Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[CH3:11][C:12]([O-])=[O:13].[Na+].CC(O)=O.CC(OC(C)=O)=O>C1(C)C=CC=CC=1>[CH3:8][C:6]1[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH:1][C:12](=[O:13])[CH3:11])[N:7]=1
Reactant: Cc1nc(N)ncc1C#N
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ncc(C#N)c(C)n1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
A 250 ml 3-neck flask was equipped with an overhead stirrer, reflux condenser, and a thermocouple. The flask was charged with 2-amino-4-methyl-5-cyanopyrimidine (8.00 g, 59.64 mmol) and an anhydrous NaOAc ((0.035 g, 0.43 mmol) in a mixture of HOAc (16.00 g, 266.43 mmol) and Ac2O (16.00 g, 156.72 mmol). The resultant suspension was stirred and heated to 115° C. to yield a brown suspension, which was stirred at 115° C. for 2 h during which time all starting material dissolved to yield a solution. The resultant mixture was heated at 115° C. for 6.5 hours and then cooled to room temperature to afford a suspension. Toluene (69.70 g) was added to the suspension, and the resultant mixture was then heated to about 108-114° C. to distill about 70 ml of solvent atmospherically (solution was effected at 70° C.). The resultant solution was cooled, fresh toluene (69.70 g) was added, and about 90 ml of solvent was distilled atmospherically at about 110-115° C. The resultant solution was cooled to 90° C., whereupon the mixture began to solidify. Toluene (8.7 g) and heptane (61.2 g) were added and the resultant suspension was stirred and gradually cooled to room temperature. After stirring at room temperature for 1 h, the suspension was filtered and the solid was washed twice with heptane (27.2 g portions) and then dried in a vacuum oven at 70° C. overnight. The title compound—N-(4-Methyl-5-cyano-2-pyrimidinyl)-acetamide—was isolated as a solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][N:25]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:22])[NH:20][OH:21])=[CH:15][CH:14]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][N:25]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([NH:20][OH:21])=[O:22])=[CH:15][CH:14]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(O)cn1)C(=O)NCc1ccc(C(=O)NO)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1ccc(O)cn1)C(=O)NCc1ccc(C(=O)NO)cc1
Yield: 71.7 %

Procedure:
A solution of tert-butyl1-(4-(hydroxycarbamoyl)benzylamino)-3-(5-hydroxypyridin-2-yl)-1-oxopropan-2-ylcarbamate (0.10 g, 0.19 mmol) with 1 mL of TFA in 10 mL of CH2Cl2 (25 mL) was stirred for 4 h at room temperature. The solvent was evaporated (monitored by TLC). The residue was purified by chromatography to give oily Compound 10 (0.045 g, 71%). NMR (400 MHz in CDCl3, Bruker AVANCE-400): δ 3.08 (m, 2H, CH2), 4.20 (m, 2H, CH2), 4.36 (m, 1H, CH), 7.08-7.28 (m, 4H, Ar—H), 7.62-7.70 (m, 2H, Ar—H), 7.82-7.88 (m, 1H, Ar—H), 8.96 (m, 2H, NH2), 9.13 (br, 1H, NH), 9.97 (br, 1H, NH), 11.15 (br, 1H, OH).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11](=[O:14])[CH2:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15](O)[CH2:16][CH2:17][OH:18].C(OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C.C(OCC)(=O)C>[C:1]([O:9][CH2:10][C:11]1([CH2:12][CH3:13])[O:18][CH2:17][CH2:16][CH2:15][O:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCO
Reactant: CCC(=O)COC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCC1(COC(=O)c2ccccc2)OCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
A mixture of 2-oxobutyl benzoate (5 g, 26 mmol), 1,3-propanediol (5.94 g, 78 mmol), triethyl orthoformate (3.85 g, 26 mmol) and p-toluenesulfonic acid monohydrate (448 mg, 2.36 mmol) was stirred at room temperature for 3 hours and 30 minutes. To the reaction mixture, ethyl acetate and diethyl ether were added and the mixture was washed with water and a saturated saline solution. The organic layer was dried over sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The residue was dissolved in heptane/ethyl acetate (12/1) and subjected to NH silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=12/1) to obtain the title compound (4.33 g, 65.5%) as a colorless viscous oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C@H:3]([CH2:7][NH:8][C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[N:10]=2)[CH2:2]1.Br[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:21]=[CH:20][C:19]([C:11]3[N:10]=[C:9]([NH:8][CH2:7][C@H:3]4[O:4][CH2:5][CH2:6][N:1]([C:32]5[N:37]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:2]4)[C:18]4[C:13](=[N:14][CH:15]=[CH:16][N:17]=4)[CH:12]=3)=[CH:24][CH:23]=2)[CH2:26][CH2:27]1
Reactant: c1cnc2c(NC[C@@H]3CNCCO3)nc(-c3ccc(N4CCOCC4)cc3)cc2n1
Reactant: Brc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1cnc(N2CCO[C@H](CNc3nc(-c4ccc(N5CCOCC5)cc4)cc4nccnc34)C2)nc1

Procedure:
A solution of (S)—N-(morpholin-2-ylmethyl)-7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-amine (100 mg, 0.246 mmol), 2-bromopyrimidine (59 mg, 0.37 mmol) and cesiumcarbonate (193 mg, 0.592 mmol) in DMF (2 mL) was heated at 100° C. in a sealed tube for overnight. Then the mixture was extracted with EA, washed with brine, concentrated and purified by flash column chromatography, eluting with DCM/MeOH to give product as light yellow solid. MS (m/z): 485 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: CCc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-nitro-4-trifluoromethyl-5-vinyl-phenyl)-carbamic acid tert-butyl ester (Example A27) (1.20 g, 3.6 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a white solid (1.289 g, 100%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Br[CH:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([N:11]([CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C@H:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:29])=[CH:10][C:3]=1[C:2]([F:18])([F:19])[F:1])#[N:6]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(NCCC(F)(F)F)cc1C(F)(F)F
Product: C[C@@H](C(=O)OC(C)(C)C)N(CCC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 1B using 2-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]benzonitrile and 1,1-dimethylethyl 2-bromopropanoate. 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J=8.8 Hz, 1H), 7.0 (d, J=2.6 Hz, 1H), 6.85 (dd, J=8.8, 2.6 Hz, 1H), 4.37 (q, J=7.3 Hz, 1H), 3.74 (t, J=8.1 Hz, 2H), 2.62-2.38 (m, 2H), 1.61 (d, J=7.3 Hz, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=O)=[C:24]([F:33])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:34])[CH:8]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:47]1([CH2:53][S:54]([NH2:57])(=[O:56])=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH2:53]([S:54]([NH:57][C:30](=[O:32])[CH2:29][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][CH2:20][C:16]2[CH:15]=[C:14]([C:10]3[C:9]([CH3:34])=[CH:8][C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:12][C:11]=3[CH3:13])[CH:19]=[CH:18][CH:17]=2)=[CH:23][C:24]=1[F:33])(=[O:56])=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Reactant: NS(=O)(=O)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)NS(=O)(=O)Cc4ccccc4)c(F)c3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.4 %

Procedure:
To a solution of 3-[4-({[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)-2-fluorophenyl]propanoic acid (0.186 g, 0.400 mmol) in tetrahydrofuran (5 mL) was added 1,1′-carbonyldiimidazole (97.3 mg, 0.600 mmol), and the mixture was heated under reflux under a nitrogen atmosphere for 1 hr. After cooling the reaction mixture, 1-phenylmethanesulfonamide (91.5 mg, 0.480 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.0897 mL, 0.600 mmol) were added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 24 hr. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) to give the title compound (0.189 g, yield 76%) as a colorless oil.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:42])[C@@H:10]([NH:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([Cl:40])[C:33]=1[CH3:41])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([O:23][Si](C(C)(C)C)(C)C)[CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:40][C:34]1[C:33]([CH3:41])=[C:32]([NH:31][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([OH:23])[CH:17]=3)=[N:14][N:15]=2)[C@H:9]([OH:8])[CH3:42])[CH:39]=[CH:38][C:35]=1[C:36]#[N:37]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(O[Si](C)(C)C(C)(C)C)c3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(O)c3)o2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: -55 °C
Yield: 91.7 %

Procedure:
4-((1R,2R)-2-(tert-butyldimethylsilyloxy)-1-(5-(3-(tert-butyldimethylsilyloxy)-4-fluoro phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (1.11 g, 1.76 mmol) was dissolved in THF (40 mL) and cooled down to −55° C. under N2 atmosphere. TBAF (1.0 M solution in THF, 4.21 ml, 4.22 mmol) was added to the pre-cooled solution slowly and the temperature allowed to rise gradually. After the reaction was complete, it was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc. Purification with column chromatography gave the desired product (650 mg) Mp 106-110° C., 1H NMR (400 MHz, acetone-d6, δ in ppm): 7.63 (dd, J=3.9 Hz, 1H), 7.49 (m, 2H), 7.30 (m, 1H), 6.89 (d, J=9 Hz, 1H), 5.87 (d, J=9 Hz, 1H), 5.05 (m, 1H), 4.52 (m, 1H), 2.37 (s, 3H), 1.40 (d, J=6 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]([S:10][CH2:11][CH2:12][OH:13])([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.CCN(C(C)C)C(C)C.[C:26](Cl)(=[O:29])[CH:27]=[CH2:28]>CO>[C:26]([O:13][CH2:12][CH2:11][S:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8])(=[O:29])[CH:27]=[CH2:28]
Reactant: CC(C)(SCCO)c1ccccc1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: C=CC(=O)OCCSC(C)(C)c1ccccc1
Temperature: -77 °C
Reaction time: 8 h

Procedure:
2-(2-Phenylpropan-2-ylthio)ethanol (45.0 g, 229 mmol) was weighed into a 1 L 3-neck round-bottomed flask which was then attached to a 125 mL pressure-equalising funnel (centre-socket), a Suba-seal (side-arm) and a double layer coil condenser (side-arm) which was connected in turn to a nitrogen-vacuum manifold. The apparatus was then purge-filled with nitrogen three times. Dichloromethane (anhydrous, 300 mL) was then cannula transferred into the reaction flask. DIPEA (anhydrous, 60 mL) was then added to the reaction solution using a 20 mL gastight syringe (3×20 mL transfers). Freshly distilled acryloyl chloride (22.35 mL) was then placed in the pressure-equalising addition funnel. The reaction flask was then surrounded with a dry-ice/acetone cooling bath and the reaction mixture cooled to a temperature of −77° C. The acryloyl chloride was then added slowly dropwise to the chilled reaction mixture under nitrogen over a period of 90 minutes (ca. 1 drop every 2 seconds). The reaction mixture was then stirred in the cooling bath under nitrogen overnight and allowed to warm slowly to room temperature. Next day the reaction flask was surrounded with a water/ice cooling bath and methanol (50 mL) was added to the pressure-equalising addition funnel. The reaction mixture was cooled to <5° C. and the methanol then added dropwise over a period of 30 minutes in order to quench the excess acryloyl chloride. The reaction mixture was then allowed to warm to room temperature before being extracted with 1×300 mL portion of 1M HCl (aq) and 2×300 mL portions of brine. The organic layer was then partitioned and separated and then dried over anhydrous magnesium sulfate for a period of 1 hour. The drying mixture was then filtered and the collected solid washed with 3×40 mL portions of dichloromethane. The filtrate and washings were combined and then CAREFULLY stripped to dryness in vacuo (rotary evaporator) at a bath temperature of 25° C. The resultant orange liquid (with a small quantity of white “gel-like” material on the walls of the evaporation flask, presumably polymer) was distilled in vacuo through a Claisen head with a spatula measure of 5,5′,6,6′-tetrahydroxy-3,3,3′,3′-tetramethyl-1,1′-spirobisindane inhibitor added to the distillation mixture.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:22])[N:16]([CH2:18][C:19]([NH2:21])=[O:20])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:22])[N:16]([CH2:18][C:19]([NH2:21])=[O:20])[CH:17]=2)=[N:31]\[OH:32])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(CC(N)=O)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(CC(N)=O)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 2-{5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-2-oxo-2H-pyridin-1-yl}-acetamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI−): m/z=466.1 [M−H]−.
Reaction SMILES: CC1N=C(C(F)(F)F)C=CC=1C(Cl)=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:35])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[N:26][C:25]=2[CH3:34])=[CH:18][C:17]=1[C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][N:45]=1)[C:39](OC)=[O:40].[BH4-].[Na+]>CCO>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:35])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[N:26][C:25]=2[CH3:34])=[CH:18][C:17]=1[C:36]1[CH:37]=[C:38]([CH2:39][OH:40])[CH:43]=[CH:44][N:45]=1
Reactant: COC(=O)c1ccnc(-c2cc(NC(=O)c3ccc(C(F)(F)F)nc3C)ccc2Cl)c1
Agent: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2cc(CO)ccn2)c1

Procedure:
75 mL of (4-methylpyridin-2-yl)zinc(II) bromide was reacted with 4 g of 1-chloro-2-iodo-4-nitrobenzene via Procedure B. To 300 mg of 2-(2-chloro-5-nitrophenyl)-4-methylpyridine in 1.5 mL of Sulfuric Acid was slowly added 362 mg of Chromium (III) Oxide and the reaction was stirred for several hours at room temperature until complete. Icewater was added to dilute the reaction and the aqueous layer was extracted 3 times with Ethyl Acetate. The organic layers were combined, dried over Magnesium Sulfate, filtered and concentrated to give 2-(2-chloro-5-nitrophenyl)isonicotinic acid. 300 mg of 2-(2-chloro-5-nitrophenyl)isonicotinic acid was esterified with 750 μL of 4N HCl in Dioxane in 10 mL of MeOH at 55° C. for 16 hours. The reaction was concentrated and subjected to basic workup, dried over Magnesium Sulfate, filtered and concentrated to give methyl 2-(2-chloro-5-nitrophenyl)isonicotinate. 259 mg of methyl 2-(2-chloro-5-nitrophenyl)isonicotinate was treated with 200 mg of Tin (II) Chloride and 500 mL of HCl in 10 mL of EtOH. Upon completion, EtOH was concentrated and the reaction was extracted with Ethyl Acetate and water with TEA to decrease emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give crude methyl 2-(5-amino-2-chlorophenyl)isonicotinate. 240 mg of methyl methyl 2-(5-amino-2-chlorophenyl)isonicotinate was treated with 204 μL of 2-methyl-6-(trifluoromethyl)nicotinoyl chloride via Procedure D. To 100 mg of methyl 2-(2-chloro-5-(2-methyl-6-(trifluoromethyl)nicotinamido)phenyl)isonicotinate at 0° C. in 5 mL of EtOH was slowly added 135 mg of Sodium Borohydride. The reaction was subsquently refluxed for 1 hour until complete, quenched with water and extracted with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate, filtered, concentrated and purified by reverse phase HPLC to give pure N-(4-chloro-3-(4-(hydroxymethyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide. MS (Q1) 422.1 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13]SC3C([N+]([O-])=O)=CC=CN=3)[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.Br[CH2:66][C:67]([C:69]1[CH:78]=[CH:77][C:72]2[O:73][CH2:74][CH2:75][O:76][C:71]=2[CH:70]=1)=[O:68]>CC(C)=O.O>[O:73]1[C:72]2[CH:77]=[CH:78][C:69]([C:67](=[O:68])[CH2:66][S:13][C@H:10]3[C:11](=[O:12])[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C@@H:9]3[C:24]3[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:70][C:71]=2[O:76][CH2:75][CH2:74]1
Reactant: CC(C)(C)OC(=O)COc1ccc([C@@H]2[C@@H](SSc3ncccc3[N+](=O)[O-])C(=O)N2c2ccc(F)cc2)cc1
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)OCCO4)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (4-{(2R,3R)-1-(4-fluorophenyl)-3-[(3-nitropyridin-2-yl)dithio]-4-oxoazetidin-2-yl}phenoxy)acetate (0.100 g, 0.179 mmol) in acetone (2 ml) and water (0.5 ml) was added triphenylphosphine (0.047 g, 0.179 mmol). After 30 minutes, the mixture was concentrated. To the residue was added dichloromethane (3 ml) followed by the addition of triethylamine (0.073 g, 0.717 mmol) and 2-bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethanone (0.115 g, 0.448 mmol). After 30 minutes, full conversion of the thiol had been achieved. The mixture was concentrated and to the residue was added formic acid (2 g) and trifluoroacetic acid (0.2 g). The mixture was allowed to stir at room temperature for 3 h. The crude product obtained was purified through preparative HPLC using an eluent of 10-50% CH3CN in 0.1M NH4OAc buffer. Freeze drying of pure fractions afforded the desired compound. 1H NMR [(CD3)2SO), 400 MHz] δ 4.21-4.32 (m, 9H), 5.09 (d, 1H), 6.78-7.44 (m, 11H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]3[O:13][CH3:14])[C:6]=2[N:7]=1.NC(N)=[S:24]>CCO>[NH2:1][C:2]1[NH:3][C:4](=[S:24])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]3[O:13][CH3:14])[C:6]=2[N:7]=1
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Reactant: NC(N)=S
Solvent: CCO
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(=S)[nH]c(N)nc21

Procedure:
A solution of the compound from Example 11, Step C (1.5 g, 5 mmol), thiourea (0.4 g, 5.2 mmol.) in abs. EtOH was refluxed for 16 hrs. The solution was evaporated and the resulting oil chromatographed on silica gel (EtOAc/MeOH: 9/1) to afford the desired product as a foam.
Reaction SMILES: [SH:1][C:2]1[N:3]=[C:4]2[CH:13]=[CH:12][CH:11]=[CH:10][N:5]2[C:6](=[O:9])[C:7]=1[CH3:8].[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][S:1][C:2]3[N:3]=[C:4]4[CH:13]=[CH:12][CH:11]=[CH:10][N:5]4[C:6](=[O:9])[C:7]=3[CH3:8])=[CH:23][CH:22]=2)=[O:20])=[CH:17][N:16]=1
Reactant: Cc1c(S)nc2ccccn2c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(SCc2ccc(C(=O)c3ccc(Cl)nc3)cc2)nc2ccccn2c1=O
Yield: 27.9 %

Procedure:
A solution of 2-mercapto-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (599 mg), 4-(6-chloronicotinoyl)benzyl bromide (1.179 g) and potassium carbonate (1.148 g) in DMF (40 ml) was stirred at room temperature for 2 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was recrystallized from tetrahydrofuranethyl acetate to provide the title compound as colorless solid (367 mg).
Reaction SMILES: F[C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][C:3]=1[O:12][C:13]1[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: Oc1ccccc1Cl
Reactant: CS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(N)cc2F)cn1
Product: CS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2Cl)cn1

Procedure:
The entitled compound was obtained in the same method as in Example 196 (step 4) to (step 5) or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(6-methanesulfonyl-pyridin-3-yloxy)-2-nitro-phenylamine obtained in Example 196 (step 3) and 2-chlorophenol.
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=[O:46])[C:8]2[N:9]=[CH:10][N:11]([C:44]=2[N:45]=1)[C@@H:12]1[O:43][C@H:17]([CH2:18][O:19][C:20]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:15]([OH:16])[C@H:13]1[OH:14])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:56]([CH2:58][CH2:59][O:60][CH2:61]Cl)#[N:57].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([NH:4][C:5]1[NH:6][C:7](=[O:46])[C:8]2[N:9]=[CH:10][N:11]([C:44]=2[N:45]=1)[C@@H:12]1[O:43][C@H:17]([CH2:18][O:19][C:20]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C@@H:15]([OH:16])[C@H:13]1[O:14][CH2:61][O:60][CH2:59][CH2:58][C:56]#[N:57])(=[O:3])[CH3:2]
Reactant: N#CCCOCCl
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(C)=O)nc43)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(C)=O)nc43)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 63.3 %

Procedure:
N2-Acetyl-5′-O-(4,4′-dimethoxytrityl)guanosine (627 mg, 1 mmol) was dissolved in 4 mL of 1,2-dichloroethane, and 452 mg of diisopropylethylamine (3.5 mmol) was added, and then 365 mg of dibutylstannyl dichloride (1.2 mmol) was added. And then, the reaction solution was reacted at room temperature for 1 hour. Then, the reaction was performed at 80° C., and 155.4 mg of chloromethyl 2-cyanoethyl ether (1.3 mmol) was added dropwise, and the solution was stirred for 60 minutes. After the reaction completed, the reaction solution was mixed with an aqueous saturated sodium bicarbonate solution, and was subjected to extraction with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained mixture was purified by 30 g of silica gel column chromatography to obtain N2-acetyl-5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxymethyl) guanosine (450 mg, yield 63%).