Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:15][C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[CH3:17].[C:26]([O:30][C:31]([NH:33][CH:34]1[CH2:38][CH2:37][NH:36][CH2:35]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:36]3[CH2:37][CH2:38][CH:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:35]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:15][C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: C[C@@H](Nc1cc(N2CCC(=O)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C[C@@H](Nc1cc(N2CCC(N3CCC(NC(=O)OC(C)(C)C)C3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Temperature: 80 °C
Yield: 50 %

Procedure:
To a stirred solution of (R)-1-(4-chloro-3-(1-(2,4-dichlorophenyl)ethylamino)phenyl)piperidin-4-one (0.13 g, 0.32 mmol) and 3-(t-butoxycarbonylamino)pyrrolidine (0.24 g, 1.3 mmol) in dichloroethane (DCE) (2 mL) was added NaBH(OAc)3 (0.094 g, 0.44 mmol). The reaction mixture was heated at 80° C. for 4 h. The reaction mixture was quenched with aqueous saturated sodium bicarbonate and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude was purified by flash chromatography (SiO2, 1-7% methanol in dichloromethane) to give t-butyl 1-(1-(4-chloro-3-((R)-1-(2,4-dichlorophenyl)ethylamino)phenyl)piperidin-4-yl)pyrrolidin-3-ylcarbamate (0.092 g, 0.16 mmol, 31%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[CH:12]([C:15]1[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][N:17]2[N:16]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NCCCN(C(C1N(CC2C=CC(F)=CC=2)C(=O)C2=CC=CN2N=1)CC)C(=O)C1C=CC(C)=CC=1)(C)(C)C.Br[CH2:78][C:79]([O:81][CH3:82])=[O:80]>>[CH3:82][O:81][C:79](=[O:80])[CH2:78][N:20]1[C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][N:17]2[N:16]=[C:15]1[CH:12]([N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:34])[C:25](=[O:33])[C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)[CH2:13][CH3:14]
Reactant: COC(=O)CBr
Reactant: CCC(c1nn2cccc2c(=O)[nH]1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Agent: CCC(c1nn2cccc2c(=O)n1Cc1ccc(F)cc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Product: CCC(c1nn2cccc2c(=O)n1CC(=O)OC)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Yield: 30.9 %

Procedure:
(±)-(3-{(4-Methylbenzoyl)-[1-(4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4] triazin-2-yl)-propyl]amino}propyl)carbamic acid tert-butyl ester (Example 3 A, 100 mg, 0.21 mmol) was converted to the title compound (35 mg, 31%) in a manner similar to the preparation of (±)-{3-[{1-[3-(4-fluorobenzyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl]-propyl}-(4-methylbenzoyl)-amino]-propyl}-carbamic acid tert-butyl ester, except that methyl bromoacetate (42 mg, 0.27 mmol) was used instead of 4-fluorobenzyl bromide: 1H NMR (CDCl3) δ 7.43 (m, 1H), 7.26–7.21 (m, 4H), 7.07 (m, 1H), 6.58 (m, 1H), 5.84 (m, 1H), 5.10 (m, 1H), 4.78 (m, 1H), 3.91 (m, 1H), 3.78 (m, 3H), 3.71 (m, 1H), 3.31 (m, 2H), 2.74 (m, 2H), 2.40 (s, 3H), 2.21 (m, 1H), 2.05 (m, 1H), 1.52 (m, 1H), 1.39 (s, 9H), 1.04 (t, 3H, J=7.15 Hz); MS (ESI+) 540.21 (M++H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.[CH:19]([O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27])([CH3:21])[CH3:20]>>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([O:22][CH:19]([CH3:20])[CH3:21])[CH:24]=3)[CH2:10]2)=[CH:7][CH:8]=1
Reactant: OCCC1(c2ccc(C(F)(F)F)cc2)CCNC1
Reactant: CC(C)Oc1cccc(C(=O)Cl)c1
Product: CC(C)Oc1cccc(C(=O)N2CCC(CCO)(c3ccc(C(F)(F)F)cc3)C2)c1

Procedure:
Prepare by the method of example 3.1 using 2-[3-(4-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-ethanol (23 mmol) and 3-isopropoxy-benzoyl chloride (23 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].Cl.[CH:7]1[N:11]2[C:12]3[CH2:23][C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:13]=3[NH:14][C:15](=[O:16])[C:10]2=[N:9][CH:8]=1>S(=O)(=O)(O)O>[N+:1]([C:20]1[CH:19]=[CH:18][C:17]2[C:13]3[NH:14][C:15](=[O:16])[C:10]4[N:11]([CH:7]=[CH:8][N:9]=4)[C:12]=3[CH2:23][C:22]=2[CH:21]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2c(n3ccnc13)Cc1cc([N+](=O)[O-])ccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
5H,10H-8--Nitroimidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one may be prepared in the following way: 1 g of potassium nitrate is added over 10 minutes, at a temperature in the region of 5° C., to a solution of 2.6 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride in 20 ml of concentrated sulphuric acid (d=1.83). The mixture is stirred for 30 minutes at the same temperature and for 3 hours at 25° C., then is poured onto 150 ml of ice-water. The crystals formed are isolated by filtration, washed with distilled water and then with acetone and dried under reduced pressure (1 mmHg; 0.13 kPa) at 80° C. 2.1 g of 8-nitro-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are thus obtained, decomposing without melting above 300° C. [NMR spectrum: (200 MHz; DMSO-d6 ; δ in ppm): 4.23 (s, 2H: --CH2-- at 10); 7.68 and 8.12 (2 broad s, 1H each: --H of the imidazole); 8.07 (dd, J=8.5 Hz, 1H: --H6); 8.38 (dd, J=8.5 and 1.5 Hz, 1H: --H7; 8.50 (d, J=1.5 Hz, 1H: --H9); 12.64 (mult., 1H: --CONH--)].
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([CH:43]=[CH:44][CH:45]=[O:46])=[C:31]([CH:40]([CH3:42])[CH3:41])[S:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:25][CH:24]=1>C1COCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([CH:43]=[CH:44][CH:45]([OH:46])[CH2:17][C:15](=[O:16])[CH2:14][C:13]([O:19][CH2:20][CH3:21])=[O:18])=[C:31]([CH:40]([CH3:42])[CH3:41])[S:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:25][CH:24]=1
Reactant: CC(C)c1sc(-c2ccccc2)c(-c2ccc(F)cc2)c1C=CC=O
Reactant: CCOC(=O)CC(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=Cc1c(C(C)C)sc(-c2ccccc2)c1-c1ccc(F)cc1
Reaction time: 1 h
Yield: 121.5 %

Procedure:
To a solution of 2.6 g of diisopropylamine in 30 ml of THF at 0° was added 1.67 g of n-butyllithium (1.16 m in hexane). Then a solution of 1.7 g of ethyl acetoacetate in 10 ml of THF was added dropwise. After stirring at 0° for 1 hour, the mixture was cooled to -20°, then a solution of 3.3 g of the title product of Step 3, above, in 20 ml of THF was added dropwise. The reaction was stirred at -20° for 1 hour. Then was quenched with saturated aqueous ammonium chloride solution. The mixture was extracted with MTBE and then methylene chloride and the organic solutions were combined and dried, adn the solvent evaporated under reduced pressure to give 5.5 g of crude title product of this step as an oil. This was used without further purification in the next step (Step 5).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[O:16][N:15]=[CH:14][C:13]=2[CH3:17])=[C:10]([Cl:18])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].S(=O)(=O)(O)O>O1CCOCC1>[Cl:1][C:2]1[C:11]([C:12]2[O:16][N:15]=[CH:14][C:13]=2[CH3:17])=[C:10]([Cl:18])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(Cl)c(-c2oncc2C)c1Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1cnoc1-c1c(Cl)ccc(C(=O)O)c1Cl
Reaction time: 15.5 h

Procedure:
To 20 ml dioxane, was dissolved methyl 2,4-dichloro-3-(4-methylisoxazol-5-yl)benzoate in an amount of 0.83 g, and the resulting solution was then added with concentrated sulfuric acid in an amount of 5 ml and subsequently stirred for 15.5 hours under reflux and heating. After cooling the mixture, dioxane therein was distillated out, and the mixture was then extracted with ethyl acetate. The organic layer obtained was washed with saturated saline solution, then dried with anhydrous magnesium sulfate. The solvent in the layer was condensed under reduced pressure, and the residue obtained was purified by using a silica gel column chromatography to obtain an objective product, 2,4-dichloro-3-(4-methylisoxazol-5-yl)benzoic acid in an amount of 0.48 g in crystalline form. The melting point of the product was found to be in a range of 248-252° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:12])[C:5]([O:10][CH3:11])=[CH:6][C:7](=[O:9])[CH:8]=1.O.CCN(C(C)C)C(C)C.[SH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]>C(O)C.C1COCC1>[CH3:11][O:10][C:5]1[CH:6]=[C:7]([OH:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[OH:12].[SH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: COC1=CC(=O)C=C(OC)C1=O
Agent: O=C(O)CCS
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(O)cc(OC)c1O
Reaction time: 1.5 h
Yield: 26.5 %

Procedure:
2,6-Dimethoxybenzoquinone (2.0 g) was dissolved in ethanol (95%, 22 ml), water (6 ml), THF (15 ml) and DIEA (1.55 g). 3-mercaptopropionic acid (0.64 g) in ethanol (10 ml) was added in a dropwise fashion within 20 minutes, with stirring and cooling in an ice bath. The reaction was then allowed to proceed at room temperature. After 1.5 hours the reaction medium changed to a deep reddish color. The mixture was filtered and the filtrate evaporated in vacuo to give a solid mixture. This solid mixture was eluted via a silical gel chromatographic column (silica gel 60, [230-400 mesh], Merck) by using CHCl3 /MeOH/AcOH (97:2:1) as the mobile phase. The purified product DMQ-MP was crystallized from ether in a 26.5% yield (0.53 g). Melting point: 113°-115° C. Anal. calcd. for C11H14SO6, C 48.16, H 5.16; Found C 48.16, H 5.17. FABMS (fast atom bombardment mass spectrometry) [M-H]- (Xe beam) 273.19.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])=[O:3].Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC(C)=O>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[C:5]([O:11][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:6]=1
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(F)cc1OCCN1CCOCC1

Procedure:
0.5 g (3.24 mmol) 4-fluoro-2-hydroxyacetophenone, 720 mg (3.87 mmol) N-(2-chloroethyl)morpholine hydrochloride, 900 mg K2CO3 and a catalytic amount of NaI in 20 ml acetone were heated for 20 hours at reflux. The mixture was concentrated, was dissolved in dichloromethane, was washed with water and saturated NaCl solution, was dried and was concentrated once again. Chromatography of the crude product on silica gel (dichloromethane/methanol 0-4%) yielded 730 mg of a clear, colorless oil; ESI-MS [M+H+]=268.15.
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:3]=1[O:4][C@@H:5]([CH3:9])[C:6]([OH:8])=[O:7].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1B(O)O>>[Cl:16][C:17]1[CH:18]=[C:19]([Cl:23])[CH:20]=[CH:21][C:22]=1[C:2]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:3]=1[O:4][C@@H:5]([CH3:9])[C:6]([OH:8])=[O:7]
Reactant: OB(O)c1c(Cl)cccc1Cl
Reactant: C[C@H](Oc1ccc(C#N)cc1Br)C(=O)O
Product: C[C@H](Oc1ccc(C#N)cc1-c1ccc(Cl)cc1Cl)C(=O)O

Procedure:
The title compound was prepared by the method of example 16 step (iii) using the product from step (i) and 2,6-dichlorophenylboronic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:42]1[CH2:41][CH2:40][CH:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:44][CH2:43]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCC(c2ccccc2)CC1
Yield: 8.3 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 4-phenyl-piperidine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (12.5 mg, 8.3%) as light yellow oil. MS m/e=490.5 [M+H]+.
Reaction SMILES: [OH-].[Na+].OO.CS(C)=O.CC[OH:11].[ClH:12].[C:13]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]2[C:30]([F:31])=[CH:29][C:26]([C:27]#[N:28])=[C:25]([NH:32][C:33]3[CH:34]=[N:35][CH:36]=[C:37]([CH3:39])[CH:38]=3)[N:24]=2)[CH:18]([NH2:40])[CH2:17]1)(=[O:15])[CH3:14]>O>[ClH:12].[C:13]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]2[C:30]([F:31])=[CH:29][C:26]([C:27]([NH2:28])=[O:11])=[C:25]([NH:32][C:33]3[CH:34]=[N:35][CH:36]=[C:37]([CH3:39])[CH:38]=3)[N:24]=2)[CH:18]([NH2:40])[CH2:17]1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1CCC(Nc2nc(Nc3cncc(C)c3)c(C#N)cc2F)C(N)C1
Reactant: CCO
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)N1CCC(Nc2nc(Nc3cncc(C)c3)c(C(N)=O)cc2F)C(N)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 5M sodium hydroxide aqueous solution (0.038 ml) and a 30% hydrogen peroxide solution (0.008 ml) were added to a DMSO/EtOH (0.1 ml/0.1 ml) solution containing 6-((1-acetyl-3-aminopiperidin-4-yl)amino)-5-fluoro-2-((5-methylpyridin-3-yl)amino)nicotinonitrile hydrochloride (6 mg), followed by stirring at room temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. Ethyl acetate (0.5 ml) and 4M hydrochloric acid/1,4-dioxane (0.004 ml) were added to the obtained residue, followed by stirring at room temperature for 0.5 hours. The solvent was removed under reduced pressure. The obtained residue was washed with ethyl acetate. A yellow solid of 6-((1-acetyl-3-aminopiperidin-4-yl)amino)-5-fluoro-2-((5-methylpyridin-3-yl)amino)nicotinamide hydrochloride (3.2 mg) was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]([CH3:27])([CH3:26])[C:22]([NH:24][CH3:25])=[O:23]>>[CH3:26][C:21]([NH:20][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:22](=[O:23])[NH:24][CH3:25])[CH3:27]
Reactant: O=C(O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1
Reactant: CNC(=O)C(C)(C)N
Product: CNC(=O)C(C)(C)NC(=O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48 e) and 2-amino-N,2-dimethyl-propanamide (CAN 106914-07-2) as starting materials, MS (EI) m/e: 372.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH3:5][C:6]1[C:14]2[O:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][C:7]=1[N:15]=[C:16]=[S:17]>C(Cl)Cl>[NH2:3][CH2:2][CH2:1][NH:4][C:16](=[S:17])[NH:15][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][CH2:12][O:13][C:14]=2[C:6]=1[CH3:5]
Reactant: NCCN
Reactant: Cc1c(N=C=S)ccc2c1OCC2
Solvent: ClCCl
Product: Cc1c(NC(=S)NCCN)ccc2c1OCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.205 g of ethylenediamine in 1 mL of methylene chloride is added dropwise a solution of 0.13 g of 7-methyl-6-isothiocyanato-2,3-dihydrobenzofuran in 2 mL of methylene chloride. The mixture is stirred at room temperature for 1 hour and evaporated to provide 6-[N'-(2-aminoethyl)thioureido]-7-methyl-2,3-dihydrobenzofuran as the crude product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([Cl:22])[CH:15]=[CH:16][C:17]=2Br)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][S:24]([O-:26])=[O:25].[Na+].N1CCC[C@H]1C(O)=O.[OH-].[Na+]>CS(C)=O.[Cu]I>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([Cl:22])[CH:15]=[CH:16][C:17]=2[S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)[O-]
Reactant: O=C(OCc1ccccc1)N1CCc2c(Br)ccc(Cl)c2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(Cl)c2c1CCN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C

Procedure:
A mixture under Ar of 5-bromo-8-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (190 mg, 0.5 mmol, 1.0 eq.), sodium methanesulfinate (72 mg, 0.6 mmol, 1.2 eq.), L-proline (12 mg, 0.1 mmol, 0.2 eq.), 1M aq. NaOH soln. (0.1 mL, 0.1 mmol, 0.2 eq.), and copper (I) iodide (10 mg, 0.05 mmol, 0.1 eq.) in DMSO (5 mL) was stirred at 150° C. under microwave irradiations for 1 hour. The mixture was allowed to cool to r.t. and partitioned between AcOEt (125 mL), and H2O (125 mL). The layers were separated and the aq. phase was extracted with AcOEt (2×125 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters Xbridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:3]([OH:38])[CH2:4][C@@H:5]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=[CH:28][CH:27]=2)[C:21]1=[O:36])[C@@H:16]([CH3:19])[CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:46][O:47][C:48]([NH:50][C@@H:51]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:52](O)=[O:53])=[O:49].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH2:39]([C@H:2]([NH:1][C:52]([C@@H:51]([NH:50][C:48](=[O:49])[O:47][CH3:46])[C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@@H:3]([OH:38])[CH2:4][C@@H:5]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=[CH:28][CH:27]=2)[C:21]1=[O:36])[CH:16]([CH3:19])[CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1)N1CCN(Cc2ccnc3ccccc23)C1=O
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2ccnc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.6 %

Procedure:
A solution containing the product from Example 134B (0.147 mmol) in DMF (2 mL) was treated with the product from Example 1F (0.035 g, 0.185 mmol), EDAC (0.045 g, 0.235 mmol), HOBT (0.030g, 0.222 mmol), and NMM (0.050 mL, 0.455 mmol) at 0° C., stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and water. The organic phase was washed with 10% citric acid, dilute sodium bicarbonate, and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column, eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.019 g, 17% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.68 (d, J=6.6 Hz, 3 H), 0.93 (m, 12 H), 0.88-0.97 (m, 1 H), 1.22-1.33 (m, 1H), 1.47-1.56 (m, 2H), 1.72-1.84 (m, 1H), 2.38-2.45 (m, 1H), 2.62-2.73 (m, 3H), 2.79-2.86 (m, 1H), 2.98-3.10 (m, 3H), 3.55-3.63 (m, 4H), 3.89-3.94 (m, 2H), 4.07-4.21 (m, 2H), 4.80 (s, 2H), 6.79 (d, J=9.56 Hz, 1 H), 6.93-7.20 (m, 10 H), 7.41 (d, J=4.41 Hz, 1 H), 7.48-7.53 (m, 1H), 7.57-7.62 (m, 1H), 7.75-7.80 (m, 1H), 7.87 (d, J=9.19 Hz, 1 H), 8.06 (d, J=8.45 Hz, 1 H), 8.30 (d, J=8.08 Hz, 1 H), 8.88 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23].Cl.[CH3:26][C:27]1[N:31]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[C:30]2[CH:38]=[CH:39][CH:40]=[CH:41][C:29]=2[N:28]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(CC)CC)C.C(O)(=O)C>CN(C=O)C>[CH3:26][C:27]1[N:31]([CH:32]2[CH2:33][CH2:34][N:35]([CH2:12][C:11]3[CH:14]=[CH:15][C:8]([C:6]4[N:7]=[C:2]([NH2:1])[C:3]([N+:22]([O-:24])=[O:23])=[CH:4][C:5]=4[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:9][CH:10]=3)[CH2:36][CH2:37]2)[C:30]2[CH:38]=[CH:39][CH:40]=[CH:41][C:29]=2[N:28]=1
Reactant: Nc1nc(-c2ccc(C=O)cc2)c(-c2ccccc2)cc1[N+](=O)[O-]
Reactant: Cc1nc2ccccc2n1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1nc2ccccc2n1C1CCN(Cc2ccc(-c3nc(N)c([N+](=O)[O-])cc3-c3ccccc3)cc2)CC1

Procedure:
4-(6-Amino-5-nitro-3-phenylpyridin-2-yl)benzaldehyde (4-2; 0.150 g, 0.470 mmol), 2-methyl-1-piperidin-4-yl-1H-benzimidazole hydrochloride (0.142 g, 0.564 mmol), and NaBH(OAc)3 (0.120 g, 0.564 mmol) were stirred in 2 ml of anhydrous DMF. Triethylamine (0.079 ml, 0.564 mmol) was added followed by addition of acetic acid (0.108 ml, 1.88 mmol). After 2 h the reaction was quenched with saturated aqueous NaHCO3 and extracted 3× with DCM. The combined extracts were dried over Na2SO4, filtered, and concentrated to afford pure 6-(4-{[4-(2-methyl-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-3-nitro-5-phenylpyridin-2-amine (4-3). 1H NMR (CDCl3) δ 8.48 (s, 1H), 7.68 (m, 1H), 7.57 (m, 1H), 7.36 (d, 2H, J=8.1 Hz), 7.27 (m overlapping with CHCl3), 7.20 (m, 2H), 7.16 (m, 2H), 4.15 (m, 1H), 3.58 (s, 2H), 3.05 (d, 2H, J=11.5 Hz), 2.63 (s, 3H), 2.55 (m, 2H), 2.17 (t, 2H, J=11.5 Hz), 1.83 (d, 2H, J=12.0 Hz). MS m/z (M+H)=519.18.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]([NH:21][NH2:22])=[O:20])[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[C:25]([O:28][C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31])(=[O:27])[CH3:26]>>[C:25]([O:28][C:29]([CH3:34])([CH3:33])[C:30](=[O:31])[NH:22][NH:21][C:19]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]=[CH:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:23])[F:24])=[CH:9][CH:8]=3)[C:14]=2[CH:15]=1)=[O:20])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: NNC(=O)c1ccc2ncn(-c3ccc(OC(F)(F)F)cc3)c2c1
Product: CC(=O)OC(C)(C)C(=O)NNC(=O)c1ccc2ncn(-c3ccc(OC(F)(F)F)cc3)c2c1
Yield: 66 %

Procedure:
In the same manner as in Reference Example 129 and using 1-[4-(trifluoromethoxy)phenyl]-1H-benzimidazole-6-carbohydrazide instead of 3-bromo-1-benzofuran-5-carbohydrazide and 2-chloro-1,1-dimethyl-2-oxoethyl acetate instead of (1S)-2-chloro-1-methyl-2-oxoethyl acetate, the title compound (yield 66%) was obtained as colorless crystals.