Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.Br[CH2:11][C:12]([O:14][CH3:15])=[O:13].[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[C:24]([F:27])([F:26])[F:25].O>CN(C=O)C>[CH3:15][O:14][C:12](=[O:13])[CH2:11][NH:21][C:20]1[CH:22]=[CH:23][C:17]([Br:16])=[C:18]([C:24]([F:27])([F:25])[F:26])[CH:19]=1
Reactant: COC(=O)CBr
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNc1ccc(Br)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 25 h
Yield: 67.1 %

Procedure:
N,N-Diisopropylethylamine (1.22 ml, 7.00 mmol) and methyl bromoacetate (1.00 g, 6.54 mmol) were sequentially added to a solution of 4-bromo-3-(trifluoromethyl)aniline (1.40 g, 5.83 mmol) in DMF (10 ml), and the mixture was heated with stirring at 80° C. for 25 hours. The reaction mixture was cooled and water was then added, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was triturated with hexane:dichloromethane=9:1 to give (4-bromo-3-trifluoromethyl-phenylamino)-acetic acid methyl ester (1.22 g, 67%).
Reaction SMILES: C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.[I:22][C:23]1[CH:24]=[N+:25]([O-])[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][C:32]1[CH:36]=[CH:35][S:34][CH:33]=1.[C:38]([NH2:42])([CH3:41])([CH3:40])[CH3:39]>C(Cl)(Cl)Cl>[C:38]([NH:42][C:26]1[CH:27]=[C:28]([O:29][CH2:30][CH2:31][C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)[C:23]([I:22])=[CH:24][N:25]=1)([CH3:41])([CH3:40])[CH3:39]
Reactant: [O-][n+]1ccc(OCCc2ccsc2)c(I)c1
Reactant: CC(C)(C)N
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)Nc1cc(OCCc2ccsc2)c(I)cn1
Reaction time: 0.5 h

Procedure:
A solution of p-toluenesulfonic anhydride (1.47 g, 4.49 mmol) in 15 ml of chloroform was added dropwise to a stirred mixture of 0.78 g (2.25 mmol) of 3-iodo-4-(2-(thiophen-3-yl)ethoxy)pyridine 1-oxide and 1.18 ml (11.2 mmol) of tert-butylamine in 15 ml of chloroform at 0° C. After 30 minutes, the addition of the same quantities of p-toluenesulfonic anhydride and tert-butylamine was repeated to complete the reaction. The reaction mixture was concentrated and partitioned between 100 ml of diethylether and 1 M aqueous sodium carbonate. The aqueous layer was extracted with 50 ml of diethylether again and combined organic extracts were washed with water, brine, dried over sodium sulfate and concentrated in vacuum. The residue was purified by flash chromatography eluting with 10% of ethyl acetate in hexane to give N-tert-butyl-5-iodo-4-(2-(thiophen-3-yl)ethoxy)pyridin-2-amine (0.473 g (52%). 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.28 (dd, J=3.0, 4.8, 1H), 7.18 (s, 1H), 7.12 (d, J=4.9, 1H), 5.85 (s, 1H), 4.44 (s, 1H), 4.15 (t, J=6.5, 2H), 3.18 (t, J=6.5, 2H), 1.39 (s, 9H). MS: (ESI+) 403.2
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:4]([CH3:13])[N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[CH2:9]([C:5]1[C:6]([Cl:16])=[N:7][C:2]([NH2:1])=[N:3][C:4]=1[CH3:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1c(C)nc(N)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCc1c(C)nc(N)nc1Cl
Yield: 29 %

Procedure:
2-Amino-5-butyl-6-methylpyrimidine-4-ol (1.0 g, 5.52 mmol) and phosphorus oxychloride (12 ml) were refluxed for 3 hours. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1) to give the object compound (325 mg, 29%).
Reaction SMILES: [CH3:1][C:2]1[C:11](Br)=[C:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2Br)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Li+].[Cl-:25].[ClH:26]>CN(C=O)C>[CH3:1][C:2]1[C:11]([Cl:25])=[C:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[Cl:26])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: Cc1cc2ccccc2c(-c2c(Br)ccc3ccccc23)c1Br
Reactant: Cl
Reactant: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1cc2ccccc2c(-c2c(Cl)ccc3ccccc23)c1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
(R)-2,2′-Dibromomethyl-1,1′-binaphthyl (4, 40 g, 90.8 mmol) and LiCl (30 g, 707 mmol) in DMF (800 mL) was mixed together and stirred at room temperature for 6 h. To this mixture was added carefully 5% aqueous HCl (300 mL) (exothermomic reaction occurred). The mixture was then extracted with ether (4×400 mL). The organic layer was dried over sodium sulfate, concentrated and recrystallized from CH2Cl2/hexane to gave 5 as white solid (30 g, 93%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][CH2:19][C:20]4([CH2:24][OH:25])[CH2:23][CH2:22][CH2:21]4)=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:26]([C:28]1([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=O.C(C1(C(OC)=O)CCC1)=O>>[OH:25][CH2:24][C:20]1([CH2:19][O:18][C:14]2[C:13]3[C:9]([O:8][CH2:7][CH:4]4[CH2:5][CH2:6][N:1]([CH2:26][C:28]5([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH2:2][CH2:3]4)=[N:10][O:11][C:12]=3[CH:17]=[CH:16][CH:15]=2)[CH2:21][CH2:22][CH2:23]1
Reactant: OCC1(COc2cccc3onc(OCC4CCNCC4)c23)CCC1
Reactant: COC(=O)C1(C=O)CCOCC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OCC5(CO)CCC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using [1-({[3-(piperidin-4-ylmethoxy)-1,2-benzisoxazol-4-yl]oxy}methyl)cyclobutyl]methanol (EXAMPLE 49, Step 2) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (EXAMPLE 18, Step 1) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutane-carboxylate.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([NH:30]C(=O)C)(C(OCC)=O)[C:20]([O:22]CC)=[O:21])([O:6]CC)=[O:5])C>Cl>[P:4]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH:19]([NH2:30])[C:20]([OH:22])=[O:21])([OH:6])([OH:5])=[O:3]
Reactant: CCOC(=O)C(Cc1ccccc1CCCP(=O)(OCC)OCC)(NC(C)=O)C(=O)OCC
Agent: Cl
Product: NC(Cc1ccccc1CCCP(=O)(O)O)C(=O)O
Temperature: 25 °C

Procedure:
A solution of 3.0 g (6.9 mmol) of ethyl 3-[2-(diethylphosphonopropyl)phenyl]-2-acetamido-2-carboethoxypropanoate in 25 mL of 6N HCl was stirred at vigorous reflux 12 h. After cooling to room temperature the reaction mixture was concentrated at reduced pressure yielding an oil. The oil was washed with three 25 mL portions of water then dissolved in 25 mL 95% ethanol and propylene oxide added dropwise. The precipitated acid was collected by filtration. Recrystallization from dilute ethanol yield 0.76 g (38%) as a white solid mp>95° C. (dec.). IR(nujol): 1717.6 cm-1 (C=O). 1H NMR(D2O) δ 1.1-2.0 (complex m, 4H); 2.6-3.1 (m, 4H); 3.35-3.65 (m, 1H); 7.3 (m, 4H). Anal. Calcd. for: C12H18NO5P.H2O: C, 47.21; H, 6.60; N, 4.58. Found: C, 47.47; H, 6.72; N, 4.53.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[N:10]=[C:9](Cl)[C:8]([F:12])=[C:7]([O:13][CH3:14])[N:6]=1.O.C(OCC)(=O)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[N:6]=[C:7]([O:13][CH3:14])[C:8]([F:12])=[C:9]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:10]=1
Reactant: COC(=O)Cc1nc(Cl)c(F)c(OC)n1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1nc(OC)c(F)c(N2CCOCC2)n1

Procedure:
A solution of 8.36 g of (4-chloro-5-fluoro-6-methoxypyrimidin-2-yl)acetic acid methyl ester in 76 ml of morpholine is stirred at ambient temperature for one and a half hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up with 50 ml of water and 200 ml of ethyl acetate. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure, so as to give 8.86 g of (5-fluoro-4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)acetic acid methyl ester in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: C([C:3]1[C:17]([Cl:18])=[C:16]([Cl:19])[C:6]2[O:7][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][O:10][C:5]=2[CH:4]=1)=O.C1C=CC=CC=1.C[C:27](C)=[O:28]>>[CH:27]([C:4]1[C:5]2[O:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:7][C:6]=2[C:16]([Cl:19])=[C:17]([Cl:18])[CH:3]=1)=[O:28]
Reactant: CCOC(=O)C1COc2cc(C=O)c(Cl)c(Cl)c2O1
Reactant: CC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)C1COc2c(C=O)cc(Cl)c(Cl)c2O1
Yield: 49 %

Procedure:
This is passed through Lober column B (made by Merck) with benzene/acetone (30/1) as an eluent. The product in the earliest fraction is recrystallized from acetone/ether/petroleum ether to give 1.031 g (yield 47%) of the objective ethyl 6-formyl-7,8-dichloro-1,4-benzodioxane-2-carboxylate (Ib'-51), m.p. 101°-102° C. And the product in the later fractions are also recrystallized in the same manner as above to give 1.057 g (yield 49%) of ethyl 5-formyl-7,8-dichloro-1,4-benzodioxane-2-carboxylate (Ib'-50), m.p. 110°-113° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=2[F:22])[N:7]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:34])(=O)=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[N:6]([CH3:34])[N:7]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)/[C:8](=[N:10]/[C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[C:13]=2[F:22])/[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)c1cc(NC(=O)c2cccc(C(F)(F)F)c2F)n(C[C@H]2CCCO2)n1
Solvent: Cc1ccccc1
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cccc(C(F)(F)F)c2F)n1C[C@H]1CCCO1
Yield: 80 %

Procedure:
A mixture of Example 6C (400 mg, 0.97 mmol) and dimethyl sulfate (0.37 mL, 3.88 mmol) in toluene (2 mL) was heated in a microwave reactor (300 W, CEM Explorer®) at 150° C. for 1 hour. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel; solvent A=EtOAc/MeOH/Et3N (90:10:0.5); solvent B=hexane in 10-60% gradient A/B) to yield 331.5 mg (80%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44 (s, 9H), 1.50-1.67 (m, 1H), 1.75-1.96 (m, 2H), 1.99-2.14 (m, 1H), 3.64-3.84 (m, 2H), 4.12 (s, 3H), 4.18-4.26 (m, 1H), 4.55-4.77 (m, 2H), 6.98 (s, 1H), 7.63 (t, J=7.73 Hz, 1H), 8.00-8.13 (m, 2H); MS (ESI) m/z 428 (M+1H).
Reaction SMILES: CS(N)(=O)=O.[CH3:6][NH:7][S:8]([NH2:11])(=[O:10])=[O:9].C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:39]12[CH2:48][CH:43]3[CH2:44][CH:45]([CH2:47][CH:41]([CH2:42]3)[CH:40]1[C:49]1[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][C:50]=1[Cl:58])[CH2:46]2>>[CH:39]12[CH2:48][CH:43]3[CH2:44][CH:45]([CH2:47][CH:41]([CH2:42]3)[CH:40]1[C:49]1[CH:57]=[CH:56][C:52]([C:53]([NH:11][S:8](=[O:10])(=[O:9])[NH:7][CH3:6])=[O:54])=[CH:51][C:50]=1[Cl:58])[CH2:46]2
Reactant: CNS(N)(=O)=O
Reactant: O=C(O)c1ccc(C2C3CC4CC(C3)CC2C4)c(Cl)c1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: CNS(=O)(=O)NC(=O)c1ccc(C2C3CC4CC(C3)CC2C4)c(Cl)c1

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with methyl sulfamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-2-yl)-3-chlorobenzoic acid, the title compound was obtained following trituration with hexanes as a colorless solid (0.11 g, 66%): 1H NMR (300 MHz, DMSO-d6) δ 11.81 (s, 1H) 7.98-7.97 (m, 1H), 7.88-7.85 (m, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.64-7.60 (m, 1H), 3.22 (s, 1H), 2.50 (d, J=4.4 Hz, 3H), 2.23 (s, 2H), 1.95-1.85 (m, 8H), 1.72 (s, 2H), 1.63-1.59 (m, 2H); MS (ES−) m/z 381.2, 383.2 (M−1).
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.O>[NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[C@@H:2]([C:13]([NH:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: O=C(N[C@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
Z-DTrp-OH (3.21 g) and βAla-OEt.HCl (1.49 g) were suspended in dichloromethane (30 ml), and N-methylmorpholine (1.05 g) and HOBT.H2O (1.59 g) were added at room temperature, and then EDCI.HCl (11.99 g) was added at 0°~5° C. The reaction mixture was stirred at room temperature overnight, diluted with dichloromethane, washed successively with sat. NaHCO3, 1N HCl and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by dry column flash chromatography (Merck, Kieselgel 60) with dichloromethane/methanol=30/1 for elution to give the product (3.02 g).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.C([Li])CCC.[N:35]1([CH2:40][C:41](=O)[CH2:42][O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[CH:39]=[CH:38][N:37]=[CH:36]1.C(OCC)(=O)C>O1CCCC1.CCCCCC>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:41]([CH2:42][O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[CH2:40][N:35]2[CH:39]=[CH:38][N:37]=[CH:36]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(COCC(=O)Cn2ccnc2)cc1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C=C(COCc2ccc(OC)cc2)Cn2ccnc2)cc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A stirred suspension containing [(4-methoxyphenyl)methyl]triphenylphosphonium bromide (8.3 g, 0.020 mol) in dry tetrahydrofuran (50 ml) at -20° C. under a nitrogen atmosphere was treated with a solution containing n-butyl lithium (14.3 ml of 1.4M; 0.020 mol) in hexane. The resulting deep-red solution was stirred at -20° C. for 20 minutes and was allowed to warm to room temperature. Stirring was maintained for an additional 20 minutes and the solution was cooled to -20° C. The cooled solution was treated with a solution of 1-(1H-imidazol-1-yl)-3-[(4-methoxyphenyl)methoxy]-2-propanone (Example 1c; 2.6 g, 0.010 mol) in dry tetrahydrofuran (20 ml) and the resulting mixture was stirred at room temperature for 14 hours. Ethyl acetate (500 ml) was added to the mixture and the resulting mixture was washed with water (3×150 ml) and dried over sodium sulfate. The solvent was evaporated off under reduced pressure to yield a crude product which was purified by column chromatography (silica gel, 30% hexane in chloroform) to give an isomeric mixture of E- and Z-1-[3-(4-methoxyphenyl)-2-[[(4-methoxyphenyl)methoxy]methyl]-2-propenyl]-1H-imidazole as a pale-yellow oil having the following structural characteristics:
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>CN(C)C=O.O>[C:25]([NH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: Cc1cccc(C)c1NC(=O)c1ccc(N)cc1
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)Nc2c(C)cccc2C)cc1
Temperature: 4 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 2.0 g of 4-amino-N-(2,6-dimethylphenyl)benzamide in dimethylformamide were added 1 ml of pyridine followed by 710 μl of acetyl chloride. The reaction was stirrred at room temperature for 2 hours, diluted with water, and chilled to approximately 4° C. The title product was recovered by filtration in 85% yield, m.p. 293°-295° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[N+:17]([O-])=O.O>C(O)(=O)C.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH2:17]
Reactant: O=[N+]([O-])c1ccc(OCc2ccc(Cl)cc2)cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(OCc2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A stirred solution of 9.0 grams (0.032 mole) of 2-fluoro-4-(4-chlorophenylmethoxy)nitrobenzene and 10 mL of water in 150 mL of glacial acetic acid was maintained at 50° C. while 9.0 grams of iron powder was slowly added. Upon completion of addition, the reaction mixture was cooled to 25° C. where it was stirred for about one hour. After this time the reaction mixture was filtered ,and the filtrate was poured into water. The mixture was then extracted with ethyl acetate. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography using silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 7.1 grams of 2-fluoro-4-(4-chlorophenylmethoxy)aniline, mp 73°-75° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: NC([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:24][C@H:25]3[CH2:30][CH2:29][C@H:28]([C:31]([CH3:34])(C)C)CC3)[C:16]=2C(F)(F)F)[N:11]=1)(C)COP(=O)(O)O.[CH2:35](O)CCCCCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:25]([O:24][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:19]=[CH:18]2)[CH2:30][CH2:29][CH2:28][CH2:31][CH2:34][CH3:35]
Reactant: CCCCCCCO
Reactant: CC(N)(COP(=O)(O)O)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc2ncccc2c1
Temperature: 23 °C
Reaction time: 15 h
Yield: 87.8 %

Procedure:
Quinolin-6-ol (1, 2.00 g, 0.0138 mol), 1-heptanol (1.60 g, 0.0138 mol) and triphenylphosphine (4.34 g, 0.0165 mol) were placed in a flask, and dissolved in tetrahydrofuran (200 mL, 2 mol) at 23° C. A solution of diisopropyl azodicarboxylate (3.46 mL, 0.0165 mol) in THF (5 mL) was then added dropwise. The reaction mixture was then allowed to stir at 23° C. for 15 hours. Solvent was removed, and the residue was then purified via chromatography (SiO2, 120 g, 5% MeOH in DCM) to give 2.95 g product (88%). 1H NMR (CHLOROFORM-d) δ: 8.76 (dd, J=4.0, 1.5 Hz, 1H), 8.02 (dd, J=15.9, 8.7 Hz, 2H), 7.31-7.44 (m, 2H), 7.07 (d, J=2.8 Hz, 1H), 4.09 (t, J=6.5 Hz, 2H), 1.79-1.96 (m, 2H), 1.45-1.60 (m, 4H), 1.14-1.45 (m, 4H), 0.82-0.99 (m, 3H). MS (M+1): 244.20.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([C:63]1[CH:92]=[CH:91][CH:90]=[CH:89][C:64]=1[CH2:65][O:66][C:67]([NH:69][CH2:70][CH2:71][CH2:72][CH2:73][C@H:74]([NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[C:75](OCC#N)=[O:76])=[O:68])=[N+:61]=[N-:62].C(#N)C>O.O1CCCC1>[N:60]([C:63]1[CH:92]=[CH:91][CH:90]=[CH:89][C:64]=1[CH2:65][O:66][C:67]([NH:69][CH2:70][CH2:71][CH2:72][CH2:73][C@@H:74]([NH:81][C:82]([O:84][C:85]([CH3:86])([CH3:87])[CH3:88])=[O:83])[C:75]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:76])=[O:68])=[N+:61]=[N-:62]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 14.6 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (46.3 mg, 0.073 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk41) (134 mg, 0.291 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (14 mL), and the mixture was stirred at room temperature for 1.75 hours. Acetonitrile (0.6 mL) was added and the mixture was stirred at the same temperature for 1.25 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk42) (11.1 mg, 15%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[C:13]([NH:20][C@H:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)[CH3:22])[N:12]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1>C(OCC)(=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([NH:20][C@H:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)[CH3:22])[N:12]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)cc1Nc1nc(N[C@@H](C)c2ccc(F)cn2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COc1ncc(Cl)cc1Nc1nc(N[C@@H](C)c2ccc(F)cn2)ccc1N
Yield: 67.7 %

Procedure:
A solution of N2-(5-chloro-2-methoxypyridin-3-yl)-N6-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-3-nitropyridine-2,6-diamine (Preparation 24b, 160 mg, 0.38 mmol) in ethyl acetate (11 mL) was hydrogenated using a H-Cube® Continuous-flow hydrogenation reactor and a Raney®-Nickel catalyst cartridge under a 80 bar pressure (flow=0.3 ml/min). Solvent was then concentrated to dryness under reduced pressure to yield the title compound (100 mg, 64%) as a green oil which was used in the next synthetic step without further purification.