Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18](O)=[O:19])=[N:10]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:54][O:55][C:56]1[N:61]=[CH:60][C:59]([C:62]([NH2:65])([CH3:64])[CH3:63])=[CH:58][CH:57]=1>CN(C=O)C>[O:55]([C:56]1[N:61]=[CH:60][C:59]([C:62]([NH:65][C:18]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:17][C@H:15]4[C:16]=3[N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[N:10]=2)=[O:19])([CH3:63])[CH3:64])=[CH:58][CH:57]=1)[CH3:54]
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Reactant: COc1ccc(C(C)(C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(C)NC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a stirred solution of Intermediate 1 (see Example 1.1, 100 mg, 0.362 mmol), HATU (165 mg, 0.434 mmol) and DIEA (0.126 mL, 0.724 mmol) in DMF was added 2-(6-methoxypyridin-3-yl)propan-2-amine (72.2 mg, 0.434 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound (138 mg) as white solid. LCMS m/z=425.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.47 (td, J=4.6 and 3.5 Hz, 1H), 1.12-1.15 (m, 1H), 1.76 (s, 3H), 1.77 (s, 3H), 2.08-2.12 (m, 1H), 2.22-2.27 (m, 1H), 2.91 (d, J=16.6 Hz, 1H), 3.00 (dd, J=6.2 and 16.5 Hz, 1H), 3.91 (s, 3H), 6.69 (d, J=8.7 Hz, 1H), 7.00-7.07 (m, 2H), 7.14 (s, 1H), 7.62-7.68 (m, 2H), 8.25 (d, J=2.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][OH:20])=[NH:18])=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29](OCC)=[O:30]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[NH:18][C:29](=[O:30])[O:20][N:19]=4)=[CH:16][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: N=C(NO)c1ccc2[nH]c(-c3ccc(F)cc3)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1[nH]c(-c2ccc3[nH]c(-c4ccc(F)cc4)nc3c2)no1
Temperature: 80 °C
Yield: 21.4 %

Procedure:
2-(4-Fluoro-phenyl)-N-hydroxy-1H-benzoimidazole-5-carboxamidine (501.9 mg, 1.86 mmol, example 3), triethylamine (645 μl, 4.63 mmol) and ethyl chloroformate (229 μl, 2.4 mmol) was dissolved in 35 ml of DMF. The mixture was heated to 80° C. for 7 hours. The mixture was evaporated. Ethyl acetate and water were added, the organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 118 mg (21%) of the desired product. MS: m/e=297.05 (M+H+).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[N:18]1([C:24]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:25]=2[C:26](Cl)=[O:27])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[N:18]1([C:24]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:25]=2[C:26]([N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)=[O:27])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: FC(F)(F)Oc1ccc(N2CCNCC2)cc1
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 1-(4-Trifluoromethoxy-phenyl)-piperazine and 2-Morpholin-4-yl-5-nitro-benzoyl chloride (74%%, yellow solid, MS (m/e): 481.2 (M+H, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(OC2CCCC2)C(=O)O)cc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)c1ccc(C(OC2CCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a stirred solution of rac-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxy-acetic acid (50 mg, 0.15 mmol) in dichloromethane (10 mL) at 25° C. was added 2-aminothiazole (23 mg, 0.23 mmol), BOP reagent (100 mg, 0.23 mmol) and triethylamine (0.06 mL, 0.45 mmol). The mixture was stirred at 25° C. for 16 h, then it was diluted with water (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with water (1×10 mL), 1N sodium hydroxide (1×10 mL), 1N hydrochloric acid (1×10 mL) and brine ( 1×10 mL), then were dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (Biotage Flash 40S column, 60/40 hexanes/ethyl acetate) to give rac-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxy-N-thiazol-2-yl-acetamide(44 mg, 71% yield) as a white solid: EI-HRMS m/e calculated for C17H19N2O4S2Cl (M+) 414.0475, found 414.0481.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10]1(C(O)=O)[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1.CCN(CC)CC>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1)[C:8]#[N:9]
Reactant: N#Cc1ccc(C2(C(=O)O)CCc3cncn32)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N#Cc1ccc(C2CCc3cncn32)c(Cl)c1

Procedure:
The 5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid (0.02 g, 70 μmol) is dissolved in DMSO (2 mL) and Et3N (0.2 mL) and heated at 100° C. for 2 h. The solution is evaporated to dryness and residue purified via reverse phase HPLC (5-100% MeCN/water w/0.1% TFA) to give 3-chloro-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile as a white solid. MS (ESI) m/z 244.2, 246.2 (M+H); 1H NMR (400 MHz, CDCl3) (TFA salt) δ ppm 2.60-2.73 (m, 1H), 3.08-3.20 (m, 2H), 3.22-3.36 (m, 1H), 6.04 (dd, J=7.6, 5.8 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 7.24 (s, 1H), 7.61 (d, J=8.1 Hz, H), 7.81 (d, J=1.5 Hz, 1H), 8.53 (s, 1H).
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([OH:11])=[O:10])[CH3:8])=[O:5])[CH3:3].C1COCC1.O[N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([O:11][N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34])=[O:10])[CH3:8])=[O:5])[CH3:3]
Reactant: O=C1CCC(=O)N1O
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The active ester Z-Ala-Ala-OSu (1) was prepared according to a procedure described in Bodansky, M., Bodansky, A., The Practice of Peptide Synthesis 2nd Edition, Springer-Verlag. To a stirred solution of Z-Ala-Ala-OH (4.0 g, 13.6 mmol, obtained from Bachem) in 25 ml dry THF N-hydroxysuccinimide (1.56 g, 13.6 mmol) was added at 0° C. and the mixture was stirred for 10 minutes. A solution of dicyclohexylcarbodiimide (2.81 g, 13.6 mmol) in 3 ml dry THF was added. The mixture was stirred for 14 h, during which time it was allowed to warm to room temperature. The separated N,N′-dicyclohexylurea was removed by filtration and the solvent was evaporated in vacuo. The residue was twice recrystallized from isopropanol to give the active ester as a white solid (4.47 g, 84%) of m.p. 140° C.—TLC(MeOH/CHCl3, 1:50): Rf=0.5.—1H NMR (400 MHz, DMSO-d6): δ=1.20 (d, 3 H, J=7.0 Hz, CH3), 1.44 (d, 3 H, J=7.4 Hz, CH3), 2.79 (s, 4 H, 2×CH2), 4.04-4.10 (m, 1 H, CH), 4.63-4.69 (m, 1 H, CH), 4.96-5.04 (m, 2 H, CH2), 7.28-7.38 (m, 5 H, aryl-H), 7.45 (d, 1 H, J=7.8 Hz, NH), 8.58 (d, 1 H, J=7.0 Hz, NH).—MS (EI) m/z (%): 392 [M+H+], 414 [M+Na+], 430 [M+K+].
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH2:18](Br)[CH:19]=[CH:20][CH3:21].[In].Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH:20]([CH3:21])[CH:19]=[CH2:18])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: CC=CCBr
Agent: Cl
Agent: [In]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(C)C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F

Procedure:
1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (0.31 g; 1.09 mmol), crotyl bromide (1.2 mL; 11.8 mmol) and indium (1.26 g; 11.0 mmol) were suspended in THF (10 mL) and 0.02 M HCl (15 mL) and stirred vigorously over 18 hours. The reaction mixture was then diluted with water (60 mL) and ethyl acetate (40 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4 to yield a crude oil. The crude oil was purified by column chromatography (SiO2; 20% ethyl acetate/hexanes) to yield the title compound as a 2:1 mixture of diastereomers as an off-white solid.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4C(=O)CCCC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:55]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:54][C:53]4[C:52](=[O:62])[N:51]([CH2:63][C:64]#[N:65])[CH2:50][CH2:49][C:48]=4[N:47]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[NH2:35][C:36]1([C:40]2[CH:41]=[CH:42][C:43]([C:46]3[C:55]([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)=[CH:54][C:53]4[C:52](=[O:62])[N:51]([CH2:63][C:64]#[N:65])[CH2:50][CH2:49][C:48]=4[N:47]=3)=[CH:44][CH:45]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)N(CC#N)CC4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Product: N#CCN1CCc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Yield: 122.4 %

Procedure:
Following the procedure for 2-(4-(1-aminocyclobutyl)phenyl)-3-phenyl-7,8-dihydroquinolin-5(6H)-one, tert-butyl(1-(4-(6-(cyanomethyl)-5-oxo-3-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (17 mg, 0.03 mmol) was reacted to afford the title compound (15 mg, 71%). LCMS (Method A): RT=3.80 min, M-NH2=392. 1H NMR (500 MHz, MeOD): 8.33 (1H, S), 7.50 (2H, d), 7.42 (2H, d), 7.31-7.29 (3H, m), 7.22-7.20 (m, 2H), 4.66 (2H, s), 3.92 (2H, t), 3.38 (2H, t), 2.78-2.72 (m, 2H), 2.60-2.54 (m, 2H), 2.27-2.18 (m, 1H), 2.00-1.91 (m, 1H).
Reaction SMILES: C(OC1C=CC=CC=1[CH2:8][N:9]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH2:15][CH2:14]1)(C)(C)C.COC1[CH2:45][CH:44]([C:46]2C=CC=CC=2)[CH2:43]CN1.[C:52]([O-:55])([O-])=[O:53].[K+].[K+]>>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH:16]1[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][CH2:10][N:9]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:8][C:52]([O:55][C:44]([CH3:46])([CH3:45])[CH3:43])=[O:53])[CH2:18][CH2:17]1
Reactant: O=C([O-])[O-]
Reactant: COc1ccccc1C1CCN(CCCN(Cc2ccccn2)Cc2ccccc2OC(C)(C)C)CC1
Reactant: COC1CC(c2ccccc2)CCN1
Agent: [K+]
Product: COc1ccccc1C1CCN(CCCN(CC(=O)OC(C)(C)C)Cc2ccccn2)CC1
Yield: 66 %

Procedure:
Using procedures similar to that used for compound 21, [×6] was synthesized with 2-methoxy-4-phenylpiperidin (0.36 g, 1.90 mmol), compound [X5] (0.38 g, 1.27 mmol), KI (0.63 g, 3.8 mmol) and K2CO3 (0.876 g, 6.35 mmol). Purification was carried out on a silica gel preparative plate that was developed in with a 1% methanolic NH3 (7 M NH3 in methanol/99% CH2Cl2. The product was isolated as pale yellow oil (66%). 1H NMR (CDCl3) δ 8.521 (dd, 1H, Ar), 7.643 (ddd, 1H, Ar), 7.528 (d, 1H, Ar), 7.193-7.126 (m, 3H, Ar), 6.910 (t, 1H, Ar), 6.860 (d, 1H, Ar), 3.921 (s, 2H, —CH2—), 3.906 (s, 3H, —OCH3), 3.309 (s, 2H, —CH2—), 3.039 (s(br), 2H, —CH2—), 2.943 (m, 1H, —CH—), 2.696 (t, 2H, —CH2—), 2.416 (s(br), 2H, —CH2—), 2.088 (s(br), 2H, —CH2—), 1.775 (m(br), 6H), 1.459 (s, 9H, —C(CH3)3).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([Cl:19])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6]2.[C:20](=N)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.CCOC(C)=O>[C:20](=[N:1][CH2:2][C:3]1[C:4]([Cl:19])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH:7]=[CH:6]2)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CN)ccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CN=C(c3ccccc3)c3ccccc3)ccc21
Temperature: 40 °C
Reaction time: 96 h
Yield: 67.1 %

Procedure:
A mixture of tert-butyl 5-(aminomethyl)-4-chloro-1H-indole-1-carboxylate (1.147 g, 4.087 mmol) and benzophenone imine (0.75 mL, 4.496 mmol) in anhydrous DCM (39.3 mL) was stirred at 40° C. under N2 for 4 d. The reaction mixture was diluted with EtOAc, and the organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with and EtOAc/heptane gradient (0 to 70% EtOAc) to afford 1.22 g (67%) of tert-butyl 5-[(benzhydrylideneamino)methyl]-4-chloro-1H-indole-1-carboxylate (322) as an oil: 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=8.5 Hz, 1H), 7.82-7.77 (m, 1H), 7.69 (d, J=7.2 Hz, 2H), 7.60-7.56 (m, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.43 (d, J=8.9 Hz, 2H), 7.37 (d, J=7.0 Hz, 1H), 7.33 (t, J=7.3 Hz, 2H), 7.25-7.20 (m, 2H), 6.66 (d, J=3.7 Hz, 1H), 4.75 (s, 2H), 1.66 (s, 9H); MS (ESI) m/z=445.2 [M+1]+.
Reaction SMILES: Cl.[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:4])[CH3:3].[CH3:21][O:22][C:23]1[CH:43]=[CH:42][C:26]([CH2:27][NH:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([C:39](O)=[O:40])[CH:37]=3)[CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1>>[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][N:17]([C:39]([C:36]4[CH:37]=[C:38]5[C:33]([CH:32]=[CH:31][N:30]=[C:29]5[NH:28][CH2:27][C:26]5[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:43][CH:42]=5)=[CH:34][CH:35]=4)=[O:40])[CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1ccc(CNc2nccc3ccc(C(=O)O)cc23)cc1
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Agent: Cl
Product: COc1ccc(CNc2nccc3ccc(C(=O)N4CCC5(CC4)Cc4cn(C(C)(C)C)nc4C(=O)N5)cc23)cc1

Procedure:
The title compound was prepared by a method analogous to that described in Example 3, using 2′-tert-butyl-4′,6′-dihydrospiro[piperidine-4,6-pyrazolo[3,4-c]pyridin]-7′(2′H)-one hydrochloride salt (Intermediate 4) and 1-(4-methoxybenzylamino)isoquinoline-7-carboxylic acid (Intermediate 27). +ESI (M+H) 553.5.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3C=[CH:22][CH:21]=[CH:20][C:16]=3[C:17](O)=O)=[O:14])[CH:10]=[CH:11][C:5]=2[N:4]=1.NC1C=CC2N=C(N(C(OC(C)(C)C)=O)[C:34]([O:36]C(C)(C)C)=[O:35])N(C(OC(C)(C)C)=O)C=2C=1>>[ClH:1].[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([NH:12][C:13](=[O:14])[CH2:15][C:16]3([CH2:17][C:34]([OH:36])=[O:35])[CH2:20][CH2:21][CH2:22]3)[CH:10]=[CH:11][C:5]=2[N:4]=1
Reactant: Nc1nc2ccc(NC(=O)c3ccccc3C(=O)O)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2ccc(N)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Product: Nc1nc2ccc(NC(=O)CC3(CC(=O)O)CCC3)cc2[nH]1
Yield: 85 %

Procedure:
Following the same procedure to synthesize 2-(2-amino-1H-benzo[d]imidazol-6-ylcarbamoyl)benzoic acid hydrochloride, tert-butyl 6-amino-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate (0.167 g, 0.372 mmol) was reacted with (S)-7-oxaspiro[3.5]nonane-6,8-dione (0.057 g, 0.372 mmol) to give the title product (0.107 g, 85% yield) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.49 (s, 1H), δ 6.95 (s, 2H), δ 2.24 (m, 4H), δ 1.32 (m, 8H) ppm; 13C NMR (75 MHz, CD3OD) δ 175.2, 173.8, 171.8, 151.9, 135.0, 129.7, 116.7, 111.3, 103.9, 44.4, 43.9, 42.0, 39.7, 37.8, 24.1 ppm; HRMS (ESI) Calcd for C15H18N4O3(M+) 302.1379. Found 302.1373.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].C(N(CC)CC)C.[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][N:14]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH2:13][CH2:12]1)[C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])=[O:4]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C(=O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-methylcyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester (100 mg, 0.23 mmol) in dichloromethane (3 mL) was added triethylamine (3 mL) and isobutyryl chloride (28 μL, 0.27 mmol). The reaction mixture was stirred at room temperature for 12 h and then quenched with a saturated solution of NaHCO3. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:1) as eluent to obtain 5-cyclohex-1-enyl-3-[(1-isobutyryl-piperidin-4-yl)-(trans-4-methyl cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (55 mg, 47%) as a white solid.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]#[CH:3].S(Cl)([Cl:18])(=O)=O>C(O)(=O)C>[Cl:18][CH2:13][C:12](=[O:14])[C:6](=[N:5][O:4][CH2:1][C:2]#[CH:3])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: C#CCON=C(C(C)=O)C(=O)OCC
Solvent: CC(=O)O
Product: C#CCON=C(C(=O)CCl)C(=O)OCC
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
A mixture of ethyl 2-propargyloxyimino-3-oxobutyrate (syn isomer, 71.2 g), acetic acid (81 ml) and sulfuryl chloride (50.2 g) was stirred at 40° C. for 10 minutes and then at room temperature for 5.5 hrs. The reaction mixture was treated in a conventional manner to give ethyl 4-chloro-3-oxo-2-propargyloxyiminobutyrate (syn isomer, 61.6 g.), oil.
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.[P:28](=[O:32])([OH:31])([OH:30])[OH:29]>O>[P:28]([OH:32])([OH:31])([OH:30])=[O:29].[S:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[B:15]([OH:20])[OH:16]
Reactant: c1cc2ccsc2cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: O
Product: OB(O)c1cc2ccncc2s1
Temperature: -44 °C
Reaction time: 1.25 h
Yield: 113.3 %

Procedure:
A three neck flask fitted with an internal thermometer containing the material from Step iii (4.12 g, 30.5 mmol) was evacuated and then filled with nitrogen atmosphere. THF (50 mL) was added and the solution cooled to −44° C. (CH3CN/dry ice). n-Butyllithium (1.6M/hexane, 21 mL, 34 mmol) was added over 10 minutes, while maintaining the internal temperature at or below −35° C. The reaction was stirred at −33 to −45° C. for 75 minutes. Triisopropyl borate (8.4 mL, 36.6 mmol) was added and the cooling bath removed. The reaction was stirred for one hour then phosphoric acid (85% aqueous, 2.5 mL, 33.5 mmol) was added. The reaction was diluted with 10 mL water resulting in a precipitate. The reaction was stirred vigorously for 15 minutes. A yellow solid was collected by filtration, rinsing with EtOAc (about 50 mL) to provide a white powdery solid (9.57 g). Approximately half of the material was washed with 50 mL water to isolate 3.16 g of a pale pink solid. Both crops of material are the same as determined by spectral data. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.87 (1H, d, J=5.5 Hz), 7.95 (1H, s), 8.41 (1H, d, J=5.7 Hz), 9.11 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][OH:12])[C:9]=1[Cl:10])=[O:4].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])[C:9]=1[Cl:10])=[O:4]
Reactant: COC(=O)c1scc(CO)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1scc(COS(C)(=O)=O)c1Cl
Reaction time: 6 h

Procedure:
To a solution of 2-methoxycarbonyl-3-chloro-4-hydroxymethylthiophene (6 g, 29 mmol) in methylene chloride (100 mL) were added triethylamine (8.1 mL, 58 mmol) and methanesulfonyl chloride (2.5 mL, 32 mmol) at ambient temperature. After stirring for 6 hours, the reaction mixture was concentrated to afford 2-methoxycarbonyl-3-chloro-4-(methylsulfonyloxy)methylthiophene. The crude product was dissolved in DMF (150 mL) and excess potassium cyanide was added to the solution. The reaction mixture was stirred at ambient temperature for 16 hours, then poured into water, and extracted with methylene chloride. The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford 2-methoxycarbonyl-3-chloro-4-cyanomethylthiophene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:50])=[C:17]([C@:19]2([CH3:49])[CH2:24][O:23][CH2:22][C:21]([NH:25]C(C3C=CC(OC)=CC=3)(C3C=CC(OC)=CC=3)C3C=CC=CC=3)=[N:20]2)[CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O>ClCCl>[ClH:1].[NH2:25][C:21]1[CH2:22][O:23][CH2:24][C@:19]([C:17]2[CH:18]=[C:13]([NH:12][C:8]([C:5]3[C:4]([F:11])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])[CH:14]=[CH:15][C:16]=2[F:50])([CH3:49])[N:20]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(N)ccc3F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(O)c1ncc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@]1(c2cc(NC(=O)c3ncc(Cl)cc3F)ccc2F)COCC(N)=N1
Product: Cl
Yield: 24 %

Procedure:
In analogy to example 22 a) the reaction of 5-chloro-3-fluoro-pyridine-2-carboxylic acid and Building block J, [(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine, using O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate as the condensating agent in presence of Huenig's base, followed by the cleavage of the [bis-(4-methoxy-phenyl)-phenyl-methyl]-(DMTr) amino protecting group with trifluoroacetic acid in dichloromethane yielded the title compound (yield: 24% of theory). Mass (calculated) C17H15ClF2N4O2.ClH [417.241]; (found) [M+H]+=381.