Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.CC(C)([O-])C.[Na+].[NH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[OH:32]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C[C@@H](P(C1CCCCC1)C1CCCCC1)[C]1[C](P(C2C=CC=CC=2)C2C=CC=CC=2)[CH][CH][CH]1.[CH]1[CH][CH][CH][CH]1.[Fe]>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[CH:7]=[C:2]([NH:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]4[OH:32])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][N:14]=1
Reactant: COc1cc(-c2cnc3ccc(Cl)cn23)ccn1
Reactant: NC1CCCCC1O
Agent: [Fe]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: COCCOC
Product: COc1cc(-c2cnc3ccc(NC4CCCCC4O)cn23)ccn1

Procedure:
6-Chloro-3-(2-methoxy-pyridin-4-yl)-imidazo[1,2-a]pyridine (Intermediate G) (1 eq, 200 mg, 0.769 mmol), sodium tert-butoxide (2.4 eq, 1.8 mmol, 177 mg), palladium acetate (17 mg, 0.1 eq), (R)-1-[(1S)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine (43 mg, 0.1 eq) are stirred at RT under an inert atmosphere of argon in DME (3 ml) and degassed thoroughly before adding 2-aminocyclohexanol (2 eq, 1.53 mmol, 176 mg) The reaction is heated using microwave radiation at 100° C. for 2 hours. The majority of the solvent is removed in vacuo and the resulting residue is loaded onto a SCX-2 cartridge (resin loading 0.67 mmol/g) eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and further purified by flash chromatography (10% MeOH/EtOAc) to afford the title compound; [M+H]+=339
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15](=[O:17])[CH3:16])[C:10]([CH2:18]Br)=[C:9]2[CH3:20])=[O:5])[CH3:2].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15](=[O:17])[CH3:16])[C:10]([CH2:18][C:22]1[NH:21][CH:25]=[CH:24][N:23]=1)=[C:9]2[CH3:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)c(C)c(CBr)n2C(C)=O
Reactant: c1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc2c(c1)c(C)c(Cc1ncc[nH]1)n2C(C)=O
Reaction time: 18 h
Yield: 86.9 %

Procedure:
A mixture of 1-acetyl-2-bromomethyl-3-methylindole-5-carboxylic acid ethyl ester (5.74 g), imidazole (11.56 g), sodium bicarbonate (2.9 g) and acetone was stirred for 18 hours and then evaporated. The residue was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with water and dried (Na2SO4). The solvent was evaporated and the residue was chromatograhed on silica gel. Elution with chloroform first gave some impurity followed by pure product. Evaporation of the product-containing fractions gave 1-acetyl-2-[1-imidazolylmethyl]-3-methylindole-5-carboxylic acid ethyl ester (4.80 g) which was used without further characterisation.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[CH3:25][O:26][CH2:27][O:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32]([C:36]2[CH:41]=[CH:40][C:39]([C:42](O)=[O:43])=[CH:38][CH:37]=2)=[CH:31][C:30]=1[CH3:45].C(N1C=CN=C1)(N1C=CN=C1)=O>>[CH3:25][O:26][CH2:27][O:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([NH:1][CH2:2][CH2:3][O:4][C:5]3[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([O:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:10]=3)=[O:43])=[CH:38][CH:37]=2)=[CH:31][C:30]=1[CH3:45]
Reactant: COCOc1c(C)cc(-c2ccc(C(=O)O)cc2)cc1C
Reactant: CCOC(=O)C(Cc1ccc(OCCN)cc1)Oc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3cc(C)c(OCOC)c(C)c3)cc2)cc1)Oc1ccccc1
Yield: 23 %

Procedure:
In a similar manner to that described in Example 5, a reaction was carried out using ethyl 3-[4-(2-aminoethoxy)phenyl]-2-phenoxypropionate (2.07 g), which is the product of Reference example 4, 4′-methoxymethoxy-3′,5′-dimethylbiphenyl-4-carboxylic acid (1.50 g), which is the product of reference example 17(b), and carbonyldiimidazole (1.10 g) and the reaction mixture was treated to afford the desired compound (720 mg) as a colorless oil.
Reaction SMILES: [OH-].[Na+].[NH:3]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C@H:4]([C:11]([NH:13][C@H:14]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:34]([O:36]C)=[O:35])[CH3:33])=[O:30])[CH2:25][C:26](=[O:28])[NH2:27])=[O:22])[CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:12])[CH2:5][O:6][C:7]([CH3:10])([CH3:9])[CH3:8].Cl>CO>[NH:3]([C:38]([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])[C@H:4]([C:11]([NH:13][C@H:14]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:34]([OH:36])=[O:35])[CH3:33])=[O:30])[CH2:25][C:26](=[O:28])[NH2:27])=[O:22])[CH2:15][O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:12])[CH2:5][O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: COC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)O

Procedure:
34 ml of 0.5 N-sodium hydroxide is added to 3.54 g of Z-Ser(But)Ser(But)-Asn-Ala-OMe in 34 ml of methanol. After 3 minutes 17 ml of 1 N-hydrochloric acid is added, the methanol is removed by evaporation for the most part and the product which has separated out is filtered. By crystallization from methanol-ether there is obtained pure Z-Ser(But)-Ser(But)-Asn-Ala-OH of melting point 180°-181°.
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[K+].[Si:15]([O:22][CH2:23][CH2:24][CH2:25][C@H:26]([C@@H:28]1[C@:45]2([CH3:46])[C@H:31]([C@H:32]3[C@H:42]([CH2:43][CH2:44]2)[C@:40]2([CH3:41])[C@H:35]([CH2:36][C@@H:37]([O:47][CH:48]4[CH2:53][CH2:52][CH2:51][CH2:50][O:49]4)[CH2:38][CH2:39]2)[CH2:34][C:33]3=[O:54])[CH2:30][CH2:29]1)[CH3:27])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C1COCC1>[Si:15]([O:22][CH2:23][CH2:24][CH2:25][C@H:26]([C@@H:28]1[C@:45]2([CH3:46])[C@H:31]([C@H:32]3[C@H:42]([CH2:43][CH2:44]2)[C@:40]2([CH3:41])[C@H:35]([CH2:36][C@@H:37]([O:47][CH:48]4[CH2:53][CH2:52][CH2:51][CH2:50][O:49]4)[CH2:38][CH2:39]2)[CH2:34][C@H:33]3[OH:54])[CH2:30][CH2:29]1)[CH3:27])([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 500 °C
Reaction time: 5 h
Yield: 92.4 %

Procedure:
K-Selectride® (potassium tri-sec-butylborohydride) (8.9 ml, 1M in THF, 8.9 mmol) was added dropwise via syringe to a solution of ketone 2005 (1.7 g, 3.0 mmol) in dry THF (50 ml) at room temperature under argon. The reaction mixture was heated to 500° C. in an oil bath and stirred for 5 hours. The mixture was allowed to cool to room temperature and then quenched by adding 30% H2O2 dropwise until the evolution of gas ceased. Saturated aqueous NH4Cl solution was added and the aqueous solution was extracted (3×) with Et 20. The combined organic extracts were washed with aqueous saturated NaHCO3 solution (2×), distilled H2O (2×), and aqueous saturated NaCl solution, dried over anhydrous MgSO4, filtered, and the solvent was removed in vacuo. The crude product was purified by flash chromatography (SiO2, hexanes:EtOAc 10:1) giving alcohol 2006 as a white solid (1.6 g, 94%). 1H NMR (500 MHz, CDCl) δ 4.73-4.66 (m, 1 H, THP methine H), 3.95-3.85 (m, 1 H, THP CH2), 3.82 (s, 1 H, C-7 H), 3.66-3.52 (m, 3 H, THP CH2C & C-24 H), 3.50-3.45 (m, 1H, C-3 H), 1.08 (s, 3H, C-19 H), 0.91 (d, J=6.6 Hz, C-21 H), 0.89 (s, 9 H, t-Bu), 0.64 (s, 3 H, C-18 H), 0.04 (s, 6 H, TBDMS CH3); MS (CI/isobutane) m/z 577 (M+1, 5%), 493 (M+1-THP, 22%), 475 (M+1-THPOH, 26%), 458 (M+1-THPOH-H2O, 38%), 343 (M+1-THPOH-TBDMSOH, 80%), 325 (M+1-THPOH-TBDMSOH-H2O, 100%); IR (CHCl3) 3430, 2860 cm-1 ; m.p. 130°-133° C.; Anal. calcd. for C35H64 O4Si: C=72.86, H=11.18; Found: C=72.69, H=11.32.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[O-:16][C:17]#[N:18].[K+]>C(O)(=O)C.O>[CH2:12]([CH:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][C:17]([NH2:18])=[O:16])=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCC1OC(=O)c2cc(NC(N)=O)ccc21
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a solution of 8.27 g (0.04 mol) of the compound obtained in Example 4 in 39.4 ml of glacial acetic acid there are added, with sting, 25 ml of water, and to this solution there is slowly added a solution of 6.54 g of potassium cyanate in 10 ml of water. Once a white precipitate appears, the remaining potassium cyanate solution is added in one portion immediately. The mixture is warmed at 55° C., and stirred for 1 hour, then put aside at room temperature for 3 hours. 50 ml of water are added and the mixture is cooled to 5° C.; the separated solid is collected and dissolved in 10% sodium carbonate solution. Any insoluble material is filtered off and the filtrate is acidified with dilute sulphuric acid. The solid is collected and washed with water and dried, giving the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CCN(CC)CC>C1COCC1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 81.6 %

Procedure:
4-Nitrobenzyl chloride (0.086 g, 0.501 mmol) is dissolved in THF (1 mL), and to this solution, is added piperidine (0.059 mL, 0.601 mmol) followed by Et3N (0.210, 1.50 mmol). After stirring the mixture at 50° C. for 5 h, the resulting solution is filtered, and then the solvent is removed via high vacuum to afford the product (0.090 g, 82%); 1H NMR (DMSO-d6) δ 1.25-1.35 (m, 2H), 1.40-1.48 (m, 4H), 2.23-2.32 (m, 4H), 3.47 (s, 2H), 7.50 (d, J=8.8 Hz, 2H), 8.11 (d, J=8.8 Hz, 2H); mass spectrum [(+) ESI], m/z 221 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:4](=[O:17])[CH:3]=1.Cl.[N:19]([O-])=[O:20].[Na+].[OH-].[NH4+]>O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:4](=[O:17])[C:3]=1[N:19]=[O:20]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)n(Cc2ccccc2F)c(=O)[nH]1
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: Nc1[nH]c(=O)n(Cc2ccccc2F)c(=O)c1N=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
A mixture of 6-amino-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione (2.4 g, 10.6 mmol) in a 1.0N aqueous hydrochloric acid solution at 25° C. was treated with a solution of sodium nitrite (0.95 g, 13.78 mmol) in water (10 mL). The mixture was stirred at 25° C. for 3 h. At this time, the reaction was brought to pH=5 through treatment with a 1.0N aqueous ammonium hydroxide solution. The resulting solid was collected by filtration and washed with cold water to afford 6-amino-3-(2-fluoro-benzyl)-5-nitroso-1H-pyrimidine-2,4-dione (2.58 g, 92%); LRMS for C11H9FN4O3 (M+H)+ at m/z=265.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1N.N([O-])=O.[Na+].N#N.[BrH:19]>C(O)(=O)C.O.[Cu]Br>[Br:19][C:3]1[C:2]([Br:1])=[CH:10][C:9]([CH3:11])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Br
Reactant: Cc1cc(Br)c(N)c(C(=O)O)c1
Agent: [Cu]Br
Agent: N#N
Agent: O=N[O-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Br)c(Br)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-bromo-5-methylanthranilic acid (2.3 g, 10 mmol) in acetic acid (12 mL) at 0° C. was added 18% hydrobromic acid (30 mL, 30 mmol) followed by drop wise addition of a solution of sodium nitrite (690 mg, 10 mmol) in water (5 mL). After 10 min, this solution was added to a mixture of copper (I) bromide (2.15 g, 15 mmol) in 48% hydrobromic acid (7 mL) at 0° C. The mixture was allowed to warm to ambient temperature (15 minutes) and then refluxed at 50° C. until evolution of N2 was completed. The mixture was then extracted with ethyl acetate, washed with water, brine, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to provide 2.8 g of crude of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.27 (s, 3H), 7.43 (s, 1H), 7.72 (s, 1H), 13.60 (br s, 1H); MS (DCI/NH3) m/e 310 (M+NH4)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:9]([C:11]#[N:12])[CH:10]=[C:5]2[C:4]([CH3:20])=[N:3]1.[OH-:21].[Na+]>OS(O)(=O)=O>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:9]([C:11]([NH2:12])=[O:21])[CH:10]=[C:5]2[C:4]([CH3:20])=[N:3]1
Reactant: Cc1nn(C)c2nc(CCN3CCCC3)c(C#N)cc12
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1nn(C)c2nc(CCN3CCCC3)c(C(N)=O)cc12
Temperature: 60 °C
Reaction time: 48 h

Procedure:
1,3-Dimethyl-6-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrazolo [3,4-b]pyridine-5-carbonitrile was dissolved in concentrated H2SO4 (55 mL) and the solution stirred at 60° C. for 2 days. The mixture was cooled to 0° C., treated with 6N NaOH to pH 14, and extracted with ethyl acetate. The organic extract was evaporated under reduced pressure and the residue washed with ether to give 1,3-dimethyl-6-[2-(pyrrolidin-1-yl)ethyl)-1H-pyrazolo [3,4-b]pyridine-5-carboxamide (2.5 g).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].F[C:7]1[CH:8]=[CH:9][C:10]([N+:17]([O-:19])=[O:18])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].CCN(CC)CC.C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C>C1COCC1>[F:1][CH:2]([F:5])[CH2:3][O:4][C:7]1[CH:8]=[CH:9][C:10]([N+:17]([O-:19])=[O:18])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: OCC(F)F
Agent: CC(C)CN1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCC(F)F)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
8.53 g of 2,2-difluoroethanol are added to a solution of 17.31 g of methyl 5-fluoro-2-nitrobenzoate, 9.64 g of NEt3 and 32.71 g of 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane in 250 ml of anhydrous THF. The mixture is stirred at AT for 30 min. The solvent is evaporated under reduced pressure. Water is added and extraction is carried out with AcOEt. The extract is washed with a 1N aqueous HCl solution, with water and then with a saturated NaCl solution. It is dried over MgSO4 and filtered, and the solvent is evaporated under reduced pressure to give 21 g of the expected product.
Reaction SMILES: [C:1]1([CH3:37])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:13][CH:12]([NH:28]C(OC(C)(C)C)=O)[C:11]2=[O:36])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1>Cl.O1CCOCC1>[C:1]1([CH3:37])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:13][CH:12]([NH2:28])[C:11]2=[O:36])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)=CC(=O)N1CC(NC(=O)OC(C)(C)C)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)=CC(=O)N1CC(N)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.00 g) was suspended in 4N HCl-dioxane (10 ml), the suspension was stirred for one hour at 50° C. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, the solution was washed with diethyl ether, alkalified with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, to thereby obtain 694 mg of the titled compound (Yield: 86.5%).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O.Cl>O1CCCC1.CO>[CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][C:12]=3[C:13]=2[CH3:14])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCOc1ccc2oc(C(=O)C3CCCCC3)c(C)c2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCCOc1ccc2oc(C(O)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Cyclohexyl[5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl]methanone (10.3 g) synthesized in the above-mentioned (2) was dissolved in a mixed solvent of tetrahydrofuran (180 mL) and methanol (20 mL). The reaction mixture was ice-cooled, and sodium borohydride (90%, 2.7 g) was added, and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was ice-cooled again, water (10 mL) and 1N hydrochloric acid (100 mL) were carefully added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product (10.3 g) of the title object compound as a pale-yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[O:15])=[CH:12][C:11]([C:26]([F:29])([F:28])[F:27])=[N:10]2)[CH:6]=[CH:7][CH:8]=1)=[O:2].[CH3:30][Mg]Br>C1COCC1>[OH:2][CH:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[O:15])=[CH:12][C:11]([C:26]([F:28])([F:29])[F:27])=[N:10]2)[CH:6]=[CH:7][CH:8]=1)[CH3:30]
Reactant: C[Mg]Br
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(C=O)c1
Solvent: C1CCOC1
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(C(C)O)c1
Temperature: 0 °C
Yield: 81.3 %

Procedure:
To a solution of 149 (764.1 mg, 1.894 mmol) in THF (18.9 ml) 78° C. was added drop-wise a solution of methyl magnesium bromide (1.579 ml, 4.74 mmol). The temperature was allowed to slowly warm to 0° C. and the reaction was stirred an additional hour at 0° C., then it was quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated and the residue was purified by chromatography (Biotage, 20 to 70% EtOAc in hexane) to afford 153 (646 mg, 1.54 mmol, 87%) as peach oil. LRMS (ESI): (calc.) 419.2 (found) 442.2 (MNa)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22](OC)([O:24]C)[CH3:23])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O.C(OCC)(=O)C>[C:22]([C:19]1[N:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:28][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)=[N:17][CH:18]=1)(=[O:24])[CH3:23]
Reactant: COC(C)(OC)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 60 °C
Yield: 96.7 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(1,1-dimethoxy-ethyl)-pyrazin-2-yl]-propionamide (1.22 g, 2.459 mmol) in acetone (28 mL) and water (3 mL) was treated with p-toluenesulfonic acid monohydrate (142.5 mg, 0.738 mmol). The reaction mixture was heated to 60° C. for 30 min and then was diluted with ethyl acetate (100 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (100 mL), water (100 mL), and a saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/3 ethyl acetate/hexanes) afforded the N-(5-acetyl-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide as a white foam (1.07 g, 96%): mp 77–80° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H24ClN3O4S (M+H)+ 450.1249, found 450.1253.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([Br:14])[CH:7]=1)[CH3:2].IC.[CH3:18][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([Br:14])[CH:7]=1)[CH3:18])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Br)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(OC)c(Br)c1
Temperature: -78 °C

Procedure:
To (3-bromo-4-methoxy-phenyl)-acetic acid ethyl ester (12.2 mmol) in THF was added iodomethane (0.75 mL, 12.2 mmol), and the mixture was cooled to −78° C. Sodium bis(trimethylsilyl)amide (1M in THF; 12.2 mL, 12.2 mmol) was added, and subsequent work-up gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>C(COC)OC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(Br)cc1
Solvent: COCCOC
Product: O=Cc1ccc(-c2ccc(Cl)cc2)cc1
Yield: 94 %

Procedure:
A mixture of 4-chlorobenzeneboronic acid (19.4 g, 1 equiv), 4-bromobenzaldehyde (22.9 g, 1 equiv), palladium(H) acetate (1.4 g, 0.05 equiv) aqueous sodium carbonate (30.3 g in 144 ml solution, 2 equiv) and dimethoxyethane (500 ml) was stirred at reflux under argon for 2.5 h, then evaporated to low volume and diluted with dichloromethane: Workup continued as in (a) above to give identical material (25.2 g, 94%). 1H-NMR (CDCl3) δ 10.05 (1H, s), 7.96 (2H, d), 7.73 (2H, d), 7.57 (2H, d), 7.46 (2H, d); MS (AP+) found (M+1)=217, C13H935ClO requires 216.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12]N1C(=O)CCC1=O>CC(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[Cl:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cccc2cccnc12
Solvent: CC(C)O
Product: Nc1cccc2c(Cl)ccnc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34 %

Procedure:
8-amino quinoline (4.5 g, 31.3 mmol), N-chlorosuccinimide (4.80 g, 36 mmol) was taken up in iPrOH (50 mL) at 60° C. The mixture was heated to reflux and stirred for 20 min. The solution was cooled to 25° C. and concentrated to ⅓ original volume. The mixture was partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (5:1 hexanes/EtOAc) to afford 1.90 g (34%) of a 8-amino-4-chloro-quinoline product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]2([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]2([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[S:17][C:16](=[O:18])[N:15]([CH3:33])[C:14]2=[O:19])=[CH:4][CH:3]=1
Reactant: CI
Reactant: COc1ccc(S(=O)(=O)C2(CCCC#Cc3ccc(Cl)cc3)SC(=O)NC2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(CCCC#Cc3ccc(Cl)cc3)SC(=O)N(C)C2=O)cc1

Procedure:
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione (Example 100) is reated with sodium hydride in DMF, followed by methyl iodide to give the title compound as colorless crystals, mp 113-11 5° C.