Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]2[N:15]=[C:14]([S:16]([NH2:19])(=[O:18])=[O:17])[S:13][N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=O>>[N:22]1([CH:20]=[N:19][S:16]([C:14]2[S:13][N:12]=[C:11]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:15]=2)(=[O:18])=[O:17])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: O=CN1CCOCC1
Reactant: NS(=O)(=O)c1nc(-c2ccccc2)ns1
Solvent: O=S(Cl)Cl
Product: O=S(=O)(N=CN1CCOCC1)c1nc(-c2ccccc2)ns1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (4.5 ml) was added dropwise to 3.0 g of 3-phenyl-1,2,4-thiadiazole-5-sulfonamide in 15 ml of dry N-formylmorpholine at -5°. The resulting mixture was stirred at room temperature for 3 hours, poured into ice water and stirred for 15 minutes. The solids were collected, washed with water, dried, triturated with ether, washed with hexane and dried (in vacuo, P2O5). Recrystallization from benzene/hexane gave 1.1. g of solid, m.p. 185°-187°.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[F:14][C:15]1[CH:28]=[CH:27][C:18]2[S:19][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:21]([CH3:22])[C:17]=2[CH:16]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:23]([C:20]2[S:19][C:18]3[CH:27]=[CH:28][C:15]([F:14])=[CH:16][C:17]=3[C:21]=2[CH3:22])(=[O:25])=[O:24])=[C:4]([O:9][C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Reactant: Nc1ccc(Br)cc1OC(F)(F)F
Solvent: c1ccncc1
Product: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2OC(F)(F)F)sc2ccc(F)cc12
Yield: 24.8 %

Procedure:
This compound was prepared in analogy to Example 1, starting from 4-bromo-2-(trifluoromethoxy)aniline (CAS: 175278-09-8, 2.82 g) and 5-fluoro-3-methylbenzo[b]thiophene-2-sulphonyl chloride (0.265 g) in pyridine (2.0 ml) for 18 h to obtain the desired compound (0.12 g) as a colorless foam. MS (ISP): 501.0, 503.0 (M+NH4)+
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CN3CCOCC3)cc2C)ncn1
Reaction time: 15 h
Yield: 92.4 %

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 80 mg; 0.23 mmol) in DCM was treated with morpholine (40 mL; 0.46 mmol) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 15 hours the mixture was filtered and washed with water. The organic fraction was passed through a hydrophobic fit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid (90 mg, 92%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].C1(C)C=CC=CC=1.[CH2:17]([N:19]([CH2:24][CH3:25])[C:20](=[O:23])[CH2:21]Cl)[CH3:18].C(N(CC)CC)C>O>[C:4]([O:6][CH2:21][C:20](=[O:23])[N:19]([CH2:24][CH3:25])[CH2:17][CH3:18])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: CCN(CC)C(=O)CCl
Reactant: COC(=O)/C=C/C(=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)COC(=O)/C=C/C(=O)OC
Temperature: 15 °C

Procedure:
At a temperature of about 50-70° C., under a nitrogen atmosphere, a slurry of mono-methyl fumarate (130 g), toluene (800 mL) and N,N-diethylchloroacetamide (157 g) is added to triethylamine (1.07 g). The temperature is adjusted to 85-95° C. and maintained there for 4 hours. Then the temperature is then adjusted to 15-25° C. and the mixture is subjected to vigorous agitation. After 30 minutes of vigorous agitation in 200 mL of water, the agitation is stopped and the phases are allowed to separate for 30 minutes. The upper organic phase is washed with additional deionized water (75 mL) with vigorous agitation for 30 minutes. The agitation is then stopped and the phases are allowed to separate for 30 minutes. The organic layer is dried over anhydrous sodium sulfate (25 g) for 2 hours. The reaction is filtered and the solution is cooled to 10-20° C. Heptane (1600 mL), at −5 to −20° C. is added over 5 minutes. The reaction is cooled to −5° C. to −10° C. for 24 to 48 hours. The resulting product is air dried for 12 hours. XRPD analysis confirms product is form 4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]1[CH:10]=[C:11]([CH:15]2[O:19][CH2:18][CH2:17][O:16]2)[CH:12]=[CH:13][CH:14]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CCOCC.C1(C)C=CC=CC=1>[O:16]1[CH2:17][CH2:18][O:19][CH:15]1[C:11]1[CH:10]=[C:9]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccn1
Reactant: Brc1cccc(C2OCCO2)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: c1ccc(Nc2cccc(C3OCCO3)c2)nc1

Procedure:
Combine 2-aminopyridine (8.25 g, 95 mmol), 2-(3-bromo-phenyl)-[1,3]dioxolane (13.8 mL, 90 mmol), sodium t-butoxide (12.2 g, 126 mmol), BINAP (210 mg, 0.62 mmol), Pd2(dbu)3 (630 mg, 0.21 mmol) and toluene (100 mL) and heat to reflux for 48 hours. Cool the reaction to room temperature, dissolve in ether and filter and concentrate the resulting solution. Purification by flash chromatography (hexanes/EtOAc (8.5:1.5) and then hexanes/EtOAc (7:3)) provides the title compound as a yellow oil.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH:18]=[C:19]2[S:23][C:22](=[S:24])[N:21]([CH2:25][C:26]([OH:28])=[O:27])[C:20]2=[O:29])[N:17]=1.C(OCC)(=O)C>CN(C)C=O>[C:1]([NH:9][C:10](=[S:11])[NH:12][C:13]1[S:14][CH:15]=[C:16]([CH:18]=[C:19]2[S:23][C:22](=[S:24])[N:21]([CH2:25][C:26]([OH:28])=[O:27])[C:20]2=[O:29])[N:17]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(C=C2SC(=S)N(CC(=O)O)C2=O)cs1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)CN1C(=O)C(=Cc2csc(NC(=S)NC(=O)c3ccccc3)n2)SC1=S
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2.6 g of benzoyl isothiocyanate were added dropwise, at room temperature, to a solution of 4 g of 5-(2-aminothiazol-4-ylmethylene)rhodanine-3-acetic acid in 70 ml of dimethylformamide. The reaction mixture was stirred at room temperature for 6 hours. then ethyl acetate was added and precipitated solids were filtered off. The ethyl acetate solution was washed with water and concentrated under reduced pressure, and the crystalline solid thus obtained was separated by filtration and recrystallized from acetic acid, giving the title compound as a yellow powder.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:30]([N:39]2[CH:43]=[N:42][N:41]=[CH:40]2)[C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:30]([N:39]2[CH:43]=[N:42][N:41]=[CH:40]2)[C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(N(C(c2ccc(OCc3ccccc3)cc2)c2ccc(OCc3ccccc3)cc2)n2cnnc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1ccc(N(C(c2ccc(O)cc2)c2ccc(O)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-{[Bis-(4-benzyloxy-phenyl)-methyl]-[1,2,4]triazol-4-yl-amino}-benzonitrile (CAB02068, 564 mg, 1.0 mmol) was dissolved in ethanol, (50 mL) and palladium on charcoal (50 mg, 10% Pd) was added. The mixture was stirred under hydrogen atmosphere (balloon) for 48 h (TLC monitored) until all starting material was consumed. The Pd/C was filtered off (celite) and the solution was concentrated under reduced pressure. A yellow solid was obtained, which was dissolved in ethyl acetate (10 mL) upon heating. After cooling to room temperature the white precipitate was filtered off and dried under high vacuum. Yield: 312 mg (81%). 1H-NMR (400 MHz, d6-DMSO)=5.74 (s, 2H, 2×—OH); 6.28 (s, 1H), 6.53 (d, J=9.0 Hz, 2H), 6.61 (d, J=8.6 Hz, 4H), 7.10 (d, J=8.6 Hz, 4H), 7.65 (d, J=−9.0 Hz, 2H), 8.83 (s, 2H). LRMS (FAB+): 199.1 (100), 384.1 (50, [M+H]+). LRMS (FAB−) 184.1 (100), 382.1 (41, [M−H]−).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])=[CH:22][CH:21]=1>C(#N)C>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])=[CH:24][CH:25]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Reactant: CC(C)(C#N)c1ccc(N)cc1
Solvent: CC#N
Product: CC(C)(C#N)c1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cc1
Yield: 88.2 %

Procedure:
A mixture of 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (40 mg, 0.14 mmol), 2-(4-aminophenyl)-2-methylpropanenitrile (100 mg, 0.63 mmol) (prepared according to the reference: Axton, C. A. et al, J. Chem. Soc. Perkin Trans. 1, 1992, 2203.), and acetonitrile (0.5 mL) was heated in a sealed tube via microwave at 180° C. for 60 min. The solvent was removed in vacuo and the residue was purified by chromatography to give a light yellow solid (50 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16]([CH2:18][CH3:19])=[N:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.[Br-]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]2[N:15]=[C:16]([CH2:18][CH3:19])[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1nc2cccc(OCc3ccccc3)c2[nH]1
Reactant: BrCc1ccccn1
Agent: Br
Agent: [Br-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CCc1nc2c(OCc3ccccc3)cccc2n1Cc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution cold solution (ice bath) of 7-benzyloxy-2-ethyl-1H-benzimidazole prepared above (0.8 g, 3.17 mmol) in DMF (10 mL) was added sodium hydride (0.41 g, 10.47 mmol), followed by 2-(bromomethyl)pyridine hydrobromide (0.88 g, 3.49 mmol). After addition of the bromide the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was partitioned between water and ethyl acetate. Ethyl acetate layer was separated, dried (MgSO4), and concentrated to give 4-benzyloxy-2-ethyl-1-pyridin2-ylmethyl-1H-benzoimidazole as a solid which was crystallized in ethyl acetate to give 4-benzyloxy-2-ethyl-1-pyridin2-ylmethyl-1H-benzoimidazole, 0.35 g. LCMS 344 (M+1). 1HNMR (400 MHz, CDCl3) δ 1.38 (t, 3H), 2.90 (q, 2H), 5.40-5.42 (m, 4H), 6.65-8.60 (12H, Ar) 4-benzyloxy-2-ethyl-1-pyridin2-ylmethyl-1H-benzoimidazole (0.35 g, 1.2 mmol) was dissolved in ethanol and in presence of Pd/C, 10% and stirred under a hydrogen balloon overnight. The solution was filtered through celite and concentrated to give 2-ethyl-1-pyridin-2-ylmethyl-1H-benzoimidazole-4-ol. 1HNMR (400 MHz, CDCl3) δ 1.28 (t, 3H), 2.87 (q, 2H), 5.40 (s, 2H), 6.49 (d, 1Har), 6.51 (m, 2H, Ar), 6.92 (m. 1H Ar), 7.09 (m, 1H, Ar), 7.73 (m, 1H, Ar), 8.49 (m, 1H, Ar), 9.57 (1H, OH).
Reaction SMILES: C([Li])CCC.C1(NC(C)C)CCCCC1.[C:16](Cl)(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl.[C:35]([O:38][CH2:39][CH3:40])(=[O:37])[CH3:36]>CCCCCC.O1CCCC1.C(OCC)C>[O:32]=[C:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:36][C:35]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(C)=O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: CC(C)NC1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCC(=O)CC(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
502 ml of a 15.12% by weight solution of butyllithium in hexane was added dropwise at -78° C. over a period of 30 minutes to a solution of 128 ml of cyclohexylisopropylamine in 800 ml of tetrahydrofuran. After the addition was complete, the reaction mixture was allowed to warm up to 0° C. over a period of 30 minutes. It was then again cooled to -78° C., after which 38 ml of ethyl acetate were added over a period of 5 minutes. The mixture was then stirred at the same temperature for 10 minutes, after which 75.0 g of palmitoyl chloride were added dropwise to it over a period of 5 minutes. The mixture was then stirred at -78° C. for 10 minutes, after which 250 ml of 20% v/v aqueous hydrochloric acid was added dropwise to the reaction mixture. The reaction mixture was then allowed to warm to room temperature, and 1 liter of diethyl ether was added. The resulting two layers were separated, and the aqueous layer was extracted with diethyl ether. The organic layer was combined with the extract, and this was washed, in turn, with a saturated aqueous solution of sodium bicarbonate and with an aqueous solution of sodium chloride. It was then dried and concentrated by evaporation under reduced pressure. The residue was allowed to stand to produce crystals, which were collected by filtration, to give 55.61 g of the title compound. Recrystallization of the product from cold ethanol gave white prisms melting at 38°-39° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(N(CC)CC)C.Br[CH2:37][CH2:38][OH:39]>O1CCCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([CH2:37][CH2:38][OH:39])[CH2:26]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: OCCBr
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(CCO)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (chiral intermediate from Example 261) (400 mg, 1.0 mmol) in tetrahydrofuran (14 mL) was treated with triethylamine (350 μL, 2.5 mmol) and 2-bromoethanol (85 μL, 1.2 mmol) and stirred at 60° C. overnight. The reaction mixture was concentrated, diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.14 g, 31%). The product was isolated as a single enantiomer. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.46 (s, 1H), 6.24 (q, J=6.9 Hz, 1H), 4.41 (t, J=5.4 Hz, 1H), 4.12-4.03 (m, 1H), 3.97-3.88 (m, 2H), 3.64 (s, 3H), 3.38-3.34 (m, 2H), 3.09-3.01 (m, 2H), 2.55 (s, 3H), 2.41 (t, J=5.9 Hz, 2H), 1.72 (d, J=7.0 Hz, 3H). LCMS for C21H25ClN7O2 (M+H)+: m/z=442.2; Found: 442.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH:26]1([NH2:33])[CH2:31][CH2:30][CH2:29][CH:28]([NH2:32])[CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][CH:28]3[CH2:29][CH2:30][CH2:31][CH:26]([NH2:33])[CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NC1CCCC(N)C1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3CCCC(N)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and cyclohexane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J=7.8 Hz, 1 H), 7.57 (d, J=7.3 Hz, 1 H), 7.53-7.47 (m, 2 H), 7.37 (t, J=7.7 Hz, 1 H), 7.32-7.26 (m, 2 H), 5.86 (s, 1 H), 5.16-5.00 (m, 2 H), 3.65-3.50 (brs, 4 H), 3.16 (brs, 1 H), 2.42 (s, 3 H), 2.45-2.38 (m, 1 H), 2.29 (d, J=11.1 Hz, 1 H), 2.03-1.85 (m, 3 H), 1.54-1.42 (m, 1 H), 1.40-1.24 (m, 3 H).
Reaction SMILES: [OH:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].FC(F)(F)C(O[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=O>N1C=CC=CC=1>[OH:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:9]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: O=C(O)c1ccnnc1O
Solvent: c1ccncc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccnnc1O
Yield: 84.7 %

Procedure:
3-Hydroxypyridazine-4-carboxylic acid (1.40 g) was dissolved in pyridine (20 ml) at 40°C, and p-nitrophenyl trifluoroacetate (2.82 g) was dropwise added thereto. The resultant mixture was stirred at 40° to 50°C for 1 hour and concentrated under reduced pressure to dryness. The residue was washed with chloroform and acetone in order and dried to give the objective compound (2.21 g). M.P. 233°C (decomp.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:15][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:13](=[O:24])[N:12]2[CH2:25][CH2:26][CH3:27])=[CH:4][CH:3]=1.Br[C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].[O-]S([O-])(=O)=O.[Mg+2].C([O-])([O-])=O.[K+].[K+].N#N.Cl>C(O)C.CCOC(C)=O>[CH2:33]([O:32][C:30](=[O:31])[C:29]([CH3:36])([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:15][N:14]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[C:13](=[O:24])[N:12]2[CH2:25][CH2:26][CH3:27])=[CH:4][CH:3]=1)[CH3:35])[CH3:34]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCN1C(=O)N(Cc2ccc(C)cc2)CC1CCCc1ccc(O)cc1
Agent: Cl
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCN1C(=O)N(Cc2ccc(C)cc2)CC1CCCc1ccc(OC(C)(C)C(=O)OCC)cc1
Yield: 72.1 %

Procedure:
A mixture of 4-[3-(4-hydroxy-phenyl)-propyl]-1-(4-methyl-benzyl)-3-propyl-imidazolidin-2-one (0.687 g, 1.87 mmol), ethyl 2-bromoisobutyrate (2.55 g, 13.1 mmol), MgSO4 (0.22 g, 1.83 mmol) and 325 mesh K2CO3 (0.77 g, 5.57 mmol) in ethanol (60 mL) was heated at 70° C. for under N2 for 16 h. The reaction mixture was cooled and the solvent removed in vacuo to give a residue that was acidified with 1 N HCl (20 mL). The reaction was diluted with EtOAc and washed with water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to give crude product that was purified by flash chromatography using 5:1 hexanes:acetone to afford 0.648 g (72%) 2-methyl-2-(4-{3-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-propyl}-phenoxy)-propionic acid ethyl ester. MS (ES+) Calc'd for C29H41N2O4 (M+1) 481. Found m/z 481 (100%). 1H NMR.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20](=O)/[CH:21]=[CH:22]/N(C)C>>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[N:2]([C:4]2[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=2)[N:3]=[CH:22][CH:21]=1
Reactant: CN(C)/C=C/C(=O)c1ccc(F)cc1F
Reactant: N#Cc1ccnc(NN)c1
Agent: Cl
Product: N#Cc1ccnc(-n2nccc2-c2ccc(F)cc2F)c1
Yield: 83 %

Procedure:
The title compound was prepared in 83% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-1-(2,4-difluorophenyl)-3-(dimethylamino)prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 6.51 (1H, d, J=1.6 Hz), 6.77-6.82 (1H, m), 6.92-6.97 (1H, m), 7.34-7.40 (2H, m), 7.80 (1H, d, J=2.0 Hz), 8.20 (1H, s), 8.27 (1H, dd, J=5.2, 1.2 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][C:9]1[N:14]=[C:13]([CH2:15][CH:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([OH:19])=[O:18])[CH:12]=[CH:11][C:10]=1[F:28])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:29])/[CH:7]=[CH:8]/[C:9]1[N:14]=[C:13]([CH2:15][CH:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([OH:19])=[O:18])[CH:12]=[CH:11][C:10]=1[F:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1nc(CC(NC(=O)OC(C)(C)C)C(=O)O)ccc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1nc(CC(NC(=O)OC(C)(C)C)C(=O)O)ccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(6-(3-tert-Butoxy-3-oxopropyl)-5-fluoropyridin-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid. To a solution of 139C (0.68 g, 1.551 mmol) in THF (10 mL) and water (3 mL) was added LiOH (0.074 g, 3.10 mmol) at 0° C. The reaction was stirred under argon at 0° C. for 2 hrs. 1.0 N HCl (3.1 mL) was added to neutralize the reaction. The reaction mixture was diluted with EtOAc, washed with H2O and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to give a tan solid of (E)-3-(6-(3-tert-butoxy-3-oxoprop-1-enyl)-5-fluoropyridin-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid. MS (ESI) m/z: 411.1 (M+H)+. To the above obtained intermediate were added catalytic amount of 10% Pd/C and MeOH (15 mL). The reaction mixture was stirred under a hydrogen balloon at rt for 1 h. Catalyst was filtered off and solvent was removed to give 139D as a tan solid. MS (ESI) m/z: 413.1 (M+H)+.
Reaction SMILES: C(OC([NH:11][C:12]1[C:13]([C:29]([NH:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][C:37]=2[N:38]2[CH2:43][C@H:42]([CH3:44])[C@H:41]([NH:45][C:46](=[O:49])[O:47][CH3:48])[C@H:40]([NH:50]C(=O)OC(C)(C)C)[CH2:39]2)=[O:30])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22]1[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH:27]=1)[CH:16]=2)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:50][C@H:40]1[C@@H:41]([NH:45][C:46](=[O:49])[O:47][CH3:48])[C@@H:42]([CH3:44])[CH2:43][N:38]([C:37]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[NH:31][C:29]([C:13]2[C:12]([NH2:11])=[CH:21][C:20]3[C:15](=[CH:16][C:17]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:39]1
Reactant: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2NC(=O)c2nc3cc(C4=CCN(C)CC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)N[C@@H]1[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(C4CCN(C)CC4)ccc3cc2N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
To a solution of tert-butyl methyl {(3R,4S,5S)-1-[3-({[3-{[(benzyloxy)carbonyl]amino}-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-methylpiperidine-3,4-diyl}biscarbamate (40 mg, 0.051 mmol) in MeOH (3.0 mL), 10% Pd on carbon (9 mg). The reaction mixture was deoxygenated under reduced pressure and hydrogen was introduced via a balloon. The reaction mixture was stirred at room temperature under hydrogen for 16 h. The mixture was filtered and concentrated under reduced pressure. The resulting residue was dissolved in DCM (2 mL), and TFA (2 mL) was added. The mixture was stirred at room temperature for 30 min. then concentrated under reduced pressure. The residue was purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a yellow powder (18 mg, 66%). LCMS calc. for C29H39N8O3 (M+H)+: m/z=547.3. Found: 547.4.