Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[N:37]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:36](=[O:49])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:50][CH2:51][CH2:52][CH2:53][CH2:54][C:55](Cl)=[O:56]>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:55](=[O:56])[CH2:54][CH2:53][CH2:52][CH2:51][Br:50])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][C:36](=[O:49])[N:37]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[S:38]3(=[O:39])=[O:40])=[CH:30][CH:29]=2)[CH:17]=1
Reactant: O=C(Cl)CCCCBr
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N)cc4)cc3)cc2)S1(=O)=O
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(NC(=O)CCCCBr)cc4)cc3)cc2)S1(=O)=O

Procedure:
5-{4-[2-(4′-Amino-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (74 mg, 0.1 mmol) was treated as described in general procedure U using 5-bromovaleryl chloride (40 mg, 0.2 mmol) to give the intermediate 5-bromo-pentanoic acid [4′-(4-(2,4-dichloro-phenyl)-1-{-4-[1,1,4-trioxo-5-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-2-yl]-phenyl}-1H-imidazol-2-ylmethyl)-biphenyl-4-yl]-amide, which was treated with 1,8-diazabicyclo[5,4,0]undec-7-ene (46 mg, 0.3 mmol) at 0° C. in 1 mL anhydrous DMF (stirring at room temperature under nitrogen over night), followed by regular ethyl acetate/water workup and silica gel column chromatography to give 1-[4′-(4-(2,4-dichloro-phenyl)-1-{-4-[1,1,4-trioxo-5-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thia-diazolidin-2-yl]-phenyl}-1H-imidazol-2-ylmethyl)-biphenyl-4-yl]-piperidin-2-one, which was finally treated as described in general procedure W to give the desired compound 1-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-piperidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:12]3=[C:13]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:14]4[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:19]=4[N:11]3[CH2:10][C:9](=O)[N:8]([CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[CH2:7][C:6]=2[CH:36]=1.B.C1COCC1.Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:12]3=[C:13]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:14]4[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:19]=4[N:11]3[CH2:10][CH2:9][N:8]([CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[CH2:7][C:6]=2[CH:36]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)N(CCN(C)C)Cc1cc(Cl)ccc1-3
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN(C)C)Cc1cc(Cl)ccc1-3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 3-chloro-14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate (from Step 6) in THF (0.02 M), BH3.THF (1 M solution in THF, 5 eq) was added and the solution allowed to stir at RT for 2 h. MeOH (0.02 M) and a 1.25 M solution HCl in MeOH (0.24 M) were added carefully and stirred overnight at RT before being heated at 60° C. for 3 h. The volatiles were then removed in vacuo. The volume of the solution was reduced in vacuo before diluting with EtOAc. The organic phase was washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound. The crude was then used in the next step without any further purification (quant); MS (ES+) 494 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C@H:7]2[N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[C:20]([NH2:25])=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:14][CH2:13]1.[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27].O>O1CCCC1>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C@H:7]2[N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][C:26]2=[O:27])[CH2:16][CH2:17]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cccc2c1CCC[C@H]2N1CCC(Nc2ccccc2N)CC1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2c1CCC[C@H]2N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 60.9 %

Procedure:
(R)-N-[1-(5-Methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (1.83 g) was dissolved in tetrahydrofuran (100 ml), 1,1′-carbonyldiimidazole (973 mg) was added, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) and crystallized with hexane/ethyl acetate to give the title compound (1.2 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:20])[C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:21][C:22]1[N:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:20][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[N:30][C:22]=3[CH3:21])[C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Cc1ncccc1C(=O)O
Reactant: Nc1c(OCC2CC2)c(Cl)cc2c1[nH]c1cnccc12
Product: Cc1ncccc1C(=O)Nc1c(OCC2CC2)c(Cl)cc2c1[nH]c1cnccc12
Yield: 40 %

Procedure:
The desired compound was prepared according to Method A from 6-chloro-7-cyclopropylmethoxy-9H-β-carbolin-8-ylamine and 2-methylnicotinic acid in a 40-60% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][N:40]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:24]=[N:25][N:26]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][N:40]=2)[CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCl)nc1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: COc1ccc(N(Cc2cnn(Cc3ccc(C)cn3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 81.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.94 g) and 2-chloromethyl-5-methylpyridine hydrochloride (0.71 g) as starting materials, 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-({1-[(5-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.94 g) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:29]=[CH:28][CH:27]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(-c2ccccc2)c1

Procedure:
Compound is prepared from 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide and phenyl boronic acid according to conditions described in general procedure K. 1H NMR 300 MHz (DMSO-d6) δ 10.4 (s, 1H), 8.4 (s, 1H), 8.2 (m, 1H), 8.05 (d, 1H, J=7.2 Hz), 7.9 (m, 2H), 7.8 (m, 2H), 7.4-7.7 (m, 7H), 7.0 (d, 1H, J=10.1Hz), 4.3 (m, 2H), 3.6 (s, 4H), 2.9 (m, 2H), 2.6 (m, 4H).
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17](=[O:25])[C:16]=1[C:26]#[N:27]>C1(C)C=CC=CC=1>[O:25]=[C:17]1[C:16]([C:26]#[N:27])=[C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[O:8])[CH2:2][CH2:3]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18]1
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: N#Cc1c(Cl)c2ccccc2[nH]c1=O
Solvent: Cc1ccccc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2ccccc2[nH]c1=O
Temperature: 110 °C
Yield: 87.8 %

Procedure:
Piperazine-1-yl-thiophen-2-yl-methanone (8.0 g, 41 mmol) was added to a solution of Compound 115 (4.1 g, 20 mmol) in toluene (50 mL) and heated overnight at 110° C. The solvent was removed under vacuum. The residue was suspended in water, sonicated, and filtered. The crude product was purified by flash chromatography eluting with 0-2% methanol in dichloromethane gradient to yield 6.4 g (88%) of white solids. M.P. 264° C. 1H NMR (DMSO-d6): δ 3.7 (m, 4H), 3.9 (m, 4H), 7.16 (t, J=4.8 Hz, 1H), 7.23 (t, J=5.9 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.49 (d, J=4.0 Hz, 1H), 7.61 (t, J=8.3 Hz, 1H), 7.8 (m, 2H), 11.90 (b, 1H); EIMS: 364 (M+H).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10]([F:13])([F:12])[F:11])[N:9]=[N:8]2)[CH:2]=1.[Br:15]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:1]1[CH:2]=[C:3]([C:7]2([C:10]([F:12])([F:11])[F:13])[N:9]=[N:8]2)[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(C2(C(F)(F)F)N=N2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)C1(c2cccc(CBr)c2)N=N1
Temperature: 85 °C
Yield: 53.8 %

Procedure:
To a solution of intermediate 63, 3-m-tolyl-3-trifluoromethyl-3H-diazirine, (200 mg, 1 mmol) in CCl4 (4 mL) was added N-bromosuccinimide (200 mg, 1.1 mmol, re-crystallized from water), and the stirred mixture heated at 85° C. To this was added AIBN (50 mg) and the mixture heated at reflux for an additional 2.5 hrs. After cooling, the mixture was purified by column chromatography (SiO2, pentane) to provide 150 mg (Yield 54%) of the title compound as a clear oil. 1H NMR (300 MHz, CDCl3) δ ppm: 4.42 (2 H, s) 7.10-7.17 (2 H, m) 7.31-7.45 (2 H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11]>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: Nc1cccnc1
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)Nc1cccnc1

Procedure:
In a manner similar to that described in Referential Example 242, 3-aminopyridine was condensed with methyl 2-chloro-2-oxoacetate to form methyl 2-[(pyridin-3-yl)amino]-2-oxoacetate. In a manner similar to that described in Example 271, the title compound was obtained from the thus-condensed ester product and the compound obtained in Referential Example 310.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]([CH3:17])[CH2:15][N:14]([CH3:18])[NH:13]2)=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:20]([O:22][CH2:23][CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][CH:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][C:43]2([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:47][CH2:46][NH:45][CH2:44]2)[CH2:37][CH2:36]1)[CH3:21]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]([CH3:17])[CH2:15][N:14]([CH3:18])[NH:13]2)=[CH:8][C:4]=1[C:5]([N:45]1[CH2:46][CH2:47][C:43]([CH2:42][CH2:41][N:38]2[CH2:39][CH2:40][CH:35]([NH:34][C:26]3[N:25]([CH2:24][CH2:23][O:22][CH2:20][CH3:21])[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=3)[CH2:36][CH2:37]2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:44]1)=[O:7]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(N2NN(C)CC2C)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(N5NN(C)CC5C)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-(3,5-dimethyl-4H-triazol-1-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([CH3:14])[O:11][CH:10]([CH3:15])[CH2:9]1)C1C=CC=CC=1.[C:16]([OH:19])(=[O:18])[CH3:17]>C(O)C.[OH-].[OH-].[Pd+2]>[C:16]([OH:19])(=[O:18])[CH3:17].[CH3:15][CH:10]1[O:11][CH:12]([CH3:14])[CH2:13][NH:8][CH2:9]1
Reactant: CC1CN(Cc2ccccc2)CC(C)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC1CNCC(C)O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
4-Benzyl-2,6-dimethylmorpholine (10.72 mg, 45.76 mmol) was dissolved in acetic acid (10 mL) and ethanol (200 mL), and 10% palladium hydroxide/carbon (5 g) was added thereto. The mixture was stirred for two days at room temperature under a hydrogen stream at normal pressure. The catalyst was separated by filtration, and then the reaction liquor was concentrated under reduced pressure and dried, to obtain the title compound (7.36 g, 92%) as an oily matter. This compound was used in the subsequent reaction without performing further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[CH:4][N:3]=1.C1COCC1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]2=[O:19])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cncnc1Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1c1cncnc1Cl
Temperature: 100 °C
Yield: 77 %

Procedure:
To a vial charged with 4-chloropyrimidin-5-amine (commercially available from Frontier Scientific, Inc., Logan Utah) (0.500 g, 3.86 mmol) were added THF (6.43 mL), toluene (6.43 mL), TEA (1.345 mL, 9.65 mmol) and phthalic anhydride (1.310 mL, 13.51 mmol). The mixture was heated to 100° C. for 72 hours. The mixture was then dried under reduced pressure and purified with a 50 g SNAP column (Biotage) ramping EtOAc in heptane from 0-45%, then isocratic at 45% to elute 2-(4-chloropyrimidin-5-yl)isoindoline-1,3-dione (0.773 g, 2.98 mmol, 77% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=9.23 (d, J=0.4 Hz, 1H), 9.09 (d, J=0.4 Hz, 1H), 8.12-8.05 (m, 2H), 8.04-7.96 (m, 2H). m/z (ESI) 260.1 (M+H)+.
Reaction SMILES: Br.N1(C(OCC2C=CC=CC=2)=O)CCC[C@H]1C(O)=[O:5].CN.[CH2:22]1[CH2:27][CH2:26][CH:25]([N:28]=[C:29]=[N:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:24][CH2:23]1>C(Cl)Cl>[C:29]([NH:28][CH:25]1[CH2:24][CH2:23][CH2:22][CH2:27][CH2:26]1)([NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:5]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Br
Agent: CN
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.17 h
Yield: 52 %

Procedure:
To a cooled solution of the phosphonate 4-CN-PheP (OPh)2.HBr (0.41 g, 0.9 mmole) and Cbz-Pro-OH (0.25 g, 1.0 mmole) in 20 mL CH2Cl2 was added 0.14 mL Methyl amine. After stirring for 10 min, DCC (0.21 g, 1.0 mmole) was added and the mixture was stirred at 0° C. for 2 h and at r.t. for 24 h. During this period, dicyclohexylurea (DCU) formed, was removed by filtration and the filtrate was evaporated. The residue was dissolved in 50 mL ethyl acetate, filtered, the filtrate was washed with 50 mL 1N HCl, water, 6% NaHCO3, and water. The organic layer was dried, filtered, and evaporated to give crude product which was then recrystallized from ether to give white crystals, yield 52% (0.29 g); mp 131°-132° C.; 1H NMR (DMSO) δ8.75(m, 1H), 7.8-7.2(m, 19H), 5.06 (m, 2H), 4.95 (m, 1H), 4.6 (q, 1H), 4.2 (m, 1H), 3.5-3.1 (m, 3H), 2.0-1.4 (m, 4H); MS (FAB+) m/e 610 (M+1). Anal. (C34H32N3O6P) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:6]=1[C:7]([NH2:9])=[O:8].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:22]
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1F
Reactant: O=C(Cl)c1ccccc1F
Product: NC(=O)c1c(NC(=O)c2ccccc2F)ncn1Cc1ccccc1F
Yield: 97 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 22, using 1.50 g (6.40 mol) of 4-amino-1-(2-fluorobenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 113 and 2-fluorobenzoyl chloride instead of benzoyl chloride to obtain 2.21 g of 4-(2-fluorobenzoylamino)-1-(2-fluorobenzyl)-5-imidazolecarboxamide (yield 97%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([C:11]2[CH:16]=[C:15]([F:17])[C:14](B(O)O)=[C:13]([F:21])[CH:12]=2)=[C:6]([F:22])[CH:5]=1)[CH2:2][CH3:3].[Cl:23][C:24]1[N:29]=[CH:28][C:27](Br)=[CH:26][N:25]=1>>[CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([C:27]3[CH:26]=[N:25][C:24]([Cl:23])=[N:29][CH:28]=3)=[C:13]([F:21])[CH:12]=2)=[C:6]([F:22])[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc(F)c(-c2cc(F)c(B(O)O)c(F)c2)c(F)c1
Reactant: Clc1ncc(Br)cn1
Product: CCCc1cc(F)c(-c2cc(F)c(-c3cnc(Cl)nc3)c(F)c2)c(F)c1

Procedure:
0.25 mol of 39A is coupled to 0.29 mol of 2-chloro-5-bromopyrimidine analogously to Example 1A. The product obtained in this way is processed further without purification.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[Cl:13][CH2:14][CH2:15]O>>[OH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH2:15][CH2:14][Cl:13])=[O:4]
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Reactant: OCCCl
Product: O=C(OCCCl)C(O)Cc1ccccc1

Procedure:
2-Chloroethyl 2-hydroxy-3-phenylpropionate was prepared from (S)-2-hydroxy-3-phenylpropionic acid and excess 2-chloroethanol essentially by the method described in Step 1 of Example 1; however, the distillate solidified after standing at 4° C.: b.p. 120° C./0.35 mm Hg; 1H NMR δ2.86 (bs, 1H), δ2.98 (dd, 1H, J=6.7 Hz and 14.0 Hz), δ3.13 (dd, 1H, J=4.6 Hz and 14.0 Hz), δ3.63 (t, 2H, J=5.6 Hz), δ4.35 (m, 2H), δ4.48 (dd, 1H, J=4.7 Hz and 6.6 Hz), δ7.2-7.3 (5H); 13C NMR 40.5, 41.0, 64.8, 71.3, 126.8, 128.3, 129.4, 136.2, 173.6 ppm; HRMS calcd for C10H9ClO3Tms (M-CH3) 285.0714, obsd 285.0756.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH2:12].[CH3:13][N:14]([CH3:20])[CH2:15][CH2:16][N:17]=[C:18]=[S:19]>>[CH3:13][N:14]([CH3:20])[CH2:15][CH2:16][NH:17][C:18]([NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]1[O:5][CH:4]=[N:3][C:2]=1[CH3:1])=[S:19]
Reactant: CN(C)CCN=C=S
Reactant: Cc1ncoc1CCNCCN
Product: Cc1ncoc1CCNCCNC(=S)NCCN(C)C

Procedure:
By the procedure of Example 40(a)(ii) N-[2-(4-methyl-5-oxazolyl)ethyl]ethylenediamine [prepared by reacting ethylenediamine with 5-(2-chloroethyl)-4-methyloxazole] is reacted with 2-dimethylaminoethyl isothiocyanate to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])([O-:15])=[O:14]>C(Cl)Cl>[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=1)=[O:20])([O-:15])=[O:14]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(=O)c2cccc([N+](=O)[O-])c2)cc1
Reaction time: 2 h
Yield: 36.5 %

Procedure:
Under an inert atmosphere, to a stirred solution of methyl 4-(aminomethyl)benzoate (50 g, 0.436 mol) and TEA (210 mL, 1.5 mol) in anhydrous DCM (1.0 L) was added a solution of freshly prepared 3-nitro benzoyl chloride (0.59 mol) in DCM (250 mL). The resulting mixture was allowed to stir for 2 hrs. The reaction was quenched with a 10% aqueous solution of sodium hydrogenocarbonate. The organic layer was washed with a 1.5N HCl solution and water. After drying over MgSO4 and evaporation of the solvent in vacuo, a solid was obtained and purified by flash chromatography to give the title compound (50 g) in a 52% yield as a white powder.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([Cl:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[C:31]([NH2:32])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[NH2:32][C:31]1[CH:30]=[C:29]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([Cl:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:28]=[N:27][C:26]=1[O:25][CH3:24]
Reactant: Cn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(Cl)n1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2Cl)c(=O)n4C)cc1N

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate K) and 2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (Stage 89.1.1) to give the title compound as an off-white solid. (HPLC: tR 2.45 min (Method A); M+H=436 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.38 (s, 1H), 8.11-8.07 (m, 1H), 7.80-7.75 (m, 1H), 7.48-7.42 (m, 2H), 7.03-7.00 (m, 1H), 5.15-5.07 (s, br, 2H), 4.00 (s, 3H), 3.90 (s, 3H), 3.59 (s, 3H))
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:33])[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[NH2:64][CH2:65][C:66]([O:68][CH3:69])=[O:67]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:33])[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]([NH:64][CH2:65][C:66]([O:68][CH3:69])=[O:67])=[O:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)CN
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(N3CCC(C(=O)O)CC3)cc2)c2ccccc2C)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)C1CCN(c2ccc([C@@H](CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 112 %

Procedure:
A mixture of (R)-1-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)-piperidine-4-carboxylic acid (example 367, step 1; 100 mg, 226 μmol) triethylamine (68.6 mg, 94.5 μl, 678 μmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (79.8 mg, 249 μmol) in tetrahydrofuran (5 mL) was stirred at room temperature for 15 min, then treated with methyl 2-aminoacetate hydrochloride (42.6 mg, 339 μmol). The reaction mixture was stirred for 20 h at room temperature, then partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated to afford the crude title compound (130 mg), which was directly used in the next step. Yellow oil, MS (ESI+): m/z=514.6 ([M+H]+).