Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:4](=[O:6])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cccc(C(=O)O)c1N
Reactant: Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)Nc2ccccn2)c1N
Yield: 65.1 %

Procedure:
A solution of 2-amino-3-(methoxycarbonyl)benzoic acid 20 (1 g, 5.1 mmol), 2-aminopyridine 21 (723 mg, 7.7 mmol), HOBT (1.39 g, 10.3 mmol), EDCI (1.9 g, 10.3 mmol) and DMAP (1.25 g, 10.3 mmol) in DMF (40 mL) was stirred at 70° for 12 h. The reaction mixture was poured into H2O. The resulting precipitate was collected by filtration, rinsed with H2O, and dried under vacuum to give 22 (0.9 g, 58% yield).
Reaction SMILES: [CH:1]1([O:5][C:6]2[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Ca+2].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20].C(Cl)Cl.CO>C1(C)C=CC=CC=1>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19](=[O:20])[NH:12][C:9]2[CH:10]=[N:11][C:6]([O:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[CH:7][CH:8]=2)=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: Nc1ccc(OC2CCC2)nc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccc(OC2CCC2)nc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 68.6 %

Procedure:
A mixture of 6-cyclobutoxy-pyridin-3-ylamine (4.41 g, assume 25 mmol), as prepared in the previous step, and CaCO3 (3.25 g, 32.5 mmol) (10 micron powder) was treated with a homogeneous solution of 4-nitrophenyl chloroformate (5.54 g, 27.5 mmol) in toluene (28 mL) in one portion at rt, and was stirred at “rt” (reaction warmed spontaneously) for 2 h. The reaction mixture was then directly loaded onto a flash silica column (95:5 DCM/MeOH→9:1 DCM/MeOH) to afford 5.65 g of material, which was further purified by trituration with hot toluene (1×200 mL) to provide the title compound (4.45 g, 54%). 1H NMR (400 MHz, CDCl3) δ 8.28 (m, 2H), 8.12 (d, 1H), 7.81 (m, 1H), 7.39 (m, 2H), 6.85 (br s, 1H), 6.72 (d, 1H), 5.14 (m, 1H), 2.45 (m, 2H), 2.13 (m, 2H), 1.84 (m, 1H), 1.68 (m, 1H). LC-MS (ESI): calcd mass 329.1, found 330.1 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[CH:10][CH:9]=2)[CH2:4]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][N:2]([CH3:21])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: CN(C)[C@H]1CCN(c2ccc(C(=O)OC(C)(C)C)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)[C@H]1CCN(c2ccc(C(=O)O)cc2)C1

Procedure:
A solution of tert-butyl ester 98 (0.595 g, 2.05 mmol) in 1:1 trifluoroacetic acid:DCM (6 mL) was stirred at room temperature for 3 h then concentrated to give title compound 99 (used as is in the next reaction). LRMS: 234.14 (calc) 235.1 (obs)
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14](F)=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:10]=2)[CH2:5][CH2:4]1.[Br:28]C1C(Cl)=NC(Cl)=NC=1>>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([Br:28])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:10]=2)[CH2:5][CH2:4]1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2F)CC1
Product: NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2Br)CC1

Procedure:
The titled compound was synthesized analogously as compound 6-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one, by using 5-bromo-2,4-dichloropyrimidine. MS 431.4 and 433.3 (M+H, Br pattern); UV 222.3, 263.9 nm.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][CH:19]=2)[CH:4]=1.C(N(CC)CC)C.[CH2:43]([N:45]=[C:46]=[O:47])[CH3:44]>C(Cl)Cl>[CH2:43]([NH:45][C:46](=[O:47])[NH:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:20][CH:19]=2)[CH:4]=1)[CH3:44]
Reactant: CCN=C=O
Reactant: CCOC(=O)COc1ccc(N)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc(OCC(=O)OCC)c(NC(=O)c2ccc(OCCCCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 200 ml of ethyl 4-amino-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate hydrochloride, 40.5 mg of triethylamine and 5 ml of methylene chloride was added 30 mg of ethyl isocyanate followed by stirring at room temperature overnight. The reaction mixture was treated in a manner similar to Example 68 to obtain 130 mg of ethyl 4-(3-ethylureido)-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:28])([CH3:27])[O:19][C:20]=3[C:21]([C:23]([O:25]C)=O)=[CH:22][C:12]=2[N:11]=1.[F:29][C:30]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:31]=1[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:28])([CH3:27])[O:19][C:20]=3[C:21]([C:23]([NH:32][C:31]3[CH:33]=[CH:34][C:35]([CH3:37])=[CH:36][C:30]=3[F:29])=[O:25])=[CH:22][C:12]=2[N:11]=1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)n(C)c2c2c1OC(C)(C)C2
Reactant: Cc1ccc(N)c(F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2cc3nc(Nc4c(F)cccc4Cl)n(C)c3c3c2OC(C)(C)C3)c(F)c1
Yield: 20.4 %

Procedure:
The title compound was prepared following the procedure described for Example-137 using methyl 2-((2-chloro-6-fluorophenyl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Step-7 of Intermediate-49, 0.100 g, 0.247 mmol), 2-fluoro-4-methyl aniline (0.046 g, 0.371 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.025 g of the desired product. 1HNMR (DMSO-d6): δ 1.58 (s, 6H), 2.29 (s, 3H), 3.48 (s, 2H), 3.56 (s, 3H), 7.00 (d, J=8.4 Hz, 2H), 7.13-7.30 (m, 4H), 8.29 (t, J=9 Hz, 1H), 9.94 (s, 1H), 10.51 (s, 1H). MS [M+H]+: 497.23.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:20])[CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1>CO>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:20])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(Cl)s2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)s2)cc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 52.3 %

Procedure:
A mixture of 4-[4-(5-chloro-thiophen-2-yl)-phenyl]-4-oxo-butyric acid, methyl ester (5.99 g, 0.0194 mol), 1.0 M aqueous sodium hydroxide (23 mL, 0.023 mol), tetrahydrofuran (50 mL), and methanol (50 mL) was stirred at room temperature for 26 hours. The resulting suspension was filtered, and the filtercake was washed with methanol. The filtercake was partitioned between dichloromethane-tetrahydrofuran-ethyl acetate (100 mL each) and 0.5 M aqueous hydrochloric acid (50 mL). The organics were washed with brine, dried (Na2SO4), and rotary evaporated to give 2.99 g of 4-[4-(5-chloro-thiophen-2-yl)-phenyl]-4-oxo-butyric acid as a bright yellow solid; mp 212-213° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=[O:13])=O)C.[Li+].[BH4-].C(OCC)(=O)C>O1CCOCC1>[OH:3][CH2:4][CH2:6][N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=[O:13]
Reactant: CCOC(=O)Cn1ccccc1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=c1ccccn1CCO
Reaction time: 0.08 h
Yield: 41.3 %

Procedure:
In 100 ml of dioxane, was dissolved N-ethoxycarbonylmethyl-2-pyridone (3.62 g, 20 mmol). To the solution was added 90% LiBH4 (0.96 g, 40 mmol) and the mixture was refluxed for 20 minutes. Subsequently, ethyl acetate (20 ml) was added to the mixture and the refluxing was carried out for five minutes. The reaction mixture was evaporated to dryness and water was added to the residue. The aqueous solution was extracted with chloroform (three times), dried, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, to thereby obtain the title compound (1.15 g, yield 41%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:32][NH2:33]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[CH:30]=[CH:29][N:28]=[C:27]([NH:32][NH2:33])[N:26]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccnc(Cl)n4)ccc32)n1)c1ccccc1
Reactant: NN
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccnc(NN)n4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 433, Step A, starting from 2-[(S)-1-Phenylethylamino]-4-[5-(2-chloropyrimidin-4-yl)benzimidazol-1-yl]pyrimidine and hydrazine. Mass spectrum (ESI) 424.3 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.Cl[C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:35]4[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCNCC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.2 %

Procedure:
A solution of [(3R,4S)-4-(3,4-Dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (50 mg, 0.10 mmol), 6-chloronicotinonitrile (21 mg, 0.15 mmol) in N-methylpyrrolidinone (0.5 mL) was treated with N,N-diisopropyl ethyl amine (52 μl, 0.30 mmol). The solution was stirred for 6 h at ambient temperature before it was diluted with ethyl acetate (15 mL) and washed with an aqueous solution of sodium carbonate (1 M, 15 mL). The organic layer was separated and washed with brine (15 mL) and the aqueous layers were extracted with ethyl acetate (20 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=80:20:0 to 0:90:10) afforded the title compound (52 mg, 86%) as an off-white foam. MS m/e: 596.2 [M]+.
Reaction SMILES: ClC1C=CC=C(Cl)C=1C=O.[CH:11]1([CH:17]=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[C:19]12([O:29][CH2:30][C:31]3[NH:35][C:34]([C:36]4[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=4[Cl:43])=[N:33][C:32]=3[C:44](O)=[O:45])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2.[CH3:47][O:48][C:49](=[O:57])[C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([NH2:56])[CH:51]=1>>[CH2:17]([O:18][C:44]([C:32]1[N:33]=[C:34]([C:36]2[C:37]([Cl:43])=[CH:38][CH:39]=[CH:40][C:41]=2[Cl:42])[NH:35][C:31]=1[CH2:30][O:29][C:19]12[CH2:20][CH:21]3[CH2:22][CH:23]([CH2:24][CH:25]([CH2:27]3)[CH2:26]1)[CH2:28]2)=[O:45])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:47][O:48][C:49](=[O:57])[C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([NH:56][C:44]([C:32]2[N:33]=[C:34]([C:36]3[C:37]([Cl:43])=[CH:38][CH:39]=[CH:40][C:41]=3[Cl:42])[NH:35][C:31]=2[CH2:30][O:29][C:19]23[CH2:20][CH:21]4[CH2:22][CH:23]([CH2:24][CH:25]([CH2:27]4)[CH2:26]2)[CH2:28]3)=[O:45])[CH:51]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(O)c1nc(-c2c(Cl)cccc2Cl)[nH]c1COC12CC3CC(CC(C3)C1)C2
Reactant: O=CC1CCCCC1
Agent: O=Cc1c(Cl)cccc1Cl
Product: COC(=O)c1cccc(NC(=O)c2nc(-c3c(Cl)cccc3Cl)[nH]c2COC23CC4CC(CC(C4)C2)C3)c1
Product: O=C(OCc1ccccc1)c1nc(-c2c(Cl)cccc2Cl)[nH]c1COC12CC3CC(CC(C3)C1)C2

Procedure:
5-(Adamantan-1-yloxymethyl)-2-(2,6-dichloro-phenyl)-1H-imidazole-4-carboxylic acid benzyl ester was prepared according to the procedure of Example 216, steps a, b, c and d with the modification that 2,6-dichloro-benzaldehyde was used in step d instead of cyclohexanecarboxaldehyde. The benzyl ester was hydrolysed according to the procedure of Example 211, step b and the resulting 5-(adamantan-1-yloxymethyl)-2-(2,6-dichloro-phenyl)-1H-imidazole-4-carboxylic acid was reacted with 3-amino-benzoic acid methyl ester according to the procedure of Example 20, step d to afford 3-{[5-(adamantan-1-yloxymethyl)-2-(2,6-dichloro-phenyl)-1H-imidazole-4-carbonyl]-amino}-benzoic acid methyl ester. The methyl ester was hydrolysed according to the procedure of Example 36, step d to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.87 (2H, s), 10.00 (1H, s), 8.58 (1H, s), 7.94 (1H, d), 7.58 (4H, m), 7.39 (1H, t), 4.93 (2H, s), 2.11 (3H, s), 1.79 (6H, s), 1.58 (6H, s). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](N)=[N:6][CH:7]=1.S(=O)(=O)(O)O.[N:14]([O-:16])=[O:15].[Na+].[N+]([O-])(O)=[O:19]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([OH:19])=[N:6][CH:7]=1
Reactant: O=N[O-]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(Cl)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cnc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
321 g of 5-chloro-2-aminopyridine are added dropwise to 1.25 l of concentrated sulfuric acid. The reaction mixture is then stirred until the educt has completely dissolved. Then 172.5 g of sodium nitrite, dissolved in 240 ml of water, are added at a temperature of 40°-45° C. and the reaction mixture is stirred for 15 minutes. Subsequently 125 ml of 100% nitric acid are added dropwise at 50° C. over 40 minutes. The reaction mixture is kept for 1 hour at 55° C. and then poured onto 5 kg of ice-water. The product in the form of a yellow precipitate is isolated by filtration, washed copiously with water and subsequently dried at 60° C., giving 351 g of 5-chloro-2-hydroxy-3-nitropyridine (80.5% of theory) with a melting point of 229°-231° C.
Reaction SMILES: CCCCCCC=CCCC.[C:12]([O:16][C:17]([NH:19][CH:20](P(OC)(OC)=O)[C:21]([O:23][CH3:24])=[O:22])=[O:18])([CH3:15])([CH3:14])[CH3:13].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O>C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][C:20](=[CH:36][C:35]1[CH:38]=[CH:39][CH:40]=[C:33]([O:32][CH3:31])[CH:34]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:18])([CH3:13])([CH3:14])[CH3:15]
Reactant: COc1cccc(C=O)c1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Agent: CCCC=CCCCCCC
Solvent: ClCCl
Product: COC(=O)C(=Cc1cccc(OC)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.70 mL (4.7 mmol) of 1,8-diazabicyclo[5.4.0.]undec-7-ene (DBU) and 1.40 g (4.7 MMOL) of tert-butoxycarbonylamino-(dimethoxyphosphoryl)acetic acid, methyl ester of Example 29 in 14 mL of methylene chloride is stirred at room temperature for 25 minutes. A quantity of 0.64 g (4.7 mmol) of 3-methoxybenzaldehyde is added and the solution is stirred at room temperature overnight. Methylene chloride (100 mL) is added and the solution is washed with 80mL of 1N hydrochloric acid and then with 80 mL of brine. The dried (magnesium sulfate) organic phase is evaporated and the product is purified by silica gel chromatography, eluting with 18% ethyl acetate to give pure product as a white powder; wt 1.25 g (86%);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[N:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[N:24]=[CH:23][C:22]([C:25](=[NH:42])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cn1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cn1)n2C)c1ccccn1

Procedure:
Prepared analogously to Example 25d from 1-Methyl-2-[N-(3-cyano-pyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[S:19][CH:20]=[C:21]([CH:23]=O)[N:22]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[CH3:7].O.C(OCC)(=O)C.O1C[CH2:35][CH2:34][CH2:33]1>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1>[CH2:6]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[S:19][CH:20]=[C:21]([CH:23]=[CH:4][C:3]3[CH:35]=[CH:34][CH:33]=[CH:1][CH:2]=3)[N:22]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[CH3:7]
Reactant: CCOc1ccc(-c2nc(C=O)cs2)cc1OCC
Reactant: C1CCOC1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccc(-c2nc(C=Cc3ccccc3)cs2)cc1OCC
Temperature: -50 °C

Procedure:
4.2 ml of n-butyllithium was dropwise added in small portions to a suspension of 2.6 g of benzyltriphenylphosphonium chloride in 10 ml of tetrahydrofuran, with stirring at -50° C. The mixture was heated to room temperature and, after cooling again to -50° C., was mixed with 12 ml of a tetrahydrofuran solution of 2 g of 2-(3,4-diethoxyphenyl)-4-formylthiazole. The mixture was stirred at the same temperature for 30 minutes and at room temperature for 14 hours. 10 ml of water and 40 ml of ethyl acetate were added to conduct extraction and phase separation. The solvent layer was dried and subjected to distillation to remove the solvent. The residue was purified by silica gel column chromatography to obtain 2 g of 2-(3,4-diethoxyphenyl)-4-styrylthiazole as a 1:1 mixture of cis form and trans form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[CH:7]=[N:6]2.COC1C=C2C(N=CC(=O)N2)=CC=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:8]1[CH:7]=[N:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2[nH]c(=O)cnc2c1
Agent: COc1ccc2ncc(=O)[nH]c2c1
Product: COc1ccc2nc(Cl)cnc2c1
Yield: 35 %

Procedure:
A mixture of 6-methoxyquinoxalin-2(1H)-one and 7-methoxyquinoxalin-2(1H)-one (5.67 g, 32.20 mmol) was refluxed in phosphorus oxychloride (120 mL) for 1 h. The reaction was concentrated and quenched by addition of ice, then basified with sodium carbonate, and extracted with ethyl acetate (3×200 mL). The organic layers were combined and concentrated in vacuo. The crude product was absorbed onto sodium sulfate and purified by column chromatography (0 to 5% ethyl acetate/hexanes) to afford 2-chloro-6-methoxyquinoxaline (2.21 g, 11.36 mmol, 35% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.69 (s, 1H), 7.88 (d, J=9.32 Hz, 1H), 7.43 (dd, J=9.32, 2.77 Hz, 1H), 7.37 (d, J=2.77 Hz, 1H), 3.95 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:41]1([O:50]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.NO.Cl>CN(C)C=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:41][OH:50])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(ethoxycarbonyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 4) (140 mg, 0.41 mmol) and N,N-diisopropylethylamine (320 μl, 2.07 mmol) in N,N-dimethylformamide (5 ml) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (235 mg, 0.61 mmol) and the resulting solution was stirred at room temperature under a nitrogen atmosphere for 30 minutes. Hydroxylamine hydrochloride (113 mg, 0.61 mmol) was then added and the mixture was stirred at room temperature for 20 hours. The mixture was poured into hydrochloric acid (1M, 20 ml) and extracted with ethyl acetate (×3). The combined organic layers were washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99.5:0.5) gradually changing to dichloromethane:methanol (97:3) to afford the title compound as a yellow oil (62 mg).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:21][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: NC1CCCc2ccccc21
Reactant: Clc1nc2ccccc2[nH]1
Product: c1ccc2c(c1)CCCC2Nc1nc2ccccc2[nH]1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and racemic 1,2,3,4-tetrahydro-l-naphthylamine by Procedure A (10 min at 170° C. followed by 15 min at 200° C.). The product was isolated from the crude reaction mixture by preparative LCMS to give the title compound as the free base and as a mixture of enantiomers (white solid, mp 230-234° C.). MS(ES+) m/z 264 ([M+1]+, 100). 1NMR (DMSO-d6) δ 1.73-1.82 (m, 1H), 1.85-1.96 (m, 2H), 2.01-2.09 (m, 1H), 2.70-2.85 (m, 2H), 5.04 (m, 1H), 7.01-7.05 (m, 2H), 7.12-7.28 (m, 5H), 7.33-7.37 (m, 1H), 8.05 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([CH:9]3[O:14][CH2:13][CH2:12][NH:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:32]=[C:31](Cl)[N:30]=[C:29]([NH2:34])[N:28]=1>C(O)C>[Cl:26][C:27]1[CH:32]=[C:31]([N:11]2[CH2:12][CH2:13][O:14][CH:9]([C:7]3[NH:6][C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=4[N:8]=3)[CH2:10]2)[N:30]=[C:29]([NH2:34])[N:28]=1
Reactant: Fc1ccc2[nH]c(C3CNCCO3)nc2c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(Cl)cc(N2CCOC(c3nc4cc(F)ccc4[nH]3)C2)n1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
To a suspension of 5-fluoro-2-(2-morpholinyl)-1H-benzimidazole (200 mg, 0.904 mmol) and Hunig's base (409 mg, 3.16 mmol) in ethanol (10 mL) stirred at room temperature was added 4,6-dichloro-2-pyrimidinamine (148 mg, 0.904 mmol), and the reaction mixture was stirred overnight at 85° C. The reaction mixture was cooled to room temperature and partitioned between EtOAc (25 mL) and water (25 mL). The organic solvent was evaporated in vacuo to give the crude product. The residue was triturated with EtOAc (1×5 mL). The resulting solid was filtered and collected to afford the title compound (250 mg). LC-MS (ES) m/z=349 [M+H]+.