Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[BrH:20]>O.C(O)C>[Br:20][C:6]1[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: Br
Reactant: COC(=O)c1cc(N)cc2ccccc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(Br)cc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4.34 g (62.9 mmol) of sodium nitrite in 40 mL of water was added dropwise to a 0° C. solution of 11.5 g (57.2 mmol) of methyl 3-amino-1-naphthoate in 300 mL of ethanol and 60 mL of 48% aqueous hydrobromic acid while maintaining an internal reaction temperature below 10° C. After complete addition of the aqueous solution the resulting dark red reaction mixture was stirred at 0° C. for an additional 30 min. The cooled (0° C.) reaction mixture was then added over 20 min. to a suspension of 8.21 g (57.2 mmol) of cuprous bromide in 60 mL of ethanol and 60 mL of 48% aqueous hydrobromic acid heated to 95° C. After stirring for 30 min. the reaction mixture was cooled to 0° C. and carefully partitioned between ethyl ether (250 mL) and water (600 mL). The organic layer was separated and the aqueous layer was extracted with ethyl ether (2×300 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was passed through a plug of silica gel eluting with 30% dichloromethane in hexanes and the filtrate concentrated in vacuo. Flash chromatography on a Biotage® purification apparatus (silica gel, 7% dichloromethane/hexanes) yielded the title compound as a colorless solid. 1H NMR (DMSO-d6): δ 8.67 (d, J=8.4 Hz, 1 H), 8.50 (s, 1 H), 8.15 (s, 1 H), 8.02 (d, J=8.0 Hz, 1 H), 7.68-7.71 (m, 1 H), 7.63-7.66 (t, J=7.6 Hz, 1 H), 3.94 (s, 3H). LC/MS 265.0 (M+1) and 267.0 (M+3).
Reaction SMILES: [OH:1][C:2]12[CH2:6][C:4]([NH:7][C:8](=[O:10])[CH3:9])([CH2:5]1)[CH2:3]2.[CH3:11][C:12]([O:14][C:15]1[C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13]>>[C:12]([O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=1[C:21]([O:1][C:2]12[CH2:6][C:4]([NH:7][C:8](=[O:10])[CH3:9])([CH2:5]1)[CH2:3]2)=[O:22])(=[O:13])[CH3:11]
Reactant: CC(=O)NC12CC(O)(C1)C2
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Product: CC(=O)NC12CC(OC(=O)c3ccccc3OC(C)=O)(C1)C2

Procedure:
The general procedure of Example 1 Step 3 is repeated starting with N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1) and using O-acetylsalicyloyl chloride in place of the acetyl chloride to produce compound 8.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:34]1([CH2:39][N:40]2[C:45](=[O:46])[C:44]([CH2:47]OS(C)(=O)=O)=[CH:43][C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.CN1CCNCC1>>[CH:34]1([CH2:39][N:40]2[C:45](=[O:46])[C:44]([CH2:47][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[CH:43][C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CCCC3)n2)cc1F
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC3CCCC3)n2)cc1F
Yield: 61.4 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 61.4%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:12](=[O:14])[CH:13]=[CH:17][N:18]([CH3:20])[CH3:19])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ncc(C(F)(F)F)cc1Cl
Solvent: Cc1ccccc1
Product: CN(C)C=CC(=O)c1ncc(C(F)(F)F)cc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
5.0 g of 3-chloro-5-trifluoromethyl-2-acetylpyridine (Example P8) are introduced into 30 ml of toluene and 3.60 ml of N,N-dimethylformamide-dimethylacetal are added. The resulting yellow solution is stirred overnight at 100° C. After cooling to 25° C., the mixture is concentrated to dryness in vacuo, yielding 6.17 g of the desired target compound in the form of a dark-yellow oil which later solidifies.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:24][C@@H:25]2[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]2[F:31])=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:24][C@@H:25]2[CH2:30][CH2:29][N:28]([CH3:34])[CH2:27][C@H:26]2[F:31])=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(O[C@@H]2CCNC[C@H]2F)cc1-c1ccc(OC2CCCCC2)cc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nnc(O[C@@H]2CCN(C)C[C@H]2F)cc1-c1ccc(OC2CCCCC2)cc1

Procedure:
To a stirred solution of (±)-trans-3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(3-fluoro-piperidin-4-yloxy)-pyridazine (20 mg, 0.047 mmol) in DCM (4 mL) was added 37% aqueous formaldehyde (0.1 mL, 1 mmol) and sodium triacetoxyborohydride (106 mg, 0.5 mmol). After 2 hrs the mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM. The organics were dried over sodium sulfate, filtered, concentrated, and purified by column chromatography using 2-5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to give (±)-trans-3-Butyl-4-(4-cyclohexyloxy-phenyl)-6-(3-fluoro-1-methyl-piperidin-4-yloxy)-pyridazine. The free base was dissolved in DCM, treated with 4.0 M HCl in dioxane and concentrated. The resultant salt was washed with ether and dried to provide the title compound (20 mg). LCMS: m/z 443 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.93 (1H, s), 7.51 (2H, d), 7.14 (2H, d), 5.54-5.60 (1H, m), 5.29 (1H, d), 4.41-4.50 (1H, m), 3.64-3.94 (2H, m), 3.46-3.53 (2H, m), 3.14-3.21 (2H, m), 3.00 (3H, t), 2.40-2.50 (2H, m) 1.96-2.05 (2H, m), 1.77-1.86 (2H, m), 1.23-1.66 (10H, m), 0.82 (3H, t).
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[N:34]1[C:49]2[N:48]=[C:47]([Cl:50])[N:46]=[C:38]([NH:39][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[C:37]=2[N:36]=[CH:35]1)(=O)C1C=CC=CC=1>N>[Cl:50][C:47]1[N:46]=[C:38]([NH:39][N:40]2[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]2)[C:37]2[N:36]=[CH:35][N:34]([C:49]=2[N:48]=1)[C@@H:11]1[O:12][C@H:13]([CH2:24][OH:25])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
The above 2',3',5'-tri-O-benzoyl-2-chloro-N-(1-piperidinyl)adenosine (19.2 g, 27.5 mmol) was dissolved in methanolic ammonia (150 ml) (previously saturated at -10° C.) and stirred at room temperature for 18 hours. The precipitated benzamide was removed by filtration, and the filtrate was evaporated to a fawn oil, which was triturated with diethyl ether to provide the title compound (6.0 g, 57%) as a white foam, 1H NMR (400 MHz, Me2SO-d6) δ 3.55 (1H, m, H-5'a), 3.66 (1H, m, H-5'b), 3.94 (1H, q, H-4'), 4.12 (1H, m, H-3'), 4.50 (1H, q, H-2'), 5.82 (1H, d, H-1'), 8.40 (1H, s, H-8); HPLC retention time 26.57 (gradient elution, 5-25% acetonitrile/0.1M pH 3.3 ammonium sulphate buffer: 214 nm detector); purity 99%.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C[N:20](C=O)C>ClCCl>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH2:20])=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)COc1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of (4-bromophenoxy)acetic acid (500 mg, 2.00 mmol) in dichloromethane (10 mL) and DMF (0.2 mL) was added 2 M oxalyl choride in methylene chloride (5 mL, 10 mmol). The reaction mixture was stirred at room temperature for 2 hours, and the solvent was removed under reduced pressure. Ammonium hydroxide (15 mL) was added dropwise via additional funnel. After addition, the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried and concentrated in vacuo to give 2-(4-bromophenoxy)acetamide (350 mg, 70% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.37-7.35 (m, 2 H), 6.81-6.79 (m, 2 H), 4.59 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[O:10][C:9]2[C:4](=[N:5][C:6]([CH3:11])=[CH:7][CH:8]=2)[C:3]=1[Cl:12].[Br:13]N1C(=O)CCC1=O.[C:21]1([P:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)(Cl)Cl.CC#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br-:13].[Cl:1][C:2]1[O:10][C:9]2[C:4](=[N:5][C:6]([CH2:11][P+:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:7][CH:8]=2)[C:3]=1[Cl:12]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc2oc(Cl)c(Cl)c2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1oc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2c1Cl
Product: [Br-]
Yield: 74.5 %

Procedure:
To a solution of 2,3-dichloro-5-methylfurano[3,2-b]pyridine (0.5 g, 2.47 mmol) in CCl4 (15 mL) was added N-bromosuccinimide (0.44 g, 2.47 mmol) and benzoyl peroxide (2 mg). The mixture was stirred and photolyzed using a sun lamp for 1 hr. The resulting mixture was cooled and filtered through celite. Evaporation of the filtrate gave an oil which was then dissolved in CH3CN (10 mL). Triphenylphosphine (1.29 g, 4.94 mmol) was added and the mixture was stirred at r.t. for 20 hr. The solvent was removed and the residue was triturated with ether to afford 1 g (77%) of the title compound after filtration.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[N+:36]([O-:38])=[O:37])[CH:31]=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([CH:31]([C:30]2[CH:33]=[CH:34][C:35]([N+:36]([O-:38])=[O:37])=[C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:29]=2)[OH:32])=[CH:13][CH:12]=[N:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCn2cccn2)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C(O)c2ccnn2COCc2ccccc2)cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-benzyloxymethyl-1H-pyrazole (Example 279, step A) (278 mg, 1.48 mmol) in THF (4 mL) at −78° C. is added n-BuLi (2.5 M in hexanes, 0.60 mL, 1.5 mmol) dropwise. The mixture is stirred at −78° C. for 20 min then a solution of 3-benzyloxy-4-nitrobenzaldehyde (Example 83, step A) (315 mg, 1.23 mmol) in THF (4 mL) is added dropwise. The mixture is stirred at −78° C. for 30 min and then is partitioned between EtOAc and aq. NH4Cl. The organic phase is dried over MgSO4 and concentrated. The crude material is chromatographed to afford the title compound as a light brown oil: (M+1)+=446, (M+HCO2−)=490.
Reaction SMILES: [F-:1].[K+].[N+:3]([C:6]1[CH:19]=[CH:18][CH:17]=[C:16]([N+]([O-])=O)[C:7]=1[C:8]([NH:10][C@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:9])([O-:5])=[O:4].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[F:1][C:16]1[CH:17]=[CH:18][CH:19]=[C:6]([N+:3]([O-:5])=[O:4])[C:7]=1[C:8]([NH:10][C@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:9]
Reactant: [F-]
Reactant: C[C@@H](NC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-])C(=O)O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](NC(=O)c1c(F)cccc1[N+](=O)[O-])C(=O)O
Temperature: 175 °C
Reaction time: 0.75 h
Yield: 64.3 %

Procedure:
A mixture of spray-dried KF (1.02 g, 17.6 mmol), intermediate 14 (500 mg, 1.76 mmol) and catalytic amount of 18-crown-6 in dry DMSO (10 mL) was stirred at 170-180° C. for 45 min. Work-up of the reaction mixture as described in example 1 gave the product as a pale brown color solid (290 mg, 64%), mp 158-160° C. 1H NMR (400 MHz, DMSO-d6): δ 12.72 (1H, br s), 9.10 (1H, d, J=7.2 Hz), 8.01 (1H, d, J=7.2 Hz), 7.70-7.78 (2H, m), 4.46 (1H, pentet, J=7.0 Hz), 1.34 (3H, d, J=7.2 Hz); LC-MS (positive ion mode): m/z 279 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[N:28]=[CH:27][N:26](C3CCCCO3)[N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1.[NH2:35][CH2:36][CH2:37][NH:38][C:39](OC(C)(C)C)=O.C(Cl)Cl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.FC(F)(F)C(O)=O>>[CH3:39][N:38]([CH2:10][C:7]1[CH:8]=[CH:9][C:4]2[N:5]([C:12]([C:13]3[S:14][C:15]([C:24]4[NH:28][CH:27]=[N:26][N:25]=4)=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=3)=[C:2]([CH3:1])[N:3]=2)[CH:6]=1)[CH2:37][CH2:36][NH2:35]
Reactant: Cc1nc2ccc(C=O)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2ccc(CN(C)CCN)cn2c1-c1nc(-c2ccccc2)c(-c2nnc[nH]2)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 14.1 %

Procedure:
The mixture of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine-6-carbaldehyde (0.0300 g, 0.0638 mmol) and N-(2-aminoethyl)(tert-butoxy)carboxamide (15.3 mg, 0.0956 mmol) in dry Methylene chloride (2.0 mL, 31 mmol) and Acetic acid (50 mg, 0.8 mmol) was stirred at r.t. for 20 min. Sodium triacetoxyborohydride (23.3 mg, 0.110 mmol) was added and the mixture was stirred at r.t. for 21 hours. Paraformaldehyde (25 mg, 0.28 mmol) was added, followed by Acetic acid (100 mg, 2 mmol). The mixture was stirred at r.t. for 10 min. Sodium triacetoxyborohydride (172 mg, 0.812 mmol) was added and the mixture was stirred at r.t. for 17 hours. The mixture was quenched with saturated NaHCO3, extracted with DCM. The DCM solution was washed with water, brine, dried over Na2SO4, filtered. The filtrate was chromatographed in a 24 g ISCO column using MeOH/DCM (0/100 to 5/95) to give a solid. LCMS: (FA) ES+ 629. This solid was treated with Trifluoroacetic Acid (1.0 mL, 13 mmol) in Methylene chloride (1.0 mL, 16 mmol) at r.t. for 18 hours. The mixture was rotavaped, azeotroped with DCM. The residue was triturated with Et2O and decanted to give a solid residue, dried in hi-vac to give 30 mg of crude product. HPLC purification gave a solid product (0.0040 g, 13.8% yield). LCMS: (FA) ES+ 445, ES− 443. 1H NMR (400 MHz, d4-methanol) δ 9.88 (s, 1H), 8.47 (s, 1H), 7.78-7.81 (m, 2H), 7.61 (s, 2H), 7.41-7.43 (m, 3H), 3.68 (s, 2H), 3.00-3.03 (m, 2H), 2.75 (s, 3H), 2.66-2.69 (m, 2H), 2.32 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[O:25][C:26]=1[CH3:27].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[O:25][C:26]=1[CH3:27])[CH3:2]
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCl
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2ccccc2Cl)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-2-(2-chloro-phenyl)-5-methyl-oxazole in N,N-dimethylformamide in the presence of sodium hydride to yield rac-3-{1-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-2-ethoxy-propionic acid ethyl ester, which was subsequently saponified to yield rac-3-{1-[2- (2-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-2-ethoxy-propionic acid as light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][NH2:12])[CH:5]=1.COC(=O)C1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][NH:12][S:25]([CH3:24])(=[O:27])=[O:26])[CH:5]=1
Reactant: COC(=O)c1cccc(CCN)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: COC(=O)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CCNS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
To a solution of 3-(2-amino-ethyl)-benzoic acid methyl ester (500 mg) in CH2Cl2 (35 mL) at 0° C. was added amino-ethyl)-benzoic acid methyl ester (500 mg) in CH2Cl2 (35 mL) at 0° C. was added methanesulfonyl chloride (292 mg, 2.55 mmol) and triethylamine (1.6 mL, 11.5 mmol). The reaction was stirred at room temperature for 18 h and was washed consecutively with 5.5% HCl, water, saturated NaHCO3, and brine. The organic solution was dried over MgSO4, filtered, and concentrated to yield the title compound (522 mg) as a white solid. MS 275 (M+18).
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C@@H:10]([O:15][CH2:16][C:17]2[C:18](=[O:32])[NH:19][C:20](=[O:31])[N:21]([CH:30]=2)[C@@H:22]2[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24]([OH:25])[CH2:23]2)[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:33]([O-:35])=[O:34])[CH:3]=1.[CH2:36]([N-:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])[C:37]#[CH:38].CCN(CC)CC>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:9][O:8][C:7]1[C:2]([C:38]#[C:37][CH2:36][NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])=[CH:3][C:4]([N+:33]([O-:35])=[O:34])=[C:5]([C@@H:10]([O:15][CH2:16][C:17]2[C:18](=[O:32])[NH:19][C:20](=[O:31])[N:21]([CH:30]=2)[C@@H:22]2[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24]([OH:25])[CH2:23]2)[C:11]([CH3:14])([CH3:12])[CH3:13])[CH:6]=1
Reactant: COc1cc([C@@H](OCc2cn([C@H]3C[C@H](O)[C@@H](CO)O3)c(=O)[nH]c2=O)C(C)(C)C)c([N+](=O)[O-])cc1I
Reactant: C#CC[N-]C(=O)C(F)(F)F
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc([C@@H](OCc2cn([C@H]3C[C@H](O)[C@@H](CO)O3)c(=O)[nH]c2=O)C(C)(C)C)c([N+](=O)[O-])cc1C#CCNC(=O)C(F)(F)F
Yield: 91.8 %

Procedure:
A solution of compound 61 (80 mg, 0.13 mmol), N-propargyltrifluoroacetylamide (196 mg, 1.30 mmol), tetrakis(triphenylphosphine)-palladium(0) (30 mg, 0.026 mmol), CuI (9.9 mg, 0.052 mmol), and Et3N (80 μL) in anhydrous DMF (3.0 mL) was stirred at 50° C. for 12 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography to yield 5-{(S)-1-[5-methoxy-4-(3-trifluoroacetamido-1-propynyl)-2-nitrophenyl]-2,2-dimethyl-propyloxy}methyl-2′-deoxyuridine 62 (75 mg, 90%). 1H NMR (400 MHz, MeOD-d4): δ 8.11 (s, 1H, H-6), 8.08 (s, 1H, Ph-H), 7.36 (s, 1H, Ph-H), 6.27 (t, 1H, J=6.4 Hz, H-1′), 5.33 (s, 1H, Ph-CH), 4.47 (m, 1H, H-3′), 4.44 (s, 2H, 5-CH2), 4.32 (d, 2H, J=2.0 Hz, CH2), 4.08 (s, 3H, OCH3), 3.99 (m, 1H, H-4′), 3.87 (m, 1H, H-5′a), 3.79 (m, 1H, H-5′b), 2.30 (m, 2H, H-2), 0.93 (s, 9H, C(CH3)3).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.9 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (220 mg, 1.16 mmol) in THF (2 mL) was added sodium hydride (55% dispersion in mineral oil, 996 mg, 22.8 mmol). After stirring for 0.5 h at ambient temperature 6-chloronicotinonitrile (161 mg, 1.16 mmol) was added and the reaction mixture was stirred for 5 h at ambient temperature. It was diluted with ethyl acetate (10 mL), washed with aqueous citric acid (10%, 10 mL), water (10 mL) and aqueous sodium chloride (saturated, 10 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL). After drying over sodium sulfate and concentration purification by chromatography (SiO2, heptane:ethyl acetate=90:10 to 60:40) afforded the title compound (307 mg, 91%) as a white solid. MS: m/e=292.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=3)=[CH:10][NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>C(O)C>[CH2:30]([N:9]1[CH:10]=[C:11]([C:14]2[CH:15]=[C:16]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:18][CH:19]=2)[C:12](=[O:13])[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:31]
Reactant: O=c1c(-c2cccc(C(F)(F)F)c2)c[nH]n1-c1ccc(F)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCn1cc(-c2cccc(C(F)(F)F)c2)c(=O)n1-c1ccc(F)cc1

Procedure:
A 6 gram portion of 1-(4-fluorophenyl)-4-(α,α,α-trifluoro-3-tolyl)-3-pyrazolin-5-one (prepared according to the teaching outlined above) was mixed with 4 grams potassium carbonate and 15 ml. ethyl iodide in 100 ml. ethanol and refluxed overnight. The desired product was isolated in the usual way, yield 1.8 grams, m.p. approximately 92° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[CH:19]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([CH3:26])[CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:25][C:24]1[CH:19]=[CH:20][C:21]([CH3:26])=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(COc3ccc(C)cc3)c(C)o2)cc1
Yield: 93.7 %

Procedure:
A solution of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (3.1 g, 11.70 mmol, 1.00 equiv), p-cresol (2.0 g, 18.52 mmol, 1.58 equiv), Cs2CO3 (4.5 g, 13.80 mmol, 1.18 equiv) in N,N-dimethylformamide (60 mL) was stirred under nitrogen overnight at 50° C. The resulting solution was diluted with 100 mL of water and extracted with 3×100 mL of ethyl acetate. The combined organic layers was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 3.7 g (94%) of methyl 4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)benzoate as a yellow solid. LC-MS: (ES, m/z): 379 [M+CH3CN+H]+, 338 [M+H]+, 271, 230, 203, 146, 91.