Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[C:12]([O:22][CH3:23])[CH:11]=2)[N:3]=1.[CH3:24][O-:25].[Na+]>CO>[CH3:23][O:22][C:12]1[CH:11]=[C:10]([NH:9][C:4]2[N:3]=[C:2]([O:25][CH3:24])[CH:7]=[C:6]([CH3:8])[N:5]=2)[CH:15]=[CH:14][C:13]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1
Reactant: C[O-]
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Yield: 30.7 %

Procedure:
A mixture of (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (99 mg, 0.3 mmol) and sodium methoxide (25 mg, 0.45 mmol) in methanol (3 mL) was heated for 30 min to 160° C. in a microwave oven. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound as a yellow solid (30 mg, 31%). MS ISP (m/e): 326.2 (100) [(M+H)+].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=1)[O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=1)[O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])#[N:7]
Reactant: CNCCc1cccc(OCC(=O)OC)c1
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Product: COC(=O)COc1cccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)c1

Procedure:
Reaction of 1f with 2l produced 3aq. MS found M+H=483. The oxalate salt of 3aq was recrystallized from methanol/ether; mp 96-100° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH:19]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:25]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:27])=[O:26])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)C1CCCCC1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with cyclohexanesulfonyl chloride to obtain the desired product. 1H NMR (300 MHz, CDCl3): δ 7.43 (dd, J=1.5 & 10.2 Hz, 1H), 7.37 (ddd, J=2.4, 4.8 & 9.6 Hz, 1H), 7.27 (m, 1H), 7.11 (dd, J=9.3 & 18.0 Hz, 1H), 6.64 (br s, 1H), 6.18 (dt, J=1.5, 9.0 & 17.4 Hz, 1H), 5.63 (br s, 1H), 2.95 (triplet of triplet, 2.10-1.16 (m, 10H); n/z=509 [M−1]−.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([CH:17]([N:19]=[N+]=[N-])[CH3:18])([F:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Ni]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([CH:17]([NH2:19])[CH3:18])([F:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(N=[N+]=[N-])C1(F)CCN(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CC(N)C1(F)CCN(C(=O)OCc2ccccc2)C1
Yield: 90.1 %

Procedure:
A solution of 3-(1-azidoethyl)-3-fluoropyrrolidine-1-carboxylic acid benzyl ester (Example A16, 0.16 g, 0.5 mmol) in methanol (10 mL) is treated with Raney nickel (100 mg, wet weight) and shaken in a hydrogen atmosphere at room temperature and at 55 psi for 17 hours. The catalyst is removed by filtration through Celite, and the solvent is removed in vacuo to afford the title compound (0.12 g). 1H NMR (200 MHz, CDCl3): δ 7.30 (s, 5H), 5.12 (s, 2H), 3.84-3.22 (m, 5H), 2.23-1.79 (m, 4H), 1.20 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]([C:15]([O:28][CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([O:13]C)=[O:12])[CH:6]=[C:5]([O:30][CH3:31])[N:4]=1.[OH-].[K+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]([C:15]([O:28][CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([OH:13])=[O:12])[CH:6]=[C:5]([O:30][CH3:31])[N:4]=1
Reactant: COC(=O)C(Oc1cc(OC)nc(OC)n1)C(OC)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC(C(=O)O)C(OC)(c2ccccc2)c2ccccc2)nc(OC)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
550 mg (1.3 mmol) of methyl 2-(2,6-dimethoxy-4-pyrimidinyl-oxy)-3-methoxy-3,3-diphenylpropionate were dissolved in 5 ml of dioxane, 2.6 ml of 1N KOH solution were added, and the mixture was stirred at 100° C. for 3 h. The solution was diluted with 300 ml of water and extracted with ethyl acetate to remove unreacted ester. The aqueous phase was then adjusted to pH 1-2 with dilute hydrochloric acid and was extracted with ethyl acetate. After drying over magnesium sulfate and removal of the solvent by distillation, the residual foam (425 mg) was purified by MPLC, resulting in 205 mg (40%) of product as foam.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N+]([O-])=O)=[CH:15][C:14]=3[N+:22]([O-:24])=[O:23])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1>>[N:1]1([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:27]4[CH:28]=[CH:29][O:25][CH:26]=4)=[CH:15][C:14]=3[N+:22]([O-:24])=[O:23])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: OB(O)c1ccoc1
Reactant: O=[N+]([O-])c1ccc(Nc2cccc(-n3cccc3)c2)c([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cc(-c2ccoc2)ccc1Nc1cccc(-n2cccc2)c1
Yield: 86 %

Procedure:
N-(3-(1-Pyrrolyl)phenyl)-4-(3-furanyl)-2-nitroaniline (7k) was prepared analogously from 6k (Example 9) and 3-furanylboronic acid. Yield: 86%. Mp 129-131° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:18])[C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH:32][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH3:18])=[CH:17][CH:16]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CN(c1ccc(C(=O)O)cc1)c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(c1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A mixture of 4-((3-fluorophenyl)(methyl)amino)benzoic acid (0.100 g, 0.407 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.094 g; 0.407 mmol), HATU (0.170 g; 0.448 mmol) and N,N-diisopropylethylamine (0.176 mL; 1.02 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 20% ethyl acetate in dichloromethane) to yield 0.048 g (28%) of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:18])([CH2:8][CH2:9][C:10]([O:13][C:14](=[O:17])[CH2:15]Cl)([CH3:12])[CH3:11])[CH3:7])=[O:4].[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(Cl)Cl>[CH2:20]([NH:19][CH2:2][C:3]([O:5][C:6]([CH3:18])([CH2:8][CH2:9][C:10]([O:13][C:14](=[O:17])[CH2:15][NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:12])[CH3:11])[CH3:7])=[O:4])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCN
Reactant: CC(C)(CCC(C)(C)OC(=O)CCl)OC(=O)CCl
Solvent: ClCCl
Product: CCCCCCNCC(=O)OC(C)(C)CCC(C)(C)OC(=O)CNCCCCCC

Procedure:
The cleavable diol is made by the following manner. Compound (61) is reacted with 5 equivalents of 1-aminohexane (65) in methylene chloride. Wash with brine and dry to yield 2,5-dimethylhexane-2,5-diyl bis(2-(hexylamino)acetate) (66).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:13])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH2:23][CH:22]=[CH2:21])[CH:5]=1
Reactant: C=CCBr
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Yield: 98.7 %

Procedure:
To a solution of 3-hydroxy-4-nitro-benzoic acid methyl ester (50.0 g, 253.6 mmol) in acetone (1 L) was added potassium carbonate (105.0 gram, 759.7 mmol) and allyl bromide (44.0 mL, 508.4 mmol). The reaction mixture was heated to reflux overnight and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure to give 3-allyloxy-4-nitro-benzoic acid methyl ester as solid (59.4 g, 98.8%). 1H NMR (CDCl3) δ 3.96 (s, 3H), 4.75 (dt, 2H, J=5.0 Hz, 1.6 Hz), 5.36 (ddt, 1H, J=10.6 Hz, 1.4 Hz, 1.4 Hz), 5.50 (ddt, 1H, J=17.2 Hz, 1.6 Hz, 1.6 Hz), 6.05 (ddt, 1H, J=17.3 Hz, 10.6 Hz, 5.0 Hz), 7.69 (dd, 1H, J=8.33 Hz, 1.58 Hz), 7.75 (d, 1H, J=1.55 Hz), 7.83 (d, 1H, J=8.34 Hz).
Reaction SMILES: CN(C)[CH:3]=[N:4][C:5]1[S:6][CH:7]=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11].C(O)=[O:15]>O>[Cl:12][C:8]1[C:9]([C:10]#[N:11])=[C:5]([NH:4][CH:3]=[O:15])[S:6][CH:7]=1
Reactant: CN(C)C=Nc1scc(Cl)c1C#N
Reactant: O=CO
Solvent: O
Product: N#Cc1c(Cl)csc1NC=O
Temperature: 25 °C
Yield: 77 %

Procedure:
4.5 parts of N,N-dimethyl-N'-(4-chloro-3-cyano-thien-2-yl)-formamidine in a mixture of 20 parts of formic acid and 20 parts of water are heated at the boil for 1 hour. After the mixture has cooled to room temperature, the product is filtered off under suction, washed with water and dried. 3 parts (77% of theory) of N-(4-chloro-3-cyanothien-2-yl)-formamide are obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>>[CH3:1][NH:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=[S:30]
Reactant: CNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CNC(=S)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared by a similar method to Example 20 from N2-methyl-(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxamide [see Preparation 43] and Lawesson's reagent. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 25:75 (in 5% increments), by volume, ethyl acetate:hexane, to afford N2-methyl-(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarbothioamide as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:24]=[C:25]([CH:30]=[C:31]([CH2:33]O)[CH:32]=1)[C:26]([NH:28][CH3:29])=[O:27]>C(#N)C>[Br:20][CH2:33][C:31]1[CH:30]=[C:25]([CH:24]=[C:23]([Cl:22])[CH:32]=1)[C:26]([NH:28][CH3:29])=[O:27]
Reactant: CNC(=O)c1cc(Cl)cc(CO)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CNC(=O)c1cc(Cl)cc(CBr)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
(Step 2) Triphenylphosphine (1.45 g) was suspended in acetonitrile (50 ml), bromine (0.29 ml) was added, and the suspension was stirred at 40° C. for 30 min. A solution (10 ml) of 3-chloro-5-(hydroxymethyl)-N-methylbenzamide (1.1 g) obtained in Step 1 in acetonitrile was added to the reaction mixture, and the mixture was stirred at 90° C. for 5 hr. The reaction solution was quenched with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by basic silica gel chromatography (ethyl acetate:hexane=2:3) to give 3-(bromomethyl)-5-chloro-N-methylbenzamide (0.44 g).
Reaction SMILES: [CH:1]1CC(C(CC)CC=O)C[CH:5]=1.[CH:12]1([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[O:22])[CH2:16][CH2:15][CH:14]=[CH:13]1.C([Mg]Br)C.S(=O)(=O)(O)O>O.O1CCCC1>[OH:22][CH:21]([CH2:1][CH3:5])[CH2:20][CH2:19][CH2:18][CH2:17][CH:12]1[CH2:16][CH2:15][CH:14]=[CH:13]1
Reactant: O=CCCCCC1C=CCC1
Reactant: CCC(CC=O)C1CC=CC1
Agent: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)CCCCC1C=CCC1
Temperature: -30 °C

Procedure:
All work is performed an inert atmosphere using anhydrous tetrahydrofuran. The starting material, 3-(5-cyclopenten-3-yl) valeraldehyde {2-cyclopentene-1-pentanal} (75 g, 0.493 moles) is diluted in tetrahydrofurar (750 ml) and cooled in a -30° C. ethanol/dry ice bath. Ethyl magnesium bromide (0.493 moles) is added dropwise to the stirring reaction mixture for a period of over 2 hours. The mixture is warmed to 0° C. and water (100 ml), followed by 15% sulfuric acid (200 ml), is added and the organic phase separated. The aqueous layer is extracted with ether (2×300 ml) and the organic extracts are combined. The volume is reduced and the residue washed with brine (400 ml). The product is dried over anhydrous sodium sulfate and the remaining solvent removed under vacuum leaving a clear yellow oil. The crude product is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving clear, colorless oil (10.2 g, 0.056 moles).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([S:23][CH3:24])=[CH:18][CH:19]=2)[N:14]=1.CC(O)C>O>[CH3:24][S:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: CSc1ccc2ccc(N)nc2n1
Reactant: COc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(C(=O)Nc2ccc3ccc(SC)nc3n2)cc1
Temperature: 4 °C
Yield: 83.3 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (11.8 g), N,N'-carbonyldiimidazole (12.6 g) and 2-amino-7-methylthio-1,8-naphthyridine (9.6 g). The product produced by precipitation in water (15.8 g; m.p. 100° C.) is dissolved in boiling 2-propanol (180 cc). After 1 hour's cooling at 4° C., the crystallised solid is separated by filtration, washed with 2-propanol (10 cc) and then isopropyl ether (2×10 cc), and dried at 40° C. under reduced pressure (0.067 kPa . N-(7-methylthio-1,8-naphthyridin-2-yl)-4-methoxybenzamide (13.6 g) is produced, m.p. 130° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@:4]1([CH2:17][OH:18])[CH2:8][C@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5]1.[C:19]1([Se:25]N2C(=O)C3=CC=CC=C3C2=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.B(F)(F)F>C(Cl)Cl>[OH:18][CH2:17][C@:4]12[CH2:8][C@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14])[C@H:6]([Se:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@H:5]1[O:1][CH2:2][CH2:3]2
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@](CO)(CCO)C1
Reactant: O=C1c2ccccc2C(=O)N1[Se]c1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@]2(CO)CCO[C@@H]2[C@H]1[Se]c1ccccc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a 12-L three-neck round bottom flask equipped with a mechanical stirrer, Claisen adapter with a nitrogen inlet and a temperature probe, and a nitrogen outlet was charged with the product of Step B (382 g, 1.26 mol, 1 eq) and CH2Cl2 (6.5 L). N-(phenylseleno)phthalimide (419 g, 1.39 mol, 1.1 eq) was added followed by BF3 etherate (16 mL, 0.126 mol, 0.1 eq) directly added by graduated cylinder. The reaction steadily climbed from 15° C. to 24° C. and within 10 min, the reaction formed a pink precipitate. Ten min later, the reaction became thick with a white precipitate and the temperature began to decrease. The reaction was checked by HPLC and found to be complete. The reaction was filtered through Celite (removing the phthalimide impurity), the filter cake was washed with CH2Cl2 (750 mL) until the filtrate was no longer orange. The filtrate was transferred to a separatory funnel, washed with aqueous NaOH (0.5 M, 2×1350 mL), brine (2×1 L), and the organic layer was dried over Na2SO4. [A second run was conducted with 382 g of the product of Step B, under the same conditions, and was worked up and combined at this point]. With about 3 L organics left, toluene (3 L, ˜4 mL/g starting material) was added and the evaporation continued. Shortly after the toluene addition, crystallization occurred. The 20-L round bottom flask was transferred to a heating mantel, and the contents heated to 80° C., until the solid dissolved. The flask was transferred back to the rotary evaporator, reference material was used to seed the crystallization, and the flask swirled (no heat) until the product started to crystallize. Ice was added to the bath and the contents of the flask swirled at 15° C. (external temp) for 30 min. The product was filtered, washed with ice-cold toluene and air-dried for 1 h, and afforded the product of Step C. 1H NMR (CHLOROFORM-d) δ: 7.49-7.56 (m, 2H), 7.23-7.29 (m, 3H), 5.05 (br. s., 1H), 4.46 (br. s., 1H), 4.29 (s, 1H), 3.86-3.97 (m, 2H), 3.57-3.69 (m, 3H), 1.98-2.08 (m, 1H), 1.86-1.97 (m, 2H), 1.73-1.86 (m, 2H), 1.41 (s, 9H). Calculated for C19H27NO4Se: 436.1 (M+23). found: 436.1.
Reaction SMILES: [Cl:1][C:2]([N:5]=[C:6]=[O:7])([Cl:4])[Cl:3].[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][OH:17])[CH:12]=[CH:13][C:14]=1[Cl:15]>C(OCC)C>[Cl:1][C:2]([Cl:4])([Cl:3])[NH:5][C:6]([N:16]([C:11]1[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([Cl:8])[CH:10]=1)[OH:17])=[O:7]
Reactant: O=C=NC(Cl)(Cl)Cl
Reactant: ONc1ccc(Cl)c(Cl)c1
Solvent: CCOCC
Product: O=C(NC(Cl)(Cl)Cl)N(O)c1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
A solution of trichloromethyl isocyanate (16 grams; 0.1 mol) in diethyl ether (40 ml) is added dropwise, with stirring, to a solution of N-(3,4-dichlorophenyl) hydroxylamine (17.8 grams; 0.1 mol) in diethyl ether (60 ml) at room temperature. Stirring is continued for a period of about 1 hour resulting in the formation of a precipitate. The precipitate is recovered by filtration, is washed and dried to yield 1-trichloromethyl-3-(3',4'-dichlorophenyl)-3-hydroxyurea.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[N:2]1.C(N(C(C)C)CC)(C)C.[CH3:39][N:40]1[CH:44]=[C:43]([S:45](Cl)(=[O:47])=[O:46])[N:42]=[C:41]1[CH3:49]>C(Cl)Cl>[S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[S:45]([C:43]2[N:42]=[C:41]([CH3:49])[N:40]([CH3:39])[CH:44]=2)(=[O:47])=[O:46])=[N:2]1
Reactant: COc1ccc(-c2ccc(CNCCCNc3nsc4ncccc34)cc2)cc1
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-c2ccc(CN(CCCNc3nsc4ncccc34)S(=O)(=O)c3cn(C)c(C)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
N1-(Isothiazolo[5,4-b]pyridin-3-yl)-N3-((4′-methoxybiphenyl-4-yl)methyl)propane-1,3-diamine (100 mg, 0.25 mmol) was dissolved in anhydrous methylene chloride with diisopropylethylamine (0.11 mL, 0.63 mmol). The mixture was cooled in an ice-bath under nitrogen and a solution of 1,2-dimethylimidazole-4-sulfonyl chloride (58.4 mg, 0.30 mmol) in methylene chloride (5 mL) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and then washed successively with saturated sodium bicarbonate solution and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-scale reverse phase high performance liquid chromatography to yield N-(3-(isothiazolo[5,4-b]pyridin-3-ylamino)propyl)-N-((4′-methoxybiphenyl-4-yl)methyl)-1,2-dimethyl-1H-imidazole-4-sulfonamide (45 mg). 1H NMR (300 MHz, DMSO-d6): 8.64-8.66 (d, 1H), 8.45-8.50 (d, 1H), 7.52-7.75 (m, 8H), 7.28 (s, 1H), 6.95 (s, 1H), 6.82 (s, 1H), 3.99 (s, 2H), 3.89 (s, 3H), 3.55-3.65 (m, 5H), 2.88-2.90 (t, 2H), 2.50 (s, 3H), 1.99-2.10 ppm (t, 2H). MW=563 confirmed by LC-MS, tr=4.31 min (Method E) MH+=564.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].[C:11](/[CH:13]=[C:14](/[O-])\[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:12].[Na+].FC(F)(F)C(O)=O>O1CCOCC1>[NH2:12][C:11]1[N:5]([CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[N:6]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=1
Reactant: CCOC(=O)/C([O-])=C\C#N
Reactant: NNCc1ccccc1Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(N)n(Cc2ccccc2Cl)n1

Procedure:
2.29 g (14.60 mmol) of 1-(2-chlorobenzyl)hydrazine from Example 1 A are dissolved in 60 ml of dioxane under argon. To this are added 2.38 g 814.60 mmol) of sodium (1E)-1-cyano-3-ethoxy-3-oxo-1-propen-2-olate from Example 6 A and 2.66 g (1.80 ml; 23.36 mmol) of trifluoroacetic acid. The mixture is boiled under reflux overnight and reacted further without further workup. LC/MS (Method 2): Rt=2.45 min MS (EI): m/z=280 (M+H)+
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1([CH3:32])[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([CH3:31])[C:11]([CH3:30])=[C:12]([S:18]([NH:21][C:22](=[NH:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:20])=[O:19])[C:13]=2[CH3:17])[O:8]1)=[O:5])C.CCOC(C)=O.Cl>C(O)C.[OH-].[Na+]>[C:4]([CH2:6][C:7]1([CH3:32])[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([CH3:31])[C:11]([CH3:30])=[C:12]([S:18]([NH:21][C:22](=[NH:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)(=[O:19])=[O:20])[C:13]=2[CH3:17])[O:8]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CC1(C)CCc2c(C)c(S(=O)(=O)NC(=N)c3ccccc3)c(C)c(C)c2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(C)c(S(=O)(=O)NC(=N)c2ccccc2)c(C)c2c1OC(C)(CC(=O)O)CC2
Temperature: 25 °C
Reaction time: 30 h
Yield: 103.1 %

Procedure:
A solution of N-(2-ethoxycarbonylmethyl-2,5,7,8-tetramethylchroman-6-sulfonyl)benzamidine (1.54 g) in a mixture of ethanol (EtOH) (30 ml) and 1N NaOH (7.05 ml) was stirred at room temperature for 30 hours. EtOH was evaporated under reduced pressure to give a residue. A mixture of AcOEt and 1N HCl was added to the residue. The organic phase was washed with water and brine, and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give N-(2-carboxymethyl-2,5,7,8-tetramethylchroman-6-sulfonyl)benzamidine as a glass (1.49 g).