Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C(F)=CC2OCC(O)(C)C3SC(C(OCC)=O)=[N:11]C=3C=2C=1.C([C@]1(O)CCN(C)C1=O)#C.[F:34][C:35]1[C:36]([C:56]#[C:57][C@:58]2([OH:65])[CH2:62][CH2:61][N:60]([CH3:63])[C:59]2=[O:64])=[CH:37][C:38]2[C:44]3[N:45]=[C:46]([C:48]([O:50]CC)=O)[S:47][C:43]=3[C:42]([OH:54])([CH3:53])[CH2:41][O:40][C:39]=2[CH:55]=1>>[F:34][C:35]1[C:36]([C:56]#[C:57][C@:58]2([OH:65])[CH2:62][CH2:61][N:60]([CH3:63])[C:59]2=[O:64])=[CH:37][C:38]2[C:44]3[N:45]=[C:46]([C:48]([NH2:11])=[O:50])[S:47][C:43]=3[C:42]([OH:54])([CH3:53])[CH2:41][O:40][C:39]=2[CH:55]=1
Reactant: CCOC(=O)c1nc2c(s1)C(C)(O)COc1cc(F)c(C#C[C@]3(O)CCN(C)C3=O)cc1-2
Reactant: CCOC(=O)c1nc2c(s1)C(C)(O)COc1cc(F)c(Br)cc1-2
Agent: C#C[C@]1(O)CCN(C)C1=O
Product: CN1CC[C@@](O)(C#Cc2cc3c(cc2F)OCC(C)(O)c2sc(C(N)=O)nc2-3)C1=O

Procedure:
Similar to as described in General Procedure G, racemic ethyl 9-bromo-8-fluoro-4-hydroxy-4-methyl-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give a diasteromeric mixture of ethyl 8-fluoro-4-hydroxy-9-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4-methyl-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate. Following aminolysis of the ethyl ester (similar to as described in General Procedure M) a diasteromeric mixture of the titled compounds was obtained after purification by prep HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[O:18][C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:16][C:15]=2[CH3:31])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][OH:7])=[NH:5].N1C=CC=CC=1.[C:38]1([O:44]C(Cl)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>ClCCl.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[O:18][C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=3)=[N:16][C:15]=2[CH3:31])[CH:9]=[CH:8][C:3]=1[C:4]1[NH:5][C:38](=[O:44])[O:7][N:6]=1
Reactant: Cc1nc(CCc2ccc(C(F)(F)F)cc2)oc1COc1ccc(C(=N)NO)c(Cl)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1nc(CCc2ccc(C(F)(F)F)cc2)oc1COc1ccc(-c2noc(=O)[nH]2)c(Cl)c1
Temperature: 25 °C

Procedure:
4.4 g crude 2-Chloro-N-hydroxy-4-{4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazol-5-ylmethoxy}-benzamidine were dissolved in 20 ml dichloromethane. 0.94 ml pyridine and 1.46 ml phenylchloroformate were added and the mixture stirred at room temperature for ten minutes. The mixture was diluted by the addition of 40 ml acetonitrile and 7.25 ml 1,8-diazabicyclo[5.4.0]undec-7-ene were added. The mixture was stirred at room temperature for 10 minutes. The mixture was evaporated in vacuo and the resulting crude material was purified by reversed phase HPLC to obtain 460 mg 3-(2-chloro-4-{4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazol-5-ylmethoxy}-phenyl)-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.Cl.[NH2:40][OH:41].C(N(CC)CC)C>C(Cl)Cl.O1CCCC1.O>[OH:41][NH:40][C:14](=[O:15])[C@H:13]([N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: NO
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](CC(C)C)C(=O)O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](CC(C)C)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2(R)-[[4-Methoxybenzenesulfonyl](benzyl)amino]-4-methylpentanoic acid (4.38 g, 11.2 mmol) is dissolved in methylene chloride (56.0 mL). To this solution is added oxalyl chloride (1.95 mL, 22.4 mmol) and dimethylformamide (0.86 mL, 11.2 mmol), and the reaction is stirred at room temperature for 90 minutes. Meanwhile, in a separate flask, hydroxylamine hydrochloride (3.11 g, 44.8 mmol) and triethylamine (9.36 mL, 67.1 mmol) are stirred in tetrahydrofuran (50.0 mL) and water (3.5 mL) at 0° C. for 15 minutes. After 90 minutes, the methylene chloride solution is added in one portion to the second flask, and the combined contents are stirred for three days as the flask gradually warms up to room temperature. The reaction is then diluted with acidic water (pH=~3), and extracted several times with ethyl acetate. The combined organic layers are dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (1% methanol/methylene chloride) to give N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-methylpentanamide, m.p. 48°-52° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.[N+:14]([O-])([OH:16])=[O:15].O.N>S(=O)(=O)(O)O>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:9][CH:8]=2
Reactant: COCc1cc2ccccc2cn1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: COCc1cc2c([N+](=O)[O-])cccc2cn1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Methoxymethylisoquinoline (68.8 g) is dissolved in 95% sulphuric acid (density 1.83; 300 cc). The solution is cooled to 0° C. and a mixture of 70% nitric acid (density 1.42; 25 cc) and 95% sulphuric acid (density 1.83; 100 cc) is added dropwise in the course of 30 minutes so as not to exceed 10° C. Stirring is continued for 16 hours, whilst allowing the temperature to return to about 20° C. The mixture is then poured into a mixture of ice and water (2 liters), and an ammonia solution containing 20% of NH3 (density 0.9) is added, without exceeding 30° C., until a pH of about 10 is obtained. The resulting yellow solution is extracted with methylene chloride (4×400 cc). The organic extracts are combined, washed with water (2×50 cc), dried over magnesium sulphate and filtered, and the filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). 3-Methoxymethyl-5-nitroisoquinoline (78 g), m.p. 91° C., is obtained.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[CH:30]2.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:32]3[C:33]4[C:29](=[CH:28][C:27]([CH3:26])=[CH:35][CH:34]=4)[CH:30]=[N:31]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc2c(cnn2-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c1
Temperature: 125 °C

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (140 mg, 328 μmol), 5-methyl-1H-indazole (41.7 mg, 316 μmol) in dioxane (2 mL) was added sodium tert-butoxide (66.8 mg, 695 μmol) and bis(tri-tert-butylphosphine)palladium(0) (16.1 mg, 31.6 μmol). The mixture was degassed then heated in sealed tube at 125° C. for two days. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-butyl-2-(5-methyl-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide. 1H NMR (CDCl3) δ: 9.18 (s, 1H), 8.50 (d, J=8.5 Hz, 1H), 8.34 (s, 1H), 8.20 (d, J=0.8 Hz, 1H), 7.95-8.07 (m, 1H), 7.78 (s, 1H), 7.24 (d, J=8.3 Hz, 1H), 5.71 (s, 2H), 3.55-3.60 (m, 2H), 2.53 (s, 3H), 1.63 (s, 9H), 0.92-0.98 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]2[CH2:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]2[CH2:33][CH2:32][CH2:31]2)(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N2CCC2)cc1Br
Product: Cc1ccc(S(=O)(=O)N2CCC2)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-(3-bromo-4-methyl-benzenesulfonyl)-azetidine (Intermediate 155), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[NH:12]CC(O)COC1C=CC=C2C=1C=C(C(OCC)=O)N2>C(O)C>[NH2:12][CH:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1
Reactant: CCOC(=O)c1cc2c(OCC(O)CNC3CCc4ccccc4C3)cccc2[nH]1
Agent: Cl
Solvent: CCO
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure described in Example 27, but starting from ethyl 4-(2,3-epoxypropoxy)indole-2-carboxylate (25.1 g), obtained from ethyl 4-hydroxyindole-2-carboxylate and epichlorohydrin according to the method of Belgian Patent 739,545, and 2-aminotetralin (14.8 g) in ethanol (120 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-ethoxycarbonylindol-4-yloxy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 15 wherein Z is ethoxy, and the chain is attached to position 2 of the tetralin moiety) which is crystallized from a mixture ethanol/isopropanol 2/1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[C:13]([CH3:22])=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[C:13]([CH3:22])=[C:14]([S:18]([NH:8][C:5]2[C:4]([O:9][CH3:10])=[N:3][C:2]([Cl:1])=[CH:7][N:6]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1nc(Cl)cnc1N
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1cccc(Cl)c1C

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.1 g) and 3-chloro-2-methylbenzenesulphonyl chloride (0.15 g). Yield 0.085 g.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[O:29][CH:28]=[N:27][CH:26]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:36]>CO.C(OCC)(=O)C>[ClH:36].[NH2:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[O:29][CH:28]=[N:27][CH:26]=1)=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3cnco3)ccc2c1=O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(-c3cnco3)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
Tert-butyl[2-isobutyl-6-(1,3-oxazol-5-yl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.14 g, 0.30 mmol) was dissolved in methanol (4 mL) and a solution (10 mL) of 4N hydrogen chloride in ethyl acetate were added thereto. This mixture was stirred at room temperature for 1 h and the precipitated crystals were collected by filtration to give the title compound (0.084 g, 69%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][C:9]([O-:11])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[Na+].[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([NH:17][C:9](=[O:11])[CH2:8][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1c(N)cccc1Br
Reactant: O=C([O-])Cc1ncccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Br)cccc1NC(=O)Cc1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of sodium 2-(3-chloropyridin-2-yl)acetate (7.39 g, 38 mmol), 3-bromo-2-methylaniline (4.7 mL, 38.4 mmol), DIEA (13.3 mL, 76 mmol) and HATU (14.6 g, 38.4 mmol) in DMF (127 mL) was stirred at room temperature. After 90 min the mixture was diluted with EtOAc and washed twice with 10% LiCl, then with brine. The combined aqueous layers were extracted with EtOAc, and the combined organic phases were dried and concentrated to a small volume. The solution was seeded with a crystal from an earlier batch and allowed to stand overnight to provide a precipitate which was collected by filtration and washed with 50% EtOAc-hexanes to provide a white solid. The filtrate was concentrated and recrystallized similarly three times to provide additional solid. The solids were combined to give N-(3-bromo-2-methylphenyl)-2-(3-chloropyridin-2-yl)acetamide as a white solid (11.43 g, 89% yield). Mass spectrum m/z 339, 341 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 9.76 (br. s., 1H), 8.52 (d, J=3.5 Hz, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.80 (dd, J=8.1, 1.1 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.32-7.23 (m, 1H), 7.06 (t, J=8.0 Hz, 1H), 4.16 (s, 2H), 2.39 (s, 3H).
Reaction SMILES: C[C@@H](N(C)C)[C@@H](O)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:20]([C:23]1[C:24]([C:41](=[O:43])[CH3:42])=[C:25]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:26]([CH2:32][CH3:33])=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:28]=1)([CH3:22])[CH3:21]>C(OCC)C>[CH:20]([C:23]1[C:24]([CH:41]([OH:43])[CH3:42])=[C:25]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[C:26]([CH2:32][CH3:33])=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:28]=1)([CH3:21])[CH3:22]
Reactant: CCc1c(C(C)C)cc(C(C)C)c(C(C)=O)c1-c1ccc(F)cc1
Agent: C[C@H]([C@@H](O)c1ccccc1)N(C)C
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCc1c(C(C)C)cc(C(C)C)c(C(C)O)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a solution of (1S,2R)-(+)-N-methylephedrine (6.29 g, 35.1 mol) in diethyl ether (45 mL) was added lithium aluminum hydride (1M/diethyl ether, 1.5 eq., 35 mL) dropwise at 0° C. under argon. The reaction was refluxed for 1.5 h. turning from a clear solution to a white milky solution. The reaction was cooled to room temperature and then −78° C. The intermediate obtained in Step J (6.64 g, 20.3 mmol) was dissolved in 60 mL of dry diethyl ether for a dropwise addition to the reaction mixture (˜2 mL/min., the temperature should not rise above −60° C.). The reaction was kept at −78° C. for 2.0 hours and then allowed to warm overnight. The reaction was quenched at 0° C. with water (30 mL) and diluted with diethyl ether (250 mL), washed with water (3×200 mL), brine (100 mL) and dried with MgSO4 Filtration and concentration afford a residue which was filtered through a pad of silica (400 g, 80% dichloromethane/hexane) to give the titled compound (99% e.e.) as a white solid (5.85 g, 17.8 mmol, 88%). mp 143-145° C.; Rf=0.1 (50% CH2Cl2/hexane); 1H NMR (300 MHz, CDCl3): δ 7.34 (s, 1H), 7.15 (m, 4H), 4.68 (dq, J=3.3, 7 Hz, 1H), 3.88 (septet, J=7 Hz, 1H), 3.18 (septet, J=7 Hz, 1H), 2.29 (q, J=7.7 Hz, 2H), 1.68 (s, 1H), 1.37 (d, J=4.8 Hz, 3H), 1.26 (m, 12H), 0.890 (t, J=7.4 Hz, 3H); FAB-MS calcd for (C22H29FO) 328, found 328 (M+); Anal. Calcd for C22H29FO: C, 80.45; H, 8.90; F, 5.78. Found: C, 80.19; H, 8.77; F, 5.84; [α]22=+26.6.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[CH2:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]>CO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: C=C(C(=O)O)c1ccc(CC(C)C)cc1
Solvent: CO
Product: CC(C)Cc1ccc([C@H](C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
In an atmosphere of argon, 4.6 mg (5.4×10-3 mmol) of Ru(OAc)2 [(S)-(-)-OcH-binap] complex and 220.4 mg (1.08 mmol) of 2-(4-isobutylphenyl)-propenoic acid were dissolved in 5.4 ml of methanol, and the resulting solution was put into a 100 ml capacity autoclave and stirred at 25° C. for 24 hours under a hydrogen pressure of 100 atm. The reaction solution was concentrated and then subjected to a silica gel column chromatography (eluting solution, ether) to obtain 211 mg of (S)-2-(4-isobutylphenyl)propionic acid with a yield of 94%.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:18]4[NH:22][C:21]5[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=5[N:19]=4)=[N:14][NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.COC1C=C(B(O)O)C=CC=1>>[NH:22]1[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=[C:18]1[C:13]1[C:12]2[C:16](=[CH:17][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=3)=[CH:10][CH:11]=2)[NH:15][N:14]=1
Reactant: COc1cccc(-c2ccc3c(-c4nc5ccccc5[nH]4)n[nH]c3c2)c1
Agent: COc1cccc(B(O)O)c1
Product: Oc1cccc(-c2ccc3c(-c4nc5ccccc5[nH]4)n[nH]c3c2)c1

Procedure:
Example 24(o) was prepared in a similar manner to that described for Example 24(f), except that 6-(3-methoxy-phenyl)-3-1H-benzoimidazol-2-yl-1H-indazole, prepared in a similar manner to that described for example 24(a) except that 3-methoxy-phenylboronic acid was used instead of 5-methoxy-2-methyl-4-[2-(trimethylsilanyl)-ethoxymethoxy]-phenylbororic acid in step (viii), was used instead of 6-(2-methoxy-4-hydroxyphenyl)-31H-benzoimidazol-2-yl-1H-indazole. 1H NMR (300 MHz, DMSO-d6) δ 13.67 (s, 1H), 13.00 (s, 1H), 9.58 (s, 1H), 8.55 (d, 1H, J=8.4 Hz), 7.71-7.75 (m, 2H), 7.49-7.57 (m, 2H), 7.30 (t, 1H, J=7.8 Hz), 7.12-7.24 (m, 4H), 6.80 (dd, 1H, J=8.1, 1.5 Hz). MS (ES) [m+H]/z calc'd 327, found 327; [m−H]/z calc'd 325, found 325.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([N:11]=[N+:12]=[N-:13])[CH2:6]1)=[O:4].[CH2:14](I)[CH3:15]>C(#N)C.C1COCC1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([O:10][CH2:14][CH3:15])[C@@H:7]([N:11]=[N+:12]=[N-:13])[CH2:6]1)=[O:4]
Reactant: CCI
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Solvent: CC#N
Solvent: C1CCOC1
Product: CCO[C@H]1C[C@H](C(=O)OC)C[C@@H]1N=[N+]=[N-]
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (1R,3S,4S)-3-azido-4-hydroxy-cyclopentanecarboxylic acid methyl ester (500 mg) at r.t. in acetonitrile/THF 3:1 (8 ml) under an argon atmosphere were added Ag2O (1.88 g) and ethyl iodide (2.18 ml). The black suspension was stirred for 18 h at 60° C., then cooled to r.t. The black solid was filtered off and washed with ethyl acetate. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 7:3) to give (1R,3S,4S)-3-azido-4-ethoxy-cyclopentanecarboxylic acid methyl ester (474 mg) as light yellow oil. MS: 214.1 ([M+H]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:17]=1[CH:18]=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:17]=1[CH:18]=[N:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1cccnc1
Reactant: O=Cc1cc(Cl)ccc1OCc1ccccc1
Solvent: ClCCl
Product: Clc1ccc(OCc2ccccc2)c(C=Nc2cccnc2)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of pyridin-3-amine (2.13 mmol), 2-(benzyloxy)-5-chlorobenzaldehyde (1.93 mmol) and Mg(ClO4)2 (0.579 mmol) was stirred at 50° C. in dichloromethane (10 mL) for 4 h. After cooling to room temperature, the solution was filtered through 0.45 micron filter and the solvent was evaporated to afford solid. Yield 96%. 1H NMR: 5.16 (s, 2H), 6.97 (d, 1H, J=8.96 Hz), 7.28-7.40 (m, 8H), 7.48-7.52 (m, 1H), 8.15 (d, 1H, J=2.70 Hz), 8.45-8.48 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH:16]1([CH2:19][O:20][C:21]2[C:22]([CH3:30])=[CH:23][C:24]([CH:27]([NH2:29])[CH3:28])=[N:25][CH:26]=2)[CH2:18][CH2:17]1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH:27]([C:24]3[CH:23]=[C:22]([CH3:30])[C:21]([O:20][CH2:19][CH:16]4[CH2:18][CH2:17]4)=[CH:26][N:25]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)ncc1OCC1CC1
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCC1CC1
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (321 mg, colorless oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (344 mg, 1.24 mmol, Step-1 of Intermediate-1) and 1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (300 mg, 1.24 mmol, Amine-73, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20]C)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of 9-bromo-5-methoxycarbonylmethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (25.0 g, 0.071 mol) in a mixture of THF (350 mL) and methanol (350 mL) was added aqueous 1N NaOH (440 mL). The mixture was stirred for 2 h at room temperature, concentrated to ca. 500 mL, and acidified by addition of aqueous 1N HCl. The precipitates formed were collected by filtration, washed with distilled water, and dried in vacuo to give 22.9 g of the title compound (95%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:2]=1.[CH2:16]([NH:20][C:21]([N:23]1[C:31]2[C:26](=[C:27]([CH:32]=[O:33])[CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1)=[O:22])[CH2:17][CH2:18][CH3:19].[OH-].[K+].O>CO>[CH2:16]([NH:20][C:21]([N:23]1[C:31]2[C:26](=[C:27]([CH:32]([OH:33])[C:15]3[C:9]4[C:10](=[N:11][CH:12]=[C:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[CH:8]=4)[NH:13][CH:14]=3)[CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1)=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Reactant: CCCCNC(=O)n1ccc2c(C=O)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCNC(=O)n1ccc2c(C(O)c3c[nH]c4ncc(-c5cccnc5)cc34)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 51 mg, 0.26 mmol, prepared as in Example 17) in methanol (2 mL), was added 4-Formyl-indole-1-carboxylic acid butylamide (519, 84 mg, 0.34 mmol) and potassium hydroxide (44 mg, 0.78 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtrated and concentrated. The desired compound was isolated with silica gel column chromatography to give an off-white solid (520, 7 mg, 6%). MS (ESI) [M+H+]+=440.3.