Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C@H:9]([C@H:11]([OH:20])[C@H:12]([CH:18]=[CH2:19])[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH3:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:26][CH:27]1[CH2:29][CH2:28]1>CN(C=O)C>[CH:27]1([CH2:26][O:20][C@H:11]([C@H:12]([CH:18]=[CH2:19])[CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C@@H:9]([O:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=2)[CH3:10])[CH2:29][CH2:28]1
Reactant: BrCC1CC1
Reactant: C=C[C@H](CCC(C)C)[C@@H](O)[C@H](C)OCc1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C[C@H](CCC(C)C)[C@@H](OCC1CC1)[C@H](C)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
A solution of (2S,3R,4S)-2-((4-methoxybenzyl)oxy)-7-methyl-4-vinyloctan-3-ol (2.0 g, 6.53 mmol) in anhydrous DMF (12 mL) was added at room temperature to a solution of NaH (NaH; 0.326 g, 8.16 mmol, 60% dispersion in mineral oil) in anhydrous DMF (12 ml). The reaction was stirred for 15 minutes (min) at room temperature, treated with (bromomethyl)cyclopropane (0.823 ml, 8.48 mmol) at room temperature, and then was heated to 40° C. for and stirred for 6 h. The reaction was cooled to room temperature and additional NaH (0.131 g, 3.27 mmol) and (bromomethyl)cyclopropane (0.317 mL, 3.27 mmol) were added, and the reaction was heated at 45° C. for 4 h. The reaction was again cooled to room temperature and a third batch of NaH (0.131 g, 3.27 mmol) followed by (bromomethyl)cyclopropane (0.317 mL, 3.27 mmol) was added and the reaction was heated at 45° C. for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (NH4Cl) and the phases were separated. The aqueous phase was extracted with diethyl ether (Et2O), and the combined organic phases were washed with brine, dried over magnesium sulfate (MgSO4), concentrated, and purified by column chromatography on SiO2 (gradient, hexanes/ethyl acetate) to furnish the title product as a colorless oil (1.94 g, 82%): IR (neat) 2953, 2868, 1613, 1513, 1247, 1084 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.25-7.20 (m, 2H), 6.89-6.81 (m, 2H), 5.52 (dt, J=17.0, 10.0 Hz, 1H), 5.03-4.92 (m, 2H), 4.52-4.32 (m, 2H), 3.78 (s, 3H), 3.65-3.56 (m, 2H), 3.34 (dd, J=10.0, 6.9 Hz, 1H), 3.28-3.22 (m, 1H), 2.09 (tdd, J=10.1, 7.7, 3.1 Hz, 1H), 1.81-1.67 (m, 1H), 1.55-1.42 (m, 1H), 1.28-1.13 (m, 2H), 1.19 (d, J=6.3 Hz, 3H), 1.13-0.95 (m, 2H), 0.87 (d, J=6.4 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H), 0.56-0.45 (m, 2H), 0.25-0.14 (m, 2H); ESIMS m/z 383.4 ([M+Na]+).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([OH:12])=[O:11].[C:17](=O)([O-])[O-].[Na+].[Na+]>CO>[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([O:12][CH3:17])=[O:11]
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C)c(F)c1
Yield: 73 %

Procedure:
Sulfuric acid (2 mL) was added to the solution of 3-fluoro-4-methylbenzoic acid (0.831 g, 5.23 mmol) in methanol (30 mL). The mixture was refluxed for 24 hours. After cooling, the solution was made alkaline by addition of an aqueous solution of sodium carbonate, concentrated under reduced pressure in order to remove methanol, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and was evaporated to give 0.641 g (73%) of methyl 3-fluoro-4-methylbenzoate as an oily residue which was directly used in the next step.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:18][C@H:19]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:20][OH:21]>C(#N)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:18][C@H:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:20][OH:21])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cl)nc1N[C@@H](CO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
To a mixture of 2,6-dichloro-3-nitropyridine (0.933 g, 4.83 mmol) and potassium carbonate (0.58 g, 4.19 mmol) in anhydrous acetonitrile (10 ml) was added (R)-2-amino-2-(4-fluoro phenyl)ethanol (1.00 g, 7.19 mmol) at 0° C. The resulting reaction mixture was stirred at 25° C. for 18 hours. The solid was removed by filtration and washed with EtOAc (20 ml). After evaporation of the solvent, the resulting residue was purified by column chromatography (hexane-EtOAc=5:1) to give the title compound as a yellow solid (0.77 g, 61%). 1H NMR (400 MHz) δ 8.96 (d, J=7.6 Hz, 1H), 8.46 (d, J=8.4 Hz, 1H), 7.45 (m, 2H), 7.15 (m, 2H), 6.81 (d, J=8.8 Hz, 1H), 5.27 (m, 2H), 3.80 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:36]([N:43]1[CH2:47][C@H:46]2[C@@H:48]([NH2:51])[CH2:49][CH2:50][C@H:45]2[CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[CH2:36]([N:43]1[CH2:47][C@H:46]2[C@@H:48]([NH:51][C:4](=[O:6])[CH:3]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:2]([CH3:1])[CH3:13])[CH2:49][CH2:50][C@H:45]2[CH2:44]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)C(C(=O)O)c1ccccc1
Reactant: N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Methyl-2-phenylbutanoic acid (1.049 mmol), 1-hydroxybenzotriazole hydrate (1.049 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (185 μL, 1.049 mmol) were combined in dichloromethane (4 mL). The mixture was stirred at room temperature for 10 minutes, then (3aS,4S,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine (1.049 mmol) from Step C was added in 2 mL of dichloromethane. The reaction was stirred at room temperature for 3.5 hours, and then quenched with 0.5 mL of water. The organic layer was separated and chromatographed using a silica gel cartridge (Analogix®, Burlington, Wis., RS-12) eluting with 1-10% methanol(ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.08 (dd, J=7.2, 14.4, 1H), 7.64 (dd, J=7.5, 14.5, 1H), 7.56-7.52 (m, 1H), 7.43 (d, J=4.4, 2H), 7.42-7.40 (m, 1H), 7.38-7.22 (m, 5H), 4.40 (dt, J=7.2, 14.3, 0.5H), 4.35-4.28 (m, 0.5H), 3.55 (d, J=12.7, 0.5H), 3.40 (dd, J=4.5, 12.8, 1H), 3.26 (d, J=12.9, 0.5H), 3.15 (d, J=10.5, 0.5H), 3.05 (d, J=10.5, 0.5H), 2.83-2.74 (m, 1H), 2.70-2.55 (m, 1.5H), 2.43-2.26 (m, 3H), 2.23-2.13 (m, 1H), 1.94-1.83 (m, 1H), 1.74-1.57 (m, 1.5H), 1.50 (dt, J=7.1, 15.3, 0.5H), 1.37 (td, J=6.5, 12.1, 0.5H), 1.31-1.23 (m, 0.5H), 1.18 (d, J=6.5, 1.5H), 1.10 (dt, J=6.5, 11.5, 0.5H), 1.03 (d, J=6.5, 1.5H), 0.73 (dd, J=6.7, 10.7, 3H); MS (ESI+) m/z 377 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:32]([OH:34])=O)[CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([NH2:30])=[C:22]([Cl:31])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.[N:39]1([CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:41][CH2:40]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[C:23]([NH2:30])=[C:22]([Cl:31])[CH:21]=3)[C:32]([N:55]3[CH2:54][CH2:53][CH:52]([N:39]4[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:41][CH2:40]4)[CH2:57][CH2:56]3)=[O:34])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)CCC1CCN(C2CCNCC2)CC1
Product: CCOC(=O)CCC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 24 from 500 mg (0.90 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f) and 341 mg (1.00 mmol) ethyl 3-[1,4′]bipiperidinyl-4-yl-propionate (Example A15b).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][C:10]23[CH2:17][CH2:16][C:13]([C:18]4[O:19][C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[C:29]([F:32])([F:31])[F:30])=[N:21][N:22]=4)([CH2:14][CH2:15]2)[CH2:12][CH2:11]3)OCC[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[F:32][C:29]([F:30])([F:31])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1[O:19][C:18]([C:13]23[CH2:14][CH2:15][C:10]([CH2:9][CH2:8][CH2:7][C:2](=[O:3])[CH3:1])([CH2:11][CH2:12]2)[CH2:17][CH2:16]3)=[N:22][N:21]=1
Reactant: CC1(CCCC23CCC(c4nnc(-c5ccccc5C(F)(F)F)o4)(CC2)CC3)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)CCCC12CCC(c3nnc(-c4ccccc4C(F)(F)F)o3)(CC1)CC2

Procedure:
2-{4-[3-(2-Methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]oct-1-yl}-5-[2-(trifluoromethyl)phenyl]-1,3,4-oxadiazole (4-G) (0.158 g) was stirred in a mixure of 90% acetone/10% water (20 mL). p-Toluenesulfonic acid (10 mg) was added to the solution. The reaction was heated to reflux for 1 h. The volume was reduced by evaporation of acetone in vacuo. The mixture was then layered with ethyl acetate (25 mL) and saturated sodium bicarbonate solution (25 mL). The ethyl acetate layer was extracted and dried (MgSO4). Solvent was removed in vacuo to afford pure 5-(4-{5-[2-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]oct-1-yl)pentan-2-one (4-H).
Reaction SMILES: [OH:1][CH:2]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH2:39][OH:40])([CH3:38])[C:33]([O:35]CC)=[O:34])=[CH:28][CH:27]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[OH-].[Na+].Cl>CO.O1CCCC1>[OH:1][CH:2]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH2:39][OH:40])([CH3:38])[C:33]([OH:35])=[O:34])=[CH:28][CH:27]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:25])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)C(C)(CO)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(CO)(C(=O)O)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
Dissolve 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-methyl-benzeneacetic acid, ethyl ester (200 mg, 0.37 mmol) in methanol (8 mL) and tetrahydrofuran (12 mL). Add 1.6 mL (1.6 mmol) of a 1 molar solution of aqueous sodium hydroxide. After 4 hours, cool the solution to room temperature and add 10% hydrochloric acid (ca. 1 mL) dropwise until pH is 5-6. Concentrate the solution and purify by flash chromatography (50 g of silica gel, methanol/chloroform gradient elution) to give the title compound (127 mg, 66%). Additionally, the following compounds can be prepared by the synthetic procedure depicted in Step J:
Reaction SMILES: [CH2:1]([C:3]1[C:8]([OH:9])=[C:7]([NH2:10])[CH:6]=[CH:5][CH:4]=1)[CH3:2].Cl[CH2:12][C:13](Cl)=[O:14].C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[C:8]2[O:9][CH2:12][C:13](=[O:14])[NH:10][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1cccc(N)c1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1cccc2c1OCC(=O)N2
Yield: 60.8 %

Procedure:
6-Ethyl-2-aminophenol (0.88 g, 6.4 mmol), 2-chloroacetyl chloride (0.80 g, 7.0 mmol) and K2CO3 (1.86 g, 13.5 mmol) were mixed according to GP1. Purified by column chromatography (SiO2; CH2Cl2/MeOH 99:1) to give the title compound (0.69 g, 61%). Rf=0.54 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) δ 9.29 (s, 1H), 6.92-6.85 (m, 2H), 6.71 (dd, J=7.0 Hz, J=2.6 Hz), 4.62 (s, 2H), 2.65 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H); 13C NMR (CDCl3) δ 166.8, 141.6, 133.0, 126.1, 124.4, 122.5, 114.0, 67.3, 22.9, 14.4.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1.Cl.[N:32]1([CH:37]2[CH2:41][CH2:40][NH:39][CH2:38]2)[CH:36]=[CH:35][N:34]=[N:33]1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:39]4[CH2:40][CH2:41][CH:37]([N:32]5[CH:36]=[CH:35][N:34]=[N:33]5)[CH2:38]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: c1cn(C2CCNC2)nn1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCC(n4ccnn4)C3)c(F)cc2c1=O
Temperature: 80 °C

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (120 mg, 0.486 mmol), DBU (190 mg, 1.25 mmol), 3-(1,2,3-triazol-1-yl)pyrrolidine hydrochloride (216 mg, 1.25 mmol) in pyridine (8 ml) was heated at 80° C. for 18 h. The reaction mixture was concentrated and treated with water. The separated solid was collected by filtration, washed with water and acetonitrile to give light brown solid. Yield: 71 mg (38%), m.p. 284° C. (dec). 1H NMR (TFA) δ: 1.5 (m, 4H), 3.0 (m, 2H), 4.0 (m, 4H), 4.65 (bs, 1H), 5.9 (bs, 1H), 7.5 (d, 1H),8.20 (d, 1H), 8.6 (s, 1H), 8.7 (s, 1H), 9.2 (S, 1H).
Reaction SMILES: CO[N:3]=[C:4]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[CH2:5]1>[Ni]>[CH3:12][N:9]1[CH2:8][CH2:7][C:6]2([C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:4]([NH2:3])[CH2:5]2)[CH2:11][CH2:10]1
Reactant: CON=C1CC2(CCN(C)CC2)c2ccccc21
Agent: [Ni]
Product: CN1CCC2(CC1)CC(N)c1ccccc12

Procedure:
The product of Example 138C and Raney/nickel were processed according to the method of Example 131C to provide the product. MS (ESI+) m/z 217 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]([F:31])([CH3:30])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([NH2:28])[CH3:27])=[CH:22][C:21]=1[CH3:29]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:28]([CH:26]([C:23]3[CH:24]=[CH:25][C:20]([O:19][CH2:18][C:17]([F:16])([F:31])[CH3:30])=[C:21]([CH3:29])[CH:22]=3)[CH3:27])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)ccc1OCC(C)(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ccc1OCC(C)(F)F
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (437 mg, yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (419 mg, 1.51 mmol, Step-1 of Intermediate-1) and 1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethanamine hydrochloride (400 mg, 1.51 mmol, Amine-81, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[ClH:16].[CH2:17]([NH2:20])[CH:18]=[CH2:19]>>[ClH:16].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:20][CH2:17][CH:18]=[CH2:19])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Reactant: C=CCN
Agent: Cl
Product: C=CCNC1CCc2c(cccc2NC(C)=O)C1

Procedure:
Starting from 3.04 g (0.015 mol) of 5-acetylamino-2-tetralone and 4.2 g (0.045 mol) of allylaminehydrochloride the title compound is obtained analogously to Example 4.1.11 in a yield of 3.30 g (78.4% of theory) and with a melting point of 263° C. which does not change after recrystallisation from methanol/water/ether.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH3:18][NH:19][C:20]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.FC(F)(F)S(O)(=O)=O>ClCCl>[CH3:18][NH:19][C:20]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][C:23]([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:22][CH2:21]1
Reactant: CNC1(c2ccccc2)CCC(=O)CC1
Reactant: c1ccc2c(CCc3ccncc3)c[nH]c2c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1(c2ccccc2)CCC(c2[nH]c3ccccc3c2CCc2ccncc2)(c2[nH]c3ccccc3c2CCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
3-(2-pyridin-4-ylethyl)-1H-indole (667 mg, 3 mmol, synthesis cf. WO2008009415, indole unit Ind-14) together with 4-(methylamino)-4-phenylcyclohexanone (610 mg, 3 mmol, synthesis cf. WO2008009415, ketone unit Ket-15) was dissolved in abs. dichloromethane (45 ml) and mixed with trifluoromethane sulphonic acid (0.613 ml, 6.9 mmol). The batch was stirred for 64 h at RT, and a brown oil separated out. For work up the reaction solution was mixed with 1N NaOH (30 ml) and methanol (10 ml). The mixture was stirred a further 60 min. After separation of the phases the aqueous phase was extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over Na2SO4 and then concentrated to low volume. The raw product obtained (1.47 g) was purified by column chromatography [silica gel 60 (90 g); ethyl acetate/methanol 5:1 (1200 ml); ethyl acetate/methanol 1:1 (1200 ml)].
Reaction SMILES: C([Li])CCC.C(OCC)C.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[B:18](OC)([O:21]C)[O:19]C>CCCCCC>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([B:18]([OH:21])[OH:19])[CH:13]=1
Reactant: Brc1cccnc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of n-butyllithium (16 mL of a 2.5M solution in hexane=50 mL dry diethyl ether) at -78° C. was added a solution of 3-bromopyridine (6 g in 15 mL diethyl ether) and the mixture stirred for 25 minutes. At this time trimethyl borate (4.3 mL) was added and the mixture allowed to warm to room temperature. After 1 hour the reaction was quenched by the addition of 10 mL glacial acetic acid and 60 mL water and the mixture stirred for 18 hours at room temperature. The pH of the mixture was adjusted to pH12 by the addition of 2M sodium hydroxide and extracted with diethyl ether. The aqueous layer was acidified to pH 6 by the dropwise addition of 1N hydrochloric acid and extracted with methylene chloride. The combined organics were dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with 20 mL acetonitrile:water (1:1) and filtered to give the title compound (1.0 g).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([C:9](=O)[C:10]([OH:12])=[O:11])=[CH:7][N:8]=1)=[O:2].Cl.[O:15]([NH2:17])[CH3:16].C(=O)(O)[O-].[Na+]>O>[CH:1]([NH:3][C:4]1[S:5][C:6]([C:9](=[N:17][O:15][CH3:16])[C:10]([OH:12])=[O:11])=[CH:7][N:8]=1)=[O:2]
Reactant: CON
Reactant: O=CNc1ncc(C(=O)C(=O)O)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)O)c1cnc(NC=O)s1
Temperature: 25 °C
Reaction time: 4.7 h
Yield: 32.7 %

Procedure:
A suspension of (2-formamidothiazol-5-yl)glyoxylic acid (2.4 g) and methoxylamine hydrochloride (5.0 g) in water (144 ml) was adjusted to pH 4.9-5.0 with a saturated aqueous sodium bicarbonate and the mixture was stirred at ambient temperature for 4.7 hours. After water was added thereto in order to dissolve the insoluble material therein, the aqueous solution was concentrated to a volume of 100 ml. The precipitated material was collected by filtration, washed with water, followed by dissolving in a mixture of tetrahydrofuran and water. This solution was poured into a mixture of ethyl acetate and water, and the organic layer was separated out. After the aqueous solution was extracted with ethyl acetate, the combined ethyl acetate solution was washed with an aqueous sodium chloride and then dried over anhydrous magnesium sulfate. Removal of the solvent gave 2-(2-formamidothiazol-5-yl)-2-methoxyiminoacetic acid (anti isomer) (0.9 g), mp 159° C. (dec.). The filtrate obtained above was further concentrated to a volume of 70 ml, and the precipitated material was collected by filtration to recover the same product (0.23 g). Total yield: 1.13 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[C:40]1([S:46](Cl)(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:30])[CH2:25][CH2:26][N:27]([S:46]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)(=[O:48])=[O:47])[CH2:28][CH2:29]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNCC3)s2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCN(S(=O)(=O)c4ccccc4)CC3)s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol (Example 46, 50 mg, 0.115 mmol) was dissolved in CH2Cl2 (1 mL). N,N-diisopropylethylamine (50 μL, 0.287 mmol) and benzenesulfonyl chloride (29 μL, 0.230 mmol) were added sequentially. The solution was stirred overnight at room temperature, then concentrated in vacuo on a Genevac. The resultant residue was dissolved in DMSO and purified via HPLC (48-82% CH3CN:H2O) to provide 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1-(phenylsulfonyl)piperidin-4-ol. MS ESI: [M+H]+ m/z 576.1. 1H NMR (600 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.80 (d, J=5.2 Hz, 1H), 7.93 (d, J=9.2 Hz, 2H), 7.75 (dd, J=8.7, 10.3 Hz, 2H), 7.73 (s, 1H), 7.65 (t, J=8.1 Hz, 1H), 7.43 (s, 1H), 7.25 (d, J=5.1 Hz, 1H), 7.12 (s, 1H), 6.10 (s, 1H), 3.54 (d, J=12.3 Hz, 1H), 2.58 (t, J=12.3 Hz, 2H), 2.54-2.37 (m, 1H), 2.28 (s, 3H), 2.08 (t, J=16.1 Hz, 2H), 1.80 (d, J=14.6 Hz, 2H). rhSYK activity=++
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[C:18]([O:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])(=[O:29])=[O:28])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[ClH:36].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[C:18]([O:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])(=[O:28])=[O:29])[CH:17]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(OS(=O)(=O)c3ccccc3Cl)cc3ccccc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=S(=O)(Oc1cc(OCC2CCNCC2)c2ccccc2c1)c1ccccc1Cl
Reaction time: 1 h
Yield: 201.3 %

Procedure:
To a solution of 319 mg (0.596 mmol) of 2-chlorobenzenesulfonic acid 1-[[1-N-(tert-butoxycarbonyl)piperidin-4-yl]methoxy]naphthalen-3-yl ester, as prepared in the preceding step, in 2 mL of methylene chloride was added 1.5 mL (6 mmol) of 4 N HCl in dioxane. The reaction mixture was stirred for 1 h and triturated with diethyl ether to afford 281 mg of the title compound as a colorless powder. 1H-NMR (300 MHz, DMSO-d6) δ 8.94 (bd, 1 H, J=9 Hz), 8.68 (bd, 1 H, J=10 Hz), 8.6 (d, 1 H, J=8 Hz), 7.8-7.98 (m, 4 Hz), 7.50-7.6 (m, 3 H), 7.18 (d, 1 H, J=2 Hz), 6.69 (d, 1 H, J=2 H), 3.94 (d, 2 H, J=7 Hz), 2.93 (q, 2 H), 2.16 (bm, 1 H), 1.96 (d, 2 H), and 1.57-1.71 (m, 2 H). Mass spectrum (MALDI-TOF; gentisic acid matrix) calcd. for C22H22ClNO4S: 432.1 (M+H). Found: 431.5.