Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:9][C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-]>CC(=O)CC>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCBr
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCC(C)=O
Product: CCOC(=O)CCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
1,4,5-Triphenylimidazole-2-one was treated with ethyl 3-bromo-propionate and potassinm carbonate in butanone to give after work-up the title compound. m.p. 111°-112 ° C. Found: C. 76.0;H, 5.9;N, 6.7%;C26H24N2O3 requires:C, 75.7;H, 5.9;N, 6.8%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([N:18]=[CH:19]NO)=[C:16]([S:22]([C:24]([F:27])([F:26])[F:25])=[O:23])[C:15]([C:28]2[N:32]=[CH:31][O:30][N:29]=2)=[N:14]1.Cl.O.C(=O)([O-])[OH:36].[Na+]>CC(C)=O.C(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([NH:18][CH:19]=[O:36])=[C:16]([S:22]([C:24]([F:27])([F:25])[F:26])=[O:23])[C:15]([C:28]2[N:32]=[CH:31][O:30][N:29]=2)=[N:14]1
Reactant: O=S(c1c(-c2ncon2)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N=CNO)C(F)(F)F
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=CNc1c(S(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 13 %

Procedure:
1-(2,6-Dichloro-4-trifluoromethylphenyl)-5-hydroxyaminomethylideneamino-3-(1,2,4-oxadiazol-3-yl)-4-trifluoromethylsulfinylpyrazole (3.50 g, 6.69 mmol) was dissolved in 30 ml of acetone and 1.2 N hydrochloric acid (12 ml, 14.4 mmol) was added, and then the mixture was stirred at room temperature for 3 days. After 20 ml of water was added, the reaction mixture was neutralized with sodium hydrogencarbonate (powder). The solvent was distilled off and 20 ml of water and 100 ml of ethyl acetate were added, followed by partitioning. The aqueous layer was extracted with 30 ml of ethyl acetate and combined with the ethyl acetate layer, followed by washing with 50 ml of an aqueous saturated sodium hydrogencarbonate solution, then with 50 ml of an aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a colorless amorphous. The amorphous was subjected to silica gel column chromatography [eluent: mixed solvent of ethyl acetate and chloroform (volume ratio=1:10)] to obtain 453 mg (0.89 mmol) of the title compound as a colorless crystal. Yield 13%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([NH:12]C2C(NC3C=C(OC)C=C(OC)C=3)=NC3C(=CC=CC=3)N=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[N:34]1[NH:35][N:36]=[N:2][C:1]=1[C:3]1[CH:4]=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(C#N)c2)cc(OC)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cccc(-c2nn[nH]n2)c1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
To a stirred solution of 3-cyano-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide (0.20 g, 0.44 mmol), prepared using procedures similar to those described in Example 115, in dimethylformamide (1.2 mL) at 50° C. were added sodium azide (0.11 g, 1.76 mmol) and ammonium chloride (94 mg, 1.76 mmol). The crude mixture was heated at 100° C. overnight. The reaction was cooled to room temperature treated with ice water (20 mL) followed by concentrated hydrochloric acid (10 mL). The solid obtained was filtered under reduced pressure and washed with hexane (20 mL), diethyl ether (20 mL), and ethyl acetate (5 mL) to afford N-(3-{[3,5-bis(methoxy)phenyl]amino}) quinoxalin-2-yl)-3-(2H-tetrazol-5-yl)benzenesulfonamide (55 mg, 25%) as light yellow solid. MS (EI) m/z for C23H20N8O4S: 505.0 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32]CC)=[O:31])=[CH:4][CH:3]=1.ClCC1C=CC2C(=CC=C([F:51])C=2)N=1>>[Br:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[C:23]([F:51])[CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Br)cc1
Reactant: Fc1ccc2nc(CCl)ccc2c1
Product: CC(C)(Cc1nc2cc(OCc3ccc4cc(F)ccc4n3)ccc2n1Cc1ccc(Br)cc1)C(=O)O

Procedure:
The title compound was prepared with similar methods to those for ethyl 3-(1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate using 2-(chloromethyl)-6-fluoroquinoline and similar methods described in Example 26. MS (ESI): mass calcd. for C29H25BrFN3O3, 561.11; m/z found, 562.0 [M+H]+. (500 MHz, CD3OD) δ 8.35 (d, J=8.6, 1H), 8.13-8.04 (m, 1H), 7.74 (d, J=8.6, 1H), 7.67-7.57 (m, 2H), 7.55-7.43 (m, 3H), 7.35 (d, J=2.2, 1H), 7.26 (dd, J=9.1, 2.4, 1H), 7.12 (d, J=8.5, 2H), 5.73 (s, 2H), 5.45 (s, 2H), 3.42 (s, 2H), 1.38 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[C@H:4]1[O:50][C@@H:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]5)=[CH:37][CH:36]=4)[C:18]4[C:23]([C:24]=3[CH3:25])=[CH:22][C:21]([O:26]CC3C=CC=CC=3)=[CH:20][CH:19]=4)=[CH:12][CH:11]=2)[C@:7]([C:52](=[O:54])[CH3:53])([OH:51])[C@@:6]([C:56](=[O:58])[CH3:57])([OH:55])[C@@H:5]1[O:59][C:60](=[O:62])[CH3:61]>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:63])[C@H:4]1[O:50][C@@H:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([CH2:34][C:35]4[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH2:43][N:44]5[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]5)=[CH:39][CH:40]=4)[C:18]4[C:23]([C:24]=3[CH3:25])=[CH:22][C:21]([OH:26])=[CH:20][CH:19]=4)=[CH:12][CH:11]=2)[C@:7]([C:52](=[O:54])[CH3:53])([OH:51])[C@@:6]([C:56](=[O:58])[CH3:57])([OH:55])[C@@H:5]1[O:59][C:60](=[O:62])[CH3:61]
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc(-c3c(C)c4cc(OCc5ccccc5)ccc4n3Cc3ccc(OCCN4CCCCC4)cc3)cc2)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc(-c3c(C)c4cc(O)ccc4n3Cc3ccc(OCCN4CCCCC4)cc3)cc2)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@@H]1OC(C)=O
Yield: 98.9 %

Procedure:
Glycosidated indole 33 (34 g, 0.039 mol) in 400 mL THF/MeOH (1:1) was treated with 10% Pd/C (5.4 g) and hydrogenated in a Parr apparatus at 50 psi for 30 h. The mixture was filtered through Siluflock and 0.34 g of L-Ascorbic acid was added to the filtrate. The cake of Siluflock was washed with THF and the combined filtrates were concentrated to yield product 35 (29.8 g, 98%) as a yellowish-white solid: 1H NMR (CDCl3) δ 6.95 (m, 11 H), 5.34 (m, 2 H), 5.14 (d, 1 H, J=2 Hz), 5.01 (s, 2 H), 4.21 (m, 1 H), 4.06 (t, 2 H),2.83 (t, 2 H), 2.62 (br s, 4 H), 2.13 (s,3H), 1.65 (t, 4 H), 1.44(brs,2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].CCN(C(C)C)C(C)C.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:26][O:25][C:21](=[O:24])[CH:22]=[CH:23][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11]
Reactant: C=CC(=O)OC
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C=Cc1ccc([N+](=O)[O-])cc1C
Temperature: 110 °C
Yield: 91.1 %

Procedure:
To a solution of 2-bromo-5-nitrotoluene (3.11 g, 14.39 mmol) in propionitrile (105 mL) is added DIPEA (5.1 mL, 29.28 mmol). The mixture is degassed three times. Methyl acrylate (5.2 mL, 57.74 mmol) is added and the mixture is degassed. Tri-o-tolylphosphine (1.77 g, 5.82 mmol) and Pd(OAc)2 (0.64 g, 2.85 mmol) are added and the mixture is degassed a final two times followed by heating at 110° C. for 4 h. Upon cooling, the mixture is passed through Celite and the filtrate is concentrated. The residue is partitioned between Et2O and 1N HCl. The organics are washed with saturated NaHCO3 and brine, and dried with Na2SO4. The crude material is purified by flash chromatography to yield the title compound (2.90 g, 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C.CCO>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:22]3[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=3)[C:29]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CCCCc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=c1c(CCCc2ccncc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq., prepared in Synthetic Example 10) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 209 to 210° C./DMF-EtOH.
Reaction SMILES: [C:1]([N:9]1[CH:15]=[CH:14][N:13]=[CH:12][CH2:11][N:10]1[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)=[CH2:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(O)C>[C:1]([N:9]1[CH2:15][CH2:14][N:13]([CH2:25][CH2:24][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:12][CH2:11][N:10]1[C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1C=CN=CCN1C(=O)c1ccccc1
Reactant: C=Cc1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CO
Product: O=C(c1ccccc1)N1CCN(CCc2ccncc2)CCN1C(=O)c1ccccc1

Procedure:
A mixture of 1,2-dibenzoyl-1H-1,2,5-triazepine (2.0 g), 4-vinylpyridine (1.42 g) and p-toluenesulfonic acid (1.21 g) in methanol (70 ml) was stirred and heated at 60° under a nitrogen atmosphere for 3 days. The foam, obtained after evaporation of the solvent, was mixed with dichloromethane and 10% sodium carbonate solution. The organic phase was washed with water until neutral washings were obtained and dried (Na2SO4). Evaporation of the solvent gave a foam, 2.25 g. The crude product was chromatographed on a column of silica gel; elution with ethanol-ethyl acetate-dichloromethane (1:4:5) giving a major component. A hydrochloride salt, 1/3 hydrate of the titled compound was formed in ethanol; wt. 1.2 g (38%), mp 247° dec.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=[O:5])C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]2[CH2:41][CH2:40][NH:39][C:38](=[O:42])[CH2:37]2)=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[O:42]=[C:38]1[NH:39][CH2:40][CH2:41][N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:5])=[N:34][CH:33]=2)[CH2:37]1
Reactant: Nc1ccc(CN2CCNC(=O)C2)cn1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCNC(=O)C4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 4-(6-amino-pyridin-3-ylmethyl)-piperazin-2-one (Step 103.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at 80° C., pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 551.0 [M+H]+; tR=3.59 min (System 1); TLC: Rf=0.13 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Li+].[OH-].CS([O:7][CH2:8][CH2:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]2[N:27]([C:28]3[CH:33]=[CH:32][C:31]([N:34](S(C)(=O)=O)[S:35]([CH3:38])(=[O:37])=[O:36])=[CH:30][CH:29]=3)[C:26](=[O:43])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:13][C:12]=1[CH3:44])(=O)=O>O1CCOCC1.O.C([O-])(O)=O.[Na+]>[OH:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([CH3:44])=[CH:13][C:14]([C:18]2[N:27]([C:28]3[CH:33]=[CH:32][C:31]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])=[CH:30][CH:29]=3)[C:26](=[O:43])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:15][C:16]=1[CH3:17]
Reactant: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)cc(C)c1OCCOS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(NS(C)(=O)=O)cc2)cc(C)c1OCCO
Yield: 52.1 %

Procedure:
LiOH (0.100 g, 4.10 mmol) was added to a solution of 2-(2,6-dimethyl-4-(3-(4-(N-(methylsulfonyl)methylsulfonamido)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)ethyl methanesulfonate (0.280 g, 0.44 mmol) in dioxane (20 mL) and H2O (20 mL), before heating at reflux temperature for 3.5 hours. The mixture was diluted with saturated NaHCO3, extracted with CH2Cl2, and concentrated in vacuo. Purification was effected by reverse phase chromatography eluting with 10% to 90% CH3CN in H2O with 0.1% TFA. The desired fractions were collected, basified, extracted, and concentrated, to afford the title compound as a white solid (0.110 g, 52%). 1H-NMR (300 MHz, DMSO-d6): δ 9.83 (s, 1H), 8.17 (dd, J=6.7, 1.1 Hz, 1H), 7.86-7.92 (m, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.52-7.65 (m, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 7.01 (s, 2H), 4.83 (t, J=5.5 Hz, 1H), 3.56-3.69 (m, 4H), 2.92 (s, 3H), 2.09 (s, 6H). MS (APCI) m/z: 480 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C=CC=CC=1>[S:30]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCCC2=O)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(N2CCCCC2=S)CC1
Yield: 128.7 %

Procedure:
A solution of tert-butyl 2-oxo-1,4′-bipiperidin-1′-carboxylate (2.8 g) and Lawesson's reagent (2.0 g) in toluene (30 mL) was refluxed for one hour. Toluene was distilled off under reduced pressure, and the residue was diluted with dichloromethane, and washed with an aqueous 1N sodium hydroxide solution and saturated saline solution. This dichloromethane solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1 to 1/2) to obtain the title compound (1.9 g, 64%) as a white powder.
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([S:28][CH3:29])=[CH:22]2)=[O:18].[Cl:30][C:31]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:32]=1[CH:33]=O>C(Cl)Cl>[Cl:30][C:31]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:32]=1[CH2:33][C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[CH:20]=2)[NH:24][C:23]=1[S:28][CH3:29]
Reactant: COC(=O)c1ccc2[nH]c(SC)cc2c1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2[nH]c(SC)c(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 0 °C
Yield: 52.9 %

Procedure:
To a methylene chloride (10 ml) solution of trifluoroacetic acid (1.238 g) and triethylsilane (2.52 g), added is a methylene chloride (10 ml) solution of 5-methoxycarbonyl-2-methylthioindole (0.800 g), which had been prepared according to the method described in “Tetrahedron, 42 (16), 4511 (1986)”, and 2,4-dichlorobenzaldehyde (0.760 g), in an ice-water bath. This is stirred for 3 hours in the ice-water bath. The crystal formed is taken out through filtration and dried to obtain 3-(2,4-dichlorobenzyl)-5-methoxycarbonyl-2-methylthioindole (152) (0.727 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:3]1[C:2]([Cl:1])=[C:12]([Cl:13])[CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(Cl)c(Cl)c1C
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(Cl)c(Cl)c1CBr
Reaction time: 3 h
Yield: 112.1 %

Procedure:
A mixture of ethyl 3,4-dichloro-2-methylbenzoate (34.0 g), N-bromosuccinimide (30.0 g) and carbon tetrachloride was irradiated with u.v. light in a photochemical reactor for 3 hours. The cooled mixture was filtered and the filtrate washed with water, dried (magnesium sulphate) and evaporated to give ethyl 2-bromomethyl-3,4-dichlorobenzoate (51.0 g) as an oil, NMR (CDCl3) 1.45 (t,3H), 4.4 (q,2H), 5.15 (s,2H), 7.7 (m,2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:15])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]#[N:14])[CH2:8][CH2:7][CH2:6]2.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1.CCOC(C)=O>[C:13]([CH:9]1[CH2:8][CH2:7][CH2:6][C:5]2[C:4]([NH:15][S:17]([CH3:16])(=[O:19])=[O:18])=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]1=2)#[N:14]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1N)CCCC2C#N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc2c(c1NS(C)(=O)=O)CCCC2C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 445.9 %

Procedure:
To a solution of 6-methoxy-5-amino-1, 2,3,4 -tetrahydronaphthalene-1-carbonitrile (1.7 g, 8.3 mmol) in 20 ml of anhydrous pyridine was added methanesulfonyl chloride (1.9 ml, 1.2 mmol). The resulting solution was stirred for 2 h at 25° C. The reaction mixture was concentrated in vacuo to yield an oily residue which was redissolved in EtOAc and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated in vacuo to provide an oily residue which was purified by column chromatography (EtOAc, neat) to yield 1.5 g (65%) of the desired product. 1H NMR (300 MHz, CDCl3): δ 6 1.82 (m, 1H), 1.94 (m, 1H), 2.14 (m, 2H), 2.96 (s, 3H), 3.03 (q, 2H, J=8.8 Hz), 3.84 (s, 3H), 3.96 (t, 1H, J=6.3 Hz), 6.85 (d, 1H, J=8.9 Hz), 7.39 (d, 1H, J=8.9 Hz).
Reaction SMILES: [OH-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH2:12][CH2:13][OH:14])[CH:10]=[CH:11][C:4]1=2.Br[CH2:16][CH2:17][CH2:18][Cl:19].O>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:19][CH2:18][CH2:17][CH2:16][O:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:4]2[S:3][CH:7]=[CH:6][C:5]=2[CH:8]=1
Reactant: OCCc1ccc2sccc2c1
Reactant: ClCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: ClCCCOCCc1ccc2sccc2c1

Procedure:
In a mixture of 4 mL of toluene and 8 mL of 50% (W/V) aqueous solution of sodium hydroxide is suspended 2.0 g of 2-benzo[b]thiophen-5-yl-1-ethanol, to which are added 4.4 mL of 1-bromo-3-chloropropane and 0.11 g of tetra-n-butylammonium hydrogen sulfate. The mixture is heated under reflux for 2 hours. The reaction mixture is introduced into a mixture of water and toluene, and the organic layer is separated. The organic layer is washed with water and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: n-hexane:ethyl acetate=10:1 to 5:1) to obtain 1.85 g of 5-[2-(3-chloropropyloxy)ethyl]benzo[b]thiophene as an oily product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[O:29]=[C:24]1[NH:25][C:26](=[O:28])[CH2:27][N:23]1[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNC(=O)N1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CC(=O)NC2=O)c1
Temperature: 120 °C
Reaction time: 12 h
Yield: 38.2 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (360 mg, 1 mmol), imidazolidine-2,4-dione (500 mg, 5 mmol), copper(I) iodide (115 mg, 0.6 mmol), N,N-dimethylglycine hydrochloride (112 g, 0.8 mmol) and potassium carbonate (415 mg, 3 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 12 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(2,4-dioxo-imidazolidine-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (145 mg, 38%) as a light yellow solid: LC/MS m/e calcd for C21H21N3O4 (M+H)+: 380.42, observed: 380.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14][CH:15]([CH:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:35](Br)[CH:36]=[CH2:37]>CN(C)C=O>[CH2:37]([C:24]([CH:15]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH2:14][C:5]1[C:6]([C:10]([F:11])([F:12])[F:13])=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[CH:36]=[CH2:35]
Reactant: C=CCBr
Reactant: COC(=O)C(C(=O)OC)C(Cc1c([N+](=O)[O-])cccc1C(F)(F)F)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1c([N+](=O)[O-])cccc1C(F)(F)F)c1ccc(OC)cc1
Yield: 97.6 %

Procedure:
[2-(2-Nitro-6-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (14.55 g; 31.96 mmole) was dissolved in dry dimethylformamide (90 ml) under argon. Prewashed 50% sodium hydride (1.85 g; 38.5 mmole) was added with stirring and stirring was continued for 20 minutes before allyl bromide (19.33 g; 159.8 mmole; 13.8 ml; d=1.398; 5 eq.) was added dropwise. The mixture was quenched (1N hydrochloric acid) after a few minutes of reaction time, and extracted with ethyl acetate (two times). The organic extract was washed with saturated potassium carbonate (two times), saturated sodium chloride, and dried (magnesium sulfate). The solution was concentrated on a high vacuum pump leaving 23.0 g. This material was flash chromatographed (silica gel/9:1-hexane:ethyl acetate) and the appropriate fractions were combined and concentrated giving 15.45 g of the title compound as an oil.