Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)=[CH:7][C:8](=O)[NH:9][N:10]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:27])=O>>[CH2:1]([C:5]1[N:10]=[N:9][C:8]([Cl:27])=[CH:7][C:6]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 90 °C

Procedure:
A suspension of the pyridazin-3-one (58.4 mmol, 19.1 g) in phosphorous oxychloride (292 mmol, 26.7 mL) was heated at 90° C. for 30 min with stirring during which period the starting material was fully consumed as judged by TLC. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with saturated NaHCO3 (3×100 mL), brine (100 mL), dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was purified on a 330 g SiO2 cartridge eluating with 0-10% ethyl acetate in hexanes to afford 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine.
Reaction SMILES: [N+](C1C=CC([O:8][C:9]([N:11]([C:13]2[CH:55]=[CH:54][C:16]([O:17][CH2:18][C:19]([NH:21][C@H:22]([C:27]([NH:29][C@@H:30]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@H:31]([OH:46])[C:32]([N:34]3[CH2:45][CH2:44][CH2:43][C@H:35]3[C:36]([NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:33])=[O:28])[CH2:23][C:24](=[O:26])[NH2:25])=[O:20])=[CH:15][CH:14]=2)[CH3:12])=O)=CC=1)([O-])=O.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>>[O:61]1[CH2:62][CH2:63][N:58]([C:9]([N:11]([C:13]2[CH:55]=[CH:54][C:16]([O:17][CH2:18][C:19]([NH:21][C@H:22]([C:27]([NH:29][C@@H:30]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@H:31]([OH:46])[C:32]([N:34]3[CH2:45][CH2:44][CH2:43][C@H:35]3[C:36]([NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:33])=[O:28])[CH2:23][C:24](=[O:26])[NH2:25])=[O:20])=[CH:15][CH:14]=2)[CH3:12])=[O:8])[CH2:59][CH2:60]1
Reactant: CN(C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Reactant: C1COCCN1
Product: CN(C(=O)N1CCOCC1)c1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Reaction time: 144 h

Procedure:
A solution of 47 mg (0.060 mmol) of 1-[(2S,3S)-3-{N2 -[4-(P-N-nitrophenoxycarbonyl-N-methylamino)-phenoxy]acetyl-L-asparaginyl}amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide (prepared as described in Example 42) dissolved in 0.5 ml of morpholine was allowed to stand at room temperature for 6 days. At the end of this time, the reaction mixture was freed from an excess of morpholine by distillation under reduced pressure, and the residue was diluted with chloroform and then washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by preparative thin layer chromatography, using a 8:1 by volume mixture of methylene chloride and methanol as the developing solvent, to give 30 mg of the title compound as a colorless powder, melting at 112°-114° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:32]([C:34]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:35]=1B(O)O)#[N:33]>>[C:32]([C:34]1[CH:39]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:37]=[CH:36][C:35]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1)#[N:33]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Reactant: N#Cc1cc(C(F)(F)F)ccc1B(O)O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4C#N)nccc3c2)c(OC)c1

Procedure:
The titled compound was prepared in an analogous manner to that of INTERMEDIATE DD, except that 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate OOO) and (2-cyano-4-(trifluoromethyl)phenyl)boronic acid were used as the coupling partners. The material was purified via silica gel column chromatography (12 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 1-(2-cyano-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. m/z (ESI) 629.3 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]=[C:8](Cl)Cl)=[CH:3][CH:2]=1.C(N(CC)CC)C.[OH:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1>C(Cl)Cl>[C:4]1([N:7]=[C:8]2[N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]3[CH2:19][O:18]2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: ClC(Cl)=Nc1ccccc1
Reactant: OCC1CCCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(N=C2OCC3CCCCN23)cc1
Reaction time: 12 h

Procedure:
3 g Phenyl isocyanide dichloride in 10 ml methylene chloride was treated at room temperature with a solution of 5.4 ml triethylamine and 1.7 g 2-hydroxymethylpiperidine in 20 ml methylene chloride. After 12 hours at room temperature, the mixture was washed with water, the organic phase was dried over magnesium sulphate, the solvent was distilled and the residue recrystallised from diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][N:29]1[C:25](=[O:35])[C:26]3[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:28]1=[O:30])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(CCl)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 45 °C
Yield: 82.1 %

Procedure:
To a solution of ethyl 6-chloro-2-(chloromethyl)-4-phenylquinoline-3-carboxylate (539 mg, 1.5 mmol) in dry N,N-dimethylformamide (5 ml) at room temperature was added potassium phthalimide (278 mg, 1.5 mmol). The mixture was heated at 45° C. for 48 hours, then diluted with ethyl acetate and poured into a separatory funnel. The organic phase was washed with saturated sodium bicarbonate, water (2×), then brine. The organic phase was separated, and the solvent removed under reduced pressure, leaving a white solid, which was washed with a cold solution of 10% diethylether/hexanes, dried under reduced pressure, to provide ethyl 6-chloro-2-((1,3-dioxoisoindolin-2-yl)methyl)-4-phenylquinoline-3-carboxylate (580 mg, 82%) as a white powder. TLC Rf=0.41 using 1:1 ethyl acetate:hexanes eluent on a glass backed silica gel plate. 1H NMR (CDCl3, 400 MHz) δ 7.98 (m, 2H); 7.78 (m, 3H); 7.58 (m, 5H); 7.38 (m, 2H); 5.30 (s, 2H); 4.04 (q, 2H, J=7.0 Hz); 0.89 (t, 3H, J=7.0 Hz). LC MS (CI) shows M+H 471.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH2:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[C:43](Cl)=[O:44].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH:25][C:43]([C:34]1[CH:35]=[CH:36][C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=1)=[O:44])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2c1
Yield: 64.3 %

Procedure:
A solution of 249 mg of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester, 106 mg of 2-naphthoyl chloride and 72 mg of diisopropylethylamine in 10 ml of dry dichloromethane was stirred at 20° C. for 20 hours. The gelatinous reaction mixture was partitioned between dichloromethane and water. The organic phase was evaporated and the resulting oil was crystallized from ethyl acetate/n-hexane to give 215 mg of N-[2(R)-hydroxy-3(S)-[[N-(2-naphthoyl)-L-asparaginyl]amino]-4-phenylbutyl]-L-proline tert.butyl ester, as a white solid; MS: m/e 603 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][OH:11].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.CCOC(C)=O.C(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: OCc1ccc(F)c(F)c1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1ccc(F)c(F)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 119.1 %

Procedure:
(2-Bromo-3,4-difluorophenyl)methanol (Compound AR) (2.55 g, 11.4 mmol, Eq: 1.00) was dissolved in dichloromethane (15 ml). Dess-Martin periodinane (4.85 g, 11.4 mmol, Eq: 1.00) was added. The reaction mixture was stirred for 2 hrs at room temperature. The reaction mixture was filtered over a plug of celite and washed with DCM (30 ml). Filtrate was concentrated to give a semi solid. Crude product was dissolved in EtOAc/DCM and loaded into a silica gel column (4 g). Silica gel column was flushed with EtOAc to give a light yellow solid (3 g). 1H NMR (DMSO) δ 10.13 (s, 1H), 7.74-7.82 (m, 1H), 7.70 (ddd, J=9.5, 7.3, 0.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[CH:3]=1.[NH3:10].[O-2].[Mg+2]>O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:9])[CH:3]=1)[NH2:10]
Reactant: N
Reactant: Fc1cc(F)cc(F)c1
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Product: Nc1cc(F)cc(F)c1
Temperature: 225 °C
Reaction time: 6 h

Procedure:
A 600 ml Hastelloy pressure reactor (Parr Instrument Co., Moline, Ill.) equipped with the standard stirrer, thermowell, and valves was used. The reactor was charged with 0.833 moles of 1,3,5-trifluorobenzene (110 g), 4.6 moles of 29% ammonia in water (270 g), and 0.44 moles of magnesium oxide (17.8 g). The reactor was purged with argon, and heated to 225° C. until the maximum pressure (about 1400 psig) was reached. As the reaction proceeded, the pressure dropped at a rate of about 20 lbs./hour for about 6 hours. The reactor was then cooled and the contents allowed to settle. The oils were drained from the reactor bottom until salts/water are observed. The salts float on the oils and settle slowly in the aqueous ammonia. The aqueous salts were extracted 2 or 3 times with MTBE. The MTBE was combined with the oils and charged to a distillation column packed with stainless steel packing (ProPak). The salts were centrifuged, washed with water, and discarded. The product was isolated by distilling MTBE at atm. Pressure, then distilling DFA at 20 to 50 mm.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:45])[CH2:14][CH2:15][N:16]([C:23]([C:25]1[CH:44]=[CH:43][C:28]2[N:29]([CH3:42])[C:30]([CH2:32][NH:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)=[N:31][C:27]=2[CH:26]=1)=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(C)(C)C.C(=O)([O-])[O-].[NH4+:51].[NH4+]>Cl.C(O)C>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH2:14][CH2:15][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]([C:25]1[CH:44]=[CH:43][C:28]2[N:29]([CH3:42])[C:30]([CH2:32][NH:33][C:34]3[CH:39]=[CH:38][C:37]([C:40](=[NH:41])[NH2:51])=[CH:36][CH:35]=3)=[N:31][C:27]=2[CH:26]=1)=[O:24])=[O:45]
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)NCCCCNC(=O)OC(C)(C)C)c3ccccc3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)NCCCCN)c3ccccc3)ccc21
Temperature: 25 °C

Procedure:
The product of 1f (4.81 mmol) was dissolved in a saturated solution of HCl in ethanol (250 mL), the mixture stirred at room temperature over night and then evaporated to dryness at 30° C. The remaining raw material was dissolved in 200 mL dry ethanol, then ammonium carbonate (48.1 mmol) was added and the mixture stirred at room temperature over night. After evaporation of the solvent the remaining raw material was triturated with ca. 5 mL ethanol, the undissolved material separated by filtration and the solvent evaporated at 30° C. The product was then dissolved in 30 mL water, the solution stirred with ca.2g charcoal, filtered and evaporated to dryness.
Reaction SMILES: [N:1]1([C:5](=[O:26])[CH2:6][C:7]2[CH:24]=[CH:23][C:10]([O:11][CH2:12][CH2:13][C@@H:14]3[CH2:16][C@@H:15]3[CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:9][C:8]=2[F:25])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:34](=O)([O:40]N1C(=O)CCC1=O)[O:35][CH2:36][CH:37]1[CH2:39][CH2:38]1>ClCCl.[NH4+].[Cl-]>[CH:37]1([CH2:36][O:35][C:34]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][O:11][C:10]3[CH:23]=[CH:24][C:7]([CH2:6][C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)=[O:26])=[C:8]([F:25])[CH:9]=3)[CH2:22][CH2:21]2)=[O:40])[CH2:39][CH2:38]1
Reactant: O=C(Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)cc1F)N1CCC1
Reactant: O=C(OCC1CC1)ON1C(=O)CCC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCC3CC3)CC2)cc1F)N1CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-((1R,2S)-2-{2-[4-(2-azetidin-1-yl-2-oxoethyl)-3-fluorophenoxy]ethyl)cyclopropyl)piperidine (Step B, Example 11; 0.30 g, 0.93 mmol) in dichloromethane (4.6 mL) under a nitrogen atmosphere was added triethylamine (0.36 mL, 2.6 mmol) and cyclopropylmethyl 2,5-dioxopyrrolidin-1-yl carbonate (0.35 g, 1.67 mmol). The resulting solution was stirred for 18 h at ambient temperature. The solution was diluted with saturated NH4Cl(aq.) (10 mL). The resulting layers were separated and the aqueous phase extracted with dichloromethane (2×30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the obtained residue by CombiFlash chromatography (12 g silica gel, 0 to 25% EtOAc in heptane) provided the title compound as an off white semi-solid. LC/MS (m/z): 459.3 (M+H)+. GPR119 Human EC50: 2.0 nM.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[NH:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:14][CH:13]=[CH:12][CH:11]=2)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:2][CH2:3][C:4]1[N:17]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1c(NC(=O)CCl)cnc2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3cccnc3c21
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
To a solution of tert-butyl 3-({3-[(chloroacetyl)amino][1,5]naphthyridin-4-yl}amino)propylcarbamate hydrochloride (from Part E, approximately 57.6 mmol) in 3:1 ethanol/water (240 mL) was added 6 M aqueous potassium carbonate. The reaction mixture was stirred at room temperature for 1 hour, 40° C. for 1.5 hour, then at room temperature overnight. The volatiles were removed under reduced pressure and the residue was partitioned between dichloromethane (250 mL) and water (150 mL). The aqueous layer was extracted with dichloromethane (2×75 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 18.9 g of tert-butyl 3-[2-(chloromethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propylcarbamate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][CH2:24][CH3:25])=[C:8]([C:10]2[NH:15][C:14](=[O:16])[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)=[CH:12][N:11]=2)[CH:9]=1)([O-])=O.[H][H]>COCCO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][CH2:24][CH3:25])=[C:8]([C:10]2[NH:15][C:14](=[O:16])[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)=[CH:12][N:11]=2)[CH:9]=1
Reactant: CCCOc1ccc([N+](=O)[O-])cc1-c1ncc(-c2nnn[nH]2)c(=O)[nH]1
Reactant: [H][H]
Solvent: COCCO
Product: CCCOc1ccc(N)cc1-c1ncc(-c2nnn[nH]2)c(=O)[nH]1
Reaction time: 19 h
Yield: 78.9 %

Procedure:
A mixture of 2-(5-nitro-2-n-propoxyphenyl)-5-(5-1H-tetrazolyl)pyrimidine-4(3H)-one (5.0 g.) and 10% paladium-on-carbon (4.0 g.) in 2-methoxyethanol (900 ml.) was shaken in an atmosphere of hydrogen at an initial pressure of 3.5 kg./cm2 for 19 hours. The mixture was filtered and the filtrate evaporated to dryness to give the title compound (3.6 g., 79%), m.p. 250°-253° (decomp). Recrystallization from 2-methoxyethanol gave analytical material, m.p. 261°-262°.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)#[N:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[ClH:17].O1CCOCC1>C(O)C>[ClH:17].[ClH:17].[NH:2]=[C:1]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1
Reactant: C1CCNC1
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: N=C(c1ccc(C(=O)O)cn1)N1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6-Cyanonicotinic acid (4.15 g, 28.0 mmol) was dissolved in anhydrous ethanol (3.2 ml) and 4N hydrochloric acid/1,4-dioxane (30 ml), and the mixture was stirred in a closed system at room temperature for two nights. The solvent was evaporated under reduced pressure, and the obtained residue was suspended in anhydrous ethanol (90 ml). Pyrrolidine (2.34 ml, 28.0 mmol) was added thereto, and the mixture was stirred at room temperature for 3 days. Pyrrolidine (3.51 ml, 42.0 mmol) was added again, and the mixture was stirred for 2.5 hours. The solvent was evaporated under reduced pressure, and water aid ethanol were added to the obtained residue. The precipitate was removed by filtration, ethanol was evaporated under reduced pressure, and the obtained aqueous solution was lyophilized to give the title compound without purification operation.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][NH:7][NH:6]1)=[O:4].[CH3:11][S:12][C:13]1[N:18]=[C:17]([C:19](Cl)=[O:20])[CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([S:12][CH3:11])[N:18]=2)=[O:20])[NH:6]1)=[O:4]
Reactant: COC(=O)C1CCCNN1
Reactant: CSc1nccc(C(=O)Cl)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCN(C(=O)c2ccnc(SC)n2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
To a solution of hexahydro-pyridazine-3-carboxylic acid methyl ester (1.5 g, 8.3 mmol) in CH2Cl2 (80 mL) is added 2-methylsulfanyl-pyrimidine-4-carbonyl chloride, 16, (1.41 g, 7.5 mmol) and triethylamine (1.2 mL, 8.3 mmol). The mixture is stirred at room temperature for 3 hours. The reaction solution is then diluted with1 N HCl (100 mL) and the organic phase is decanted. The aqueous phase is extracted with additional solvent and the organic layers are combined, dried, and concentrated in vacuo. The crude product is purified over silica(ethyl acetate/hexane 1:1) to afford 0.9 g (36% yield) of the desired product as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[C@H:8]1[CH2:12][CH2:11][C@@H:10]([C:13](=[O:18])N(OC)C)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br-].O.Cl>O1CCCC1>[C:1]([O:5][C:6](=[O:32])[N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)[C@H:8]1[CH2:12][CH2:11][C@@H:10]([C:13](=[O:18])[CH2:10][CH2:9][CH:8]=[CH2:12])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)[C@@H]1CC[C@H](N(Cc2ccc(-c3ccccc3)cc2)C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(=O)[C@@H]1CC[C@H](N(Cc2ccc(-c3ccccc3)cc2)C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 188.5 %

Procedure:
While under a nitrogen atmosphere, a solution of tert-Butyl-biphen-4-ylmethyl-{(1S,3R)-3-(methoxy(methyl)carbamoyl)-cyclopentyl}-carbamate (1.2 g, 2.74 mmol), in tetrahydrofuran (20 mL) was cooled to 0° C. and treated with 3-butenylmagnesiun bromide (0.5 M in THF, 13.7 mL, 6.85 mmol) in a drop wise manner. The solution was stirred for 1 hour at 0° C. then allowed to warm to room temperature overnight. The resulting solution was poured into water, acidified to pH 3-4 with 1 N hydrochloric acid, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-30% ethyl acetate in heptane) gave tert-Butyl-biphen-4-ylmethyl-{(1S,3R)-3-pent-4-enoylcyclopentyl}-carbamate as a colorless oil (1.12 g, 94%); 1H NMR (CDCl3, 400 MHz) δ 7.62 d, J=7.5 Hz, (2H), 7.56 (d, J=7.5 Hz, 2H), 7.46 (t, J=7.5 Hz, 2H), 7.36 (m, 1H), 7.28 (m, 2H), 5.80 (m, 1H), 5.01 (m, 2H), 4.48 m, (3H), 2.92 (m, 1H), 2.54 (m, 2H), 2.37 (m, 2H), 2.04 (m, 1H), 1.74-1.94 (m, 4H), 1.48-1.66 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:14][C:13]([C:16]([F:19])([F:18])[F:17])([OH:15])[CH2:12]1)(=[O:10])=[O:9].[F:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[C:36]1[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=1>>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:22]2[CH:23]=[CH:24][C:25]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]([N:11]3[CH2:14][C:13]([C:16]([F:19])([F:18])[F:17])([OH:15])[CH2:12]3)(=[O:10])=[O:9])=[CH:26][C:21]=2[F:20])=[CH:37][N:38]=1
Reactant: O=S(=O)(c1ccccc1Br)N1CC(O)(C(F)(F)F)C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)N3CC(O)(C(F)(F)F)C3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 1-((2-bromophenyl)sulfonyl)-3-(trifluoromethyl)azetidin-3-ol and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H16F4N4O3S, 468.09; m/z found, 469.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 8.53-8.47 (d, J=1.4, 2H), 8.06-8.01 (dd, J=8.0, 1.3, 1H), 7.81-7.76 (m, 1H), 7.70-7.65 (m, 1H), 7.64-7.58 (m, 1H), 7.51-7.45 (m, 2H), 7.35-7.29 (dd, J=11.7, 1.8, 1H), 7.28-7.24 (dd, J=7.8, 1.7, 1H), 6.94 (s, 2H), 3.81-3.76 (d, J=9.3, 2H), 3.71-3.66 (m, 2H)
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C([O-])([O-])=O.[K+].[K+].[CH3:27][NH2:28]>C(Cl)Cl>[CH3:27][NH:28][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CN
Reactant: Nc1ccc(-c2ccc([N+](=O)[O-])c(F)c2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CNc1cc(-c2ccc(N)c([N+](=O)[O-])c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
3′-Fluoro-3,4′-dinitrobiphenyl-4-amine (285 mg, 1.03 mmol) was suspended in DCM (10 mL). K2CO3 (284 mg, 2.06 mmol) was added, followed by MeNH2 (40% in H2O, 10 mL). The mixture was stirred at room temperature for 72 h. The solution was then washed with H2O and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford the product as a red solid (296 mg, 100%).