Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:25][CH:24]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21][CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].ClC1C=CC=C(C(OO)=[O:46])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:23]2[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:25][CH:24]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21](=[O:46])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]1=[O:14]
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCSC4)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)C4)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the compound obtained in Example 112 (2.7 g) in methylene chloride (50 ml) was added m-chloroperbenzoic acid (70%, 1.2 g) under ice-cooling and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and then water and dried (MgSO4) and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain tert-butyl (4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno(2,3-b]pyridin-4-yl}phenoxy)-acetate from the fraction eluted with ethyl acetate. It was recrystallized from ethyl acetate-hexane (2.2 g, 79%). Colorless prisms. Melting point 175-176° C.
Reaction SMILES: Cl.Cl.Cl.Cl.[N:5]1([C@H:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([C@H:21]4[CH2:26][NH:25][CH2:24][CH2:23][NH:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.Cl[C:35]1[N:40]([CH3:41])[C:39](=[O:42])[CH:38]=[C:37]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)[N:36]=1>O1CCCC1>[N:5]1([CH:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([C@@H:21]4[NH:22][CH2:23][CH2:24][N:25]([C:35]5[N:40]([CH3:41])[C:39](=[O:42])[CH:38]=[C:37]([C:43]6[CH:44]=[CH:45][N:46]=[CH:47][CH:48]=6)[N:36]=5)[CH2:26]4)=[CH:19][CH:20]=3)[CH2:11]2)[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: c1cc(N2CC[C@H](N3CCCC3)C2)ccc1[C@H]1CNCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCN[C@@H](c3ccc(N4CCC(N5CCCC5)C4)cc3)C2)nc(-c2ccncc2)cc1=O
Reaction time: 24 h
Yield: 82.4 %

Procedure:
To a suspension of (S)-2-(4-((S)-3-(pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl) piperazine tetrahydrochloride (98 mg, 0.22 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.20 mL, 1.40 mmol) and 2-chloro-3-methyl-6-(4-pyridyl)-3H-pyrimidin-4-one (44 mg, 0.20 mmol) at room temperature. After stirring for 24 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and sodium bicarbonate aqueous solution, and the solution was passed through CHEM ELUT CE1010 (manufactured by VARIAN). The filtrate was concentrated, and the resulting crystals were washed in a mixture of diisopropyl ether and ethanol to afford (S)-2-(3-(4-(3-(pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl)piperazin-1-yl)-3-methyl-6-(4-pyridyl)pyrimidin-4-one (80 mg, 82%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2].[C:16](=[O:18])=[O:17].CC(C)=O.C([Li])CCC.C(=O)=O.[OH-].[Na+]>C(OCC)C.O>[C:1]([O:5][C:6]([NH:7][C:8]1[C:13]([C:16]([OH:18])=[O:17])=[CH:12][N:11]=[CH:10][C:9]=1[Cl:14])=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1Cl
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1c(Cl)cncc1C(=O)O
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
(3-Chloro-pyridin-4-yl)-carbamic acid tert-butyl ester (1.50 g) was dissolved in dry diethyl ether (35 mL), N,N,N′,N′-tertamethylenethylendiamine (2.35 mL) was added and the reaction mixture was cooled in a dry ice/acetone cool bath to −78° C. n-Butyl lithium (9.9 mL, 1.59M in hexane) was added to the suspension, the cool bath was replaced by a sodium chloride/ice mixture and the reaction mixture was stirred at −10° C. for 1.5 h. The suspension was slowly poured on crushed dry ice (2.0 g) in dry diethyl ether (20 mL) and stirred for 1 h. Water was added and the pH was adjusted to −12 by addition of 2N sodium hydroxide solution. The aqueous layer was washed 2× with MTB-ether, 2 M hydrochloric acid was added to the aqueous layer and the pH was adjusted to −2 and the aqueous layer was 3× extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum to afford 1.03 g of the title compound of the formula
Reaction SMILES: Br[CH:2]([CH3:37])[C:3]([C:5]1[CH:6]=[C:7]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C:8](=[O:22])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:10]=1[CH3:11])=O.[C:38]([NH2:41])(=[O:40])[CH3:39].C1(C)C(C)=CC=CC=1.OS(O)(=O)=O>O.CC#N>[CH3:39][C:38]1[O:40][C:2]([CH3:37])=[C:3]([C:5]2[CH:6]=[C:7]([C:23]([NH:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=3)=[O:24])[C:8](=[O:22])[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[C:10]=2[CH3:11])[N:41]=1
Reactant: CC(N)=O
Reactant: Cc1c(C(=O)C(C)Br)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CC#N
Product: Cc1nc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)c(C)o1
Reaction time: 2 h
Yield: 36.6 %

Procedure:
A mixture of 5-(2-bromopropanoyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide (130 mg, 0.22 mmol), acetamide (262 mg, 4.4 mmol), xylene (300 μl) and conc. H2SO4 (10 μl) was heated with stirring for 2 h. The reaction was diluted with water and CH3CN and purified on preparative HPLC, affording the title compound (45 mg, 36%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:25])[CH:6]=[C:7]([CH3:24])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]([Cl:37])=[CH:34][CH2:35]Cl>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[C:5]([O:25][CH2:35][CH:34]=[C:33]([Cl:37])[Cl:32])[CH:6]=[C:7]([CH3:24])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][N:15]=1)[CH3:2]
Reactant: CCc1cc(O)cc(C)c1OCCCOc1ccc(C(F)(F)F)cn1
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(OCC=C(Cl)Cl)cc(C)c1OCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 0.7 g of 3-ethyl-5-methyl-4-[3-(5-trifluoromethyl-2-pyridyloxy)propyloxy]phenol and 0.27 g of potassium carbonate, to which a solution of 0.34 g of 1,1,3-trichloropropene dissolved in 5 ml of N,N-dimethylformamide was added dropwise, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice-water, and extracted twice with 100 ml of diethyl ether. The combined diethyl ether was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude produce was subjected to silica gel chromatography, which afforded 0.6 g of 3-ethyl-5-methyl-4-[3-(5-trifluoromethyl-2-pyridyloxy)propyloxy]-1-(3,3-di-chloro-2-propenyloxy)benzene (65% yield), nD23.0 1.5188.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:22]2[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Reactant: Brc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 80 °C
Yield: 58.5 %

Procedure:
4-tert-Butoxycarbonylamino-phenylboronic acid (500 mg, 2.11 mmol), 1,4-dibromo-benzene (2.00 g, 8.44 mmol) Pd(PPh3)4 (122 mg, 0.106 mmol) and a 2 M aqueous solution of potassium carbonate (4.2 mL, 8.44 mmol) were degassed in 1,2-dimethoxyethane (20 mL) for 10 min. The stirred suspension was heated to 80° C. for 3 hours then diluted with ethyl acetate (60 mL) and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by silica column chromatography (0% to 20% EtOAc/hexanes) to provide (4′-Bromo-biphenyl-4-yl)-carbamic acid tert-butyl ester (430 mg, 59%).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH3:25])[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15]([OH:21])=[C:14]([CH:22]([CH3:24])[CH3:23])[CH:13]=1)=[O:11].Cl[S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=1)(=[O:34])=[O:33]>>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH3:25])[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([CH:18]([CH3:19])[CH3:20])[C:15]([O:21][S:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=2)(=[O:34])=[O:33])=[C:14]([CH:22]([CH3:23])[CH3:24])[CH:13]=1)=[O:11]
Reactant: Cc1oc(Cc2ccccc2Br)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1oc(Cc2ccccc2Br)c(C(=O)c2cc(C(C)C)c(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C(C)C)c2)c1C
Yield: 46.7 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone (0.300 g, 0.639 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.197 g, 0.831 mmol). Purification on Dynamax C18 (90% CH3CN/H2O) gave 0.20 g (47%) of the title compound as a yellow solid, mp 90-95° C. 1H NMR (DMSO-d6) δ 1.06 (d, 12 H), 1.85 (s, 3 H), 2.19 (s, 3 H), 3.07 (septet, 2 H), 3.91 (s, 2 H), 7.14-7.16 (m, 2 H), 7.29 (dt, 1 H), 7.44 (d, 1 H), 7.47-7.52 (m, 4 H), 8.05 (d, 1 H). IR (KBr) 3400, 2950, 1690, 1380 and 1190 cm-1. mass spectrum (-ESI) m/z 667/669 (M -H). Anal. Calcd. for C33H33BrO8S: C, 59.19; H, 4.97; N, 0.00. Found: C, 58.82; H, 5.13; N, 0.13.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C1CCN2C(=NCCC2)CC1.CS(C)=O.[CH2:20]([O:22][C:23](=[O:30])[CH:24]=[CH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:21]>C(Cl)Cl>[CH2:20]([O:22][C:23](=[O:30])[CH2:24][CH:25]([CH2:4][N+:1]([O-:3])=[O:2])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:21]
Reactant: CCOC(=O)C=CCC(C)C
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)CC(CC(C)C)C[N+](=O)[O-]

Procedure:
7.0 g of nitromethane and 3.3 mL of DBU (1,8-diazabicyclo[5.4.0]undece-7-en) were added to the DMSO solution of α,β-unsaturated ester VII. The reaction mixture was stirred until complete conversion was detected by GC. 20 mL of CH2Cl2 were added and the resulting mixture was washed with 2×20 mL of 1M aqueous H2SO4 and 1×20 mL of 0.5M aqueous NaHCO3. The organic layer was dried and the solvent was removed under reduced pressure. 3.6 g of γ-nitroester VIII were obtained (yield over two steps: 75%).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=NC=C1.ClC1C=CC=CC=1C(=O)C1C=[C:24]([N+:26]([O-])=O)[CH:23]=CC=1N1C(CN2C(=O)C3=CC=CC=C3C2=O)=NN=C1CN(C)C.O.NN>C(O)C>[NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:23][CH:24]=[N:26]1
Reactant: CN(C)Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Reactant: C1=CNc2ccccc2C=N1
Agent: NN
Solvent: CCO
Solvent: O
Product: C1=Cc2ccccc2NN=C1

Procedure:
In the manner [1,4]benzodiazepin. in Example 27, 2'-chloro-5-nitro2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-nitro-1-[(dimethylamino)methyl] -6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]1,4]benzodiazepin.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.N[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][N:22]1C(OC(C)(C)C)=O.C([N:36](C(C)C)C(C)C)C>O1CCCC1>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:36][CH:25]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:26]3)=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCCC1N
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Solvent: C1CCOC1
Product: Clc1nc(SCc2ccccc2)nc2nc(NC3CCNCC3)sc12
Reaction time: 16 h

Procedure:
A solution of the product from Example 219 (0.3 g) in tetrahydrofuran (2 ml) containing 4 amino-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0. 161 g) and N-ethyldiisopropylamine (0.5 ml) was stirred for 16 hours before evaporating to dryness. The residue was taken into dichloromethane (30 ml) and trifluoroacetic acid (3 ml) added. The solution was stirred for 30 minutes then concentrated to give the title compound (310 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C[C@@H]2CNCCN2Cc2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)N1CCN(Cc2ccccc2)[C@H](Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a stirred solution of (2R)-1,2-dibenzylpiperazine (2.0 g; 7.5 mmol) in dichloromethane (30 ml), methanesulfonyl chloride (0.86 g; 7.5 mmol) was added and the mixture was stirred at ambient temperature for 1 h. Potassium carbonate (1.1 g) was added and stirring was continued for another hour. Dichloromethane (20 ml) and water (10 ml) were added and the phases were separated. The organic phase was washed with water (10 ml) and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 2.2 g of (2R)-1,2-dibenzyl-4-methanesulfonylpiperazine.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:3][CH2:6][C:7]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: OCc1cccc2cc(-c3ccccc3)oc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: ClCc1cccc2cc(-c3ccccc3)oc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Thionyl chloride (0.65 ml) is added to a mixture of 7-hydroxymethyl-2-phenylbenzofuran (1.0 g), pyridine (0.38 ml) and methylene chloride (8 ml) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. The mixture is concentrated under reduced pressure to remove solvent, and the residue is dissolved in ethyl acetate. The solution is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is recrystallized from n-hexane, whereby 7-chloromethyl-2-phenylbenzofuran (0.9 g) is obtained. Yield: 83%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[CH3:20])=[O:11])=[CH:2]1.[CH3:21][I:22]>C1C=CC=CC=1>[I-:22].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N+:15]2([CH3:21])[CH3:20])=[O:11])=[CH:2]1
Reactant: CN1CCCCC1COC(=O)c1c[nH]c2ccccc12
Reactant: CI
Solvent: c1ccccc1
Product: C[N+]1(C)CCCCC1COC(=O)c1c[nH]c2ccccc12
Product: [I-]
Yield: 71.8 %

Procedure:
In benzene (10 ml) was dissolved by heating (1-methyl-2-piperidyl)methyl 1H-indole-3-carboxylate (0.10 g, 0.37 mmol) followed by addition of a benzene (5 ml) solution of methyl iodide (0.14 g, 0.99 mmol). The mixture was allowed to react in a stainless steel sealed tube at 100° C. for 2 hours. The reaction tube was cooled, and a reaction product was scraped out by a spatula, washed with IPE and dried (70° C.) under reduced pressure to give 0.11 g of the title compound as a yellow foamy solid. m.p. 95°-97° C.;
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.[C:11]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of benzo[d][1,3]dioxol-5-ol (5.000 g; 36.20 mmol), and K2CO3 (5.503 g; 39.80 mmol) in anh. acetone (100 ml) was stirred at rt, under nitrogen, for 1 h. Iodomethane (28.258 g; 199.00 mmol) was then added, and the resulting mixture was heated at reflux, under nitrogen, for 20 h. After cooling to rt, the reaction mixture was filtered over a pad of celite, and the filtrate was concentrated to dryness under reduced pressure. Et2O and water were added, and the organic layer was further washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 5-methoxybenzo[d][1,3]dioxole as a yellow oil. LC-MS (conditions A): tR=0.66 min.; no ionisation.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.Cl.[NH2:14][CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1.C(Cl)CCl.C(OCC)(=O)C>CCCCCC>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][CH2:15][NH:14][C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:12][CH:11]=2)=[CH:18]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1ccc(O)cc1)NCCc1c[nH]c2ccccc12

Procedure:
(E)-N-(2-(1H-indol-3-yl)ethyl)-3-(4-hydroxyphenyl) acrylamide (2e) was synthesized by the condensation of 4-hydroxy cinnamic acid (150 mg, 0.914 mmol) and tryptamine hydrochloride (215 mg, 1.09 mmol) using standard EDC coupling method. 2e was isolated as yellowish solid (178 mg, 64%) by elution with 45% ethyl acetate in hexane. Rf: 0.593 (80% ethyl acetate in hexane); mp: 135-138° C.;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][CH:10](OCC)OCC)=[C:4]([NH:17][CH2:18][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[OH-].[NH4+]>Cl.C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]2[CH:9]=[CH:10][N:17]([CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[C:4]=2[N:3]=1
Reactant: CCOC(Cc1c(Cl)nc(N)nc1NCc1cccs1)OCC
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(Cl)c2ccn(Cc3cccs3)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.3 %

Procedure:
A suspension of 2-amino-4-chloro-6-[(2-thienylmethyl)amino]-5-(2,2-diethoxyethyl)pyrimidine (1.0 g, 2.80 mmol) in 65 ml of 0.3N HCl and ethanol (2.25:1) was stirred at 25° C. for 24 hours. The reaction mixture was neutralized with ammonium hydroxide solution and the product collected by filtration. TLC analysis showed that the reaction was not complete, so, the product was resuspended in 50 ml of 0.2N HCl and stirred for 48 hours. The reaction mixture was neutralized with NH4OH solution and concentrated. The residue was taken up in water and then evaporated to dryness to give yellow solid (573 mg) (77.3%). This was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:8]=2)[N:3]1[CH2:22][C:23]([O:25]C(C)(C)C)=[O:24].Cl.O1CCOCC1>>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=3)[CH:8]=2)[N:3]1[CH2:22][C:23]([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)CN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To tert-butyl 2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetate (202 mg, 0.50 mmol) in a 50 mL round-bottom flask was added 4N hydrochloric acid in 1,4-dioxane (6.0 mL, 24.0 mmol). The reaction mixture was stirred at room temperature for 4 hours, and the solvent removed under reduced pressure. A second portion of 4N HCl in 1,4-dioxane (6.0 mL, 24.0 mmol) was added with stirring for another 13 hours, and again the solvent was removed under reduced pressure, to afford 2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetic acid as a solid (162 mg, 0.46 mmol, 92%). LCMS mz 350.0 (M+H), 372.0 (M+Na), anal HPLC >97% in purity, 1H NMR (400 MHz; CDCl3) δ 7.67 (m, 4H); 7.40-7.50 (m, 2H); 6.92 (d, J=8.6 Hz, 1H); 4.76 (s, 2H); 3.04 (m, 2H); 2.79 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH2:17].CCO.C([O-])([O-])=O.[Na+].[Na+].[C:27]1(B(O)O)[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1>C1(C)C=CC=CC=1.CCOC(C)=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>[C:27]1([C:2]2[CH:7]=[C:6]([S:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=2[NH2:17])[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1
Reactant: Nc1ccc(S(=O)(=O)N2CCOCC2)cc1Br
Reactant: OB(O)C1=CCCCC1
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: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
A solution of 50.0 mg (0.156 mmol) of 2-bromo-4-(morpholine-4-sulfonyl)-phenylamine (as prepared in the previous step) in toluene (4 mL) and EtOH (2 mL) was treated with 623 μL (1.25 mmol) of 2.0 M aqueous Na2CO3 and 20.6 mg (0.163 mmol) of cyclohex-1-enylboronic acid. The mixture was degassed via sonication, placed under Ar, treated with 12.6 mg (0.0109 mmol) of Pd(PPh3)4, and heated to 80° C. for 3.5 h. The mixture was cooled to RT, stirred for 16 h, diluted with EtOAc (10 mL) and washed with saturated aqueous NaHCO3 (1×10 mL) and brine (1×10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 25-g Varian MegaBond Elut SPE column with 25-50% EtOAc-hexane afforded 20.0 mg (40%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C16H22N2O3S, 323.1 (M+H), found 323.1.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH:7]([N:14]1[C:18]2[CH:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:17]=2[N:16]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:15]1=[O:36])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:23]([C:20]1[CH:21]=[CH:22][C:17]2[N:16]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)(=[O:27])=[O:26])[C:15](=[O:36])[N:14]([CH:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:6]([OH:37])=[O:5])[C:18]=2[CH:19]=1)#[N:24]
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)OC(C)(C)C)c3ccccc3)c3cc(C#N)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)O)c3ccccc3)c3cc(C#N)ccc32)cc1
Temperature: 25 °C

Procedure:
1.75 g (3.37 mmol) of tert-butyl[6-cyano-3-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydrobenzimidazol-1-yl]phenylacetate (XIIc) were dissolved in dichloromethane (20 ml) and, while stirring at room temperature, trifluoroacetic acid (10 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 1.49 g (96%) of white solid