Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]2([CH3:14])[CH3:13].[H-].[Na+].CI.O.[C:20](C#N)(C)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:20])[C:8]2([CH3:14])[CH3:13]
Reactant: COc1cccc2c1C(=O)NC2(C)C
Reactant: CC(=O)C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: COc1cccc2c1C(=O)N(C)C2(C)C

Procedure:
7-methoxy-3,3-dimethyl-2,3-dihydro-isoindol-1-one (3.16 g) is dissolved in THF (50 mL) and NaH (7.88 g) is added batchwise. After 5 min methyl iodide (7.18 mL) is added. After 18 h at 0° C. the reaction mixture is combined with H2O/AcCN as well as Isolute and purified by RP HPLC.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:5]1=[O:34])[CH:2]=[CH2:3].[C:36](Cl)(=[O:38])[CH3:37].C(N(C(C)C)CC)(C)C>ClCCCl>[C:36]([N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C@@H:24]([N:6]2[C@H:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C@@H:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=3)[CH2:9][C@@:4]([CH2:1][CH:2]=[CH2:3])([CH3:35])[C:5]2=[O:34])[CH2:32][CH3:33])[CH2:31][CH2:30]1)(=[O:38])[CH3:37]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCNCC2)C1=O
Reactant: CC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCN(C(C)=O)CC2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(piperazin-1-yl)butan-2-yl)piperidin-2-one (Example 95, Step B) (80 mg, 0.155 mmol) in DCE (1.5 mL) was added acetyl chloride (22.1 μL, 0.31 mmol) followed by diisopropylethylamine (54.1 μL, 0.311 mmol). The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure to provide the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]1([SH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:2]1([S:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: SC1CCCCC1
Reactant: Ic1ccccc1
Product: c1ccc(SC2CCCCC2)cc1

Procedure:
The general procedure was used to convert iodobenzene and cyclohexylmercaptan to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (297 mg, 77% yield). 1H NMR (300 MHz, CDCl3) δ 7.44 (dd, J=6.97, 2H; Ha, Ha′), 7.35–7.22 (m, 3H; Hb, Hb′, Hc,), 3.19–3.11 (m, 1H; Hd), 2.04 (m, 2H; He, Hi), 1.82 (m, 2H; He′, Hi′), 1.65 (m, 1H; Hg), 1.48–1.26 (m, 5H; Hh, Hf, Hh′, Hf′, Hg′). 13C NMR (75 MHz, CDCl3) δ 135.11 (C1), 131.75 (C3, C5), 128.64 (C2, C6), 126.46 (C4), 46.44 (C7), 33.26 (C8, C12), 25.97 (C10), 25.69 (C9, C11). Anal. Calcd. for C12H16S: C, 74.94; H, 8.39; S, 16.67; Found C, 75.06; H, 8.40; S, 16.54.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[CH:18]1[C:23]([CH:24]=O)=[CH:22][C:21]2[O:26][CH2:27][O:28][C:20]=2[CH:19]=1.[Cl:29]CCl>S1(CCCC1)(=O)=O>[ClH:29].[CH3:2][O:3][C:4]([C@@H:5]1[CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C@H:24]([C:23]2[CH:18]=[CH:19][C:20]3[O:28][CH2:27][O:26][C:21]=3[CH:22]=2)[NH:6]1)=[O:17]
Reactant: ClCCl
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: O=S1(=O)CCCC1
Product: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccc3c(c2)OCO3)N1
Reaction time: 14 h

Procedure:
D-tryptophan methyl ester hydrochloride of Step 1 (100 g) and piperonal (65 g) were suspended in sulfolane (500 mL) at 25° C. to 30° C. The reaction mixture was heated to 80° C. to 85° C., stirred for 14 hours, and then cooled to 25° C. to 30° C. To the cooled mixture, dichloromethane (500 mL) was added and the resultant mixture was stirred continuously for 1 hour. The solid obtained was filtered, washed with dichloromethane (500 mL), and dried in air at 40° C. to 45° C. to afford cis 1-benzo[1,3]dioxol-5-yl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][NH:4][N:3]=1.[C:13]([Cl:19])(=O)[CH2:14][C:15]([Cl:17])=O>O1CCCC1.[OH-].[Na+]>[Cl:17][C:15]1[CH:14]=[C:13]([Cl:19])[N:3]2[N:4]=[CH:5][C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:2]2[N:1]=1
Reactant: Nc1n[nH]cc1-c1ccccc1
Reactant: O=C(Cl)CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Clc1cc(Cl)n2ncc(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
There was dissolved, in tetrahydrofuran (4 mL), 3-amino-4-phenyl-pyrazole (208 mg, 1.31 mM), then malonyl chloride (153 μL, 1.57 mM) was added to the solution with ice-cooling and the mixture was stirred at room temperature for 30 minutes. To the reaction solution, there was added malonyl chloride (15 μL, 0.16 mM) and the mixture was further stirred at room temperature for 30 minutes. This reaction liquid was diluted with a 1M aqueous sodium hydroxide solution, washed with ethyl acetate, the aqueous phase was acidified (pH 2) by the addition of hydrochloric acid and then it was extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was then distilled off and the resulting solid was washed with diethyl ether. Phosphoryl chloride (4 mL) was added to the resulting solid with ice-cooling, and then the resulting suspension was stirred for 6 hours while refluxing the same with heating. The phosphoryl chloride was distilled off from the reaction liquid, ethanol was added to the resulting residue with ice-cooling and the mixture was stirred for 15 minutes. After the reaction liquid was concentrated, the concentrate was diluted with water and then extracted with methylene chloride. The extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting residue was purified by the silica gel column chromatography (ethyl acetate/hexane=1:10) to thus give the title compound (47.7 mg, overall yield of these two steps: 14%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[S:8])SC.[N-:9]=[N+:10]=[N-:11].[Na+].O>O1CCOCC1>[OH:1][CH2:2][CH2:3][N:4]1[C:5]([SH:8])=[N:11][N:10]=[N:9]1
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCCO
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCCn1nnnc1S
Yield: 4.8 %

Procedure:
A mixture of methyl N-(2-hydroxyethyl)dithiocarbamate (3.7 g.), sodium azide (2.4 g.), water (20 ml.) and dioxane (20 ml.) was heated under reflux for four hours. After the dioxane was removed from the mixture under reduced pressure, the aqueous solution was washed with ether. The solution was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was concentrated under reduced pressure to give oily product (0.47 g.). The oily product was purified by column chromatography on silica gel to give 1-(2-hydroxyethyl)-1H-tetrazole-5-thiol (0.17 g.). m.p. 135° to 137° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:15]=[C:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][C:19]2[CH:27]=[CH:28][C:29]([CH:31]=[O:32])=[CH:30][C:18]=2[NH:17]1>C(#N)C.C(OCC)(=O)C>[CH2:7]([N:17]1[C:16](=[O:15])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][C:19]2[CH:27]=[CH:28][C:29]([CH:31]=[O:32])=[CH:30][C:18]1=2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccc2c(c1)NC(=O)c1ccccc1O2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1ccc2c(c1)N(Cc1ccccc1)C(=O)c1ccccc1O2
Temperature: 25 °C
Yield: 63 %

Procedure:
Potassium carbonate anhydrous (0.207 g, 1.5 mmole) and benzyl bromide (0.205 g, 1.2 mmole) were added to a solution of the 11-oxo-10,11dihydrodibenzo[b,f][1,4]oxazepine-8-carbaldehyde (0.240 g, 1 mmole) in acetonitrile under N2 at room temperature. The reaction mixture then was refluxed for 4 hours, and cooled to room temperature. Diluted the reaction mixture with ethyl acetate and filtered through a magnesol pad and concentrated. Purified with silica gel column and 50% ethyl acetate in hexane. Obtained the desired compound (light yellow oil) in 63% yield.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:11])[C:9]=1[NH2:10])=O.[CH:12]([NH2:14])=O>>[CH3:11][C:8]1[C:9]2[N:10]=[CH:12][NH:14][C:3](=[O:2])[C:5]=2[S:6][CH:7]=1
Reactant: COC(=O)c1scc(C)c1N
Reactant: NC=O
Product: Cc1csc2c(=O)[nH]cnc12
Temperature: 200 °C
Yield: 91 %

Procedure:
3-amino-4-methyl-thiophene-2-carboxylic acid methyl ester (10.2 g, 59.6 mmol) was dissolved in formamide (25 mL), followed by refluxing for 24 hours at 200° C. The reaction solution was slowly cooled to room temperature. The resulting solid was filtered, washed with diethyl ether, and dried to obtain the title compound (9 g, 91%).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][C:37](O)=[O:38])=[CH:35][C:30]=2[O:29][CH2:28]1>>[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][C:37]([NH:26][C@H:23]3[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]4[CH2:16][CH2:17][CH:12]([C:11]5[C:6]6[CH2:5][CH2:4][O:3][C:7]=6[CH:8]=[CH:9][CH:10]=5)[CH2:13][CH2:14]4)[CH2:25][CH2:24]3)=[O:38])=[CH:35][C:30]=2[O:29][CH2:28]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(Cc1ccc2c(c1)OCO2)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (112 mg, 92%), MS (ISP) m/z=491.3 [(M+H)+], mp 209° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2-benzo[1,3]dioxol-5-yl-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[CH:21](O)[C:22]2[CH:27]=[C:26]3[O:28][CH2:29][O:30][C:25]3=[CH:24][C:23]=2[CH3:31])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:8]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[CH2:21][C:22]2[CH:27]=[C:26]3[O:28][CH2:29][O:30][C:25]3=[CH:24][C:23]=2[CH3:31])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COCCOCN(c1noc(C)c1Cl)S(=O)(=O)c1c(C(O)c2cc3c(cc2C)OCO3)sc2ncccc12
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COCCOCN(c1noc(C)c1Cl)S(=O)(=O)c1c(Cc2cc3c(cc2C)OCO3)sc2ncccc12
Yield: 53.9 %

Procedure:
The title compound was prepared by the method of Example 5(A) using N-(4-chloro-5-methyl-3-isoxazolyl)-N-(methoxyethoxymethyl)-2-[α-hydroxy-2-methyl-4,5-(methylenedioxy)benzyl]thieno[2,3-b]pyridine-3-sulfonamide (0.11 g, 0.19 mmoles), CH2Cl2 (5 ml), triethyl silane (0.31 ml, 1.9 mmoles) and boron trifluoride etherate (0.12 ml, 0.97 mmoles). Flash chromatography (35% EtOAc/hexanes) provided 58 mg (53%) of the title compound as a tan solid.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([Cl:15])[N:12]=[C:11]3[N:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]4)[N:17]=[CH:18][C:10]=13)[CH2:2]2.F[C:33](F)(F)[C:34](O)=O.FC(F)(F)C([O-])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:60]([N:62](CC)[CH2:63]C)[CH3:61]>ClCCl>[Cl:15][C:13]1[N:12]=[C:11]2[N:16]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:25][C:61]4[CH:60]=[N:62][CH:63]=[CH:33][CH:34]=4)[CH2:23][CH2:24]3)[N:17]=[CH:18][C:10]2=[C:9]([N:3]2[CH2:2][CH:1]3[O:8][CH:5]([CH2:6][CH2:7]3)[CH2:4]2)[N:14]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCN(Cc4cccnc4)CC3)c2n1
Reaction time: 8 h
Yield: 100 %

Procedure:
Tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (0.20 g, 0.45 mmol) was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (2 mL). When LC/MS analysis revealed the deprotection of the Boc group, the mixture was concentrated to dryness under reduced pressure. Diethyl ether was evaporated three times from the crude material in order to afford a solid residue. The trifluoroacetate salt was dissolved in dichloromethane (10 mL) and then treated with triethylamine (0.18 mL). The mixture was concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (10 mL) and treated with 3-pyridinecarboxaldehyde (0.064 mL). The mixture was allowed to stir for 10 minutes before the addition of sodium triacetoxyborohydride (0.15 g, 0.68 mmol). After stirring overnight, the mixture was diluted with dichloromethane and washed with 1 M aqueous sodium hydroxide solution. The aqueous phase was back extracted once with dichloromethane and then the combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. 3-(6-Chloro-1-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.20 g, 100%) was thus obtained as a yellow crystalline solid. MS (ES+): 440.0, 441.2 (M+H)+
Reaction SMILES: [C-]#N.[Na+].Br[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][C:7]=1[Cl:21].[CH3:22][N:23](C=O)C.O>[Cl-].[Na+].O>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:22]#[N:23])=[C:7]([Cl:21])[CH:8]=1
Reactant: Clc1cc(-c2nc3ccccc3o2)ccc1CBr
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1Cl

Procedure:
A slurry of NaCN (435 mg, 8.9 mmol), 2-[4-(bromomethyl)-3-chlorophenyl]-1,3-benzoxazole (940 mg, 2.9 mmol), DMF (30 mL) and H2O (30 mL) was stirred at rt for 12 h. The reaction mixture was poured into brine (250 mL) and filtered. The resultant colorless solid was purified by flash chromatography on silica gel (EtOAc:hexanes 1:9) to afford the desired [4-(1,3-benzoxazol-2-yl)-2-chlorophenyl]acetonitrile as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.32 (s, 1H), 8.19 (dd, 1H), 7.77–7.80 (m, 1H), 7.70 (d, 1H), 7.59–7.61 (m, 1H), 7.38–7.41 (m, 2H), 3.92 (s, 2H). MS (ESI) 269 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:19][C:20]4[CH:25]=[N:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=4)[N:16]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)ncn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)ncn12
Temperature: 60 °C
Yield: 16.9 %

Procedure:
To a stirred suspension of 7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (738 mg, 3.0 mmol) in DMF (5 mL) at room temperature under argon was added 5-(chloromethyl)-2-(trifluoromethyl)pyridine (647 mg, 3.3 mmol), followed by K2CO3 (828 mg, 6.0 mmol). The resulting mixture was heated at 60° C. for 48 h, after which time analysis by HPLC/MS indicated that the reaction was complete. After cooling the reaction mixture to room temperature, water (50 mL) was added. The resulting mixture was extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NaCl, then dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting residue was triturated with chloroform (3×20 mL) and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography eluted with ethyl acetate-dichloromethane to obtain 206 mg of the title compound as a solid. HPLC/MS (methanol-water with 10 mM NH4OAc): retention time=3.58 min, [M+H]30 =406.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][CH2:15][CH2:14][S:13]1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19].CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:15][CH2:14][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NCCS1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCSC1=Nc1ccc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine (prepared in a manner analogous to that described in Method C1a; 0.084 g, 0.35 mmol) in CH2Cl2 (5 mL) was added propionyl chloride (0.033 g, 0.35 mmol) and Et3N (0.049 mL, 0.35 mmol). The mixture was allowed to stir at room temp for 1 h, then was diluted with CH2Cl2 (40 mL). The resulting solution was sequentially washed with H2O (10 mL) and a saturated NaCl solution (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by preparative TLC (40% EtOAc/hex) to give 2-(2-methyl-4-nitrophenylimino)-3-propanoyl-1,3-thiazolidine (0.036 g, 35%): FAB-MS m/z 294 ((M+H)+).
Reaction SMILES: CO[CH2:3][Br:4].[I:5][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[CH:9]=[CH:10][CH:11]=1.IC1C=C(O)C=CC=1C[C@@H](C(O)=O)N>C(O)(=O)C.O>[Br:4][CH2:3][C:11]1[CH:10]=[CH:9][C:8]([O:12][CH3:13])=[CH:7][C:6]=1[I:5]
Reactant: COc1cccc(I)c1
Reactant: COCBr
Agent: N[C@@H](Cc1ccc(O)cc1I)C(=O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(CBr)c(I)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.4 %

Procedure:
Bromomethyl methyl ether (5.14 ml, 63.2 mmol) was added to a solution of 3-iodoanisole 19 (7.4 g, 31.6 mmol) in glacial acetic acid (17.0 mL) and the colorless solution was stirred for 2 days at room temperature as set forth in T. J. McCord, D. E. Thornton, K. L. Hulme and A. L. Davis, “Synthesis and Microbiological Properties of 2-Iodotyrosine and Related Compounds.” Texas J. Sci., 30, pp 357-363 (1978). The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered and evaporated to produce a yellow oil which was purified by silica gel column chromatography to yield 1-bromomethyl-2-iodo-4-methoxybenzene (20) as a white solid (4.59 g, 45%).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[CH:16]=O.[C:23](#[N:27])[CH2:24][C:25]#[N:26].N1CCCCC1>C(O)C.O>[NH2:27][C:23]1[O:11][C:1]2[C:2]([CH:16]([C:15]3[CH:14]=[C:13]([F:12])[C:20]([F:21])=[C:19]([F:22])[CH:18]=3)[C:24]=1[C:25]#[N:26])=[CH:3][CH:4]=[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=21
Reactant: Oc1cccc2ccccc12
Reactant: N#CCC#N
Reactant: O=Cc1cc(F)c(F)c(F)c1
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC1=C(N)Oc2c(ccc3ccccc23)C1c1cc(F)c(F)c(F)c1
Temperature: 80 °C
Yield: 81 %

Procedure:
1-Naphthol (170 mg, 1.2 mmol), 3,4,5-trifluorobenzaldehyde (160 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 μl) and then stirred at 80° C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with water to about 15 ml and stirred for about 1 h room temperature. The solids were collected by filtration, washed with 60% aq. ethanol and dried under high vacuum to yield the title compound (284 mg, 0.81 mmol, 81%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:22]([O:29][C:30](=[O:33])[CH2:31]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30](=[O:33])[CH2:31][N:14]([S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:13][CH:12]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: O=C(CBr)OCc1ccccc1
Product: CCCCS(=O)(=O)N(CC(=O)OCc1ccccc1)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidine-1-yl)-phenyl]-amide (which was obtained in Example 228) and benzyl-2-bromoacetate according to the procedure of Example 251 as an orange oil; 1H NMR (300 MHz, CDCl3) δ 0.91 (t, J=7.29 Hz, 3H), 1.34-1.47 (m, 2H), 1.75-1.86 (m, 2H), 2.55 (t, J=6.09 Hz, 4H), 3.17-3.23 (m, 2H), 3.62 (t, J=6.00 Hz, 4H), 4.45 (s, 2H), 5.18 (s, 2H), 6.87-6.92 (m, 2H), 7.30-7.40 (m, 7H); MS (ES) m/z: 459.0 (MH+); HRMS found for C24H30N2O5S: 459.1944.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][N:3]=1.[BH4-].[Na+].[ClH:17]>CO>[ClH:17].[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CC1=NCCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1NCCc2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h

Procedure:
To a solution of 1-methyl-7-nitro-3,4-dihydroisoquinoline (397 g, 20.9 mmol) in methanol (80 ml) was added sodium borohydride (0.87 g, 23.0 mmol) portionwise. The mixture was stirred for 30 min., acidified with 6N HCl, the solvent was evaporated and the solid was stirred in isopropanol, collected and washed with ether: 5.33 g (>100%); MS (M+H)+ 193.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=NC2C=CC=CC=2)=[CH:5][CH:4]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:9][C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C=Nc2ccccc2)cc1
Solvent: CO
Product: COc1ccc(C#Cc2ccccc2)cc1
Yield: 67 %

Procedure:
Procedure similar to that of Example 16 using [phenylmethyl]-1Hbenzotriazole (10 mmol) and N-[(4-methoxyphenyl)methylene]benzenamine (10 mmol): 67% yield: mp 57°-58° C. (MeOH) (lit.1 58°-60° C.); 1H NMR (300 MHz, CDCl3) δ 3.84 (s, 3H, OCH3), 6.89 (d, 1.9H, 2H, C(3 and 5)H), 7.30-7.38 (m, 3H(), 7.45-7.54 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:5]([CH:9]=[C:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27]C)=[O:25].OC1C2N=NNC=2C=CC=1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C.O>[C:1]([C:3]1[C:4]2[N:5]([CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:18])=[CH:19][CH:20]=3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CCN
Reactant: N#Cc1cccn2cc(-c3ccc(C(=O)O)cc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCNC(=O)c1ccc(-c2cn3cccc(C#N)c3n2)cc1

Procedure:
4.0 g Of 4-(8-cyanoimidazo[1,2-a]pyridin-2-yl)benzoic acid and 2.14 g of ethyl 3-aminopropionate in 40 ml of DMF are stirred in the presence of 2.28 g of hydroxybenzotriazole, 3.0 g of N-methylmorpholine and 2.9 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide at room temperature for 4 h. After addition of 400 ml of water, the precipitate is filtered off with suction and washed successively with dilute bicarbonate solution and water. Methyl 3-[4-(8-cyanoimidazo[1,2-a]pyridin-2-yl)benzamido]propionate, m.p 201-204° is obtained.