([O:8][C:9](=[O:39])[CH2:10][CH:11]([N:22]1[CH:26]=[CH:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:23]1)[C:12]([NH:14][C@H:15]([CH2:20][OH:21])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CCO>[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:29]=[CH:28][C:27]([N:24]2[CH:25]=[CH:26][N:22]([CH:11]([C:12]([NH:14][C@H:15]([CH2:20][OH:21])[C:16]([CH3:17])([CH3:19])[CH3:18])=[O:13])[CH2:10][C:9]([OH:39])=[O:8])[CH2:23]2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)[C@@H](CO)NC(=O)C(CC(=O)OCc1ccccc1)N1C=CN(c2ccc(-c3ccccc3)cc2)C1
Solvent: CCO
Product: CC(C)(C)[C@@H](CO)NC(=O)C(CC(=O)O)N1C=CN(c2ccc(-c3ccccc3)cc2)C1

Procedure:
According to the procedure described in Example 1(a), a suspension of 3(RS)-(3-biphenyl-4-yl-1H-imidazol-1-yl)-N-(2,2-dimethyl-1(S)-hydroxymethylpropyl)succinamic acid benzyl ester in EtOH was hydrogenated to provide 3(RS)-(3-biphenyl-4-yl-1H-imidazol-1-yl)-N-(2,2-dimethyl-1(S)-hydroxymethylpropyl)succinamic acid as a solid, mp 145-50° C. FABMS: 436.1 (C25H30N3O4 ; M+H+).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([NH:12][C:13]([C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3C(OC(C)(C)C)=O)=[O:14])[CH:9]=[CH:8][C:6]=2[N:7]=1>C(O)(=O)C>[ClH:1].[ClH:1].[NH2:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([NH:12][C:13]([C@@H:15]3[CH2:19][CH2:18][CH2:17][NH:16]3)=[O:14])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc2nc(N)sc2c1
Agent: Cl
Solvent: CC(=O)O
Product: Nc1nc2ccc(NC(=O)[C@@H]3CCCN3)cc2s1
Yield: 54 %

Procedure:
HCl gas was bubbled for 50 minutes through a solution of tert-butyl (2S)-2-{[(2-amino-1,3-benzothiazol-6-yl)amino]carbonyl}-1-pyrrolidinecarboxylate (2.21 g, 6.1 mmol) in 6 mL of anhydrous acetic acid at room temperature. Acetic acid was evaporated under reduced pressure and the residue was triturated several times with diethyl ether and dried above NaOH to yield 1.35 g (54%) of the title compound as brownish solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:15][NH:14][C:13](=O)[C@H:12]([CH3:17])[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[AlH4-].[OH-].[Na+].O=[Si]=O>C1COCC1.O>[CH2:1]([O:8][CH2:9][C@H:10]1[O:11][C@@H:12]([CH3:17])[CH2:13][NH:14][CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1O[C@H](COCc2ccccc2)CNC1=O
Agent: O=[Si]=O
Agent: [AlH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CNC[C@@H](COCc2ccccc2)O1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 46.2 %

Procedure:
To a stirred solution of (2S,6S)-6-((benzyloxy)methyl)-2-methylmorpholin-3-one (6.12 g, 0.026 mol) in THF (20 mL) under a nitrogen atmosphere at rt was added 1 M tetrahydroaluminate in THF (30 mL, 0.030 mol) dropwise over a 15-min period. The reaction mixture was stirred for 2.5 h after which time it was cooled to 0° C. followed by the slow addition of water (13 mL) and then 1 N aq. NaOH (0.9 mL). The quenched reaction was stirred until the precipitate became granular after which time Celite 545 (10 g) was added followed by filtering over a Celite pad and rinsing three times with DCM (30 mL) and ethyl ether (30 mL). The combined filtrates were concentrated and purified over silica gel (Biotage, eluting with a gradient of 0-5% MeOH in DCM) to provide (2S,6S)-2-((benzyloxy)methyl)-6-methylmorpholine (2.7 g, 0.012 mol, 46.2% yield) after combining the desired fractions, concentration and drying in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([N:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1)[C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)=[O:5].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[Cl:1][C:2]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([C:9]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11][CH:10]=1)[N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)=[O:5]
Reactant: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(O)CC2)cn1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(=O)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a solution of 2,3-dichloro-N-(2-(4-hydroxypiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide (130 mg, 0.32 mmol) in DCM (5 mL) was added 4 A molecular sieves (1.3 g), NMO (205 mg, 1.75 mmol) and TPAP (2.2 mg). The mixture was stirred at room temperature overnight. The resulting mixture was filtered. The filtrate was washed with water, dried over Na2SO4 and concentrated. The residue was purified by preparative TLC (EtOAc:MeOH=100:3) to give 2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(4-oxopiperidin-1-yl)ethyl)benzamide (31 mg, yield: 24%) as a white solid. 1HNMR (CDCl3 400 MHz): δ8.59 (s, 2H), 7.56 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.49 (dd, J=7.6 Hz, 1.6 Hz, 1H), 7.34-7.27 (m, 1H), 6.63 (br, 1H), 4.08-3.82 (m, 3H), 2.95-2.82 (m, 2H), 2.79-2.65 (m, 5H), 2.55-2.40 (m, 4H). LCMS (MH+): m/z=425.0, tR (minutes, Method F)=1.75
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([OH:11])[C:9]#[CH:10])=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:14][C:10]#[C:9][C@H:8]([OH:11])[CH2:7][O:6][C:5]1[CH:12]=[CH:13][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: C#C[C@H](O)COc1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: O[C@@H](C#CBr)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (3S)-4-(4-fluorophenoxy)-3-hydroxy-1-butyne (2.5 g, 14 mmol), N-bromosuccinimide (NBS) (2.74 g, 15.4 mmol) and AgNO3 (0.12 g, 0.7 mmol) in acetone (70 mL) was stirred at ambient temperature. The pale solution became cloudy over 30 minutes. The mixture was concentrated under vacuum and the resulting residue was filtered through a plug of silica gel (1×5 cm) eluted with 1:4 ethyl acetate:hexane to obtain (3S)-1-bromo-4-(4-fluorophenoxy)-3-hydroxy-1-butyne, a compound of formula (CC), as a pale yellow oil containing some ethyl acetate, 4.75 g (quant.); 1H NMR (CDCl3) δ 3.95-4.15 (m, 2H),4.75 (m, 1H), 6.86 (m, 2H), 6.97 (m, 2H) ppm.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:7][C:8]=2[C:11]([OH:13])=O)[N:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O=[C:27]1NC2C(=NC(C3C=NC=CC=3)=NC=2C(N)=O)[N:28]1C1C=CC=CC=1>CS(C)=O.Cl>[CH3:27][NH:28][C:11]([C:8]1[N:7]=[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:5]=[C:4]2[C:9]=1[NH:10][C:2](=[O:1])[N:3]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:13]
Reactant: O=C(O)c1nc(-c2cccnc2)nc2c1[nH]c(=O)n2-c1ccccc1
Reactant: NC(=O)c1nc(-c2cccnc2)nc2c1[nH]c(=O)n2-c1ccccc1
Agent: Cl
Solvent: CS(C)=O
Product: CNC(=O)c1nc(-c2cccnc2)nc2c1[nH]c(=O)n2-c1ccccc1
Temperature: 90 °C
Yield: 54 %

Procedure:
8-Oxo-9-phenyl-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxylic acid. 8-Oxo-9-phenyl-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide (0.2 g, 0.55 mmol) was dissolved in a mixture of DMSO (3 mL) and aqueous 6N hydrochloric acid solution (1.2 mL). The mixture was heated to 90° C. for 24 h and then poured into an ice/water slurry. The pH was adjusted to 5 and the resulting precipitate was filtered and dried to afford the title compound as a solid (0.108 g, 0.323 mmol, 54% yield), which was used directly in the next step. MS (ESI) m/z 334.1 [M+1]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:23]([NH:25][C@H:26]([C:28]2[CH:40]=[CH:39][C:31]([C:32]([O:34]C(C)(C)C)=[O:33])=[CH:30][CH:29]=2)[CH3:27])=[O:24])[C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:13][CH:14]=1>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([C:23]([NH:25][C@H:26]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:39][CH:40]=2)[CH3:27])=[O:24])[C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:13][CH:14]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 86 %

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of tert-butyl 4-[(1S)-1-({[5-Chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoate (step 4, 2.1 g; 4.3 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at room temperature until the starting material was fully consumed (4 h). The solvent and most of the trifluoroacetic acid were removed under reduced pressure. The residue was purified by flush silica gel column chromatography on silica gel (50 g) eluting with dichloromethane/methanol (20/1) and recrystallization (ethyl acetate-diisopropyl ether) to give 1.24 g, (86%) of the title compounds as white crystals: mp 198.2° C.;
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1B(O)O.Br[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].C(P1C2C(C3C(OC)=CC=CC=3OC)=CC=CC=2OC1)(C)(C)C.C1(C)C=CC=CC=1>[C:10]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(C)c(Br)c(C)c1
Reactant: OB(O)c1ccccc1-c1ccccc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1cccc2c1P(C(C)(C)C)CO2
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(-c2ccccc2-c2ccccc2)c(C)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a mixture of biphenyl-2-ylboronic acid (0.15 g, 0.75 mmol, 1.5 equiv) and 2-bromo-1,3,5-trimethylbenzene (100 mg, 0.5 mmol, 1.0 equiv), tris(dibenzylideneacetone)dipalladium (0.46 mg, 0.0005 m mol, 0.1 mol %), 3-tert-butyl-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole (0.66 mg, 0.04 mmol, 0.4 mol %), and potassium phosphate (0.318 g, 1.5 mmol, 3 equiv) was charged dagassed toluene (4 mL). The mixture was stirred at 70° C. under nitrogen for 3 h, then quenched with water (4 mL). The organic phase was separated, washed with brine, dried over sodium sulfate, concentrated, and purified by column chromatography to provide pure desired product as oil (129 mg, 0.48 mmol, 95%). ESI-MS: m/z 273 [M+H]+.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:27]=[CH:26][N:25]=[C:24]3[C:15]=2[CH:16]=[CH:17][C:18]2[C:23]3=[N:22][CH:21]=[CH:20][C:19]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:10][CH:9]=1>CO.C(Cl)Cl>[C:1]1([C:26]2[CH:27]=[C:14]([C:11]3[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=3)[C:15]3[C:24](=[C:23]4[C:18](=[CH:17][CH:16]=3)[C:19]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:20][CH:21]=[N:22]4)[N:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccccc1
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Solvent: CO
Solvent: ClCCl
Product: c1ccc(-c2cc(-c3ccccc3)c3ccc4c(-c5ccccc5)ccnc4c3n2)cc1
Yield: 75 %

Procedure:
This yellow compound was prepared in a process analogous to the synthesis of PBP in which 2 equivalents of phenyllithium were used for each equivalent of bathophenanthroline. The clean product was obtained after running chromatography in a silica/mixture of methanol/CH2Cl2 (1:1) column with a yield of 75 percent. 1H NMR (500 MHz, CDCl3), ppm: 9.26 (d, J=7.7 Hz, 1H), 8.37 (d, J=7.0 Hz, 2H), 8.04 (s, 1H), 7.82 (m, 2H), 7.59-7.45 (m, 14H). Analysis for mono-PBP.⅛CH2Cl2. Found: C, 86.10, H, 4.50, N, 6.79. Calculated: C, 86.33, H, 4.87, N, 6.68.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][N:5]1[CH:9]=[C:8]([N:10]2[C:22]3[C:21]4[CH:20]=[C:19]([Br:23])[CH:18]=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[NH:12][C:11]2=[O:24])[C:7]([CH3:25])=[N:6]1.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>C(Cl)Cl>[Br:23][C:19]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[NH:12][C:11](=[O:24])[N:10]([C:8]4[C:7]([CH3:25])=[N:6][N:5]([CH2:4][C:3]([OH:26])=[O:2])[CH:9]=4)[C:22]=3[C:21]=2[CH:20]=1
Reactant: COC(=O)Cn1cc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)c(C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1nn(CC(=O)O)cc1-n1c(=O)[nH]c2cnc3ccc(Br)cc3c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of [4-(8-bromo-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid methyl ester (Stage 101.1.3, 3.22 g, 7.73 mmol) and tetrabutylammonium (250 mg, 0.773 mmol) in CH2Cl2 (150 ml) was added 1 M aqueous NaOH (80 ml). The reaction mixture was energetically stirred for 4 h 30 at rt. The organic layer was separted and the aqueous layer washed with CH2Cl2 (2×), adjusted to pH 4 with concentrated aqueous HCl and extracted with n-butanol (5×). The combined organic layers were washed with brine adjusted to pH 4 with HCl and evaporated to dryness. The residue was dry loaded on Isolute, washed with water/1-propanol 3% and eluted with acetonitrile/1-propanol 3% on reverse phase silica gel plug. To acetonitrile filtrate was added water and solution was concentrated. The formed precipitate was filtered, washed with water and dried to give the title compound as a yellow solid. (HPLC: tR 2.08 min (Method A); M+H=402, 404 Br-Pattern MS-ES)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:19][CH2:20][C:21]#[N:22])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].Cl.C(N(CC)CC)C.Cl>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:19][CH2:20][C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: N#CCCc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2c(CCc2nnn[nH]2)c1-c1ccccc1
Temperature: 150 °C
Reaction time: 48 h
Yield: 9.8 %

Procedure:
To a solution of 7-chloro-4-(2-cyanoethyl)-3-phenyl-quinolin-2(1H)-one (Example 39, 0.45 g) in 1-methyl-2-pyrrolidinone (50 ml) under nitrogen at room temperature, was added sodium azide (0.28 g) followed by triethylamine hydrochloride (0.30 g). The reaction mixture was heated to 150° C. and stirred for 48 h. After allowing to cool, the mixture was poured into water (100 ml), acidified to pH 1 with concentrated HCl and extracted with ethyl acetate (3×75 ml). The combined organic layers were extracted with 1N sodium hydroxide (3×75 ml) and the combined aqueous phases were washed with diethyl ether (2×75 ml), then acidified to pH 1 using concentrated HCl. The aqueous layer was extracted with ethyl acetate (3×75 ml) and the combined organic layers were dried (MgSO4), filtered and the solvent was removed in vacuo to leave a solid residue. Recrystallisation from a water/methanol mix then from ethyl acetate gave the title compound (0.05 g). Mp 231°-233° C. Found: C, 61.31; H, 4.20; N, 19.41; C18H14N5OCl. 0.1 H2O requires C, 61.14; H, 4.05; N, 19.81%. δ (360 MHz, DMSO-d6) δ 3.05 (4H, bs, CH2CH2Tet)), 7.10-7.42 (7H, m, Ph+6-H+8-H), 7.86 (1H, d, J=8.73 Hz, 5-H), 12.00 (1H, bs, NH). m/z (CI+), 352, (M+1).
Reaction SMILES: C([S:9][CH:10]([CH3:21])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=O)C1C=CC=CC=1>O.[OH-].[NH4+]>[SH:9][CH:10]([CH3:21])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12]
Reactant: CC(SC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(S)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
1-(2-Benzoylthiopropanoyl)-L-proline (5.7 g.) is dissolved in a mixture of water (12 ml.) and concentrated ammonium hydroxide (9 ml.) with stirring. After one hour, the mixture is diluted with water (10 ml.) and filtered. The filtrate is extracted twice with ethyl acetate, concentrated to one-third of the original volume, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride, dried and concentrated to dryness in vacuo. The residue, 1-(2-mercaptopropanoyl)-L-proline, is crystallized from ethyl acetate-hexane, yield 3 g., m.p. (105) 116°-120°.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH3:16])[CH:8]=[O:9])[CH2:2][CH3:3].CO.[BH4-].[Na+]>O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH3:16])[CH2:8][OH:9])[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=O)cc1OCCC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCOc1ccc(CO)cc1OCCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
To a mixture of 3,4-dipropoxybenzaldehyde (6.65 g) and methanol (90 ml) was added sodium borohydride (1.13 g) at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 3,4-dipropoxybenzyl alcohol (6.22 g) as a yellow oily substance.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=2)=[C:6]([O:19][CH3:20])[C:5]([O:21][CH:22]([F:24])[F:23])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[C:44](=[O:48])[NH:43][CH2:42]3)O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:23][CH:22]([F:24])[O:21][C:5]1[C:6]([O:19][CH3:20])=[C:7]([C:2]([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[C:44](=[O:48])[NH:43][CH2:42]3)=[CH:3][CH:4]=1)[O:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=1
Reactant: COc1c(OC(F)F)ccc(Br)c1OCc1ccc(C(N)=O)cc1
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1c(OC(F)F)ccc(-c2ccc3c(c2)CNC3=O)c1OCc1ccc(C(N)=O)cc1
Temperature: 85 °C
Yield: 17.7 %

Procedure:
To a stirring solution of 4-((6-bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)benzamide (500 mg, 1.24 mmol) in dimethylformamide (10 mL) was purged with argon for 1 h. To this cesium carbonate (1.2 g, 3.73 mmol), tetrakis(triphenylphosphine) palladium(0) (72 mg, 0.06 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (386 mg, 1.49 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a solid (100 mg, 17.7%).