Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][S:32]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)(=[O:34])=[O:33])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=S(=O)(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)c1ccccc1

Procedure:
The title compound, white solid (25.7 mg, 66.8%), MS (ISP) m/z=471.3 [(M+H)+], was prepared in accordance with the general method of example 69 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and benzenesulfonyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[NH:13][C:14]3[C:19]([C:20]=1[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=[CH:5]2.CC([O-])=O.[K+].[Br:31]Br>CC(O)=O.O>[Br:31][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:12]1[NH:13][C:14]3[C:19]([C:20]=1[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8]2
Reactant: CCCCCc1c(-c2ccc3cc(O)ccc3c2)[nH]c2ccccc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCc1c(-c2ccc3c(Br)c(O)ccc3c2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.7 %

Procedure:
To a stirred solution of 2-(6-hydroxy-2-naphthyl)-3-pentyl-1H-indole (1.27 g, 3.85 mmol) in HOAc (25 mL) at 0° C. was added KOAc (0.453 g, 4.62 mmol). The reaction was stirred at this temperature for 10 min., and then a solution of Br2 (0.218 mL, 4.24 mmol) in HOAc (5 mL) was added dropwise to it over a period of −10 min. The reaction mixture was allowed to warm to rt and stirred for 4 h. The reaction mixture was then diluted with H2O (50 mL) and extracted with EtOAc (200 mL). The organic layer was washed with brine (20 mL) and then dried (Na2SO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (10 to 30% EtOAc:petroleum ether gradient) to afford the product (0.782 g, 50%) as a solid (inseparable mixture of mono- and di-bromo-substituted analogs which were separated in the next step); monobrominated compound: mass spectrum [(−) ESI], m/z 406/408 (M−H)− and dibrominated analog: mass spectrum [(−) ESI], m/z 486 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[N:41]1([CH2:45][C@@H:46]([NH:50][CH3:51])[CH2:47][CH2:48][CH3:49])[CH2:44][CH2:43][CH2:42]1>CN(C=O)C>[N:41]1([CH2:45][C@@H:46]([N:50]([CH3:51])[C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=2[Cl:1])[CH2:47][CH2:48][CH3:49])[CH2:44][CH2:43][CH2:42]1
Reactant: CCC[C@@H](CN1CCC1)NC
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCC[C@@H](CN1CCC1)N(C)C(=O)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
2,4-Dichlorobenzoic acid (92 mg, 0.48 mmol) and TBTU (162 mg, 0.50 mmol) was mixed in DMF (1.5 mL). The mixture was cooled to 0° C. and NMM (0.063 mL, 0.58 mmol) was dropwise added. After 10 min at 0° C. was (S)-1-(azetidin-1-yl)-N-methyl-pentan-2-amine (Compound J1) (75 mg, 0.48 mmol) added. The resultant mixture was stirred at 0° C. for 30 min and at rt for 16 h. The mixture was concentrated and the residue dissolved in DCM (5 mL). The organic phase was washed with NaHCO3 (saturated, 2×5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (98 mg, 62%). Mixture of rotamers: 1H NMR (400 MHz, DMSO-d6): 0.59-0.87, 0.90, 0.98-1.66, 1.72-2.11, 2.22-2.47, 2.5, 2.78, 4.26-4.70, 7.24-7.36, 7.43-7.64, 7.65-7.79. Total no of protons: 22. HRMS (M+H)+: calculated 329.1187. found 329.1161
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](/[C:33]2[CH:42]=[CH:41][C:36]3[O:37][C:38]([CH3:40])=[CH:39][C:35]=3[CH:34]=2)\[C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:20][CH:19]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8]C)=[O:7].O.[OH-].[Li+]>C(O)C.O>[CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](/[C:33]2[CH:42]=[CH:41][C:36]3[O:37][C:38]([CH3:40])=[CH:39][C:35]=3[CH:34]=2)\[C:18]2[CH:19]=[CH:20][C:21]([C:24]#[C:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:22][CH:23]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc3oc(C)cc3c2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc2cc(/C(=C/COc3ccc(OCC(=O)O)c(C)c3)c3ccc(C#CCN4CCOCC4)cc3)ccc2o1
Reaction time: 48 h

Procedure:
The above ester (0.34 g, 0.60 mmol) was dissolved in ethanol (30 mL), a solution of lithium hydroxide monohydrate (0.08 g, 1.9 mmol) in water (3 mL) was added and the mixture was left to stand for 48 h. The solvents were evaporated in vacuo; the residue was diluted with water (25 mL) and acidified with acetic acid (0.3 mL). The formed precipitate was filtered off and dried in the air yielding the title compound as amorphous solid.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:32]([F:34])[F:33])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+].Cl>O1CCCC1>[F:34][CH:32]([F:33])[O:31][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:35])=[O:2])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A solution of [4-difluoromethoxy-2-ethyl-8-fluoro-3-(4-trifluoromethoxybenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.054 g) in tetrahydrofuran (4.0 mL) was treated with 1.0M aqueous lithium hydroxide solution (0.21 mL), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was acidified by the addition of 0.1M aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative reverse-phase HPLC gave title compound as a white solid (0.042 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:28][CH:29]([CH2:32][OH:33])[CH2:30][OH:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:10]=2[N:11]=[C:12]([NH:28][CH:29]([CH2:32][OH:33])[CH2:30][OH:31])[N:13]=1
Reactant: NC(CO)CO
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(S(C)(=O)=O)nc21
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(NC(CO)CO)nc21

Procedure:
The product of Example 58, and serinol were reacted by the procedure of Example 60 to afford the title compound 4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 0.84 (m, 6H), 1.91 (m, 2H), 2.32 (m, 2H), 3.02 (m, 2H), 3.95 (m, 4H), 4.14 (m, 1H), 5.30 (m, 0.5H), 5.52 (m, 0.5H), 6.28 (br d, 1H, J=9.6), 6.40 (br s, 1H), 7.12 (d, 1H, J=9.6 Hz), 7.30-7.58 (m, 4H). LC MS (m/e)=417 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([OH:14])=O)[CH2:4][CH2:3]1.[CH3:16][Li].[Cl-].[NH4+]>CCOCC>[CH3:15][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12](=[O:14])[CH3:16])[CH2:4][CH2:3]1
Reactant: [Li]C
Reactant: CC1(C)CCC(C(=O)O)c2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)C1CCC(C)(C)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
16.8 g of 1,1-dimethyl-tetralin-4-carboxylic acid are treated dropwise in 200 ml of absolute ether under a nitrogen or argon atmosphere with 99.2 ml of a 2 molar solution of methyl lithium in ether (198.4 mmol). The mixture is stirred at room temperature for 1 hour and subsequently held at reflux temperature for a further 1 hour. The mixture is poured into saturated ammonium chloride solution, extracted with ether, washed neutral with water and dried over sodium sulphate. The ether is evaporated and the residue is fractionally distilled. There are obtained 8.4 g of 1,1-dimethyl-4-acetyl-tetralin of boiling point 69° C./0.07 mmHg; nD20 =1.5333; yield 50%. Odour: see (5).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH3:20])[C:13]=2[CH3:21])=[N:7][CH:8]=1)[CH3:2].[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([O:24][C:23]([F:22])([F:33])[F:34])[CH:26]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:20])[C:13]=2[CH3:21])=[N:7][CH:8]=1)[CH3:2]
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: CCc1cnc(NCCc2ccc(OC)c(C)c2C)nc1
Product: CCc1cnc(N(CCc2ccc(O)c(C)c2C)Cc2cccc(OC(F)(F)F)c2)nc1

Procedure:
Similarly prepared from 5-ethyl-N-[2-(4-methoxy-2,3-dimethylphenyl)ethyl]pyrimidin-2-amine and 3-trifluoromethoxy benzyl bromide.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>O1CCCC1.CCCCCC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:32])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexane solution, 0.701 ml, 1.10 mmol) was added to a tetrahydrofuran (5 ml) solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (303 mg, 1.00 mmol) obtained in Example 5. The temperature of the resulting mixture was raised to room temperature and then stirred for 10 minutes. After cooling the reaction mixture to −78° C., benzoyl chloride (0.140 ml, 1.20 mmol) was added thereto dropwise. The reaction mixture was stirred at −78° C. for 30 minutes. The temperature of the mixture was then raised to OC over 3 hours. After addition of 1N hydrochloric acid (2.0 ml), the mixture was extracted with ethyl acetate. The extracts were combined, washed successively with water, a saturated aqueous solution of sodium bicarbonate, and brine, dried over MgSO4, and then concentrated. The residue was purified by medium-pressure chromatography on a silica gel column (10% ethyl acetate-hexane). The solid thus obtained was washed with hexane, whereby the title compound (200 mg, 49%) was obtained as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C@@H:6]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[C:8]1=[O:25])[CH3:2].[H][H]>CCO.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C@@H:6]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:16]=2)[C:8]1=[O:25])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCC(CCCc2ccc3cccnc3n2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCC(CCCc2ccc3c(n2)NCCC3)C1=O

Procedure:
A mixture of 2-8 (340 mg, 0.7991 mmol) and 10% Pd/carbon (170 mg) in EtOH (10 mL) was stirred under a balloon of hydrogen for 4 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH) to give 2-9 as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1.[CH3:18][C:19]([CH3:25])([CH2:22][CH2:23][CH3:24])[CH2:20][OH:21].[H-].[Na+]>>[CH3:18][C:19]([CH3:25])([CH2:22][CH2:23][CH3:24])[CH2:20][O:21][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: CCCC(C)(C)CO
Agent: [H-]
Agent: [Na+]
Product: CCCC(C)(C)COc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
To a suspension of 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (500 mg) and 2,2-dimethylpentanol (3.8 mL) at 50° C. was added sodium hydride (396 mg, 60% dispersion) in portions. To the resultant viscous foam was added a further portion of 2,2-dimethylpentanol (1.5 mL). The reaction was stirred at 50° C. for 72 h. The reaction mixture was cooled then carefully quenched with water (10 mL) and extracted with EtOAc (3×25 mL). The organics were combined, washed with brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. This was azeotroped with toluene (×3) and the resulting viscous yellow oil was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (30-80%) to afford the title compound as a brown solid (372 mg).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.CC([O-])(C)C.[K+].Br[CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:26]=[C:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[S:24][C:23]=2[S:31]([NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])=[O:32])[CH:19]=[CH:20][CH:21]=1>CS(C)=O.C(Cl)Cl>[N:5]1([CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[CH:26]=[C:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[S:24][C:23]=3[S:31]([NH:34][C:35]([CH3:37])([CH3:36])[CH3:38])(=[O:32])=[O:33])[CH:19]=[CH:20][CH:21]=2)[C:4](=[O:6])[CH2:3][CH2:2][C:1]1=[O:7]
Reactant: O=C1CCC(=O)N1
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)Cc1cc(-c2cccc(CN3C(=O)CCC3=O)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of succinimide (66.6 mg, 0.672 mmol) in DMSO (1 mL) and t-BuOK (52.8 mg, 0.470 mmol), that had been stirred for 40 min at ambient temperature, was added a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (99.5 mg, 0.224 mmol; see step (e)) in DMSO (1 mL) dropwise. The reaction mixture was stirred for 1 h at ambient temperature and then diluted with CH2Cl2 (15 mL). The organic layer was washed with water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (3:97) as eluent to give the sub-title compound in 94% yield as a colourless syrup (97.1 mg, 0.210 mmol).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCN(C(=O)CCC)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN(C(=O)CCC)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(n-butanoyl)-n-pentylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=O)#[N:2].[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[Li]>>[C:17]([O:16][C:13](=[O:15])[CH2:14][C:6]([C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:8])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(C#N)c1
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
The title compound was prepared from methyl 3-cyanobenzoate [CAS-No. 13531-48-1] by treatment with lithium tert.-butyl acetate according to general procedure K (method b). Obtained as a light brown oily semisolid.
Reaction SMILES: [CH:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:12]([C:14]([CH3:16])=[O:15])=[CH2:13].[OH-].[K+].N#N.C(N(CC)CC)C>>[CH3:16][C:14](=[O:15])[CH2:12][CH2:13][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C=CC(C)=O
Reactant: CCCCCCCCCC=O
Agent: N#N
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)CCC(C)=O
Reaction time: 12 h

Procedure:
78.1 g (0.5 mol) of caprinaldehyde, 35.1 g (0.5 mol) of methyl vinyl ketone and 13.5 g (0.05 mol) of Cat. 1 are introduced into a 250 ml three-necked flask equipped with a stirrer, reflux condenser (high efficiency, KOH drying tube) and N2 inlet. After adding 40.4 g (0.4 mol) of triethylamine, a N2 atmosphere is set up, the mixture is stirred and the surrounding oil bath is brought to 80° C. The initially undissolved catalyst dissolves and after some time triethylamine hydrochloride precipitates. The mixture is kept at 80° C for 12 hours. For working up, it is first cooled, and then the procedure described in Example 21 is followed. Tetradecane-2,5-dione is obtained. Recrystallization from methanol.
Reaction SMILES: [NH2:1][C:2]1[C:3](/[CH:9]=[CH:10]/[C:11]([O:13]CC)=O)=[N:4][C:5](I)=[N:6][CH:7]=1.[BrH:16].C(O)(=O)C>>[Br:16][C:5]1[N:6]=[CH:7][C:2]2[N:1]=[C:11]([OH:13])[CH:10]=[CH:9][C:3]=2[N:4]=1
Reactant: Br
Reactant: CCOC(=O)/C=C/c1nc(I)ncc1N
Solvent: CC(=O)O
Product: Oc1ccc2nc(Br)ncc2n1
Reaction time: 1.5 h

Procedure:
A 3-necked roundbottom flask, was charged with (E)-ethyl 3-(5-amino-2-iodopyrimidin-4-yl)acrylate (120 g, 388 mmol) followed by hydrogen bromide/acetic acid (1500 ml). The resulting solution was allowed to react, with stirring, for 1.5 hours while the temperature was maintained at 40˜50° C. Upon completion, the mixture was concentrated under reduced pressure. The resulting residue was dissolved in 500 ml of methanol and the pH was adjusted to 7 by the addition of sodium bicarbonate. The resulting mixture was washed once with a solution of 46 g of NaHSO3 in 200 mL of water. The organic layer was concentrated under reduced pressure. The resulting slurry was filtered and the solids collected to afford the title compound.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:24][N:25]([CH:33]=[O:34])[O:26]C2CCCCO2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C>O>[CH:1]1([CH2:6][C@H:7]([CH2:24][N:25]([CH:33]=[O:34])[OH:26])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1NCC[C@H]1C(=O)Nc1ncccn1)OC1CCCCO1
Solvent: O
Solvent: CC(=O)O
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1NCC[C@H]1C(=O)Nc1ncccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A mixture of (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-N-2-pyrimidinyl-3-pyrazolidinecarboxamide (20 mg, 0.042 mmol) in the solution of Acetic Acid (2 ml) and Water (0.500 ml) was stirred at 25° C. for overnight. The solvent was removed to give a residue. The residue was purified by RP-HPLC to give (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-2-pyrimidinyl-3-pyrazolidine carboxamide (9 mg, 0.023 mmol, 54% yield). MS (ES+) m/z 391.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:12][OH:13]>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH:12]=[O:13]
Reactant: Cc1c(CO)[nH]c2c(C)cccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1c(C=O)[nH]c2c(C)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
A mixture of (3,7-dimethyl-1H-indol-2-yl)methanol (440 mg, 2.5 mmol) and manganese dioxide (1.09 g, 12.5 mmol) in dichloromethane (15 mL) was stirred overnight at rt. The mixture was filtered and evaporated. The crude was chromatographed over silica gel eluting with ethyl acetate/hexane (5% and 7.5%) to afford the title compound (200 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 8.75 (s, 1H), 7.51 (d, J=7.2 Hz, 1H), 7.15 (d, J=7.4 Hz, 1H), 7.05 (t, J=7.3 Hz, 1H), 2.61 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Cl:7][C:8]1[N:16]=[C:15](Cl)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>CO>[Cl:7][C:8]1[N:16]=[C:15]([O:4][CH3:2])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)[O-]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: [K+]
Solvent: CO
Product: COc1ccc(C(=O)O)c(Cl)n1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Potassium tert-butoxide (220 g, 1956 mmol) was added to a solution of 2,6-dichloronicotinic acid (180 g, 938 mmol) in MeOH (3000 mL). The mixture was stirred at 80° C. for 48 h. The solvent was evaporated in vacuo. The crude product was dissolved in H2O and treated with HCl (until the pH was 1). The solid was filtered and dried in vacuo to yield 2-chloro-6-methoxy-nicotinic acid as hydrochloride salt (130 g, 70% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>O.[N+](C)([O-])=O>[C:13]1([S:9]([C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: O=S(=O)(c1ccccc1)c1cc(Cl)ccc1Cl
Temperature: 100 °C
Yield: 85.2 %

Procedure:
A modification of the published procedures of Hagberg, Olson, and Sheares in Macromolecules, 2004, 37, 4748 was used. A 200 mL round-bottom flask equipped with a reflux condenser, stirring bar, and gas inlet was charged with 2,5-dichlorobenzenesulfonyl chloride (12.28 g, 50 mmoles), benzene (13.4 mL, 150 mmoles), and anhydrous nitromethane (50 mL). Aluminum chloride (7.33 g, 55 mmoles) was added and the mixture stirred until dissolved under nitrogen. The solution was heated to 100° C. overnight. The solution was cooled to room temperature and poured into 100 g water mixed with 25 mL hydrochloric acid. The mixture was extracted several times with dichloromethane. The organic extracts were dried with sodium sulfate, filtered, and evaporated, then the solids were dried in a vacuum oven to give 14.38 g (100% crude yield). The solids were recrystallized from ethanol after treating with decolorizing carbon to give about 14 g in two crops. The solids were recrystallized from ethanol to give 12.24 g (85% yield) of 2-benzenesulfonyl-1,4-dichlorobenzene. 1H NMR (DMSO-d6): 7.65 (ddd, 8.4, 7.5, 1.7 Hz, 2H), 7.67 (d, 8.6 Hz, 1H), 7.76 (tt, 7.5, 1.2 Hz, 1H), 7.83 (dd, 8.6, 2.6 Hz, 1H), 7.98 (ddd, 8.4, 1.7, 1.2 Hz, 2H), 8.27 (d, 2.6 Hz, 1H).