Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:30](Cl)(Cl)=[S:31].[CH2:34]([N:36]([CH2:40][CH3:41])[CH2:37][CH2:38][NH2:39])[CH3:35]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30]([NH:39][CH2:38][CH2:37][N:36]([CH2:40][CH3:41])[CH2:34][CH3:35])=[S:31])=[CH:18][CH:17]=1
Reactant: S=C(Cl)Cl
Reactant: CCN(CC)CCN
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCNC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 6 hr. Next, N,N-diethylethylenediamine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 14 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (25 mg, yield 33%).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[NH:10][C:9](=[O:11])[CH2:8][CH2:7][O:6][CH2:5]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:12]([N:10]1[C:9](=[O:11])[CH2:8][CH2:7][O:6][CH2:5][CH:4]1[CH3:3])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CC1COCCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1COCCC(=O)N1Cc1ccccc1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (95%, 553 mg, 21.9 mmol, 1.15 equiv) was added to a solution of 3-methyl-1,4-oxazepan-5-one (4-2, 2.46 g, 19.0 mmol, 1 equiv) in DMF (40 mL) at 0° C. and the resulting mixture was stirred for 20 min. Benzyl bromide (2.49 mL, 20.9 mmol, 1.10 equiv) was added and the mixture was warmed to 23° C. and stirred for 20 h. The reaction mixture was partitioned between brine (100 mL) and ethyl acetate (2×100 mL), and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (20% EtOAc in hexanes initially, grading to 100% EtOAc) to give 4-benzyl-3-methyl-1,4-oxazepan-5-one (4-3) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.36-7.25 (m, 5H), 5.05 (d, 1H,J=14.6 Hz), 4.17 (d, 1H,J=14.6 Hz), 4.00 (ddd, 1H,J=12.5, 6.1, 3.3 Hz), 3.80 (dd, 1H,J=12.8, 4.0 Hz), 3.56 (dd, 1H,J=12.5 Hz), 3.42 (d, 1H,J=12.8 Hz), 3.31 (m, 1H), 3.02 (ddd, 1H,J=15.0, 11.9, 3.4 Hz), 2.75 (ddd, 1H,J=16.2, 4.9, 1.2 Hz), 1.31 (d, 3H,J=7.3 Hz). LRMS m/z (M+H) 220.3 found, 220.1 required.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[B:22](OC)([O:25]C)[O:23]C.Cl>C1COCC1>[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[B:22]([OH:25])[OH:23]
Reactant: COB(OC)OC
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(F)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 69.6 %

Procedure:
n-BuLi (1.9 M, 26.3 mL, 50 mmol) was added dropwise to a solution of diisopropylamine (7.71 mL, 55 mmol) in 100 mL anhydrous THF under N2 at 0° C. After 10 minutes, the reaction was cooled to −78° C. A solution of 4-fluorobenzonitrile (6.06 g, 50 mmol) in 20 mL anhydrous THF was added dropwise, at such a rate to maintain an internal temperature of −78° C. After stirring for 1 h at this temperature, trimethyl borate (8.41 mL, 75 mmol) was added dropwise at such a rate to maintain an internal temperature of −78° C. The reaction was stirred and gradually warmed to room temperature over 16 h. The reaction was cooled to 10° C. and 25 mL 6N HCl was added. After stirring at room temperature for 4 h, the reaction was partitioned between water and ethyl acetate. The organic layer was washed three times with 100 mL 2N NaOH. The aqueous layers were pooled and adjusted to pH 6 with 6N HCl. The white solid which forms was extracted by three washes of 100 mL Ethyl acetate. The organic layers were pooled, dried over sodium sulfate, concentrated and dried under high vacuum to give 2-fluoro-5-cyanophenyl boronic acid (5.74 g, 70%). 1H NMR (500 MHz, acetone-d6) 8.08 (1H, dd, J=2.14, 5.5 Hz), 7.90 (1H, m), 7.31 (1H, t, J=8.85 Hz). Anal. calcd. for C7H5BFNO2: C, 50.97; H, 3.05; N, 8.49. Found: C, 51.19; H, 3.19; N, 8.26.
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([O:8][CH:9]([CH3:19])[CH2:10][N:11]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH3:12])=[O:7])([CH3:3])[CH3:2].[CH3:24][I:25]>ClCCCl>[I-:25].[CH:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([O:8][CH:9]([CH3:19])[CH2:10][N+:11]([CH3:24])([CH3:12])[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:7])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(CN(C)C1CCCCC1)OC(=O)c1ccccc1C(C)C
Solvent: ClCCCl
Product: CC(C[N+](C)(C)C1CCCCC1)OC(=O)c1ccccc1C(C)C
Product: [I-]
Reaction time: 16 h

Procedure:
To a stirred solution of 1-(cyclohexyl(methyl)amino)propan-2-yl 2-isopropylbenzoate (0.45 g, 1.41 mmol) in DCE (3 mL) was added methyl iodide (0.35 mL, 5.67 mmol) and the reaction mixture was stirred at it for 16 hours in a sealed tube. The reaction mixture was concentrated and the crude material was purified by Combiflash® chromatography, eluting with 3-4% CH3OH/DCM to provide a solid which was crystallized from methanol-ether to provide white N-[2-((2-isopropylbenzoyl)oxy)propyl]-N,N-dimethylcyclohexanaminium iodide. Yield: 0.415 g (64%). 1H NMR (DMSO-d6) δ 7.71 (d, J=8 Hz, 1H), 7.58-7.50 (m, 2H), 7.31 (t, J=7 Hz, 1H), 5.57-5.54 (m, 1H), 3.93-3.87 (m, 1H), 3.67-3.57 (m, 2H), 3.38-3.34 (m, 1H), 3.05 (s, 3H), 3.02 (s, 3H), 2.17-2.08 (m, 2H), 1.87-1.84 (m, 1H), 1.75-1.72 (m, 1H), 1.54-1.42 (m, 3H), 1.40 (d, J=6 Hz, 3H), 1.24-1.19 (m, 7H), 1.13-0.99 (m, 2H). LCMS: m/z=332.0 [M+], RT=3.01 min, (Column: Y, Program: P1). UPLC: 98.43% (200 nm), RT=3.60 min (Mobile Phase A. 0.05% TFA in water, B. Acetonitrile; Column: Zorbax® SB-C18 (4.6×50 mm) 1.8μ)
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH:11]([O:19][CH3:20])[CH2:10]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH:11]([O:19][CH3:20])[CH2:10]1
Reactant: COC(=O)C1CCC(NCc2ccccc2)CC1OC
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1CCC(N)CC1OC
Reaction time: 24 h

Procedure:
Methyl 4-(benzylamino)-2-methoxycyclohexanecarboxylate (1.84 g, 6.63 mmol, racemic mixture of diastereomers) and palladium hydroxide on carbon (20 weight %, 0.233 g, 0.332 mmol) in methanol (35 mL) were combined, and the atmosphere was exchanged for hydrogen (balloon) via four vacuum hydrogen flush cycles. After 24 hours, additional palladium hydroxide on carbon (20 weight %, 0.233 g, 0.332 mmol) was added, and the reaction mixture was again placed under a hydrogen atmosphere. Following another 24 hours, the reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give methyl 4-amino-2-methoxycyclohexanecarboxylate as a racemic mixture of three diastereomers, which was carried forward without further purification. MS ESI calcd. for C9H18NO3 [M+H]+ 188. found 188.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:18][C:17]2[CH:19]=[C:20]([CH:37]3[CH2:41][CH2:40][CH2:39][NH:38]3)[C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([N:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]4=[O:36])=[N:28][CH:29]=3)=[CH:22][C:16]=2[N:15]=1>C(Cl)(Cl)Cl>[C:1]([N:38]1[CH2:39][CH2:40][CH2:41][CH:37]1[C:20]1[C:21]([O:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]3=[O:36])=[N:28][CH:29]=2)=[CH:22][C:16]2[N:15]=[C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=3)[NH:18][C:17]=2[CH:19]=1)(=[O:3])[CH3:2]
Reactant: O=c1ccccn1-c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cn1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(-n2ccccc2=O)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.003 ml of acetic anhydride was added to a chloroform (1 ml) solution of 5.8 mg of 5′-((2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazol-5-yl)oxy)-2H-1,2′-bipyridin-2-one enantiomer B obtained in Example 554, and the reaction liquid was stirred at room temperature for 30 minutes. The reaction solvent was evaporated away, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain one chiral form of the entitled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][NH:13][CH3:14])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[C:15]1([C:25](Cl)=[O:26])[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.O>C(Cl)Cl.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:9][CH2:10][OH:11])[CH2:12][N:13]([CH3:14])[C:25]([C:15]2[C:24]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[O:26])=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cccc2c1CCCC2
Reactant: CNCC(CCO)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CN(CC(CCO)c1ccc(Cl)cc1)C(=O)c1cccc2c1CCCC2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 90.4 %

Procedure:
To a stirred cooled (0° C.) mixture of 3-(4-chloropenyl)-N-methyl-4-amino-1-butanol (0.706 g, 3.30 mmol) in DCM (25 mL) and 1N NaOH (4.13 mL) was added dropwise a solution of 5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride (0.643 g, 3.30 mmol) in DCM (10 mL). The mixture was stirred at 0° C. for 2.5 h, H2O and DCM were added and the mixture was extracted with DCM (2×20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. Purification by chromatography (0%, 50%, 100% EtOAc in Et2O) provided the title compound (1.11 g, 90%) as a solid. MS m/z 372 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[C@:9]([CH3:29])([C:25]([F:28])([F:27])[F:26])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:16]=2[F:24])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(C)C.C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[C@:9]([CH3:29])([C:25]([F:28])([F:27])[F:26])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:24])([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)CO[C@@]1(C)C(F)(F)F
Agent: [Pd]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CO[C@@]1(C)C(F)(F)F

Procedure:
A solution of [(2R,5R)-5-(2-fluoro-5-nitro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (0.98 g, 2.25 mmol) in isopropanol-THF 2:1 (24 ml) was hydrogenated over 5% Pd—C for 4 h at 50° C. The catalyst was filtered off over Celite and the filtrate was concentrated to provide the title compound after crystallization from TBME-hexane as beige crystals: TLC (hexane-EtOAc 1:1): Rf=0.42; HPLC RtH5=0.955 min; ESIMS: 406 [(M+H)+]; 1H NMR (360 MHz, CDCl3): δ 6.82 (dd, 1H), 6.52 (m, 2H), 4.30 (dd, 1H), 3.97 (dd, 1H), 3.06 (br s, 2H), 1.58 (s, 3H), 1.48 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([CH3:15])=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].[Br:16]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([CH2:15][Br:16])=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2ccc(C)cc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc2ccc(CBr)cc2n1
Yield: 64.1 %

Procedure:
Compound 20 (0.265 g, 1.32 mmol) was diluted in anhydrous benzene (10 mL). N-Bromosuccinimide (0.247 g, 1.39 mmol) and a catalytic amount (0.020 g) of benzoyl peroxide were added, and the mixture was heated to reflux under argon until an orange tint was no longer visible in the solution refluxing in the condenser (typically 4 h). The mixture was cooled, concentrated, and purified by flash column chromatography (SiO2), eluting with a gradient of 7% to 14% EtOAc in CH2Cl2, to yield the product (0.236 g, 64%) as a flocculent yellow solid. 1H NMR chemical shifts for this compound are consistent with those reported in the literature for the 7-isomer. 1H-NMR (500 MHz; CDCl3): δ 8.43-8.41 (m, 2 H), 8.16 (d, J=8.9 Hz, 1 H), 7.79-7.77 (m, 2 H), 7.49 (dd, J=8.4, 1.7 Hz, 1 H), 4.65 (s, 2 H), 2.27 (s, 3 H).
Reaction SMILES: C1C2C(OC([NH:17][C:18]3([C:48]([OH:50])=[O:49])[CH2:23][CH2:22][C:21]([OH:47])([C:24]4[S:25][C:26]([C:29]5[CH:34]=[C:33]([NH:35][C:36]6[N:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][N:37]=6)[CH:32]=[C:31]([CH3:46])[CH:30]=5)=[CH:27][N:28]=4)[CH2:20][CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.C(O)(C(F)(F)F)=O>CN(C=O)C>[NH2:17][C:18]1([C:48]([OH:50])=[O:49])[CH2:23][CH2:22][C:21]([OH:47])([C:24]2[S:25][C:26]([C:29]3[CH:34]=[C:33]([NH:35][C:36]4[N:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][N:37]=4)[CH:32]=[C:31]([CH3:46])[CH:30]=3)=[CH:27][N:28]=2)[CH2:20][CH2:19]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC(NC(=O)OC4c5ccccc5-c5ccccc54)(C(=O)O)CC3)s2)c1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCNCC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC(N)(C(=O)O)CC3)s2)c1
Reaction time: 0.25 h
Yield: 9.1 %

Procedure:
1-{[(9H-Fluoren-9-yloxy)carbonyl]amino}-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (0.079 g, 0.11 mmol) was dissolved in DMF (1.0 mL). Piperidine (0.086 g, 1.01 mmol) was added. After 15 minutes, the reaction mixture was directly purified by reverse phase HPLC to yield 1-amino-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (0.005 g, 0.01 mmol) as its TFA salt. MS ESI: [M+H]+ m/z 494.1. 1H NMR (600 MHz, CD3OD) δ 8.70 (d, J=4.9, 1H), 8.04 (s, 1H), 7.94-7.80 (m, 2H), 7.69 (d, J=7.6, 1H), 7.52-7.42 (m, 1H), 7.42-7.34 (m, 1H), 7.18-7.00 (m, 2H), 2.60-2.42 (m, 2H), 2.36 (s, 3H), 2.28-2.07 (m, 4H), 2.05-1.89 (m, 2H). rhSYK activity=+++. The starting material was prepared generally following the procedures described in Examples 32 and 33 using commercially available 1-{[{9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxocyclohexanecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH2:10][C:11]([CH3:13])=[CH2:12])[C:3]=1[OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:12][C:11]1([CH3:13])[CH2:10][C:4]2[C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[C:3]=2[O:14]1
Reactant: C=C(C)Cc1c(C)cc(C)c(C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(c1C)OC(C)(C)C2
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A mixture of 2,3,5-trimethyl-6-(2-methylprop-2-en-1-yl)phenol (13.0 g, 68.3 mmol) synthesized in Reference Example 2, p-toluenesulfonic acid monohydrate (1.30 g, 6.83 mmol) and toluene (130 mL) was stirred under heated reflux for 1.5 hours. After cooled to room temperature, the reaction solution was distributed by addition of 1N sodium hydroxide aqueous solution. The organic layer was washed with 1N sodium hydroxide aqueous solution and saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by basic silica gel chromatography (hexane-ethyl acetate 49:1 to 24:1) to give 11.1 g of the title compound (yield: 85%).
Reaction SMILES: [C:1]([C:3]1([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[H][H]>CO.[Ni]>[NH2:2][CH2:1][C:3]1([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: Cc1cccnc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Cc1cccnc1C1(CN)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of tert-butyl 4-cyano4-(3-methylpyridin-2-yl)piperidine-1-carboxylate (2 g, 6.6 mmol) in methanol (70 mL containing 2 M ammonia) was reacted with Raney nickel (1 mL of 50% slurry in water) under 45 psi hydrogen for 24 hours. The catalyst was filtered off and washed thoroughly with methanol. Evaporation of solvent afforded the desired product: tert-butyl 4-aminomethyl)4-(3-methylpyridin-2-yl)piperidine-1-carboxylate: 1H NMR δ (ppm)(CDCl3): 8.44 (1 H, br s), 7.41 (1 H, d, J=7.4 Hz), 7.07 (1 H, br s), 3.80 (2 H, br s), 3.01 (4 H, br s), 2.66 (2 H, s), 2.48 (3 H, s), 1.62-1.54 (2 H, m), 1.44 (9 H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[CH2:13](Br)[CH:14]=[CH2:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([Cl:8])=[CH:7][C:2]=1[NH2:1])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc([N+](=O)[O-])c(Cl)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a mixture of 2-amino-4-chloro-5-nitrophenol (10 g, 0.053 mol) and allyl bromide (5.05 mL, 0.058 mol) in DMF (100 mL) was added K2CO3. The reaction mixture was stirred at room temperature for 3 hours, and then the inorganic salts were filtered off. The filtrate was concentrated, and the residue was dissolved in ethyl acetate and washed with aqueous NH4Cl. The organic layer was dried over MgSO4 and concentrated to provide the desired product (10.9 g, 90%) as yellow solid. MS (DCI/NH3) m/z 246.04 (M+NH4)+; 1H NMR (500 MHz, DMSO-D6) δ ppm 4.68 (d, J=4.99 Hz, 2 H) 5.29 (dd, J=10.60, 1.56 Hz, 1 H) 5.48 (dd, J=17.47, 1.56 Hz, 1 H) 6.05 (m, 1 H) 6.48 (s, 2 H) 6.76 (s, 1 H) 7.59 (s, 1 H).
Reaction SMILES: C(OC([N:8]1[C:11]2([CH2:14][N:13]([C:15](=[O:26])[NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:15]([N:13]1[CH2:12][C:11]2([N:8]([S:34]([C:31]3[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=3)(=[O:36])=[O:35])[CH2:9][CH2:10]2)[CH2:14]1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC12CN(C(=O)NCc1ccc(Cl)cc1Cl)C2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CC2(CCN2S(=O)(=O)c2ccc(Cl)cc2)C1

Procedure:
In analogy to the experimental procedure of example 6b) 6-(2,4-Dichloro-benzylcarbamoyl)-1,6-diaza-spiro[3.3]heptane-1-carboxylic acid tert-butyl ester instead of tert-butyl 1-(2,4-dichlorobenzylcarbamoyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate was converted using 4-chlorobenzene-1-sulfonyl chloride into the title compound which was obtained as an off-white solid (41 mg, 23%). MS m/e: 474 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[C:24]([CH:28]=1)[C:25](O)=[O:26]>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]2[N:30]=[CH:31][CH:32]=[CH:33][N:34]=2)=[C:24]([C:25]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:26])[CH:28]=1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Product: O=C(c1cc(F)ccc1-c1ncccn1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and Intermediate 13. MS (ESI): mass calculated for C25H21FN6O, 440.48; m/z found 441.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.71 (d, J=4.9, 2H), 8.37-8.30 (m, 2H), 7.92-7.88 (m, 1H), 7.72-7.69 (m, 1H), 7.63-7.57 (m, 1H), 7.43-7.37 (m, 1H), 7.23-7.17 (m, 1H), 7.11-7.05 (m, 2H), 4.03-3.93 (m, 2H), 3.87-3.70 (m, 3H), 3.67-3.56 (m, 2H), 3.26-3.03 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C=CC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.27 g (7 mmol) of methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-oct-2-enoate in 32 mL methanol, 0.446 g (1.87 mmol) cobalt (II) chloride hexahydrate is added. The solution is cooled in an ice bath and 0.573 g (15 mmol) sodium borohydride is added in small portions. Vigorous gas evolution and formation of a black precipitate is observed during the addition of sodium borohydride. After completion of the addition, the ice bath is removed and the mixture stirred at room temperature for 1 hour. The black precipitate is filtered off and washed with methanol. The combined filtrate is evaporated and the residue suspended in a mixture of 30 mL methylene chloride and 150 mL ether. The organic layer is washed with water. The aqueous phase is extracted with ether (2×50 mL). The combined organic extract is dried (MgSO4), filtered and the solvent evaporated. The residue is subjected to flash chromatography on silica using 3:2 EtOAc, hexane as the eluent to give methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate, m.p. 81-82°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1>>[F:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1)=[N:3][CH:4]=[CH:5]2
Reactant: Fc1ccc2c(Cl)nccc2c1
Reactant: OCCC1CCNCC1
Product: OCCC1CCN(c2nccc3cc(F)ccc23)CC1
Yield: 39.1 %

Procedure:
The process is performed as described in Example 4 (step 4.1). Starting with 1.52 g (8.39 mmol) of 1-chloro-6-fluoroisoquinoline and 1.20 g (9.23 mmol) of 2-(4-piperidyl)ethanol, and after chromatography on silica gel, eluting with a 95/5/0.5 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.90 g of pure product is obtained in the form of a yellow paste.