Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.[CH2:6]([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14]>ClCCl>[Si:17]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][OH:12])([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCCCCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCCCCO)(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 41.1 %

Procedure:
Imidazole (0.65 g, 9.60 mmol) was added to a stirring solution of pentan-1,5-diol (1.00 g, 9.60 mmol) in dry dichloromethane (10 mL) at 0° C. under an argon atmosphere followed by the dropwise addition of tert-butylchlorodiphenylsilane (3.85 mL, 9.60 mmol) in CH2Cl2 (2 mL). The reaction was allowed to slowly reach room temperature. After 12 hours, the reaction mixture was washed with water (2×30 mL), brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue which was purified by SiO2 flash chromatography using 30% ethyl acetate/hexane as eluent to furnish 2 (1.35 g, 46%), recovered SM and di-protected compound. TLC: 30% EtOAc/hexanes, Rf˜0.38; 1H NMR (CDCl3, 400 MHz) δ 7.67-7.62 (m, 4H), 7.45-7.35 (m, 6H), 3.67 (t, 2H, J=6.0 Hz), 3.52 (t, 2H, J=6.7 Hz), 2.03-1.93 (m, 2H), 1.72-1.64 (m, 4H), 1.04 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:9]#[N:10])=[C:5]([C:7]#[N:8])[N:6]=1.Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[NH2:1][C:2]1[N:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([C:9]#[N:10])=[C:5]([C:7]#[N:8])[N:6]=1
Reactant: N#Cc1nc(N)[nH]c1C#N
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)n1c(N)nc(C#N)c1C#N

Procedure:
1.33 G OF 2-AMINO-4,5-DICYANOIMIDAZOLE WAS DISSOLVED IN 10 ML OF SUSPENSION OF ACETON CONTAINING 0.7 G OF ANHYDROUS POTASSIUM CARBONATE AND THEN 1.1 G OF ETHYL CHLOROFORMATE WAS ADDED DROPWISE TO THE SOLUTION AT A ROOM TEMPERATURE.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]([CH2:14][OH:15])[CH2:12][CH:11]3[CH:9]2[CH2:10]3)[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:15][CH2:14][CH:13]1[CH2:12][CH:11]2[CH:9]([CH2:10]2)[N:8]1[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CC2CC2N1c1cncc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CC2CC2N1c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To an ice-cold solution of [2-(5-Bromopyridin-3-yl)-2-azabicyclo[3.1.0]hex-3-yl]methanol (462 mg, 2.43 mmol) in dry dichloromethane (10 mL) was added triethylamine (0.51 mL, 3.6 mmol) followed by methanesulfonyl chloride (334 mg, 2.92 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 1 hour. The volatiles were removed under reduced pressure and the crude product was purified by flash column chromatography to obtain title compound of 586 mg as gummy liquid. Yield: 90%.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@@H:43]1[C:49](=[O:50])[N:48]2[CH2:51][CH2:52][CH2:53][CH2:54][C@@H:47]2[CH:46]=[CH:45][CH2:44]1>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:11])[NH:42][C@@H:43]1[C:49](=[O:50])[N:48]2[CH2:51][CH2:52][CH2:53][CH2:54][C@@H:47]2[CH:46]=[CH:45][CH2:44]1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CC=C[C@H]2CCCCN2C1=O
Agent: Cl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CC=C[C@H]4CCCCN4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((7S,10aR,Z)-6-oxo-1,2,3,4,6,7,8,10a-octahydropyrido[1,2-a]azepin-7-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 53 (4.6 mg, 0.021 mmol) to give a white solid (12 mg, 90% yield). Anal. Calcd. for C41H52N4O6S m/z 728.4. found: 729.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.29-7.10 (11H, m), 7.05 (1H, d, J=7.1 Hz), 5.63-5.48 (2H, m), 5.39-5.30 (2H, m), 5.14-5.09 (1H, m), 5.04-4.96 (1H, m), 4.80-4.71 (1H, m), 4.02-3.93 (1H, m), 3.68 (3H, s), 3.21-3.10 (1H, m), 3.05-2.94 (1H, m), 2.87-2.69 (6H, m), 2.50-2.36 (3H, m), 2.31-2.18 (1H, m), 2.07-1.99 (2H, m), 1.89-1.45 (15H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:12]1[C:11]([C:15]#[N:16])=[CH:10][C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: CSc1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1ccc(-c2cc(C#N)c(Cl)nc2-c2ccc(F)cc2)cc1

Procedure:
A solution of 6-(4-fluorophenyl)-1,2-dihydro-5-[4-(methylthio)phenyl]-2-oxo-pyridine-3-carbonitrile (Example 1, Step 5) (3.7 g, 0.011 mole) in phosphorus oxychloride (45 ml) was stirred at 100° C. for 20 hours. After evaporation of the phosphorus oxychloride the residue was purified by silica gel chromatography and recrystallized from ethyl acetate-hexane.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CC(O)=O.[C:18]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C:26]1=O)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:12][C:10]1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([CH3:13])=[C:2]([NH:1][CH:28]2[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 23 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (1.40 g, 7.04 mmol) in CH2Cl2 (30 mL) and AcOH (2.50 g, 42.2 mmol) was added N-Boc piperidinone (1.96 g, 9.85 mmol) and sodium triacetoxyborohydride (4.40 g, 21.1 mmol). The reaction mixture was stirred at 23° C. for 18 hours and then saturated NaHCO3 was added and the mixture was separated. The aqueous layer was extracted with CH2Cl2 (3×20 mL) and the combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO2 heptane/ethylacetate=10/1 to 1/1) to give the titled compound as oil (2.40 g, 89% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.09 (s, 1H), 6.69 (s, 1H), 4.05 (m, 2H), 3.88 (s, 3H), 3.63 (m, 1H), 3.42 (m, 1H), 2.97 (m, 2H), 2.23 (s, 3H), 2.05 (m, 2H), 1.45 (s, 9H), 1.27 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4[CH:24]=[CH:25][O:26][C:20]=4[CH2:19]3)=[O:17])=[CH:11][C:10]=2[S:9](=[O:28])(=[O:27])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:29][NH:30][CH3:31].[CH2:32]=O>C(O)(=O)C>[CH3:29][N:30]([CH2:32][C:25]1[O:26][C:20]2[CH2:19][N:18]([C:16]([C:12]3[CH:13]=[CH:14][C:15]4[C:2](=[O:1])[C:3]5[C:8]([S:9](=[O:28])(=[O:27])[C:10]=4[CH:11]=3)=[CH:7][CH:6]=[CH:5][CH:4]=5)=[O:17])[CH2:23][CH2:22][C:21]=2[CH:24]=1)[CH3:31]
Reactant: O=C1c2ccccc2S(=O)(=O)c2cc(C(=O)N3CCc4ccoc4C3)ccc21
Reactant: C=O
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)c1ccc3c(c1)S(=O)(=O)c1ccccc1C3=O)CC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.240 g (0.610 mmol) of 6-(9,10,10-trioxo-9,10-dihydro-10λ6 -thioxanthene-3-carbonyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 20 ml of acetic acid, 0.083 ml (0.92 mmol) of 50% aqueous dimethylamine and 0.075 ml (0.92 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 60 minutes. Additionally, 0.083 ml (0.92 mmol) of 50% aqueous dimethylamine and 0.075 ml (0.92 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 60 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate, and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform to chloroform/methanol=25/1) to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:5]([C:46]([O:48]CC)=[O:47])=[CH:4][N:3]=1.[OH-].[Na+]>>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26]([C:27]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:5]([C:46]([OH:48])=[O:47])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(C)nc1NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ncc(C(=O)O)c(NCc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)n1

Procedure:
Ethyl 2-methyl-4-{N-[(2'-[N-triphenylmethyl-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine-5-carboxylate was hydrolyzed with sodium hydroxide and neutralized with one equivalent of hyochloric acid to give 2-methyl-4-{N-[(2'-[N-triphenylmethyl-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine-5-carboxylic acid. This compound was treated with thionyl chloride at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained dissolved in methylene chloride and cooled to 0° C. Ammonia was added, and the reaction mixture was stirred at 0° C. for several hours. The solvent was removed under reduced pressure and the residue obtained chromatographed on silica gel. The triphenylmethyl protecting group was removed with aqueous hydrochloric acid in dioxane to give the title compound in high yield. 1H NMR (DMSO-d6, 300 MHz) d 0.85 (t, J=7 Hz, 3H), 1.22 (m, 2H), 1.55 (m, 2H), 2.55 (s, 3H), 3.58 (m, 2 H), 5.00 (s, 2H), 7.08 (d, J=7 Hz, 2H), 7.25 (d, J=7 Hz, 2H), 7.55 (d, J=7 Hz, 1H), 7.59 (d, J=7 Hz, 1H), 7.68 (m, 2H), 8.01 (s, 1H), 8.40 (s, 1H), 8.42 (s, 1H). MS (DCl/NH3) m/e 443 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][NH+:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=O.[Cl-].C1C([C@@H](O)[C@H](N[C:25]([CH:27](Cl)Cl)=[O:26])CO)=CC=C([N+]([O-])=O)C=1.CC(S[C@@H]1[O:43][C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C>>[CH:9]1[CH:10]=[CH:11][C:12]2[NH:6][CH:5]=[C:4]([CH2:2][CH2:1][CH2:27][C:25]([OH:43])=[O:26])[C:7]=2[CH:8]=1
Reactant: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=C(N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1)C(Cl)Cl
Reactant: CC(=O)CC[NH+]1CCCCCC1
Agent: [Cl-]
Product: O=C(O)CCCc1c[nH]c2ccccc12

Procedure:
The expression of the TG-1 F cells on pMORPHx9-FS-coded Fab fragments in E. coli was performed in shaking bottle cultures with 0.75 l of 2×TY medium and 34 μg/ml of chloramphenicol. After induction with 0.75 mmol of IPTG, the cells were cultivated for 16 hours at 30° C. As an alternative, Fab clones, which had been obtained from the second maturation pool 2, were induced with 0.1 mmol of IPTG and then cultivated at 22° C. Periplasmatic extracts from cell pellets were produced by osmotic shock, and the Fab fragments were isolated by Strep-Tactin® chromatography (IBA, Göttingen, Germany). The apparent molecular weights were determined by size-exclusion chromatography (SEC) with calibrating standards. The concentrations were determined by UV spectrometry.
Reaction SMILES: C[C:2]1[CH:26]=[CH:25][C:5]([C:6]([O:8][CH:9]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=S)=[CH:4][CH:3]=1.CC1C=CC([C:32](OC(C2C=CC(F)=CC=2)C(C2C=CN=CC=2)=O)=[S:33])=CC=1.C([O-])(=O)C.[NH4+:57].[NH4+].[OH-]>C(O)(=O)C.O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[N:57]=[C:6]([C:5]3[CH:25]=[CH:26][C:2]([S:33][CH3:32])=[CH:3][CH:4]=3)[O:8][C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:13][CH:14]=1
Reactant: [NH4+]
Reactant: Cc1ccc(C(=S)OC(C(=O)c2ccncc2)c2ccc(F)cc2)cc1
Reactant: Cc1ccc(C(=S)OC(C(=O)c2ccc(F)cc2)c2ccncc2)cc1
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)o2)cc1

Procedure:
To a solution containing a mixture of 2-(4-fluorophenyl)-1-(4-pyridyl)-2-oxoethyl 4-methylthiobenzoate and 1-(4-fluorophenyl)-2-(4-pyridyl)-2-oxoethyl 4 methylthiobenzoate (1.0 g, 2.62 mmol) in glacial acetic acid (50 mL) was added ammonium acetate (2.0 g, 26.2 mmol). The resulting mixture was heated at reflux for 1.5 h, then allowed to cool. The mixture was poured into H2O, neutralized with conc. NH4OH and extracted with CH2Cl2. The combined organic extracts were washed with sat'd NaCl and dried over MgSO4. Purification by column chromatography, eluting with 5:1 to 1:1 Hex/EtOAc afforded the title compound (77.6 mg) as a yellow solid: ESMS (m/z): 363.0 (M++H).
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([OH:24])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12])[CH3:6].Cl[C:27]1[N:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[F:25][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:23]=[C:22]([CH:21]=[C:10]([C:11](=[O:12])[NH:13][C:14]2[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=2)[CH:9]=1)[O:24][C:27]1[N:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=1)[CH3:6]
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)COC(F)F)c2)cn1
Reactant: CN(C)C(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3cnc(C(=O)N(C)C)cn3)cc(O[C@@H](C)COC(F)F)c2)cn1
Temperature: 140 °C
Reaction time: 5 h
Yield: 55.3 %

Procedure:
A mixture of 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide (0.19 g, 0.54 mmol), 5-chloro-N,N-dimethyl-pyrazine-2-carboxamide (100 mg, 0.54 mmol) and potassium carbonate (149 mg, 1.08 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 140° C. for 5 hours and the mixture reduced in vacuo. Ethyl acetate (50 mL) was added and the mixture washed with water (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo. The crude residue was chromatographed on silica, eluting with 0-5% methanol in DCM, to give the desired compound (150 mg).
Reaction SMILES: [CH:1]([OH:5])(O)[CH2:2][CH3:3].[H-].[Na+].Br[CH2:9][C:10]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[OH2:24]>CN(C=O)C>[OH:24][CH2:3][CH2:2][CH2:1][O:5][CH2:9][C:10]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CCC(O)O
Reactant: O
Reactant: Cc1cccc(CBr)c1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(COCCCO)c1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
25.5 ml of propane diol are slowly added dropwise at RT to a suspension of 3.37 g of sodium hydride (60% by weight in mineral oil) in 400 ml of DMF. After gas evolution ceases, 20 g of tert-butyl 2-bromomethyl-6-methylbenzoate are added, and the solution is stirred at RT for 72 h. Water is added and the solution is extracted twice with MTBE, and the org. phases are combined, washed with water and sat. NaCl solution, dried over MgSO4 and concentrated. The residue is chromatographed on silica gel with a heptane/ethyl acetate gradient, resulting in 16 g of tert-butyl 2-(3-hydroxypropoxymethyl)-6-methylbenzoate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].C([NH2:15])=O>O>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([NH:15][C:8](=[O:7])[C:3]=12)=[O:6]
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Reactant: NC=O
Solvent: O
Product: O=C1NC(=O)c2c(Cl)cccc21
Temperature: 100 °C
Yield: 92.2 %

Procedure:
(b 1) 300 parts of 3-chlorophthalic anhydride in 1,200 parts by volume of formamide are stirred for 2 hours at 140° C. The mixture is then allowed to cool to 100° C. after which the solution is poured into 5,000 parts by volume of water. The precipitate which forms is filtered off, washed with water and dried under reduced pressure. 275 parts (92.2% of theory) of 3-chlorophthalimide, of melting point 236°-238° C., are obtained.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[F:5][C:6]([C:21]([F:24])([F:23])[F:22])([O:10][C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[C:7](F)=[O:8]>CCOCC>[F:5][C:6]([C:21]([F:22])([F:23])[F:24])([O:10][C:11]([F:19])([F:20])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[C:7]([NH:4][CH2:3][CH2:1][OH:2])=[O:8]
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: NCCO
Solvent: CCOCC
Product: O=C(NCCO)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 15 °C
Reaction time: 1 h
Yield: 335 %

Procedure:
A mixture of ethanolamine (13 g, 28 mmol) and ether (30 mL) was cooled to 15° C. Perfluoro-2-methyl-3-oxahexanoyl fluoride (33 g in ether 50 mL) was added dropwise to keep the reaction temperature below 25° C. After the addition, the reaction mixture was stirred at room temperature for one hour. The solid was removed by filtration and the filtrate was washed with hydrochloric acid (0.5N, 30 mL), water (2 times 30 mL), sodium hydrogen carbonate solution (0.5N, 20 mL), water (30 mL), and sodium chloride solution (saturated, 20 mL). It was then concentrated and dried in vacuum over night at room temperature to give N-(perfluoro-2-methyl-3-oxahexanoyl)-2-aminoethanol as a white solid 35 g, yield 95%. mp. 69-72° C. 1H NMR (CDCl3) δ 1.67 (bs, 1H), 3.57 (m, 2H), 3.80 (t, J=5 Hz, 2H), 6.91 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](OC(=O)C)(=O)[CH3:14]>>[I:11][C:10]1[C:2]2[N:1]=[C:13]([CH3:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][C:9]=1[CH3:12]
Reactant: Cc1ccc(C(=O)O)c(N)c1I
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2c(I)c(C)ccc2c(=O)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
2-Amino-3-iodo-4-methylbenzoic acid (10 g, 36 mmol) was treated with acetic anhydride (70 mL) and the mixture stirred at reflux for 4 h. The reaction was allowed to cool down to RT and placed in an ice bath for ˜2 h. The resulting precipitate was collected by filtration, washed with diethyl ether and dried to give 8-iodo-2,7-dimethyl-4H-benzo[d][1,3]oxazin-4-one (8.9 g, 82%) as a tan solid. MS (M+H)+ 302.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[Cl:39][C:40]1[CH:54]=[CH:53][C:43]([O:44][C:45]2[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=2)[CH:48]=[O:49])=[CH:42][CH:41]=1>>[Cl:39][C:40]1[CH:54]=[CH:53][C:43]([O:44][C:45]2[CH:46]=[C:47]([CH:48]([OH:49])[C:35]3[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=3)[C@@H:8]3[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]3[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])[CH:50]=[CH:51][CH:52]=2)=[CH:42][CH:41]=1
Reactant: O=Cc1cccc(Oc2ccc(Cl)cc2)c1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C(O)c3cccc(Oc4ccc(Cl)cc4)c3)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
5-((3-(4-Chlorophenoxy)phenyl)hydroxymethyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using 3-(4-chlorophenoxy)-benzaldehyde instead of benzophenone) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9](O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Pd]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCC(O)c1cccc(F)c1F
Agent: [Pd]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCCCCCCc1cccc(F)c1F

Procedure:
Quantities: compound from Example 18 (93.2 g, 0.41 mol), phosphorus pentoxide (174 g, 1.2 mol) and 5% palladium-on-charcoal (4.6 g). The experimental procedure was as described in Example 22.
Reaction SMILES: [C:1]12([P:11]([C:16]34CC5CC(C[CH:18]([CH2:19]5)[CH2:17]3)C4)[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C12([Mg]Br)CC3CC(CC(C3)C1)C2.ClP(CCCC)CCCC>>[C:1]12([P:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Agent: Br[Mg]C12CC3CC(CC(C3)C1)C2
Agent: CCCCP(Cl)CCCC
Product: CCCCP(CCCC)C12CC3CC(CC(C3)C1)C2

Procedure:
di-1-Adamantyl-n-butylphosphine was procured from Strem, 77672 Kehl, Germany; 1-adamantyldi-n-butylphosphine was prepared from adamantylmagnesium bromide (J. Org. Chem. 47 1982 4120-4128) and chlorodi-n-butylphosphine (from Aldrich, 82018 Taufkirchen, Germany).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1>>[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH:28][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])=[CH:22][CH:21]=1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCCc1ccncc1
Product: CCc1cc(-c2cncc(C(=O)NCCc3ccncc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(pyridin-4-yl)-ethyl-amine to afford the title compound. MS: m/e=363 (M+H). 1H NMR (δ ppm): 11.72 (s, 1H); 8.87 (d, 1H, J=2.1 Hz); 8.77 (t, 1H, J=5.4 Hz); 8.67 (d, 1H, 2.1 Hz); 8.47 (m, 2H); 8.04 (t, 1H, J=2.1 Hz); 7.29 (m, 3H); 3.57 (q, 2H, J=7.1 Hz); 2.89 (t, 2H, J=7.1 Hz); 2.42 (q, 2H, J=7.4 Hz); 2.17 (s, 3H); 1.11 (t, 3H, J=7.4 Hz).