Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Cl:8][C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([N:16]2[C:21]([CH3:23])([CH3:22])[CH2:20][C:19]3([O:27][CH2:26][CH2:25][O:24]3)[CH2:18][C:17]2([CH3:29])[CH3:28])[N:10]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:8][C:9]1[N:14]=[C:13]([N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[N:12]=[C:11]([N:16]2[C:21]([CH3:23])([CH3:22])[CH2:20][C:19]3([O:27][CH2:26][CH2:25][O:24]3)[CH2:18][C:17]2([CH3:29])[CH3:28])[N:10]=1
Reactant: CC1(C)CC2(CC(C)(C)N1c1nc(Cl)nc(Cl)n1)OCCO2
Reactant: CC(C)NC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(c1nc(Cl)nc(N2C(C)(C)CC3(CC2(C)C)OCCO3)n1)C(C)C
Reaction time: 24 h

Procedure:
26.1 g (258 mmol) of diisopropylamine are added with stirring to a solution of 29.9 g (86 mmol) of the product from Example 17 in 100 ml of toluene. The mixture is heated to reflux and kept at this temperature for 24 hours. After cooling, a solution of 4.1 g of NaOH in 21 ml of water is added. The solid product is filtered off and recrystallized from 25 ml of toluene. A yellowish powder which melts at 179°-184° is obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C:10]1[N:11]=[C:12]([C:15]([OH:17])=O)[S:13][CH:14]=1)([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C.[CH3:27][C:28]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([C:37](=[O:39])[CH3:38])[C:29]=1[NH2:30]>C1(C)C=CC=CC=1>[C:37]([C:31]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:28]([CH3:27])[C:29]=1[NH:30][C:15]([C:12]1[S:13][CH:14]=[C:10]([CH:7]([CH3:8])[CH3:9])[N:11]=1)=[O:17])(=[O:39])[CH3:38]
Reactant: COc1ccc(C(C)=O)c(N)c1C
Reactant: CC(C)c1csc(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Temperature: 25 °C
Yield: 91.3 %

Procedure:
Oxalyl chloride (5.71 g, 45 mmol., 3.0 eq) was added dropwise, at ambient temperature, to a solution of 4-isopropyl-thiazole-2-carboxylic acid (3.85 g, 22.5 mmol., 1.5 eq) in toluene (40 mL). Stirring was continued at ambient temperature until the bubbling stopped. The reaction mixture was then heated under reflux for a further 1 hour. LCMS analysis of an aliquot quenched with methanol revealed full conversion of the acid to the acid chloride. The reaction mixture was left to cool to ambient temperature and the solvent removed under vacuum. The residue was diluted with dry dioxane (40 mL). Diisopropylethylamine (3.9 g, 30 mmol., 2 eq.) was added dropwise followed by 2-methyl-3-methoxy-6-acetyl-aniline (2.7 g, 15.0 mmol., 1.0 eq). The reaction mixture was stirred at ambient temperature for 15 hours. LCMS analysis showed full conversion of the starting material to product. The solvent was removed under vacuum and the residue dissolved with ethyl acetate (75 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL), water (50 mL), and brine (50 mL), dried over sodium sulphate, filtered and the solvent removed under vacuum. The residue was purified by flash column chromatography using a gradient of heptanes:ethyl acetate (4:1 to 6:4). The relevant fractions were combined and the solvent removed under vacuum to give 4.55 g (91%) of the title compound as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 11.28 (br. s, 1 H), 7.76 (d, J=8.70 Hz, 1 H), 7.17 (s, 1 H), 6.79 (d, J=8.70 Hz, 1 H), 3.94 (s, 3 H), 3.23 (spt, J=6.89 Hz, 1 H), 2.59 (s, 3 H), 2.17 (s, 3 H), 1.42 (d, J=6.87 Hz, 6 H). LC-MS: 99% (UV), tR 2.24 min, m/z [M+1]+ 333.05.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.[C:20](C1C=CC2N(C=C(C(OCC)=O)N=2)C=1)#[N:21]>>[C:14]1([NH:13][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:20]#[N:21])=[CH:7][N:6]3[CH:8]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Nc1ccccc1)c1cn2cc(Br)ccc2n1
Reactant: CCOC(=O)c1cn2cc(C#N)ccc2n1
Product: N#Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1

Procedure:
By working in the same manner as for the preparation of Intermediate 1, replacing the ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate with ethyl 6-cyanoimidazo[1,2-a]pyridine-2-carboxylate (J. Med. Chem. (1998), 41(22), 4317), N-phenyl-6-cyanoimidazo[1,2-a]pyridine-2-carboxamide is obtained in the form of a yellow solid
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[S:4][N:3]=1.[CH2:16]([C:18]1[CH:23]=[C:22](O)[CH:21]=[CH:20][C:19]=1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:17].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>>[Cl:1][C:2]1[C:6]([CH2:7][O:8][C:22]2[CH:21]=[CH:20][C:19]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:18]([CH2:16][CH3:17])[CH:23]=2)=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[S:4][N:3]=1
Reactant: Cc1ccccc1-c1snc(Cl)c1CO
Reactant: CCOC(=O)CCc1ccc(O)cc1CC
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Product: CCOC(=O)CCc1ccc(OCc2c(Cl)nsc2-c2ccccc2C)cc1CC
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed [3-chloro-5-(2-methylphenyl)-1,2-thiazol-4-yl]methanol (80 mg, 0.33 mmol, 1.00 equiv), ethyl 3-(2-ethyl-4-hydroxyphenyl)propanoate (89.17 mg, 0.40 mmol, 1.20 equiv), ADDP (210.87 mg, 0.84 mmol, 2.52 equiv), n-Bu3P (101.42 mg), Tol (1.5 mL). The resulting solution was stirred overnight at 60° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6). This resulted in 123 mg (83%) of ethyl 3-(4-[[3-chloro-5-(2-methylphenyl)-1,2-thiazol-4-yl]methoxy]-2-ethylphenyl)propanoate as colorless oil. Mass spectrum (ESI, m/z): Calcd. for C21H21FO5, 444.1 (M+H). found 444.1.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.O.C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH3:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][O:4][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([CH3:7])=[CH:9][CH:10]=1
Reactant: CC[C@H](C)CO
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC[C@H](C)COC(=O)c1ccc(C)cc1
Reaction time: 2 h

Procedure:
28.51 g (0.23 moles) of a commercially available (S)-2-methylbutanol was dissolved in 100 ml of pyridine. The mixture was cooled and 50 g (0.23 moles) of a commercially available 4-methylbenzoic chloride was added thereto while cooling. The mixture was then allowed to react with stirring at 50° to 60° C. for 2 hours. On completion of the reaction, 300 ml of water and 300 ml of toluene were added, and after vigorous stirring, the toluene layer was separated out and washed with 6N HCl. Washing was continued until this layer was neutral. This toluene layer was dried with anhydrous magnesium sulfate, after which the toluene was distilled away. The residue was further subjected to evaporation under reduced pressure at 118° to 120° C. (5 mm Hg) and the distillate recovered, whereby 59.61 g of the objective 4-methylbenzoic((S)-2-methylbutyl) ester was obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:13][CH2:14]Br>>[Cl:9][C:10]1[CH:11]=[C:12]([CH2:13][CH2:14][CH:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH3:2])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: CCc1ccncc1
Reactant: Clc1ccc(CCBr)cc1Cl
Product: CC(CCc1ccc(Cl)c(Cl)c1)c1ccncc1
Yield: 44.7 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 2.37 g (9.35 mmol) of 3,4-dichlorophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.17 g of the desired compound (yield: 44.6%).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:13][CH:12]([OH:14])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:11][CH:12]([OH:14])[CH2:13]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)cn1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CC(O)C2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
A 100-mL single-neck round-bottomed flask was purged with nitrogen and charged with 314a (1.0 g, 5.1 mmol), 10% palladium on carbon (10% wet, 100 mg), and ethanol (40 mL). The mixture was evacuated, charged with hydrogen gas, and stirred at room temperature for 5 h. The hydrogen was then evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 314b as a yellow solid (792 mg, 85%). MS-ESI: [M+H]+ 166.1.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[OH-].[Na+].[CH:14]1([N:20]=[N:21][C:22]2(Cl)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O>CN(C)C=O>[CH:22]1([N:21]=[N:20][C:14]2([N:5]3[C:1](=[O:11])[C:2]4=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]4[C:4]3=[O:6])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: ClC1(N=NC2CCCCC2)CCCCC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1(N=NC2CCCCC2)CCCCC1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 10.45 grams (.071 moles) phthalimide in 80 mls of N,N-dimethylformamide in a 250 ml 4-neck flask equipped with a magnetic stirrer, thermometer and addition funnel was added 4.0 grams (.05 moles) of 50% sodium hydroxide and the solution stirred for 15 minutes at 40° C. To this solution was added dropwise 11.45 grams (.05 moles) of 1-cyclohexylazo-1chlorocyclohexane (from Example 3-11) over 20 minutes at 40° to 45° C. After the addition was complete, the reaction was stirred an additional 60 minutes at 40° C, poured into 250 ml cold water and the white solid that formed was filtered off and dissolved in 100 ml of pentane. The insolubles were filtered off and the pentane filtrate washed with water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a white solid and weighed 11.5 grams (68% crude yield). The infrared spectrum of the product was in agreement with the structure of 1-cyclohexylazo-1-phthalimidocyclohexane (absence of NH and OH bands and a strong carbonyl band at 1700-1730 cm-1).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[C:19]([O:23][C:24]([N:26]1[CH2:31][C@H:30]([CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][C@H:34]2[CH3:39])[NH:29][CH2:28][C@H:27]1[CH3:40])=[O:25])([CH3:22])([CH3:21])[CH3:20]>C(#N)C>[C:19]([O:23][C:24]([N:26]1[CH2:31][C@H:30]([CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][C@H:34]2[CH3:39])[N:29]([CH2:2][C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH2:28][C@H:27]1[CH3:40])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
Benzyl bromoacetate (25.2 mL, 126 mmol) and K2CO3 (50 g, 389 mmol) were added to a solution of (2R,5S)-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (30.5 g, 97.4 mmol) in acetonitrile (300 mL) and the reaction was stirred at room temperature for 18 h. The solid was removed by filtration and the solvent was removed in vacuo. The crude material was purified by chromatography using a pad of silica eluting with EtOAc/Petrol (1/9 to 4/6) to give the title compound (39 g). MS: [M+H]+=462.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[S:23]1[CH:27]=[C:26]([C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[N:25]=[N:24]1>>[S:23]1[CH:27]=[C:26]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=4[CH3:21])[CH:5]=[CH:6][C:7]=3[Cl:8])=[O:33])=[CH:35][CH:36]=2)[N:25]=[N:24]1
Reactant: O=C(O)c1ccc(-c2csnn2)cc1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccc(-c3csnn3)cc2)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.15 mmol) was used in general procedure 2 with 4-(1,2,3-thiadiazol-4-yl)benzoic acid (0.167 mmol). The product was purified by RP-HPLC to give N-(3-(4-(1,2,3-thiadiazol-4-yl)benzamido)-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide. MS (Q1) 518.1 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](O)=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:21]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:21])=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2cc(OC)ccc2c1Cl
Reaction time: 0.25 h

Procedure:
7-Methoxy-4-hydroxy-3-ethoxycarbonylquinoline (Step A, 21 g, 0.08 mol) and POCl3 (100 mL) were mixed together and the mixture was heated at reflux for 6 h. The excess POCl3 was removed under vacuum. The solid residue was suspended in ice-cold 1N NaOH and the mixture was stirred for 15 min. The solid was filtered off, washed several times with water and then by a minimum amount of MeOH to give 7-methoxy-4-chloro-3-ethoxycarbonylquinoline as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl.[CH2:33]([O:35][C:36](=[O:47])[CH:37]([NH2:46])[C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:34].CN1CCOCC1>C1COCC1>[CH2:33]([O:35][C:36](=[O:47])[CH:37]([NH:46][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:34]
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: CCOC(=O)C(N)C(=O)c1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)C(NC(=O)c1cc2cc(Cl)ncc2[nH]1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (100 mg, 0.51 mmol) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) (183 mg, 0.66 mmol) were dissolved in THF (20 ml). After 5 min, 2-amino-3-oxo-3-phenylpropionic acid ethyl ester hydrochloride (Tetrahedron Lett., 1993, 34(2), 211–214; 124 mg, 0.51 mmol) and 4-methylmorpholine (56 μl, 0.51 mmol) were added and the reaction mixture stirred at rt for 72 h. The solvent was removed in vacuo and the residue partitioned between water (40 ml) and EtOAc (3×30 ml). The combined organics were dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol:dichloromethane (1:19). This material was further triturated with methanol:diethyl ether (1:19) to give the title compound as a pale yellow solid. m/z (ES+)=386 [M+H]+; RT=3.56 min.
Reaction SMILES: [CH:1]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]56[CH2:30][CH2:29][C:26]([CH2:31][C:32]([O:34]C)=[O:33])([CH2:27][CH2:28]5)[CH2:25][O:24]6)=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)=[N:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].O1CCCC1.C(O)C>O>[CH:1]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]56[CH2:28][CH2:27][C:26]([CH2:31][C:32]([OH:34])=[O:33])([CH2:29][CH2:30]5)[CH2:25][O:24]6)=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[N:7][N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CCC6)o5)cc4)cc3)(CC1)OC2
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CCC6)o5)cc4)cc3)(CC1)OC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
A flask was charged with methyl 2-(1-(4′-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-4-yl)acetate (0.040 g, 0.034 mmol), lithium hydroxide monohydrate (0.043 g, 1.040 mmol), tetrahydrofuran (1 ml), ethanol (0.3 ml) and water (0.3 ml), and stirred at 50° C. for 2 hours. The mixture was purified by HPLC (0.1% NH4OH, 10-50% acetonitrile/water, 20 minutes run, retention time ˜7 minutes) to afford {1-[4′-(5-cyclobutyl-[1,3,4]oxadiazol-2-ylamino)-biphenyl-4-yl]-2-oxa-bicyclo[2.2.2]oct-4-yl}-acetic acid (6 mg, 39%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.89 (m, 5H) 1.89-2.00 (m, 1H) 2.00-2.14 (m, 5H) 2.26-2.39 (m, 5H) 3.62-3.73 (m, 1H) 3.86 (s, 2H) 7.43 (d, J=8.40 Hz, 2H) 7.55 (d, J=8.50 Hz, 2H) 7.62 (s, 4H) 10.39-10.59 (br. s, 1H). LC/MS, [MS+] 459.22, RT: 2.61 (Condition M).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[C:6]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[C:15]([O:22][CH3:23])[CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].N1C2C(=CC=CC=2C(C2C=CC=CC=2)CC(NC)=O)C=C1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[C:15]([O:22][CH3:23])[CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1cc(OC)c2cc[nH]c2c1)c1ccccn1
Agent: CNC(=O)CC(c1ccccc1)c1cccc2cc[nH]c12
Product: CCOC(=O)CC(c1cc(OC)c2cc[nH]c2c1)c1ccccn1

Procedure:
3-(4-Methoxy-1H-indol-6-yl)-3-pyridin-2-yl-propionic acid ethyl ester CLXXV was prepared from 3-(4-methoxy-1H-indol-6-yl)-3-pyridin-2-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-propionamide XIX (Example 4).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)[N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:7]3[CH:8]=[CH:9][S:10][C:6]=3[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:3]=2)[CH2:22][CH2:21]1
Reactant: COc1ccc(-c2cc3sccc3c(Cl)n2)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(c2nc(-c3ccc(O)cc3)cc3sccc23)CC1

Procedure:
4-(4-Methylpiperazin-1-yl)-6-(4-hydroxyphenyl)thieno[3,2-c]pyridine (413 mg) obtained from 4-chloro-6-(4-methoxyphenyl)thieno[3,2-c]pyridine and N-methylpiperazine in the same manner as in Example 289-6 was dissolved in DMF (10 ml), followed by the addition of potassium carbonate (526 mg) and 2-bromoethanol (0.18 ml). The resulting mixture was stirred at 80° C. for 2 days, and then the resulting reaction mixture was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried and evaporated. The resulting residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system) to give a yellow oil (202 mg, yield; 43%). The resulting oil was converted into a hydrochloride in a conventional manner, to give the title compound as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH:37][CH2:38][CH2:39][N:40]1C2=C3C(=CC=C2[CH:42]=[N:41]1)C(=O)C(I)=C(C1C=CC=CC=1)O3.OCCN1N=C2C3OC(C4C=CC=CC=4)=C(I)C(=O)C=3C=CC2=C1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21]([O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]3[N:40]([CH2:39][CH2:38][OH:37])[N:41]=[CH:42][C:23]3=[CH:24][CH:25]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccc1cnn(CCO)c12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Agent: O=c1c(I)c(-c2ccccc2)oc2c1ccc1cn(CCO)nc12
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5cnn(CCO)c54)c3=O)cc2)CCC1
Yield: 37 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, the crude mixture of 1-(2-hydroxy-ethyl)-7-iodo-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one and 2-(2-hydroxy-ethyl)-7-iodo-8-phenyl-2H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was reacted to give (1-{4-[1-(2-hydroxy-ethyl)-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (53.3 mg, 37%), LCMS (Method H): RT=3.86 min, [M+H]+=552, as the earlier eluted compound and (1-{4-[2-(2-hydroxy-ethyl)-6-oxo-8-phenyl-2,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (57.1 mg, 40%), LCMS (Method H): RT=3.68 min, [M+H]+=552, as the later eluted compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH:16]=O.C([BH3-])#N.[Na+]>C1COCC1.C(OC)(C)(C)C.O.C(O)(=O)C>[CH3:1][N:2]([CH2:16][CH:15]([O:18][CH3:19])[O:14][CH3:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1
Reactant: CNCc1ccc([N+](=O)[O-])cc1
Reactant: COC(C=O)OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: COC(CN(C)Cc1ccc([N+](=O)[O-])cc1)OC
Reaction time: 2 h

Procedure:
A mixture of 1.56 g N-methyl-N-(4-nitrobenzyl)amine in 40 ml THF is combined with 2.85 ml of a 45% solution of 2,2-dimethoxyacetaldehyde in tert.-butylmethylether. Then 24 mg of p-TsOHx H2O and 1.12 ml glacial acetic acid are added and the mixture is stirred for 2 h. Then 1.81 g of sodium cyanoborohydride are added batchwise and the mixture is stirred for another 2 h. 5 ml of water are added to the mixture, then it is evaporated down to approx. 30% of the volume, the residue is combined with water and extracted 3× with EtOAc. The combined organic phases are dried with Na2SO4, concentrated and the crude product is purified by chromatography (Alox; petroleum ether/EtOAc 8/2->7/3).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:21]=[C:22]2[CH:28]=[CH:27][N:26]([Si](C(C)(C)C)(C)C)[C:23]2=[N:24][CH:25]=1>O1CCCC1>[Br:19][C:20]1[CH:21]=[C:22]2[CH:28]=[CH:27][NH:26][C:23]2=[N:24][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(Br)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Brc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran) (58.5 mL, 58.5 mmol) was added to a solution of 5-bromo-1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine (16.5 g, 53 mmol) in tetrahydrofuran (15 mL) at 25° C. The mixture was stirred at 25° C. for 30 min and then extracted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to afford 5-bromo-1H-pyrrolo[2,3-b]pyridine (7.4 g, 71%) as a light yellow solid: LC/MS m/e calcd for C7H6BrN [M+H]+ 198.04, observed 197.1, 199.1; 1H NMR (400 MHz, CDCl3) δ ppm 6.49 (m, 1H), 7.39 (m, 1H), 8.10 (s, 1H), 8.38 (s, 1H), 10.48 (br. s., 1H).