Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[C:7](O)=[O:8])(=[O:3])[CH3:2].CN(C=O)C.S(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[C:7]([Cl:30])=[O:8])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)SCC(Cc1ccc(-c2ccccc2)cc1)C(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)SCC(Cc1ccc(-c2ccccc2)cc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 3-acetylthio-2-(4-phenylbenzyl)propionic acid (3.39 g, 10.8 mmole) in toluene (25 ml) add 1% DMF in toluene (2 drops) and thionyl chloride (1.2 ml, 1.65 g, 13.8 mmoles) and stir the resulting solution at room temperature for 18 hours. Concentrate the reaction mixture in vacuo, dissolve the residue in toluene (100 ml) and concentrate the solution in vacuo to give the title compound, a light brown oil (3.37 g).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([I:12])=[CH:14][CH:15]=1)[CH2:4]2
Reactant: O=C(O)c1ccc(I)cc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(I)cc1

Procedure:
Prepared by a method analogous to that described for the preparation of Intermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and 4-iodobenzoic acid; the compound was purified by solid phase extraction on silica gel using ammoniated methanol/chloroform mixtures as the eluent followed by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The product-containing fractions were evaporated, the residue was dissolved in methanol, excess hydrogen chloride solution (4M in 1,4-dioxane) was added and the solution was evaporated to give the hydrochloride salt of the title compound as a colourless solid; MS (ES+) 357 (MH+).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11](OC)[O:12]C)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3]>C(O)=O>[CH2:1]([N:4]([CH2:10][CH:11]=[O:12])[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(OC)OC)C(=O)OCC
Solvent: O=CO
Product: C=CCN(CC=O)C(=O)OCC

Procedure:
68 g (0.313 mol) of ethyl N-allyl-N-(2,2-dimethoxyethyl) -carbamate are heated at 100° C. for an hour with 150 ml of formic acid. The mixture is poured onto ice, extracted several times with methylene chloride, and the organic phases are washed with sodium hydrogen carbonate solution, dried over magnesium sulphate, concentrated and distilled.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1.[Cl:17][SiH:18]([Cl:20])[Cl:19]>>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Si:18]([Cl:20])([Cl:19])[Cl:17])=[CH:11][CH:10]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: Fc1ccc(CCl)cc1
Solvent: CCN(CC)CC
Product: Fc1ccc(C[Si](Cl)(Cl)Cl)cc1
Yield: 24.6 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.044 g (0.40 mmol) of triethylamine, 0.60 g (4.0 mmol) of 4-fluorobenzyl chloride, and 2.71 g (20.0 mmol) of trichlorosilane were reacted at 150° C. for 40 hrs. The resulting mixture was distilled to give 0.24 g of (4-fluorobenzyl)trichlorosilane (yield; 24%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)CCC.[C:19]([C:22]1[CH:37]=[CH:36][C:25]2[N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31](Br)[CH:30]=3)[CH:27]=[N:28][C:24]=2[CH:23]=1)(=[O:21])[CH3:20]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:19]([C:22]1[CH:37]=[CH:36][C:25]2[N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:6]4[S:7][CH:8]=[CH:9][N:10]=4)[CH:30]=3)[CH:27]=[N:28][C:24]=2[CH:23]=1)(=[O:21])[CH3:20]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 97.8 %

Procedure:
To a solution of (33) (3.6 g, 9.7 mmol) in dry THF (20 ml) was added 5-acetyl-1-(3-bromophenyl)benzimidazole (1.5 g, 4.8 mmol) and (PPh3)2PdCl2 (340 mg, 0.48 mmol) under argon. The reaction mixture was stirred at 80° C. for 24 hr in a 50 ml sealed tube. After cooling the mixture was concentrated, triturated with water (100 ml) and extracted with CH2Cl2 (200 ml×3). The extract was washed with brine, dried and concentrated under reduced pressure. The residue was washed with ether to afford crystaline (34) (1.5 g, 89%).
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([O:23]C)=O)[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O.[NH2:33][NH2:34].C(=O)=O>CN(C=O)C>[NH:1]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:33][NH2:34])=[O:23])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: NN
Agent: O=C=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)NN
Reaction time: 8 h

Procedure:
To a solution of the compound obtained in (1) (430 mg) in DMF (10 ml) was added hydrazine monohydrate (1.0 ml) at room temperature and the solution was stirred overnight. To the reaction mixture was added dry-ice and the resulting solution was concentrated to give a residue, which was triturated with water to afford the product (406 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][CH2:13]Cl)=[C:10](Cl)[C:9]2[C:4](=[C:5]([O:16][CH3:17])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH3:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>C(O)CCC>[CH3:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[N:22]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:16][CH3:17])[C:4]=3[N:3]=[C:2]([CH3:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: COc1cccc2c(Cl)c(CCCl)c(C)nc12
Reactant: Cc1ccccc1N
Agent: Cl
Solvent: CCCCO
Product: COc1cccc2c3c(c(C)nc12)CCN3c1ccccc1C
Yield: 21.6 %

Procedure:
2-Methyl-3-(2-chloroethyl)-4-chloro-8-methoxyquinoline (8.37 g, 31 mmol) and 2-methylaniline hydrochloride (4.45 g, 31 mmol) in 1-butanol (100 ml) were heated at reflux for 5 days, then the solvent evaporated, the crude product taken up in dichloromethane, washed with aqueous sodium bicarbonate, dried and evaporated. Chromatography (silica gel, 2% methanolic ammonia in dichloromethane) and recrystallisation from aqueous ethanol gave 1-(2-methylphenyl)-4-methyl-6-methoxy-2,3-dihydropyrrolo[3,2-c]quinoline (2.04 g, 22 %), m.p. 182°-183°.
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27]C)=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.C(O)(=O)C>O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH:17]3[C:26]4[C:21](=[CH:22][C:23]([OH:27])=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1)CCCC2C1CCN(CCc2ccc(F)cc2)CC1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2c(c1)CCCC2C1CCN(CCc2ccc(F)cc2)CC1
Yield: 76.4 %

Procedure:
47% hydrobromic acid (45 ml) was added to 1-[2-(4-fluorophenyl)ethyl]-4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine (2.718 g, 7.57 mmol) and the resultant mixture was heated under reflux for 1 hr. After adding glacial acetic acid (20 ml), the resultant mixture was heated under reflux for additional 1.5 hr. Then the mixture was allowed to cool followed by addition of water thereto. The resulting precipitate was collected by filtration, chloroform and a saturated aqueous solution of sodium bicarbonate were added thereto and the layers were separated. The resulting solution was dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give the title compound (2.043 g) as a brown amorphous substance (yield: 76.4%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[NH4+:14].[OH-]>CN(C)C=O.O>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:14])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: [NH4+]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(Br)n1
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc([N+](=O)[O-])cc(Br)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
1.3 g (0.00526 mol) of 6-bromo-4-nitropyridine-2-carboxylic acid were dissolved in 10 ml of dimethylformamide, treated at 5° C. with 0.94 g (0.0058 mol) of 1,1-carbonyldiimidazole and subsequently stirred at room temperature for 3 hrs. Then, 40 ml of 25% NH4OH in water was added thereto and the mixture was stirred at room temperature for 1 hr. The reaction mixture was partitioned in water and dichloromethane and the organic phase was washed with water and sat. sodium chloride solution, dried over MgSO4 and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:1. There were obtained 1.1 g (85%) of 6-bromo-4-nitropyridine-2-carboxamide as white crystals; m.p.: 179-180° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(F)cc1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
4-Fluoroiodobenzene (112 mL, 0.97 mol) and triethylamine (176 mL, 1.26 mol) are dissolved in dry tetrahydrofuran (1.2 L) and nitrogen gas was bubbled through the solution for about 20 min. Copper (I) iodide (1.08 g, 5.7 mmol) and bis(triphenyphosphine)palladium dichloride (2.15 g, 3 mmol) are added and then trimethylsilylacetylene (178 mL, 1.3 mol) was added dropwise over about 40 min with the temperature being maintained at about 23° C. A large amount of precipitate forms which necessitates mechanical stirring. Following complete addition of the trimethylsilylacetylene the mixture was allowed to stir at room temperature for about 18 hours. The mixture was filtered and the solid washed with cyclohexane. The combined filtrates are concentrated under reduce pressure to give a brown oil. Application of this oil to a pad of silica gel followed by elution with cyclohexane gave a yellow solution. Removal of the solvent gave the title compound as a yellow oil; 182.8 g (95%).
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.CO[CH:18](OC)[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1>>[N:3]1([C:8]2[CH:13]=[C:12]3[C:11](=[CH:10][CH:9]=2)[NH:14][CH:18]=[C:19]3[CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: NNc1ccc(-n2ccnc2)cc1
Reactant: COC(CCCCN1CCC(O)CC1)OC
Agent: Cl
Product: O=C1CCN(CCCc2c[nH]c3ccc(-n4ccnc4)cc23)CC1

Procedure:
The title compound was prepared from 4-(imidazol-1-yl)-phenylhydrazine dihydrochloride and 5-(4-hydroxypiperidin-1-yl)-pentanal dimethyl acetal using a similar method to that described for Example 8 (steps 3 and 4); δH (250 MHz, CDCl3) 1.96 (2H, qn, d=7.5 Hz), 2.46 (4H, t, J=6.1 Hz), 2.56 (2H, t, J=7.4 Hz), 2.76 (4H, t, J=6.1 Hz), 2.84 (2H, t, J=7.5 Hz), 7.13 (1H, d, J=2.2 Hz), 7.18-7.23 (2H, m), 7.30 (1H, t, J=1.2 Hz), 7.44 (1H, d, J=8.5 Hz), 7.58 (1H, d, J=2.1 Hz), 7.84 (1H, t, J=1.0 Hz), 8.41 (1H, br s); m/e (ES) 323 (M+ +1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]([C:7]1[NH:8][CH:9]=[CH:10][CH:11]=1)=[O:6].[CH2:14]([O:16][CH2:17][CH2:18]Br)[CH3:15]>CN(C=O)C>[CH2:14]([O:16][CH2:17][CH2:18][N:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5](=[O:6])[C:4]([F:3])([F:12])[F:13])[CH3:15]
Reactant: O=C(c1ccc[nH]1)C(F)(F)F
Reactant: CCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCn1cccc1C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 268 mg (6.70 mmol) of NaH (60% dispersion in oil) in 20 mL DMF at 0° C. was added 1.01 g (6.19 mmol) of 2-(trifluoroacteyl)pyrrole and the mixture was stirred at 0° C. for 1 h. After this time, 765 μL (6.51 mmol) of 2-bromoethyl ethyl ether was added and the mixture was warmed to 60° C. and stirred for 16 h. After this time, the reaction mixture was allowed to cool to room temperature, quenched by the addition of a saturated aqueous solution of ammonium chloride, and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (pure hexanes grading to hexanes:EtOAc, 97:3) to give the title compound.
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10].[NH2:21][C:22]1[C:23]2[C:30]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:33][CH:32]=3)=[CH:29][N:28]([CH:44]3[CH2:48][CH2:47][CH:46]([OH:49])[CH2:45]3)[C:24]=2[N:25]=[CH:26][N:27]=1>ClCCl>[C:9](=[O:10])([O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)[O:49][CH:46]1[CH2:47][CH2:48][CH:44]([N:28]2[C:24]3[N:25]=[CH:26][N:27]=[C:22]([NH2:21])[C:23]=3[C:30]([C:31]3[CH:32]=[CH:33][C:34]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:35][CH:36]=3)=[CH:29]2)[CH2:45]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(O)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
N-Methylmorpholine (0.007 ml, 0.062 mmol) was added dropwise to solution of 4-nitrophenyl chloroformate (12.5 mg, 0.062 mmol) in dichloromethane (1 ml) with stirring under nitrogen at 0° C. After 20 minutes, the ice-water bath was removed and the mixture was allowed to warm up to ambient temperature. 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentanol (20 mg, 0.052 mmol) was added to the mixture and the resulting solution was stirred for 24 hours. The reaction mixture was diluted with dichloromethane and washed with water, saturated sodium bicarbonate, and brine. The organic layer was dried (MgSO4), filtered and evaporated to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl (4-nitrophenyl) carbonate. The structure was confirmed by 1H NMR.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7](Cl)[N:6]=[CH:5]2.[NH2:15][C:16]1[CH:27]=[CH:26][C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=1>C(O)(C)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([NH:15][C:16]1[CH:27]=[CH:26][C:19]([C:20]([NH:22][CH:23]([CH3:24])[CH3:25])=[O:21])=[CH:18][CH:17]=1)[N:6]=[CH:5]2
Reactant: CC(C)NC(=O)c1ccc(N)cc1
Reactant: COc1cc2nc(Cl)ncc2cc1Br
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1cc2nc(Nc3ccc(C(=O)NC(C)C)cc3)ncc2cc1Br
Temperature: 100 °C

Procedure:
To a 0.25M suspension of 6-bromo-2-chloro-7-methoxyquinazoline in isopropanol was added 4-amino-N-isopropylbenzamide (1.0 eq). The reaction mixture was heated to 100° C. in an oil bath for 14 h. Reaction mixture was diluted with ethyl acetate and filtered to collect desired product. ES/MS m/z 415/417 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].C([N-]C(C)C)(C)C.[Li+].[CH:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1.C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:38][C:35]2[CH:36]=[CH:37][C:32]([C:29]3[CH:28]=[CH:27][CH:26]=[CH:31][CH:30]=3)=[CH:33][CH:34]=2)[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccc(-c3ccccc3)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (13.19 mmol; 3.21 g) in dry THF (100 mL) under argon at −78° C. was added, dropwise, a 2M solution of lithium diisopropylamide (2M solution in heptanes/THF/ethylbenzene; 15.83 mmol; 7.92 mL). The resulting solution was stirred at −78° C. for 2 hours. 4-Biphenylmethyl bromide (15.83 mmol; 3.91 g) was added and the resulting solution was stirred at −78° C. for 2 hours, then allowed to warm to room temperature overnight. Ethyl acetate (150 ml) was added. The resulting solution was washed with a 1M aqueous hydrochloric acid solution (2×50 mL) and brine (50 mL) and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography (eluent gradient: 0 to 50% EtOAc in heptane) to yield 4-biphenyl-4-ylmethyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester. MS (ESI) m/z 432.3 [M+Na]+.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH3:5].[CH2:7]([O:14][C:15]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([C:28](=[S:30])[NH2:29])[N:17]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:16]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCO>[CH2:7]([O:14][C:15]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([C:28]2[S:30][CH:2]=[C:3]([CH2:4][CH3:5])[N:29]=2)[N:17]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:16]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCC(=O)CBr
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(N)=S)n1-c1ccc(OC)cc1
Solvent: CCO
Product: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(-c2nc(CC)cs2)n1-c1ccc(OC)cc1
Yield: 75.9 %

Procedure:
A solution of 1-bromobutan-2-one (24 μL, 0.21 mmol) and ethyl 3,4-bis(benzyloxy)-5-carbamothioyl-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (29) [prepared under standard conditions from UL1-079 and Lawesson reagent] (100 mg, 0.19 mmol) in EtOH (4 mL) was heated at 80° C. for 45 min. The volatiles were removed in vacuo and the product was purified by silica gel chromatography (12 g cartridge, 0-25% EtOAc in isohexane) to afford ethyl 3,4-bis(benzyloxy)-5-(4-ethylthiazol-2-yl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (30) (82 mg, 75%) as a yellow oil: m/z 569 (M+H)+ (ES+).
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1>S(Cl)(Cl)=O>[ClH:15].[Cl:1][CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1
Reactant: OCc1nc[nH]c1-c1ccc(Cl)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: ClCc1nc[nH]c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 192.8 %

Procedure:
12.25 g (0.05 mole) of 4-hydroxymethyl-5-(4-chlorophenyl)-imidazole hydrochloride is added to stirred thionyl chloride (30 ml). The solution is heated to the boiling temperature and stirred for further 2 hours. After cooling to about 0° C. for about 30 min. the reaction mixture is filtered; the solid on the filter is washed with ethyl ether and dried under vacuum to give 12.7 g (yield 96.6%) of 4-chloromethyl-5-(4-chlorophenyl)-imidazole hydrochloride.
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]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.[CH2:45]1[N:50]([CH2:51][CH2:52][NH2:53])[CH2:49][CH2:48][O:47][CH2:46]1>>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:53][CH2:52][CH2:51][N:50]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[CH2:19][CH2:20]3)[N:12]=[C:11]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:26][CH:27]=3)[N:10]=1)[CH2:2]2
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Reactant: NCCN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCC(NCCN4CCOCC4)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.TFA (50 mg)and 1-(2-aminoethyl)morpholine (0.031 mL) and following the procedure as outlined in example 118, the titled compound was isolated as its tri-TFA salt after HPLC purification; MS (ES+) 615.9 (M+H)+
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[NH:25][C:24](=[O:26])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)(=O)=O)=CC=1.[Cl:28][C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][N:38]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([CH:21]4[NH:25][C:24](=[O:26])[CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCc2ccc(C3CCC(=O)N3)cc2)cc1
Reactant: Clc1cccc(N2CCNCC2)c1
Product: O=C1CCC(c2ccc(CCCCN3CCN(c4cccc(Cl)c4)CC3)cc2)N1

Procedure:
5-[4-(4-(p-Toluenesulfonyloxy)butyl)phenyl]pyrrolidin-2-one and 1-(3-chlorophenyl)piperazine are reacted together to give 5-[4-(4-(4-(3-chlorophenyl)piperazin-1-yl)butyl)phenyl]-pyrrolidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[N:10][S:11][C:12]=2[C:13]2[C:14](Cl)=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:20]([NH2:22])[CH3:21]>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[N:10][S:11][C:12]=2[C:13]2[C:14]([NH:22][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1-c1nnsc1-c1cccnc1Cl
Reactant: CCN
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCNc1ncccc1-c1snnc1-c1cccnc1Cl
Temperature: 105 °C
Yield: 66.3 %

Procedure:
A mixture of 4, 5-di-(2-chloropyridin-3-yl)-1, 2, 3-thiadiazole (1.823 g), and ethylamine (0.61 g) in dioxane (9 mL) was heated at 105° C. in a sealed tube 3 days. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel gave 4-(2-chloropyridin-3-yl)-5-(2-ethylaminopyridin-3-yl)-1, 2, 3-thiadiazole (1.243 g) as an oil.