Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:20])[CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:21][NH:22][C:23]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[N:27]([CH3:35])[C:26]=1[CH3:36])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:19][N:18]([CH3:20])[C@@H:15]1[CH2:16][CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:34][C:30]3[CH:29]=[C:28]4[C:33]([C:25]([C:23]([NH:22][CH3:21])=[O:24])=[C:26]([CH3:36])[N:27]4[CH3:35])=[CH:32][CH:31]=3)[CH:8]=2)=[O:12])[CH2:14]1
Reactant: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](N(C)C)C5)sc34)ccc12
Yield: 40.8 %

Procedure:
This material was prepared by the reaction (3R)-1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]-N,N-dimethylpyrrolidin-3-amine 27a (0.136 g, 0.44 mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.064 g, 0.294 mmole) and Cs2CO3 (0.096 g, 0.29 mmole) in a manner as previously described for example 1 to give a brown colored foam (0.059 g, 17%). 1H NMR (300 MHz, CD3OD) δ8.40 (1H, d, J=5.46 Hz), 7.84 (1H, d, J=6.59 Hz), 7.76 (1H, d, J=8.67 Hz), 7.29 (1H, d, J=2.07 Hz), 6.95 (1H, dd, J=8.57, 2.17 Hz), 6.62 (1H, d, J=5.65 Hz), 4.06 (1H, m), 3.87 (2H, m), 3.63 (3H, s) 3.03 (2H, m), 2.88 (3H, s), 2.57 (3H, s), 2.37 (3H, s), 2.32 (3H, s), 2.23 (1H, m), 1.95 (1H, m); HRMS (MH+): Calcd: 492.2085; Found: 492.2069.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Cl[CH2:10][C:11](=O)[CH3:12]>C(O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([CH3:12])[N:1]=2)[CH:4]=1
Reactant: Nc1ccc(I)cn1
Reactant: CC(=O)CCl
Solvent: CCO
Product: Cc1cn2cc(I)ccc2n1
Yield: 37.5 %

Procedure:
2-Amino-5-iodopyridine (5 g, 22.73 mmol) was dissolved in ethanol (20 mL). Chloroacetone (2.29 mL, 25 mmol) was added and the mixture was heated at reflux overnight. The reaction mixture was evaporated to dryness. The residue was dissolved in DCM (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was dried over MgSO4, filtered and evaporated. The resulting crude residue (4.8 g) was triturated with ethyl acetate to afford pure title compound (2.2 g). The filtrate was concentrated to dryness, yielding an additional quantity of less pure title compound (2.0 g). δH (CDCl3) 7.33 (m, 4H), 2.48 (s, 3H). LCMS: MH+ 259.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[O:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>C(OCC)C>[O:8]1[CH:12]2[CH:11]=[CH:10][CH:9]1[CH:3]1[C:4](=[O:6])[NH:5][C:1](=[O:7])[CH:2]12
Reactant: c1ccoc1
Reactant: O=C1C=CC(=O)N1
Solvent: CCOCC
Product: O=C1NC(=O)C2C3C=CC(O3)C12
Temperature: 25 °C
Reaction time: 70 h
Yield: 46.1 %

Procedure:
A mixture of maleimide (Sigma-Aldrich, St. Louis Mo.; 2.0 g, 0.0206 moles) and furan (Sigma-Aldrich, St. Louis Mo.; 7.49 mL, 0.103 moles) in anhydrous ethyl ether (50 mL) was stirred for 70 hours at room temperature under an argon atmosphere. A white precipitate formed during the reaction and was filtered off and dried under reduced pressure giving 1.57 g of white crystals. NMR (d6-DMSO): Mixture of exo- and endo-isomers (37:63) of ETPI: Exo-3,6-Epoxy-1,2,3,6-tetrahydrophthalimide: 2.85 ppm (s, —CH, 2H), 5.25 ppm (s, —CH, 1H), 6.55 ppm (s, —CH═CH—, 2H), Endo-3,6-Epoxy-1,2,3,6-tetrahydrophthalimide: 3.48 ppm (s, —CH, 2H), 5.11 ppm (s, —CH, 2H), 6.49 ppm (s, —CH═CH, 2H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH2:17][CH3:18])([CH3:16])[C:13](=[O:19])[C:12]=2I)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH2:17][CH3:18])([CH3:16])[C:13](=[O:19])[C:12]=2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([F:21])[CH:23]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: CCC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(I)C1=O
Product: CCC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(c2ccc(OC)c(F)c2)C1=O
Yield: 25.1 %

Procedure:
100 mg of 5-{4-(aminosulfonyl)phenyl}-2-ethyl-4-iodo-2-methyl-3(2H)-furanone was reacted with 80 mg of 3-fluoro-4-methoxybenzeneboronic acid by following a procedure similar to the procedure for the Step 2 of Example 35 to give 25 mg of 5-{4-(aminosulfonyl)phenyl}-2-ethyl-4-(3-fluoro-4-methoxyphenyl)-2-methyl-3(2H)-furanone as a solid. mp: 113-114° C. NMR: δ0.94 (t, J=7.5 Hz, 3H), 1.53 (s, 3H), 1.95 (q, J=7.5 Hz, 2H), 3.91 (s, 3H), 4.96 (br s, 2H), 6.99 (m, 3H), 7.80 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.7 Hz, 2H). IR (cm−1): 3259, 1689, 1608, 1517, 1270, 1159. MS (FAB): 406 (m+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:38])[CH:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:30][CH3:31])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:2]2[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=2)([OH:38])[CH:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:30][CH3:31])=[CH:24][CH:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCC(C(=O)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Reactant: Ic1ccc(I)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(c1ccccc1)C(O)(c1ccc(I)cc1)c1ccc(OCc2ccccc2)cc1
Yield: 108.2 %

Procedure:
A solution of 23.4 g of 1,4-diiodobenzene in 124 ml of tetrahydrofuran is mixed drop by drop at -70° C. under nitrogen with 45 ml of a 1.6 molar butyllithium solution, and it is stirred for 5 more minutes. Then, a solution of 18 g of 1-(4-benzyloxy-phenyl)-2-phenyl-butan-1-one [D. W. Robertson; J. A. Katzenellenbogen; D. J. Ellen; A. Rorke; B. S. Katzenellenbogen, J. Steroid Biochem., 1982, 16, 1-13] in 180 ml of tetrahydrofuran is added in drops, allowed to come to room temperature by completing the cooling, and it is stirred for 1 more hour. For working-up, 60 ml of saturated ammonium chloride solution is added, diluted with diethyl ether, washed neutral with water, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with pentane/diethyl ether. 31.5 g of 1-(4-benzyloxy-phenyl)-1-(4-iodophenyl)-2-phenyl-butan-1-ol is obtained as oil.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2].[CH2:21]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:33]2[CH2:34][CH2:35][N:30]([CH2:21][CH:22]=[CH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31][CH2:32]2)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2]
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)Cl)cc1
Reactant: C(=Cc1ccccc1)CN1CCNCC1
Product: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CC=Cc3ccccc3)CC2)cc1

Procedure:
Analogously to Example 55, 1.5 g of 4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl chloride are reacted with 0.81 g of cinnamylpiperazine (Example 27), yielding 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-[3-phenylprop-2-enyl]piperazine. The hydrochloride thereof melts at 188°-190°.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:21][C:22]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31]CC3C=CC=CC=3)[CH2:24][CH2:23]2)[C:5](=[O:20])[N:6]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([F:19])[C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])[CH:7]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[F:19][C:16]1[CH:15]=[C:10]([CH:9]=[C:8]([N:6]2[CH:7]=[CH:2][N:3]=[C:4]([NH:21][C:22]3([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[OH:31])[CH2:24][CH2:23]3)[C:5]2=[O:20])[C:17]=1[CH3:18])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC3(c4ccccc4OCc4ccccc4)CC3)c2=O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1cc(F)c(C)c(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c1
Temperature: 75 °C
Yield: 94.6 %

Procedure:
To 3-[5-bromo-2-oxo-3-[[1-[2-(phenylmethoxy)phenyl]cyclopropyl]amino]-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzoic acid, methyl ester (Preparation 1i, 9.2 g) in ethanol (400 mL) was added ammonium formate (14.04 g) and 10% Pd/C (1.693 g). The reaction was heated at 75° C. for 1 h, filtered through celite washing the celite with further warm ethanol (100 mL) followed by dichloromethane (2000 mL) and the combined filtrates were evaporated, diluted with dichloromethane (1000 mL) and washed with water, dried (MgSO4) and evaporated to give the subtitle compound (6.16 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]#[N:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:6][N:7]=1.[NH:18]([C:20]([C@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1)=O)[NH2:19]>O>[NH2:1][C:2]1[C:3]([C:16]2[NH:19][N:18]=[C:20]([C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]3)[N:17]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)NN)C1
Reactant: N#Cc1nc(-c2cccc(CO)c2)cnc1N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](c2n[nH]c(-c3nc(-c4cccc(CO)c4)cnc3N)n2)C1
Temperature: 180 °C
Yield: 64.2 %

Procedure:
3-Amino-6-[3-(hydroxymethyl)phenyl]pyrazine-2-carbonitrile (514.0 mg, 2.27 mmol) and 1,1-dimethylethyl (3S)-3-(hydrazinocarbonyl)piperidine-1-carboxylate (1.66g, 6.83 mmol) were combined together and heated to 180° C. for 1-2 h. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (2×35 mL) then dried over anhydrous sodium sulfate and filteration, concentration and purified by MPLC to give 1,1-dimethylethyl (3R)-3-(5-{3-amino-6-[3-(hydroxymethyl)phenyl]pyrazin-2-yl }-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate. (655.0 mg, 64.2% yield): MS (EI) for C23H29N7O3: 452.29 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]([OH:15])=O)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH2:31])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH:31][C:13]([C:11]2[O:12][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][N:10]=2)=[O:15])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(O)c1ncc(Cc2ccccc2)o1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1ncc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-Benzyl-oxazole-2-carboxylic acid (0.86 g, 2.8 mmol), (5-Aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (0.70 g, 2.8 mmol), HATU (1.4 g, 3.6 mmol) and DIPEA (2.0 mL, 11.7 mmol) in 10 mL DMF was stirred at room temperature for 16 h. The mixture was evaporated and the residue was partitioned between ethyl acetate and 1 N aq. HCl. The organic layer was dried over MgSO4 and evaporated in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min). LCMS (method A) RtA=1.719 min; [M+H]+=437.0
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].[Na+].Br[CH2:11][CH2:12][CH2:13][Cl:14]>CC(C)=O>[Cl:14][CH2:13][CH2:12][CH2:11][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: ClCCCBr
Reactant: OC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: OC1CCN(CCCCl)CC1
Yield: 28.1 %

Procedure:
4-Hydroxypiperidine (3 g, 30 mmol), acetone (60 ml, 20 vol), 5M NaOH solution (7.2 ml) and 1-bromo-3-chloropropane (14.2 g, 90 mmol, 3 eq.) were reacted together according to general procedure A to give the title compound (1.5 g, 28%) as a pale yellow oil.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]1[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=1)[CH:16]=[CH:15]2>C1COCC1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]1[C:23]3=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]3[CH:25]=[CH:26][CH:27]=1)[CH:16]=[CH:15]2
Reactant: O=S(=O)(Cl)CCCl
Reactant: COc1ccc2cc(-c3cccnc3N)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2cc(C3=CC=CN4CCS(=O)(=O)N=C34)ccc2c1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 951 mg) in THF (dry) (40 ml) was added 2-chloroethanesulfonyl chloride (1.50 ml) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(6-methoxynaphthalen-2-yl)pyridin-2-amine (1190 mg) in THF (dry) (25 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water. Water and EtOAc were added and the precipitates were collected, washed with water/EtOAc, dried in vacuo to give the title compound (835.3 mg). A part of this was recrystallized from MeCN-THF/IPE.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(O)C>[Cl:1][C:2]1[C:7]([NH:10][NH2:11])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: NN
Reactant: Clc1nccnc1Cl
Solvent: O
Solvent: CCO
Product: NNc1nccnc1Cl
Yield: 90.9 %

Procedure:
2,3-dichloropyrazine (1000 g, 6.7 mol) and hydrazine monohydrate (700 g, 14 mol) were dissolved in absolute ethanol (2 L) and refluxed under N2 overnight. A crystalline precipitate formed, which was collected by filtration, washed with ethanol (1 L), and dried to afford the desired produced as a yellow solid (880 g, 90% yield).
Reaction SMILES: C(OC([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[C@H:9]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:13][C:12](=[O:21])[CH2:11][CH2:10]1)=O)(C)(C)C.[CH3:31][C:32](C)([O-])C.[K+].C(I)C>C1COCC1>[CH2:31]([N:13]1[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:9]([NH:8][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:10][CH2:11][C:12]1=[O:21])[CH3:32]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccccc1CN(C(=O)OC(C)(C)C)[C@@H]1CCC(=O)N[C@@H]1c1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCN1C(=O)CC[C@@H](NCc2ccccc2OC)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.4 %

Procedure:
Under a nitrogen atmosphere in a round-bottom flask were placed 50 mg (0.12 mmol) of cis-5-(N-tert-butoxycarbonyl-2-methoxybenzylamino)-2-oxo-6-phenylpiperidine and 0.2 mL of THF. To the system were added 13.5 mg (0.12 mmol) of potassium tert-butoxide and 20 μL (0.24 mmol) of ethyl iodide. The reaction mixture was stirred at room temperature for 3 hours (during this period, additional potassium tert-butoxide (13.5 mg) and ethyl iodide (20 μL) were added to the system). The mixture was partitioned between methylene chloride and aqueous sodium bicarbonate, the layers were separated and the aqueous phase was extracted with three portions of methylene chloride. The combined organic fractions were dried (sodium sulfate) and concentrated with a rotary evaporator. The crude material was purified by flash column chromatography using 3:97 methanol/chloroform as the eluant to obtain 42 mg of cis-N-ethyl-5-(2-methoxybenzylamino)-2-oxo-6-phenylpiperidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:9]=[CH:10][C:3]=12
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (15 g, 76 mmol) in N,N-dimethyformamide (300 mL) was added NaH (95%, 3.96 g, 99 mmol) at 0° C. The mixture was allowed to warm up to room temperature and was stirred for another 30 minutes. Benzenesulfonyl chloride (11.78 mL, 91 mmol) was added. After stirring at room temperature for 16 hours, the reaction mixture was quenched with aqueous NaHCO3 solution and was extracted with ethyl acetate (three times with 450 mL). The combined organic layers were washed with water, dried over MgSO4, and filtered. The filtrate was concentrated and the residue was separated by flash chromatography on silica gel (Teledyne CombiFlash Rf, 5% of ethyl acetate in dichloromethane) to provide the title compound. MS (ESI+) m/z 337 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[F:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)CC)C>C(#N)C>[F:33][CH:34]1[CH2:39][CH2:38][N:37]([C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[CH:4][CH:3]=2)[CH2:36][CH2:35]1
Reactant: FC1CCNCC1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Br)nc3)cc2)CCN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(N4CCC(F)CC4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 10 h
Yield: 103.1 %

Procedure:
A mixture of 1,1-dimethylethyl (2S)-4-({4-[[(6-bromo-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D108) (0.050 g, 0.0993 mmol), 4-fluoropiperidine (0.055 g, 0.397 mmol) and triethylamine (0.069 mL, 0.497 mmol) in acetonitrile (4 mL) was heated at 85° C. overnight then in a microwave at 140° C. for 10 h. Further portions of 4-fluoropiperidine (5 eq.) and triethylamine (5 eq.) were added and the reaction heated at 170° C. for 2 h. The reaction mixture was concentrated and the residue dissolved in DCM/water. The aqueous layer was further extracted with DCM (×3) and the combined organics were dried (Na2SO4) and concentrated to give the title compound as a yellow oil (0.0538 g). MS (ES): MH+ 526.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[CH2:12])=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4].[Br:24]Br.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:10](/[CH:11]=[CH:12]/[Br:24])=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4]
Reactant: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1/C=C/Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinylpyrimidine-4-carboxylic acid methyl ester (0.720 g, 2.13 mmol) was dissolved in chloroform (20 mL) and bromine (0.511 g, 3.2 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h then concentrated under vacuum. The product was dissolved in dichloromethane (20 mL), treated with triethylamine (0.430 g, 4.26 mmol), stirred at ambient temperature for 2 h, and then concentrated under vacuum. The product was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate gradient) to provide the title compound (0.5 g, 56% yield over two steps) as a white solid, mp 171-173° C.: 1H NMR (CDCl3) δ 7.66 (dd, 1H), 7.22 (dd, 1H), 7.22 (d, 1H), 6.72 (d, 1H), 5.37 (br s, 2H), 4.0 (s, 3H), 3.97 (s, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[C:12]2[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1.[CH2:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]([CH3:31])[CH3:30]>>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][NH:18][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH2:5][CH2:4][NH:3][S:32]([CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:34])=[O:33])[CH:8]=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCN)c2n1
Agent: Cl
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCNS(=O)(=O)CC(C)C)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [8-(2-aminoethoxy)-2-methylquinolin-4-yl]-(3,4-dichlorobenzyl)-amine dihydrochloride and isobutanesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](=[O:13])(=[O:12])[NH:19][CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Cl:15]
Reactant: NCc1ccccc1Cl
Reactant: CC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(Cl)c(S(=O)(=O)NCc2ccccc2Cl)c1

Procedure:
25.5 g of 4'-chloro-3'-chlorosulfonylacetophenone were reacted with 16 g of o-chloro-benzyl amine and 25.5 g of triethyl amine and worked up. Colorless crystals from isopropanol (active charcoal), melting point: 102° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[C:32]([CH3:34])[CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31]([N:40]6[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]6)=[C:32]([CH3:34])[CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: CN1CCNCC1
Reactant: Cc1cc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cnc1F
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cnc1N1CCN(C)CC1
Temperature: 150 °C
Yield: 30.8 %

Procedure:
Compound 436 (200 mg, 0.41 mmol) was dissolved in NMP (2 mL), N-Methyl-piperazine (82 mg, 0.82 mmol) was added in it. The reaction mixture was heated by mw at 150° C. for 90 min. The reaction mixture was concentrated in vacuo, dissolved in DCM (20 mL). And the organic layer was washed by water, dried by Na2SO4, concentrated in vacuo, and separated by prep. TLC (EtOAc/Hexanes=1:3) to give 437 (72.1 mg, yield: 31%). 1H NMR (DMSO-d6, 400 MHz): δ9.759 (s, 1H), 8.58 (s, 1H), 8.47 (t, J=11.8 Hz, 1H), 8.25 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.63-7.53 (m, 2H), 7.29-7.19 (m, 2H), 7.08 (d, J=11.2 Hz, 2H), 4.36 (t, J=4.8 Hz, 2H), 4.20-4.11 (m, 2H), 3.74-3.68 (m, 2H), 3.29 (s, 6H), 2.76 (s, 3H), 2.32 (s, 3H). LC-MS (ESI): m/z=572 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[S:4][C:5]1[CH:6]=[CH:7][C:8]([C:16]([OH:18])=[O:17])=[CH:9][C:10]=1[S:11]2.OS(O)(=O)=O.[CH3:24]O>>[CH3:24][O:17][C:16]([C:8]1[CH:7]=[CH:6][C:5]2[S:4][C:3]3[C:12](=[CH:13][CH:14]=[CH:15][C:2]=3[Br:1])[S:11][C:10]=2[CH:9]=1)=[O:18]
Reactant: CO
Reactant: O=C(O)c1ccc2c(c1)Sc1cccc(Br)c1S2
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2c(c1)Sc1cccc(Br)c1S2
Temperature: 80 °C

Procedure:
To 6-bromo-thianthrene-2-carboxylic acid (9 g, 28 mmol) in methanol (180 ml) was slowly added conc. H2SO4 (5 ml). The milky white suspension was heated to 80° C. until all the solid had gone into solution (2 hrs). The suspension was concentrated in vacuo. Water (100 ml) was added and the organics were then extracted with dichloromethane (3×70 ml), dried over MgSO4 and evaporated in vacuo, yielding to a yellow solid. (4.48 g, 45%). 1HNMR (300 MHz, CDCl3): δH=3.94 (3H, s); 7.13 (1H, t), 7.44 (1H, dd), 7.54 (1H, dd) 7.61 (1H, d), 7.93 (1H, dd), 8.13 (1H, d).