Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C:16](Cl)(=O)[CH3:17].C[C:21]1[NH:22][CH:23]=[CH:24][N:25]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH:11]([CH2:21][N:22]3[CH:23]=[CH:24][N:25]=[C:16]3[CH3:17])[C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: Cc1ncc[nH]1
Reactant: CC(=O)Cl
Reactant: Cn1c2c(c3ccccc31)C(=O)CCC2
Solvent: Cc1ccccc1
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Reaction time: 0.17 h
Yield: 58 %

Procedure:
2.0 g of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one, 2 ml of N,N,N′,N′-tetramethyl- diaminomethane were suspended in 30 ml of toluene, and then 1.4 ml of acetyl chloride was slowly added thereto, which was then stirred for 10 min. 1.65 g of 2-methyl imidazole was added to the reaction mixture, which was then stirred under reflux for 10 hours. The reaction mixture was concentrated to remove the solvent, and then 150 ml dichloromethane and 50 ml of 1 N aq. sodium hydroxide were added to the resulting residue. The resulting organic layer was separated and dried over MgSO4, and then evaporated. The resulting solid was suspended in acetone, which was then stirred for 3 hours, and then filtered and dried to give 1.70 g of title compound (yield 58%).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].I[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([NH:8][CH2:9][C:10]#[C:11][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of N-Boc propargylamine (2.07 g, 13.4 mmol), methyl 4-iodobenzoate (3.50 g, 13.4 mmol) and PdCl2(PPh3)2 (0.938 g, 1.34 mmol) in DMF (20 ml) was added triethylamine (9.31 ml, 126 mmol). The reaction mixture was stirred for 30 min at room temperature. Cu(I)I (0.508 g, 2.67 mmol) was added and stirring was continued for additional 16 h. The reaction mixture was diluted with ethyl acetate (250 ml), washed with 0.5M aqueous HCl (200 ml), and finally with brine (200 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography over silica gel with ethyl acetate/hexane (1/4) provided methyl 4-(N-Boc-3-aminoprop-1-ynyl)benzoate (3.44 g) as highly viscous oil.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]=[O:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:28]([O:31][CH2:32][CH3:33])(=[O:30])[CH3:29]>CC1CCCO1.C1COCC1>[OH:26][CH:25]([C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)[CH2:29][C:28]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: CCOC(=O)CC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.33 h
Yield: 83 %

Procedure:
Under argon atmosphere, 8.3 mL (4.43 mmol, 1.5 equivalent) of the solution of ethyl bromozincacetate in 2-methyltetrahydrofuran obtained in Example 67 was added dropwise to a solution of 1 g (2.96 mmol) of 1-trityl-1H-imidazol-4-carbaldehyde in 10 mL of THF at 5˜8° C. The mixture was stirred at 3˜6° C. for 2 hours and 20 minutes. The mixture was stirred at 20˜25° C. for 1 hour and 15 minutes. 10 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 15 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, recrystallization with 5 mL of IPE afforded 1.04 g of the desired product (yield 83%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH2:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1ccc2ncccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.1 %

Procedure:
To a mixture of quinoline-6-carboxamide (0-3) (1.2 g, 7.2 mmol) and triethylamine (2.2 g, 21.8 mmol) in DCM (50 mL) at 0° C. was added trifluoroacetic acid anhydride (1.9 g, 8.9 mmol). The reaction was stirred for 10 mins at 0° C., then quenched with water. The resulting mixture was extracted with DCM. The organic layer was dried over anhydrous Na2SO4, and concentrated to afford the desired title compound (1.0 g). MS (m/z): 154 (M)+.
Reaction SMILES: [C:1]1(=[O:11])O[C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([NH:18][NH2:19])(=[O:17])[C:13]([NH:15][NH2:16])=[O:14].[OH2:20]>C1(C)C(C)=CC=CC=1>[C:4]1(=[O:5])[N:16]([NH:15][C:13]([C:12]([NH:18][N:19]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:5])=[O:17])=[O:14])[C:1](=[O:20])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: O
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NNC(=O)C(=O)NN
Solvent: Cc1ccccc1C
Product: O=C(NN1C(=O)c2ccccc2C1=O)C(=O)NN1C(=O)c2ccccc2C1=O
Yield: 94 %

Procedure:
Two moles of phthalic anhydride (296g) and one mole of oxalic dihydrazide (118 g) in xylene (2.5 l) were heated at reflux until two moles of water were removed (about 24 hours). The product was filtered and dried at 50° C. N,N'-bis(phthalimido)-oxamide was obtained in 94-6 percent yield. The compound was a white solid melting at 295° C (dec.) and having the following elemental analysis by weight percent:
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:19]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(COc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
A mixture of methyl 4-(bromomethyl)benzoate (1000 mg, 4.37 mmol), phenol (493 mg, 5.24 mmol), potassium carbonate (1200 mg, 8.73 mmol) and acetone (20 mL) was stirred at 60° C. under nitrogen atmosphere for 4 hours. The resultant mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=4:1) to give methyl 4-(phenoxymethyl)benzoate as a white solid (1100 mg, 100%). 1H NMR (300 MHz, CDCl3): δ 8.01 (d, J=8.1 Hz, 2H), 7.62 (d, J=8.1 Hz, 2H), 7.35-7.30 (m, 2H), 7.04 (d, J=7.8 Hz, 2H), 6.98 (t, J=7.2 Hz, 1H), 5.23 (s, 2H), 3.88 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:25]([C:24]2[C:23]([Cl:22])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:32])=[O:26])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.5 %

Procedure:
To a solution of 4-amino-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (127.6 mmol, 37.57 g) and 2,6-dichlorobenzoyl chloride (140.6 mmol, 29.45 g) in dichloromethane (350 mL) was added diisopropylethylamine (192 mmol, 33.4 mL) at room temperature. The brown solution was stirred for 15 h at room temperature to afford a white suspension. At this time, TLC analysis of the mixture indicated the absence of starting material. The solids were collected by filtration and were washed with dichloromethane (150 mL) and air dried to obtain 52.75 g (88.4%) of a white solid: mp 192-194° C. 1H NMR (DMSO-d6) (400 MHz) δ 10.68 (s, 1H), 7.47-7.6 (m, 5H), 7.2-7.29 (m, 3H), 4.12-4.17 (m, 1H), 3.62 (s, 3H), 2.79-2.99 (m, 2H), 1.33 (s, 9H). 13C NMR, CDCl3 (100 Mhz) d 172.49, 161.82, 155.37, 136.99, 136.36, 131.28, 131.16, 129.48, 128.19, 119.31, 78.27, 55.3, 51.76, 35.9, 27.77. HR MS: Obs. mass, 466.1069. Calcd. mass, 466.1062).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1.C(O)(=O)C>O1CCOCC1>[C:6]([O:5][C:1](=[O:4])[NH:2][N:3]1[CH:12]=[CH:16][CH:15]=[CH:14]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nn1cccc1
Yield: 12.5 %

Procedure:
A mixture of tert-butyl carbazate (5.51 g, 41.7 mmol), 2,5-dimethoxytetrahydrofuran (6.5 mL, 50.0 mmol) and acetic acid (33.6 mL) in dioxane (80 mL) was refluxed for 3 h; then cooled, the dark brown reaction mixture was concentrated, the resulting residue was directly silica gel column purified (eluents: 10% EtOAc in hexanes to 50% EtOAc in hexanes) to give the desired product (951 mg) as white solid. 1H NMR (CDCl3, δ in ppm): 7.17 (s, br, 1H), 6.66 (m, 2H), 6.11 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: CC(C)=O.[CH2:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:5]([O:20][C:17]1[CH:18]=[CH:19][C:14]([Br:13])=[CH:15][CH:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Brc1ccc(OCc2ccccc2)cc1
Yield: 73 %

Procedure:
To 200 ml of acetone were added 63.5 g of benzyl chloride, 95.15 g of 4-bromophenol, and 69.1 g of potassium carbonate, and the mixture was allowed to react at reflux for 8 hours. After completion of the reaction, the reaction mixture was added into 200 ml of water and extracted with 200 ml of chloroform. The extract was washed with 200 ml of water to obtain a crude product. The crude product was distilled by a Claisen flask to obtain 108.1 g of a distillate, which was further purified by silica gel column chromatography using benzene as an eluent to give 96 g (theoretical yield: 73%) of the entitled compound having a melting point of 47° C.
Reaction SMILES: [Zn:1].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[K+].[K+].[K+]>O>[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Zn+2:1].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Zn+2:1].[Zn+2:1]
Reactant: [Zn]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: [Zn+2]

Procedure:
Ten ml of 17% zinc solution were added to a liter of water. Later 20 grams of potassium phosphate were added and dissolved. Zinc phosphate formed a precipitate. Phosphorous acid was then added to lower the pH and clear the solution. Once clear 30 μl of the solution prepared in example 35 was added. This acidic solution, which was acidic, then remained undisturbed for a day, after which the pH was adjusted to 10 with the addition of MEA The zinc solution comprising chelated zinc remained clear, free of precipitates, and colorless.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].O.[OH-].[Li+]>CS(C)=O>[CH2:11]([O:10][C:8]([C:3]1[N:4]=[C:5]([CH3:7])[S:6][C:2]=1[NH:1][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])=[O:9])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)c1nc(C)sc1N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1nc(C)sc1Nc1ccccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Add a solution of ethyl 5-amino-2-methylthiazole-4-carboxylate (120 g; 645 mmol) and 2-fluoronitrobenzene (68 mL; 645 mmol) in dimethylsulphoxide (1 L) to a 2 L 3-necked RB flask equipped with reflux condenser, thermometer, mechanical stirrer. Add lithium hydroxide monohydrate (54 g; 1290 mmol) to the solution and heat at 50° C. for 3 hours under nitrogen. Cool the purple solution and pour onto ice/water, allow to stir for one hour, filter and wash with water, dry at 50° C. under reduced pressure to give 190 g (96%) as an orange solid: mass spectrum (m/e): 308 (M+1); 1HNMR(300 MHz, DMSO, ppm): 1.25 (tr, 3H), 2.56 (s, 3H), 4.25 (q, 2H), 7.20 (m, 1H), 7.78 (m, 2H), 8.20 (d, 1H), 11.42 (s, 1H, NH). 13CNMR(75 MHz, DMSO, ppm): 24.4, 29.2, 71.2, 127.8, 132.5, 132.8, 137.8, 146.5, 147.0, 147.5, 160.2, 161.5, 173.7. Formula: C13H13N3O4S.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]12[CH2:28][NH:27][CH2:26][C:25]=1[CH2:24][NH:23][CH2:22]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:23]4[CH2:24][C:25]5[CH2:26][NH:27][CH2:28][C:21]=5[CH2:22]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1NCC2=C1CNC2
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
0.28 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.16 g of 3,7-diazabicyclo-[3.3.0]oct-1(5)-ene and 0.3 ml of 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) were suspended in 20 ml of acetonitrile and refluxed in 100° C. oil bath for 5 hours. The reaction mixture was kept overnight at room temperature. The produced precipitate was filtered and was washed with ethanol-ethylether (1:1) solvent. 0.3 g of the title compound was obtained (yield 80%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.Br.[C:23]12[CH2:30][NH:29][CH2:28][C:27]=1[CH2:26][NH:25][CH2:24]2.C(N(C(C)C)CC)(C)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:25]4[CH2:26][C:27]5[CH2:28][NH:29][CH2:30][C:23]=5[CH2:24]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1NCC2=C1CNC2
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Temperature: 25 °C
Yield: 85.8 %

Procedure:
The suspension of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (14.7 g), 3,7-diazabicyclo[3.3.0] oct-1(5)-ene dihydrobromide (14.1 g) and diisopropyl-ethylamine (45 ml) in acetonitrile (1 l) was refluxed for 5 hours. The reaction mixture was cooled to room temperature and the produced precipitate was filtered and then washed with acetonitrile (200 ml) and water (200 ml) successively. Vacuum drying gave the title compound (16.6 g, yield 85%).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH2:9]=[O:10].[OH-].[K+].Cl>O>[OH:10][CH2:9][C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]cc(CO)c(=O)[nH]1
Temperature: 50 °C
Reaction time: 20 h
Yield: 44 %

Procedure:
A mixture of uracil (3.6 g, 32.1 mmol), formaldehyde (37% in water) (3.25 ml), KOH (1.4 g, 25 mmol) in water (45 ml) was stirred at 50° C. for 20 h. The reaction was acidified with 1 N HCl to give a white precipitate. The solids were collected dried under vacuum to give the 5-(hydroxymethyl)-2,4(1H,3H)-pyrimidinedione (2.01 g, 44%) as a white solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.[Ag]=O>[O:1]1[CH2:5][CH2:4][C@@H:3]([O:6][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O[C@@H]1CCOC1
Agent: O=[Ag]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To (R)-tetrahydro-furan-3-ol (2.0 g, 22.7 mmol), triethylamine (3.8 mL, 27.3 mmol), DMAP (277 mg, 2.26 mmol), and silver oxide (5.26 g, 22.7 mmol) in dry DCM (30 mL) at 0° C. under nitrogen, add portion wise with stirring p-toluenesulfonyl chloride (4.76 g, 25.0 mmol). Warm to ambient temperature overnight, filter from silver salts, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (7:1) to give the title compound as a clear liquid (4.7 g, 85%).
Reaction SMILES: C(OC([N:8]([O:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([O:31][S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[S:41]([N:44]([CH2:51][CH2:52][C:53]#[N:54])[CH2:45][C:46]2[O:47][CH:48]=[CH:49][CH:50]=2)(=[O:43])=[O:42])(=[O:34])=[O:33])[CH:25]=1)[C:9]([NH:11]C(OC(C)(C)C)=O)=[NH:10])=O)(C)(C)C.C(NCCC#N)C1OC=CC=1>>[CH3:30][C:28]1[CH:27]=[C:26]([O:31][S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[S:41]([N:44]([CH2:51][CH2:52][C:53]#[N:54])[CH2:45][C:46]2[O:47][CH:48]=[CH:49][CH:50]=2)(=[O:42])=[O:43])(=[O:33])=[O:34])[CH:25]=[C:24]([CH:29]=1)[O:23][CH2:22][CH2:21][CH2:20][O:19][NH:8][C:9]([NH2:11])=[NH:10]
Reactant: Cc1cc(OCCCON(C(=N)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(CCC#N)Cc2ccco2)c1
Agent: N#CCCNCc1ccco1
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(CCC#N)Cc2ccco2)c1
Yield: 49 %

Procedure:
N,N′-Bis-(tert-butoxycarbony)-3-[5-methyl-3-(2-(N-(2-cyanoethyl)-N-(2-furanylmethyl) aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy guanidine: The title compound was prepared in 49% yield from 3-(furfurylamino)propionitrile, in a manner analogous to step h of Example 20. 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 8.29 (dd, 1H, J=7.9, 1.4 Hz), 8.16 (dd, 1H, J=7.8, 1.5 Hz), 7.79 (m, 1H), 7.70 (m, 2H), 7.33 (t, 1H, J=1.3 Hz), 6.60 (m, 1H), 6.57 (m, 1H), 6.52 (t, 1H, J=2.1 Hz), 6.32 (m, 2H), 4.65 (s, 2H), 4.18 (t, 2H, J=6.2 Hz), 3.94 (t, 2H, J=6.2 Hz), 3.65 (m, 2H), 2.55 (m, 2H), 2.24 (s, 3H), 2.10 (pentet, 2H, J=6.2 Hz), 1.49 (s, 181H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.CN(C)C=O.S(Cl)([Cl:24])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Cl:24])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A 1000 mL 3-necked round-bottom flask was charged with bis(4-chlorophenyl)methanol (49.6 g, 196 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), dichloromethane (100 mL). Liquid thionyl chloride (93.3 g, 790 mmol, 4.00 equiv) was added dropwise. The resulting solution was stirred overnight at 40° C. in an oil bath. The resulting mixture was concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/5) to provide 47.8 g (88% yield) of 1-chloro-4-[chloro(4-chlorophenyl)methyl]benzene as a gray solid. 1HNMR 300 MHz (CDCl3) δ 7.30-7.39 (m, 8H), 6.07 (s, 1H). GCMS (EI, m/z): 270 [M]+.
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]1[C:17]([CH3:18])=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([CH3:19])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:27](O)[CH2:28][OH:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:20]([N:9]([CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:10]1[CH:11]=[C:12]([CH3:19])[C:13]([CH:14]2[O:29][CH2:28][CH2:27][O:15]2)=[CH:16][C:17]=1[CH3:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OCCO
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1C1OCCO1
Yield: 97.2 %

Procedure:
To a 500 mL round-bottomed flask was added 4-dibenzylamino-2,5-dimethylbenzaldehyde hydrochloride (11.5 g, 31.4 mmol) and toluene (150 mL) and the resulting mixture was stirred until the salt completely dissolved. The reaction flask was then purged with dry nitrogen for 5 minutes. Ethylene glycol (5.25 mL, 94.2 mmol) and p-toluenesulfonic acid (760 mg, 6.2 mmol) were added and the resulting mixture was heated at 60° C. to 80° C. for about 20 hours. The solvent was then removed slowly (over about 40 minutes) at 40° C. on a rotary evaporator. Toluene (100 mL) was added to the residue and the solvent was again removed slowly at 40° C. on a rotary evaporator. This process was repeated using another aliquot of toluene (100 mL) and the mixture was evaporated to dryness. Ethyl acetate (150 mL) and saturated aqueous sodium bicarbonate (100 mL) were added to the residue and the layers were separated. The organic layer was washed with brine (50 mL) and then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide crude dibenzyl-(4-[1,3]dioxolan-2-yl-2,5-dimethyl-phenyl)amine (11.4 g).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[CH3:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.CC(O)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[CH3:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@@H]1CCNC1
Reactant: CC(F)(F)Oc1ccc(NC(=O)c2cnc(Cl)c(Br)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(F)(F)Oc1ccc(NC(=O)c2cnc(N3CC[C@@H](O)C3)c(Br)c2)cc1
Temperature: 120 °C

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(1,1-difluoroethoxy)phenyl)nicotinamide (Stage 30.2, 700 mg, 1.752 mmol), (R)-pyrrolidin-3-ol (0.170 mL, 2.102 mmol) and DIPEA (0.673 mL, 3.85 mmol) and iPrOH (2 mL) in a sealed vial was heated to 120° C. for 1 h. The RM was diluted with EtOAc (80 mL), treated with citric acid 10% (40 mL; ˜pH4) and extracted with EtOAc. The combined extracts were washed with brine (2×40 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was washed with Et2O and n-hexane and the crystals were dried to give the title product as a beige solid. HPLC (Condition 5) tR=6.4 min, UPLC-MS (Condition 3) tR=1.02 min, m/z=442.1/444.0 [M+H]+.