Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28](=[O:43])[NH:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=1[CH2:38][CH:39]([OH:42])[CH2:40][CH3:41])([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([O:27][C:28](=[O:43])[NH:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=1[CH2:38][C:39](=[O:42])[CH2:40][CH3:41])([CH3:25])([CH3:24])[CH3:26]
Reactant: CCC(O)Cc1ccc(OC)cc1NC(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: CCC(=O)Cc1ccc(OC)cc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To a solution of Dess-Martin reagent (2.82 g, 6.68 mmole) in 80 ml THF cooled at 0° C. was added [2-(2-hydroxy-butyl)-5-methoxy-phenyl]-carbamic acid t-butyl ester 73a (1.64 g, 5.57 mmole) in 20 ml THF. The reaction mixture was stirred and warmed to room temperature for 2 h, quenched with half saturated NaHCO3, extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (10-15% EtOAc in hexane) to give colorless oil (1.36 g, 84%). 1H NMR (CDCl3) δ7.67 (1H, bs), 7.48 (1H, s), 6.99-7.03 (1H, m), 6.56-6.60 (1H, m), 3.79 (3H, s), 3.59 (2H, s), 2.53-2.61 (2H, q, J=7.2 Hz), 1.51 (9H, s), 1.02 (3H, t, J=7.2 Hz). ESIMS (MNa+): 316.10.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]3[C:31]4[C:26](=[C:27]([F:33])[CH:28]=[CH:29][C:30]=4[F:32])[N:25]=[CH:24][N:23]=3)=[CH:15][CH:14]=2)[CH:3]=1.C(N(CC)CC)C.[H][H]>CCO.[Pd]>[F:32][C:30]1[CH:29]=[CH:28][C:27]([F:33])=[C:26]2[C:31]=1[C:22]([NH:21][CH2:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:4]3[CH:3]=[CH:2][N:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[N:5]=3)=[CH:18][CH:17]=1)=[N:23][CH:24]=[N:25]2
Reactant: Fc1ccc(F)c2c(NCCc3ccc(Oc4cc(Cl)nc(C(F)(F)F)n4)cc3)ncnc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Fc1ccc(F)c2c(NCCc3ccc(Oc4ccnc(C(F)(F)F)n4)cc3)ncnc12
Reaction time: 8 h
Yield: 42.3 %

Procedure:
A mixture of {2-[4-(6-chloro-2-trifluoromethylpyrimidin-4-yloxy)-phenyl]-ethyl}-(5,8-difluoroquinazolin-4-yl)-amine (0.205 g, 0.46 mmol), 10% Pd on activated carbon (0.030 g) and triethylamine (0.60 mL, 4.3 mmol) in EtOH (15 mL) was charged with hydrogen to an initial pressure of 40 psi in a Parr bottle and shaken overnight. The catalyst was removed by filtration on Celite and the filtrate was concentrated in vacuo. The residue was purified on silica gel to give 0.087 g (42% yield) of (5,8-difluoroquinazolin-4-yl)-{2-[4-(2-trifluoromethylpyrimidin-4-yloxy)-phenyl]-ethyl}-amine as a white foam, 1H NMR (CDCl3): δ 8.71 (d, J=6.3 Hz, 1H), 8.69 (s, 1H), 7.32-7.40 (m, 3H), 7.16 (d, J=8.7 Hz, 2H), 6.97-7.04 (m, 2H), 6.68-6.82 (br, 1H), 3.97 (q, J=6.9 Hz, 2H), 3.08 (t, J=6.9 Hz, 2H). LC/MS: 448.18 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:14])([F:13])[O:7][C:8]2([F:12])[F:11])=[CH:4][C:3]=1[OH:15].[Cl:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[Cl:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[OH:15])[C:6]([F:14])([F:13])[O:7][C:8]2([F:11])[F:12])=[O:20]
Reactant: Nc1cc2c(cc1O)C(F)(F)OC2(F)F
Reactant: O=C(O)c1ccncc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc2c(cc1O)C(F)(F)OC2(F)F)c1ccncc1Cl
Temperature: 80 °C
Yield: 61.5 %

Procedure:
A mixture of 0.68 g of 6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran, 0.48 g of 3-chloroisonicotinic acid, 0.76 g of WSC and 7 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.68 g of 3-chloro-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:26])[C:16]([CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][C:21]4=[O:25])=[CH:17][N:18]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CO.O.[Zn]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:15]([CH3:26])[C:16]([CH2:19][N:20]5[CH2:24][CH2:23][CH2:22][C:21]5=[O:25])=[CH:17][N:18]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:30]=1
Reactant: Cn1c(CN2CCCC2=O)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: Cn1c(CN2CCCC2=O)cnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
To a solution of 135 (125 mg, 0.267 mmol) in MeOH (10 mL) was added zinc powder (140 mg, 2.14 mmol) and ammonium chloride (42.9 mg, 0.80 mmol) in water (1 mL) and the reaction mixture was heated to reflux for 4 hours. The mixture was cooled to RT, filtered and concentrated. The residue was partitioned between water and DCM/MeOH and the organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated to afford title compound 136 (77 mg, 66% yield) that was used crude in the next step with no additional purification. MS (m/z)=438.50 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1.[NH:13]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]1>>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:13]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:14]2)(=[O:11])=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Br)cnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cc(Br)cnc2Cl)C1

Procedure:
Prepared according to the methods described in reagent preparation 25 using 5-bromo-2-chloropyridine-3-sulfonyl chloride and (S)-tert-butyl pyrrolidin-3-ylcarbamate in step 1. 1H NMR (400 MHz, CDCl3) δ 8.61 (d, 1H), 8.52 (d, 1H), 4.67 (s, 1H), 4.25 (s, 1H), 3.57 (m, 4H), 3.34 (m, 1H), 2.22 (m, 1H), 1.92 (m, 1H), 1.45 (s, 9H); MS (ES) for C14H19BrClN3O4S: 440, 442 (Br isotopes, MH+).
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([C:10]3[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=3)[CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:24]1([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:14]([CH2:13][C:12]1[CH:20]=[CH:21][CH:22]=[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:38][C:35]4[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:33][CH:34]=4)[N:23]=3)[CH:9]=[CH:8][CH:7]=2)[CH:11]=1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CN(Cc1cccc(-c2cccn3nc(Cl)nc23)c1)S(C)(=O)=O
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(Cc1cccc(-c2cccn3nc(Nc4ccc(OCCN5CCCC5)cc4)nc23)c1)S(C)(=O)=O

Procedure:
N-Methyl-N-(3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-benzyl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.214 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (49.0 mg, 0.238 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (24.0 mg, 0.0439 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.050 g, 45%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.5 Hz, 1H), 8.01-7.95 (m, 2H), 7.58 (d, J=7.4 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.42 (d, J=7.5 Hz, 1H), 6.97-6.91 (m, 3H), 6.68 (s, 1H), 4.42 (s, 2H), 4.11 (t, J=6.0 Hz, 2H), 2.90 (t, J=5.9 Hz, 2H), 2.87 (s, 3H), 2.83 (s, 3H), 2.67-2.57 (m, 4H), 1.87-1.77 (m, 4H). MS=521 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([O:32]C)=[O:31])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]2[C:16]([C:17]([CH2:27][CH3:28])=[CH:18][C:19](=[O:26])[O:20]2)=[CH:15][CH:14]=1.[OH-].[K+].Cl>CO.O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([OH:32])=[O:31])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]2[C:16]([C:17]([CH2:27][CH3:28])=[CH:18][C:19](=[O:26])[O:20]2)=[CH:15][CH:14]=1
Reactant: CCCc1c(OCCCSc2ccc(CC(=O)OC)cc2Cl)ccc2c(CC)cc(=O)oc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1c(OCCCSc2ccc(CC(=O)O)cc2Cl)ccc2c(CC)cc(=O)oc12
Temperature: 40 °C

Procedure:
To a solution of methyl 3-chloro-4-(3-(4-ethyl-8-propyl-7-coumarinoxy)propylthio)phenylacetate (Example 1; 82 mg, 0.1677 mmol) in 1.2 mL methanol:water (1:1) was added a 0.5M solution of potassium hydroxide in methanol. The mixture was heated to 40° C. for two hours at which time the mixture was acidified to pH=3 with 1M aqueous hydrochloric acid. The aqueous solution was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate, filtered, and the crude residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexane/1% acetic acid) which provided the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:14][C:8]=1[C:9]([N:11]([CH3:13])[CH3:12])=[O:10]>ClCCl>[CH3:5][O:4][C:2](=[O:3])[NH:6][C:7]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:14][C:8]=1[C:9](=[O:10])[N:11]([CH3:13])[CH3:12]
Reactant: COC(=O)Cl
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Solvent: ClCCl
Product: COC(=O)Nc1ccc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)cc1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
Methyl chloroformate (42 ul, 0.53 mmol) was added dropwise to a solution of 2-amino-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4,b]pyridin-5-yl]-N,N-dimethyl-benzamide (21 mg, 0.05 mmol) in dichloromethane/saturated aqueous sodium bicarbonate (1:1) at 0° C. The mixture was stirred for another 3 hours, allowing to slowly warm to room temperature. The reaction was washed three times with water (5 ml), dried over sodium sulfate and concentrated to dryness. The crude was purified by flash chromatography on silica gel using a gradient of ethyl acetate and hexane to afford {2-dimethylcarbamoyl-4[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-carbamic acid methyl ester (4.9 mg, 21% yield). 1H NMR (500 MHz, DMSO-d6) δ 2.88 (d, 6H), 3.58 (s, 3H), 3.77 (s, 3H), 7.03 (m, 1H), 7.15 (d, 1H), 7.40 (m, 1H), 7.58 (s, 1H), 7.64 (d, 1H), 7.73 (d, 1H), 8.27 (s, 1H), 8.78 (s, 1H), 9.03 (s, 1H), 13.75 (s, 1H); MS: m/z 446.1 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17](Br)=[CH:18][C:13]=2[CH:12]=[C:11]([C:20]([O:22][CH3:23])=[O:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B([O-])([O-])O[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH3:38])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH3:38])=[CH:28][CH:27]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:20]([O:22][CH3:23])=[O:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(Cc2ccccc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A mixture of methyl 1-benzyl-7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g), 4-(2-propoxyethoxy)phenyl borate (0.24 g), 1M potassium carbonate solution (2.5 ml), ethanol (2.5 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed under argon atmosphere overnight. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-benzyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.27 g) as yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-].[Na+].[CH2:14](Br)[CH2:15][CH2:16][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]>C(O)C>[CH2:31]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOc1ccc2ccccc2c1

Procedure:
172.8 g (1.2 mol) 2-naphthol (98%) is added to a solution of 48 g (1.2 mol) sodium hydroxide (99%) in 1 l ethanol in a 4 l three-neck flask with stirrer, cooler and thermometer, after it has dissolved 417 g (1.25 mol) n-octadecylbromide are added and the reaction mixture is heated for 14 hours under reflux. After addition of a further 1 l ethanol the hot solution is aspirated over a Seitz filter to remove inorganic material and the weak pink coloured filtrate is brought to crystallization by placing it in an ice bath for 30 minutes. After aspiration of the almost colourless crystals, the filter cake is washed in portions with ca 700 ml ethanol and after drying over diphosphorus pentoxide 371.9 g (93.7% of the theoretical yield) 2-octadecyloxynaphthalene are obtained as colourless crystals, mp 64°-68° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[C:8]([F:22])[CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]4[CH:21]=3)=[C:8]([F:22])[CH:7]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1ccn2cc(-c3ccc(OCCCCl)cc3F)nc2c1
Reactant: C1CCNCC1
Product: Cc1ccn2cc(-c3ccc(OCCCN4CCCCC4)cc3F)nc2c1
Temperature: 25 °C

Procedure:
The product of Step C (118 mg) and piperidine (1.5 mL) were heated at 100° C. for 2.5 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with additional ethyl acetate (10 mL) and the organic portions combined and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (130 mg). 1H-NMR (CD3OD) δ 8.22 (d, J=8.0 Hz, 1H), 7.98 (m, 2H), 7.27 (s, 1H), 6.76 (m, 3H), 4.00 (t, J=6.0 Hz, 2H), 2.48 (m, 6H), 2.38 (s, 3H), 1.96 (m, 2H), 1.61 (m, 4H), 1.47 (m, 2H)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1OS(C(F)(F)F)(=O)=O)[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2].[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][CH2:25][CH2:26][C:27]#[CH:28]>C(NCC)C.[Pd](Cl)Cl.[Cu]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[C:28]#[C:27][CH2:26][CH2:25][CH2:24][C:23]([O:30][CH3:31])=[O:29])[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(NC(C)=O)c1
Reactant: C#CCCCC(=O)OC
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COC(=O)CCCC#Cc1ccc(C(=O)OC)cc1NC(C)=O
Temperature: 20 °C
Reaction time: 14 h
Yield: 86.5 %

Procedure:
A mixture of methyl 3-acetamido-4-trifluoromethanesulfonyloxybenzoate (1.43 g), methyl 5-hexynoate (582 mg), palladium(II) chloride (14.9 mg), triphenylphosphine (43.8 mg) and copper(I) chloride (32 mg) in diethylamine (18 ml) was stirred at 20° C. for 14 hours. The solvent was evaporated in vacuo an the residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (1:2) to give methyl 3-acetamido-4-(5-methoxycarbonyl-1-pentynyl)benzoate (1.15 g) as colorless crystals.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:36](=[O:37])[CH2:35][N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CN1CCN(CC(=O)O)CC1
Agent: Cl
Product: CN1CCN(CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)CC1

Procedure:
The title compound, white solid (22.5 mg, 58.5%), MS (ISP) m/z=472.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 2-(4-methylpiperazin-1-yl)acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[CH:7]=O.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:6]([CH2:7][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cc(Cl)ccc1N1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(Cl)ccc2N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
A 100 mL round-bottom flask was charged with 5-chloro-2-(pyrrolidin-1-yl)benzaldehyde (1.80 g, 8.58 mmol, 1.10 equiv), tert-butyl piperazine-1-carboxylate (1.45 g, 7.79 mmol, 1.00 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred 30 min at room temperature. Sodium triacetoxyborohydride (4.96 g, 23.4 mmol, 3.01 equiv) was added. The resulting solution was stirred overnight at room temperature. The resulting mixture was washed with H2O (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/4) to yield 2.50 g (77% yield) of tert-butyl 4-[[5-chloro-2-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 380 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:5].C1C(=O)N([Br:22])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][C:2]([CH3:14])([CH3:13])[CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][Br:22])=[CH:10][CH:11]=1)=[O:5]
Reactant: Cc1ccc(C(=O)CC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)CC(=O)c1ccc(CBr)cc1
Yield: 89.7 %

Procedure:
Heat a mixture of 3,3,4′-trimethylbutyrophenone (2 g, 10.52 mmol), NBS (2.061 g, 11.57 mmol), and AIBN (43 mg, 0.263 mmol) in carbon tetrachloride (60 mL) for 14 h at reflux. Cool the reaction, mixture to ambient temperature and wash sequentially with water, 1M aqueous HCl, 5% aqueous NaHCO3 and brine. Concentrate the organic layer in vacuo to provide the desired intermediate as oil (2.54 g, 90%) that was used without any further purification.
Reaction SMILES: [CH2:1]([N:3]=C=O)[CH3:2].[CH3:6][O:7][C:8](=[O:34])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:30](=[CH:31][CH:32]=1)[O:29][C:16]1([CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=[O:23])[CH2:18][CH2:17]1)[CH2:15][C:14]2=[O:33]>C(Cl)Cl>[CH3:6][O:7][C:8](=[O:34])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:30](=[CH:31][CH:32]=1)[O:29][C:16]1([CH2:17][CH2:18][N:19]([C:22](=[O:23])[NH:3][CH2:1][CH3:2])[CH2:20][CH2:21]1)[CH2:15][C:14]2=[O:33]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)OC)ccc1O2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.5 %

Procedure:
TEA (0.185 ml, 1.33 mmol) and ethylisocyanate (38 mg, 0.53 mmol) were added to a suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester hydrochloride (150 mg, 0.44 mmol, Intermediate 1) in DCM (4 ml), and the mixture was stirred at RT for 1.5 h. The mixture was partitioned between aqueous NaHCO3 (saturated solution) and DCM and the organic phase was dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (eluent: DCM/MeOH/NH4OH 97:3:0.3) to give (E)-3-{1′-ethylcarbamoyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (150 mg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][C@H:3]1[O:21][CH3:22].[CH2:23]([C:25]1[NH:29][C:28]([C:30](O)=[O:31])=[N:27][C:26]=1[C:33]([F:36])([F:35])[F:34])[CH3:24].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH2:23]([C:25]1[NH:29][C:28]([C:30]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=3)[C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:4][C@H:3]2[O:21][CH3:22])=[O:31])=[N:27][C:26]=1[C:33]([F:35])([F:36])[F:34])[CH3:24]
Reactant: CCc1[nH]c(C(=O)O)nc1C(F)(F)F
Reactant: CO[C@@H]1CN(c2cccc(C(=O)OC(C)(C)C)c2)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cccc(C(=O)OC(C)(C)C)c3)C[C@H]2OC)nc1C(F)(F)F
Yield: 67 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-3-(4-amino-3-methoxypiperidin-1-yl)benzoate obtained in Example (42d) (about 0.26 mmol), 5-ethyl-4-(trifluoromethyl)-1H-imidazole-2-carboxylic acid obtained by the method described in Example (39e) (50 mg, 0.24 mmol), WSC hydrochloride (137 mg, 0.71 mmol) and HOBT (32 mg, 0.24 mmol), to obtain 79.7 mg of the title compound as a white solid (67%).