Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:20]C)=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=3[F:17])[S:7][C:6]=2[C:18]=1[Cl:19].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=3[F:17])[S:7][C:6]=2[C:18]=1[Cl:19]
Reactant: COc1cc2cc(-c3c(F)cccc3F)sc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cc2cc(-c3c(F)cccc3F)sc2c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 71.8 %

Procedure:
A mixture of 4.5 g of 6,7-dichloro-2-(2',6'-difluorophenyl)-5-methoxybenzo[b]thiophene and 45 g of pyridine hydrochloride is stirred at 190°-195° for 5 hrs and allowed to cool. While still fluid, the reaction mixture is poured onto 200 g of ice and stirred until thoroughly mixed. The aqueous mixture is extracted with three 200-ml portions of dichloromethane and the organic layers are combined, washed, dried over anhydrous magnesium sulfate and filtered. The solvent is removed to give a solid. The solid is recrystallized from ethyl ether-hexane to give 3.1 g of 6,7-dichloro-2-(2',6'-difluorophenyl)-5-hydroxybenzo[b]thiophene, mp 161°-162°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2cccc3ccccc23)CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1=C(c2cccc3ccccc23)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A mixture of 2.8 gm (8.8 mMol) 1-benzyl-4-hydroxy-4-(naphth-1-yl)piperidine and 3.36 gm (17.6 mMol) p-toluenesulfonic acid in 50 mL toluene was heated at reflux for about 18 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and 2 N sodium hydroxide. The phases were separated and the organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure to provide 2.47 gm (94%) of the desired compound as an orange oil.
Reaction SMILES: [NH2:1][CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:19]([OH:21])=[O:20])=[C:6]([CH:9]([S:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[CH2:10][CH2:11][OH:12])[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.[CH:32]([NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:44][O:45][CH2:46][CH2:47][O:48][CH:49]=[O:50])[C:41](O)=[O:42])[N:39]=1)=[O:33].P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.CN(C)C=O>[CH:32]([NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:44][O:45][CH2:46][CH2:47][O:48][CH:49]=[O:50])[C:41]([NH:1][CH:2]2[C:22](=[O:23])[N:4]3[C:5]([C:19]([OH:21])=[O:20])=[C:6]([CH:9]([S:13][C:14]4[NH:15][N:16]=[N:17][N:18]=4)[CH2:10][CH2:11][OH:12])[CH2:7][S:8][C@H:3]23)=[O:42])[N:39]=1)=[O:33]
Reactant: O=CNc1nc(C(=NOCCOC=O)C(=O)O)cs1
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(CCO)Sc3nnn[nH]3)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=CNc1nc(C(=NOCCOC=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(C(CCO)Sc4nnn[nH]4)CS[C@H]23)cs1
Yield: 31.4 %

Procedure:
A solution of 7-amino-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (2.0 g) and trimethylsilylacetamide (5.9 g) in dry ethyl acetate (40 ml) and a solution of 2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetic acid (syn isomer, 1.8 g), dry dimethylformamide (0.5 g) and phosphoryl chloride (1.0 g) in dry ethyl acetate (22.0 ml) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer, 1.10 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].Br[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:17]([O:16][C:14]([CH2:13][CH2:19][NH:7][C:6]1[CH:8]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])=[O:15])[CH3:18]
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCNc1cc(C)ccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
A mixture of 5-methyl-2-nitroaniline (3.00 g), ethyl bromopropionate (5.35 g) and potassium carbonate (8.18 g) in N,N-dimethylformamide (20 ml) was stirred at 150° C. for 4 hours and the suspension was cooled to ambient temperature. After being filtered, the filtrate was diluted with ethyl acetate and the solution was washed successively with saturated sodium bicarbonate aqueous solution and brine. Drying over magnesium sulfate, filtering and the removal of solvents afforded a crude product. The crude product was triturated with diethyl ether-n-hexane (1:1) to give N-(2-ethoxycarbonylethyl)-5-methyl-2-nitroaniline (2.83 g) as a yellow prisms.
Reaction SMILES: Cl.[F:2][C:3]([F:7])([F:6])[CH2:4][NH2:5].C([O-])(=O)C.[Na+].[CH3:13][O:14][C:15](=[O:37])[CH2:16][C:17]1[CH:18]=[C:19]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[CH:35]=O)[C:20]([O:23][CH3:24])=[CH:21][CH:22]=1.C([BH3-])#N.[Na+]>CO>[CH3:13][O:14][C:15](=[O:37])[CH2:16][C:17]1[CH:18]=[C:19]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][C:26]=2[CH2:35][NH:5][CH2:4][C:3]([F:7])([F:6])[F:2])[C:20]([O:23][CH3:24])=[CH:21][CH:22]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: NCC(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,2,2-Trifluoroethylamine hydrochloride (0.101 g, 0.71 mmol) was treated with sodium acetate (0.061 g, 0.71 mmol) in MeOH (1 mL) with heating and sonication. (2′-Formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.207 g, 0.59 mmol) in MeOH (2 mL) was added, followed by sodium cyanoborohydride (0.069 g, 1.06 mmol), and the reaction was stirred at room temperature for 1 hour. Once no starting material was seen by analytical LCMS, the mixture was quenched with H2O and extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:31]=[CH:30][C:14]([C:15]([NH:17][C:18]4[CH:29]=[CH:28][C:21]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[CH:20][CH:19]=4)=O)=[CH:13][C:12]=3[O:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:55])=CC=1>O>[C:1]12([C:11]3[CH:31]=[CH:30][C:14]([C:15]([NH:17][C:18]4[CH:29]=[CH:28][C:21]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[CH:20][CH:19]=4)=[S:55])=[CH:13][C:12]=3[O:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C=CCOC(=O)c1ccc(NC(=O)c2ccc(C34CC5CC(CC(C5)C3)C4)c(OCOCCOC)c2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOC(=O)c1ccc(NC(=S)c2ccc(C34CC5CC(CC(C5)C3)C4)c(OCOCCOC)c2)cc1

Procedure:
2.9 g (5.6 mmol) of allyl 4-[4-(1-adamantyl)-3-methoxyethoxymethoxybenzamido]benzoate and 30 ml of toluene were introduced into a round-bottomed flask and 1.14 g (2.8 mmol) of Lawesson's reagent were added. The reaction medium was heated at reflux for three hours and was then evaporated to dryness. The residue obtained was taken up in water and dichloromethane and the organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with a mixture of heptane and ethyl acetate (80/20). After evaporation of the solvents, 1 g (33%) of the expected allylic ester was collected in the form of an orange-coloured oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([OH:9])=[CH:4][CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([O:9][C:5]1[C:6]([I:8])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(Br)nc1I
Product: CC(=O)Oc1ccc(Br)nc1I
Reaction time: 0.5 h
Yield: 100 %

Procedure:
6-bromo-2-iodopyridin-3-ol (150 mg, 0.500 mmol) was added to acetic anhydride (2.4 mL, 25 mmol) at 130° C. It was allowed to stir for 30 min then concentrated and chased with toluene to give the expected product 6-bromo-2-iodopyridin-3-yl acetate (171 mg, 0.500 mmol, 100% yield) by NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm. 7.74 (1H, d, J=8.28 Hz), 7.62 (1H, d, J=8.28 Hz), 2.36 (3H, s). LC-MS retention time: 1.66 min; m/z (MH+): 342, 344. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:17]([C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>O>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[C:1]([CH3:4])([CH3:2])[CH3:3])=[NH:26])=[CH:27][CH:28]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccccc1N
Reactant: CC(C)(C)c1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: O
Product: CC(C)(C)c1ccc(C(=N)Nc2ccccc2C(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
Procedure as described for Amidine I using the following amounts: 7.80 mL of 2-t-butylaniline (50.0 mmol); 25.0 mL of 2.0 M butyllithium (50.0 mmol), 8.50 ml of 4-t-butylbenzonitrile (50.0 mmol). After refluxing overnight, the solution was dark brown. Addition of water yielded an orange solution with suspended solid. Solution was filtered and taken to dryness. The residue was treated with 75 mL of pentane, stirred for 30 minutes, and filtered yielding 13.43 g (87%) of light orange solid. 1H NMR (400 MHz, CDCl3): 7.87 (d, 2H), 7.49 (d, 2H), 7.41 (d, 1H), 7.17 (t, 1H), 7.00 (t, 1H), 6.81 (d, 1 H), 4.75 (s, 2H), 1.41 (s, 9H), 1.36 (s, 9H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]1([CH2:40][CH2:41][CH2:42]O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:44]1(=[O:50])[NH:48][C:47](=[O:49])[CH:46]=[CH:45]1>>[C:34]1([CH2:40][CH2:41][CH2:42][N:48]2[C:44](=[O:50])[CH:45]=[CH:46][C:47]2=[O:49])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C1C=CC(=O)N1
Reactant: OCCCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1C=CC(=O)N1CCCc1ccccc1

Procedure:
Reagents: Ph3P (0.65 g, 2.5 mmol), DIAD (0.5 ml, 2.5 mmol), 3-phenyl-1-propanol (0.48 ml, 3.75 mmol) and maleimide (0.24 g, 2.5 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N+:8]([O-])=[CH:7][C:6]3[N:13]=[CH:14][N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[Cl:22])[C:5]=3[C:4]=2[CH:3]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:30].O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:30][C:7]1[C:6]2[N:13]=[CH:14][N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:5]=2[C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cc2ncn(-c3ccccc3Cl)c2c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2nc(Cl)c3ncn(-c4ccccc4Cl)c3c2c1

Procedure:
A solution of 100 mg (0.30 mmol) of 8-chloro-1-(2-chloro-phenyl)-1H-imidazo[4,5-c]quinoline 5-oxide (Example 71), 50 μl dry DMF, and 86 μl POCl3 in 2 ml toluene is stirred at 70° C. bath temperature for 3½ h. First, ice is added to the cold reaction mixture, then water and ethyl acetate. The phases are separated and the water phase is extracted with ethyl acetate. The combined organic phases are washed with water and brine, then dried over Na2SO4. After the solvent is evaporated, the residue is crystallized from ethyl acetate-hexane. mp: 194-200° C.; MS: 348 (M++1); HPLC: tret=13.54 min (Grad 1).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][C:13]3[N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16]4[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH4+:28].[OH-]>CO>[I:11][C:10]1[C:3]2[C:2]([NH2:28])=[N:7][CH:6]=[N:5][C:4]=2[N:8]([CH2:12][C:13]2[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)[CH:9]=1
Reactant: [NH4+]
Reactant: Clc1ncnc2c1c(I)cn2Cc1nc2ccccc2n1-c1ccccc1
Agent: [OH-]
Solvent: CO
Product: Nc1ncnc2c1c(I)cn2Cc1nc2ccccc2n1-c1ccccc1
Yield: 42 %

Procedure:
A solution of 4-chloro-5-iodo-7-(1-phenyl-1H-benzoimidazol-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 2 mmol) in NH4OH (5 mL) and MeOH (10 mL) was stirred at 90° C. in a sealed tube overnight. Then the mixture was filtered. The precipitate was purified by P-TLC to give 140 (0.4 g, yield 42%) as a white solid. LCMS (ESI), M+H+=465.04 1HNMR (400 MHz, DMSO) δ 5.518 (s, 2H), 6.574 (s, 2H), 7.128 (s, 2H), 7.210-7.232 (m, 2H), 7.343 (s, 1H), 7.521-7.622 (m, 6H), 7.968 (s, 1H)
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6]C(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[CH:55]=[CH:54][C:53]([C:56]([OH:58])=O)=[CH:52][CH:51]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)CCCN>C1COCC1>[CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6][C:56]([C:53]1[CH:54]=[CH:55][C:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:51][CH:52]=1)=[O:58]
Reactant: O=C(O)c1ccc(-c2ccccc2CSCCOc2ccccc2)cc1
Reactant: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1ccc(-c2ccccc2CSCCOc2ccccc2)cc1
Yield: 74 %

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (3-dimethylamino-propyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.80 g, 2.19 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.36g, 2.23 mmol, 1.02 eq.) followed by 3-(dimethylamino)propylamine (0.27 g, 2.63 mmol, 1.2 eq.) as described. When complete, the reaction was worked up leaving a yellow oil that later crystallized. The solid was purified via silica gel flash chromatography using 140:10:1 (CHCl3/MeOH/NH4OH) as the mobile phase. Fractions containing the product were pooled and the solvent removed leaving 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (3-dimethylamino-propyl)-amide (0.72 g, 74% yield) as a white solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.Cl.[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30].I.[NH2:33][C:34]1[C:35]([C:42]([NH:44][C:45](=[NH:48])SC)=[O:43])=[N:36][C:37]([Cl:41])=[C:38]([NH2:40])[N:39]=1>C(O)C>[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:45]([NH2:48])=[N:44][C:42]([C:35]1[C:34]([NH2:33])=[N:39][C:38]([NH2:40])=[C:37]([Cl:41])[N:36]=1)=[O:43]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCCCCCCCCC(=O)Nc1ncc[nH]1
Agent: Cl
Agent: I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCCCCCCCCCCCC(=O)Nc1ncc[nH]1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 43.1 %

Procedure:
Diisopropylethylamine (0.26 mL, 1.49 mmol) was added to a solution of 12-aminododecanoic acid (1H-imidazol-2-yl)amide dihydrochloride (14) (0.056 mg, 0.16 mmol) in absolute ethanol (5 mL). A white precipitate formed and the reaction was stirred at 70° C. for 10 min, then 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (0.087 g, 0.22 mmol) was added in one portion. The reaction mixture was stirred at this temperature for 16 hours then cooled to room temperature. The solvent was removed by rotary evaporation and the resulting residue was dissolved in small volume of methanol and the solution passed through an ion exchange resin column (Dowex 550A OH type). The resin was rinsed with methanol and the methanol solution was concentrated in vacuo. The resulting residue was purified by Biotage silica gel column chromatography eluting with 1% to 10% of 9:1 methanol/ammonium hydroxide in dichloromethane to give 12-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]dodecanoic acid (1H-imidazol-2-yl)amide 15 (0.034 g, 44%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 1.25 (m, 14H), 1.50 (m, 4H), 2.29 (t, 2H), 3.09 (m, 2H), 6.61 (m, 4H). m/z (ESI) 493 [C21H33ClN10O2+H]+. mp 102-104° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5](=O)[CH2:6][O:7][CH3:8].[C:11]1([NH2:18])[C:12]([NH2:17])=[CH:13][CH:14]=[CH:15][CH:16]=1.CC(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH:5]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH2:18])[CH2:6][O:7][CH3:8]
Reactant: COCC(=O)CC(=O)OC
Reactant: Nc1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: COCC(CC(=O)OC)Nc1ccccc1N
Reaction time: 6 h
Yield: 26.9 %

Procedure:
4-Methoxy-3-oxo-butyric acid methyl ester (0.67 mL, 5.0 mmol) and Benzene-1,2-diamine (560 mg, 5.5 mmol) are dissolved in DCM (20 mL) and HOAc (0.63 mL, 11 mmol) is added into it. The mixture is stirred for 6 hrs and then NaBH(OAC)3 (3.7 g, 17 mmol) is added and the mixture is stirred for another 60 hr. Then 50 mL of sat. NaHCO3 along with 50 mL of water are added and the mixture is extracted with EtOAc (3×100 mL). The organic layers are combined, dried and concentrated to give crude product. Purification by flash column choromatography affords 320 mg (27%) of 3-(2-Amino-phenylamino)-4-methoxy-butyric acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18](O)=[O:19])[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:49]([NH2:52])[CH2:50][CH3:51]>CN(C=O)C.O>[Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18]([NH:52][CH2:49][CH2:50][CH3:51])=[O:19])[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:33])([F:34])[F:32])[CH:25]=2)=[CH:4][CH:3]=1
Reactant: CCCN
Reactant: Cn1c(=O)n(CC(=O)O)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
2-(7-(4-Chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetic acid (0.25 g, 0.48 mmol, Example 361) and CDI (0.93 g, 0.57 mmol) were combined in DMF (4 mL) and stirred at room temperature for 20 min. Propan-1-amine was added and the reaction was stirred at room temperature for 3 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were washed with 1N lithium chloride (2×75 mL), dried with magnesium sulfate, filtered and evaporated under reduced pressure to a white solid. Solid was purified using a 25 g silica gel flash column eluted with 1% methanol/DCM to give 2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-propylacetamide (0.13 g, 47% yield) as a white solid. LCMS retention time=4.070 min and 99% purity, LCMS MH+ 566. 1H NMR (DMSO-d6) δ 7.99 (t, NH), 7.60 (t, 1H, J=8 Hz), 7.48-7.52 (m, 1H), 7.39-7.46 (m, 5H), 7.32 (d, 1H, J=8 Hz), 5.42 (s, 2H), 4.42 (s, 2H), 3.31 (s, 3H), 3.00 (dd, 2H, J=8 Hz and 16 Hz), 1.34-1.45 (m, 2H), 0.83 (t, 3H, J=8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[CH:7]=[CH:8][C:9]4=[O:16])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Yield: 62 %

Procedure:
A mixture of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (530 mg, 2.431 mmol) and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis see WO2004/058144 Example 99(h)) (848 mg, 2.431 mmol) in chloroform (20 ml) and MeOH (1 ml) was stirred for 2 h before addition of NaBH(OAc)3 (1.546 mg, 7.293 mmol). The reaction was stirred for 0.5 h before addition of sat. aq NaHCO3 (50 ml). The reaction was then extracted with 20% MeOH in DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the desired compound (833 mg, 62%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:9])[CH:15]=2)=[CH:3][CH:4]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Brc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cccc(-c2ccc(Br)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
1,4-Dibromobenzene (311 mg, 1.3 mmol) and 201 mg (1.3 mmol) of 3-aminophenylboronic acid were dissolved in 17 ml of N,N-dimethylformamide and 4.2 ml of water. Tetrakistriphenylphosphine palladium (154 mg, 0.13 mmol) and 211 mg (2.0 mmol) of sodium carbonate were added to the solution, and the mixture was stirred at 80° C. for 3 hr. Ethyl acetate (60 ml) and 8.5 ml of water were added to the reaction solution, and the mixture was filtered through Celite. The organic layer as the filtrate was washed five times with 30 ml of water. The organic layer was dried over anhydrous sodium sulfate and was filtered. The solvent was then removed by distillation. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give 182 mg (yield 57%) of the title compound.
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][N:4]([CH2:7][CH3:8])[CH2:5]2.[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>Cl>[CH:9]1([NH:15][C@@H:2]2[CH2:3][N:4]([CH2:7][CH3:8])[CH2:5][C@H:6]2[OH:1])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCN1CC2OC2C1
Reactant: NC1CCCCC1
Agent: Cl
Product: CCN1C[C@@H](O)[C@H](NC2CCCCC2)C1
Temperature: 130 °C
Yield: 70.6 %

Procedure:
A mixture of 11.3 g (0.10 mole) of 3,4-epoxy-1-ethyl-pyrrolidine, 11.9 g (0.12 mol) of cyclohexylamine and one drop of conc. hydrochloric acid was heated at 130° C. under a nitrogen atmosphere for 18 hr. The mixture was cooled and diluted with 200 ml of petroleum ether. The precipitate was collected and recrystallized from petroleum-ether-cyclohexane to give 15 g (71%) of a white powder; m.p. 68°-71° C.