Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[CH:11][NH:12][C:13]1[N:17]([CH2:18][CH3:19])[N:16]=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:18]([N:17]1[C:13]2=[N:12][CH:11]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([OH:20])=[C:14]2[CH:15]=[N:16]1)[CH3:19]
Reactant: CCOC(=O)C(=CNc1ccnn1CC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(cnn2CC)c1O
Temperature: 25 °C

Procedure:
(1-Ethylpyrazol-5-ylamino)methylenemalonate diethyl ester (180 mmol from previous reaction) was dissolved in diphenyl ether (200 mL), and the resulting solution was placed in a preheated oil bath at 255° C. The reaction solution was heated for 5 h, and then the diphenyl ether was removed via distillation. The resulting brown reaction mixture was cooled to room temperature and poured into hexane (1 L). This solution was cooled to −78° C., and the resulting precipitate was filtered to afforded the title compound as a beige colored needle shaped solid that was >90% pure by HPLC and was used directly (25 g, 60% for 2 steps). A portion was recrystallized using ethanol-H2O to afford a white solid: mp 85-86° C.; LRMS (m/z) 236 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[S:33](Cl)(=[O:35])=[O:34]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[S:33]([C:29]2[S:28][CH:32]=[CH:31][N:30]=2)(=[O:35])=[O:34])[CH:7]=1
Reactant: O=S(=O)(Cl)c1nccs1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3ncccn3)cc2)S(=O)(=O)c2nccs2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 1 from 3-{3-[(4-pyrimidin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11z, and thiazole-2-sulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.80 (d, 2H), 8.30 (d, 2H), 7.96 (d, 1H), 7.59 (m, 1H), 7.24-7.13 (m, 4H), 7.05 (d, 1H), 6.96 (d, 1H), 6.92 (s, 1H), 4.54 (s, 2H), 4.49 (s, 2H), 3.64 (s, 3H), 2.82 (t, 2H), 2.51 (t, 2H); MS 509 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)=O)[N:10]=2)[CH2:4][C:3]1([CH3:21])[CH3:20].[F:22][C:23]([F:35])([CH3:34])[CH2:24][O:25][C:26]1[C:31]([CH2:32][NH2:33])=[CH:30][N:29]=[CH:28][N:27]=1>O1CCOCC1>[F:35][C:23]([F:22])([CH3:34])[CH2:24][O:25][C:26]1[C:31]([CH2:32][NH:33][C:11]2[N:10]=[C:9]([NH:8][C@@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[C:3]([CH3:21])([CH3:20])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:30][N:29]=[CH:28][N:27]=1
Reactant: CC(F)(F)COc1ncncc1CN
Reactant: CS(=O)c1ncc(C#N)c(N[C@H]2CC[C@@H](O)C(C)(C)C2)n1
Solvent: C1COCCO1
Product: CC(F)(F)COc1ncncc1CNc1ncc(C#N)c(N[C@@H]2CC[C@H](O)C(C)(C)C2)n1
Yield: 69.6 %

Procedure:
A solution of 4-(((1S,4R)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfinyl)pyrimidine-5-carbonitrile (1.0 equiv) and (4-(2,2-difluoropropoxyl)pyrimidin-5-yl)methanamine (1.5 equiv) in dioxane (0.15 M) was heated at 110° C. for 1 h. Standard work-up provided 2-(((4-(2,2-difluoropropoxyl)pyrimidin-5-yl)methyl)amino)-4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)pyrimidine-5-carbonitrile (69.6% yield). 1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.72 (s, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 7.99 (t, J=5.66 Hz, 1H), 7.17 (d, J=7.81 Hz, 1H), 4.64 (t, J=12.89 Hz, 2H), 4.39-4.49 (m, 2H), 4.29 (d, J=3.51 Hz, 1H), 3.85-4.00 (m, 1H), 3.12 (br. s., 1H), 1.73 (t, J=19.14 Hz, 4H), 1.42-1.55 (m, 3H), 1.21-1.33 (m, 3H), 1.10 (br. s., 1H), 0.59-0.78 (m, 5H). MS (ESI) m/z 448.2 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)=[C:6]([C:22]([O:24][CH3:25])=[O:23])[C:5]([N:26](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:26][C:5]1[C:6]([C:22]([O:24][CH3:25])=[O:23])=[C:7]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)[C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(N)ccc(Br)c1OC[C@H]1CCCN1
Yield: 100.2 %

Procedure:
A solution of tert-butyl (R)-2-[6-bromo-3-bis-(tert-butoxycarbonyl)amino-2-methoxycarbonylphenoxymethyl]pyrrolidine-1-carboxylate (Intermediate 8, 3.15 g) in TFA (20 mL) and DCM (20 mL) was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with aqueous potassium carbonate solution. The aqueous layer was extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to give methyl 6-amino-3-bromo-2-((R)-1-pyrrolidin-2-ylmethoxy)benzoate (1.65 g) as a colourless gum.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[O:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.[BH3-]C#N.[Na+]>>[O:23]1[CH2:28][CH2:27][CH:26]([NH:1][CH2:2][CH:3]2[CH2:12][CH2:11][CH2:10][C:9]3[C:8]([O:13][C:14]4[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=4)=[CH:7][CH:6]=[CH:5][C:4]2=3)[CH2:25][CH2:24]1
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2cccc3c2CCCC3CNC2CCOCC2)nc1
Yield: 45.2 %

Procedure:
Using a method similar to Example 204, using 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide (intermediate 20, 238 mg, 0.800 mmol), tetrahydro-4H-pyran-4-one (160 mg, 1.60 mmol), and NaBH3CN (100 mg, 1.60 mmol) gives the title compound (138 mg) as a white foam. Mass spectrum (ion spray): m/z=382 (M+1); 1HNMR (CDCl3): 8.57 (s, 1H), 8.16 (d, 1H), 7.23-7.16 (m, 2H), 6.94-6.90 (m, 2H), 5.86 (br. s, 2H), 4.00 (d, 2H), 3.40 (t, 2H), 3.15-2.78 (m, 3H), 2.65-2.41 (m, 2H), 1.97-1.46 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1[Cl:8]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[NH2:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: Nc1ccc(Cl)c(Cl)c1
Yield: 96.5 %

Procedure:
22.1 g of 3,4-dichloro-nitrobenzene and 70 g of toluene are placed in an agitator autoclave, and the catalyst suspension is flushed in with 4 g of water. Hydrogenation subsequently takes place at a temperature of 100° C. and at a hydrogen pressure of 5 bar. When the hydrogen up-take is complete, the autoclave is cooled and rendered inert with nitrogen. The catalyst is filtered off and washed with toluene. After working up by distillation, 18.0 g of 3,4-dichloroaniline (yield 96.8% of theory) are obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])(=[O:3])[CH3:2].Br[C:11]1[CH:12]=[CH:13][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH:32]4[CH2:34][CH2:33]4)=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[N:15][CH:16]=1>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:11]2[CH:16]=[N:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[C:30]([CH3:31])=[CH:29][C:28]([CH:32]5[CH2:34][CH2:33]5)=[CH:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)[C:5]1=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cn2)CC1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C)CC3)nc2)C1=O
Yield: 11.5 %

Procedure:
Using 1-acetyl-2-imidazolidinone (316 mg) and (5-bromopyridin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (900 mg) described in Preparation Example 135 and by the reaction and treatment in the same manner as in Example 1, the title compound (116 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:23][CH3:24])=[C:5]([O:21][CH3:22])[C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1.O.O.Cl[Sn]Cl>C(O)C>[CH3:1][O:2][C:3]1[C:4]([O:23][CH3:24])=[C:5]([O:21][CH3:22])[C:6]2[S:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)=[N:8][C:7]=2[CH:20]=1
Reactant: COc1cc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c(OC)c1OC
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1cc2nc(-c3ccc(N)cc3)sc2c(OC)c1OC

Procedure:
To a stirred solution of 3,4,5-trimethoxybenzenamine (16d, 5g, 27.2 mmol) in pyridine as solvent and base to this 4-nitrobenzoyl chloride (17, 5.5g, 29.9 mmol) is added slowly and reflux for 3h, after completion of the reaction, reaction mixture is poured in water, filter and washed with dil HCl and dried to afford compound 4-nitro-N-(3,4,5-trimethoxyphenyl)benzamide (18d). To a stirred solution of amide (18d, 6g, 18.0 mmol) taken in toluene lawessons reagent (5.1g, 12.6 mmol) is added and refluxed at 110° C. for 6h. after completion of the reaction toluene is evaporated under vacuum and water is added and extracted into chloroform and finally purified by column chromatography to afford pure compound 4-nitro-N-(3,4,5-trimethoxyphenyl) benzothioamide (19d). Treating the thioamide product (19d, 4g, 11.4 mmol) with potassium ferricyanide (4 eq) in aqueous sodium hydroxide (8 eq) solution at 90° C. for 2h cyclization takes place to obtain the 5,6,7-trimethoxy-2-(4-nitrophenyl) benzo[d]thiazole (20d) solid is precipitated from the reaction mixture filtered and washed with water and dried to afforded product 20d. Reduction of the nitro compound (20d, 1 g, 2.8 mmol) is proceeded with SnCl2.2H2O in ethanol and reflux at 80° C. for 2h, after completion of reaction ethanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered in celite bed and purified in silica column (60-120) to afforded pure compound (21d). The compound 4-(5,6,7-trimethoxybenzo[d]thiazol-2-yl)benzenamine (21d, 250 mg, 0.79 mmol) on reaction with 3,5-dimethoxybenzaldehyde (22d, 131 mg, 0.79 mmol) in ethanol using catalytic amount of acetic acid and refluxed for 2h after completion reaction mixture is cooled to 0° C. solid is precipitated from the reaction mixture it is filtered and washed with ethanol to gave the enamine product, and immediately proceeded for the next reaction with using (p-tolylsulfonyl) methyl isocyanide (tosmic) (1.5 eq), and potassium carbonate (2 eq) as base, in 10 mL of methanol and 5 mL of DME was heated under reflux for 12 h after completion of reaction as monitored by TLC. It was cooled to room temperature (27° C.); the solution was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc and Hexane to gave compound 7d as a brown solid (62%).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>>[ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:22])[CH2:17][CH2:18][N:19]([CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:20][CH2:21]2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: BrCCCc1ccccc1
Reactant: FC1(c2cccc(OCc3ccccc3)c2)CCNCC1
Agent: Cl
Product: FC1(c2cccc(OCc3ccccc3)c2)CCN(CCCc2ccccc2)CC1

Procedure:
This material was prepared by the alkylation of 4-(3-benzyloxyphenyl)-4-fluoropiperidine hydrochloride with 1-bromo-3-phenylpropane and subsequent salt formation with methanolic hydrogen chloride as described in Step 3 of Example 1 in 43% overall yield.
Reaction SMILES: [Li].C([N:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[CH:11][S:10]1(=[O:20])=[O:19])C1C=CC=CC=1.CCO.N>C1COCC1>[NH:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][S:10]1(=[O:19])=[O:20]
Reactant: O=S1(=O)C=Cc2ccccc2N1Cc1ccccc1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCO
Product: O=S1(=O)CCc2ccccc2N1
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
Freshly polished lithium flakes (2.0 g, 0.28 mol) were added to a solution of 1-benzyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (6.5 g, 24 mmol) in THF (120 mL)/EtOH (12 mL) and liquid NH3 (150 mL) at −40° C. with stirring over 0.5 h. The reaction was quenched with NH4Cl powder (10 g). Water (200 mL) and EtOAc (200 mL) were added. The two layers were separated and the aqueous phase was extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (200 mL×3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane=1:4) to afford 3,4-dihydro-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.5 g, 34% yield).
Reaction SMILES: [C:1]1([CH:7]2[C:19]3[NH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]=3[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[F:30])[C:24](Cl)=[O:25]>ClCCCl>[F:20][C:21]1[CH:22]=[C:23]([C:24]([N:8]2[CH2:9][CH2:10][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[NH:18][C:19]=3[CH:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:25])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Solvent: ClCCCl
Product: O=C(c1ccc(F)c(F)c1)N1CCc2c([nH]c3ccccc23)C1c1ccccc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 35.6 %

Procedure:
The title compound was prepared by the addition of 1-phenyl-2,3,4,9-tetrahydro-1H-beta-carboline (95 mg, 383 μmol), DCE (5 mL), 3,4-difluorobenzoyl chloride (88 mg, 498 μmol), and TEA (1.0 mL) to a 25 mL flask. The solution was allowed to stir at 55° C. for 16 hours. The reaction solution was concentrated, and the crude sample was chromatographed (SiO2, 100% hexane to 25% EtOAc) to yield 53 mg of title compound; 1H NMR (CDCl3) δ 8.02 (1H, br s), 7.53 (1H, d), 7.30-7.33 (6H, m), 7.15-7.23 (5H, m), 7.07 (1H, br s), 3.75 (1H, m), 3.41 (1H, m), 2.93 (1H, m), 2.84 (1H, dd); MS (ESI): 389 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.S(=O)(=O)(O)O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][O:6][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: C1=COCCC1
Reactant: COC(=O)C(C)(C)CO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)C(C)(C)COC1CCCCO1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 117 %

Procedure:
To a solution of 66.3 mL (0.51 mol) of hydroxypivalic acid methyl ester in DCM (325 mL) are added 95.8 mL (1.04 mol) of 3,4-dihydro-2H-pyran. The reaction mixture is cooled to 0° C. and sulfuric acid on silica gel (2.04 g, 0.2 mL sulfuric acid/10 g silica gel) is added and the reaction mixture is stirred at room temperature for 25 minutes. After this time, the reaction mixture is filtered and concentrated under reduced pressure to yield 129 g of 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propionic acid methyl ester as a yellow oil, which is used in the next step without further purification. Yield: quantitative; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (6H, s), 1.13 (6H, s), 1.4-1.7 (6H, m), 3.3 (1H, m), 3.4 (1H, m), 3.6 (3H, s), 3.65 (1H, d), 3.7 (1H, m), 4.55 (1H, t).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c(Br)c1

Procedure:
A mixture of 18.9 g (100 mmol) of 2-bromo-4-fluorotoluene, 17.8 g (100 mmol) of N-bromosuccinimide, 400 mg of benzoyl peroxide, and 200 ml of CCl4 were refluxed for 2 h. The reaction mixture was filtered through a glass frit (G2), and the precipitate was additionally washed with 3×50 ml of CCl4. The combined filtrate was evaporated to dryness. Fractional distillation of the residue (bp 92-96° C./4 mm Hg) gave the title product as colorless oil. Yield 20.4 g (76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[CH2:16][CH2:15][N:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:13](=[O:24])[C:12]=2[C:11]([CH3:25])=[C:10]1[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:13](=[O:24])[C:12]=2[C:11]([CH3:25])=[C:10]1[C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1
Reactant: Cc1c2c(n(-c3ccc(Cl)cc3Cl)c1-c1ccc(O)cc1)CCN(N1CCCCC1)C2=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(O)cc2)n(-c2ccc(Cl)cc2Cl)c2ccn(N3CCCCC3)c(=O)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
A suspension of 1-(2,4-dichlorophenyl)-2-(4-hydroxyphenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (153 mg, 0.325 mmol) and DDQ (295 mg, 1.301 mmol) in 1,4-dioxane (12 ml) was stirred at rt for 1 h and 20 min followed by 1 h and 50 min at 35° C. and 2 h and 50 min at 45° C. The solvent was evaporated and the product purified by hplc. The solvent was evaporated and water added. The product was extracted from the water phase with DCM and EtOAc. The combined organic phases were evaporated and the residue was re-suspended in toluene and evaporated to yield the product as a yellow solid (74 mg, 49%). MS m/z 468 (M+H)+.
Reaction SMILES: [S:1]1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]([C:8]([OH:10])=[O:9])[CH2:2]1.[CH3:11]SC>>[CH3:11][CH:2]1[CH:3]([C:8]([OH:10])=[O:9])[C:4](=[O:7])[CH2:5][CH2:6][S:1]1
Reactant: CSC
Reactant: O=C(O)C1CSC=CC1=O
Product: CC1SCCC(=O)C1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of methyl cuprate in dimethylsulfide (prepared from 1.05 g copper (I) iodide/4.0 mL dimethylsulfide and 4.0 mL methyllithium/ether at -78° C.) at -78° C. was added a solution of 2,3-dihydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.910 g, 4.6 mmol) in dimethylsulfide (5 mL). The resulting yellow-colored solution was stirred for 30 min. at the same temperature. The reaction mixture was quenched with a saturated solution of ammonium chloride and ammonia solution and then warmed to room temperature for and 1 h. The reaction mixture was added to ether (100 mL) and the etheral layer washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the product purified by flash column chromatography on silica gel eluted with hexane:ether (4:1) to give 2-methyl-tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.794 g) as a 7:3 mixture of enol:keto tautomers.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[C:29]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:36][CH2:37][C:38](=[O:44])[N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)([CH2:30][CH2:31][C:32]([O:34]C)=[O:33])[CH2:3]1.[OH-].[Na+].O>CO>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[C:29]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:36][CH2:37][C:38](=[O:44])[N:39]2[CH2:40][CH2:41][CH2:42][CH2:43]2)([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:3]1
Reactant: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)OC)(CCC(=O)N1CCCC1)CC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)O)(CCC(=O)N1CCCC1)CC2=O
Reaction time: 1 h
Yield: 25.8 %

Procedure:
To a solution of 240 mg (0.40 mmol) of the title product of Example 51 in 4 ml of methanol was added 0.15 ml of a 50% aqueous solution of sodium hydroxide and 1 ml of water. The mixture was stirred for 1 hour at reflux and then permitted to cool. The cooled reaction mixture was partitioned between ethyl acetate and 3N hydrochloric acid, and the aqueous layer was further extracted with two portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. Chromatography of the residue over silica gel, using methanol/ethyl acetate/acetic acid as eluent, gave a glass which was triturated with diethyl ether to give the title compound (61 mg) as a solid, m.p. 160°-164° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[S:3]([C:6]1[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][N:7]=1)(=[O:5])=[O:4].[CH3:15][C:16]([CH3:27])([CH:20]1[O:25][CH:24]([CH3:26])[CH2:23][CH2:22][O:21]1)[CH2:17][NH:18][CH3:19]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:14])[S:3]([C:6]1[S:10][C:9]([NH:11][C:12]([N:18]([CH2:17][C:16]([CH3:15])([CH3:27])[CH:20]2[O:25][CH:24]([CH3:26])[CH2:23][CH2:22][O:21]2)[CH3:19])=[O:13])=[N:8][N:7]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1nnc(N=C=O)s1
Reactant: CNCC(C)(C)C1OCCC(C)O1
Solvent: CCOC(C)=O
Product: CC1CCOC(C(C)(C)CN(C)C(=O)Nc2nnc(S(=O)(=O)N(C)C)s2)O1

Procedure:
5-(N,N-Dimethylaminosulfonyl)-1,3,4-thiadiazol-2-yl isocyanate dimer (6 grams) N-[2,2-dimethyl-2-(4-methyl-1,3-dioxan-2-yl)ethyl]methylamine (6 grams) and ethyl acetate (20 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer. The reaction mixture is heated on a steam bath for a period of about 2 hours. Solvent is then stripped off using a rotary evaporator to yield the desired product N-[5-(N,N-dimethylaminosulfonyl)-1,3,4-thiadiazol-2-yl]-N-[2,2-dimethyl-2-(4-methyl-1,3-dioxan-2-yl)ethyl]-N-methylurea as the residue.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=[O:7])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[OH:11])[CH3:2]
Reactant: CCc1cc(C=O)ccc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1cc(CO)ccc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of 3-ethyl-4-hydroxybenzaldehyde (4.7 g, 26 mmol) in anhydrous THF (150 mL) at 0° C. under N2 was added dropwise 1 M LiAlH4 in Et2O (52 mL, 52.2 mmol). The resulting mixture was stirred at 0° C. for 2 h and then quenched by cautious addition of water and stirred for 15 minutes. The reaction mixture was then absorbed onto silica and loaded onto a silica pad which was washed with EtOAc. The EtOAc washings were collected and concentrated in vacuo to afford the title compound as a colourless oil (3.67 g).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([NH:9][C:10]([NH:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[N:8][C:4]=2[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[S:27](Cl)(=[O:29])=[O:28].O>[OH-].[Na+]>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[S:27]([O:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([NH:9][C:10](=[O:11])[NH:12][CH2:13][CH2:14][O:15][CH3:16])=[N:8][C:4]=2[CH:3]=1)(=[O:29])=[O:28]
Reactant: COCCNC(=O)Nc1nc2cc(O)ccc2[nH]1
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCNC(=O)Nc1nc2cc(OS(=O)(=O)c3c(Cl)cccc3Cl)ccc2[nH]1
Temperature: 5 °C

Procedure:
To a solution of 175 mg of 1-(5-hydroxy-1H-benzimidazol-2-yl)-3-(2-methoxyethyl)urea in 15 cm3 of 0.1N aqueous sodium hydroxide solution are added 189 mg of finely ground 2,6-dichlorobenzenesulfonyl chloride. The suspension is stirred for about 20 hours at a temperature in the region of 20° C., 10 cm3 of water are then added and the mixture is cooled to about 5° C. for about 15 minutes. The precipitate is filtered off by suction, washed with three times 2 cm3 of water and dried under reduced pressure (13 kPa) over phosphorus pentoxide. After flash chromatography on a column of silica [eluent: dichloromethane/methanol/acetonitrile (95/3/2 by volume)], 65 mg of 2-{[(2-methoxyethyl)carbamoyl]amino}-1H-benzimidazol-5-yl 2,6-dichlorobenzenesulfonate are obtained in the form of a cream-coloured powder, the characteristics of which are as follows: