Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:47]=[CH:48][CH:49]=1)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([CH2:42][C:43]([O:45]C)=[O:44])=[CH:38][CH:37]=3)[C:31]([O:33]C)=[O:32])=[CH:26][CH:25]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:50]([F:53])([F:52])[F:51])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:47]=[CH:48][CH:49]=1)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([CH2:35][C:36]3[CH:37]=[CH:38][C:39]([CH2:42][C:43]([OH:45])=[O:44])=[CH:40][CH:41]=3)[C:31]([OH:33])=[O:32])=[CH:26][CH:25]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:50]([F:53])([F:51])[F:52])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(CC(C(=O)OC)c2ccc(COc3cccc(-c4c(C(=O)c5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(CC(C(=O)O)c2ccc(COc3cccc(-c4c(C(=O)c5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)cc1

Procedure:
The title compound was prepared from methyl 2-[4-({3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenoxy}methyl)phenyl]-3-[4-(2-methoxy-2-oxoethyl)phenyl]propanoate by LiOH hydrolysis. MS (ES) m/z 688.0.
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[S:10][C:9]([CH2:11][N:12]2[N:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[N:13]2)=[N:8][CH:7]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][O:4][CH2:5][C:6]1[S:10][C:9]([CH2:11][N:12]2[N:16]=[C:15]([NH2:17])[CH:14]=[N:13]2)=[N:8][CH:7]=1
Reactant: COCc1cnc(Cn2ncc([N+](=O)[O-])n2)s1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COCc1cnc(Cn2ncc(N)n2)s1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 5-(methoxymethyl)-2-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)thiazole (80 mg, 0.31 mmol), iron powder (53 mg, 0.93 mmol) and NH4Cl (84 mg, 1.56 mmol) in a mixture of EtOH (1.0 mL) and water (0.5 mL) was stirred at 85° C. for 30 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (5 mL) was added followed by 1N NaOH (5 mL). The layers were separated and the aq. layer was extracted with CH2Cl2 (2×5 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.49 min; [M+H]+=226.17.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.ClC(OCC)=O.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=[C:27]2[C:33]3[CH:34]=[C:35]([CH2:38][NH2:39])[CH:36]=[CH:37][C:32]=3[CH:31]=[CH:30][C:29]3[CH:40]=[CH:41][CH:42]=[CH:43][C:28]2=3)[CH2:23][CH2:22]1>C(Cl)Cl>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:39][CH2:38][C:35]2[CH:36]=[CH:37][C:32]3[CH:31]=[CH:30][C:29]4[CH:40]=[CH:41][CH:42]=[CH:43][C:28]=4[C:27](=[C:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)[C:33]=3[CH:34]=2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccc(CN)cc32)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NCc1ccc2c(c1)C(=C1CCN(C)CC1)c1ccccc1C=C2
Reaction time: 0.5 h

Procedure:
To a solution of 0.6 g (3.2 mmole) of 4-amino-5-chloro-2-methoxybenzoic acid in 15 ml of methylene chloride cooled to -15° C. was added 0.347 g (3.7 mmol) of ethyl chloroformate. The solution was stirred for 30 minutes and 1.0 g (3.2 mmole) of 1-methyl-4-(3-aminomethyl-5H-dibenzo[a,d]cycloheptene-5-ylidene)piperidine in 10 ml of methylene chloride was added. The solution was allowed to stir at room temperature for 2 hours. The solution was washed with 1N sodium hydroxide solution, water, and brine, and then was dried (MgSO4). After filtration, the solvent was removed under reduced pressure to give 4-amino-5-chloro-2-methoxy-N-((5-(l-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cyclohepten-3-yl)methyl)benzamide as an amorphous foam.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:10]([C:22]#[C:23][Si](C)(C)C)=[CH:9][C:8]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])(C)C.[OH-].[Na+].O>C1COCC1.CO>[C:6]([C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:10]([C:22]#[CH:23])=[CH:9][C:8]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])#[CH:5]
Reactant: CCCCCCCCOc1cc(C#C[Si](C)(C)C)c(OCCCCCCCC)cc1C#C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(OCCCCCCCC)c(C#C)cc1OCCCCCCCC
Reaction time: 3 h

Procedure:
1,4-Bis(trimethylsilylethynyl)-2,5-di-n-octyloxybenzene (2.331 g, 4.42×10−3 mol) was dissolved in a mixture of THF (25 ml) and MeOH (25 ml). 5N NaOH (2.0 ml, 1.0×10−2 mol) was added and the solution was stirred for 3 h under Ar. Water was added to the reaction mixture. The organic layer was extracted three times with CHCl3. The combined organic layers were dried over Na2SO4. The residue was chromatographed on silica gel with 1:1 hexane:CHCl3 as the eluent. Yield=1.419 g (84% based on 2.331 g of 1,4-bis(trimethylsilylethynyi)-2,5-di-n-octyloxybenzene). 1H NMR (300 MHz, CDCl3): δ 6.95 (s, 2H, Ph-H), 3.97 (t, 8H, J=6.6 Hz, —OCH2—), 3.33 (s, 2H, —CC—H), 1.80 (quint, 4H, J=7.0 Hz, —OCH2CH2—), 1.39-1.52 (m, 4H, —OCH2CH2CH2—), 1.15-1.39 (m, 16H, —CH2—), 0.88 (t, 6H, J=6.7 Hz, —CH3). CI MS m/z: 382.285 (M+) (calcd 382.287).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:15]([N+:16]([O-])=O)=[C:14]([O:19][CH3:20])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(O)(=O)C.[Fe]>[NH2:16][C:15]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][Cl:1])=[C:7]([CH:12]=[CH:13][C:14]=1[O:19][CH3:20])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(OC)c([N+](=O)[O-])c1NCCCCl
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OC)c(N)c1NCCCCl
Temperature: 80 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A mixture of methyl 2-[(3-chloropropyl)amino]-4-methoxy-3-nitrobenzoate (1.61 g, 5.23 mmol) and iron (1.46 g, 26.1 mmol) in acetic acid (32 mL) was stirred at 80° C. for 3 hr. Iron (0.58 g, 10.4 mmol) was added to the reaction mixture at room temperature and the mixture was stirred at 80° C. for 1 hr. To the reaction mixture was added iron (0.88 g, 15.8 mmol) at room temperature and the mixture was stirred at 80° C. for 1 hr. The solid was removed by filtration and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated in vacuo. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound (967.5 mg, 3.55 mmol, 68%) as a yellow amorphous.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(C(F)(F)F)nc(-c2ccc(C(F)(F)F)nc2)n1
Product: FC(F)(F)c1ccc(-c2nc(Cl)cc(C(F)(F)F)n2)cn1
Temperature: 25 °C

Procedure:
A mixture of 4-hydroxy-6-trifluoromethyl-2-(6-trifluoromethyl-3-pyridinyl)-pyrimidine (145 mg, 0.469 mmol) and phosphorus oxychloride (10 ml) was refluxed for 3 h. The mixture was cooled to room temperature and rotary evaporated to leave an oily residue. The residue was extracted with ethyl acetate (50 ml), washed with water (2×20 ml) and dried over anhydrous sodium sulfate. The ethyl acetate solution was concentrated in vacuo to give a crude solid (80 mg).
Reaction SMILES: [CH:1]1([C:7]2([OH:20])[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]1([Mg]Cl)CCCCC1.C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1>>[CH3:21][C:5]1[CH:6]=[C:1]([C:7]2([OH:20])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:2]=[CH:3][CH:4]=1
Reactant: Cl[Mg]C1CCCCC1
Reactant: OC1(C2CCCCC2)c2ccccc2-c2ccccc21
Agent: O=C1c2ccccc2-c2ccccc21
Product: Cc1cccc(C2(O)c3ccccc3-c3ccccc32)c1

Procedure:
9-Cyclohexyl-9H-fluoren-9-ol: from cyclohexylmagnesium chloride and 9-fluorenone;
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][C:5]=1[NH:13][C:14](=[O:16])[CH3:15])([O-:3])=[O:2].[OH2:17]>CC(O)=O>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:17])=[CH:6][C:5]=1[NH:13][C:14](=[O:16])[CH3:15])([O-:3])=[O:2]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Reactant: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Temperature: 17.5 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of CrO3 (26.5 g) in a mixture of 15 ml of H2O and 235 ml of AcOH was prepared by sonicating the suspension for 45 min. The resulting solution was added dropwise to a cooled solution of N-(6-nitro-indan-5-yl)-acetamide (22 g, 0.1 mol) in Ac20 (2.5 L) while maintaining the temperature between 15-20° C. After the addition was completed, the mixture was stirred at 25° C. overnight, poured into 10 L of water, and stirred for 1 h. The solution was then extracted with two 2-L portions of CH2Cl2. The organic layers were combined, and concentrated to 500 ml, washed with two 50-ml portions of 10% NaOH followed by water, and then dried (Na2SO4). The solvent was removed, leaving a yellow powder (16 g, 75%), which was used for next step without further purification.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][C:26]([CH2:32][CH3:33])([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:34]1(C2(C(O)=O)CCNCC2)[CH:39]=CC=[CH:36][CH:35]=1.C(C1CCC(OC2C=C3C(=CC=2)C=C(C=O)C=C3)CC1)(C)(C)C.C(O)(=O)C.CO.C([BH3-])#N.[Na+]>>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][C:26]([C:32]4[CH:36]=[CH:35][CH:34]=[CH:39][CH:33]=4)([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1(C(=O)O)CCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)C1CCC(Oc2ccc3cc(CN4CCC(C(=O)O)(c5ccccc5)CC4)ccc3c2)CC1
Yield: 5 %

Procedure:
The compound was prepared in a manner similar as to that described for 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-4-ethyl-piperidine-4-carboxylic acid using 4-Phenyl-piperidine-4-carboxylic acid (0.198 g, 0.967 mmol), 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.250 g, 0.805 mmol), acetic acid (0.16 mL, 2.8 mmol), Methanol (1.6 mL, 4.0E1 mmol) and sodium cyanoborohydride (75.314 mg, 1.1985 mmol) to give 21 mg of the title compound as a white solid (5%). ESI-LCMS (500 M+H). 1H NMR (DMSO-d6, 400 MHz): Shift (ppm) 7.80-7.98 (m, 3H), 7.16-7.63 (m, 8H), 4.51 (br. s., 3H), 3.45-3.64 (m, 2H), 2.96-3.18 (m, 2H), 2.68 (m, 2H), 2.13-2.31 (m, 2H), 1.74-2.09 (m, 4H), 1.00-1.53 (m, 5H), 0.89 (s, 9H)
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:18])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([OH:16])[CH:11]=[C:10]([OH:17])[CH:9]=2)[CH2:2][CH2:3][CH3:4].[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]1>C(O)C>[CH2:1]([C:5]1[C:6](=[O:18])[O:7][C:8]2[C:13]([C:14]=1[O:15][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1)=[C:12]([O:16][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1)[CH:11]=[C:10]([O:17][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1)[CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(O)c2c(O)cc(O)cc2oc1=O
Reactant: ClCCN1CCOCC1
Solvent: CCO
Product: CCCCc1c(OCCN2CCOCC2)c2c(OCCN3CCOCC3)cc(OCCN3CCOCC3)cc2oc1=O
Yield: 45 %

Procedure:
7.5 g. (0.03 mol) of 3-butyl-4,5,7-trihydroxy-coumarin are treated with 17.5 g. (0.117 mol) of 2-morpholino-1-chlorethane, as in Example 1. A beige-coloured solid is obtained. M.P. 131° C. (ethanol). Weight 7.7 g.; yield 45% (theoretical yield 17.7 g.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[C:18](OC([O-])=O)(=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH:16][C:18]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1csc(N)n1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of 2-(2-amino-4-thiazolyl)malonic acid diethyl ester in t-butyl pyrocarbonate (2.25 equivalents). After stirring at 80° C. overnight, the mixture is diluted with ethyl acetate, washed with diluted hydrochloric acid, aqueous sodium hydrogen carbonate, and water, dried and concentrated under vacuum to give 2-(2-t-butoxycarbonylamino-4-thiazolyl)malonic acid diethyl ester. Yield: 73.3%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)=O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].CCOCC>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCCC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(c2ccc(Cl)cc2)CCCC1

Procedure:
To a solution of Example 8A (2.88 g, 10 mmol), 4-chlorophenylboronic acid (1.88 g, 12 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.578 g, 0.5 mmol) in toluene (40 ml) and ethanol (10 ml) was added 2N Na2CO3 (10 mL). The mixture was stirred at reflux overnight. The mixture was diluted ether (300 mL) and washed with water, brine and dried over Na2SO4. After evaporation of solvent, the residue was loaded on a column and eluted with 3% ethyl acetate in hexane to give title compound.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[C:11]([NH:12][C:13](=[O:32])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[C:10]2[CH2:33][NH:34][C:35]([CH3:37])([CH3:36])[C:9]2=[N:8]1)=[O:6])[CH3:3].C(N(CC)C(C)C)(C)C.[F:47][C:48]1[CH:49]=[C:50]([S:55](Cl)(=[O:57])=[O:56])[CH:51]=[C:52]([F:54])[CH:53]=1>ClCCl>[CH2:2]([O:4][C:5]([N:7]1[C:11]([NH:12][C:13](=[O:32])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[C:10]2[CH2:33][N:34]([S:55]([C:50]3[CH:49]=[C:48]([F:47])[CH:53]=[C:52]([F:54])[CH:51]=3)(=[O:57])=[O:56])[C:35]([CH3:36])([CH3:37])[C:9]2=[N:8]1)=[O:6])[CH3:3]
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccccc1CN1C(=O)c3ccccc3C1=O)CNC2(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)n1nc2c(c1NC(=O)c1ccccc1CN1C(=O)c3ccccc3C1=O)CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester hydrochloride (1.24 g, 2.4 mmol) in dry dichloromethane (30 mL) was added N,N-diisopropylethylamine (1.67 mL, 9.6 mmol) and 3,5-difluorobenzenesulfonyl chloride (0.77 g, 3.6 mmol). After stirring at room temperature for 3 hours the mixture was diluted with dichloromethane (50 mL), washed with 1N HCl, water, saturated solution of NaHCO3, brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel eluting with ethyl acetate and then with dichloromethane/methanol 98:2 affording the title compound as white solid (1.4 g).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:6]1)=[O:4].[Li+].[OH-].Cl>CO>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([CH:7]1[CH2:8][CH2:9][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]1)(=[O:12])=[O:11]
Reactant: COC(=O)C1CCC(S(=O)(=O)c2ccccc2Cl)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCC(S(=O)(=O)c2ccccc2Cl)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-(2-chloro-benzenesulfonyl)-cyclopentanecarboxylic acid methyl ester (0.25 g, 1.0 eq) in methanol (8.0 mL) was treated with 1N LiOH (1.6 mL, 2.0 eq). The mixture was stirred at RT for 3 h and then acidified to pH 4 with HCl 1N. The methanol was evaporated and the residue extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. The title compound was obtained as a colorless oil (0.25 g, 100%) and was used crude. MS (ESI): m/z=287.3 [M−H]−.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])[C:4](OC)=[O:5].[BH4-].[Na+].Cl.O>O1CCCC1.C(O)C.C(OCC)(=O)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:9]([NH:8][CH:3]([CH2:4][OH:5])[CH2:2][OH:1])=[O:10])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: COC(=O)[C@H](CO)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: O=C(NC(CO)CO)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 68.7 %

Procedure:
To a solution of methyl (2S)-3-hydroxy-2-[(4-nitrobenzyloxycarbonyl)amino]propionate (2.12 g) in tetrahydrofuran (20 ml) and ethanol (20 ml) was added sodium borohydride(0.54 g) at 0° C. under nitrogen atmosphere. After stirring at 0° C. for 5 hours, to the mixture was added a mixture of concentrated hydrochloric acid (1.7 ml), water (40 ml) and ethyl acetate (40 ml). The organic layer was separated, washed with 10% aqueous sodium hydrogen carbonate and brine successively, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (160 ml) eluting with a mixture of acetone and dichloromethane (1:9, V/V) to give 2-[(4-nitrobenzyloxycarbonyl)amino]-1,3-propanediol (1.32 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([N:22]([CH3:24])[CH3:23])=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>CO>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([N:22]([CH3:23])[CH3:24])=[N:7][C:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:41](=[O:42])[C:40]3[CH:44]=[CH:45][C:37]([C:36]([F:35])([F:46])[F:47])=[CH:38][CH:39]=3)=[CH:19][CH:20]=2)=[N:9][C:10]=1[N:11]([CH3:12])[CH3:13]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(N)cc2)nc1N(C)C
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)nc1N(C)C
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a stirred suspension of [4,6-bis-dimethylamino-2-(4-aminobenzyl)pyrimidin-5-yl]acetic acid methyl ester (100 g, obtained according to step C) in 700 mL of methanol in a 1500 mL double jacketed vessel at 20±5° C. is added diisopropylethylamin (41.4 g) over a period of 30 minutes while heating the reaction mixture to 50±5° C. 4-Trifluoromethylbenzoic acid chloride (63.8 g) is added during further 30 minutes. The reaction mixture is stirred for 15 minutes at 50±5° C. and subsequently heated to 65±5° C. (reflux conditions) and stirred for another 30 minutes. The resulting suspension is gradually cooled to 5±5° C. over a period of 2 hours and stirred at this temperature for 1 hour. The solid is filtered off, washed with 200 mL of isopropanol and dried in vacuo at 50° C. to yield [4,6-bis-dimethylamino-2-[4-(4-trifluoromethylbenzoylamino)benzyl]pyrimidin-5-yl]acetic acid methyl ester in an amount of 135.8 g (yield: 90%; HPLC-purity: 99.5%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:10]2[NH:11][C:12]([C:14]([O:16]C)=[O:15])=[CH:13][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:10]2[NH:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)C(Cc1cccc(O)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)C(Cc1cccc(O)c1)CC2

Procedure:
The title compound was synthesized from methyl 6-(3-hydroxybenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (57 mg, 0.21 mmol) and lithium hydroxide (88 mg, 2.10 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 50% EtOAc. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.04-2.16 (m, 1H) 2.36-2.53 (m, 3H) 2.55-2.64 (m, 1H) 2.96-3.04 (m, 1H) 3.31-3.37 (m, 1H) 6.57 (s, 1H) 6.59-6.67 (m, 3H) 7.04-7.11 (m, 1H). LCMS m/e 258 (M+H). Purity 92% (HPLC).
Reaction SMILES: [CH:1]([N:3]1[CH2:6][CH2:5][C:4]1([CH3:8])[CH3:7])=[O:2].[CH:9](N1CCC1(OC)OC)=[O:10]>F[B-](F)(F)F.C[N+](C)(C)C.CO>[CH:1]([N:3]1[CH:6]([O:10][CH3:9])[CH2:5][C:4]1([CH3:8])[CH3:7])=[O:2]
Reactant: COC1(OC)CCN1C=O
Reactant: CC1(C)CCN1C=O
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Solvent: CO
Product: COC1CC(C)(C)N1C=O

Procedure:
In the same manner as indicated in Example 6 there are electrolyzed 19.3 g of 1-formyl-2,2-dimethylazetidine and 54.7 g of methanol in the presence of 0.27 g of tetramethylammonium tetrafluoroborate as conducting salt. After throughput of 2.5 Faraday per mol of 1-formyl-2,2-dimethoxyazetidine the current is switched off. The calculated mean cell voltage is 32.6 volts. Work-up of the electrolysis solution gives 12.2 g of 1-formyl-4-methoxy-2,2-dimethylazetidine (boiling point 52° C./0.26 mbar; nD25 =1.4496), which corresponds to a product yield of 49.9% and a current efficiency of 39.9%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([NH:31][CH3:32])[CH2:27][CH2:26]1.[OH-].[Na+]>O1CCOCC1>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:7]=[C:2]([N:31]([CH3:32])[CH:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[N:3]=[C:4]([NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[N:5]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC(CO)CO)n2)cc1Cl
Reactant: CNC1CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(NC(CO)CO)nc(N(C)C3CCN(C)CC3)n2)cc1Cl
Yield: 46.1 %

Procedure:
To 131 (0.979 g, 0.271 mmol) dissolved in 3 mL 1,4-dioxane was added methyl-4-(methylamino)piperidine (0.05 mL, 0.34 mmol) dissolved in 2 mL 1,4-dioxane followed by the addition of 2.5 N NaOH (aq) (0.11 mL, 0.275 mmol). The mixture was heated at reflux for 3 h 45 min, cooled to about room temperature, and then concentrated under reduced pressure. The resulting material was diluted with dichloromethane and filtered. The filtrate was then concentrated affording 56.5 mg of material. The crude material was purified by silica gel pipet column eluting with 100% methanol affording an white solid 132 (21.1 mg, 18%), mp 84° C.; MS (ESI): m/z 454 (34.7), 452 (M+H, 100), 422 (11.3), 248 (25.3), 247 (51.3), 157 (60.3), 129 (27.5).