Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][O:30]CC5C=CC=CC=5)[CH:22]=4)=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[N:2]=1.B(Br)(Br)Br>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][OH:30])[CH:22]=4)=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[N:2]=1
Reactant: O=C(Nc1cccnn1)N1CC(Oc2ccc(-c3cccc(OCCOCc4ccccc4)c3)cn2)C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Nc1cccnn1)N1CC(Oc2ccc(-c3cccc(OCCO)c3)cn2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 4.9 %

Procedure:
3-{5-[3-(2-Benzyloxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylic acid pyridazin-3-ylamide (Example 9, 325 mg, 0.65 mmol) was dissolved in anhydrous dichloromethane (10 mL) under a nitrogen atmosphere. The mixture was cooled with an ice water bath and boron tribromide in dichloromethane solution (1M, 0.98 mL, 0.98 mmol) was added drop-wise affording a precipitate. The reaction mixture was stirred at 0° C. for 2 hr. The precipitate was collected by filtration and purified by flash chromatography on silica gel eluting with ethyl acetate, then 5-10% methanol in DCM. Further purification by preparative HPLC at pH4 afforded title compound (13 mg, 5%) as colourless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[CH:4][N:3]=1.[S:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:13]2[CH2:14][CH2:15][S:10][CH2:11][CH2:12]2)=[CH:4][N:3]=1
Reactant: Nc1cnc(Cl)nc1Cl
Reactant: O=C1CCSCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Clc1ncc(NC2CCSCC2)c(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a mixture of 2,4-dichloropyrimidin-5-amine (1.58 g, 9.63 mmol) and dihydro-2H-thiopyran-4 (3H)-one (1.45 g, 12.5 mmol) in dichloromethane (50 ml) at 0° C. was added dropwise a 1 M solution of titanium tetrachloride (10.6 ml, 10.6 mmol) in dichloromethane. After the reaction mixture was stirred at room temperature for 2 h, sodium cyanoborohydride (1.91 g, 28.9 mmol) was added in single portion and the reaction mixture was stirred at room temperature for 16 hours. After the reaction mixture was diluted with dichloromethane, the reaction mixture was poured carefully into iced-saturated NaHCO3 solution. EtOAc was added and then the insoluble materials were filtered off. The phases of the filtrate were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and saturated NaCl, dried with Na2SO4 and concentrated in vacuo to give a crude oil. The crude residue was purified by silica gel chromatography (hexane/ethyl acetate, 100:0 to 3:1) to afford 2,4-dichloro-N-(tetrahydro-2H-thiopyran-4-yl)pyrimidin-5-amine (864 mg, 3.27 mmol, 34% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.59-1.76 (m, 2H) 2.07-2.20 (m, 2H) 2.58-2.69 (m, 2H) 2.70-2.85 (m, 2H) 3.42-3.57 (m, 1H) 5.78 (d, J=8.84 Hz, 1H) 8.25 (s, 1H). MS [M+H] 264.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[NH2:4].[CH3:12]OC(OC)OC>C(O)C>[O:1]1[CH:12]=[N:4][C:3]([C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)=[N:2]1
Reactant: NC(=NO)c1ccc(O)cc1
Reactant: COC(OC)OC
Solvent: CCO
Product: Oc1ccc(-c2ncon2)cc1

Procedure:
N′,4-Dihydroxybenzenecarboximidamide (1.28 g, 8.4 mmol) was suspended in 3 mL ethanol and 3 mL trimethylorthoformate in a 20 mL biotage microwave reaction tube. The mixture was sealed and microwaved at 150° C. for 10 min. The solvent was removed by concentration and the residue was purified by column chromatography eluting with 20% DCM/hexanes to give the desired product as white solid. LRMS calc: 162.0; obs: 163.2 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:7]([CH3:10])(=[O:9])=[O:8].[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(OCC)C>[C:29]([O:1][CH:2]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:7]([CH3:10])(=[O:9])=[O:8])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)N(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Solvent: CCOCC
Product: CC(=O)OC(CCCN(CCCCCCC(=O)O)S(C)(=O)=O)COc1ccc(F)cc1
Reaction time: 18 h

Procedure:
A mixture of 7-{N-[4-hydroxy-5-(4-fluorophenoxy)-pentyl]methanesulfonamido}heptanoic acid (12.3 g., 0.03 mole) (Example 1, Step E) and acetic anhydride (6.1 g., 0.06 mole) is kept at room temperature for 18 hours. This mixture is taken up in 80 ml. of ethyl ether. The solution is extracted with an ice-cold solution of 8 g. of sodium hydroxide in 150 ml. of water. The basic solution is separated and acidified with concentrated hydrochloric acid. The crude product that separates is extracted into ether, washed with water and dried over sodium sulfate. The ether is evaporated and the residual oil is purified by chromatography on silica gel using 2% methanol in chloroform as the eluting solvent. There is obtained 7-{N-[4-acetoxy-5-(4-fluorophenoxy)pentyl]methanesulfonamido}-heptanoic acid as a viscous oil.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][CH:29]([NH2:31])[CH3:30]>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][NH:31][CH:29]([CH3:30])[CH3:28])[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CC(C)N
Solvent: CC#N
Product: CC(C)NCC1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), propan-2-amine (0.5 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 303 (M+, 2), 288 (17), 84 (6), 72 (bp), 56 (6).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>C1C=CC=CC=1.CN(C)C=O>[O:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCCCCCCCOc1ccccc1
Reactant: C=CC(N)=O
Agent: [K+]
Agent: [OH-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: C=CC(=O)NCCCCCCCCOc1ccccc1
Yield: 79.2 %

Procedure:
Added to 20 ml of N,N-dimethylformamide were 0.62 g of acrylic amide and 2.0 g of (8-bromooctyloxy)benzene. With stirring, 0.49 g of flaky potassium hydroxide which had been ground in a mortar was added. Phenothiazine was added in an amount of 0.5% based on the acrylic amde. After they were reacted at 0°-5° C. for 6 hours, insoluble filtered off from the liquid reaction mixture. The solvent and unreacted raw materials were distilled off from the filtrate. The residue was extracted with benzene-water, thereby obtaining the intended product in the benzene layer. Benzene was then driven off from the benzene layer to obtain 1.53 g of N-(8-phenoxyoctyl)acrylic amide (yield: 79%). It was purified further with column chromatography in which silica gel and benzene were used as an adsorbent and developer respectively. Its melting point was measured and its elementary analysis was also conducted. The following results were obtained. Melting point: 45°-47° C. Elementary analysis data: C, 74.21% (Calculated: 74.14%); H, 9.09% (9.15 %); N, 5.12% (5.09%).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:23]([F:26])([F:25])[F:24])=[C:13]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:27]>>[ClH:27].[O:20]1[CH2:21][CH2:22][CH:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][C:12]=2[C:23]([F:26])([F:24])[F:25])[CH2:9][NH:8][CH2:16]3)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(C3CCOCC3)c(C(F)(F)F)cc2C1
Agent: Cl
Product: FC(F)(F)c1cc2c(cc1C1CCOCC1)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-(tetrahydro-pyran-4-yl)-6-trifluoromethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Yellow solid. MS (m/e): 272.3 ([M+H]+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:12].[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>>[F:1][C:2]1[C:3]([NH:12][C:22]([NH:21][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:27])[F:26])=[CH:25][CH:24]=2)=[O:23])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2
Reactant: Nc1c(F)ccc2cnccc12
Reactant: O=C=NCc1ccc(OC(F)(F)F)cc1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)Nc1c(F)ccc2cnccc12

Procedure:
Prepared from 6-fluoroisoquinolin-5-amine (Description 89) and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to Description 61. m/z (ES+) 394 (M+H)+.
Reaction SMILES: C[C:2]1[N:7]=[C:6]([C:8]([O-:10])=O)[C:5]([C:11]([O-:13])=O)=[N:4][C:3]=1C.[NH2:15][C:16]([CH3:21])([CH2:19][OH:20])[CH2:17][OH:18]>C(O)C>[OH:18][CH2:17][C:16]([NH:15][C:8]([C:6]1[C:5]([C:11]([NH:15][C:16]([CH3:21])([CH2:19][OH:20])[CH2:17][OH:18])=[O:13])=[N:4][CH:3]=[CH:2][N:7]=1)=[O:10])([CH3:21])[CH2:19][OH:20]
Reactant: Cc1nc(C(=O)[O-])c(C(=O)[O-])nc1C
Reactant: CC(N)(CO)CO
Solvent: CCO
Product: CC(CO)(CO)NC(=O)c1nccnc1C(=O)NC(C)(CO)CO
Yield: 83.5 %

Procedure:
Pyrazine-2,3-dicarboxylic acid (34 mg, 0.2 mmol), PyBOP (229 mg, 0.44 mmol), HOBt (60 mg, 0.44 mmol) and NMM (0.7 mL, 0.64 mmol) were dissolved in DMF (2 mL) and allowed to react for 10 min. 2-Amino-2-methyl-1,3-propanediol (46 mg, 0.44 mmol) was then added and stirring was continued overnight. The entire reaction mixture was then fractionated on a RP-HPLC column (Vydac 218TP1022, 22×250 mm, 10 mL/min, 0 to 15% MeCN in 0.1% aq CF3COOH over 40 min). Appropriate fractions were pooled, rechromatographed and lyophilised to yield the pure title compound. Alternatively, the title compound was synthesised as follows: dimethylpyrazine-2,3-dicarboxylate (1.5 g, 7.7 mmol) and 2-amino-2-methyl-1,3-propanediol (1.6 g, 15.4 mmol) in absolute ethanol (5 mL) were heated under reflux during 4 hours. The reaction mixture was then cooled and the solvent was removed under reduced pressure. The residue was chromatographed on a flash silica gel column using CHCl3 /MeOH (4:1) as the eluant. Solvents were removed in vacua and the pure title compound (2.2 g, 85%) was obtained after recrystallisation from isopropanol/hexane.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)=[O:7])([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>COCCOC.CCOC(C)=O.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>[C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:21])[CH:27]=2)=[CH:13][CH:12]=1)[C:18]([OH:20])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)O
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of Boc-L-4-bromophenylalanine (15.0 g, 43.6 mmol), 3-chlorophenylboronic acid (8.52 g, 54.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.51 g, 1.31 mmol) in 1,2-dimethoxyethane (180 mL) was added 2M solution of aqueous NaCO3 (33 mL). The reaction mixture was heated to 85° C. After stirred for 2 hours, the reaction mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with 1M HCl and brine. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: 10% MeOH in dichloromethane) to give (S)-2-tert-butoxycarbonylamino-3-(3′-chloro-biphenyl-4-yl)-propionic acid. 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 3.08-3.17 (m, 1H), 3.21-3.31 (m, 1H), 4.65 (bs, 1H), 5.01 (bs, 1H), 7.23-7.32 (m, 3H), 7.45-7.50 (m, 2H), 7.52-7.60 (m, 1H), 7.63-7.70 (m, 2H); MS: m/z (MH+) 376.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:17])[N:14](C)C)[CH:8]=[CH:9][C:10]=1[OH:11].[Na].[CH3:19][C:20]([O:24][CH2:25]Cl)([CH3:23])[C:21]#[CH:22].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:17])[NH2:14])[CH:8]=[CH:9][C:10]=1[O:11][CH2:25][O:24][C:20]([CH3:23])([CH3:19])[C:21]#[CH:22]
Reactant: CN(C)C(=O)Nc1ccc(O)c(Cl)c1
Reactant: C#CC(C)(C)OCCl
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C#CC(C)(C)OCOc1ccc(NC(N)=O)cc1Cl

Procedure:
Sodium methoxide (0.54 gram, 0.01 mole) is added to a methanolic solution of 3-(3-chloro-4-hydroxyphenyl)-1,1-dimethylurea (2.14 grams, 0.01 mole) and the mixture heated at reflux during 2 hours. The solvent is removed under reduced pressure and to the residual material dry benzene is added and evaporated off. This procedure is repeated until a dry white powder is obtained. The sodium salt is suspended in dry acetone (50 ml.) and chloromethyl 1,1-dimethyl-2-propynyl ether (1.45 grams, 0.011 mole) is added dropwise with stirring. After the initial exothermic reaction the reaction mixture is allowed to stir for a further 4.5 hours, then cold aqueous sodium carbonate solution (10% w/v, 100 ml.) followed by water (50 ml.) are added(1) and stirred. The resulting solid(2) is filtered off, water washed and air dried. Crystallization from benzene-hexane affords 2.2 grams, 70%; melting point 150° C. to 151° C. of Compound 1.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[NH2:11][C:12]1[C:17]([O:18][CH2:19][C@@H:20]([C:29](O)=[O:30])[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][CH:15]=[CH:14][C:13]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C=O)C>CCOC(C)=O>[O:30]=[C:29]1[NH:11][C:12]2[C:13]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:14][CH:15]=[CH:16][C:17]=2[O:18][CH2:19][C@@H:20]1[NH:21][C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1cccc(-c2ccccc2)c1N)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1COc2cccc(-c3ccccc3)c2NC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
0.143 ml of diethyl cyanophosphonate (156 mg, 0.96 mmol) is introduced, at 0° C., into a 25 mL three-necked flask containing 260 mg of 42 (0.70 mmol) and 6.5 mL of DMF, followed 10 minutes later by 0.109 ml of TEA (0.77 mmol). The reaction medium is stirred at 0° C. for 2 h. 25 ml of AcOEt are added and then the mixture is washed with twice 25 mL of distilled water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. The crude product is chromatographed on a silica cartridge (24 g, eluent heptane/AcOEt, in an AcOEt gradient: 25 to 75%). 85 mg of expected product 43 are obtained.
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:20]=[CH:19][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([Li])CCC.CN(C)C=O>C(OCC)(=O)C>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH2:11][C:10]1[CH:19]=[CH:20][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=1
Reactant: C1CCOC1
Reactant: Brc1ccc(COc2ccccn2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(COc2ccccn2)cc1
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran solution (120 mL) of 2-(4-bromo-benzyloxy)-pyridine (34 g, 128 mmol) described in Manufacturing Example 2-2-1 was added n-butyl lithium (50 mL, 2.6 M, hexane solution, 134 mmol) dropwise at −78° C. After 30 minutes of stirring, to the reaction solution was added N,N-dimethylformamide (10 mL, 134 mmol) dropwise at −78° C., which was stirred at room temperature. The reaction solution was partitioned into water and ethyl acetate, and the ethyl acetate layer was washed with water (2 times) and aqueous sodium chloride (once). The water layers were combined and extracted with ethyl acetate. The resulting ethyl acetate layer was washed with water (2 times) and aqueous sodium chloride (once). The ethyl acetate layer thus obtained was combined with the ethyl acetate layer obtained previously, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was then concentrated under a reduced pressure to obtain the title compound (26.8 g) as a crude product.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)(O)CC.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)[CH:27]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1Cc2ccc(Br)cc2N1
Agent: CCC(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1Cc2ccc(-c3cccnc3)cc2N1
Temperature: 100 °C
Yield: 42 %

Procedure:
To a solution of 6-bromo-2-oxindole (4 g, 26.3 mmol) dissolved in 60 mL of toluene and 60 mL of ethanol with stirring and a little heating tetrakis(triphenyl-phosphine)palladium(0) (2.3 g, 1.9 mmol) was added followed by a 2M aqueous solution of sodium carbonate (50 mL, 100 mmol) and pyridine-3-boronic acid propane diol (5 g, 30.7 mmol). The mixture was heated in a 100° C. oil bath for 12 hours. The cooled reaction was diluted with ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate (200 mL), water (200 mL) and brine (200 mL). The organic layer was dried with magnesium sulfate and concentrated to afford a brown solid. The residue was triturated with methylene chloride/diethyl ether to give 2.32 g (42%) of 6-pyridin-3-yl-1,3-dihydro-indol-2-one as a brown solid.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH:16]=2)[CH:10]=[CH:11][CH:12]=1>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(CCc2cccc(OC)c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(CCc2cccc(O)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
BBr3 (11.3 g, 45 mmol) was added to a solution of 1,2-bis(3-methoxyphenyl)ethane (Brunner et al., Inorg. Chim. Acta 2003, 350:39-48; 11.56 g; 47.8 mmol) in CH2Cl2 at −78° C. The reaction mixture was slowly warmed to room temperature, and stirred overnight. The reaction mixture was quenched with water, diluted with CH2Cl2, and the reaction mixture extracted with 2 M solution of NaOH (3×100 mL). The aqueous layer was slowly acidified at 0° C. with concentrated HCl to approximately pH=1, the grey precipitate was filtered, washed with water, dried in the air at room temperature, and then under vacuum at 85° C. over 5 hours to provide 10.3 g of crude 1,2-bis(3-hydroxyphenyl)ethane as grey solid.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[C:9]([OH:20])(=[O:19])[C:10]1[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:12]([OH:14])=O.C(O)(=O)/C(=C\C(O)=O)/C.C(O)(=O)C1C=CC=CC=1>CC1C=CC=CC=1C>[C:12]1(=[O:14])[O:20][C:9](=[O:19])[C:10]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:11]12
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: C/C(=C/C(=O)O)C(=O)O
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: O=C1OC(=O)c2ccccc21

Procedure:
3200 parts of a 22% solution of maleic acid which contains 4% of other acids such as phthalic acid, citraconic acid and benzoic acid is supplied per hour through a tubular heater which preheats to 100°C to a falling-film evaporator. This solution has been obtained by scrubbing offgas obtained in the manufacture of phthalic anhydride by catalytic oxidation of o-xylene with air at a temperature of 40°C. In the first evaporator the solution is concentrated at atmospheric pressure and at 120°C to a content of 40% of maleic acid. The aqueous condensate is returned to the offgas scrubber.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:11]=[C:10]([CH3:12])[C:6]([C:7](O)=[O:8])=[C:5]([F:13])[CH:4]=1.C(N1C=CN=C1)([N:17]1C=CN=C1)=O>C1COCC1>[CH3:1][N:2]([CH3:14])[C:3]1[CH:11]=[C:10]([CH3:12])[C:6]([C:7]([NH2:17])=[O:8])=[C:5]([F:13])[CH:4]=1
Reactant: Cc1cc(N(C)C)cc(F)c1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1cc(N(C)C)cc(F)c1C(N)=O
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
To a suspension of 4-Dimethylamino-2-fluoro-6-methyl-benzoic acid (0.896 g, 4.54 mmol) in THF (11 mL) was added carbonyldiimidazole (0.958 g, 5.91 mmol). The solution became homogeneous with bubbling. After 30 min., this solution was added to concentrated ammonium hydroxide (7 mL), and the solution became cloudy. Following removal of solvent after 1 h, the residue was taken up in H2O and filtered to give 4-dimethylamino-2-fluoro-6-methyl-benzamide as a white solid (0.696 g, 78%).
Reaction SMILES: [N:1]1[S:2][CH:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10](OC)=[O:11])=[CH:6][C:5]=12.CC(C[AlH]CC(C)C)C>O1CCCC1>[OH:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]2=[CH:3][S:2][N:1]=[C:5]2[CH:6]=1
Reactant: COC(=O)c1ccc2csnc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1ccc2csnc2c1

Procedure:
5.8 g (0.03 mole) of 10a are stirred analogously to Example 1a in 80 ml of tetrahydrofuran with 58.8 ml (0.09 mole) of DIBAL (1.53 molar solution in toluene) at -60° C. to -70° C. overnight.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1>C(O)(=O)C>[Br:1][CH2:12][C:11]([C:6]1[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([Cl:10])[CH:7]=1)=[O:13]
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1cc(Cl)cc(Cl)c1
Reaction time: 12 h
Yield: 81 %

Procedure:
1.03 ml (0.02 mol) of bromine are added, at room temperature, to 3.77 g (0.019 mol) of (3,5-dichlorophenyl)ethanone in solution in 50 ml of acetic acid. After stirring for 12 hours, evaporation of the acetic acid leads to the production of a yellow precipitate: 2-bromo-1-(3,5-dichlorophenyl)-1-ethanone (yield 81%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C@H:9]2[C@@H:13]([CH2:14][OH:15])[O:12][C:11]([CH3:17])([CH3:16])[N:10]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=[CH:4][N:3]=1.[CH3:25][O-:26].[Na+]>CO.O>[OH:15][CH2:14][C@H:13]1[O:12][C:11]([CH3:17])([CH3:16])[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:9]1[CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:26][CH3:25])[CH:7]=1
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccnc(Cl)c2)[C@@H](CO)OC1(C)C
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C[C@H]2[C@@H](CO)OC(C)(C)N2C(=O)OC(C)(C)C)ccn1

Procedure:
(4S,5S)-Tert-butyl 4-((2-chloropyridin-4-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (0.200 g, 0.560 mmol) was dissolved in a 25% solution of SODIUM METHOXIDE (12.8 ml, 56.0 mmol) in methanol and refluxed for 12 hrs and cooled. The reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated to give (4S,5S)-tert-butyl 5-(hydroxymethyl)-4-((2-methoxypyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate, MS m/z: 353.3 (100%, M+1).