Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH2:6][CH2:5]2.CN(C)C=O.[Br:24]N1C(=O)CCC1=O>O>[Br:24][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([C@@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH2:8]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C2CCc3cc(O)ccc3C2)COC(=O)N1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]1([C@H]2CCc3c(ccc(O)c3Br)C2)COC(=O)N1
Reaction time: 6 h
Yield: 95.8 %

Procedure:
To a mixture of 4-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one (100 mg, 0.0004 mol) (pure isomer 2) in N,N-Dimethylformamide (0.5 mL, 0.006 mol) was added N-Bromosuccinimide (72.0 mg, 0.000404 mol) in N,N-Dimethylformamide (0.5 mL, 0.006 mol) and was stirred at for 6 hrs. Water was added, and the mixture was extracted with dichloromethane. The solvent was removed and residue was purified with Isco (12 g silica gel, 0-40% MeOH:DCM) to give a white precipitate (125 mg, 95% yield). 1H NMR showed a single isomer. The solid (10.1 mg) was dissolved in MeOH (3 mL) and the solvent allowed to evaporate slowly to give white needles, which was washed with MeOH and collected (5.0 mg). LCMS 1.23 min 328.21 ([M+2], 100%). X-ray shows (S,S) configuration, see FIG. 2.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:61][CH:62]=[CH2:63].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:63][CH:62]=[CH2:61])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: C=CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CC1OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg in 3.0 ml 33% methylene chloride in cyclohexane), allyl trichloroacetimidate (88 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid as (4.5 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 18 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:2)+1% methanol) gave the title compound (156 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.Cl.[CH3:11][C@@H:12]1[CH2:17][O:16][CH2:15][CH2:14][NH:13]1.C(N(CC)CC)C>CO>[Cl:8][C:6]1[CH:7]=[C:2]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][C@H:12]2[CH3:11])[N:3]=[C:4]([NH2:9])[N:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C[C@@H]1COCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H]1COCCN1c1cc(Cl)nc(N)n1
Temperature: 120 °C
Yield: 75.1 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (500 mg, 3.05 mmol) in CH3OH (10 mL) were added (3R)-3-methylmorpholine hydrochloride (441 mg, 3.2 mmol) and triethylamine (1.28 mL, 9.2 mmol), and the reaction mixture was heated in a microwave at 120° C. for 35 minutes. Side-product started to form. An additional 0.5 eq of (3R)-3-methylmorpholine hydrochloride and 0.2 mL of triethylamine were added, and the mixture was heated in an oil bath at 50° C. for 3 days and in a microwave at 100° C. for 3 hours. The mixture was cooled down, evaporated under vacuum, and the resulting residue was partitioned between EtOAc and water, and extracted with EtOAc (2×) and CH2Cl2 (2×). The combined organics were washed with water and brine, dried (MgSO4), filtered, and evaporated. The resulting material was triturated with Et2O and dried in vacuo to afford the title compound (524 mg). LC-MS (ES) m/z=229, 231 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1>>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:11]([O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N:12][C:13]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1)=[CH:14]2
Reactant: COc1ccc(O)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc(Oc2nc(Nc3cc(C)[nH]n3)cc3cc(OC)ccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-methoxy-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [6-methoxy-1-(4-methoxy-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 377(MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]([CH3:30])=[CH2:29])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:32])[C:19](=[O:31])[NH:20][N:21]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH:28]([CH3:29])[CH3:30])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:32])[C:19](=[O:31])[NH:20][N:21]=2)([CH3:12])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(C)c1cc2c(cc1OC1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cc2c(cc1OC1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
A suspension of 3-(7-isopropenyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.054 g, 0.122 mmol) and Pd/C (10%, 0.015 g) in MeOH (10 mL) was stirred under H2 (50 psi) at ambient temperature overnight. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by preparative TLC (eluting with 30% EtOAc in petroleum ether) to give 3-(7-isopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester as a white solid (0.049 g, 95%). LC/MS (Table 1, Method 2) Rt=1.327 min.; MS m/z: 467 [M+23]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)#[CH:2].[CH2:10]([O:12][C:13](=[O:17])/[CH:14]=[CH:15]\I)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:17])[CH:14]=[CH:15][C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)[CH3:11]
Reactant: C#Cc1ccc(N)cc1
Reactant: CCOC(=O)/C=C\I
Product: CCOC(=O)C=CC#Cc1ccc(N)cc1

Procedure:
The general procedure was used to convert 4-Ethynyl-phenylamine and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (30% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (350 mg, 90% yield). 1H NMR (400 MHz, CDCl3) δ 7.34-7.32 (d, J=8.4, 2H), 6.60-6.58 (d, J=8.4, 2H), 6.36-6.34 (d, J=11.4, 1H), 6.05-6.02 (d, J=11.4, 1H), 4.28-4.23 (q, J=7.1, 2H), 3.96 (s, 2H), 1.35-1.31 (t, J=7.1, 3H). 13C NMR(100 MHz, CDCl3) δ 165.21, 148.01, 133.78, 125.92, 123.66, 114.54, 111.33, 103.46, 85.59, 60.28, 14.32. Anal. Calcd. for C13H13NO2: C, 72.54; H, 6.09; N, 6.51; Found C, 72.63; H, 6.26; N, 6.32.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1>CN(C)C=O>[Si:17]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: COC(=O)c1ccc(CO)cc1C(=O)OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
19 g (84.8 mmol) of dimethyl 4-hydroxymethylphthalate are placed in 250 ml of dimethylformamide in a round-bottomed flask and under a stream of nitrogen. 14 g (93 mmol) of tert-butyldimethylsilyl chloride and 8 g (118 mmol) of imidazole are added. The reaction medium is stirred for 3 hours at room temperature, it is then concentrated and the residue is dissolved in ether and then filtered. The filtrate is evaporated and the product is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (50/50) to give 23.7 g (83%) of the expected product in the form of a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:16])/[CH:3]=[N:4]/[C:5]1[NH:6][C:7](=[O:15])[C:8]([N+:12]([O-:14])=[O:13])=[C:9]([CH3:11])[N:10]=1.C1CCN2C(=NCCC2)CC1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>CN(C=O)C>[CH2:28]([N:6]1[C:7](=[O:15])[C:8]([N+:12]([O-:14])=[O:13])=[C:9]([CH3:11])[N:10]=[C:5]1/[N:4]=[CH:3]/[N:2]([CH3:1])[CH3:16])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1nc(/N=C/N(C)C)[nH]c(=O)c1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1nc(/N=C/N(C)C)n(Cc2ccccc2)c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 85493.2 %

Procedure:
To a suspension of (E)-N,N-Dimethyl-N′-(4-methyl-5-nitro-6-oxo-1,6-dihydropyrimidin-2-yl)formimidamide (53.4 g, 0.24 mmol) in DMF (690 mL) was added DBU (44.6 mL, 0.30 mol) and benzyl bromide (44.4 mL, 0.29 mol) and stirred at room temperature for 1 h. The excess of DBU was neutralized with HCl, and the mixture was concentrated in vacuo. The residue was dissolved in methylene chloride and extracted twice with 2M HCl and water, then dried over Na2SO4 and concentrated. Trituration with ethanol afforded the crystalline product which was washed with ethanol to give the product (64.7 g, 86% yield) and used in the next step without further purification.
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](Cl)Cl.CO>>[I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1I
Reactant: ClCCl
Solvent: CO
Product: COC(=O)c1cccc(C)c1I

Procedure:
2-iodo-3-methylbenzoic acid (595 mg, 2.27 mmol) was dissolved in DCM/MeOH=1/1 (5 ml) at 0° C., then TMS-CH2N2 (2M in Et2O, 1.4 ml, 2.8 mmol) was added. After 1.5 hours at RT solvents were evaporated. Yield 630 mg yellow oil.
Reaction SMILES: C1C=CN=CC=1.[FH:7].[CH3:8][O:9][C:10]1[C:11]([N+:18]([O-:20])=[O:19])=[CH:12][C:13]([CH3:17])=[C:14](N)[CH:15]=1.N([O-])=O.[Na+]>N1C=CC=CC=1>[F:7][C:14]1[CH:15]=[C:10]([O:9][CH3:8])[C:11]([N+:18]([O-:20])=[O:19])=[CH:12][C:13]=1[CH3:17]
Reactant: F
Reactant: COc1cc(N)c(C)cc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cc(F)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 76 %

Procedure:
Under nitrogen in a nalgene bottle, a stirring solution of pyridine (17.1 mL, 3.2 M, −70° C.) was treated dropwise with HF-pyridine (51.91 mL). Next, 5-methoxy-2-methyl-4-nitro-phenylamine (10.0 g, 54.9 mmol) was added followed by sodium nitrite (6.4 g, 92.76 mmol). The dry ice/acetone bath was removed and the reaction was allowed to warm to room temperature. The solution was then heated at 60° C. for 2 h (or until nitrogen evolution stops.) After cooling to room temperature, the nalgene bottle was placed in an ice bath and 375 mL of water was slowly added to the solution. The resulting orange precipitate was collected by suction filtration and washed with 250 mL of water. Purification of the solid via silica gel flash chromatography (30% ethyl acetate in heptane) provided 1-fluoro-5-methoxy-2-methyl-4-nitro-benzene (7.69 g, 76%) as a light orange solid: mp 71-74°C. Rf 0.56 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 7.82 (d, J=7.5 Hz, 1H), 6.75 (d, J=10.5 Hz, 1H), 3.93 (s, 3H), 2.25 (d, J=2.1 Hz, 3H); ESI-LC/MS m/z calcd for C8H8FNO3: 185.1; Found 186.0 (M+1)+. Anal. calcd for C8H8FNO3: C, 51.90; H, 4.36. Found C, 52.11; H, 4.47.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:9]=[N:10][N:11]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])=[O:35].[C:43](OC(=O)C)(=[O:45])[CH3:44].C([O-])(=O)C.[Na+]>>[F:32][C:30]([F:31])([F:33])[C:22]1[CH:21]=[C:20]([CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=1)[CH2:19][N:11]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([C:4]2[C:3]([C:34](=[O:35])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])=[C:2]([NH:1][C:43](=[O:45])[CH3:44])[CH:7]=[CH:6][N:5]=2)[N:9]=[N:10]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)c1C(=O)c1ccccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)Nc1ccnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)c1C(=O)c1ccccc1Cl
Temperature: 80 °C
Reaction time: 13 h

Procedure:
Combine {4-amino-2-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chloro-phenyl)-methanone (840 mg, 0.067 mmol) and 2.0 ml of acetic anhydride and sodium acetate (18.2 mg, 0.134 mmol). Seal the reaction mixture in a pyrex tube and heat to 80° C. After 13 hours, cool to RT. Pour the mixture through a plug of Celite® (1 cm) and silica gel (2 cm). Concentrate the clear liquid to 1.0 mL and apply to a 2 mm chromatotron plate and elute with a EtOAc/hexane gradient to provide 26 mg of the title compound: Exact Mass 643.1; mass spectrum (IS): m/z=643.9 (M+1), m/z=641.8 (M−1); 1H NMR (250 MHz, CDCl3) 9.69 (s, 0.6H), 8.39 (s, 1H), 7.74 (s, 1H), 7.15-7.49 (m, 5H), 7.27 (s, 2H), 6.80-7.05 (m, 5H), 5.26 (s, 2H), 2.16 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](SC)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>C1C=CC=CC=1.C(OCC)(=O)C>[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:4]2[N:5]=[N:6][C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:2]([CH3:1])[N:3]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Reactant: O=C(c1ccco1)N1CCNCC1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(N2CCN(C(=O)c3ccco3)CC2)nnc1-c1ccccc1
Yield: 29 %

Procedure:
A mixture of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (9 g) and N-(2-furoyl)piperazine (10 g) was heated at 150° to 160° C. for 89 hours with stirring. The reaction mixture was dissolved in benzene (300 ml) and subjected to chromatography on silica gel (300 g) using a mixture of benzene and ethyl acetate (3:2) as an eluent. The eluate was concentrated to dryness and the resulting solid was recrystallized from a mixture of chloroform and diisopropyl ether to give crystals of 3-[4-(2-furoyl)-1-piperazinyl]-5-methyl-6-phenyl-1,2,4-triazine (4.20 g), mp 141.5°~142.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]1=[O:13].B.[Na].Cl.[CH3:18]O>CO>[CH3:18][O:13][CH:3]1[C:2]([CH3:14])([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4]1
Reactant: CO
Reactant: CC1(C)C(=O)NC(=O)c2ccccc21
Agent: B
Agent: Cl
Agent: [Na]
Product: COC1NC(=O)c2ccccc2C1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (2.0 g) obtained in step (c) just above was dissolved in methanol (100 ml). Sodium boron hydride (1.7 g) was added to the solution. The mixture was stirred at room temperature for 3 hr. Hydrochloric acid-methanol (50 ml) was added to the reaction solution, and the mixture was stirred at room temperature for one hr. The reaction solution was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 3-methoxy-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (1.8 g).
Reaction SMILES: [F:1][C:2]1[C:10]2[C:6](=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[N:8]([CH:11]([CH3:13])[CH3:12])[N:9]=2)[C:5](C)=[CH:4][CH:3]=1.B(Br)(Br)Br.C1CCCCC=1>>[F:1][C:2]1[C:10]2[C:6](=[C:7]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)[N:8]([CH:11]([CH3:12])[CH3:13])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2c3c(C)ccc(F)c3nn2C(C)C)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CC(C)n1nc2c(F)cccc2c1-c1ccc(O)cc1
Yield: 88.8 %

Procedure:
Prepared according to Method D step C from 7-fluoro-2-isopropyl-3-(4-methoxyphenyl)-methyl-2H-indazole (0.007 g, 0.025 mmol), boron tribromide (0.05 mL, 0.5 mmol) and 0.2 mL of cyclohexene to give the product (0.006 g).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-:30].[K+].[K+].OO.O>CS(C)=O>[Br:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH2:28])=[O:30])=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#CCc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Br)c[nH]c(=O)c23)cc1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)Cc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Br)c[nH]c(=O)c23)cc1
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of (4-(7-bromo-1-(2,6-difluorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (126.2 mg) obtained in Example 104 and potassium carbonate (47.4 mg) in DMSO (2 mL) was added 30% aqueous hydrogen peroxide (131 μL) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration, and washed with water. The obtained crystals were purified by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)) to give the title compound (92 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.O[Li].O.Cl>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.2 %

Procedure:
To a solution of methyl 2-(1H-indazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (110.0 mg, 0.29 mmol) in methanol (20 mL) and water (1 mL), was added LiOH.H2O (50 mg, 2.08 mmol,). After stirring for 2 days at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted to pH 6 with hydrochloric acid (1N) and filtered to give 2-(1H-indazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (47.4 mg, 45%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)O.[I:16]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(O)(=O)C>[I:16][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: II
Reactant: Nc1ncccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(I)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 193.8 %

Procedure:
A mixture of 2-amino-3-nitropyridine (5.0 g, 35.9 mmol), acetic acid (22 mL), water (5 mL), sulfuric acid (0.650 mL), and HIO4×2H2O (1.7 g, 7.5 mmol) was allowed to stir at 90° C. for 10 min. Iodine crystals (3.7 g, 14.6 mmol) were added in portions. After stirring for 1 h, the reaction was poured into saturated sodium thiosulfate and extracted with ethyl acetate. The organic layers were washed with 0.1 M NaOH and saturated brine, dried with sodium sulfate, then evaporated to give orange solid (7.5 g, 79% yield).
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO.N(C(OCC)=O)=N[C:15](OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C(O)c1cccnc1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cccnc1Br
Reaction time: 2 h
Yield: 111 %

Procedure:
2-Bromonicotinic acid (7.33 g, 36 mmol) was suspended in dry Et2O (40 mL), and MeOH (2.3 mL) and diethyl azodicarboxylate (5.8 mL, 37 mmol) were added. Triphenylphosphine (9.61 g in 40 mL Et2O, 37 mmol) was added dropwise over 2.5 hours. After stirring an additional two hours, the reaction was filtered and evaporated. The resulting clear liquid was chromatographed on silica gel (10-40% EtOAc/hexanes) to yield a clear oil (8.63 g, 100%). 1H NMR (CDCl13): δ8.49 (dd, 1H, J=4.8, J′=2.2), 8.09 (dd, 1H, J=7.7, J′=1.8), 7.36 (m, 1H), 3.97 (s, 3H).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:16]CC[N:13]2[CH3:17])[CH:7]=[N:8][CH:9]=1)[CH:2]=[CH2:3].[ClH:18].O.CO>CCOCC>[ClH:18].[CH2:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:11][C@@H:12]2[CH2:16][CH2:17][NH:13]2)[CH:7]=[N:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cncc(OC[C@H]2CCCN2C)c1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: C=CCc1cncc(OC[C@@H]2CCN2)c1

Procedure:
To a solution of 5-allyl-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine in Et2O was added hydrogen chloride (1.0 M in Et2O) carefully to afford the tittle compound: 1H NMR (D2O) δ 2.70 (q, 2H, J=8.5 Hz), 3.49 (d, 2H, J=6.5 Hz), 4.02-4.20 (m, 2H), 4.44 (d, 2H, J=4.5 Hz), 4.95 (m, 1H), 5.12-5.20 (m, 2H), 6.05 (m, 1H), 7.53 (s, 1H), 8.15 (s, 1H), 8.24 (d, 1H, J=2.0 Hz); MS (CI/NH3) m/z 205 (M+H)+. Anal. Calcd for C12H16N2O.2 HCl.0.2 H2O: C, 54.14; H. 6.82; N, 10.52. Found: C, 54.30; H, 6.82; N, 10.49. [α]25D −3.5 (c 0.63, MeOH).
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][CH3:4].[C:7]1([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>N1C=CC=CC=1.CCOC(C)=O.O>[C:13]([O:6][CH2:1][CH:2]([OH:5])[CH2:3][CH3:4])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(O)CO
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 36.2 %

Procedure:
To a solution of 1,2-butandiol (2 g) in anh. pyridine (15 mL) was added triphenylmethyl chloride (8 g). The dark reaction mixture was heated at 100° C. for 8 hr and stirred at r.t. for 18 hr. The mixture was then poured in EtOAc/H2O, the phases were separated and the organic layer was washed with sat. aq. NaCl and dried over Na2SO4. The solids were filtered and the solvent evaporated. The residual pyiridine was eliminated by filtration through a pad of silica gel (cHex/EtOAc 8/2). The solvent was evaporated and the residue was purified by flash chromatography (silica gel, cHex/EtOAc 95:5) to give the title compound (2.67 g)