Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([NH:15][NH2:16])=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:17]1([CH2:23][C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:13]([NH:15][NH:16][C:24](=[O:25])[CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)NNC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-amino-6-bromo-5-(trifluoromethyl)picolinohydrazide (Int. H) (150 mg, 0.502 mmol) in NMP (4 ml) was added phenylacetic acid (57 mg, 0.419 mmol) followed by DIPEA (366 ul, 2.093 mmol). To this solution was added HATU (239 mg, 0.628 mmol) portionwise and the reaction mixture was left to stir at RT for 1 h. The reaction mixture was added to EtOAc (25 ml) and the organic portion was separated and washed with 0.1M HCl (2×15 ml), water (25 ml), 0.1M NaOH (2×15 ml), water (25 ml), brine (25 ml) dried (Mg SO4) and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 1:1 EtOAc/iso-hexane to afford the title compound as a yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 10.30 (1H, s), 10.20 (1H, s), 7.70 (1H, s), 7.38 (4H, m), 7.25 (3H, m), 3.55 (2H, s). LC-MS Rt=1.43 min [M+H]+ 417.1 Method 2minLC_v002.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32])[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[O:42][C:43]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][C:44]=3[N:45]=2)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[O:42][C:43]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][C:44]=3[N:45]=2)=[CH:37][CH:36]=1)[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc2oc(-c3ccc(CCl)cc3)nc2c1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1O)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1OCc1ccc(-c2nc3cc(C)ccc3o2)cc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
5 g (11.35 mmol) of ethyl 5-{(tert-butoxycarbonyl)[2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate, 3.51 g (13.62 mmol) of 2-[4-(chloromethyl)phenyl]-5-methyl-1,3-benzoxazole and 3.92 g (28.37 mmol) of potassium carbonate in 50 ml of acetonitrile were heated to 110° C. and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed repeatedly with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1→2:1). This gave 6.59 g (9.96 mmol, 87% of theory) of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:5]=1[C:6]#[N:7])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>CN(C)C=O>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:12][C:10]1[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:3][CH2:1][CH3:2])[N:11]=1
Reactant: CCOc1nc(C)c([N+](=O)[O-])cc1C#N
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCOc1nc(C=CN(C)C)c([N+](=O)[O-])cc1C#N
Temperature: 25 °C

Procedure:
To a stirred solution of the compound prepared in Example 444 (0.86 g) in N,N-dimethylformamide (10 mL) at ambient temperature was added N,N-dimethylformamide dimethyl acetal (94%, 0.65 mL). The resulting solution was stirred and heated to reflux for 30 minutes. After cooling to ambient temperature, the solution was concentrated to provide the title compound (1.07 g) with the following physical data.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=1.[NH:24]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]1>CC(O)C>[CH:18]([NH:17][C:15]([C@H:12]1[CH2:13][CH2:14][C@@H:9]([NH:8][C:6]2[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=[C:2]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)[CH:7]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:20])[CH3:19]
Reactant: O=S1(=O)CCNCC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Solvent: CC(C)O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(N3CCS(=O)(=O)CC3)ncc2[N+](=O)[O-])CC1

Procedure:
A suspension of cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (100 mg, 0.293 mmol) and thiomorpholine-1,1-dioxide (198 mg, 1.467 mmol) in 2-propanol (1 mL) was irradiated in the microwave for 90 minutes at 170° C. The reaction mixture was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide cis-N-isopropyl-4-(5-nitro-2-(1,1-dioxido-4-thiomorpholinyl)pyridin-4-ylamino)cyclohexanecarboxamide as a yellow powder (112 mg, 87% yield). MS, m/z (C19H29N5O5S): Calcd, 439.2. found, 440.1 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:6]([N+:11]([O-])=O)=[CH:7][C:8]=1[CH2:9][CH3:10])[NH2:5].O.O.Cl[Sn]Cl>>[NH2:11][C:6]1[CH:7]=[C:8]([CH2:9][CH3:10])[C:2]([Cl:1])=[CH:3][C:4]=1[NH2:5]
Reactant: CCc1cc([N+](=O)[O-])c(N)cc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: CCc1cc(N)c(N)cc1Cl
Yield: 99.4 %

Procedure:
A solution of 271 mg (1.35 mmol) of 34 and 1.24 g (5.49 mmol) of SnCl2.2H2O, in 5 mL of absolute alcohol was refluxed for 2 h. It was evaporated and the residue was treated with 1 N NaOH to pH=10. The mixture was extracted with CH2Cl2 (3×10 mL). The extract was dried (MgSO4) and evaporated to leave 229 mg (99%) of a yellow solid. 1H NMR (CDCl3), 1.165 (t, 3, J=7.5), 2.594 (q, 2, J=7.2), 6.560 (s, 1), 6.696 (s, 1).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]2[N:11]3[C:12](=[O:24])[NH:13][C:14]3[C:15]2=[N:21][NH:22][CH:23]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CN1C(=O)CCC1.O>[CH:25]1([NH:28][C:12]([NH:13][C:14]2[C:15]([C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:8]([CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:9][C:10]=4[N:11]=3)=[N:21][NH:22][CH:23]=2)=[O:24])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: O=c1[nH]c2c[nH]nc2c2nc3ccc(CN4CCOCC4)cc3n12
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)NC1CC1
Temperature: 100 °C
Yield: 72.5 %

Procedure:
To a mixture of 7-morpholin-4-ylmethyl-2,4-dihydro-1,2,4,5a,10-pentaaza-cyclopenta[a]fluoren-5-one (10.7 g, 32.9 mmol) in NMP (65 mL) was added cyclopropylamine (6.9 mL, 99 mmol). The mixture was heated at 100° C. for 5 h. LC/MS analysis indicated ˜75% conversion to product, therefore a further portion of cyclopropylamine (2.3 mL, 33 mmol) was added, the mixture heated at 100° C. for 4 h and then cooled to ambient. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic portion was washed with sat. aq. NH4Cl (2×50 mL) and brine (50 mL) and then the aqueous portions re-extracted with EtOAc (3×100 mL). The combined organic portions were dried over MgSO4 and reduced in vacuo to give 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea as an orange glassy solid (9.10 g).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:10]=[C:9]([C:11](=[O:16])N(C)OC)[CH:8]=[CH:7][N:6]=1.S([O-])(O)(=O)=O.[K+]>C1COCC1.O>[Cl:4][C:5]1[CH:10]=[C:9]([C:11](=[O:16])[CH3:1])[CH:8]=[CH:7][N:6]=1
Reactant: CON(C)C(=O)c1ccnc(Cl)c1
Reactant: C[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methylmagnesium bromide (30 mL of 3.0 M in THF) was added a solution of 2-chloro-4-(N-methyl-N-methoxycarbamoyl)pyridine (6.0 g, 0.03 mol) in 20 mL of THF at 0 C. The reaction mixture was stirred overnight while allowing to warm up to room temperature. A solution of potassium hydrogensulfate (12 g) in 300 mL of water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated 4.0 g (86%) of product as a yellow oil. This was used in next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH2:10].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]([NH:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[O:22])[N:20]=2)[CH:17]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNC(=O)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using (2-methoxyphenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@@H:9]3CC[CH2:15][N:8]3[C:7](=[O:16])[C:6]=2[CH:17]=1.N1CCC[C@H]1C(O)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]([CH3:15])[C:7](=[O:16])[C:6]=2[CH:17]=1
Reactant: Cc1ccc2c(c1)C(=O)N1CCC[C@H]1C(=O)N2
Agent: O=C(O)[C@@H]1CCCN1
Product: Cc1ccc2c(c1)C(=O)N(C)CC(=O)N2

Procedure:
(S)-7-methyl-1,2,3,11a-tetrahydro-5H-pyrrolo (2,1-c) (1,4) benzodiazepine-5,11(10H)-dione by reaction with L-proline. M.p. 243.1°-244.5° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])[CH2:12][CH:11]([C:22](O)=[O:23])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:26]=[C:27]([CH:29]1[CH2:31][CH2:30]1)[NH2:28]>>[CH:29]1([C:27]2[N:28]=[C:22]([CH:11]3[CH2:10][CH:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=4)[CH2:14][N:13]([C:15]([N:17]4[CH2:18][CH:19]([OH:21])[CH2:20]4)=[O:16])[CH2:12]3)[O:23][N:26]=2)[CH2:31][CH2:30]1
Reactant: NC(=NO)C1CC1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CC(O)C3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CC(O)C3)C2)cc1

Procedure:
60 mg (0.18 mmol) of the compound from Example 138A and 27 mg (0.27 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 24 mg (33% of theory)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14]3)[C:6]=2[N:19]=1.IC.[CH3:22]N(C)C(=O)C.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:22])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14]3)[C:6]=2[N:19]=1
Reactant: CC1CCC(N2CCC(=O)Nc3cnc(Cl)nc32)C1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC1CCC(N2CCC(=O)N(C)c3cnc(Cl)nc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.14 g (0.0005 mole) of (rac)-2-chloro-9-(3-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-58), 0.047 mL (0.00075 mole) of iodomethane and 1 mL of N,N-dimethylacetamide at 0 degrees, was added 0.03 g (0.00075 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.132 g of (rac)-2-chloro-5-methyl-9-(3-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-58) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][OH:12])[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH:11]=[O:12])[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C=O

Procedure:
To a well stirred mixture of (3S*,4S*)-4-hydroxymethyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butylester 3-ethyl ester (3.21 g, 11.74 mmol) and Dess-Martin periodinane (2.63 g, 11.74 mmol) in CH2Cl2 (30 mL), slowly wet CH2Cl2 (232 μL of water in 10 mL of CH2Cl2) is added. The clear solution becomes cloudy toward the end of wet CH2Cl2 addition. The mixture is diluted with Et2O, then concentrated to a few mL of solvent by rotary evaporation. The residue is taken up in Et2O and then washed with a 1:1 10% Na2S2O3 saturated aqueous NaHCO3, followed by H2O and brine. The aqueous washings are back-extracted with Et2O, and this organic layer is washed with H2O and brine. The combined organic layers are dried with Na2SO4, filtered and concentrated. The crude mixture is used in the next step without further purification. TLC, Rf (c-hexane/AcOEt 8:2)=0.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]1)[CH2:9][CH2:10][NH:11][C:12](=[O:14])[O-:13])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+].Cl.[OH2:32]>C(Cl)(Cl)(Cl)Cl.C(#N)C.O.[Ru](Cl)(Cl)Cl>[CH3:4][C:1]([CH3:3])([O:5][C:6](=[O:24])[NH:7][CH:8]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]([OH:32])=[O:23])[CH2:17][CH2:16]1)[CH2:9][CH2:10][NH:11][C:12](=[O:13])[O:14][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:2]
Reactant: O
Reactant: CC(C)(C)OC(=O)NC(CCNC(=O)[O-])C1CCC(CCO)CC1
Agent: Cl[Ru](Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCC(NC(=O)OC(C)(C)C)[C@H]1CC[C@H](CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the tert-butyl-1-(4-(2-hydroxyethyl)cyclohexyl)propane-1,3-diyldicarbamate (1.95 mmol), ruthenium (III) chloride hydrate (0.008 g, 0.039 mmol), sodium periodate (1.67 g, 2.8 mmol) in carbon tetrachloride (10 mL), acetonitrile (10 ml) and water (10 mL) was stirred at rt for 2 h. The reaction mixture was cooled to 0° C. and added 0.5N HCl (10 mL), extracted with DCM, dried over Na2SO4. Purification by flash column chromatography (eluent: 40% EtOAc in hexanes) gave the titled acid as white foam (0.67 g, 83%). LC/MC: 437.1 (MNa)+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11](/[CH:13]=[CH:14]\[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[C:10]([O:27][Si](C(C)(C)C)(C)C)=[C:9]([O:35][Si](C(C)(C)C)(C)C)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+]>CO.CN(C)C=O.C(O)(=O)C.C(OC)(C)(C)C>[C:1]1([C:7]2[CH:12]=[C:11](/[CH:13]=[CH:14]\[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[C:10]([OH:27])=[C:9]([OH:35])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(/C=C\c2cc(-c3ccccc3)cc(O[Si](C)(C)C(C)(C)C)c2O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc(/C=C\c2cc(-c3ccccc3)cc(O)c2O)cc(OC)c1OC
Reaction time: 6 h

Procedure:
To a solution of 24 (0.05 g, 0.082 mmol) in methanol:dimethylformamide 1:1 (2 mL), acetic acid was added (0.025 mL, 0.41 mmol) followed by potassium fluoride (0.024 mg, 0.41 mmol). The mixture was stirred for 6 hours then diluted with tertbutylmethyl ether (50 mL) and washed with water (10 mL) then brine (50 mL), then dried over sodium sulphate. The solvent was removed under reduced pressure to give a crude which was purified by column (cyclohexane:AcOEt 6:4+1% AcOH) to give 0.097 g of ZSB-80:
Reaction SMILES: Cl[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1.NC(N)=[S:24].CCO.Cl.O.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>>[SH:24][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccc(Cl)nc1
Reactant: NC(N)=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccc(S)nc1
Reaction time: 16 h
Yield: 88.2 %

Procedure:
6-Chloro-N-(4-trifluoromethyl-benzyl)-nicotinamide (Preparation 85, 4.0 g, 13 mmol) was added to a warm solution of thiourea (1.01 g, 13.2 mmol) in EtOH (20 mL, 300 mmol). The mixture was heated 1 h at reflux. LC/MS indicated mostly SM. 1 additional equivalent of thiourea was added, and the reaction mixture was heated at reflux. After 16 h, LC/MS shows conversion to the intermediate along with a small amount of product. The reaction mixture was concentrated in vacuo. To the intermediate 6-carbamimidoylsulfanyl-N-(4-trifluoromethyl-benzyl)-nicotinamide; hydrochloride in water (32 mL, 1800 mmol) was added sodium carbonate (1.07 g, 10.1 mmol). After stirring for 15 minutes, sodium hydroxide (1.61 g, 40.3 mmol) in water (2.0E1 mL, 1100 mmol) was added. The reaction mixture was filtered, and the filtrate was slowly acidified with 6 N HCl. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to afford the product as a bright yellow solid (3.58 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([Cl:12])[C:5]=1[NH2:13].C(N(CC)C(C)C)(C)C.[S:24](Cl)(Cl)=O>C(#N)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH2:13])=[C:6]([Cl:12])[C:7]2[C:8]([CH:9]=1)=[N:10][S:24][N:11]=2)=[O:14]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(N)c(N)c(Cl)c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc2nsnc2c(Cl)c1N
Temperature: 80 °C
Yield: 56846.2 %

Procedure:
To a suspension of 20 mg (93 mmol) of 2,4,5-triamino-3-chloro-benzoic acid methyl ester in 1 ml of acetonitrile, is added 32 ml (0.19 mmol) of N,N-diisopropylethylamine followed by 9 ml (0.13 mmol) of thionyl chloride. The mixture is stirred at 80° C. over the night. Then, 32 ml of N,N-diisopropylethylamine is added again as well as 9 ml of thionyl chloride and the mixture is again stirred for 5 hours at a temperature of 80° C. The solvent is evaporated and the residue is suspended in EtOAc. After filtration, EtOAc is evaporated and 18 mg (73.9 mmol, 80%) of a yellowish-brown solid is obtained. LC/MS: 244/246 (M+1)+.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=2)[CH:23]=1)[C:5](=[O:20])[CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[S:8]([N:7]1[CH2:2][CH2:3][N:4]([CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[CH:23]=2)[C:5](=[O:20])[CH2:6]1)(=[O:10])=[O:9])([O-:19])=[O:18]
Reactant: COc1cc(-c2cc(CN(CCO)C(=O)CNS(=O)(=O)c3ccccc3[N+](=O)[O-])ccn2)cc(OC)c1OC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(-c2cc(CN3CCN(S(=O)(=O)c4ccccc4[N+](=O)[O-])CC3=O)ccn2)cc(OC)c1OC

Procedure:
N-(2-Hydroxyethyl)-N-[[2-(3,4,5-trimethoxy-phenyl)pyridin-4-yl]methyl]-Nα-(2-nitrobenzenesulfonyl)-glycine amide (2.22 g) was dissolved in THF, and to the solution triphenylphosphine (1.55 g) was added. DEAD (1.03 g) was slowly added to the mixture at room temperature, and the resultant mixture was stirred overnight at room temperature under an argon atmosphere. After the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue. The mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:19](CC=C)[C:18]([O:23][C@H:24]3[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]3)=[N:17][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]#[N:16])[CH:9]=1.C1([SiH3])C=CC=CC=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:19][C:18]([O:23][C@H:24]3[CH2:25][CH2:26][C@H:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:29]3)=[N:17][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]#[N:16])[CH:9]=1
Reactant: C=CCn1c(O[C@H]2CC[C@H](C(=O)OCC)CC2)nc2nc(-c3ccc(F)c(C#N)c3)c(Cl)cc21
Agent: [SiH3]c1ccccc1
Solvent: CS(C)=O
Product: CCOC(=O)[C@H]1CC[C@H](Oc2nc3nc(-c4ccc(F)c(C#N)c4)c(Cl)cc3[nH]2)CC1
Temperature: 90 °C

Procedure:
To a solution of ethyl trans-4-{[6-chloro-5-(3-cyano-4-fluorophenyl)-1-(prop-2-en-1-yl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy}cyclohexanecarboxylate (980 mg, 2.029 mmol) in DMSO (4 mL) was added 1,1′-bis(diphenylphosphinoferrocene-Palladium (II) dichloride dichloromethane complex (148 mg, 0.203 mmol) followed by phenylsilane (220 mg, 2.029 mmol). The reaction was heated at 90° C. for 1 h. The reaction was then cooled, quenched with citric acid (10% w/v, 5 mL) and then extracted with EtOAc (2×10 mL). The organic layers were collected, dried and then concentrated in vacuo. The residue was purified via flash chromatography (40 g column, 40 mL/min flow, 0-100% EtOAc/hexane to afford ethyl trans-4-{[6-chloro-5-(3-cyano-4-fluorophenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy}-cyclohexanecarboxylate as a yellow foam.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C:17]([OH:19])=[O:18].[CH:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[N:33]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:34]=[C:35]([C:36]([O:38][CH3:39])=[O:37])[C:28]=12)=O>C(Cl)Cl>[C:43]([O:42][C:40]([N:33]1[C:29]2=[N:30][CH:31]=[CH:32][C:27]([CH2:25][NH:15][C@H:16]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]([OH:19])=[O:18])=[C:28]2[C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34]1)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: N[C@@H](C(=O)O)C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)O)C3CCCC3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 10 mL round bottom flask was added sodium triacetoxyborohydride (104 mg, 0.493 mmol), (R)-2-amino-2-cyclopentylacetic acid (47.1 mg, 0.329 mmol) and DCM (2 mL). The reaction mixture was stirred at room temperature for 30 min after which was added 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (50 mg, 0.164 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 2 h and then quenched with MeOH (3 drops). The mixture was concentrated to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C22H29N3O6, 432; found, 432.4.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26].O>CC(C)=O>[CH2:25]([O:1][C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH3:26]
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOc1cc([N+](=O)[O-])ccc1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-hydroxy-4-nitrobenzoate (500 mg) obtained in Step A of Example 139 in acetone (5.0 mL) were added potassium carbonate (580 mg) and iodoethane (340 μL), and the mixture was stirred overnight with heating under reflux. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (550 mg).