Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:28]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37](Br)[N:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([CH2:28][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:36]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(Cc2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Cc5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-benzyl-6-bromo-pyridine.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[NH:19][C:20]3=[O:23])=[CH:15][CH:14]=2)[CH2:8]1)(=O)=O.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(#N)C>[O:12]=[C:10]1[N:9]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:31])([F:33])[F:32])[NH:19][C:20]3=[O:23])=[CH:15][CH:14]=2)[CH2:8][C@H:7]([CH2:6][N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[O:11]1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Reactant: C1CCNCC1
Solvent: CC#N
Product: O=C1O[C@@H](CN2CCCCC2)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Yield: 73 %

Procedure:
The methanesulfonic acid (R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl(20 mg, 0.0415 mmol) obtained in step A was dissolved in acetonitrile (0.1 ml). Thereafter, piperidine (8.2 μl) was added to the solution, and the obtained mixture was stirred under heating to reflux for 12 hours. Thereafter, the reaction solution was concentrated, and the obtained residue was then purified by silica gel column chromatography (methylene chloride:methanol=30:1), so as to obtain 7-((S)-2-oxo-5-piperidin-1-ylmethyloxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (14.3 mg, 73%) in the form of a colorless amorphous substance.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>C(#N)C>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:2][C:3]([NH:5][C:6]2[CH:19]=[CH:18][C:9]3[O:10][C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:8]=3[CH:7]=2)=[O:4])[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCC3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN1CCN(CC(=O)Nc2ccc3oc4c(c3c2)CCCCC4)CC1
Yield: 25.4 %

Procedure:
Following the procedure of Example 40, 2-chloro-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.13 g, 0.45 mmol), N-methylpiperazine (0.062 mL, 0.56 mmol), and cesium carbonate (0.29 g, 0.90 mmol) in acetonitrile (5 mL) provided 2-(4-methylpiperazin-1-yl)-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.039 g) as its trifluroacetic acid salt after reverse-phase HPLC purification. MS (ESI) m/z 342 ([M+H]+).
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([F:27])([F:26])([F:25])([F:24])[F:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([F:27])([F:23])([F:24])([F:25])[F:26])=[CH:18][CH:17]=2)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Reactant: Oc1ccc(S(F)(F)(F)(F)F)cc1
Solvent: c1ccncc1
Product: CCCCCc1ccc(C(=O)Oc2ccc(S(F)(F)(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 11.6 g of p-pentylbenzoyl chloride, 11.1 g of p-hydroxyphenyl sulfur pentafluoride and 100 ml of pyridine is stirred it room temperature for 20 hours. Concentrating the mixture and working it up in the customary manner gives 4-(4-pentylbenzoyloxy)-phenylsulfur pentafluoride.
Reaction SMILES: [CH:1]1([C:7]2C=[CH:11][C:10]([C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.II.[Cl:22]Cl.[C:24]([Cl:28])(Cl)(Cl)Cl>>[Cl:22][C:8]1[CH:9]=[C:10]([C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[C:24]([Cl:28])[C:7]=1[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCl
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)cc1
Agent: II
Product: CCOC(=O)C(=O)c1cc(Cl)c(C2CCCCC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ethyl p-cyclohexylphenylglyoxylate, 49.5 g. (0.19 mole) and 6.1 g. of iodine are dissolved in 100 ml. of carbon tetrachloride. To this solution is added a solution of 56.7 g. (0.8 mole) of chlorine dissolved in 500 ml. of carbon tetrachloride over a period of 3 hours. During the addition, the temperature of the reaction mixture is maintained at 0° C. The mixture is stirred for 3 hours and allowed to stand with gradual warming to room temperature over 30 hours. The solvent is removed in vacuo. The residue is fractionally distilled to obtain ethyl 3,5-dichloro-4-cyclohexylphenylglyoxylate.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13](=[O:15])[CH3:14])=[O:4].[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].[ClH:21]>C1(C)C=CC=CC=1.CCOCC>[ClH:21].[CH2:16]([N:18]([CH2:19][CH3:20])[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13](=[O:15])[CH3:14])=[O:4])[CH3:17]
Reactant: CC(=O)c1cccc(C)c1NC(=O)CBr
Reactant: CCNCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCN(CC)CC(=O)Nc1c(C)cccc1C(C)=O

Procedure:
To a solution of 4.0 g of 2-bromo-2'-acetyl-6'-methylacetanilide in 60 ml of toluene was added 2.5 g of diethylamine at room temperature. The resultant mixture was stirred at room temperature overnight. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and evaporated to give an oily residue. The residue was dissolved in ether and hydrogen chloride was added to the solution to give crystals. Recrystallization from ethanol-ether gave 2-(diethylamino)-2'-acetyl-6'-methylacetanilide hydrochloride having a melting point of 141° to 143° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][C:16]([NH:19][CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)=[CH:17][CH:18]=2)=[C:9]([O:30][C:31]([F:34])([F:33])[F:32])[CH:8]=1)(=[O:5])=[O:4].C(O)(=[O:39])C.C(O)(=O)C.IC1C=CC=CC=1>CC(O)=O.CC(OC(C)=O)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:36][C:2]([F:35])([F:1])[S:3]([O:6][C:7]1[CH:8]=[C:9]([O:30][C:31]([F:32])([F:33])[F:34])[C:10]([C:13]2[N:14]=[N:15][C:16]([NH:19][CH:20]3[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23][C:24]([CH3:26])([CH3:27])[CH2:25]3)=[CH:17][CH:18]=2)=[C:11]([OH:39])[CH:12]=1)(=[O:4])=[O:5]
Reactant: CC(=O)O
Reactant: CC1(C)CC(Nc2ccc(-c3ccc(OS(=O)(=O)C(F)(F)F)cc3OC(F)(F)F)nn2)CC(C)(C)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: Ic1ccccc1
Product: CC1(C)CC(Nc2ccc(-c3c(O)cc(OS(=O)(=O)C(F)(F)F)cc3OC(F)(F)F)nn2)CC(C)(C)N1
Temperature: 75 °C
Reaction time: 4 h
Yield: 35.8 %

Procedure:
A mixture of 4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenyl trifluoromethanesulfonate (86 mg, 0.16 mmol), iodobenzene diacetate (71.5 mg, 0.222 mmol) and Pd(OAc)2 (3.6 mg, 0.016 mmol) in AcOH (0.6 mL) and Ac2O (0.6 mL) was heated at 75° C. for 3 hours. The mixture was then heated at 80° C. overnight after addition of another 40 mg of iodobenzene diacetate. The reaction mixture was cooled to room temperature and concentrated. The residue was loaded onto an SCX column, washed with MeOH and diluted with 2 M NH3 in MeOH. The product-containing fractions were concentrated. The residue was treated with 7 M NH3/MeOH and stirred at 40° C. for 4 h. The crude material was purified via flash column chromatography to give the title compound as a beige solid (32 mg, 36.1%). MS (M+1)=559.4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCN=C=NCC.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:34]([F:44])[CH:33]=1>ClCCl.CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][C:3]=1[C:4]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:34]([F:44])[CH:33]=1)=[O:6]
Reactant: CCOC(=O)Cc1ccc(N)cc1F
Reactant: O=C(O)c1cc(OCc2cccc(Cl)c2)ccc1Cl
Agent: CCN=C=NCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc(OCc3cccc(Cl)c3)ccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
A solution of 2-chloro-5-{[(3-chlorophenyl)methyl]oxy}benzoic acid (207 mg, 0.7 mmol) in dichloromethane (3 ml) was treated with N-[2-(dimethylamino)ethyl]-N′-ethylcarbodiimide hydrochloride (201 mg, 1.05 mmol, 1.5 eq) and stirred at room temperature for 30 minutes. A solution of ethyl (4-amino-2-fluorophenyl)acetate (207 mg, 1.05 mmol, 1.5 eq) in dichloromethane (2 ml) was added and the resulting mixture heated at 40° C. overnight. On cooling, the mixture was diluted with methanol and purified by SCX cartridge eluting with methanol to afford the title compound as a yellow oil (110 mg). MS (ES+) m/z 476 [M+H]+ (C24H2035Cl2FNO4). 1H-NMR (400 MHz, d6-DMSO) δ 1.19 (3H, t, J 7.2), 3.68 (2H, s), 4.09 (2H, q, J 7.2), 5.20 (2H, s), 7.15-7.68 (10H, m).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([CH:63]([CH3:65])[CH3:64])([CH:60]([CH3:62])[CH3:61])[CH:57]([CH3:59])[CH3:58])[CH2:5][C:4]1=[O:66])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:76]([C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][C:80]=1[S:85](Cl)(=[O:87])=[O:86])([O-:78])=[O:77]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][S:85]([C:80]3[CH:81]=[CH:82][CH:83]=[CH:84][C:79]=3[N+:76]([O-:78])=[O:77])(=[O:86])=[O:87])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([CH:60]([CH3:62])[CH3:61])([CH:57]([CH3:59])[CH3:58])[CH:63]([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C(OC)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
A solution of 17-ethyl-1-hydroxy-14-triisopropylsilyloxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone(1.0 g, 1.06 mmol) in MeCl2 (20 ml) containing 4-dimethylaminopyridine (312 mg, 2.55 mmol) and diisopropylethylamine (319 mg, 2.47 mmol) was treated with o-nitrobenzenesulfonyl chloride (476 mg, 2.14 mmol). After stirring at RT for 18 hr, the reaction mixture was diluted with MeCl2 (20 ml). The resultant suspension was filtered and the filtrate passed over SiO2 (90 g). Elution with n-hexane/ethyl acetate (1:1) yielded 17-ethyl-1-hydroxy-14-triisopropylsilyloxy-12-[2'-(4"-o-nitrobenzenesulfonyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (933 mg, 78%) and starting material (206 mg, 20%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([N:16]=[C:17]=S)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([NH2:37])[C:24]([NH2:36])=[CH:25][C:26]=1[N:27]1[CH2:31][CH2:30][CH:29]([CH2:32][N:33]([CH3:35])[CH3:34])[CH2:28]1.CC(C)N=C=NC(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17]2[NH:36][C:24]3[CH:25]=[C:26]([N:27]4[CH2:31][CH2:30][CH:29]([CH2:32][N:33]([CH3:35])[CH3:34])[CH2:28]4)[C:21]([Cl:20])=[CH:22][C:23]=3[N:37]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CC1CCN(c2cc(N)c(N)cc2Cl)C1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CN(C)CC1CCN(c2cc3[nH]c(Nc4cc(CNC(=O)OC(C)(C)C)ccc4Cl)nc3cc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4-Chloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester (111 mg, 0.4 mmol) was added to 4-chloro-5-(3-dimethylaminomethyl-pyrrolidin-1-yl)-benzene-1,2-diamine (100 mg, 0.4 mmol) in DMF (3 mL). The mixture was stirred at rt overnight, DIC (62.4 μL, 0.4 mmol) was added and stirring was continued at 80° C. for 3 h. The mixture was concentrated and the crude was purified by chromatography to give the sub-title compound.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]2[CH:9]3[CH2:18][CH:6]([CH2:7][CH2:8]3)[C:5]1=2)#[N:2]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][N:4]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]2[CH:9]3[CH2:18][CH:6]([CH2:7][CH2:8]3)[C:5]1=2
Reactant: CCOC(=O)c1cc2c(n1CC#N)C1CCC2C1
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)c1cc2c(n1CCN)C1CCC2C1
Reaction time: 8 h
Yield: 50.3 %

Procedure:
A suspension of 334d (4.0 g, 16 mmol) and Raney Ni (400 mg) in methanol (60 mL) was hydrogenated in a Parr apparatus at 50 psi for overnight. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with 20:1 methylene chloride/methanol to give 334e as a yellow solid (2 g, 50%). MS: [M+H]+ 249.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:12]=[CH:11]2)(=[O:5])=[O:4].[CH3:24][N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.[OH-].[K+].O>CO>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:12]=[C:11]2[C:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH:27]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)CCc1ccc2c(ccn2Cc2ccccc2)c1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNS(=O)(=O)CCc1ccc2c(c1)c(C1=CCN(C)CC1)cn2Cc1ccccc1
Temperature: 62.5 °C
Reaction time: 0.25 h

Procedure:
2-(1-benzyl-1H-indol-5-yl)-ethanesulfonic acid methylamide (100 g) was dissolved in methanol (1000 ml) and N-methyl-4-piperidone (100 ml) was added thereto at 25° C. The reaction mass was stirred for 15 minutes and potassium hydroxide (200 g) was added at 25° C. The reaction mass was heated to 60-65° C. for 8 hours and cooled gradually to 25° C. Water (2500 ml) was added slowly and stirred the mixture till solid is obtained. The solid was filtered and dried at 50-55° C. under vacuum to obtain the title compound (Yield: 98 g, HPLC Purity: 99%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:22]1[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[N:23]=1>O1CCCC1>[CH2:1]([C@@H:8]1[NH:9][CH2:10][CH2:11][N:12]([C:22]2[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)[N:23]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: c1ccc(C[C@H]2CNCCN2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN[C@@H](Cc3ccccc3)C2)nc(-c2ccncc2)cc1=O
Yield: 81.4 %

Procedure:
To a solution of (S)-2-benzylpiperazine (48 mg, 0.27 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.10 mL, 0.74 mmol) and then 2-chloro-3-methyl-6-(4-pyridyl)-3H-pyrimidin-4-one (55 mg, 0.248 mmol) at room temperature. After refluxing for 24 h, the resulting mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated sodium bicarbonate aqueous solution, and the organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by a reverse phase chromatography eluting 0.05% TFA in water-acetonitrile to afford (S)-2-(3-benzylpiperazin-1-yl)-3-methyl-6-(4-pyridyl) pyrimidin-4-one (73 mg 81%), which was treated with 4 N hydrogen chloride in ethyl acetate to yield its dihydrochloride salt as a yellow powder.
Reaction SMILES: [Br:1]Br.[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:12]3[N:13]4[CH2:19][CH2:18][N:17]=[C:14]4[S:15][CH:16]=3)[CH:10]=[CH:11][C:4]1=2>ClCCl>[BrH:1].[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:12]3[N:13]4[CH2:19][CH2:18][N:17]=[C:14]4[S:15][C:16]=3[Br:1])[CH:10]=[CH:11][C:4]1=2
Reactant: C1=C(c2ccc3sccc3c2)N2CCN=C2S1
Reactant: BrBr
Solvent: ClCCl
Product: Br
Product: BrC1=C(c2ccc3sccc3c2)N2CCN=C2S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of bromine (0.4 ml) in dichloromethane (5 ml) was added dropwise under nitrogen to a stirred suspension of 3-(benzo[b]thiophen-5-yl)-5,6-dihydroimidazo[2,1-b]thiazole (1.9 g) in dichloromethane (20 ml), then the mixture was stirred at ambient temperature for 30 minutes. The resulting solid was collected by filtration and dried in vacuo at ambient temperature to give 3-(benzo[b]thiophen-5-yl)-2-bromo-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (1.9 g) as a yellow solid which was used without further purification. Concentration of the filtrate yielded a second crop of 3-(benzo[b]thiophen-5-yl)-2-bromo-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (0.4 g) as a yellow solid.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C@@H:21]4[CH2:26][CH2:25][NH:24][CH2:23][C@@H:22]4[O:27][CH3:28])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:8][C:9]=1[F:10].Cl[C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32][N:31]=1.CCN(C(C)C)C(C)C>ClCCl.O1CCOCC1>[F:3][C:4]1[CH:5]=[C:6]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C@@H:21]4[CH2:26][CH2:25][N:24]([C:30]5[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32][N:31]=5)[CH2:23][C@@H:22]4[O:27][CH3:28])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: Cc1cc(Cl)ncn1
Reactant: CO[C@H]1CNCC[C@H]1Nc1nc2c(-c3ccc(F)c(F)c3)cccn2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: CO[C@H]1CN(c2cc(C)ncn2)CC[C@H]1Nc1nc2c(-c3ccc(F)c(F)c3)cccn2n1
Temperature: 130 °C
Yield: 61.5 %

Procedure:
8-(3,4-Difluorophenyl)-N-((3S,4R)-3-methoxypiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine dihydrochloride (28 mg, 64.8 μmol) was extracted with dichloromethane/2 M NaOH. The organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was dissolved in dioxane (0.5 mL) and to this solution 4-chloro-6-methylpyrimidine (9.2 mg, 71.2 μmol) and DIPEA (17.0 μL, 97.2 μmol) were added. Argon was bubbled through the solution for 5 minutes, and then heated in the microwave at 130° C. for 2×30 minutes. After evaporation, purification by chromatography (silica gel, 10 g, 0 to 10% methanol in dichloromethane) afforded the title compound (18 mg, 62%) as an off white foam.
Reaction SMILES: [OH:1][C@H:2]([C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>O.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>[OH:1][C@H:2]([C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][C:13]([C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)=[CH:12][CH:11]=1
Reactant: CN1C(=O)C[C@H](c2ccc(I)cc2)[C@@H]1[C@H](O)c1ccc(-c2ccccc2)s1
Reactant: OB(O)c1ccc(F)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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1C(=O)C[C@H](c2ccc(-c3ccc(F)cc3)cc2)[C@@H]1[C@H](O)c1ccc(-c2ccccc2)s1
Temperature: 25 °C
Yield: 50 %

Procedure:
(±)-(4R*,5R*)-5-[(1S*)Hydroxy(5-phenyl(2-thienyl))methyl]-4-(4-iodophenyl)-1-methylpyrrolidin-2-one prepared as described in Example 21, step 1, (0.100 g, 0.204 mmol), Pd(PPh3)4 (0.025 g, 0.02 mmol) and 4-flourophenylboronic acid (0.037 g, 0.26 mmol) were stirred in anhyd. DME (1 mL). A 1M solution of Na2CO3 (0.55 mL, 0.55 mmol) in water was added and the resulting mixture was heated at the reflux temperature for 18 h. The reaction was cooled to room temperature and diluted with water. The resulting mixture was extracted with EtOAc, dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (75% EtoAc/hex) to yield (±)-(4R*,5R*)-5-[(1S*)hydroxy(5-phenyl(2-thienyl))methyl]-4-[4-(4-fluorophenyl)phenyl]-1-methylpyrrolidin-2-one (0.046 g, 50%) as a yellow solid: mp 191-193° C.; 1H NMR (CDCl3) δ 2.29 (dd, J=14.5, 7.8 Hz, 1H), 2.96-3.06 (m, 1H), 3.30 (s, 3H), 3.85-3.89 (m, 1H), 4.23 (d, J=7.8 Hz, 1H), 4.50 (d, J=6.5 Hz, 1H), 5.99 (d, J=6.1 Hz, 1H), 6.88 (d, J=3.6 Hz, 1H).
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:28])=O>>[CH2:1]([O:10][C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([Cl:28])=[O:22])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCOc1cnc(-c2ccc(C(=O)O)cc2)nc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCOc1cnc(-c2ccc(C(=O)Cl)cc2)nc1

Procedure:
4-(5-n-Nonyloxylpyrimidine-2-yl)benzoic acid (1.88 g) was heated together with excess thionyl chloride for 8 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 4-(5-n-nonyloxypyrimidine-2-yl)benzoic acid chloride.