Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[CH2:30])=[CH:27][CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:24][C:25]4[CH:32]=[CH:31][C:28]([CH:29]=[CH2:30])=[CH:27][CH:26]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: C=Cc1ccc(N)cc1
Product: C=Cc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 20 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-aminostyrene (46.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-vinylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (13.1 mg).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:18]([N:25]1[C:29]([CH:30]=[O:31])=[CH:28][N:27]=[CH:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O1CCCC1>[CH2:18]([N:25]1[C:29]([CH:30]([OH:31])[CH2:3][CH2:4][CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:28][N:27]=[CH:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1cncn1Cc1ccccc1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(CCC(c1ccccc1)c1ccccc1)c1cncn1Cc1ccccc1
Temperature: 25 °C

Procedure:
Magnesium turnings (0.5 g) were covered with dry tetrahydrofuran (4 ml). 1-Bromo-3,3-diphenylpropane (5.6 g) in 20 ml of dry tetrahydrofuran was added dropwise. The mixture was stirred at reflux for one hour. After being cooled to room temperature, 3-benzyl-3H-imidazole-4-carbaldehyde (3.8 g) in 20 ml of dry tetrahydrofuran was added dropwise to the Grignard reagent and the mixture was refluxed for two hours. The cooled reaction mixture was poured into a cold diluted hydrochloric acid solution. Work-up of the mixture gave the crude product, which was converted to its hydrochloride salt in ethyl acetate using dry hydrochloric acid.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][CH3:17])[CH2:11]2)[S:7][N:6]=1)(=O)=O.[CH2:18]([OH:22])[C:19]#[C:20][CH3:21].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH2:16]([CH:12]1[CH2:13][CH2:14][CH2:15][CH:10]([C:8]2[S:7][N:6]=[C:5]([O:22][CH2:18][C:19]#[C:20][CH3:21])[N:9]=2)[CH2:11]1)[CH3:17]
Reactant: CCC1CCCC(c2nc(S(C)(=O)=O)ns2)C1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1nsc(C2CCCC(CC)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
170 mg of 3-methylsulfonyl-5-(3-ethylcyclohexyl)-1,2,4-thiadiazole and 52 mg of 2-butyn-1-ol were dissolved in 1.5 ml of N,N-dimethylformamide, 32 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 1 hour under ice-cooling and for 12 hours under room temperature. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 80 mg of 5-(3-ethylcyclohexyl)-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (14)).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([Br:10])[S:8][CH:9]=1)(=[O:3])[CH3:2].S(C1C=CC(C)=CC=1)(O[CH3:15])(=O)=O.[H-].[Na+]>C(#N)C>[Br:10][C:7]1[S:8][CH:9]=[C:5]([N:4]([CH3:15])[C:1](=[O:3])[CH3:2])[N:6]=1
Reactant: CC(=O)Nc1csc(Br)n1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)N(C)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32 %

Procedure:
A solution of 4-acetamido-2-bromothiazole (prepared as described in Example 1) and methyl tosylate (4.65g, 25mM) in dry acetonitrile (125 ml.) was treated with a 60% dispersion of sodium hydride in oil (1g, 25mM) and the mixture stirred 72 hours at ambient temperature. The reaction mixture was filtered and the filtrate evaporated under reduced pressure. The residue was chromatographed on silica (Woelm grade 1, 150g) using 2% methanol in chloroform as eluant. Evaporation of the appropriate fractions followed by recrystallisation from hexane gave the title compound (1.9g, 32%) mp 84° C. Found: C, 30.55; H, 2.95; N, 11.8%. C6H7N2BrOS requires C, 30.7; H, 3.0; N,.11.9%).
Reaction SMILES: C(C1C=CC(S([N:13]=[N+:14]=[N-])(=O)=O)=CC=1)(O)=O.[CH:16]1([C@@H:19]([NH:28][S@@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])[CH2:20][C:21](=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:17]1>CC#N.CCOC(C)=O>[CH:16]1([C@@H:19]([NH:28][S@@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])[CH2:20][C:21](=[O:27])[C:22](=[N+:13]=[N-:14])[C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:17]1
Reactant: COC(=O)CC(=O)C[C@H](N[S@](=O)C(C)(C)C)C1CC1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)C(=[N+]=[N-])C(=O)C[C@H](N[S@](=O)C(C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Carboxybenzenesulfonyl azide (28) (8.79 g, 38.7 mmol) was added to a solution of (5S)-methyl 5-cyclopropyl-5-[(R)-1,1-dimethylethylsulfinamido]-3-oxopentanoate (27) (10.2 g, 35.2 mmol) in CH3CN (230 mL) and the resulting solution was stirred at rt for 5 h. The resulting solution was diluted with EtOAc (200 mL) and washed with sat. brine (100 mL). The organic phase was dried (Na2SO4), filtered and concentrated under vacuum to give (5S)-methyl 5-cyclopropyl-2-diazo-5-[(R)-1,1-dimethylethylsulfinamido]-3-oxopentanoate (29). Retention time (min)=1.634 method [1], MS (m/z) 316.2 (M+H)+.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.N1C=CC=CC=1>O>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([O:6][C:5]2[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=2[O:8][CH3:9])[CH:2]=[O:1])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C=O)cc1OS(=O)(=O)c1ccc(C)cc1
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
A mixture of 3-hydroxy-4-methoxybenzaldehyde 12 (5.0 g, 32 mmol) and p-toluenesulfonyl chloride (10.0 g, 52.5 mmol) was dissolved in pyridine (12.5 mL, 154 mmol). The reaction mixture stirred for 5 min and maintained at 70-80° C. The clear reaction mixture becomes turbid and becomes slurry. The stirring was continued for a period of 2 h at 70-80° C. The reaction completion was determined by TLC and the contents of the flask were cooled to room temperature and poured in to cold water. The white crystalline solid formed was filtered, washed successively with 5 mL 1:1 HCl:H2O, 5 mL of 5% NaOH solution and water till the filtrate is free from pyridine, dried to constant weight to get the desired product 21. Yield: 98%; white solid mp 148-151° C. 1H NMR: δ 2.40 (s, 3H, CH3), 3.71 (S, 3H, OCH3), 6.91-7.83 (m, 7H, Ar—H), 9.83 (s, 1H, CHO). Anal. Calcd for C15H14O5S: C, 58.81, H, 4.61. Found: C, 58.79, H, 4.59.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([C:14]([NH2:21])=[CH:15][C:16]=1[O:17][CH2:18][CH:19]=[CH2:20])[C:8]([O:10]CC=C)=[O:9])[CH:2]=[CH2:3].[OH-].[K+]>C(O)C.O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([C:14]([NH2:21])=[CH:15][C:16]=1[O:17][CH2:18][CH:19]=[CH2:20])[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cc(OCC=C)c(OCC=C)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOc1cc(N)c(C(=O)O)cc1OCC=C

Procedure:
To a suspension of allyl 3,4-diallyloxy-6-aminobenzoate * (16 mmol) in ethanol (50 ml) was added a solution of potassium hyroxide (48 mmol) in water (2ml). The mixture was heated at reflux for 40 minutes. The solution was partially evaporated at reduced pressure, acidified with acetic acid and extracted with ethylaceate. The organic layer was washed with water, a saturated solution of sodium chloride, dried (MgSO4) and decolourised with charcoal. Evaporation of the solvent gave 3,4-diallyloxy-6-aminobenzoic acid as a sandy solid. NMR (DMSO-d6): 4.5(m,4H); 5.33 ,4H); 6.60(s,1H); 7.3(s,1H): M/S +ve FAB (M+H)hu +=250.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[N:20]=[C:19]3[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2].S(=O)(=O)(O)O.[CH3:35]O>>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][N:18]3[C:22]([CH2:23][O:24][CH3:35])=[C:21]([Cl:25])[N:20]=[C:19]3[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: CO
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2cccc(C(=O)OC)c2)cc1
Agent: O=S(=O)(O)O
Product: CCCCc1nc(Cl)c(COC)n1Cc1ccc(-c2cccc(C(=O)OC)c2)cc1

Procedure:
A solution of 5.00 g of 1-[(3'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole and 1.0 mL of conc. sulfuric acid in 200 mL of methanol was refluxed for 20 hours. After cooling, the solvent was removed in vacuo, and the residue was poured into saturated sodium bicarbonate solution. The resulting mixture was extracted with methylene chloride, and the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel (elution: 0-20% ethyl acetate/benzene) furnished 5.35 g of 1-[(3'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-methoxymethylimidazole; NMR (200 MHz, CDCl3): δ 8.26 (t, 1H); 8.03 (d of t, 1H); 7.76 (d of t, 1H); 7.51 (t, 1H); 7.33 (A2M2, 4H); 5.20 (s, 2H); 4.31 (s, 2H); 3.94 (s, 3H); 3.27 (s, 3H); 2.59 (t, 2H); 1.68 (quint., 2H); 1.34 (sext., 2H); 0.87 (t, 3H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:8]([N:13]2[C:17]3=[N:18][CH:19]=[N:20][C:21](O)=[C:16]3[CH:15]=[N:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1>>[Cl:3][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:13]([C:8]3[C:7]([Cl:6])=[CH:12][CH:11]=[CH:10][N:9]=3)[N:14]=[CH:15][C:16]=12
Reactant: Oc1ncnc2c1cnn2-c1ncccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Phosphoryl trichloride (235 mL, 2455.17 mmol) was added to 1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol B15b (30.4 g, 122.76 mmol). The resulting solution was stirred at 100° C. for 4 hours. The mixture was concentrated in vacuo and to the residue was added an ice/water mixture. The resulting mixture was stirred for 1 hour during which time a solid precipitated. The solid was collected by filtration and washed with water (3×75 mL). The crude product was dissolved in EtOAc (500 mL) and dried over MgSO4, filtered and evaporated to afford 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (28.7 g). 1H NMR (400 MHz, DMSO-d6) δ 7.78 (1H, dd), 8.37 (1H, dd), 8.69 (1H, dd), 8.83 (1H, s), 8.92 (1H, s), m/z (ESI+) (M+H)+=266; HPLC tR=1.72 min.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:26][CH2:27][CH3:28])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:24])[C:8]=2[N:25]=1)[CH3:2].[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:26][CH2:27][CH3:28])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH:18]4[CH2:19][CH2:20][N:21]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:22][CH2:23]4)[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:24])[C:8]=2[N:25]=1)[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OC4CCNCC4)cc3c21
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OC4CCN(C(=O)C(C)C)CC4)cc3c21

Procedure:
A modification of the procedure described in Example 413 was used. 2-(Ethoxymethyl)-8-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 411, 0.650 g, 1.69 mmol) was treated with isobutyryl chloride instead of the methanesulfonic anhydride. After the work up, the crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-25% CMA in chloroform) followed by recrystallization from acetonitrile to yield 0.500 g of 2-(ethoxymethyl)-8-[(1-isobutyrylpiperidin-4-yl)oxy]-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 177-179° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11](=[O:35])[C@H:12]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[NH:18][C:19](=[O:21])[O:20][C:16]=2[CH:15]=1>C(O)(=O)C>[CH3:9][O:10][C:11](=[O:35])[C@H:12]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[CH2:13][C:14]1[C:23]([Cl:1])=[CH:22][C:17]2[NH:18][C:19](=[O:21])[O:20][C:16]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]c(=O)oc2c1)NC(=O)OCc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)[C@@H](Cc1cc2oc(=O)[nH]c2cc1Cl)NC(=O)OCc1ccccc1
Temperature: 100 °C
Yield: 31.6 %

Procedure:
N-Chlorosuccinimide (315 mg, 2.36 mmol) was added to a solution of (R)-2-benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester (700 mg, 1.89 mmol) in acetic acid (50 mL) at room temperature. The mixture was heated at 100° C. for 16 h. After it was cooled down to room temperature, solvents were removed in vacuo. The residue was subjected to silica gel chromatography using ethyl acetate/hexanes (4:6) then (1:1) as eluent to afford the title compound as an off-yellow solid (242 mg, 32%). The structure of the product was confirmed by 2D NMR. 1H-NMR (CD3COCD3, 500 MHz) δ 10.47 (s, 1H), 7.36-7.28 (m, 6H), 7.20 (s, 1H), 6.80 (d, J=8.5 Hz, 1H), 5.05 (d, J=12.5 Hz, 1H), 5.00 (d, J=12.5 Hz, 1H), 4.65-4.60 (m, 1H), 3.73 (s, 3H), 3.43 (dd, J=14.0, 5.0 Hz, 1H), 3.08 (dd, J=14.0, 10.5 Hz, 1H); 13C-NMR (CD3COCD3, 125 MHz) δ 172.2, 156.5, 154.5, 143.1, 137.5, 130.8, 129.0, 128.9, 128.7, 128.2, 128.0, 112.8, 110.9, 66.3, 54.3, 52.1, 35.8; Mass spec. 405 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7]([O:35][CH3:36])=[CH:8][C:9]2[CH2:10][CH2:11][N:12]3[C:18]4[C:19](=[O:29])[N:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=4[C:16]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)=[C:13]3[C:14]=2[CH:15]=1)=[O:4].[CH2:37]([N:39](CC)[CH2:40]C)C.CNC>CN(C=O)C.C1COCC1>[CH3:37][N:39]([CH3:40])[CH2:2][C:3]([NH:5][C:6]1[C:7]([O:35][CH3:36])=[CH:8][C:9]2[CH2:10][CH2:11][N:12]3[C:18]4[C:19](=[O:29])[N:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=4[C:16]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)=[C:13]3[C:14]=2[CH:15]=1)=[O:4]
Reactant: COc1cc2c(cc1NC(=O)CCl)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: CCN(CC)CC
Agent: CNC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1NC(=O)CN(C)C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 60 °C

Procedure:
A suspension of 392 mg of 22a in 3 ml of DMF was treated with 0.5 ml of triethylamine and 2 ml of a 2M solution of dimethylamine in THF. The reaction mixture was sealed and heated at an oil bath at 60° C. for 40 min. The clear solution was poured onto water and extracted with ethyl acetate. The extract was washed, dried and concentrated and the residue was purified by chromatography over silicagel, using a gradient of CH2Cl2-methanol. The material thus isolated was triturated with diethylether, to provide 438 mg of crystalline material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:31][CH2:32][CH2:33][OH:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]([CH2:32][CH2:33][OH:34])[C:21](=[O:23])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCCNCc1ccccc1
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Product: COc1ccccc1N(CC(=O)N(CCO)Cc1ccccc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with 2-benzylamino-ethanol
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:34])[CH:26]=[CH:25]2)=[CH:19][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:34])[CH:26]=[CH:25]2)=[CH:19][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cn3ccc(=O)c4ccccc43)ccc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc(Cn2ccc(=O)c3ccccc32)ccc1F)N1CCNCC1

Procedure:
B1 from step 1 was stirred in a 1:1 mixture of DCM and TFA (0.1M) for 30 min. The solvents were removed under reduced pressure and the residue was dissolved in MeOH. The solution was applied on a SCX cation exchange resin, the resin was washed with H2O and MeOH and the product was eluted with ammonia in MeOH (2N). The solvents were removed under reduced pressure to a afford the title compound as a beige solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]2=[O:24])(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].Cl[CH2:32][C:33]1[S:34][CH:35]=[CH:36][CH:37]=1>C(#N)C>[O:15]=[C:11]1[C:12]2[C:8](=[CH:7][C:6]([N:5]([CH2:32][C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=2)[C:9](=[O:24])[N:10]1[CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O
Reactant: ClCc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(Cc3cccs3)S(C)(=O)=O)cc2C1=O
Temperature: 120 °C
Yield: 94.4 %

Procedure:
To a solution of tert-butyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (500 mg, 1.411 mmol) (prepared in an analogous manner as previously described in Example 34, Scheme 34, Steps 1, 2, 3) in acetonitrile (10 ml), K2CO3 (390 mg, 2.82 mmol) and 2-(chloromethyl)thiophene (281 mg, 2.116 mmol) (obtainable as described in U.S. Pat. No. 5,716,943, which is incorporated herein by reference in its entirety) were added, and the reaction was heated under microwave irradiation at 120° C. for 3 hours. The mixture was filtered and the filtrate was evaporated to dryness. The resulting crude was purified by flash chromatography on silica gel (hexane/EtOAc 2/1) affording tert-butyl 2-(1,3-dioxo-5-(N-(thiophen-2-ylmethyl)methylsulfonamido)-isoindolin-2-yl)acetate (600 mg, 1.332 mmol, 94% yield, MS/ESI+ 472.9 [MNa]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].O[CH2:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[O:28][CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[O:22][CH2:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[O:28][CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: COC(=O)C(C)Oc1cccc(CO)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)Oc1cccc(COc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)c1
Yield: 35.3 %

Procedure:
Into 10 ml of anhydrous tetrahydrofuran were dissolved 0.3 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidine-1-yl]phenol, 0.186 g of methyl 2-[3-(hydroxymethyl)phenoxy]propionate and 0.232 g of triphenylphosphine; 0.179 g of diisopropyl azodicarboxylate was added dropwise under ice-cooling and stirring and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure; the obtained residue was subjected to silica gel column chromatography to give 0.166 g of methyl 2-[3-({2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidine-1-yl]phenoxy}methyl)phenoxy]propionate [Compound 2-1].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:22](O)=[O:23])[C:7]([C:10]2[C:11]([C:19](O)=[O:20])=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2].O.Cl>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:22][OH:23])[C:7]([C:10]2[C:11]([CH2:19][OH:20])=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2CO)c(CO)c1
Reaction time: 19 h

Procedure:
3.6 g (10.83 mmol) 4,4′-Dinitro-1,1′-biphenyl-2,2′-dicarboxylic acid is dissolved in 25 ml tetrahydrofuran and added drop wise in a the course of 1 hours to 65 ml (65.02 mmol) of a borane-tetrahydrofuran complex 1.0 M solution in tetrahydrofuran. After 19 hours at 25° C., 50 ml water is carefully added. After 1 h the solution is acidified to pH=1-2 with 10 ml 1N HCl solution and allowed to stirred for 30 min. The reaction mixture is then partitioned between ethyl acetate and water; the organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue, 4.2 g of 4,4′-Dinitro-1,1′-biphenyl-2,2′-dimethanol as white powder is used without further purification.
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9](=[O:11])[O-:10])[CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].[CH2:12]([S:20](O)(=[O:22])=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:12]([S:20]([O:1][C@H:2]([CH2:8][C:9](=[O:10])[O-:11])[CH2:3][N+:4]([CH3:7])([CH3:5])[CH3:6])(=[O:22])=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Reactant: CCCCCCCCS(=O)(=O)O
Product: CCCCCCCCS(=O)(=O)O[C@H](CC(=O)[O-])C[N+](C)(C)C

Procedure:
The carnitine inner salt solution is mixed with the octanesulphonic acid solution at ambient temperature under agitation for 20 minutes, and the homogeneous solution obtained is lyophilised.