Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[N:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=4)[C:16]3=[O:29])[C:10]=2[CH2:30][OH:31])[N:3]=1.Br[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)(C)(C)C.CCOC(C)=O.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]>[C:25]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:29])[N:15]([C:11]1[C:10]([CH2:30][OH:31])=[C:9]([N:4]3[CH:5]=[C:6]([C:7]#[N:8])[C:2]([NH:1][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[N:3]3)[CH:14]=[CH:13][CH:12]=1)[N:24]=[CH:23]2)([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c(N)n4)c3CO)ncc2c1
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccccn5)n4)c3CO)ncc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.9 %

Procedure:
To a 5 mL microwave reaction vial were introduced 3-amino-1-(3-(6-tert-butyl-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-pyrazole-4-carbonitrile (25 mg, 0.060 mmol), 2-bromopyridine (11 mg, 0.072 mmol), Pd2(dba)3 (3.9 mg, 0.004 mmol), 2-(DICYCLOHEXYLPHOSPHINO)-3,6-DIMETHOXY-2′-4′-6′-TRI-I-PROPYL-1,1′-BIPHENYL (Brett-Phos) (4.5 mg, 0.008 mmol), cesium carbonate (29.5 mg, 0.091 mmol) and suspended in t-butanol (0.609 mL). The reaction vessel was inerted three times by alternating vacuum and an Ar purge, then stirred at room temperature for 5 minutes to give a heterogeneous mixture that turned color from purplish-red to reddish-orange. The reaction was heat to 100° C. (external), during which the color of the reaction mixture changed to orange after ˜2 minutes of heating. After 2 hr, the reaction was judged complete by TLC. The mixture was diluted with EtOAc, filtered through a pad of diatomaceous earth and bound to silica gel. The crude product was purified over silica gel using a 12 g RediSep silica gel cartridge eluting the column with a 30%-100% EtOAc/hexanes gradient to give 1-[3-(6-tert-Butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-(pyridin-2-ylamino)-1H-pyrazole-4-carbonitrile (15 mg, 51%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:36])[N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[O:34][CH3:35])[C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:37][CH3:38])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:45](Br)[CH:46]=[CH2:47]>CN(C)C=O.O.C(OCC)(=O)C>[CH2:47]([N:11]1[C:10]2[CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:20]3[C:21](=[O:36])[N:22]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])[C:23](=[O:24])[C:19]=3[C:18]=2[C:17]2[CH:16]=[C:15]([O:37][CH3:38])[CH:14]=[CH:13][C:12]1=2)[CH:46]=[CH2:45]
Reactant: C=CCBr
Reactant: COc1ccc(CN2C(=O)c3c(-c4ccccc4Cl)cc4[nH]c5ccc(OC)cc5c4c3C2=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c2ccc(OC)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)N(Cc1ccc(OC)cc1OC)C3=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
To a solution of carbazole (287) (150 mg, 0.28 mmol) prepared as described in example 297 in dimethylformamide (10 mL) under nitrogen was added potassium carbonate (0.39 g, 2.80 mmol) and allyl bromide (720L, 0.84 mmol). The resulting suspension was warmed to 90° C. with stirring for 3 hours before being diluted with water and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (1:2), followed by crystallization from diethyl ether/hexane gave carbazole (288) (90 mg, 57%) as a yellow powder, mp 171–173° C. 1H NMR δ [(CD3)2SO] 8.51 (d, J=2.6 Hz, 1H), 7.84 (s, 1H), 7.67 (d, J=8.9 Hz, 1H), 7.58 (m, 1H), 7.53–7.46 (m, 3H), 7.32 (dd, J=8.9, 2.6 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 6.45 (dd, J=8.4, 2.4 Hz, 1H), 5.99 (m, 1H), 5.18 (d, J=4.9 Hz, 2H), 5.14 (dd, J=10.3, 1.3 Hz, 1H), 4.99 (dd, J=17.2, 1.3 Hz, 1H), 4.69 (s, 2H), 3.90 (s, 3H), 3.80 (s, 3H), 3.72 (s, 3H). Found: C, 69.97; H, 4.75; N, 5.12. C33H27ClN2O5 requires: C, 69.90; H, 4.80; N, 4.94.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].O1C[CH2:26][CH2:25][CH2:24]1.C(Br)C=C>CN1CCCN(C)C1=O.O>[CH2:26]([NH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1)[CH:25]=[CH2:24]
Reactant: CCOC(=O)c1cn(C)nc1N
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C=CCBr
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: C=CCNc1nn(C)cc1C(=O)OCC
Temperature: -40 °C
Reaction time: 0.13 h
Yield: 34 %

Procedure:
Ethyl 3-amino-1-methylpyrazole-4-carboxylate, prepared by the method of Schmidt et al., Helvetica Chim. Acta. 42 349 (1959), (12.5 g, 7.40 mmol) was dissolved in 80 mL of 1,3-dimethyl-3,4,5,6-tetrahydro2(1H)-pyrimidinone (DMPU) and cooled to -40° C. A 1M solution of sodium hexamethyldisilazide in tetrahydrofuran (80 mL, 8.0 mmol) was added dropwise. After 8 minutes at -35° C., the reaction was cooled to -40° C. and 13.16 g (10.8 mmol) of allyl bromide was added dropwise. The reaction mixture was allowed to warm to 10° C. over 90 minutes. Water was added and the mixture was extracted with ether. The combined organic extracts were washed with water (3×), dried over sodium sulfate and concentrated in vacuo to afford a mixture of mono- and di-allyl products plus 10% unreacted starting material. Separation by column chromatography on silica gel eluting with 30% ethyl acetate in hexane afforded 5.26 g (34%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]3[NH:19][C:18]4[CH:20]=[CH:21][C:22](I)=[CH:23][C:17]=4[S:16](=[O:26])(=[O:25])[N:15]=3)=[C:10]([OH:27])[C:9]3=[CH:28][CH:29]=[CH:30][N:8]23)=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N(CC(O)=O)C.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49]>CN(C)C=O.C(OCC)(=O)C.[Cu]I.C(OCC)C.CO>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[CH:23][C:17]=4[S:16](=[O:26])(=[O:25])[N:15]=3)=[C:10]([OH:27])[C:9]3=[CH:28][CH:29]=[CH:30][N:8]23)=[CH:4][CH:3]=1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn2n1Cc1ccc(F)cc1
Reactant: CS(N)(=O)=O
Agent: [Cu]I
Agent: CNCC(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCOCC
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccn3n(Cc3ccc(F)cc3)c1=O)N2
Temperature: 100 °C
Yield: 46.2 %

Procedure:
1-(4-Fluoro-benzyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-pyrrolo[1,2-b]pyridazin-2-one (Example 9b, 0.257 g, 0.455 mmol), potassium phosphate (tribasic) (0.483 g, 2.28 mmol), copper(I) iodide (0.022 g, 0.11 mmol), sarcosine (0.024 g, 0.273 mmol, and methanesulfonamide (0.433 g, 4.55 mmol) were dissolved in N,N-dimethylformamide (9 mL) at 25° C. The mixture was heated to 100° C. for 6 h, then was allowed to cool to 25° C., diluted with ethyl acetate (10 mL), and filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm, 0→10% methanol in dichloromethane) to afford a yellow solid. Sequential trituration of this material with methanol and diethyl ether afforded the desired product, N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.113 g, 0.21 mmol, 47% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.08 (3H, s), 5.65 (2H, s), 6.59-6.61 (1H, m), 7.01-7.02 (1H, m), 7.14-7.18 (2H, m), 7.42-7.46 (2H, m), 7.54 (1H, dd, J1=2.3 Hz, J2=8.6 Hz), 7.62 (1H, d, J=2.5 Hz), 7.66 (1H, d, J=8.9 Hz), 7.71 (1H, s), 10.21 (1H, s), 13.66 (1H, s). LC-MS (ESI) calcd for C22H18FN5O6S2 531.07, found 532.10 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:38])[C:7]=1[C:8]1[C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]=[C:26]([C:31]([O:33]C)=[O:32])[CH:25]=[CH:24]4)=[CH:17][CH:16]=2)=[C:11]([CH:35]([CH3:37])[CH3:36])[O:10][N:9]=1.CO.[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:38])[C:7]=1[C:8]1[C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]=[C:26]([C:31]([OH:33])=[O:32])[CH:25]=[CH:24]4)=[CH:17][CH:16]=2)=[C:11]([CH:35]([CH3:36])[CH3:37])[O:10][N:9]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1onc(-c2c(Cl)cncc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 100 °C

Procedure:
A solution of methyl 6-[4-({[3-(3,5-dichloro-4-pyridinyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (98 mg, 0.18 mmol) in THF (1.8 mL) was placed in a microwave reaction tube. Methanol (0.9 mL) was added followed by 1.0 N sodium hydroxide (0.27 mL, 0.27 mmol) before the tube was sealed and heated at 100° C. for 600 seconds. The solution was neutralized with 1 N HCl. The resulting mixture was partitioned between brine and ethyl acetate. The organic layer was separated and concentrated to yield 6-[4-({[3-(3,5-dichloro-4-pyridinyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid as a yellow powder (0.08 g, 80% as 0.25 ethyl acetate). 1H NMR (400 MHz, DMSO-d6): δ 13.37 (br s, approximately 1H), 8.81 (s, approximately 2H), 8.53 (d, J=9 Hz, 1H), 8.27 (s, 1H), 8.17-8.08 (m, 3H), 7.73 (d, J=9 Hz, 2H), 6.89 (d, J=9 Hz, 2H), 4.97 (s, 2H), 3.49 (septet, J=7 Hz, 1H), 1.34 (d, J=7 Hz, 6H). HRMS C28H21N3O4Cl2 m/z 534.0982 (M+H)+Cal; 534.0981 (M+H)+Obs.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]=[O:17].[OH-].[Na+]>C(O)C>[OH:17][CH2:16][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1
Reactant: c1ccc(-c2n[nH]c3ccccc23)cc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCn1nc(-c2ccccc2)c2ccccc21
Yield: 77.6 %

Procedure:
3-Phenylindazole (9.71 g), paraformaldehyde (2.25 g) and 5% aqueous sodium hydroxide solution (1 ml) were added to ethanol (40 ml) and the mixture was heated under reflux for 3 hours. After cooling the reaction mixture, the precipitated crystals were recovered by filtration to obtain 8.7 g of 1-hydroxymethyl-3-phenylindazole having a melting point between 103°-105° C after recrystallization from ligroine.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH2:4]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:36]>>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH2:4][Cl:36]
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2ccccc2)cc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(-c2ccccc2)cc1CCl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
500 mg (2.52 mmol) of 2-methyl-5-phenylbenzyl alcohol (produced in the same manner as in Reference Production Example 1 (4)) was dissolved in 2 ml of carbon tetrachloride, and to this solution was added 1.0 g (3.28 mmol) of triphenylphosphine under nitrogen atmosphere. The reaction mixture was stirred for 1.5 hours under reflux with heating, cooled to room temperature, then, concentrated. The residue was subjected to silica gel column chromatography (eluant: hexane/ethyl acetate=10/1 (v/v)), to obtain 508 mg of 2-methyl-5-phenylbenzyl chloride.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:13]([CH2:14][CH3:15])[NH:12][C:11](=[O:16])[CH2:10]1)(C(C)(C)C)(C)C.I[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([O:26][CH3:27])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.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>[CH2:14]([C@H:13]1[C@@H:9]([OH:8])[CH2:10][C:11](=[O:16])[N:12]1[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([O:26][CH3:27])[CH:19]=1)[CH3:15]
Reactant: CC[C@@H]1NC(=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: COc1cc(I)ccc1C#N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
A solution of (4S,5S)-4-(tert-butyldimethylsilyloxy)-5-ethylpyrrolidin-2-one (340 m), 4-iodo-2-methoxybenzonitrile (434 mg), cesium carbonate (683 mg), tris(dibenzylideneacetone)dipalladium(0) (64.0 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (121 mg) in dioxane (10 mL) was stirred at 80° C. for 6.5 hr under an argon atmosphere. After allowing to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=99:1→1:1). The obtained residue was dissolved in ethanol (10 mL)-tetrahydrofuran (10 mL), 6 mol/L hydrochloric acid (4.66 mL) was added, and the mixture was stirred overnight at room temperature. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=9:1→1:9), and recrystallized from tetrahydrofuran-hexane to give the title compound as colorless crystals (yield: 115 mg, 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH2:12][N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=O)[C:10](=[O:21])[CH:9]=2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:60][C:61]1([CH3:73])[O:65][C@H:64]([CH2:66][N:67]2[CH:71]=[CH:70][C:69]([NH2:72])=[N:68]2)[CH2:63][O:62]1>CN(C)C=O.C(OCC)(=O)C>[CH3:60][C:61]1([CH3:73])[O:65][C@H:64]([CH2:66][N:67]2[CH:71]=[CH:70][C:69]([NH:72][C:14](=[O:16])[C@@H:13]([N:11]3[CH2:12][C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=4)=[CH:9][C:10]3=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:68]2)[CH2:63][O:62]1
Reactant: COc1ccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)cc1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
A solution of (S)-2-[4-(4-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.36 g, 1.14 mmol) in N,N-dimethylformamide (4.41 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.57 mL, 3.44 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.76 g, 1.72 mmol) and a solution of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.24 g, 1.26 mmol) in N,N-dimethylformamide (0.5 mL). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (50 mL) and was washed with a saturated aqueous ammonium chloride solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 50-100% ethyl acetate/hexanes) afforded (S)-2-[4-(4-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.38 g, 68%) as a white solid: HR-ES-MS m/z calculated for C26H34N4O6 [M+H]+ 499.2551, observed 499.2551; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.45 (br. s., 1H), 1.50-1.63 (m, 1H), 1.63-1.82 (m, 1H), 3.67-3.76 (m, 1H), 3.77 (s, 3H), 4.00 (dd, J=8.5, 6.3 Hz, 1H), 4.05-4.22 (m, 3H), 4.28-4.41 (m, 1H), 4.53 (d, J=18.1 Hz, 1H), 4.75 (s, 1H), 4.88 (dd, J=10.7, 4.7 Hz, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.00 (d, J=8.9 Hz, 2H), 7.23 (d, J=8.9 Hz, 2H), 7.60 (d, J=2.1 Hz, 1H), 10.78 (s, 1H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:19])=[N+]=[N-]>CO.[H][H]>[NH2:1][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:19]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Reactant: [H][H]
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O

Procedure:
The thus-obtained 5′-azido-5′-deoxythymidine was then dissolved in methanol and reduced with hydrogen using 10% palladium/carbon as a catalyst, whereby 5′-amino-5′-deoxythymidine was obtained. Yield 1.734 g, 71.6%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:2]1([S:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1ccccc1
Reactant: Ic1ccccc1
Product: c1ccc(Sc2ccccc2)cc1

Procedure:
The general procedure was used to convert iodobenzene and thiophenol to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (360 mg, 98% yield). 1H NMR (300 MHz, CDCl3) δ 7.48–7.44 (m, 4H; Ha, Ha′, Hd, Hd′), 7.42–7.39 (m, 4H; Hb, Hb′, He, He′), 7.37–7.31 (m, 2H; Hc, Hc′). 13C NMR (75 MHz, CDCl3) δ 135.70 (C1), 130.94 (C2), 129.10 (C3), 126.94 (C4). Anal. Calcd. for C12H10S: C, 77.37; H, 5.41; S, 17.21; Found C, 77.50; H, 5.45; S, 17.00.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[H-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH2:14]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(ccn2Cc2ccccc2)c1
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
5-Cyanoindole (1.0 g, 7.0 mmol) was dissolved in N,N-dimethylformamide (14 mL) and cooled in an ice-water bath. Sodium hydride (0.31 g, 60%, 7.8 mmol) was added, and the resulting suspension was stirred for 30 min. Benzyl chloride (0.85 mL, 0.94 g, 7.4 mmol) was added, and the cooling was discontinued. The stirring was continued for 65 hours at room temperature. Water (150 mL) was added, and the mixture was extracted with ethyl acetate (3×25 mL). The combined organic phases were washed with brine (30 mL) and dried with sodium sulfate (1 hour). Filtration and concentration yielded the crude material. Purification by flash chromatography on silica gel eluting with ethyl acetate/heptanes=1:3 afforded 1.60 g 1-benzyl-1H-indole-5-carbonitrile.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([Cl:14])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:15][S:16][CH2:17][CH:18]([NH2:20])[CH3:19]>C1(C)C=CC=CC=1>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:20][CH:18]([CH3:19])[CH2:17][S:16][CH3:15])[N:7]=2)[CH:13]=[CH:12][N:11]=1
Reactant: CSCC(C)N
Reactant: Clc1cc(-c2ccnc(Cl)n2)ccn1
Solvent: Cc1ccccc1
Product: CSCC(C)Nc1nccc(-c2ccnc(Cl)c2)n1
Temperature: 60 °C
Yield: 88 %

Procedure:
To a solution of 2-chloro-4-(2-chloro-4-pyridinyl)pyrimidine (i.e., the product of Example 6, Step A) (350 mg, 1.5 mmol) in toluene (4.0 mL) was added 1-(methylthio)-2-propanamine (i.e., the product of Step B) (1 mL, 9.5 mmol) in one portion; this mixture was heated at 60° C. for 18 h. The mixture was allowed to cool and silica gel (300 mg) was added. The excess solvent was removed under reduced pressure, and the resulting solid was chromatographed on silica gel eluted with a solvent gradient of 5% to 60% ethyl acetate in hexanes to give 400 mg (88%) of the title compound as a tan solid, m.p. 103-106° C.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[Si](C(C)(C)C)(C)C.[O:17]1C=C(C2C=CC(OCCN)=CC=2)N=C1.C(N(C(C)C)CC)(C)C.O>CS(C)=O.C(Cl)(Cl)Cl.CO.ClCCl>[Br:1][CH2:2][C@@H:3]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[OH:17]
Reactant: NCCOc1ccc(-c2cocn2)cc1
Reactant: CC(C)(C)[Si](C)(C)[C@@H](CBr)c1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: O[C@@H](CBr)c1cccnc1
Temperature: 90 °C
Yield: 121.9 %

Procedure:
A stirred mixture of 1.24 g (3.91 mmol) of (R)-3-(2-bromo-1-(tert-butyl-dimethyl-silanyl)-ethyl)-pyridine, 1.6 g (7.83 mmol) of 2-(4-oxazol-4-yl-phenoxy)-ethylamine, and 1.4 ml (7.83 mmol) of diisopropylethylamine in 20 ml of dry dimethylsulfoxide was heated at about 90° C. for about 18 hours. The mixture was poured into 400 ml of water and extracted with ethyl acetate (2×400 ml). The organic extracts were combined, washed successively with water (2×100 ml) and brine (1×100 ml), dried over magnesium sulfate, and concentrated in vacuo to furnish an oil. Chromatography on silica gel eluting with methanol:dichloromethane (1:19, v/v) yielded 963 mg (56% yield) of the title compound as an amber-colored oil, αD=−45.7° (c=0.49, chloroform).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([NH2:20])=O)[CH2:13]1>S(Cl)(Cl)=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]#[N:20])[CH2:13]1
Reactant: NC(=O)C1CCCN(CC2COc3ccccc3O2)C1
Solvent: O=S(Cl)Cl
Product: N#CC1CCCN(CC2COc3ccccc3O2)C1

Procedure:
Thionyl chloride (20 ml) was added under cooling to 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidine-3-carboxylic acid amide (2.34 g, 8.46 mmol). The reaction mixture was refluxed for 3 h. Excess of thionyl chloride was evaporated. Water was slowly added to the residue, the mixture was made alkaline with aq NaOH and extracted with DCM (3×5 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (DCM/MeOH, 90:10).