Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C@H:7]1[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@H:11]([CH3:22])[O:10][CH:8]1[OH:9])(=[O:5])[CH3:4].[Cl:23][C:24]([Cl:28])([Cl:27])[C:25]#[N:26]>ClCCl>[Cl:23][C:24]([Cl:28])([Cl:27])[C:25](=[NH:26])[O:9][C@@H:8]1[O:10][C@@H:11]([CH3:22])[C@@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:7]1[O:6][C:3](=[O:5])[CH3:4]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)OC(O)[C@H]1OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](OC(=N)C(Cl)(Cl)Cl)O[C@@H](C)[C@H]1OC(C)=O
Reaction time: 12 h
Yield: 71 %

Procedure:
Sodium hydride (0.25 g, 10.9 mmol) is added under nitrogen and at room temperature to a mixture of 2,3,4-tri-O-acetyl-L-fucopyranose (anomer mixture) (2.00 g, 6.89 mmol) and trichloroacetonitrile (7.0 ml, 70 mmol) in 20 ml of dry dichloromethane. The mixture is stirred for about 12 h and then filtered through kieselguhr and concentrated. After chromatographic purification (petroleum ether/ethyl acetate 3:1), O-(2,3,4-tri-O-acetyl-α-L-fucopyranosyl) trichloroacetimidate (3) is obtained in a yield of 71% (2.13 g).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23]O)[C:12]2=[O:25])[CH2:10][CH2:9]1)=[O:7].[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1>>[F:33][C:31]([F:32])([F:34])[C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([C:2]([F:36])([F:1])[F:35])[CH:30]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23][N:37]3[CH:41]=[CH:40][N:39]=[CH:38]3)[C:12]2=[O:25])[CH2:26][CH2:27]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCO)CN2c1ccccc1
Reactant: c1c[nH]cn1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCn1ccnc1)CN2c1ccccc1

Procedure:
The title compound, MS: m/e=566.2 (M+H+), was prepared in accordance with the general method of example 49 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy-ethyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and imidazole.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:12]1([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:21][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(C=NS(=O)(=O)c2ccccc2)cc1

Procedure:
In a manner similar to Example 2, 1.00 g (6.6 mmol) of 4-carboxybenzaldehyde, 1.05 g (6.6 mmol) of benzenesulfonamide and 20 mg of TsOH in 120 mL of toluene were heated for 2.5 hours to afford 1.82 g (90%) of SULF-2 as a white powder; IR (Nujol) 3400-2400 (br), 1680, 1605, 1283, 1160, 1083 cm-1 ; 1H NMR (DMSO-d6, TMS ext std) δ 9.17 (s, 1), 8.1-7.3 (m, 9).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:3][CH2:2]1.Br[CH:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2.C(Cl)(Cl)Cl.[OH-].[Na+]>C(#N)C>[CH:25]1[C:24]2[CH:23]([N:1]3[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH2:3][CH2:2]3)[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Reactant: BrC1c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C2c3ccccc3-c3ccccc32)CC1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
8.0 g (27.7 mmol) N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propionamide and 5.6 g (55.3 mmol) TEA are placed in 100 ml acetonitrile and cooled to ca. 0° C. under moisture exclusion. 6.8 g (27.7 mmol) 9-bromofluorene are added in solid form and the mixture is stirred two days at ca. 65° C. and two days at RT. Subsequently, the solvent is drawn off under vacuum to a large extent, and the residue is dispersed between CHCl3 and 10% NaOH. The organic phase is washed twice with water and dried over sodium sulfate. After the removal of the solvent, the residue is chromatographically purified over silica gel with CHCl3/CH3OH (98/2 to 94/6) and crystallized from 30 ml acetonitrile after drawing off the solvent. Colorless crystals with an MP of 131-132° C.; yield 2.5 g (20%).
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[CH2:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[NH:29][CH2:28][CH2:27][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:24]=3[CH:34]=2)=[CH:16][CH:15]=1)[CH3:9]>C1COCC1>[CH2:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH:1]=[O:3])[CH2:28][CH2:27][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:24]=3[CH:34]=2)=[CH:18][CH:19]=1)[CH3:9]
Reactant: CC(=O)O
Reactant: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Solvent: O=CO
Solvent: C1CCOC1
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To anhydrous acetic acid (0.25 ml) was added formic acid (0.13 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at 50° C. for 2 hours. To the mixture was added THF (2 ml) and then was added dropwise, under ice-cooling, a solution of methyl 7-[4-(2-ethoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25 g) in THF (10 ml), and the mixture was stirred at room temperature overnight. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.O.[OH-].[Li+].[F:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([O:27][CH2:28][CH2:29][CH2:30]Br)=[CH:21][C:22]([CH3:26])=[N:23]2)=[CH:18][CH:17]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:30][CH2:29][CH2:28][O:27][C:20]2[C:19]3[C:24](=[CH:25][C:16]([F:15])=[CH:17][CH:18]=3)[N:23]=[C:22]([CH3:26])[CH:21]=2)=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: CCc1nc(N)nc(N)c1O
Reactant: Cc1cc(OCCCBr)c2ccc(F)cc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(N)nc(N)c1OCCCOc1cc(C)nc2cc(F)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A mixture of 2,4-diamino-6-ethyl-5-hydroxypyrimidine (0.5395 g, 3.5 mmol) and lithium hydroxide monohydrate (0.294 g, 7.0 mmol) in DMF (10 mL) was stirred at 25° C. for 1 hour after that 3-(7-fluoro-2-methylquinolin-4-yloxy)propyl bromide (1.043 g, 3.5 mmol) was added to the reaction mixture and the reaction mixture was left to stir at 25° C. overnight. Two thirds of the DMF was evaporated under vacuum and reaction mixture was poured in water, solid was separated by filtration and dried in oven at 80° C. The crude product was purified by column chromatography on silica gel (4% MeOH: 96% CH2Cl2 as eluent). The product was obtained as white crystalline solid (0.6629 g, 51%). 1H NMR (400 MHz, DMSO-d6): 0.89 (3H, t, J=7.5 Hz), 2.28 (4H, m), 2.60 (3H, s), 3.85 (2H, t, J=5.9 Hz), 4.42 (2H, t, J=5.9 Hz), 5.57 (2H, s), 6.15 (2H, s), 6.99 (1H, s), 7.39 (1H, dt, J=8.8, 2.5 Hz), 7.57 (1H, dd, J=10.8, 2.5 Hz), 8.15 (1H, dd, J=9.1, 6.4 Hz).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:25])[C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=[C:12](Br)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][C:35]3[CH:45]=[C:44]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[C:43](B4OC(C)(C)C(C)(C)O4)=[CH:42][C:36]=3[C:37]=2[C:38]([NH:40][CH3:41])=[O:39])=[CH:29][CH:28]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([NH:8][C:9](=[O:25])[C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=[C:12]([C:43]2[C:44]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])=[CH:45][C:35]3[O:34][C:33]([C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)=[C:37]([C:38](=[O:39])[NH:40][CH3:41])[C:36]=3[CH:42]=2)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)c1nc(Br)ccc1OCc1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)NCc4ccccc4)n3)cc12
Temperature: 110 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a solution of N-benzyl-3-(benzyloxy)-6-bromopicolinamide (107 mg, 0.27 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (prepared according to previous patents, 117 mg, 0.23 mmol) and K3PO4.3H2O (187 mg, 0.70 mmol) in dioxane/H2O (3 mL) were added Pd2(dba)3 (11 mg, 0.01 mmol) and X-Phos (11 mg, 0.03 mmol) under N2. The mixture was stirred at 110° C. for 1 hour. Then it was filtered and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (DCM:MeOH=50:1) to afford the product of N-benzyl-3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinamide (100 mg, yield: 61.7%). 1H-NMR (CD3OD, 400 MHz) δ 7.91˜7.94 (m, 2H), 7.83 (s, 1H), 7.77 (s, 1H), 7.67˜7.72 (m, 2H), 7.43˜7.45 (m, 2H), 7.29˜7.33 (m, 5H), 7.20˜7.24 (m, 5H), 5.23 (s, 2H), 4.54 (s, 2H), 3.15 (s, 3H), 2.89 (s, 3H), 2.87 (s, 3H). MS (M+H)+: 693.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][NH2:31]>C(#N)C>[O:13]1[C:14]2[CH:18]=[CH:17][S:16][C:15]=2[C:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[O:4][CH2:3][CH2:2][NH:31][CH2:30][C:26]2[S:25][CH:29]=[CH:28][CH:27]=2)=[N:12]1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OCCNCc2cccs2)cc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, C-Thiophen-2-yl-methylamine and acetonitrile essentially as described above in example 18 except that the column is eluted using a graded solvent mixture of 40% ethyl acetate in heptane, to 100% ethyl acetate. Purity by LC/MS (APCI)=100%, [M+H]+=357.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9](O)[CH:10]([OH:15])[CH2:11][CH2:12][CH2:13][CH3:14]>C1(C)C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[CH2:11]([CH:10]1[O:15][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH2:9]1)[CH2:12][CH2:13][CH3:14]
Reactant: O=Cc1ccccc1
Reactant: CCCCC(O)CO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: CCCCC1COC(c2ccccc2)O1
Temperature: 25 °C
Yield: 102.2 %

Procedure:
A solution of benzaldehyde (5.1 mL, 50.0 mmol), 1,2-hexanediol (6.5 g, 55.0 mmol), and camphorsulfonic acid (0.58 g, 2.5 mmol) in 50 mL of toluene was heated to reflux (Dean-Stark) with azeotropic removal of water. When the theoretical amount of water was distilled (4.5 hours), the mixture was cooled to room temperature and diluted with 80 mL of ether. The solution was extracted with 2M aqueous sodium carbonate, water and brine, dried (Na2SO4), filtered, and concentrated to provide 10.54 g (102%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=O)[NH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[N:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N:42]1([CH2:47][CH2:48][O:49][CH2:50][CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl>[C:1]1([C:7]2[C:15]3[C:14]([N:54]4[CH2:55][CH2:56][CH:51]([CH2:50][O:49][CH2:48][CH2:47][N:42]5[CH2:46][CH2:45][CH2:44][CH2:43]5)[CH2:52][CH2:53]4)=[N:13][C:12]([C:17]([F:20])([F:19])[F:18])=[N:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCN(CCOCC2CCNCC2)C1
Reactant: O=c1[nH]c(C(F)(F)F)nc2scc(-c3ccccc3)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: FC(F)(F)c1nc(N2CCC(COCCN3CCCC3)CC2)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
5-Phenyl-2-(trifluoromethyl)thieno[2,3-d]pyrimidin-4-one (0.20 g, 0.67 mmol) was stirred in dichloromethane (5 mL) at 0° C. Pyridine (0.11 mL, 1.3 mmol) was added, followed by trifluoromethanesulfonic anhydride (0.14 mL, 0.81 mmol) and stirring continued for 30 mins and the mixture allowed to warm to room temperature. 4-(2-Pyrrolidin-1-ylethoxymethyl)piperidine (0.29 g, 1.3 mmol) was added and the reaction stirred for 1 hour at room temperature. The reaction mixture was diluted with DCM (20 mL), washed with water (20 mL), dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by flash chromatography, eluting with a gradient of petroleum ether to 50/50 petroleum ether/ethyl acetate to afford 5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]-2-(trifluoromethyl)thieno[2,3-d]pyrimidine (0.16 g). LCMS: purity 98%, RT=4.28 min, M+1=491.2
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].[F:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:16]=O)=[CH:12][NH:13]2)=[CH:9][C:8]=1[O:18][CH3:19].C([O-])(=O)C.[NH4+]>>[F:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH3:5])=[CH:12][NH:13]2)=[CH:9][C:8]=1[O:18][CH3:19]
Reactant: COc1cc2c(C=O)c[nH]c2cc1F
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1cc2c(C=C(C)[N+](=O)[O-])c[nH]c2cc1F
Temperature: 100 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
A mixture of nitroethane (44 ml, 611 mmol), 6-fluoro-5-methoxy-1H-indole-3-carbaldehyde (11.8 g, 61 mmol), and ammonium acetate (1.78 g, 23 mmol) is stirred at 100° C. for 3 hours, allowed to cool, and is filtered to give 14 g of 6-fluoro-5-methoxy-3-(2-nitro-propenyl)-1H-indole (92%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.S(=O)(=O)(O)[OH:14].[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH2:12])=[O:14])[CH2:9][CH2:10]2)=[N:6][CH:7]=1
Reactant: N#CC1(c2ccc(Br)cn2)CC1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)C1(c2ccc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(5-bromo-pyridin-2-yl)-cyclopropanecarbonitrile (0.18 g) and sulfuric acid (95%, 1.8 mL) was stirred at room temperature overnight. The solution was poured on crushed ice and the resulting solution was basified using 4 M aqueous NaOH solution. The solution was extracted with dichloromethane, the combined extracts were dried (Na2SO4), and the solvent was evaporated to give the title compound as a colorless solid. Yield: 0.20 g (quantitative); LC (method 2): tR=2.38 min; Mass spectrum (ESI+): m/z=241/243 (Br) [M+H]+.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([C:18](=[O:28])[N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH3:20])=[C:13]([S:29][CH2:30][CH3:31])[N:12]=2)[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-].Cl>CO.C1COCC1>[CH2:30]([S:29][C:13]1[N:12]=[C:11]([N:8]2[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)[CH:16]=[C:15]([CH3:17])[C:14]=1[C:18](=[O:28])[N:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[CH3:20])[CH3:31]
Reactant: CCSc1nc(N2CCC(C(=O)OC)CC2)cc(C)c1C(=O)N(C)c1cccc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCSc1nc(N2CCC(C(=O)O)CC2)cc(C)c1C(=O)N(C)c1cccc(F)c1
Temperature: 70 °C
Yield: 81.2 %

Procedure:
A solution of 146 mg (0.32 mmol) 1-[6-Ethylsulfanyl-5-[(3-fluorophenyl)-methyl-carbamoyl]-4-methyl-pyridin-2-yl]-piperidine-4-carboxylic acid methyl ester (example 13) in a MeOH/THF mixture (1:1 v/v, 2 ml) was treated with 1 ml (2.0 mmol) 2M aq. LiOH sol. and heated to 70° C. for 16 h. Subsequently pH 3-4 was adjusted with a 2M aq. HCl sol., followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. As residue 112 mg (0.26 mmol, 79%) 1-[6-Ethylsulfanyl-5-[(3-fluorophenyl)-methyl-carbamoyl]-4-methyl-pyridin-2-yl]-piperidine-4-carboxylic acid (example 14) were obtained. [M+H]+432.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])=[C:4]([CH2:15][CH3:16])[CH:3]=1>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2=[O:14])=[C:4]([CH2:15][CH3:16])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C1C(=O)C=CC1=O
Agent: [Zn]
Solvent: CC(=O)O
Product: CCc1cc(Br)ccc1C1C(=O)CCC1=O

Procedure:
To a suspension of zinc dust (2.0 g, 0.03 mol) in glacial acetic acid (30 ml) is added a solution of 2-(4-bromo-2-ethylphenyl)cyclopent-4-ene-1,3-dione (1.20 g, 0.0043 mol) in glacial acetic acid (20 ml) dropwise over 10 minutes. After stirring of the resultant suspension for 20 hours at room temperature the reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated under reduced pressure to afford 2-(4-bromo-2-ethylphenyl)cyclopentane-1,3-dione as a pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([CH:7]=[CH2:8])[NH:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].B1C2CCCC1CCC2.[OH-:22].[Na+].OO>C1COCC1>[Cl:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][OH:22])[NH:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: [OH-]
Reactant: C=Cc1cc(Cl)c(C(=O)OC)[nH]1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c(CCO)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
A stirred solution of methyl 3-chloro-5-ethenyl-1H-pyrrole-2-carboxylate (0.100 g, 0.539 mmol) in THF (5 mL) was treated with 9-BBN (5.39 mL, 2.15 mmol). The reaction was stirred at RT overnight. The reaction mixture was treated with 1 mL of 1N NaOH and 1 mL of 30% H2O2 and stirred. The reaction mixture was partitioned between EtOAc and a solution of sodium metabisulfite. The organic layer was separated, dried over MgSO4 and evaporated to a residue. The residue was taken up in 1N LiOH (1 mL), MeOH (1 mL) and THF (1 mL) and heated until the acid was formed as seen on TLC. The reaction was evaporated, acidified and extracted with EtOAc. The organic layer was separated and dried over MgSO4 to afford methyl 3-chloro-5-(2-hydroxyethyl)-1H-pyrrole-2-carboxylate (0.028 g, 27%) as a solid. LCMS: m/z=188.0 (M−1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]([O:10]CC)=[O:9])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:4]=1.[CH3:21][O-:22].[Na+]>CO.O>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([N:5]2[C:6]([C:8]([OH:10])=[O:9])=[CH:7][C:3]([CH2:2][O:22][CH3:21])=[N:4]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cc(CBr)nn1-c1ccc(OC)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCc1cc(C(=O)O)n(-c2ccc(OC)cc2)n1
Yield: 61 %

Procedure:
Ethyl 3-(bromomethyl)-1-(4-methoxyphenyl)-1H-pyrazole-5-carboxylate (0.50 g, 1.47 mmol) is dissolved in 12 mL of 0.5 M NaOMe in methanol and heated to reflux for 14 hours. The reaction mixture was cooled and reduced to 1/10 original volume. The reaction mixture was dissolved in 20 mL of water and extracted with EtOAc. The aqueous mixture was acidified with 1N HCl and extracted with EtOAc to give 0.236 g (61%) of desired product. A mixture of ethyl and methyl esters (˜0.05 g) was found in the first EtOAc extract. 1H NMR (CDCl3): δ7.32 (d, J=8.8, 2H); 7.11 (s, 1H); 6.94 (d, J=8.8, 2H); 4.54 (s, 2H); 3.85 (s, 3H); 3.44 (s, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[N:10]1([C:16]2[C:17]3[C:24](B4OC(C)(C)C(C)(C)O4)=[CH:23][N:22]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[N:10]1([C:16]2[C:17]3[C:24]([C:2]4[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=4)=[CH:23][N:22]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: CC1(C)OB(c2cn(COCC[Si](C)(C)C)c3ncnc(N4CCOCC4)c23)OC1(C)C
Reactant: N#Cc1cccc(Br)n1
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: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(-c2cccc(C#N)n2)c2c(N3CCOCC3)ncnc21
Temperature: 120 °C

Procedure:
To a solution of 6-bromopyridine-2-carbonitrile (80 mg, 0.44 mmol) and 4-(morpholin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (P2) (241 mg, 0.523 mmol) in 1,4-dioxane (2.5 mL) and water (0.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (51 mg, 44 μmol) and sodium carbonate (140 mg, 1.32 mmol). The reaction mixture was heated at 120° C. under microwave irradiation for 15 minutes, then diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo; purification via preparative thin layer chromatography (Eluent: 1:1 petroleum ether/ethyl acetate) afforded the product as a brown oil. Yield: 110 mg, 0.252 mmol, 57%. 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.84-7.93 (m, 2H), 7.74 (s, 1H), 7.59 (dd, J=7.0, 1.2 Hz, 1H), 5.66 (s, 2H), 3.56-3.65 (m, 6H), 3.34-3.40 (m, 4H), 0.93 (dd, J=8.3, 8.0 Hz, 2H), −0.05 (s, 9H).
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.[CH3:31][NH2:32]>>[CH3:31][N:32]1[CH:2]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][N:21]([C:24]4[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=4)[CH2:22][CH2:23]3)=[CH:10][CH:9]=2)[CH2:3][CH2:4][C:5]1=[O:7]
Reactant: CN
Reactant: Cc1ccc(N2CCN(CCCCc3ccc(C(=O)CCC(=O)O)cc3)CC2)cc1
Product: Cc1ccc(N2CCN(CCCCc3ccc(C4CCC(=O)N4C)cc3)CC2)cc1

Procedure:
4-Oxo-4-[4-(4-(4-(4-methylphenyl)piperazin-1-yl)butyl)phenyl]butyric acid and methylamine are reacted together to give N-methyl-5-[4-(4-(4-(4-methylphenyl)piperazin-1-yl)butyl)phenyl]pyrrolidin-2-one.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:15]([C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([SH:25])=[N:22][C:21]=2[CH:26]=1)#[N:16]>>[N:5]1([C:3](=[O:4])[CH2:2][S:25][C:23]2[S:24][C:20]3[CH:19]=[CH:18][C:17]([C:15]#[N:16])=[CH:26][C:21]=3[N:22]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(CCl)N1CCCc2ccccc21
Reactant: N#Cc1ccc2sc(S)nc2c1
Product: N#Cc1ccc2sc(SCC(=O)N3CCCc4ccccc43)nc2c1
Yield: 74 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 2-mercaptobenzo[d]thiazole-5-carbonitrile (14) as the nucleophile to yield 32 as a white solid (74%): MS m/z: 366 (M+H)+. Anal. Calcd. For, C19H15N3OS2: C, 62.44; H, 4.14; N, 11.50; S, 17.55. Found: C, 62.47; H, 4.36; N, 11.35; S, 17.65.