Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22]([NH2:24])=O)[N:11]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:10]=1[C:33]([NH2:35])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:13]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([C:33]#[N:35])[N:11]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:12]=1[C:22]#[N:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(-n2c(C(N)=O)c(OCc3ccccc3)c(OCc3ccccc3)c2C(N)=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc(-n2c(C#N)c(OCc3ccccc3)c(OCc3ccccc3)c2C#N)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a stirred solution of 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxamide (13) [prepared using the same procedure as Example A step (ii) using ammonium chloride] (267 mg, 0.57 mmol) and triethylamine (710 μL, 5.10 mmol) in DCM (8 mL) at 0° C. was added trifluoroacetic anhydride (240 μL, 1.70 mmol) and the reaction allowed to warm to RT over 30 min. The reaction mixture was partitioned between DCM (50 mL) and 1 M HCl (aq.) (30 mL), the organic was washed with 1 M HCl (aq.) (20 mL), sat. NaHCO3 (aq.) (30 mL), and brine (20 mL), dried (MgSO4), filtered and volatiles removed in vacuo to afford a yellow solid. The crude residue was purified by silica gel chromatography (40 g, 0-50% EtOAc in isohexane) to afford 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarbonitrile (14) (240 mg, 97%) as a pale yellow solid: 1H NMR (400 MHz, DMSO-d6) δ: 7.47-7.27 (m, 10H), 7.30-7.20 (m, 2H), 7.05-6.91 (m, 2H), 5.26 (s, 4H), 3.79 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.CC1(C)C(C)(C)OB([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+].[Cl-]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Reactant: COC(=O)Cc1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(Cc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 25 °C
Yield: 20.8 %

Procedure:
A 20-mL vial, with stirrer bar, was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (318 mg, 1.20 mol, 1.0 eq.), methyl 2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate (350 mg, 1.20 mmol, 1.0 eq.), Pd(dppf)Cl2 (98 mg, 0.12 mmol, 0.10 eq.), and powdered Na2CO3 (383 mg, 3.61 mmol, 3.0 eq.). Dioxane (8 mL) and water (4 mL) were added. The resulting mixture was stirred under Ar at 90° C. for 3.5 hrs until the starting chloride was consumed. After cooling to room temperature, the reaction mixture was filtered through celite washing with ethyl acetate until the filtrate was colorless. The filtrate was washed with sat. sodium chloride (3×10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (592 mg) was purified by chromatography on silica gel using hexane/ethyl acetate (1:0 to 3:1) as eluent, to afford methyl 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)methyl)phenyl)acetate (98 mg, 21% yield) as a colorless oil. MW=392.88. 1H NMR (CDCl3, 500 MHz) δ 8.46-8.44 (m, 1H), 8.35 (m, 1H), 7.43-7.36 (m, 2H), 7.27 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 4.09 (s, 2H), 3.68 (s, 3H), 3.59 (s, 2H), 3.02 (t, J=8.0 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.11 (quintet, J=7.5 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:15]([OH:16])=[C:14]([C:17]([NH:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:18])[C:13](=[O:26])[N:12]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]2=[O:34])[CH:6]=[CH:7][CH:8]=1)#[N:2].OC1NC(=O)N(CC2C=CC=CC=2)C(=O)C=1C(NCC(OCC)=O)=O.C(C1C=C(C=CC=1)CBr)#N.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:15]([OH:16])=[C:14]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[C:13](=[O:26])[N:12]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:11]2=[O:34])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CNC(=O)c1c(O)n(Cc2cccc(C#N)c2)c(=O)n(Cc2ccccc2)c1=O
Agent: CCOC(=O)CNC(=O)c1c(O)[nH]c(=O)n(Cc2ccccc2)c1=O
Agent: Cl
Agent: N#Cc1cccc(CBr)c1
Solvent: CN(C)C=O
Product: N#Cc1cccc(Cn2c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc3ccccc3)c2=O)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Ethyl N-{[1-[(3-cyanophenyl)methyl]-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate. A mixture of ethyl N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate (350 mg, 1.0 mmoles), 3-cyanobenzyl bromide (250 mg, 1.22 mmoles) and sodium carbonate (300 mg, 2.9 mmoles) in dimethylformamide (5.0 mL) was stirred under argon at 100° C. for 2 hours. The mixture was cooled, poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined extracts were washed with water and brine. Purification by preparative HPLC (acetonitrile-water-0.1% TFA, 20-100%) gave the title compound (300 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.12 (t, J=5.81 Hz, 1 H), 7.79 (s, 1 H), 7.71-7.76 (m, 1 H), 7.66 (d, J=8.34 Hz, 1 H), 7.54 (t, J=7.83 Hz, 1 H), 7.32 (d, J=4.29 Hz, 4 H), 7.23-7.29 (m, 1 H), 5.07 (s, 2 H), 5.03 (s, 2 H), 4.22 (d, J=6.06 Hz, 2 H), 4.15 (q, J=7.07 Hz, 2 H), 1.21 (t, J=7.20 Hz, 3 H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]2[C:13](=[O:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.[BH4-].[Na+].CC(C)=O.[BH4-]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]2[CH:13]([OH:14])[CH:12]3[CH2:11][CH2:10][N:9]2[CH2:16][CH2:15]3)[CH:2]=1
Reactant: O=C1C(=Cc2cccnc2)N2CCC1CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: OC1C(=Cc2cccnc2)N2CCC1CC2

Procedure:
Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were dissolved in methanol (25 ml) and stirred for 15 mins. Pyridine-3-carboxaldehyde (3.2 g, 29.5 mmol) was then added in one portion and the mixture was stirred for an additional 20 hrs. The reaction mixture was then diluted with 40 ml water and cooled to 0° C. yielding 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was collected, washed with distilled water and dried under vacuum (5.16 g, 81.4%). 2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (3 g, 140 mmol) was dissolved in 200 ml methanol and sodium borohydride (3 g, 79.6 mmol) was added in portions (exothermic reaction) with vigorous stirring. After 1 hr of continued stirring, acetone (100 ml) was slowly added to neutralize the remaining borohydride reagent. The mixture was evaporated to dryness and the resulting residue suspended in water (200 ml) and extracted three times with 200 ml portions of chloroform. The chloroform phases were combined, dried over MgSO4, and rotary evaporated to give a clear oil; crystallization of the free base gave a quantitative yield of 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol as a white precipitate. 2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol (1 g, 4.7 mmol) was combined with neat thionyl chloride (20 ml, 26.9 mmol) stirred under a nitrogen atmosphere at 0° C., the reaction was than brought to room temperature and stirred for one additional hour. Rotary evaporation at 60° C. produced a viscous oil which when suspended in ether afforded 3-chloro-2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane dihydrochloride as a hygroscopic precipitate (0.98 g, 91%). The chloroquinuclidine (0.3 g, 1.3 mmol) was combined with 50 ml ethanol in a hydrogenation vessel, then wet Raney nickel (2.5 grams) was added in one portion. Hydrogenation (50 psig) was carried out for 6 hrs., after which time the slurry was carefully filtered through a pad of Celite filter aid. Evaporation of solvent gave the desired 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane dihydrochloride as a white reside which easily recrystallized from ethanol-ether to give a white crystalline solid (0.21 g 70%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:10]=[CH:11][N:12](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:33]>O1CCOCC1>[ClH:33].[CH2:1]([NH:8][C:9]1[N:10]=[CH:11][NH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(CNc2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Benzyl-(1-trityl-1H-imidazol-4-yl)-amine (0.15 g, 0.35 mmol) was dissolved in a 4 M solution of HCl in dioxane (5 ml). The mixture was stirred at room temperature for 90 minutes and then concentrated in vacuo. The residue was triturated in ether to yield the title compound as an off-white solid (73 mg, 100%); MS (ISP): 174.4 ([M+H]+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1>>[CH3:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:11])[CH2:17][CH2:16]2)[N:26]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Product: Cc1ccnc(NCC2CCN(S(=O)(=O)CCc3ccccc3)CC2)n1

Procedure:
EXAMPLE 94 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2-chloro-4-methyl-pyrimidine: MS (m+1)=375.5.
Reaction SMILES: [F:1][CH:2]([F:30])[CH2:3][N:4]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:7][CH:6]([C:22](=O)[NH:23][CH2:24][C:25](=[O:28])[CH2:26][CH3:27])[CH2:5]1>C1COCC1>[F:30][CH:2]([F:1])[CH2:3][N:4]1[CH2:9][C:8]2([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)[O:7][CH:6]([C:22]2[O:28][C:25]([CH2:26][CH3:27])=[CH:24][N:23]=2)[CH2:5]1
Reactant: CCC(=O)CNC(=O)C1CN(CC(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Solvent: C1CCOC1
Product: CCc1cnc(C2CN(CC(F)F)CC3(CCN(C(=O)OC(C)(C)C)CC3)O2)o1
Temperature: 75 °C
Yield: 83.7 %

Procedure:
To tert-butyl 4-(2,2-difluoroethyl)-2-((2-oxobutyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (200 mg, 0.46 mmol) in THF (2 mL) was added Burgess' salt (275 mg, 1.15 mmol) and the reaction mixture was heated at 75° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and partitioned between EtOAc and saturated aq. NaHCO3. The layers were separated and the aqueous layer was extracted once more with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give an orange oil. The residue was purified by silica gel column chromatography using 0-20% EtOAc in DCM as eluent to yield tert-butyl 4-(2,2-difluoroethyl)-2-(5-ethyloxazol-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (160 mg, 84%) as a colorless oil. ESI-MS m/z calc. 415.2. found 416.5 (M+1)+; Retention time: 2.06 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 6.69 (s, 1H), 6.06-5.68 (m, 1H), 4.89 (dd, J=10.7, 2.5 Hz, 1H), 3.85-3.58 (m, 2H), 3.37-3.01 (m, 3H), 2.87-2.59 (m, 6H), 2.45 (d, J=13.6 Hz, 1H), 2.30 (d, J=11.3 Hz, 1H), 1.65-1.48 (m, 3H), 1.45 (s, 9H), 1.25 (t, J=7.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[C:31]([F:38])[N:30]=1>>[F:28][C:29]1[CH:34]=[C:33]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:32]=[C:31]([F:38])[N:30]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cc(F)nc(F)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cc(F)nc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and 2,6-difluoropyridin-4-ylboronic acid to afford a white amorphous powder. HPLC (Condition 4) tR=5.67 min, UPLC-MS (Condition 3) tR=1.10 min, m/z=481.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.80 (m, 1H) 1.87 (m, J=9.00 Hz, 1H) 2.86 (d, J=11.34 Hz, 1H) 3.18-3.29 (m, 2H) 3.47 (m, J=7.00 Hz, 1H) 4.22 (br. s, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.23 (s, 2H) 7.34 (d, J=9.38 Hz, 2H) 7.78-7.89 (m, 2H) 8.13 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 10.18 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][NH:5][C:6](=[O:31])[N:7]([C@H:9]([CH2:16][O:17][C:18](=[O:30])[NH:19][C:20]1[N:21]=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10][CH2:11][CH2:12][C:13](O)=[O:14])[CH3:8].C(N(CC)CC)C.ClC(OC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[CH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[C:20]([NH:19][C:18](=[O:30])[O:17][CH2:16][C@@H:9]([N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]2[CH:32]=[CH:33][CH:34]=[C:35]([F:36])[C:2]=2[F:1])=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[N:21]=1
Reactant: CN(C(=O)NCc1cccc(F)c1F)[C@@H](CCCC(=O)O)COC(=O)Nc1cc2ccccc2cn1
Agent: CC(C)OC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)NCc1cccc(F)c1F)[C@@H](CCCCO)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.4 %

Procedure:
To a solution of (S)-5-(3-(2,3-difluorobenzyl)-1-methylureido)-6-(isoquinolin-3-ylcarbamoyloxy)hexanoic acid (˜2.04 mmol, 1.0 equiv.) and triethylamine (0.38 mL, 2.78 mmol, 1.2 equiv.) in anhydrous THF (7 mL) was added isopropyl chloroformate (2.80 mL, 2.80 mmol, 1.2 equiv.) dropwise at 0° C. After stirred at RT for 20 min, the mixture was filtered and transferred to a solution of NaBH4 (0.18 g, 4.76 mmol, 2.0 equiv.) in water (2.0 mL). The resulting mixture was stirred at RT for 1 h, and quenched with saturated NH4Cl. The solution was extracted with EtOAC twice. The organic layers were washed with brine, dried over Na2SO4, and concentrated. The resulting residue was purified on silica gel column (50-100% EtOAc in hexanes followed by 10% MeOH in dichloromethane) to give (S)-2-(3-(2,3-difluorobenzyl)-1-methylureido)-6-hydroxyhexyl isoquinolin-3-ylcarbamate (0.58 g, 52% for two steps). LRMS (M+H+) m/z 487.3.
Reaction SMILES: C(OC([N:8]1[CH2:15][C@H:14]2[N:16](C(OC(C)(C)C)=O)[C@H:10]([CH2:11][C:12]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=4[Cl:45])=[CH:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=O)(C)(C)C.[Cl:46][C:47]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][O:60][CH3:61])=[CH:54][C:48]=1[CH2:49][NH:50][CH:51]1[CH2:53][CH2:52]1>>[Cl:46][C:47]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][O:60][CH3:61])=[CH:54][C:48]=1[CH2:49][N:50]([CH:51]1[CH2:52][CH2:53]1)[C:24]([C:13]1[C@@H:14]2[NH:16][C@H:10]([CH2:11][C:12]=1[C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]3[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=3[Cl:45])=[CH:31][CH:32]=1)[CH2:9][NH:8][CH2:15]2)=[O:25]
Reactant: COCCc1ccc(Cl)c(CNC2CC2)c1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(C3=C(C(=O)O)[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H](C3)N4C(=O)OC(C)(C)C)cc2)c(Cl)c1
Product: COCCc1ccc(Cl)c(CN(C(=O)C2=C(c3ccc(OCCOc4c(Cl)cc(C)cc4Cl)cc3)C[C@@H]3CNC[C@H]2N3)C2CC2)c1

Procedure:
This compound was synthesized from (rac.)-(1R*,5S*)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester (WO 2005/040165) and [2-chloro-5-(2-methoxy-ethyl)-benzyl]-cyclopropyl-amine as for compound L1, and then Example 1. MS (ESI, Q+) m/z 686.0.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH2:3]1.[CH2:10]([C:13]1[C:21]2[O:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:17]=2[CH:16]=[CH:15][C:14]=1[O:26][CH2:27][CH2:28][CH2:29]Br)[CH2:11][CH3:12]>>[CH3:1][CH:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:29][CH2:28][CH2:27][O:26][C:14]2[CH:15]=[CH:16][C:17]3[C:18]([C:22]([F:24])([F:25])[F:23])=[N:19][O:20][C:21]=3[C:13]=2[CH2:10][CH2:11][CH3:12])[C:4](=[O:9])[CH2:3]1
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Reactant: CC1CC(=O)NC(=O)N1
Product: CCCc1c(OCCCN2C(=O)CC(C)NC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
6-Methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione was prepared as for Example 10 from 6-methyldihydropyrimidine-2,4(1H,3H)-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[CH2:16]([O:18][CH2:19][CH2:20]Br)[CH3:17]>>[CH2:16]([O:18][CH2:19][CH2:20][O:8][C:4]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[C:2]([NH2:1])[N:6]([CH3:7])[N:5]=1)[CH3:17]
Reactant: CCOCCBr
Reactant: Cc1ccc(-c2c(O)nn(C)c2N)cc1
Product: CCOCCOc1nn(C)c(N)c1-c1ccc(C)cc1

Procedure:
The method of Preparation 37 was used to prepare the title compound from 5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-ol (Preparation 3a) and 2-bromoethyl ethyl ether.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]([C:15](=[O:31])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])C.[OH-].[Na+]>CO>[C:11]([O:10][C:8](=[O:9])[CH2:7][CH:6]([C:15](=[O:31])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[CH2:5][C:4]([OH:32])=[O:3])([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)CC(CC(=O)OC(C)(C)C)C(=O)NCCc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)CC(CC(=O)O)C(=O)NCCc1ccc(-c2ccccc2)cc1
Reaction time: 24 h

Procedure:
To a solution of the compound of example 71 (1.09 g, 2.48 mmol) in methanol (50 mL) was added drop wise a sodium hydroxide solution (1N, 5 mL, 5 mmol). After stirring the reaction mixture for 24 h, the solvent was evaporated. The residue was partitioned between water and ether. The aqueous phase was acidified with concentrated HCl, and then extracted with ethyl acetate. The organic phase was washed with brine, dried, filtered and evaporated to give the product as a white solid. 1H-NMR(CDCl3, 400 MHz: 1.37(s, 9H); 2.28-2.61(m, 4H); 2.79(t, J=7.3 Hz, 2H); 3.08(m, 1H); 3.27(m, 1H); 3.39 (m, 2H); 6.25(m, t, 5.1 Hz, 1H); 7.26(m, 3H); 7.36(m, 2H); 7.52(m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:25]=[O:26])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
5 g of the compound [1-1] was dissolved in 100 mL of tetrahydrofuran and cooled to −78° C. Thereafter, 31.2 mL of n-butyllithium (1.6 M hexane solution) was added thereto, and the mixture was stirred for 1 hour at the same temperature. 774 μL of N, N-dimethylformamide was added to the produced white suspension, which was stirred for 5 hours while gradually heating back to room temperature. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-50/50), to obtain 514 mg of tert-butyl[(1S)-1-(4-formylphenyl) ethyl]carbamate [15-1] (hereinafter, referred to as the compound [15-1]) as a pale yellow amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-chloro-4-fluorobenzoic acid (24.4 g, 0.142 mol) in 150 ml of concentrated sulfuric acid at 0° C. was treated dropwise with 90% nitric acid (13.2 ml, 20 mol %, 0.284 mol) over a 10 min. period at 10° C., stirred for 2.5 hours at 0 to 10° C., poured onto one liter of ice. The white solid was filtered. The filtercake was air-dried and recrystallized from ethyl acetate/heptane to afford the title compound as off-white needles. Yield: 18.0 g (58.1%); identified by NMR spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=1[NH:1][S:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:26][CH:25]=1)(=[O:29])=[O:28]
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-amino-4-chlorobenzoate (2.5 g, 13.3 mmol) is added to a solution of 2.5 g (8.84 mmol) of the title B compound, 4-benzyloxybenzenesulfonyl chloride in 50 mL of DCM, then 1.4 g (1.43 mL, 17.68 mmol) of pyridine is added. The mixture is stirred overnight at RT. The organic solution is then washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to a slightly red solid. The solid is adsorbed on 13 g of silica gel and chromatographed (FlashElute 40M silica gel column) using 1 L of an EtOAc (15%)-hexane (85%) mixture as the eluent, followed by 1 L of DCM to afford 2-(4-benzyloxybenzene-sulfonylamino)-4-chloro-benzoic acid methyl ester as a white solid.