Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]1[CH3:11])=[O:4].Br[CH:13](Br)[C:14]([CH:16](Br)Br)=[O:15]>>[CH3:1][O:2][C:3]([N:5]1[C:9]2([CH3:10])[CH:8]=[CH:7][C:6]1([CH3:11])[CH2:13][C:14](=[O:15])[CH2:16]2)=[O:4]
Reactant: O=C(C(Br)Br)C(Br)Br
Reactant: COC(=O)n1c(C)ccc1C
Product: COC(=O)N1C2(C)C=CC1(C)CC(=O)C2

Procedure:
The title compound was prepared from 2,5-dimethyl-pyrrole-1-carboxylic acid methyl ester (U.S. Pat. No. 4,551,540) and 1,1,3,3-tetrabromoacetone utilizing the [4+3] cycloaddition protocol of Kim and Hoffmann (European Journal of Organic Chemistry (2000), (12), 2195-2201). Mass spectrum (ESI, m/z): Calcd. for C11H15NO3, 210.1 (M+H), found 210.0.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:22][CH2:21][C:13]3[N:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[S:16][C:12]=3[C:11]2=O)=O)=[CH:4][CH:3]=1.Cl.[Cl:25][C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=1[NH:35][NH2:36]>C(O)(=O)C>[Cl:25][C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=1[N:35]1[C:11]2[C:12]3[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=3[CH2:21][CH2:22][C:10]=2[C:8]([C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[N:36]1
Reactant: NNc1ccc([N+](=O)[O-])cc1Cl
Reactant: CC(=O)Nc1nc2c(s1)C(=O)C(C(=O)c1ccc(C)nc1)CC2
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1nc2c(s1)-c1c(c(-c3ccc(C)nc3)nn1-c1ccc([N+](=O)[O-])cc1Cl)CC2
Temperature: 60 °C
Yield: 72.9 %

Procedure:
A suspension of 5.0 g (15.2 mmol) N-[6-(6-methyl-pyridine-3-carbonyl)-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl]-acetamide (A-23) and 3.74 g (16.7 mmol) (2-chloro-4-nitro-phenyl)-hydrazine hydrochloride in 100 mL glacial acetic acid is stirred at 60° C. After stirring for 24 h at 60° C. the solvent is evaporated, the residue taken up in 200 mL of ACN and stirred for 20 min. The solid is filtered off and dried at 40° C. yielding 5.33 g of the desired product.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][C:3]=1[O:18][CH:19]([CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:23]1)[C:20]#[CH:21].[F-].[K+].O.Cl>C(N(CC)C1C=CC=CC=1)C>[F:12][C:11]1[C:2]([F:1])=[C:3]2[C:4]([CH:21]=[CH:20][CH:19]([CH:22]3[CH2:23][CH2:24][CH:25]([CH2:28][CH2:29][CH3:30])[CH2:26][CH2:27]3)[O:18]2)=[C:5]2[CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9][C:10]=12
Reactant: C#CC(Oc1cc2c(c(F)c1F)OC(CCCCC)CC2)C1CCC(CCC)CC1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CCN(CC)c1ccccc1
Solvent: O
Product: CCCCCC1CCc2c3c(c(F)c(F)c2O1)OC(C1CCC(CCC)CC1)C=C3

Procedure:
9.7 g (23.2 mmol) of 7,8-difluoro-2-pentyl-6-[1-(4-propylcyclohexyl)prop-2-ynyloxy]chroman are heated at 200° C. for 6 h together with 2.7 g (46.5 mmol) of potassium fluoride in 75 ml of N,N-diethylaniline. After cooling, water is added, and the mixture is acidified using 25% hydrochloric acid. The batch is extracted with MTBE, and the organic phase is washed with saturated sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography (SiO2, 1-chlorobutane:pentane=4:1), giving 5,6-difluoro-3-pentyl-8-(4-propylcyclohexyl)-1,2,3,8-tetrahydropyrano[3,2-f]chromene as a pale-brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C@@H:16]3[C@@H:20]([OH:21])[C@@H:19]([OH:22])[CH:18]([OH:23])[O:17]3)=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1.F[C:25](F)(F)C(O)=O>CO>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C@@H:16]3[C@@H:20]([OH:21])[C@@H:19]([OH:22])[CH:18]([O:23][CH3:25])[O:17]3)=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:8])(=[O:9])[N:7]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3OC(O)[C@H](O)[C@@H]3O)c21
Reactant: O=C(O)C(F)(F)F
Solvent: CO
Product: COC1O[C@H](COc2cccc3c2C(N)=NS(=O)(=O)N3)[C@@H](O)[C@H]1O
Yield: 100 %

Procedure:
To a solution of 4-Amino-5-(((2R,3S,4R)-3,4,5-trihydroxytetrahydrofuran-2-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide (Example 265a) (7 mg, 0.020 mmol) in dry methanol (1 mL) was added trifluoroacetic acid 0.2 mL) and the mixture was refluxed overnight. The resulting solution was evaporated to dryness to provide the title compound as a white powder (7.28 mg, 100%, mixture of diastereomers ˜4/1). 1H NMR (400 MHz, DMSO-d6): δ [3.17 (s, ¾H)], 3.22 (s, 3H), 3.81 (d, J=4.0 Hz, 1H), [3.93 (m, ½H)], 4.12 (m, 3H), 4.39 (m, 1H), 4.71 (s, 1H), [4.85 (d, J=4.0 Hz, ¼H)], 5.44 (br s, 2H), 6.65 (d, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.95 (s, 1H), 8.41 (s, 1H), 11.00 (s, 1H), [11.01 (s, ¼H)].
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH:37]([OH:41])[CH2:36]1>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH:37]([OH:41])[CH2:36]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Reactant: NCCCCN1CCCC(O)C1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCCC(O)C3)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 1-(4-amino-butyl)-piperidin-3-ol by the procedure analogous to Example 6. HPLC ret. time: 3.3 minutes. 1H NMR (400 MHz, CD3OD) δ 7.18 (dd, 1H, J=6.8, 9.6 Hz), 7.04 (dd, 1H, J=5.6, 10 Hz), 5.45 (s, 2H), 3.64 (m, 1H), 3.24-3.22 (m, 2H), 2.90 (m, 1H), 2.73 (m, 1H), 2.37 (m, 2H), 2.25 (d, 3H, J=1.6 Hz), 1.99-1.87 (m, 3H), 1.74 (m, 1H), 1.74-1.53 (m, 6H) ppm; MS (APCI, m/z): 498 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:16][CH2:15][C@H:14]([CH:17]=[CH:18][CH:19]([OH:26])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11].[OH-].[Na+]>O.CO>[O:1]=[C:2]1[CH2:16][CH2:15][C@H:14]([CH:17]=[CH:18][CH:19]([OH:26])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:24])[CH3:25])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: COC(=O)CCCCCC[C@H]1C(=O)CC[C@@H]1C=CC(O)CCC=C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)=CCCC(O)C=C[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)O
Yield: 91.5 %

Procedure:
The solution of 0.5 g of 9-keto-15-hydroxy-19-methyl-prosta-13,18-dienoic acid, methyl ester, 0.170 g of NaOH in water (1.5 ml), methanol (4.5 ml) is left for two hours at room temperature under nitrogen, then diluted with water (22 ml) and extracted with diethyl ether (10 ml). The aqueous layer is acidified (congo red) with HCl (5%), then extracted with diethyl ether (3×15 ml). The ethereal solution is washed with water to neutrality, dried over sodium sulphate and the solvent evaporated in vacuo to yield 0.44 g of 9-keto-15-hydroxy-19-methyl-prosta-13,18-dienoic acid (oil).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1.O>CC(C)=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:12][S:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:11])=[O:10])=[O:24])=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: COc1ccc(S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(S(=O)(=O)NC(=O)Nc2ccc(Br)cc2)cc1
Yield: 91.9 %

Procedure:
To a solution of 9.97 g of 4-methoxybenzenesulfonamide in 54 ml of acetone were added 54 ml of a 1N sodium hydroxide solution. With stirring, a solution of 11.55 g of 4-bromophenylisocyanate in 50 ml of acetone was added. After stirring at room temperature for three days, the reaction mixture was filtered and 55 ml of 1N hydrochloric acid were added to the filtrate providing a fine white precipitate. Two hundred milliliters of water were added, and the solid was recovered by filtration to provide 18.85 g of the desired title product.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[OH:23][CH:24]([C:33]1[N:34]=[C:35]([CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)[S:36][CH:37]=1)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[C:27]1([CH2:26][CH2:25][C:24]([C:33]2[N:34]=[C:35]([CH:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)[S:36][CH:37]=2)=[O:23])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(O)CCc3ccccc3)cs2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)CCc3ccccc3)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, 1,1,1-tri acetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (15% strength solution in dichloromethane, 8.3 g) was added dropwise to a solution of tert-butyl 4-[4-(1-hydroxy-3-phenylpropyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (790 mg) in dichloromethane (7.9 ml). The reaction mixture was stirred at room temperature overnight. 5 g of silica gel were then added, and the solvent was removed under reduced pressure. The residue was purified chromatographically. This gave tert-butyl 4-[4-(3-phenylpropanoyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (545 mg).
Reaction SMILES: Cl.[Br:2][C:3]1[S:7][C:6]2=[N:8][C:9]([NH2:11])=[CH:10][N:5]2[CH:4]=1.[C:12]([O:16][C:17]([NH:19][C@H:20]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28](O)=[O:29])=[O:22])=[O:18])([CH3:15])([CH3:14])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:12]([O:16][C:17](=[O:18])[NH:19][C@@H:20]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28](=[O:29])[NH:11][C:9]1[N:8]=[C:6]2[N:5]([CH:10]=1)[CH:4]=[C:3]([Br:2])[S:7]2)=[O:22])([CH3:15])([CH3:13])[CH3:14]
Reactant: Nc1cn2cc(Br)sc2n1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 18 %

Procedure:
To a mixture of compound 11 (0.137 mmol), compound 3a (0.206 mmol), and HATU (0.206 mmol) in dimethylformamide (1.5 mL) was added TEA (0.55 mmol) dropwise. The reaction mixture was stirred at 40° C. for 4 hrs. The solvent was removed under reduced pressure and the residue dissolved in a mixture of dichloromethane/methanol (9/1). This mixture was passed through a SCX-2 column and the column was washed three times with the same eluent. The filtrate was concentrated and the residue was purified by chromatography on a silica gel column to give compound 12a as a yellow orange solid in 18% yield. MS (ESI, EI+) m/z=548.24-550.20 (MH+).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.NN>C(O)C>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][NH2:15])=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(N2CCOCC2)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCc1ccc(N2CCOCC2)cc1
Temperature: 25 °C

Procedure:
Step 2 A solution of 2-[2-(4-morpholin-4-ylphenyl)ethyl]-1H-isoindole-1,3(2H)-dione (193 mg, 0.57 mmol) and hydrazine monohydrate (70 mg, 1.4 mmol) in ethanol (6 ml) was heated at reflux for 2 hr. The reaction was cooled to ambient temperature, and the solvent was removed in vacuo. The residue was taken up in ether, washed with 2M aqueous sodium hydroxide, and then extracted with 1M aqueous hydrochloric acid (2×10 mL). The acidic extracts were combined and the pH raised to 10-11 with 4M aqueous sodium hydroxide. This was then extracted thrice with ether, the organics combined, and dried (Na2SO4). Filtration and removal of solvent in vacuo left a brown oil, 110 mg, 0.57 mmol, 100 percent crude yield. The material was used without further purification.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:23][NH:24][C:25](=[S:28])[NH:26][NH2:27].[C:29]1([C:39](O)=O)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1>CN(C)C=O.C(N(CC)CC)C>[C:29]1([C:39]2[N:24]([CH3:23])[C:25]([SH:28])=[N:26][N:27]=2)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1
Reactant: CNC(=S)NN
Reactant: O=C(O)c1nccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(S)nnc1-c1nccc2ccccc12
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Hydroxybenzotriazole (0.078 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g) and triethylamine were added successively to a cooled solution (0° C.) of 4-methyl-3-thiosemicarbazide (0.061 g) and 1-isoquinoline carboxylic acid (0.10 g) in dimethylformamide (3 ml). Following addition the cooling bath was removed and the mixture was stirred at room temperature over night and then the reaction mixture was evaporated to dryness. To the residue was added sodium hydroxide solution (0.5 M, 5 ml) and the mixture was stirred at 80° C. for 3 h. The mixture was cooled to room temperature and the pH adjusted to pH 6 using hydrochloric acid solution (2M) and the resulting precipitate was filtered and dried in vacuo to give the title compound (0.11 g, 78%) as an off-white solid.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34]1([N:40]=[C:41]=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41]([NH:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:42])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4ccccc4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 30.6 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g. 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, phenyl isocyanate (0.33 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 7:3) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(phenylamino)carboxamide (0.23 g, 31%) as a white solid: mp 212–214° C.; 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 8.78 (s, 1H), 7.88–7.76 (m, 3H), 7.37 (d, J=7.7 Hz, 2H), 7.21 (t, J=7.7 Hz, 2H), 6.89 (t, J=7.3 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 5.20–5.13 (dd, J=5.3 and 12.5 Hz, 1H), 4.72 (d, J=5.9 Hz, 2H), 2.97–2.84 (m, 1H), 2.65–2.49 (m, 2H), 2.09–2.05 (m, 1H); 13C NMR (DMSO-d6) δ 172.72, 169.79, 167.58, 166.99, 155.22, 140.25, 134.69, 133.63, 131.59, 128.60, 127.18, 121.83, 121.18, 117.70, 48.86, 38.71, 30.92, 21.97; Anal. Calcd. For C21H18N4O5: C, 62.07; H, 4.46; N, 13.79. Found: C, 62.14; H, 4.49; N, 13.49.
Reaction SMILES: [OH:1][C:2]1([C:15]2[S:16][C:17]([C:20]3[CH:25]=[C:24]([NH:26][C:27]4[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=4)[CH:23]=[C:22]([CH3:37])[CH:21]=3)=[CH:18][N:19]=2)[CH2:7][CH2:6][N:5](C(OCCCC)=O)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:37][C:22]1[CH:21]=[C:20]([C:17]2[S:16][C:15]([C:2]3([OH:1])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]3)=[N:19][CH:18]=2)[CH:25]=[C:24]([NH:26][C:27]2[N:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=[CH:29][N:28]=2)[CH:23]=1
Reactant: CCCCOC(=O)N1CCC(O)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNCC3)s2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To text-butyl 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (50 mg, 0.093 mmol) in DCM (1 mL) was added 144 uL TFA (20 eq) and the reaction stirred at rt for 4 h. To the mixture was added saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layer was dried, filtered. The solvent was reduced in vacuo to give 40 mg (0.092 mmol, 98%) of 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol. MS ESI: [M+H]+ m/z 436.2. 1H NMR (600 MHz, DMSO-d6): δ 8.81 (d, J=4.7 Hz, 1H); 7.93 (m, 2H), 7.44 (s, 1H); 7.25 (d, J=4.9 Hz, 1H); 7.13 (s, 1H); 5.97 (br s, 1H), 2.78-2.98 (m, 4H); 2.29 (s, 3H); 1.93-1.98 (m, 2H), 1.63-1.65 (m, 2H). rhSYK activity=+++
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:11][CH2:12][C:13](=[O:23])[NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])[NH2:3].S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[C:2]([C:5]1[CH2:10][CH:9]=[CH:8][N:7]([CH2:11][CH2:12][C:13](=[O:23])[NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1)(=[O:4])[NH2:3]
Reactant: NC(=O)c1ccc[n+](CCC(=O)NCCc2ccccc2)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Br-]
Agent: [Na+]
Product: NC(=O)C1=CN(CCC(=O)NCCc2ccccc2)C=CC1
Yield: 80.2 %

Procedure:
The product of Example 124 (3.78 g, 0.01 mol) was reduced according to the procedure described in Example 126 with sodium dithionite (6.96 g, 0.04 mol). After completion of the reaction, the product was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. A yield of 2.4 g (80%) of the title compound was obtained as a yellowish amorphous powder, m.p. 121°-123° C. UV max (methanol) 350 nm; IR (KBr) 3430 (NH), 3260 (NH), 1670 (CO), 1630 (CO) cm-1. Anal. calc. for C17H21N3O2.3/4H2O: C, 65.26; H, 7.24; N, 13.43. Found: C, 65.19; H, 6.87; N, 13.61. The structure of the product was further confirmed by PMR to be: ##STR1518##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([NH:9][C:4]2[C:5]([Br:8])=[CH:6][CH:7]=[CH:2][N:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Nc1ccccc1
Product: Brc1cccnc1Nc1ccccc1
Yield: 67 %

Procedure:
A mixture of 2,5-dibromopyridine (10.2 g, 43 mmole) in aniline (25 mL) was stirred and heated at reflux for 3 h. The reaction was cooled to RT and most of the aniline was distilled off under vacuum. The remaining residue was taken up in ethyl acetate and the solution was washed with 1.0 N Na2CO3 then with brine, dried (Na2SO4), and concentrated under vacuum. Trituration with petroleum ether, filtration and drying under vacuum gave the title compound (7.20 g, 67%) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=2.4 Hz, 1H), 7.58 (dd, 1H), 7.31-7.39 (m, 4H), 7.11 (m, 1H), 6.79 (br s, 1H); MS (ES) m/e 249.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([N:14]([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[C:24]([NH2:26])=[O:25])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[O:13])=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[NH3:35]>>[Cl:1][C:2]1[C:3]([C:12]([N:14]([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[C:24]([NH2:26])=[O:25])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[O:13])=[N:4][C:5]([NH2:35])=[N:6][CH:7]=1
Reactant: COc1cccc(C(C(N)=O)N(Cc2ccc(C)cc2)C(=O)c2nc(S(C)(=O)=O)ncc2Cl)c1
Reactant: N
Product: COc1cccc(C(C(N)=O)N(Cc2ccc(C)cc2)C(=O)c2nc(N)ncc2Cl)c1

Procedure:
The title compound was prepared from the sulfone of example 248, using the method from example 244 and ammonia as the amine, to return the title compound as a foam, 22 mg, (12%)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:7]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][C:31]1=[O:35]>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:5]3[CH:4]=[CH:3][C:2]([N:30]4[CH2:34][CH2:33][CH2:32][C:31]4=[O:35])=[CH:7][C:6]=3[N:8]3[CH2:12][CH2:11][CH2:10][C:9]3=[O:13])=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: O=C1CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCCC3=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3N3CCCC3=O)CC2)c(C)c1
Yield: 31.7 %

Procedure:
Using 1-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}pyrrolidin-2-one (206 mg) described in Preparation Example 169 and pyrrolidin-2-one (43 mg) and by the reaction and treatment in the same manner as in Example 352, the title compound (73 mg) was obtained.
Reaction SMILES: [ClH:1].CCOC(C)=O.[CH3:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=1>CCOC(C)=O>[ClH:1].[ClH:1].[CH3:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][CH:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)[CH2:17][CH2:16]2)[N:14]=1
Reactant: Cc1cccc(N2CCC(CCCC3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cccc(N2CCC(CCCC3CCNCC3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 M hydrogen chloride/EtOAc (10 ml) was added to an EtOAc (25 ml) solution of tert-butyl 4-{3-[1-(6-methyl-2-pyridinyl)-4-piperidinyl]propyl}-1-piperidinecarboxylate (1.3 g), followed by stirring overnight at room temperature. The reaction liquid was concentrated, then 2-propanol/diethyl ether was added thereto, followed by stirring. The precipitated solid was collected by filtration, and dried under reduced pressure to obtain 2-methyl-6-{4-[3-(4-piperidinyl)propyl]-1-piperidyl}pyridine dihydrochloride (1.1 g).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([CH2:13][NH2:14])[OH:12]>O1CCCC1>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:14][CH2:13][CH2:11][OH:12]
Reactant: NCCO
Reactant: Clc1nc2ccccc2o1
Solvent: C1CCOC1
Product: OCCNc1nc2ccccc2o1

Procedure:
A solution of 2-chlorobenzoxazole (12.78 g) in dry tetrahydrofuran (50 ml) was added, over 10 minutes, to a stirred, ice-cooled solution of ethanolamine (15.3 g) in dry tetrahydrofuran (400 ml). The mixture was heated at reflux overnight, cooled, and the solvent evaporated. The residue was partitioned between water (500 ml) and dichloromethane (500 ml), and the resulting white solid filtered off, washed with dichloromethane and dried in vacuo to afford the title compound m.p. 162°-4° C.