Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]2[N:10]([CH3:18])[C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:5][CH:4]=1)=O.[S:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27].N1CCCCC1>C(O)C>[CH3:18][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[N:17]=[C:9]1[CH2:8][O:7][C:6]1[CH:19]=[CH:20][C:3]([CH:1]=[C:25]2[S:21][C:22](=[O:27])[NH:23][C:24]2=[O:26])=[CH:4][CH:5]=1
Reactant: Cn1c(COc2ccc(C=O)cc2)nc2cccnc21
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cn1c(COc2ccc(C=C3SC(=O)NC3=O)cc2)nc2cccnc21
Yield: 79.2 %

Procedure:
A mixture of 0.35 g of 2-(4-formylphenoxymethyl)-3-methylimidazo [5,4-b]pyridine (prepared as described in Preparation 112), 0.31 g of 2,4-thiazolidinedione, 0.26 ml of piperidine and 10 ml of ethanol was heated under reflux for 4 hours. At the end of this time, the solvent was removed by distillation under reduced pressure and the residue was crystallized by trituration with water. The crystals were collected by filtration and washed with water and then with ethyl acetate, to give 0.38 g of the title compound, melting at 279-281° C.
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:18][CH2:19][CH3:20])([CH2:15][CH2:16][CH3:17])[C:11]2[C:6](=[CH:7][C:8]([F:21])=[CH:9][CH:10]=2)[C:5]1=[O:22].CSC(SC)=C1C(=O)C(CCCC)(CCCC)C2C(=CC=CC=2)C1=O.[NH2:50][C:51]1[CH:56]=[CH:55][C:54]([NH:57][C:58](=[O:64])[O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[CH:53][C:52]=1[S:65]([NH2:68])(=[O:67])=[O:66].NC1C=CC(OCC2C=CC=CC=2)=CC=1S(N)(=O)=O>>[F:21][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([CH2:15][CH2:16][CH3:17])([CH2:18][CH2:19][CH3:20])[C:13](=[O:14])[C:4]([C:3]3[NH:50][C:51]4[CH:56]=[CH:55][C:54]([NH:57][C:58](=[O:64])[O:59][C:60]([CH3:62])([CH3:63])[CH3:61])=[CH:53][C:52]=4[S:65](=[O:66])(=[O:67])[N:68]=3)=[C:5]2[OH:22])=[CH:10][CH:9]=1
Reactant: CCCC1(CCC)C(=O)C(=C(SC)SC)C(=O)c2cc(F)ccc21
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Agent: CCCCC1(CCCC)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Agent: Nc1ccc(OCc2ccccc2)cc1S(N)(=O)=O
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2cc(F)ccc21

Procedure:
The title compound was prepared according to the procedure of Example 5D, substituting the compound of Example 14H for the compound of Example 5C, and the compound of Example 17A for the compound of Example 2D. 1H NMR (300 MHz, DMSO-d6): δ 0.62 (m, 8 H) 0.91 (m, 2 H) 1.47 (d, J=17.28 Hz, 9 H) 1.93 (m, 2 H) 2.10 (m, 2 H) 7.63 (m, 5 H) 8.03 (s, 1 H) 9.77 (s, 1 H) 14.21 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:10][C@H:9]2[N:21]([CH3:32])[C:22](=[O:31])[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:42](Cl)(=[O:44])[CH3:43].CO>C(Cl)Cl>[F:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][C:22](=[O:31])[N:21]([C@H:9]2[C@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([C:42](=[O:44])[CH3:43])[CH2:17][CH2:16]3)=[O:14])[CH2:10]2)[CH3:32])=[CH:29][CH:28]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(C(=O)N2C[C@@H](N(C)C(=O)Oc3ccc(F)cc3)[C@H](c3ccc(Cl)cc3)C2)CC1
Reaction time: 5 h
Yield: 51.8 %

Procedure:
A mixture of 94 mg (0.204 mmol) 4-fluorophenyl (3S,4R)-4-(4-chlorophenyl)-1-(piperidine-4-carbonyl)pyrrolidin-3-yl(methyl)carbamate and 132 mg (1.02 mmol) DIPEA in 5 mL DCM was added 24.1 mg (0.3 mmol) acetyl chloride and stirred for 5 h. Methanol was added and stirred over night. The reaction mixture was extracted with sat NaHCO3 and the aqueous layer extracted with DCM. The combined organic layers were dried with Na2SO4, filtered off and concentrated in vacuum. The residue was subjected to purification by column chromatography on silica eluting with a gradient formed from DCM, methanol and NH3aq. The product containing fractions were evaporated to yield 53 mg (52%) of the title compound as light yellow foam. MS m/e: 502.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=[N:34]O)[C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([CH3:33])[C:13](=[O:14])[N:12]([CH2:15][C:16]([NH:18][C@H:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[C:11](=[O:32])[NH:10]2)=[CH:5][CH:4]=1.[H][H]>C(O)(=O)C.[Pd]>[C:21]([OH:23])(=[O:22])[CH3:20].[NH2:34][C:2](=[NH:1])[C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([CH3:33])[C:13](=[O:14])[N:12]([CH2:15][C:16]([NH:18][C@H:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[C:11](=[O:32])[NH:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C[C@H](NC(=O)CN1C(=O)N[C@@](C)(c2ccc(C(N)=NO)cc2)C1=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)C[C@H](NC(=O)CN1C(=O)N[C@@](C)(c2ccc(C(=N)N)cc2)C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 168.1 %

Procedure:
11 kg (22.869 mol) of ethyl (S)-3-(2-((S)-4-(4-(amino-hydroximino-methyl)-phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenyl-propionate were dissolved in 70 l of glacial acetic acid and this solution was introduced into a 125 l autoclave. A suspension of 1.0 kg of palladium/charcoal (10%; 50% water) and 5 l of glacial acetic acid was added to the solution. The mixture was hydrogenated for 15 h at 50° C. and 10 bar hydrogen pressure. The catalyst was filtered off with suction through a pressure filter under nitrogen and washed with 5 l of glacial acetic acid. The filtrate was completely evaporated in vacuo on a rotary evaporator at a bath temperature of 60° C. The residue was dissolved in 30 l of acetone and the solution was added, over 30 min and at 20° C., to 200 l of methyl tert-butyl ether. The mixture was subsequently stirred at room temperature for 1 h and the precipitated product was centrifuged. The filter cake was subsequently washed with 10 l of methyl tert-butyl ether, removed from the centrifuge and dried in vacuo. 10.1 kg (85%) of product were obtained. FAB-MS: 466 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[C:13]2[N:14]([C:18]([Br:22])=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1)[CH3:6])=[O:4].C(O)(=O)C.[O-:32][C:33]#[N:34].[Na+]>O>[Br:22][C:18]1[N:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C:9]3[C:23]([Cl:26])=[CH:24][CH:25]=[C:7]([N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH2:34])=[O:32])[C:8]=3[Cl:27])[C:13]2=[N:20][C:19]=1[CH3:21]
Reactant: N#C[O-]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(N)=O)c3Cl)cccn2c1Br
Reaction time: 1 h
Yield: 66 %

Procedure:
To a mixture of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-3-bromo-2-methylimidazo[1,2-a]pyridine (100 mg), acetic acid (0.5 ml) and water (1.0 ml) was added an aqueous solution (1 ml) of sodium cyanate (138 mg) at 40° C. The mixture was stirred at the same temperature for 1 hour and evaporated in vacuo. The residue was partitioned into dichloromethane and a saturated aqueous solution of sodium hydrogen carbonate and the organic layer was separated. The aqueous layer was extracted with dichloromethane twice. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=10:1, V/V) followed by crystallization from ethyl acetate-diethyl ether to give 3-bromo-8-[2,6-dichloro-3-[N-methyl-N-(ureidoacetyl)amino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (72 mg) as crystals.
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:18]=1[NH2:19].CCCCCC>C(O)C>[C:1]([C:3](=[CH:12][NH:19][C:18]1[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:17]=1[CH3:16])[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Reactant: Cc1cccc(C)c1N
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)NC(=O)C(C#N)=CNc1c(C)cccc1C
Yield: 73.2 %

Procedure:
A solution of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide (0.05 mol) and 2,6-dimethylaniline (0.05 mol) in 75 ml ethanol is refluxed for several hours until the 2,6-dimethylaniline disappears as checked by thin layer chromatography. On cooling, (precipitate not formed) hexane (about 400 ml) is added and the mixture is filtered to yield 10.52 g of α-cyano-β-(2,6-dimethylanilino)-N-ethoxycarbonylacrylamide, m.p. 138°-140°, which is cyclized by heating in ortho-dichlorobenzene for about 4 hours to yield 5-cyano-1-(2,6-dimethylphenyl)uracil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][CH:9]([C:17]1([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:30])[C:10]([O:12]C(C)(C)C)=[O:11]>C(Cl)Cl>[CH3:8][CH:9]([C:17]1([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]1=[O:30])[C:10]([OH:12])=[O:11]
Reactant: CC(C)CC1(C(C)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC1(C(C)C(=O)O)CCN(CCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 11.9 %

Procedure:
TFA (10.0 mL) is added to a solution of tert-butyl α-methyl-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (780 mg, 2.09 mmol) and CH2Cl2 (10 mL) at 0° C. The solution is stirred for 2.5 hours at 0° C. and 1.5 hours at room temperature. After concentration, the residue is partitioned between EtOAc and water. The organic layer is extracted several times with 10% NaOH, the combined basic layers acidified (4N HCl), and the acidic layers extracted several times with CH2Cl2. The CH2Cl2 layers are dried (MgSO4), filtered, and concentrated to provide 79 mg (12%) of the title compound as a white solid (mp 94°-95° C.).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)COC4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1.Br[C:60]1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(O)OC(C)C)=CC=3OC)N=2)=CC=1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][CH2:35][CH2:39][N:40]4[CH:44]=[C:43]([B:45]5[O:46][C:47]([CH3:53])([CH3:52])[C:48]([CH3:50])([CH3:51])[O:49]5)[CH:42]=[N:41]4)[O:30][CH:31]([CH3:32])[CH3:60])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CP(=O)(O)OC(C)C)cc2OC)ncc1C(F)(F)F
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CP(=O)(OCCCn3cc(B4OC(C)(C)C(C)(C)O4)cn3)OC(C)C)cc2OC)ncc1C(F)(F)F

Procedure:
Prepared analogously to Compound 44A replacing Compound 38C with propan-2-yl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 72B). MS (ESI): m/z 867.90/869.91 [M+H]+. UPLC: tR=1.60 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: C[O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]3[CH:20]([N:26]([CH:28]4[CH2:30][CH2:29]4)[CH3:27])[CH2:19][CH2:18][C:17]([CH3:32])([CH3:31])[C:16]=3[CH:15]=2)=[CH:8][CH:7]=1.[OH-].[K+].Cl>CO.O1CCCC1>[CH:28]1([N:26]([CH3:27])[CH:20]2[CH2:19][CH2:18][C:17]([CH3:32])([CH3:31])[C:16]3[CH:15]=[C:14]([C:13]#[C:12][C:9]4[CH:8]=[CH:7][C:6](/[CH:5]=[CH:4]/[C:3]([OH:33])=[O:2])=[CH:11][CH:10]=4)[CH:23]=[C:22]([O:24][CH3:25])[C:21]2=3)[CH2:29][CH2:30]1
Reactant: COC(=O)/C=C/c1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C#Cc2ccc(/C=C/C(=O)O)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A solution of (E)-3-{4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acrylic acid methyl ester (Intermediate 86, 0.12 g, 0.27 mmol) in methanol (4 mL) and tetrahydrofuran (3 mL) was treated with a 3M solution of potassium hydroxide (1 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230–400 mesh) using 5% methanol in ethyl acetate as the eluent to afford the title product as a white solid (0.041 g, 35%).
Reaction SMILES: Cl.[CH2:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[CH2:19][O:20][CH3:21])[CH3:3].[NH2:22][C:23](=[N:42]O)[C:24]1[CH:33]=[C:32]2[C:27]([CH2:28][CH2:29][N:30]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]2)=[CH:26][CH:25]=1>CCOC(C)=O>[CH2:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]2[O:16][N:22]=[C:23]([C:24]3[CH:33]=[C:32]4[C:27]([CH2:28][CH2:29][N:30]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]4)=[CH:26][CH:25]=3)[N:42]=2)=[CH:12][C:11]=1[CH2:19][O:20][CH3:21])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN1CCc2ccc(C(N)=NO)cc2C1
Reactant: CCC1CCCCN1c1ccc(C(=O)O)cc1COC
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC1CCCCN1c1ccc(-c2nc(-c3ccc4c(c3)CN(CC(=O)OC(C)(C)C)CC4)no2)cc1COC

Procedure:
Title compound was prepared following general procedure 2 starting from Intermediate 22 (188 mg; 0.6 mmol) and Intermediate 5 (174 mg; 0.6 mmol). The reaction mixture was diluted with EtOAc, washed with water and brine and evaporated under vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N+:22]([O-])=O)[CH:15]=2)=[CH2:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(OCC)(=O)C.C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([NH2:22])[CH:15]=2)=[CH2:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: C=C(c1ccc(OC)c(OCC)c1)c1ccc(OC)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(c1ccc(OC)c(N)c1)c1ccc(OC)c(OCC)c1
Temperature: 70 °C
Yield: 47.7 %

Procedure:
To a stirred solution of 1-(3-ethoxy-4-methoxy-phenyl)-1-(3-nitro-4-methoxy-phenyl)-ethene (0.9 g, 2.8 mmol) in ethyl acetate (10 mL) and ethanol (20 mL) was added tin (II) chloride dihydrate (3.5 g, 15.4 mmol). The mixture was heated at 70° C. for 1 hr. The mixture was poured into ice water (100 mL) and basified with 10 N sodium hydroxide to pH=10. The mixture was extracted with ethyl acetate (5×35 mL). The combined organic layers were washed water (60 mL), brine (60 mL) and dried (MgSO4). Removal of solvent and chromatography (silica gel) gave 5-[1-(3-ethoxy-4-methoxy-phenyl) -vinyl]-2-methoxy-phenylamine as a solid (0.4 g, 48% yield): mp 91-93° C.; 1H NMR (CDCl3) δ 1.43 (t, J=7.1 Hz, 3H, CH3), 3.75 (b, 2H, NH2), 3.86 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.06 (q, J=7.1 Hz, 2H, OCH2), 5.28 (d, J=6.5 Hz, 2H, CH2), 6.91-6.72 (m, 6H, CH); 13C NMR (CDCl3) δ 14.76, 55.50, 55.94, 64.26, 109.85, 110.91, 111.53, 113.12, 115.03, 118.67, 120.92, 134.59, 134.73, 135.58, 147.14, 147.69, 148.97, 149.59; Anal. Calcd for C18H21NO3: C, 72.22; H, 7.07; N, 4.68. Found: C, 72.16; H, 7.10; N, 4.74.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]3[N:18]([C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)[N:19]=[CH:20][C:13]=23)[CH2:4][CH2:3]1.[H-].[Na+].[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[NH:39][C:40]([C:42]1[CH:43]=[CH:44][CH:45]=[C:46]2[C:51]=1[CH2:50][N:49]([C:52]1[S:53][C:54]([CH2:62][CH2:63][CH2:64]I)=[C:55]([C:57]([O:59]CC)=[O:58])[N:56]=1)[CH2:48][CH2:47]2)=[O:41].[OH-].[Na+].[C:68]([OH:74])([C:70]([F:73])([F:72])[F:71])=[O:69]>CN(C=O)C.O.CO>[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[NH:39][C:40]([C:42]1[CH:43]=[CH:44][CH:45]=[C:46]2[C:51]=1[CH2:50][N:49]([C:52]1[S:53][C:54]([CH2:62][CH2:63][CH2:64][N:11]([C:12]3[N:17]=[CH:16][N:15]=[C:14]4[N:18]([C:21]5[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=5)[N:19]=[CH:20][C:13]=34)[CH2:10][CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[C:55]([C:57]([OH:59])=[O:58])[N:56]=1)[CH2:48][CH2:47]2)=[O:41].[C:68]([OH:74])([C:70]([F:73])([F:72])[F:71])=[O:69]
Reactant: CN1CCN(CCCNc2ncnc3c2cnn3-c2ccc(O)cc2)CC1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCN(CCCN(CCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)c2ncnc3c2cnn3-c2ccc(O)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution compound 84A (50 mg, 0.136 mmol) in DMF (5 ml) was added sodium hydride (27.2 mg, 0.680 mmol)(60%). The reaction mixture was stirred for 10 min and compound 2C (77 mg, 0.122 mmol) was added. The resulting mixture was stirred for 1 hour and methanol (3 ml), 10% NaOH and water (1 ml) were added. The mixture was stirred overnight, acidified with TFA and concentrated. The residue was dissolved in a mixture of DMSO-methanol and purified by reverse phase HPLC (mobile phase: 0%-60% acetonitrile in 0.1% TFA aqueous solution during 60 min) to provide the title compound 91 as a TFA salt: 1H NMR (500 MHz, PYRIDINE-D5) δ ppm 8.62 (1H, s), 8.41 (1H, s), 8.35 (2H, d), 7.94 (1H, d), 7.89 (1H, d), 7.77-7.81 (1H, m), 7.43 (1H, t), 7.24-7.33 (5H, m), 5.15 (2H, s), 3.93-4.01 (2H, m), 3.87 (2H, d), 3.81 (2H, t), 3.45 (2H, t), 2.92 (2H, t), 2.79-2.85 (4H, m), 2.62-2.69 (4H, m), 2.42-2.47 (5H, m), 2.18-2.28 (2H, m), 1.89-1.98 (2H, m); LCMS (APCI) m/e 844 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O-:8])=[O:7].[C:12](=O)([O-])[O-:13].[K+].[K+]>CO>[CH3:12][O:13][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C([O-])c1cccc(CCl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
To a stirred solution of 3-(chloromethyl)benzoate (25.5 g, 138.1 mmol) in methanol (150 mL) at room temperature was added potassium carbonate (95.4 g, 691 mmol). The resulting suspension mixture was stirred 24 h at room temperature, then 4 h at 50° C. After cooling down to room temperature, the insolubles were filtered off, the filtrate concentrated in vacuo and diluted with dichloromethane (500 mL), and extracted with water (250 mL). The aqueous phase was acidified with aq. HCl (1 M) to pH=4 and extracted with dichloromethane (3×300 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to afford 3-(methoxymethyl)benzoic acid as a colourless solid [20.9 g, yield 91%; HPLC/MS:m/z=165 (M−H); log P(HCOOH)=1.33].
Reaction SMILES: [CH:1]1([C:4]2[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=2[CH2:6][N:7]2[C:12]3[N:13]=[C:14](S(C)=O)[N:15]=[CH:16][C:11]=3[CH:10]=[CH:9][C:8]2=[O:20])[CH2:3][CH2:2]1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>>[CH:1]1([C:4]2[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=2[CH2:6][N:7]2[C:12]3[N:13]=[C:14]([NH:36][C:35]4[CH:34]=[CH:33][C:32]([N:29]5[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]5)=[CH:38][CH:37]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[CH:9][C:8]2=[O:20])[CH2:3][CH2:2]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)c1ncc2ccc(=O)n(Cc3ccccc3C3CC3)c2n1
Product: CN1CCN(c2ccc(Nc3ncc4ccc(=O)n(Cc5ccccc5C5CC5)c4n3)cc2)CC1
Yield: 29.2 %

Procedure:
8-(2-cyclopropylbenzyl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (80 mg, 0.24 mmol) and 4-(4-methylpiperazino)aniline (45 mg, 0.24 mmol) were stirred at 140° C. for 3 h. After completion, the reaction mixture was purified by silica gel column chromatography using chloroform:methanol (100:3). The crude product was recrystallized from acetonitrile to give the title compound (31 mg, 0.07 mmol, 29%). ESMS m/z 467 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.53 (s, 1H), 7.60 (d, J=9.3 Hz, 1H), 7.14-7.20 (m, 2H), 6.99-7.13 (m, 4H), 6.71 (br. s., 2H), 6.63 (d, J=7.5 Hz, 1H), 6.54 (d, J=9.3 Hz, 1H), 5.72 (s, 2H), 3.12-3.18 (m, 4H), 2.54-2.64 (m, 4H), 2.36 (s, 3H), 2.00-2.11 (m, 1H), 0.90-0.99 (m, 2H), 0.69-0.77 (m, 2H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([CH2:16][NH2:17])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1CCN(C(C(Cl)Cl)=O)CC1)C1C=CC=CC=1.[N-]=[N+]=[N-].[Na+].Cl[C:41]1[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][C:42]=1[N+:49]([O-:51])=[O:50].C([O-])(O)=O.[Na+]>CC(C)=O.CN(C=O)C.[Pd]>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14]([CH2:16][NH:17][C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][C:42]=2[N+:49]([O-:51])=[O:50])=[O:15])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCC(=O)N1CCC(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C(C(Cl)Cl)N1CCC(Cc2ccccc2)CC1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: N#Cc1ccc(NCC(=O)N2CCC(Cc3ccccc3)CC2)c([N+](=O)[O-])c1
Yield: 49.2 %

Procedure:
(4-Benzylpiperidinecarbonyl)methylamine was made by treatment of (4-benzylpiperidinecarbonyl)methylene chloride with NaN3 in aqueous acetone, followed by hydrogenation with 5% Pd/C. Reaction of (4-benzylpiperidinecarbonyl)methylamine (8.6 mmol) with 4-chloro-3-nitro-benzonitrile (10 mmol) in DMF (10 mL) in the presence of NaHCO3 (10 mmol) at 100° C. for 16 hours gave 4-[(4-benzylpiperidinecarbonyl)methyl]amino-3-nitrobenzonitrile (1.6 g, 49.2% of yield), which was then hydrogenated in MeOH in the presence of 5% of Pd/C (10% w/w) to produce 1-(4-benzylpiperidinecarbonyl)methyl-6-cyanobenzimidazole (1.3 g, 90% of yield). 1-(4-Benzylpiperidinecarbonyl)methyl-6-cyanobenzimidazole (0.57 mmol) was then carried through the Pinner reaction, followed by purification on TLC plates with 10% MeOH in CH2Cl2, and further purification by HPLC to give the title compound: mp: 68-70° C.; 1H NMR (CD3OD) δ8.52 (s, 1H), 8.20 (s, 1H), 7.75 (s, 2H), 7.29-7.24 (m, 2H), 7.18-7.16 (m, 3H), 5.43 (dd, J=17.2 Hz, J=24.5 Hz, 2H), 4.40 (d, J=12.8 Hz, 1H), 4.00 (d, J=12.8 Hz, 1H), 3.18 (t, J=12.8 Hz, 1H), 2.68 (t, J=12.8 Hz, 1H), 2.59 (d, J=7.00 Hz, 2H), 1.87-1.78 (m, 2H), 1.72-1.68 (m, 1H, 1.42-1.35 (m, 1H), 1.22-1.15 (m, 1H); 13C NMR (CD3OD) δ168.76, 166.06, 148.73, 141.23, 139.50, 130.17, 129.45, 129.33, 127.35, 127.11, 124.04, 120.40, 113.19, 47.38, 46.36, 43.93, 43.73, 39.15, 33.35, 32.73; MS: 188.8 (M+2H)2+ ; HRMS:376.2130 (obs.), 376.2137 (calcd.); Anal.: (C22H25N5O1 +1.85TFA+0.18HCl+0.5H2O).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([OH:18])[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1>>[N+:8]([C:7]1[C:2]([O:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([OH:18])[CH2:12][CH2:13]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1F
Reactant: OC1CCC(O)CC1
Product: O=[N+]([O-])c1cccnc1O[C@H]1CC[C@H](O)CC1

Procedure:
Prepared analogously to III.1 from 3.6 g 2-fluoro-3-nitropyridine and 2.9 g 1,4-cyclohexanediol.