Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(CCN2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)CCCCCC1.Cl.Cl.[N:35]1([CH2:42][CH2:43][C:44]2C=CC(N)=CC=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[N:35]1([CH2:42][CH2:43][C:44]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:31])[CH3:32])[CH:24]=[CH:23][CH:22]=4)=[O:18])=[CH:14][CH:15]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: Nc1ccc(CCN2CCCCCC2)cc1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Agent: Cl
Product: CC(C)COc1cccc2[nH]c(C(=O)Nc3ccc(CCN4CCCCCC4)cc3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8) and amine 70.
Reaction SMILES: [Br-].[O:2]=[C:3]1[N:8]([CH3:9])[C:7](=[O:10])[N:6]([CH3:11])[CH2:5][NH+:4]1[CH3:12].[NH2:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C(=O)(O)[O-].[Na+]>O>[O:2]=[C:3]1[N:8]([CH3:9])[C:7](=[O:10])[N:6]([CH3:11])[CH:5]([C:17]2[CH:18]=[CH:19][C:14]([NH2:13])=[CH:15][C:16]=2[OH:20])[N:4]1[CH3:12]
Reactant: Nc1cccc(O)c1
Reactant: CN1C[NH+](C)C(=O)N(C)C1=O
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CN1C(=O)N(C)C(c2ccc(N)cc2O)N(C)C1=O

Procedure:
23.6 g (0.1 mol) of 2,4-dioxo-1,2,3,4-tetrahydro-1,3,5-trimethyl-s-triazinium bromide are dissolved in 50 ml of water and 10.9 g (0.1 mol) of m-aminophenol are added. After a few minutes, a clear solution has formed. 8 g of sodium bicarbonate are added to the solution. 25 g (89%) of 2,4-dioxo-hexahydro-1,3,5-trimethyl-6-[2-hydroxy-4-amino-phenyl]-s-triazine precipitate out as white crystals, which, after they have been dissolved in aqueous hydrochloric acid and the solution has been clarified with active charcoal and neutralised, melt at 240° C.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:9][N:8]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH:24](N1CCOCC1)=[O:25]>O1CCCC1>[CH:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([CH:24]=[O:25])=[CH:3][CH:4]=2)=[N:8][CH:9]=1)([CH3:16])[CH3:15]
Reactant: CC(C)Oc1ccc(Oc2ccc(Br)cc2)nc1
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Oc2ccc(C=O)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 69B (1.00 g, 3.25 mmol) in tetrahydrofuran (10 mL) was added n-butyl lithium (2.5 M in hexanes, 1.35 mL, 3.38 mmol) at −78° C. The mixture was stirred for 30 minutes, and then 4-formylmorpholine (380 μL) 3.80 mmol) was added. The mixture was stirred for 30 minutes and warmed to room temperature before quenching with water. The aqueous layer was extracted with ether (1×). The ether layer was washed with brine (1×), dried over MgSO4 and concentrated to give the title compound as colorless viscous oil.
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[F:23][CH2:24][CH2:25][N:26]1[C:35]2[C:30](=[CH:31][C:32]([F:38])=[C:33](F)[C:34]=2[F:36])[C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27]1>C(#N)C>[F:38][C:32]1[CH:31]=[C:30]2[C:35](=[C:34]([F:36])[C:33]=1[N:9]1[CH2:10][CH2:11][CH:7]([N:2]3[CH:6]=[CH:5][N:4]=[N:3]3)[CH2:8]1)[N:26]([CH2:25][CH2:24][F:23])[CH:27]=[C:28]([C:40]([OH:42])=[O:41])[C:29]2=[O:39]
Reactant: c1cn(C2CCNC2)nn1
Reactant: O=C(O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(CCF)c2c(F)c(N3CCC(n4ccnn4)C3)c(F)cc2c1=O
Yield: 34.4 %

Procedure:
3-(1,2,3-triazol-1-yl)pyrrolidinehydrochloride (87 mg) and DBU (76 mg) were added to a suspension of 1-(2-fluoroethyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (72 mg, 0.25 mmol) in acetonitrile (5 ml). The reaction mixture was refluxed for 21 hrs, concentrated and the residue was diluted with water. The separated solid was filtered, washed with water and acetonitrile to give 35 mg of the title product. m.p. 240°-243° C. (dec). 1H NMR (TFA) δ: 9.76 (s, 1H), 9.08 (s, 1H), 8.73 (s, 1H), 8.12 (d, 13.7Hz, 1H), 5.8-5.6 (m, 1H), 5.4-4.1 (m, 9H), 3.0-2.65 (m, 2H). Anal. Calcd. for C18H16F3N5O3 . 1/2 H2O; C, 51.93; H, 4.12; N, 16.32.Found: C, 51.77; H, 3.84; N, 15.6.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)([CH3:49])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:53]4[CH2:54][CH2:55][N:50]([CH:47]([CH3:49])[CH3:48])[CH2:51][CH2:52]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CC(C)N1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCN(C(C)C)CC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 1-isopropylpiperazine (Oakwood) to give the title product. LC-MS (ES+) 775 [(M+H)+].
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)([CH2:11][OH:12])[CH2:6][OH:7]
Reactant: CCCCc1ccc(CCCCC(COC(C)=O)(COC(C)=O)NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1ccc(CCCCC(N)(CO)CO)cc1
Yield: 54.6 %

Procedure:
2-Acetamido-1,3-diacetoxy-2-[4-(4-butylphenyl)butyl]propane (66.2 mg) was dissolved in 2 ml of methanol and 2 ml of a 1N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 4 hours. The solvent was distilled away and the residue was purified by silica gel thin layer chromatography (methanol:chloroform=1:4) to give 24.9 mg of 2-amino-2-[4-(4-butylphenyl)butyl]-1,3-propanediol as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][CH2:6][C:5](=[CH:8][CH2:9][N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][C:13]([NH2:20])=[N:14][C:15]=3[Cl:19])[CH2:4][O:3]1>[Pd].O1CCCC1>[NH2:20][C:13]1[N:12]=[C:11]2[C:16]([N:17]=[CH:18][N:10]2[CH2:9][CH2:8][CH:5]2[CH2:4][O:3][C:2]([CH3:1])([CH3:21])[O:7][CH2:6]2)=[C:15]([Cl:19])[N:14]=1
Reactant: CC1(C)OCC(=CCn2cnc3c(Cl)nc(N)nc32)CO1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Reaction time: 8 h
Yield: 63.6 %

Procedure:
5% Palladium on carbon (1.5 g) in tetrahydrofuran (40 ml) was prehydrogenated for 30 min at 50 p.s.i. 2,2-Dimethyl-5-[2-(2-amino-6-chloropurin-9-yl)]ethylidene-1,3-dioxane (3.0 g) in tetrahydrofuran (80 ml) was added and washed in with tetrahydrofuran (30 ml). The mixture was hydrogentated overnight at 50 p.s.i. with stirring. The catalyst was removed by filtration to give a colourless solution. The solvent was removed under reduced pressure and the residue recrystallised from IPA to give the title compound (1.92 g, 62.2% yield). Analysis: Found C: 49.98; H: 5.82; N: 22.42%; Required: C: 50.08; H: 5.82; N: 22.46%. 5-[2-(2-Amino-6-chloropurin-9-yl)ethyl]-2,2-dimethyl-1,3-dioxane can be converted to penciclovir using techniques known in the art such as those described in EP 141927.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:8][C:4]1[N:3]=[C:2]([NH:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cncc(Cl)n2)CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2,6-dichloropyrazine (5.0 g, 34 mmol) and 4-amino-1-boc-piperidine (6.7 g, 34 mmol) in DMF (67 mL) was added cesium carbonate (22 g, 67 mmol). The reaction mixture was stirred at 100° C. After 4 h, the reaction was quenched with saturated aqueous sodium bicarbonate (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford tert-butyl 4-[(6-chloropyrazin-2-yl)amino]piperidine-1-carboxylate as a yellow solid. LRMS (ESI) calculated for C14H21ClN4O2 [M+Na]+, 335.1; found 335.1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:3]=1.[CH2:22]([NH:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)CO>O>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:5][C:6]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:29]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:30]=1
Reactant: N#Cc1c(-c2ccccc2)cc(N2CCOCC2)nc1Cl
Reactant: NNCc1ccccc1
Solvent: OCCO
Solvent: O
Product: Nc1nn(Cc2ccccc2)c2nc(N3CCOCC3)cc(-c3ccccc3)c12
Temperature: 130 °C

Procedure:
A mixture consisting of 3.0 gm (0.01 mol) of 2-chloro-6-morpholino-4-phenyl-3-cyano-pyridine, 3.7 gm (0.03 mol) of benzyl-hydrazine and 30 ml of ethylene glycol was refluxed for 5 hours at about 130° C. The resulting solution was taken up in 100 ml of water, whereupon the reaction product separated out as a pasty precipitate which was collected and immediately recrystallized from methanol. 2.2 gm (57% of theory) of the compound named in the heading were obtained; after recrystallization from ethyl acetate it had a melting point of 147°-150° C.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]([N:7]1[CH2:19][C:18]2[S:17][C:16]3[N:15]=[CH:14][N:13]=[C:12]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=4)[C:11]=3[C:10]=2[CH2:9][CH2:8]1)=[O:6].[CH3:29][NH:30][CH3:31].CO.ClCCl>ClCCl>[Cl:28][C:23]1[CH:22]=[C:21]([NH:20][C:12]2[C:11]3[C:10]4[CH2:9][CH2:8][N:7]([C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:30]([CH3:31])[CH3:29])[CH2:19][C:18]=4[S:17][C:16]=3[N:15]=[CH:14][N:13]=2)[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CNC
Reactant: O=C(C=CCBr)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Solvent: ClCCl
Solvent: CO
Product: CN(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
To an ice-bathed cooled solution of 4-Bromo-1-[4-(3-chloro-4-fluoro-phenylamino)-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluoren-7-yl]-but-2-en-1-one (0.125 g, 0.00026 mol) in dichloromethane (1.25 ml) was added dimethylamine (2.0M solution in THF) (0.65 ml, 0.001 mol) over 1-2 min. The resulting mixture was stirred at RT for 2 hours. TLC (10% MeOH/Dichloromethane) indicates no SM present, a new polar spot seen. Conc. the reaction mixture to dryness under vacuum at 30° C. Purified by silica gel chromatography (ISCO system) using a gradient of dichloromethane—30% methanol/dichloromethane. The fractions combined, conc to dryness and the residue dissolved in 10% MeOH/DCM, filtered through a filter paper. The filterate was conc. to dryness and dried under vacuum at RT O/N to give 0.03 g (23%) of desired product. 1H-NMR (CD3OD-d3) δ 8.46 (m, 1H), 8.39 (s, 1H), 7.88 (m, 1H), 7.62 (m, 1H), 7.42 (t, 1H), 6.67 (m, 1H), 3.94 (m, 2H), 3.87 (m, 4H), 2.75 (m, 2H), 2.56 (s, 6H); LCMS RT=2.38 min, [M+H]+=446.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1.C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[C:9]([Br:19])=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccnc(N)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)ncc1Br
Temperature: -18 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
A solution of 2-amino-isonicotinic acid methyl ester (5.58 g, 36.7 mmol) in DMF (56 mL) was cooled to −18° C. (ice/MeOH bath), treated with NBS (7.21 g, 38.5 mmol), and stirred at −18° C. for 1 h. The reaction mixture was diluted in AcOEt (500 mL) and washed with water (2×250 mL). The organic layer was dried over Na2SO4, filtered and evaporated to yield the crude title compound (3.0 g, 13.0 mmol, 35%) as a yellow solid, which was used in the next step without further purification. MS: 231 [M+1]+; HPLC: AtRet=0.70.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=O)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[S:26])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(F)c1)c1ccccn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Fc1cccc(NC(=S)c2ccccn2)c1
Yield: 48.4 %

Procedure:
N-(3-Fluorophenyl)-2-pyridinecarboxamide (13.0 g, 60 mmol) and Lawesson's reagent (29.2 g, 72 mmol) were refluxed in toluene (180 mL) for 3 hours. The residue obtained after evaporating the solvent was flash chromatographed on silica gel (eluted with 2% ethyl acetate in petroleum ether) and then recrystallized from a mixture of dichloromethane and hexanes to yield a N-(3-fluorophenyl)-2-pyridinecarbothioamide as a yellow solid (6.75 g, 48%) m.p. 72°-76° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:23].[CH2:24]([O:26]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:25]>>[C:24]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:23])(=[O:26])[CH3:25]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1Br)CC2
Product: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1C(C)=O)CC2

Procedure:
The title compound 104 is prepared according to the procedure reported in Example 36.5 with compound 100 (175 mg, 0.47 mmol) and (l-ethoxyvinyl)tri(n-butyl)stannane (0.16 mL, 0.47 mmol) as reactants. White solid. (Yield 93.2 g, 58%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1C=CC(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:34]=[N+:35]=[N-:36])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccc(F)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: [N-]=[N+]=NC(=O)/C=C/c1ccc(F)cc1
Reaction time: 18 h
Yield: 90.7 %

Procedure:
To a solution of (E)-3-(4-fluorophenyl)acrylic acid (25 g, 150 mmol) in benzene (120 mL) was added triethylamine (30.5 g, 301 mmol) followed by DPPA (41.4 g, 150 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by conventional column chromatography (Silica gel, 60-120 mesh) using 10% ethyl acetate in pet ether as mobile phase to get the desired compound as a white solid (26 g, 90%). 1H NMR (400 MHz, CDCl3): δ ppm 7.73-7.69 (d, J=16 Hz, 1H), 7.55-7.51 (m, 2H), 7.11-7.07 (m, 2H), 6.36-6.32 (d, J=16 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([NH:12][C:13](=[O:33])[NH:14][C:15]3[N:20]=[C:19]([CH2:21][N:22]4[CH2:27][CH2:26][CH:25]([C:28]([O:30]CC)=[O:29])[CH2:24][CH2:23]4)[CH:18]=[CH:17][CH:16]=3)[N:11]=2)=[CH:3][CH:2]=1.[Li+].[OH-]>CO.O>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[S:8][CH:9]=[C:10]([NH:12][C:13](=[O:33])[NH:14][C:15]3[N:20]=[C:19]([CH2:21][N:22]4[CH2:23][CH2:24][CH:25]([C:28]([OH:30])=[O:29])[CH2:26][CH2:27]4)[CH:18]=[CH:17][CH:16]=3)[N:11]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCN(Cc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1cccc(CN2CCC(C(=O)O)CC2)n1)Nc1csc(-c2ccncc2)n1
Temperature: 45 °C

Procedure:
Ethyl 1-{6-[3-(2-(pyridin-4-yl)thiazol-4-yl)ureido]-pyridin-2-ylmethyl}-piperidine-4-carboxylate (55 mg, 0.12 mmol, Example 61) was suspended in MeOH (10 ml) followed by adding LiOH (50 mg, 1.18 mmol) in H2O (1 ml). The resulting mixture was heated at 45° C. for 15 h. After cooling to RT, the solvent was removed. The residue was suspended in H2O (20 mL). The pH was adjusted to 7 using HCl (1N). The resulting mixture was extracted with CHCl3:IpOH (3:1). The organic layer was washed with H2O and brine. After being dried over anhydrous MgSO4, the solvent was removed in vacuo to yield the final compound as light yellow solid. MS m/z: 438.7 (M+H). Calc'd. for C21H22N6O3S-438.51.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:16](=[O:25])[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[O:19][CH:20]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:16](=[O:25])[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[O:19][CH:20]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCCOc2coc(C(=O)OC)cc2=O)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1c(OCCCCCOc2coc(C(=O)O)cc2=O)ccc(C(C)=O)c1O
Reaction time: 8 h

Procedure:
To a solution of 910 mg (2.1mmole) of the title product of Example 2 in 15 ml of ethanol was added 160 mg (4 mmole) of sodium hydroxide dissolved in 15 ml of water. The mixture was stirred overnight and then acidified (ca. pH 2) with dilute hydrochloric acid. The resulting precipitate was collected by filtration, washed thoroughly with water, and dried under reduced pressure to give 680 mg of analytically pure title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[NH2:11])[C:5]([O-:7])=[O:6].[CH:13](O)=O.[OH-].[K+]>O>[Cl:12][C:9]1[C:10]2[N:11]=[CH:13][NH:1][C:2]=2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=1
Reactant: Nc1cc(C(=O)[O-])cc(Cl)c1N
Reactant: O=CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(Cl)c2nc[nH]c2c1
Temperature: 25 °C
Yield: 37.2 %

Procedure:
3,4-diamino-5-chlorobenzoate (1.2 g, 6 mmol) was added to water (10 mL) and formic acid (826 mg, 18 mmol) and heated at reflux for 4 hours. The reaction was cooled to ambient temperature and aqueous potassium hydroxide was added (21 mL, 1M). The reaction solution was washed with ethyl acetate (2×25 mL each). The aqueous layer was acidified to pH=5 with aqueous hydrochloric acid (1N) to give a precipitate which was filtered, washed with water and dried under a stream of nitrogen to give the title compound (439 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (s, 1H) 8.10 (d, J=1.17 Hz, 1H) 7.77 (d, J=1.37 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[C:8](Cl)=[N:9][CH:10]=[C:11]([CH:14]=1)[C:12]#[N:13]>O1CCOCC1>[Cl:6][C:7]1[C:8]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[N:9][CH:10]=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: N#Cc1cnc(Cl)c(Cl)c1
Reactant: COCCN
Solvent: C1COCCO1
Product: COCCNc1ncc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-methoxyethyl amine (4.11 mL, 43.9 mmol), TEA (6.11 mL, 43.9 mmol) and 5,6-dichloronicotinonitrile (Bionet GC-0755, 7.6 g, 43.9 mmol) was prepared in dioxane and stirred at RT for 24 hours. The reaction mixture was filtered to remove inorganic solids and filtrate was concentrated under reduced pressure. The residue taken up with EtOAc (100 mL) and washed with water (3×100 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, pet ether/EtOAc), the title compound was obtained as a white powder (6.9 g, 75%). LC/MS, M+(ESI): 212.1. 1H NMR (DMSO-d6, 400 MHz) δ 8.42 (1H, d), 8.07 (1H, d), 7.48 (1H, t), 3.58 (2H, m), 3.47 (2H, m), 3.23 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>O>[Cl:1][C:2]1[N:7]=[C:6]([I:15])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: II
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Cl)nc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
6-chloropyridin-3-ol (5.0 g, 38.6 mmol) was dissolved in water (50 mL) and placed under an N2 atmosphere. Na2CO3 (8.2 g, 77.4 mmol) was added followed by iodine (9.8 g, 38.8 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into 1M Na2S2O3 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to give the product of 6-chloro-2-iodopyridin-3-ol (7.0 g, yield: 70.9%). 1H-NMR (CDCl3, 400 MHz) δ 7.17 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H). MS (M+H)+: 256/258.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:9][C@H:8]1[CH2:19][OH:20])=[O:6])[CH:2]=[CH2:3].N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:9][C@H:8]1[CH2:19][O:20][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N[C@H]1C[C@@H](CO)N(C(=O)OCC=C)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCC=C)C1
Reaction time: 12 h

Procedure:
To a solution of (2S,4S)-1-allyloxycarbonyl-4-(allyloxycarbonylamino)-2-hydroxymethylpyrrolidine (8.73 g in N,N-dimethylformamide (40 ml) were added imidazole (6.76 g) and t-butyldimethylsilyl chloride (5.10 g). The resulting mixture was allowed to stand at ambient temperature for 12 hours. The mixture was diluted with ethyl acetate (200 ml), washed in turn with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (100 ml) eluting with a mixture of n-hexane and ethyl acetate (7:3 V/V) to give (2S,4S)-1-allyloxycarbonyl-4-(allyloxycarbonylamino)-2-t-butyldimethylsilyloxymethylpyrrolidine (10.97 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:18])[CH2:14][O:15][CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.F[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.[H-].[Na+].CCO>CN(C=O)C.Cl>[CH2:16]([O:15][CH2:14][C@@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[O:18][C:28]1[C:29]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][CH:27]=1)[CH3:17]
Reactant: CCOC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cccc2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC[C@H](Oc1cccc2ccccc12)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-2-Ethoxy-1-hydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (200 mg, 0.8 mmol) and 1-fluoronaphthalene were dissolved in DMF (2.7 mL). NaH (27.8 mg, 1.2 mmol) was added and the mixture was stirred at room temperature for 15 minutes, then heated at 120° C. for 4 hours. The mixture was then cooled to room temperature. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (19 mL, 23 mmol) and stirred overnight at room temperature. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (125 mg, 94% purity). MS m/z: [M+H]+ calcd for C18H23NO2, 286.17. found 286.2.