Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([NH:10][C:11]1[C:12](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:13]([O:15]C)=O)=[O:9].[H-].[Na+]>C1(C)C=CC=CC=1>[OH:15][C:13]1[C:12]2[C:11](=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:10][C:8](=[O:9])[C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:21]
Reactant: COC(=O)c1ccccc1NC(=O)Cc1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1c(O)c2ccccc2[nH]c1=O

Procedure:
A mixture of methyl N-(o-tolylacetyl)anthranilate (2.8 g.) and sodium hydride (1.1 g. of a 50% w/w dispersion in mineral oil) in toluene (50ml.) was heated at 100° for 1 hr. The reaction mixture was cooled and extracted with water (2×50 ml.). The aqueous extract was acidified to pH 2. The solid which precipitated was filtered off, stirred together with hot ethanol (25 ml.), and the mixture filtered to give 4-hydroxy-3-o-tolylquinolin-2-one, m.p. over 300°.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(OC)(C)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(F)cc1
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COC(C)(C)C
Product: Oc1ccc(Oc2ccc(F)cc2)nc1
Temperature: 170 °C

Procedure:
A mixture of 6-bromo-pyridin-3-ol (8.0 g), 4-fluorophenol (15.5 g) and cesium carbonate (30 g) was heated to 170° C. for 6 hours. After the mixture reached room temperature, it was distributed between water and MTBE. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by chromatography (SiO2; EA/heptane 1:1.5) to provide the subtitle compound. MS ESI+: m/z=206 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21]Cl.[CH3:23][C:24]1([CH3:34])[O:28][C:27]2[C:29]([OH:33])=[CH:30][CH:31]=[CH:32][C:26]=2[CH2:25]1>>[CH3:23][C:24]1([CH3:34])[O:28][C:27]2[C:29]([O:33][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:3]3[C:4]([Cl:16])=[CH:5][C:6]([O:8][CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:7][C:2]=3[Cl:1])=[CH:30][CH:31]=[CH:32][C:26]=2[CH2:25]1
Reactant: ClCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: CC1(C)Cc2cccc(O)c2O1
Product: CC1(C)Cc2cccc(OCCCCOc3c(Cl)cc(OCc4ccccc4)cc3Cl)c2O1

Procedure:
In a first step as depicted in Scheme 1, an appropriately substituted phenol, for example, the known compound 2,6-dichloro-4-phenylmethoxyphenol, was reacted under basic conditions with a haloalkane derivative of a desired carbon chain length, for example 1-bromo-4-chlorobutane, to attach the bridging group B, thereby affording the corresponding 1,3-dichloro-2-(4-chlorobutoxy)-5-(phenylmethoxy)benzene (A). Intermediate (A) was then reacted under basic conditions with, for example, the known compound 2,2-dimethyl-2,3-dihydrobenzo[b]furan-7-ol, to attach moiety D, as well as the benzo-fused ring, affording the corresponding 2-[4-(2,2-dimethyl-(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene (B). Intermediate (B), for example 2-[4-(2,2-dimethyl-(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene, as set forth above, was then reduced with hydrogen gas in the presence of a catalyst, for example 10% palladium on carbon, providing the corresponding 4-[4-(2,2-dimethyl(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-3,5-dichlorophenol (C). Intermediate (C) was then reacted under basic conditions with, for example, 1,1,1,3-tetrachloropropane, which simultaneously dehydrohalogenates, thereby introducing the moiety -E-G-C(R4)═C(R5)(R5) into the molecule to provide Compound 12, a novel compound of formula I. Example 1 set forth below, provides a detailed method to how Compound 12 shown in Scheme 1 was prepared.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.OC1C=CC=CC=1/C=N/O>>[O:15]([C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1
Reactant: Nc1ncccc1Br
Agent: O/N=C/c1ccccc1O
Product: Nc1ncccc1Oc1ccccc1

Procedure:
Prepared according to the method of Example 7 Step A, starting with bromopyridin-2-amine, phenol, and (E)-2-hydroxybenzaldehyde oxime (20.61 g, 150.3 mmol).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]#[N:22])=[CH:20][C:15]=3[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([Cl:32])[CH:25]=3)[C:13]2=[O:33])[CH2:8][CH2:7]1.Cl>O.O1CCOCC1>[NH:5]([C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]#[N:22])=[CH:20][C:15]=3[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([Cl:32])[CH:25]=3)[C:13]2=[O:33])[CH2:8][CH2:7]1)[C:2]([NH2:3])=[O:1]
Reactant: N#C[O-]
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](N)CC3)c3ccc(C#N)cc32)cc1Cl
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](NC(N)=O)CC3)c3ccc(C#N)cc32)cc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of potassium cyanate (40 mg) in water (1 mL) was added to a mixture of 1-(trans-4-aminocyclohexyl)-3-(3-chloro-4-methoxybenzyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2-one (100 mg) and 1N-hydrochloric acid (0.25 mL) in 1,4-dioxane (1.4 mL). The reaction mixture was stirred at ambient temperature for 20 hours. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was triturated with diethyl ether and washed with isopropyl alcohol to give 1-(trans-4-ureidocyclohexyl)-3-(3-chloro-4-methoxybenzyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2-one (71mg) as powders.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)=[CH:4][C:3]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][C:34]=1[C:35]([F:38])([F:37])[F:36])[NH:31][CH2:30][CH2:29]2>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:31]2[C:32]3[C:28](=[CH:27][C:26]([O:25][CH3:24])=[C:34]([C:35]([F:37])([F:38])[F:36])[CH:33]=3)[CH2:29][CH2:30]2)=[O:17])=[CH:4][C:3]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: O=C(Nc1ccc(Cl)c(-c2cccnc2)c1)Oc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1ccc(Cl)c(-c3cccnc3)c1)CC2
Temperature: 120 °C
Yield: 36.2 %

Procedure:
Phenyl N-(4-Chloro-3-(pyrid-3-yl)phenyl)carbamate (D67) (0.12 g, 0.00037 mole) in dry dimethylformamide (6 ml) was treated under argon, with 5-methoxy-6-trifluoromethylindoline (D11) (0.08 g, 0.00037 mole) and heated to 120° C. for 2 hours. After cooling to ambient temperature, the solvent was removed in vacuo. The residue was partitioned between 1N aqueous sodium hydroxide solution and dichloromethane. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was triturated in diethyl ether, filtered and dried in vacuo at 60° C. to afford the title compound (0.06 g, 36%) as a grey-green solid (mp 210-213° C.)
Reaction SMILES: [H-].[Na+].COC(CP(OC)(OC)=O)=O.C(OC1C(C)=C2C(=C(C)C=1C)OC(O)(C)CC2)(=O)C.C[CH:34]([C:38]1([CH3:55])[CH2:47][CH2:46][C:45]2[C:40](=[C:41]([CH3:54])[C:42]([CH3:53])=[C:43]([O:49]C(=O)C)[C:44]=2[CH3:48])[O:39]1)[C:35]([O-:37])=[O:36].[OH-].[Na+]>O1CCCC1.O.C(O)C>[OH:49][C:43]1[C:44]([CH3:48])=[C:45]2[C:40](=[C:41]([CH3:54])[C:42]=1[CH3:53])[O:39][C:38]([CH2:34][C:35]([OH:37])=[O:36])([CH3:55])[CH2:47][CH2:46]2
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(C)C(=O)[O-])O2
Agent: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(O)O2
Agent: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC(=O)O)O2
Reaction time: 0.25 h

Procedure:
In a dried flask under N2, a suspension of 47.2 g (1.10 mol) of 56 percent by weight sodium hydride in mineral oil in 1000 ml of tetrahydrofuran was stirred as 209.4 g (1.15 mol) of trimethyl phosphonoacetate was added over 2.25 hr. The white paste was stirred for 0.25 hr and then a solution of 132.2 g (0.50 mol) of (±)-6-acetoxy-2-hydroxy-2,5,7,8-tetramethylchroman in 1000 ml of tetrahydrofuran was added over 0.50 hr. The pale yellow suspension was stirred at 23° C for 18 hours and then heated at reflux for 4.0 hours. The cooled solutions from two such reactions were stripped of solvent and worked up and dried by the procedure given in Example 1 to give a cloudy red-brown oil containing (±)-methyl-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)acetate. To a solution of this material in 2000 ml. of ethanol, there was added 2000 ml. of H2O and 240 g. (6.0 mol.) of NaOH. The solution was stirred at 23° C. for 4 hours, washed with petroleum ether (b.p. 30°-60° C.), diluted with 6000 ml. of ice-H2O and acidified by the dropwise addition over 0.50 hour of 600 ml. of concentrated aqueous HCl. The solid was removed by filtration, washed with H2O and crystallized from ethanol-H2O to give (±) -(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid as a light tan powder: m.p. 168°-171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[F:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH:32][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCOCCCF
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCOCCCF)ccc21
Yield: 16.9 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(3-fluoro-propoxy)-ethyl]-amide (12 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (55 mg), 2-(3-fluoro-propoxy)-ethylamine (50 mg), HBTU (60 mg), and DIEA (50 uL) in DMF (800 uL). LC/MS: m/z 463.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:27])[C:10]([NH:12][NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([CH3:23])[C:16]=2[CH2:24][CH3:25])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:27])[C:10]([NH:12][NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH3:23])[C:16]=2[CH2:24][CH3:25])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCc1c(C(=O)NNC(=O)C(O)c2cc(F)cc(F)c2)ccc(OC)c1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1c(C(=O)NNC(=O)C(O)c2cc(F)cc(F)c2)ccc(O)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.8 %

Procedure:
70.0 g of N′-[2-(3,5-difluorophenyl)-2-hydroxyacetyl]-2-ethyl-4-methoxy-3-methylbenzohydrazide (A1) are suspended in 350 ml of dichloromethane. 105 ml of boron tribromide are then added dropwise. The reaction mixture is stirred at room temperature for 3 hours. The resultant solution is subsequently carefully decanted into one litre of ice-water. The aqueous phase is extracted twice with 500 ml of ethyl acetate. The combined organic phases are then extracted once with 300 ml of water, dried over sodium sulfate and subsequently filtered. The filtrate is concentrated in vacuo. The resultant residue is, then recrystallised from 500 ml of acetonitrile using activated carbon, giving 32.2 g of the title compound as colourless solid having a melting point of 187.4° C. (MS: 365 (MH+), TLC: Rf=0.29 (cyclohexane/methyl tert-butyl ether 1:4, parts by volume).
Reaction SMILES: [CH2:1]([CH:3]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][O:5][C:6]1[CH:23]=[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:15](=[O:22])[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:8](=[C:9]23)[CH:7]=1)[CH3:2].[Br:28]N1C(=O)CCC1=O>CN(C=O)C>[Br:28][C:23]1[C:6]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][C:8]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15](=[O:22])[C:14]3[C:9]=2[C:10]=1[CH:11]=[CH:12][CH:13]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC(CC)COc1cc2c3c(cccc3c1)C(=O)c1ccccc1-2
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1cc2c3c(cccc3c1Br)C(=O)c1ccccc1-2
Temperature: 50 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
A 500 ml three neck round bottom flask was equipped with a mechanical stirrer, heating mantle and condenser. To the flask was added 28.5 g 2-[(2-ethylhexyl)oxy]-7H-benzo[de]anthracene-7-one, 15 g N-bromosuccinimide and 160 g DMF. The mixture was agitated well, heated to 50° C. and held at 50° C. for two hours. The mixture was cooled to 0° C. and, after several hours, the mixture was filtered to recover the solid product. The solid was suspended in 250 g water, stirred well and filtered. The yellow solid product was dried in a 50° C. oven for ten hours to give 27.1 g of 3-bromo-2-[(2-ethylhexyl)oxy]-7H-benzo[de]anthracene-7-one with melting point of 85-88° C.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][NH2:29])=[CH:23][C:22]=3[F:30])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][NH:29][C:41]([NH:40][CH2:38][CH3:39])=[O:42])=[CH:23][C:22]=3[F:30])[CH2:19][CH2:20]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CN)cc3F)CC2)CC1
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)NCc1cc(F)c(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 16a (23 mg) and triethylamine (0.1 mL) in 1 mL of DCM was added a drop of ethyl isocyanate (excess) and the reaction mixture was stirred for 30 minutes at room temperature. The mixture was then quenched with water and extracted with DCM to give 33 mg of crude product which was purified on preparative HPLC to give 16-1: LC-MS 496.2 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)#[N:33]>>[CH:18]1([N:13]2[C:12]([C:37]3[CH:38]=[CH:39][C:34]([C:32]#[N:33])=[CH:35][CH:36]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2c3c(nn2C2CCCCC2)CCNCC3)cc1
Yield: 96.9 %

Procedure:
The title compound (135.4 mg) was prepared as in Example 177, Steps C and D, using 203.8 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 198 mg of 4-cyanophenylboronic acid. MS (ESI): exact mass calculated for C20H24N4, 320.43; found, m/z 321.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.93 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 3.92-3.84 (m, 1H), 3.43-3.38 (m, 2H), 3.19-3.15 (m, 2H), 2.80-2.75 (m, 2H), 1.98-1.80 (m, 6H), 1.71-1.64 (m, 1H), 1.32-1.20 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[C@@H:7]([NH:37]C(OC(C)(C)C)=O)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:45])[C@@H:7]([NH2:37])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:27])=[O:28])=[C:11]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (S)-3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-2-tert-butoxycarbonylaminopropionic acid tert-butyl ester (760 mg, 1.15 mmol) in methylene chloride (10 mL) is added TFA (3 mL) and the mixture is stirred at RT for 45 min. The solution is carefully poured into 8% NaHCO3 solution (50 mL) and the mixture is extracted with methylene chloride. The solvent is removed under reduced pressure to give the title compound which is used immediately in the next step.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([C:17]#[N:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]=1[F:19]>CCO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17]#[N:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]=1[F:19]
Reactant: CCOC(=O)C(C#N)=Cc1ccc(Cl)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C#N)Cc1ccc(Cl)c(F)c1
Reaction time: 0.08 h
Yield: 99 %

Procedure:
A solution NaBH4 (15 mg, 0.39 mmol) in EtOH (4 mL) was cannulated into a mixture of the ethyl 3-(4-chloro-3-fluorophenyl)-2-cyanoacrylate (200 mg, 0.79 mmol) in EtOH (2 mL) at room temperature. After 5 minutes, the mixture was quenched with 0.1N HCl, concentrated in vacuo, diluted with H2O, extracted with DCM, dried over MgSO4, concentrated and subject to flash chromatography (SiO2 with DCM) to give ethyl 3-(4-chloro-3-fluorophenyl)-2-cyanopropanoate (0.20 g, 58%). LCMS (APCI+) [M+H]+ 254.3.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH:28](=O)[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cn1cncc1CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cncn5C)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-((1-methyl-1H-imidazol-5-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.030 g, 0.076 mmol, 1 eq), EtOH (1.95 mL) and DMF (0.29 mL), p-anisaldehyde (0.011 g, 0.083 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.23 mL, 0.23 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aq NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained as a solid after trituration with diethyl ether (0.009 g, 23%); 1H-NMR (500 Mz, DMSO-d6): δ 2.55-2.62 (m, 4H, piperazine N(CH2)2), 3.54 (s, 2H, NCH2), 3.60-3.66 (m, 4H, piperazine N(CH2)2), 3.68 (s, 3H, imidazole Me), 3.84 (s, 3H, OMe), 6.80 (s, 1H, imidazole 4-H), 7.09 (d, J=9.0 Hz, 2H, ArH, C6H4), 7.57 (s, 1H, imidazole 2-H), 8.13 (d, J=9.0 Hz, 2H, ArH, C6H4), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.35 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=2.78 min—482/484 [(M+H+), Br isotopic pattern, 100%]. ESI-HRMS: Found: 482.1295, calculated for C22H25BrN7O (M+H)+: 482.1304.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[S:25](Cl)(=[O:27])=[O:26])=[CH:19][CH:18]=1>N1C=CC=CC=1>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[CH:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[S:25]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:27])=[O:26])=[CH:21][CH:22]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(-c2ccco2)cc1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccc(-c2ccco2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
2-Aminobenzenesulfonamide (61 mg, 0.35 mmol) was dissolved in pyridine (2.5 mL) and (E)-2-[4-(2-furyl)phenyl]ethenesulfonyl chloride) (see General procedure for synthesis of styrenyl sulfonyl chlorides) (95 mg, 0.35 mmol) was added. The reaction was stirred at RT overnight. The solvent was removed, the residue was partitioned between water and ethyl acetate, made acidic (HCl) and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with water, treated with brine, dried (MgSO4), and evaporated to give the title compound (140 mg, 98%).
Reaction SMILES: [NH:1]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:16][CH:17]([OH:20])[CH2:18][OH:19]>>[OH:20][CH:17]([CH2:18][OH:19])[CH2:16][N:1]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH2:9][CH2:8][N:7]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH2:6][CH2:5][N:4]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH2:3][CH2:2]1
Reactant: C1CCNCCNCCNCCNC1
Reactant: OCC(O)CCl
Product: OCC(O)CN1CCCCN(CC(O)CO)CCN(CC(O)CO)CCN(CC(O)CO)CC1

Procedure:
From 1,4,7,10-tetraazacyclotetradecane (1.1.4), 1-chloro-2,3-propanediol (commercially available) and base.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[N:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[S:27])[N:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(=O)n3c(nc2c1)CCCCC3
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(=S)n3c(nc2c1)CCCCC3

Procedure:
9 g of 3-methyl-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazolin-12-one was treated with 15 g of Lawesson's reagent in toluene at reflux under nitrogen until the starting material was consumed, checked by TLC, using chloroform as eluent (24 hours). The mixture was concentrated in vacuo and chromatographed on silica gel, using chloroform as eluent. The bright yellow material was recrystallized from hexane-ethyl acetate.
Reaction SMILES: [CH2:1]([N:8]([C:35](=[O:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:12][C:11]=1[O:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.ClCCl>>[CH2:1]([N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:12][C:11]=1[O:26][CH2:27][C:28]([OH:30])=[O:29])[C:35](=[O:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(-c2cccc3ccccc23)cc1OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(-c2cccc3ccccc23)cc1OCC(=O)O

Procedure:
A room temperature solution of Example 20D (300 mg, 0.54 mmol) in 1:1 TFA/dichloromethane was stirred for 2 hours and concentrated to provide the desired product.