Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O-:9])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([O:12]C)=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O1CCCC1>[N:14]1([C:10]([C:2]2[CH:3]=[CH:4][C:5]([C:7]([O:9][C:5]([CH3:7])([CH3:6])[CH3:4])=[O:8])=[CH:6][N:1]=2)=[O:12])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(C(=O)[O-])cn1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(C(=O)N2CCOCC2)nc1

Procedure:
For example, the 2,5-pyridinedicarboxylic acid, 2-methyl ester, 5-t-butyl ester 15 is contacted with a molar excess of morpholine in an appropriate organic solvent, such as tetrahydrofuran. The reaction is typically conducted at a temperature range of from room temperature to reflux and for a period of time ranging from 5 hours to 3 days. The 6-(morpholine-4-carbonyl)nicotinic acid, t-butyl ester 16 is isolated from the reaction mixture by standard extractive methods as is known in the art and may be purified by crystallization.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[F:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>CN(C=O)C>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][C:21]([F:20])([F:30])[F:31])=[CH:24][CH:25]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Nc2ccc(OC(F)(F)F)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 140 °C
Yield: 57.8 %

Procedure:
2-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (110 mg, 0.330 mmol) was dissolved in dry DMF (0.5 mL) under nitrogen atmosphere. [4-(Trifluoromethoxy)phenyl]amine (175 mg, 0.991 mmol) was added and the reaction mixture was heated in a microwave reactor for 25 mins at 140° C. The crude product was purified by preparative HPLC affording the title compound (84 mg, 56.6%). 1H NMR (500 MHz, CD3CN): δ 1.00 (t, 3H), 1.43-1.52 (m, 2H), 1.78-1.85 (m, 2H), 3.75 (t, 2H), 6.85-6.93 (m, 4H), 7.11-7.20 (m, 4H), 7.24-7.29 (m, 1H), 7.82 (bs, 1H).
Reaction SMILES: Br.[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][N:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[S:11][C:10]1=[NH:16].[C:17]12([C:27](O)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][N:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[S:11]/[C:10]/1=[N:16]\[C:27]([C:17]12[CH2:26][CH:21]3[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]3)[CH2:24]1)[CH2:18]2)=[O:28]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: COCCOCCn1c(C)c(C)sc1=N
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCn1c(C)c(C)s/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 100 °C

Procedure:
A mixture of 4,5-Dimethylthiazol-2-ylamine (20 mg, 0.16 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (0.20 mmol) was heated at 80° C. overnight to afford 3-[2-(2-methoxyethoxy)-ethyl]-4,5-dimethyl-1,3-thiazol-2(3H)-ylideneamine hydrobromide, which was used without purification. The alkylated thiazolylidine hydrobromide (1.25 equiv), 1-adamantane carboxylic acid (1.0 equiv), polymer-bound dicyclohexylcarbodiimide (PS-DCC, 3 equiv), 1-hydroxybenzotriazole hydrate (HOBT, 1 equiv), N,N-diisopropylethylamine (3 equiv), were combined in dimethylacetamide (DMA, 2.8 mL) and heated in a microwave to 100° C. for 420 seconds. The mixture was filtered through Si-Carbonate (6 mL-1 g cartridge from Silicycle Chemical Division, MeOH wash) and then concentrated to dryness. Purification by reverse phase HPLC afforded the title compound. 1H NMR (DMSO-d6, 500 MHz) δ ppm 11.68 (q, J=12.27 Hz, 6 H) 1.84 (d, J=2.50 Hz, 6 H) 1.94-2.02 (m, 3 H) 2.16 (s, 3 H) 2.22 (s, 3 H) 3.19 (s, 3 H) 3.39 (dd, J=5.62, 3.74 Hz, 2 H) 3.51 (dd, J=5.62, 3.74 Hz, 2 H) 3.73-3.77 (m, 2 H) 4.25 (t, J=5.46 Hz, 2 H); MS (ESI) m/z 393 (M=H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1.[CH3:26][C:27]([CH3:30])([O-])[CH3:28].[K+].BrCC1CC1>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:26][CH:27]2[CH2:30][CH2:28]2)=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])=[N:11]1
Reactant: CC(C)(C)[O-]
Reactant: O=C(Nc1ccn(Cc2cc(O)ccc2Cl)n1)c1c(F)cccc1F
Agent: BrCC1CC1
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(Nc1ccn(Cc2cc(OCC3CC3)ccc2Cl)n1)c1c(F)cccc1F
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 29.6 %

Procedure:
To a solution of N-{1-[(2-chloro-5-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for as preparation see Intermediate 13) (46 mg, 0.126 mmol) in DMSO (0.5 ml) was added potassium t-butoxide (15 mg, 0.134 mmol). The reaction was stirred for 10 min. To the reaction mixture was added (bromomethyl)cyclopropane (0.012 ml, 0.126 mmol, Lancaster). The reaction was heated to 60° C. and stirred overnight under nitrogen. The reaction mixture was filtered through a hydrophobic frit and the filtrate diluted with methanol (0.5 ml) and the sample purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a white solid (15.6 mg); LCMS: (System 4) MH+=418, tRET=3.20 min.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][N:7]([C:9]3[C:10]4[CH:17]=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:6][CH2:5][NH:4]2)[CH2:2]1.[S:18](N)([NH2:21])(=[O:20])=[O:19]>O1CCOCC1>[N:12]1[C:11]2[NH:15][CH:16]=[CH:17][C:10]=2[C:9]([N:7]2[CH2:8][C:3]3([CH2:1][CH2:2]3)[N:4]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:5][CH2:6]2)=[N:14][CH:13]=1
Reactant: c1nc(N2CCNC3(CC3)C2)c2cc[nH]c2n1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2

Procedure:
To 4-(4,7-diaza-spiro[2.5]oct-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (1 g, 4.4 mmol) (intermediate 21) in dry dioxane (20 mL) was added sulfamide (419 mg, 4.4 mmol). The reaction mixture was heated to reflux for 6 hours. After evaporation of the solvent in vacuo the crude mixture was purified by flash chromatography on silica using heptane→EtOAc:MeOH (9:1) as eluent.
Reaction SMILES: [OH:1][C:2]1([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:6][S:5][C:4](=[S:7])[N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[BH4-].[K+]>CO.O.C(Cl)(Cl)Cl.C(OCC)(=O)C>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:3][C:4](=[S:7])[S:5][CH2:6][CH:2]([OH:1])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CCC1(O)CSC(=S)N1c1ccccn1
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)CCC(O)CSC(=S)Nc1ccccn1
Reaction time: 2 h
Yield: 72.8 %

Procedure:
The procedure of Example 3 is followed, but a solution of methyl 3-[4-hydroxy-3-(pyrid-2-yl)-2-thioxothiazolidin-4-yl]-propionate (18.0 g) in methanol (200 cc) and a solution of potassium borohydride (3.25 g) in distilled water (50 cc) are used as the starting materials at a maximum of 5° C. The reaction is allowed to proceed for 2 hours at between 2° and 5° C. The crude product (17.0 g) is dissolved in a mixture of chloroform (80 cc) and ethyl acetate (20 cc). The solution is chromatographed on silica (0.063-0.2 mm) (350 g) contained in a column of diameter 4.2 cm. Elution is carried out with a mixture of chloroform (1,200 cc) and ethyl acetate (300 cc), this eluate being discarded, and then with a mixture of chloroform (2,800 cc) and ethyl acetate (700 cc), this eluate being collected and evaporated under reduced pressure (20 mm Hg) at 45° C. and then dried under reduced pressure (0.2 mm Hg) at 50° C. 2-Hydroxy-4-methoxycarbonylbutyl pyrid-2-yldithiocarbamate (13.2 g) is obtained.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[C:25]([F:26])=[C:24]([F:27])[CH:23]=[CH:22][C:21]=1B(O)O>>[O:16]=[C:15]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:23]4[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[C:24]=4[F:27])[C:10]=3[N:9]2[CH2:11][CH2:12][CH2:13][NH:14]1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccc(F)c(F)c1F
Product: N#Cc1cc(-c2ccc(F)c(F)c2F)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (18 mg, 20%), MS (ISP) m/z=356.5 [(M+H)+], mp 187° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 2,3,4-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: COc1cccc(-c2ccc([N+](=O)[O-])cn2)c1
Yield: 84.4 %

Procedure:
The title compound (612 mg) was prepared from 2-chloro-5-nitropyridine (500 mg, 3.15 mmol) and 3-methoxyphenylboronic acid (623 mg, 4.1 mmol) as a pale yellow solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.50 (d, J 2.6, 1H), 8.53 (dd, J 2.6, 8.8, 1H), 7.91 (d, J 8.8, 1H), 7.69-7.68 (m, 1H), 7.63 (d, J 7.8, 1H), 7.44 (t, J 7.9, 1H), 7.08-7.05 (m, 1H), 3.91 (s, 3H).
Reaction SMILES: C([NH:4][N:5]1[CH:9]=[C:8]([CH3:10])[N:7]([CH3:11])[C:6]1=[O:12])(=O)C.[ClH:13]>CO>[ClH:13].[NH2:4][N:5]1[CH:9]=[C:8]([CH3:10])[N:7]([CH3:11])[C:6]1=[O:12]
Reactant: CC(=O)Nn1cc(C)n(C)c1=O
Agent: Cl
Solvent: CO
Product: Cc1cn(N)c(=O)n1C

Procedure:
0.8 g of 1-acetylamino-2,3-dihydro-3,4-dimethyl-2-oxo-1H-imidazole are suspended in 800 ml of methanol, and the suspension is then heated to 42°. At this temperature, 28 g of gaseous HCl are passed into the suspension in the course of 40 minutes, during which process the suspension turns into a solution and the temperature of the reaction mixture rises to 52°. The solution is concentrated on a rotary evaporator, the residue is stirred with a small amount of tetrahydrofuran, and the crystals which have precipitated are filtered off with suction and dried, yielding the title salt melting at 162°-165°.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2]1.[CH:17]([C:19]1[C:20]([F:31])=[CH:21][N:22]=[C:23]2[C:28]=1[N:27]=[C:26]([O:29][CH3:30])[CH:25]=[CH:24]2)=[CH2:18]>CCO>[C:10]1([CH2:9][O:8][C:7](=[O:16])[NH:6][CH2:5][CH:3]2[CH2:4][N:1]([CH2:18][CH2:17][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[N:27]=4)[N:22]=[CH:21][C:20]=3[F:31])[CH2:2]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(NCC1CNC1)OCc1ccccc1
Reactant: C=Cc1c(F)cnc2ccc(OC)nc12
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3CC(CNC(=O)OCc4ccccc4)C3)c2n1
Reaction time: 24 h
Yield: 37.6 %

Procedure:
To a solution of phenylmethyl (3-azetidinylmethyl)carbamate (0.61 g, 2.76 mmole) in EtOH (1 mL) was added 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (673 mg, 3.3 mmole). After 24 h at 80° C., the reaction contents were purified on silica gel (CHCl3/MeOH, 9:1, containing 5% NH4OH) to afford the title compound (440 mg, 37%) as a light yellow oil: LC-MS (ES) m/e 425 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[NH2:17][C:12]1[C:11]2=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:34](=[O:36])[CH3:35])[CH:7]=[CH:6][CH:5]=3)[N:16]2[N:15]=[CH:14][N:13]=1
Reactant: Nc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Yield: 28 %

Procedure:
Using a procedure similar to that of Example 5 with 7-(3-amino-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and acetyl chloride as starting materials, 75 mg (28%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 2.10 (s, 3 H); ES-MS m/z 474.41 [M+H]+, HPLC RT (min) 3.04.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@@H:14]([N:16]=[N+]=[N-])[CH2:13][C@@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@@H:14]([NH2:16])[CH2:13][C@@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C[C@@H]1C(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@@H]1C(=O)O
Yield: 116.8 %

Procedure:
The trans azido acid 20b (2.0 g, 7.81 mmol) was hydrogenated as for the synthesis of 6, to give 2.1 g (97% yield) of 21 containing an equivalent of ethanol (by 1H NMR), after crystallization from ethanol, m.p.=225°-226° C. (decomp.) 1H NMR (CDCl3) δ 1.42/1.47 (2s, 9H), 2.28 (m, 1H), 2.45 (m, 1H), 3.58 (m, 1H), 3.80 (m, 1H), 3.99 (m, 1H), 4.24 (m, 1H). Anal. after high vacuum at 55° C. for 18 h; (C10H18N2O4.0.25 H2O) C, H, N.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10](/[CH:20]=[CH:21]/[C:22]([NH:24][CH2:25][C:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=O)=O)[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1>C(O)(=O)C>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[N:5]=[C:22](/[CH:21]=[CH:20]/[C:10]3[CH:11]=[CH:12][C:13]([N:14]4[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]4)=[C:8]([O:7][CH3:6])[CH:9]=3)[NH:24][CH:25]=2)=[CH:29][CH:30]=1
Reactant: [NH4+]
Reactant: COc1ccc(C(=O)CNC(=O)/C=C/c2ccc(-n3cnc(C)c3)c(OC)c2)cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc(-c2c[nH]c(/C=C/c3ccc(-n4cnc(C)c4)c(OC)c3)n2)cc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 15.7 %

Procedure:
Ammonium acetate (379 mg) was added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-[2-(4-methoxyphenyl)-2-oxoethyl]acrylamide (100 mg) in acetic acid (3 mL), and the reaction solution was stirred at 120° C. for 12 hours. The reaction solution was concentrated. Ethyl acetate and saturated sodium bicarbonate water were added to the resulting residue, and the organic layer was separated. The resulting organic layer washed with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate:2-propanol=20:1) to obtain 15 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:5]([CH3:14])=[N+:6]([O-:13])[C:7]([N+]([O-])=O)=[CH:8][CH:9]=1.[CH3:15][OH:16]>>[CH3:2][O:3][C:4]1[C:5]([CH3:14])=[N+:6]([O-:13])[C:7]([O:16][CH3:15])=[CH:8][CH:9]=1
Reactant: CO
Reactant: COc1ccc([N+](=O)[O-])[n+]([O-])c1C
Agent: [Na]
Product: COc1ccc(OC)[n+]([O-])c1C

Procedure:
1.15 g (50 mmol) of sodium were dissolved in 100 ml of anhydrous methanol, and after that 7.4 g (40 mmol) of 3-methoxy-2-methyl-6-nitropyridine N-oxide were added at 20° C. and while stirring. The mixture was then heated to reflux for 3 h and, after having been cooled down, concentrated in vacuo; the residue was taken up in water and this mixture was extracted with dichloromethane; the organic phase was dried and concentrated and the residue was crystallized using diisopropyl ether. 7 g of product were obtained, m.p. 63°-65° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:25])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:14]=2[O:21][CH2:22][O:23][CH3:24])[N:10]=1.C(P(CCCC)CCCC)CCC.[CH2:39]([N:46]1[CH:50]=[C:49]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[C:48](O)=[N:47]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:39]([N:46]1[CH:50]=[C:49]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[C:48]([O:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[O:7][C:8]=3[CH3:25])=[C:14]([O:21][CH2:22][O:23][CH3:24])[CH:15]=2)=[N:47]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Reactant: COCOc1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OCOC)c1
Reaction time: 2 h
Yield: 88 %

Procedure:
To a mixture of (4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-(methoxymethoxy)phenyl)methanol (8.50 g), tributylphosphine (9.95 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (6.06 g) and tetrahydrofuran (300 mL) was added 1,1′-(azodicarbonyl)dipiperidine (12.41 g) at room temperature, and the mixture was stirred for 2 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-(methoxymethoxy)benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (12.42 g, yield 88%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 120-121° C.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:34])[C@@H:10]([NH:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[C:25]=1[CH3:33])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:32][C:26]1[C:25]([CH3:33])=[C:24]([NH:23][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([I:22])=[CH:20][CH:21]=3)=[N:14][N:15]=2)[C@@H:9]([OH:8])[CH3:34])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(I)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(I)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -30 °C
Yield: 94.3 %

Procedure:
To a solution of 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-iodophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (2.0 g, 3.3 mmol) in THF (60 mL) was added TBAF (3.7 mL, 3.7 mmol, 1 M solution in THF) at −50° C. After addition, the reaction mixture was allowed to warm to −30° C. gradually (about 1 h), then quenched by adding saturated aqueous NH4Cl solution (20 mL) and extracted with EtOAc. The EtOAc extracts were washed with water, brine, dried over Na2SO4. Concentration provided a residue, which was purified by flash chromatography over silica gel to provide the title compound 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-(4-iodophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (1.54 g, 94%). 1H NMR (400 MHz, CDCl3, δ in ppm) 7.83 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.6 Hz, 2H), 7.40 (d, J=8.6 Hz, 1H), 6.63 (d, J=8.6 Hz, 1H), 5.24 (d, J=8.6 Hz, 1H), 4.72 (dd, J=2.6, 8.6 Hz, 1H), 4.62 (m, 1H), 3.07 (d, J=4.1 Hz, 1H), 2.35 (s, 3H), 1.42 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([S:30]([NH:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[OH:36][CH2:35][C:34]([NH:33][S:30]([C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:16][CH2:15]4)=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:21])[CH:29]=[CH:28][CH:27]=1)(=[O:32])=[O:31])([CH3:38])[CH3:37]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Pale-yellow solid. MS (ISP) 540.5 [(M+H)+].
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:19])[C:12](OCC(C)C)=[O:13])[CH3:9])[CH:4]([CH3:6])[CH3:5].CO.O>C1CCCCC1.C(OCC)(=O)C>[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:19])[CH2:12][OH:13])[CH3:9])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)COC(=O)[C@@H](C)OC(C)OCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCCCC1
Solvent: O
Product: CC(C)COC(C)O[C@H](C)CO
Yield: 96.7 %

Procedure:
5.7 g of sodium borohydride was suspended at room temperature in a solution of 25.0 g of the isobutyl (R)-(+)-2-(1-isobutoxyethoxy)propionate (obtained in Reference Example 4) dissolved in 30 ml of cyclohexane. Thereto was dropwise added slowly 24 ml of methanol with stirring, so that the internal temperature of the reaction system could be kept at 40° C. After the completion of the dropwise addition, the mixture was stirred at room temperature for 5 hours. After the reaction, the reaction mixture was added 100 ml of water, followed by stirring for a while. Thereto was added 200 ml of ethyl acetate. The resulting organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent. The resulting concentrate was subjected to distillation to obtain 17.3 g (yield: 98.0%) of an oily title compound (diastereomixture).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=C)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].I([O-])(=O)(=O)=[O:35].[Na+].C(OCC)(=O)C.O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=[O:35])[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1cc(C(=O)NCc2ccc(F)cc2)c(=O)c(OCc2ccccc2)c1C(=O)OC
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a solution of the compound 15 (7.6 g, 16.9 mmol) in 1,4-dioxane (228 ml) was added an aqueous solution (38 ml) of potassium osmate dihydrate (372 mg, 1.01 mmol), and sodium metaperiodate (14.5 g, 67.6 mmol) was further added, followed by stirring at room temperature for 2 hours. The reaction solution was added to a vessel to which ethyl acetate (300 ml) and water (300 ml) had been added, while stirring. The organic layer was washed with water, a 5% aqueous sodium hydrogen sulfite solution and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain 3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-oxo-1-(2-oxo-ethyl)-1,4-dihydro-pyridine-2-carboxylic acid methyl ester 16 (5.39 g, 71%) as a colorless crystal.