Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(C)C)(C)C.C([Li])CCC.CCCCCC.Br[C:20]1[CH:24]=[CH:23][S:22][CH:21]=1.[NH:25]1[C:33](=[O:34])[C:31](=[O:32])[C:29](=[O:30])[NH:28][C:26]1=[O:27]>O1CCCC1>[OH:32][C:31]1([C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[C:29](=[O:30])[NH:28][C:26](=[O:27])[NH:25][C:33]1=[O:34]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Brc1ccsc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: O=C1NC(=O)C(O)(c2ccsc2)C(=O)N1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
Isopropyl ether (40 ml.) was cooled to -70° C. Butyl lithium in hexane (2.4 M, 10 ml., 24 mmoles) was added over 10 minutes, keeping the temperature -70° to -60° C. 3-Bromothiophene (1.9 ml., 20 mmoles) was added over 20 minutes, keeping the temperature -72° to -68° C. The mixture was stirred for an additional 30 minutes at -72° to 70° C. Sublimed alloxan (3 g., 21 mmoles) in 25 ml. of tetrahydrofuran was added over 40 minutes, keeping the temperature -70° to -65° C. Stirring at this temperature was continued for 15 minutes. The cooling bath was removed and the reaction mixture stirred for one hour at room temperature, then cooled to 5° C. Hydrochloric acid (1 N, 40 ml.) was added slowly, and the organic phase separated. The aqueous phase was extracted with 35 ml. of ethyl acetate. The combined organic phase/extract was washed with 10 ml. of water, dried over anhydrous sodium sulfate and concentrated to yield solid 5-hydroxy-5-(3-thienyl)-2,4,6(1H,3H,5H)pyrimidinetrione (1.41 g., 31%; m/e 226).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16]O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClP(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CN=C1.[I:37]I>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][I:37])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Agent: ClP(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCCI)CC1

Procedure:
To a stirred mixture of 3-3 (22.7 g, 93 mmol), chlorodiphenylphosphine (21.7 mL, 0.12 mol), imidazole (19.0 g, 0.28 mol), and toluene (300 mL) at 0° C. was added iodine (30.6 g, 0.12 mol) in toluene (700 mL) followed by removal of the cooling bath. After 2.0 h the reaction mixture was washed with saturated Na2CO3, 5% Na2S2O3, 10% KHSO4 and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 30% EtOAc/hexanes) gave 3-4 as a colorless oil, RF 0.41 (silica, 10% EtOAc/hexanes.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[I-].[Na+].[H-].[Na+]>O.CN(C=O)C>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:3]2[N:2]=[N:1][C:5]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)=[N:4]2)=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ncccc1-c1nn[nH]n1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1nnn(Cc2ccc(OCc3ccccc3)cc2)n1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 17.2 %

Procedure:
To a solution of 3-(2H-tetrazol-5-yl)-pyridin-2-ylamine (100 mg) described in Manufacturing Example 5-1, 4-benzyloxybenzyl chloride (172 mg), sodium iodide (111 mg), and DMF (3 mL) was added NaH (18 mg), which was stirred for 40 minutes at 60° C. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=4:1, then 2:1, then 1:1). Ethyl acetate was added to the resulting residue, and the solids were filtered off to obtain the titled compound (38 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].CI.[C:21](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[N:8]([CH3:21])[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2cc(F)c(F)cc2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cc(F)c(F)cc2c1=O
Yield: 63 %

Procedure:
6,7-Difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester (10.0 g, 39.5 mmol), methyl iodide (56 g, 395 mmol) and potassium carbonate (10.9 g, 79 mmol) were combined in dimethylformamide and heated to 90° for 20 hours. The reaction mixture was cooled and poured into cold water (1.5 l). The precipitate was filtered, washed with cold water and recrystallized from ethyl acetate to yield the title product as white needles, m.p. 210°-212° (6.60 g, 24.7 mmol, 63% yield).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2cccnc2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2cccnc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(pyridin-3-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.60 min.; [M+H]+: 403.35 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]=1[CH:12]=O.[BH4-].[Na+].P(Br)(Br)[Br:17]>C(O)C.CCOCC>[Br:17][CH2:12][C:4]1[S:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:3]=1[O:2][CH3:1]
Reactant: COc1c(C=O)sc2ccccc12
Reactant: BrP(Br)Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: COc1c(CBr)sc2ccccc12
Reaction time: 1 h

Procedure:
To a solution of 3-methoxybenzothiophene-2-carboxaldehyde [3.4 g; J. Chem. Soc. C 779 (1967)] in ethanol (60 ml) was added sodium borohydride (0.34 g). After 10 minutes the solution was poured onto water (200 ml) and extracted with ether (2×50 ml). The ether extracts were washed with water (2×25 ml), dried and then evaporated to the title product as an orange oil. Yield, 3.4 g. 'HNMR (CDCl3, 60 MHz): 2.6 (s, 1H), 3.8 (s, 3H), 4.8 (s, 2H), 7.0-8.0 (m, 4H). This material (1.5 g) was dissolved in ether (20 ml). To the solution cooled in an ice-bath was added phosphorous tribromide (0.7 ml). The mixture was let to stand for 1 hour. The reaction mixture was poured onto ice-water (50 ml) and the ether layer separated, collected, dried and evaporated to obtain the title product as a light yellow oil (yield, 1.4 g). 'HNMR CDCl3, 60 MHz): 4.0 (s, 3H), 5.0 (s, 2H), 7.2-7.8 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[CH3:64][S:65]([CH2:68][C@H:69]([NH2:71])[CH3:70])(=[O:67])=[O:66]>C(#N)C.C(OCC)(=O)C.O>[CH3:64][S:65]([CH2:68][C@H:69]([NH:71][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH:19]=1)=[O:22])[CH3:70])(=[O:67])=[O:66]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: C[C@@H](N)CS(C)(=O)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@H](CS(C)(=O)=O)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 0.175 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (84 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.076 ml, 0.44 mmol) were dissolved in acetonitrile (1.75 ml). (R)-1-(Methylsulfonyl)propan-2-amine hydrochloride (36 mg, 0.21 mmol) was added and the mixture was stirred at room temperature for 3 h. Water and ethyl acetate were added, the layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 65 mg (64%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-methanesulfonyl-1-methyl-ethyl)-amide. (M+H)+=578.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:11][CH2:10][CH2:9][C:5]21[CH2:8][NH:7][CH2:6]2.F[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([NH:22][C:23]2[N:28]=[C:27]([C:29]3[CH:30]=[N:31][N:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=34)[CH:26]=[CH:25][N:24]=2)=[C:15]([O:38][CH3:39])[CH:14]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:39][O:38][C:15]1[CH:14]=[C:13]([N:7]2[CH2:8][C:5]3([N:4]([CH3:3])[CH2:11][CH2:10][CH2:9]3)[CH2:6]2)[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)[CH:26]=[CH:25][N:24]=1
Reactant: CN1CCCC12CNC2
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC3(CCCN3C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 100 °C
Yield: 83.3 %

Procedure:
8-Methyl-2,8-diazaspiro[3.4]octane (Intermediate 47, 133 mg, 0.88 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(pyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-amine (Intermediate 155, 280 mg, 0.74 mmol) and DIPEA (0.153 mL, 0.88 mmol) in DMA (3 mL) and the mixture was heated at 100° C. for 1 h. The mixture was then part-purified by ion exchange chromatography, using an SCX column, eluting with 7M methanolic ammonia. Clean fractions were combined and concentrated in vacuo. Further purification by FCC, eluting with 1-8% CH3OH in CH2Cl2 gave the title compound (300 mg) as an orange dry film; 1H NMR: 1.71 (2H, dt), 2.05 (2H, dd), 2.40 (3H, s), 2.67 (2H, t), 3.75 (2H, d), 3.95 (3H, s), 4.11 (2H, d), 6.31 (1H, s), 7.09 (1H, td), 7.28 (1H, d), 7.35-7.41 (1H, m), 8.25 (1H, s), 8.36 (1H, d), 8.47 (1H, s), 8.50 (1H, d), 8.79 (1H, s), 8.79-8.82 (1H, m); m/z: ES+ MH+ 487.30.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:11]>C(OCC)C>[CH2:18]([CH:15]1[CH2:14][CH2:13][N:12]([C:10](=[O:11])[CH2:9][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CCl)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccccc1
Solvent: CCOCC
Product: O=C(CNc1ccccc1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from aniline and 2-chloro-1-(4-benzyl-piperidin-1-yl)-ethanone (Example 200a) according to the method described in Example 206. Melting Point: 107-109° C. (diethylether)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]=[O:25])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])(O)(O)=[O:27].[Na+].Cl([O-])=O.[Na+]>O.CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:27])=[O:25])=[CH:19][CH:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)Cc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Yield: 95.5 %

Procedure:
To a solution of 0.7 g of 4-[1-(benzyloxycarbonyl)-piperidin-4-yl]phenylacetaldehyde and 0.5 g of sodium dihydrogenphosphate in 5 ml of water and 30 ml of dimethyl sulfoxide was added a solution of 0.35 g of sodium chlorite in water (5 ml) and the resulting mixture was reacted at room temperature for 20 minutes. After adding water, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 0.7 g of the title compound was obtained as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1B1OC(C)(C)C(C)(C)O1.Cl[C:26]1[N:31]=[N:30][C:29]([N:32]([CH3:43])[CH:33]2[CH2:38][C:37]([CH3:40])([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]2)=[CH:28][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1[C:26]1[N:31]=[N:30][C:29]([N:32]([CH3:43])[CH:33]2[CH2:38][C:37]([CH3:39])([CH3:40])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]2)=[CH:28][CH:27]=1
Reactant: COc1cc(-n2cc(CO)cn2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-n2cc(CO)cn2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 100 °C

Procedure:
To a microwave vial was added (1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-4-yl)methanol (87 mg, 0.26 mmol), 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine Intermediate 1-1 (74.5 mg, 0.26 mmol), potassium phosphate (168 mg, 0.79 mmol), Pd2(dba)3 (12.06 mg, 0.01 mmol), and SPhos (10.82 mg, 0.03 mmol), followed by addition of 1,4-dioxane (5 mL)/H2O (1 mL). The vial was purged with N2 for 10 min and the reaction mixture was heated at 100° C. in the microwave for one hour. The reaction mixture was concentrated in vacuo. The crude material was adjusted to pH 3 using 1 M HCl aqueous solution and loaded on an SCX column. The crude material was washed with methanol then eluted with 2 N ammonia in methanol. The product-containing fractions were concentrated to afford (1-(3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1H-pyrazol-4-yl)methanol (100 mg, MS: 451.4 [M+H+].).
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(Cl)Cl>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:2]([NH:1][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=2)[C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(CC(N)C(=O)OC(C)(C)C)ccc1O
Solvent: ClCCl
Product: COc1cc(CC(NC(=O)c2ccc([N+](=O)[O-])cc2)C(=O)OC(C)(C)C)ccc1O
Reaction time: 1 h
Yield: 44 %

Procedure:
Prepared using General Procedure 5: To a stirred solution of tert-butyl 2-amino-3-(4-hydroxy-3-methoxyphenyl)propanoate INT-1 (1.85 g, 6.93 mmol) and TEA (1.93 mL, 13.9 mmol) in DCM (15 mL) at 0° C. was added 4-nitrobenzoyl chloride (1.29 g, 6.93 mmol) in DCM (10 mL) dropwise. The reaction mixture was stirred for 1 h, diluted with DCM (100 mL) and washed with saturated aqueous NaHCO3 (100 mL). The organic layer was dried over MgSO4, and concentrated. The product was purified by chromatography (EA/hexanes) to afford 1.38 g (44%) of tert-butyl 3-(4-hydroxy-3-methoxyphenyl)-2-(4-nitrobenzamido)propanoate INT-7. LCMS-ESI (m/z) calculated for C21H24N2O7: 416; found 415 [M−H]−, tR=2.18 min (Method 4).
Reaction SMILES: C([NH:8][C:9]1[N:14]=[C:13]([C:15]2[C:16]([C:23]3[S:24][C:25]([Cl:28])=[CH:26][CH:27]=3)=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1.O.[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:28][C:25]1[S:24][C:23]([C:16]2[C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:19][N:18]([CH:20]([CH3:22])[CH3:21])[N:17]=2)=[CH:27][CH:26]=1
Reactant: CC(C)n1cc(-c2ccnc(NCc3ccccc3)n2)c(-c2ccc(Cl)s2)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)n1cc(-c2ccnc(N)n2)c(-c2ccc(Cl)s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
A mixture of N-benzyl-4-[3-(5-chloro-2-thienyl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-amine (1 eq, 3.1 mmol) in 11 mL sulfuric acid was stirred at room temperature overnight. Ice was added followed by water and a solution of NaOH 30% until pH=9. The aqueous layer was extracted with dichloromethane and the combined organic extracts were dried over MgSO4 filtered and concentrated to afford 0.55 g of 4-[3-(5-chloro-2-thienyl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-amine (50% yield).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.[C@@H:19]1([N:27]2[CH:31]=[C:30](I)[CH:29]=[C:28]2[N+:33]([O-:35])=[O:34])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[CH2:20]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[C@@H:19]1([N:27]2[CH:31]=[C:30]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)[CH:29]=[C:28]2[N+:33]([O-:35])=[O:34])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[CH2:20]1
Reactant: O=[N+]([O-])c1cc(I)cn1[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2cccs2)cn1[C@H]1C[C@H](O)[C@@H](CO)O1
Yield: 64 %

Procedure:
2-(Tributylstannyl)thiophene (476 μL, 1.5 mmol) was added to a DMF (2.5 mL) solution containing 1-(2-deoxy-β-D-ribofuranosyl)-4-iodo-2-nitropyrrole (177 mg, 0.5 mmol) and bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.025 mmol). The mixture was reacted at 100° C. for 30 minutes in a microwave machine (standard mode). The reaction solution was separated between ethyl acetate (50 mL) and water (50 mL). The organic layer was concentrated and purified by HPLC to yield 1-(2-deoxy-β-D-ribofuranosyl)-4-(thien-2-yl)-2-nitropyrrole (97 mg, 0.32 mmol, 63%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([Cl:12])=[CH:4][N:3]=1.[C:13]1([NH:19][C:20](=[O:28])[CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:20]([NH:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:28])[CH2:23][CH2:24]2)[C:5]([Cl:12])=[CH:4][N:3]=1
Reactant: O=C(CN1CCNCC1)Nc1ccccc1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3ccccc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.031 g, 0.15 mmol) and isopropanol (3.5 ml) was added N-phenyl-2-piperazin-1-yl-acetamide×2HCl salt (0.048 g, 0.16 mmol) followed by diisopropylethylamine (0.10 ml, 0.54 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 10% to 30% ethyl acetate in dichloromethane. The title compound was obtained as a yellow solid (0.041 g, 71%); 1H-NMR (500 MHz, DMSO-d6) 2.64 (br s, 4H, piperazine N(CH2)2), 3.13 (br s, 4H, piperazine N(CH2)2), 3.19 (s, 2H, NCH2CO), 7.00 (br s, 2H, 2-NH2), 7.06 (t, J=7.34 Hz, 1H, p-ArH), 7.31 (t, J=8.26 Hz, 2H, m-ArH), 7.63 (d, J=7.34 Hz, 2H, o-ArH), 8.07 (s, 1H, 6-H), 9.76 (s, 1H, CONH);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24].[OH-].[Na+].[NH2:29]O.Cl>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]2[O:22][NH:29][C:17](=[O:18])[CH:16]=2)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: NO
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)cc2Cl)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CCC(c2cc(=O)[nH]o2)CC1c1ccc(Cl)cc1Cl
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
Methyl 2-(2,4-dichlorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.55 g, 3.85 mmol) was dissolved in MeOH (15.79 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (1.014 mL, 3.85 mmol) in water (1.579 mL) was added and the mixture stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.236 mL, 3.85 mmol) was added and stirring continued at −40° C. for 3.5 h. The reaction mixture was then transferred to a preheated 80° C. solution of 6 M hydrogen chloride (19.91 mL, 119.45 mmol) and heating was continued for 20 min. The solvent was then evaporated. DCM and water were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 25-65% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Methyl 2-(2,4-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.870 g, 60.8%) was isolated as a white solid. MS m/z 371 (M+H)+
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O>CN(C=O)C>[C:3]1([C:9]2[CH:13]=[CH:12][N:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: c1ccc(-c2cc[nH]n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc(-c2ccccc2)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a slurry of 8g (0.2 mol) of sodium hydride in 100 mL of DMF at room temperature was added 23g (0.16 mol) of 3-phenylpyrazole. The mixture was stirred 1 hr and 17.8 mL (0.16 mol) of ethyl bromoacetate was added. The reaction was heated at about 100° C. for 2 hr, cooled, poured into water, extracted into methylene chloride, dried over magnesium sulfate and stripped. The resulting oil was chromatographed on silica gel HPLC using 25% ethyl acetate in hexane. The first, and major, component to elute was the 3-isomer. It was recrystallized from ether-hexane to yield 6.0g of ethyl 3-phenyl-1H-pyrazole-1-acetate having an Rf of 0.66 on silica gel in 1:1 ethylacetate-hexane. The third component to elute from the HPLC separation was a minor fraction containing the 5-isomer. Upon stripping the solvent one obtained 1.0g of ethyl 5-phenyl-1H-pyrazole-1-acetate as an oil having an Rf of 0.51 on silica gel in 1:1 ethyl acetate-hexane.