Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCO
Product: COc1ccc(CS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
A butanol (5 ml) suspension of sodium 4-chlorobenzenesulfinate (264 mg, 1.33 mmol), 4-methoxybenzyl chloride (181 μl, 1.33 mmol) and tetrabutylammonium bromide (24 mg) was stirred at 70° C. for 3 days. After cooling the reaction mixture to room temperature, the solvent was concentrated under reduced pressure. Ethyl acetate was added to the residue and the mixture was washed successively with water and brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate (=5:1) eluate was concentrated under reduced pressure, whereby the title compound (90 mg, 23%) was obtained as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[NH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:19]>C1COCC1>[CH3:6][O:5][C:3](=[O:4])[CH2:2][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:19]
Reactant: COC(=O)CBr
Reactant: O=C1CCc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN1C(=O)CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
Methyl bromoacetate (5.72 g, 37.4 mmol) was slowly added to a stirred solution of sodium hydride (1.5 g, 37.4 mmol) and 3,4-dihydro-2 (1H)quinolinone (5.0 g, 34 mmol) in THF. The mixture was stirred at RT for 3 h. After removing the solvent, the residue was diluted with water and ether. The layers were separated and the aqueous layer was extracted with ether (3×50 mL). The combined organics were dried with MgSO4 and condensed to afford the desired product, compound 49A (7.06 g, 95%) as a yellow solid. MS m/z 220 (M+1). Step 2. Preparation of (6-Chlorosulfonyl-2-oxo-3,4-dihydro-2H-quinolin-1-yl) acetic acid methyl ester (Compound 49B).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11]Br)=[CH:6][CH:5]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][N:15]=[N+:16]=[N-:17])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 4 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
4-(2-Bromo-acetyl)-benzoic acid methyl ester (15.5 mmol) was dissolved in ethanol (120 ml) and acetic acid (4.8 ml). Sodium azide (31 mmol) was added and the reaction stirred at 4° C. overnight. The ethanol was removed and the mixture diluted with ethyl acetate (100 ml). The organic layer was washed with saturated sodium hydrogen carbonate (2'50 ml) and dried (MgSO4). The solvent was removed in vacuo to give a yellow solid, which was re-crystallized from ethanol to give the title compound as a pale yellow solid (2.6 g). IR 2117 cm−1
Reaction SMILES: C[O-].[Na+].C(O)C.[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][SH:14])=[CH:9][CH:8]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>C(OCC)C>[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][S:14][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:9][CH:8]=1
Reactant: SCc1ccncc1
Reactant: O=C(CBr)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: O=C(CSCc1ccncc1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Under a nitrogen atmosphere, sodium methoxide (0.81 g., 15 mmoles) was dissoled in 17.9 ml. of stirring absolute ethanol, and cooled in an ice bath. 4-Picolyl mercaptan (1.88 g., 15 mmoles) in 3 ml. of absolute ethanol was added dropwise over approximately 5 minutes, followed by alpha-bromoacetophenone (3.05 g., 15 mmoles) in 10 ml. of warm absolute ethanol added over approximately 10 minutes. The stirring reaction mixture was warmed to room temperature and left to stir for 17 hours. Salts were removed by filtration through diatomaceous earth, and the solids repulped for 0.5 hour with additional ethanol and refiltered. The ethanol filtrates were combined and concentrated to yield a waxy solid. The waxy solid was taken up in approximately 11 volumes of diethyl ether, treated with activated carbon, filtered and the mother liquor concentrated to a solid (1.90 g.). Recrystallization from diethyl ether/hexane gave purified alpha-(4-picolylthio)acetophenone (1.25 g. in two crops, m.p. 55°-59° C., ir (KBr): 5.92, 6.18, 7.00, 7.76, 9.78, 12.38, 13.70μ).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[C@@H:5]([CH3:36])[CH2:4]1.[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[CH2:39][O:38][CH3:37])[CH2:4][C@@H:5]4[CH3:36])=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)C[C@@H]1C
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)[C@@H](C)C1

Procedure:
Starting from N-[(1S*,2S*,4S*)-4-amino-2-methylcyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f63) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][S:4][N:3]=1.C([Li])CCC.[I:15]I.Cl>C1COCC1>[I:15][C:5]1[S:4][N:3]=[C:2]([CH3:1])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1nscc1C(=O)O
Reactant: II
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nsc(I)c1C(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methylisothiazole-4-carboxylic acid (C-4) (3.9 g, 27.3 mmol) in anhydrous THF (150 mL) at −78° C. under argon, n-butyl lithium solution (27.3 mL, 68.3 mmol) is added dropwise and the resulting mixture is stirred at −78° C. for 1 h. To this mixture, a solution of iodine (13.9 g, 54.6 mmol) in THF (50 mL) is added slowly and the resulting mixture is stirred at RT for 1 h. The mixture is acidified with concentrated HCl to adjust the pH to 3-4, and then extracted with ethyl acetate. The organic layer is washed with aqueous Na2SO3 solution. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the product, 5-iodo-3-methylisothiazole-4-carboxylic acid (C-5).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N+:7]([C:10]1[CH:18]=[CH:17]C(C(O)=O)=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(Cl)(Cl)Cl.CN(C=O)C>[N+:7]([C:10]1[CH:18]=[CH:17][C:1]([C:2]([Cl:4])=[O:3])=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
Oxalyl chloride (4.78 g, 37.6 mmol) was added drop wise to a stirred solution of 4-nitrobenzoic acid (4.2 g, 25 mmol) in chloroform (50 mL). After 5 mins DMF (2 drops) was added and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed to afford 4.7 g (98%) of 4-nitro-benzoyl chloride which was used for next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[NH2:34][C:35]1[S:39][N:38]=[C:37](/[C:40](=[N:44]/[O:45][CH2:46][CH3:47])/[C:41](Cl)=[O:42])[N:36]=1.CC(N(C)C)=O>ClCCl>[NH2:34][C:35]1[S:39][N:38]=[C:37](/[C:40](=[N:44]/[O:45][CH2:46][CH3:47])/[C:41]([NH:1][C@@H:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]23)=[O:42])[N:36]=1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CCO/N=C(\C(=O)Cl)c1nsc(N)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
In 200 ml of dichloromethane is suspended 11 g of 7β-amino-3(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid. To the suspension is added 14 g of bistrimethylsilylacetamide and the mixture is stirred at room temperature until complete dissolution and cooled in an ice-water bath. To this solution, 14 g of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-ethoxyiminoacetyl chloride is added and the mixture is stirred for a while, to which 6 g of dimethylacetamide is added. The whole mixture is stirred with ice-cooling for 60 minutes. The dichloromethane is evaporated off and the residue is dissolved in methyl ethyl ketone. The solution is washed with water and dried. The solvent is then evaporated off and diethyl ether is added to the residue to give a fine precipitate, which is collected by filtration, giving 12.5 g of the above-identified compound.
Reaction SMILES: OS(O)(=O)=O.[N-:6]=[N+]=[N-].[Na+].[F:10][C:11]([F:30])([F:29])[C:12]([N:14]1[CH2:19][CH2:18][C:17]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[CH2:20]2)[CH2:16][CH2:15]1)=[O:13].C([O-])(O)=O.[Na+]>O.C(Cl)(Cl)Cl>[F:10][C:11]([F:30])([F:29])[C:12]([N:14]1[CH2:19][CH2:18][C:17]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:6][C:21](=[O:28])[CH2:20]2)[CH2:16][CH2:15]1)=[O:13]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CC2(CCN(C(=O)C(F)(F)F)CC2)c2ccccc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1CC2(CCN(C(=O)C(F)(F)F)CC2)c2ccccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Concentrated H2SO4 (1.1 mL) was added slowly to sodium azide (2.49 g, 38.3 mmol) in water (2.7 mL) and chloroform (15 mL) keeping the temperature between 0-5° C. After 10 min the cold bath was removed and the reaction was stirred for 3 h at rt. Na2SO4 was added to the solution to dry it and the resulting chloroform solution (containing HN3) was then decanted into a solution of 19a (4.55 g, 15.3 mmol) in chloroform (16 mL). Concentrated H2SO4 (4.1 mL) was added and the reaction was stirred for 30 min. at rt. The mixture was heated to 50° C. for 45 min. and then stirred at rt for 2 h. The reaction was poured into sat. NaHCO3 solution and extracted with CH2Cl2 (3×) and with EtOAc (2×). The combined organics were dried (MgSO4), filtered and evaporated to give the crude product. The crude product was purified by flash chromatography on Biotage using EtOAc/CH2Cl2 (50-80%) to give 19b as lightly colored foam (2.6 g, 54%). (M+H)+=313. 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (s, 1H); 7.29 (d, J=7.8 Hz, 1H); 7.24 (t, J=7.8 Hz, 1H); 7.10 (t, J=7.6 Hz, 1H); 6.83 (d, J=7.8 Hz, 1H); 4.44 (d, J=13.9 Hz, 1H); 3.92 (d, J=14.1 Hz, 1H); 3.48 (t, J=13.2 Hz, 1H); 3.18 (t, J=11.9 Hz, 1H); 2.77 (m, 2H); 2.00 (m, 2H); 1.85 (m, 2H).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.C(N(CC)C(C)C)(C)C.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:42]2C(=O)[CH2:46][CH2:45][CH2:44][C:43]=2[OH:49])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]>ClCCl>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:42]2[C:43](=[O:49])[CH2:44][CH2:45][CH2:46][C:6]=2[O:7][CH3:9])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]([F:39])([F:41])[F:40])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(C(NC(=O)Nc2ccnc(C(F)(F)F)c2)C2=C(O)CCCC2=O)cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC1=C(C(NC(=O)Nc2ccnc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethyloxonium tetrafluoroborate (47 mg, 0.318 mmol) is added to a solution of N,N-diisopropylethylamine (72 μL, 0.412 mmol) and 1-((4-cyanophenyl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(2-(trifluoromethyl)pyridin-4-yl)urea (intermediate 26, 90 mg, 0.209 mmol) in dichloromethane (10 mL). The mixture is stirred at room temperature for 1 h and extracted three times with water. The organic phase is dried over Na2SO4 and concentrated under reduced pressure. Yield: 100 mg; ESI mass spectrum [M+H]+=445, Retention time HPLC: 1.05 min (V012_S01).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:18]1([CH2:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:24]([NH:25][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
Combined 6-chloronicotinoyl chloride (1.76 g, 10.00 mmol) and DCM (20 mL) and cooled in an ice-bath then triethylamine (2.09 mL, 15.0 mmol) and phenylmethanamine (1.072 g, 10.00 mmol) were added. The reaction was then stirred at room temperature for 3 hours before being diluted in DCM (30 ml), washed with 1N aqueous HCl (50 ml), saturated aqueous sodium bicarbonate (50 ml), brine (50 ml), dried over Na2SO4, and concentrated to give the title compound (2.19 g, 89%) as a light beige solid which was used without further purification. MS m/z [M+H]+ 247.1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:9]=O)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:11]([O:15][C:16](=[O:24])[N:17]([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH3:18])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16](=[O:24])[N:17]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:9][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1)[CH3:18])([CH3:14])([CH3:12])[CH3:13]
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CN(CCCCN)C(=O)OC(C)(C)C
Product: Cc1cnc(CNCCCCN(C)C(=O)OC(C)(C)C)c(C)c1

Procedure:
Yellow oil prepared from 3,5-dimethyl-pyridine-2-carbaldehyde and (4-amino-butyl)-methyl-carbamic acid tert-butyl ester. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.53-1.57 (m, 4H), 2.27 (s, 6H), 2.69-2.73 (m, 2H), 2.82 (s, 3H), 3.18-3.23 (m, 2H), 3.83 (s, 2H), 7.24 (s, 1H), 8.20 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1C(C)(C)C.O.[C:19]([OH:23])(=O)[CH:20]=[O:21].O>ClCCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:6]([CH3:11])([CH3:7])[CH3:5])[C:9]2[O:12][C:20](=[O:21])[CH:19]([OH:23])[C:10]=2[CH:11]=1
Reactant: O=CC(=O)O
Reactant: COC(=O)CCc1ccc(O)cc1C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCCl
Product: COC(=O)CCc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Yield: 200 %

Procedure:
23.6 g of 3-(2-tert-butyl-4-hydroxy-phenyl)-propionic acid methyl ester (U.S. Pat. No. 43070-A2), 10.1 g of glyoxylic acid monohydrate and 0.08 g of p-toluenesulfonic acid are boiled in 80 ml of 1,2-dichloroethane for 7 hours using a water separator. The reaction solution is then cooled, washed three times with 50 ml of water each time and freed of solvent using a rotary evaporator. 29.2 g of 3-(7-tert-butyl-3-hydroxy-2-oxo-2,3-dihydro-benzofuran-5-yl)-propionic acid methyl ester are obtained in the form of a yellowish oil. That yellowish oil is placed in 50 ml of toluene with 15 ml of thionyl chloride and 3 drops of DMF and the reaction mixture is then slowly heated to 100° C. at such a rate that the evolution of HCl and SO2 remains vigorous yet controllable. The reaction mixture is then stirred at that temperature for a further hour. Approximately 50 ml of liquid are then distilled off in order to remove the excess thionyl chloride. The residue is diluted with 160 ml of toluene and, at room temperature, 14 ml of triethylamine are added dropwise thereto. The thick, red reaction mixture is then heated under reflux for 30 min. After cooling to room temperature, the triethylamine hydrochloride which has precipitated is filtered off and the filtrate is concentrated to an oily consistency using a rotary evaporator. The isoxindigo is crystallised out by adding 100 ml of acetonitrile, is filtered off, washed with acetonitrile and dried. 7.4 g (27% of the theoretical yield) of 3-[7,7′-di-tert-butyl-2,2′-dioxo-[3,3′]bibenzofuranyliden-5-yl]-5,5′-propionic acid methyl ester (LVIa) are obtained.
Reaction SMILES: CS(O[C@@:6]1([CH3:44])[CH2:10][C@H:9]([S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][N:7]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])(=O)=O.[OH:45][CH2:46][C@@H:47]1[CH2:51][CH2:50][CH2:49][NH:48]1.C(N(CC)CC)C>CN(C)C=O>[OH:45][CH2:46][C@@H:47]1[CH2:51][CH2:50][CH2:49][N:48]1[CH2:44][C@@H:6]1[CH2:10][C@H:9]([S:11][C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:8][N:7]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32]
Reactant: OC[C@@H]1CCCN1
Reactant: C[C@]1(OS(C)(=O)=O)C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCC[C@H]1CO
Temperature: 100 °C
Reaction time: 5 h
Yield: 65.1 %

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)-methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (8.76 g) in dimethylformamide (80 ml) were added (2S)-2-(hydroxymethyl)pyrrolidine (8.72 g) and triethylamine (3.86 ml) and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was poured into ice-water (300 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of dichloromethane and acetone (2:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.75 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:3][CH2:2]1.Cl.[F:20][C:21]([F:34])([F:33])[C:22]1[S:26][C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][CH:23]=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:25]3[S:26][C:22]([C:21]([F:34])([F:20])[F:33])=[CH:23][N:24]=3)[CH2:28][CH2:29]2)=[O:10])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)N2CCN(c3ncc(C(F)(F)F)s3)CC2)c1
Yield: 22 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (Example A5) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as a white crystalline solid (yield 22%). MS (m/e): 490.3 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:13][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[Cl:1])[NH:9][C:8](=[O:12])[CH2:7][CH2:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2ccc(Cl)cc2N1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Br)c(Cl)cc2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To solution of 7-chloro-3,4-dihydroquinolin-2(1H)-one (110-1; 2.92 g, 0.016 mol) in N,N-dimethylformamide (30 mL), was added N-bromosuccinimide (3.14 g, 0.0176 mol) portion-wise at room temperature. The resulting mixture was stirred at room temperature for 16 h. After 16 h, the reaction mixture was diluted with cold water, solid get precipitated, filtered the solid, washed the solid with water and dried under reduced pressure to afford the compound. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.56 (s, 1H), 7.01 (s, 1H), 2.87-2.84 (t, J=7.2 Hz, 2H), 2.45-2.41 (t, J=7.6 Hz, 2H); MS (M+1): 259.9.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1.[Li+].CC([N-]C(C)C)C.[CH2:29]([Si:31]([CH2:35][CH3:36])([CH2:33][CH3:34])Cl)[CH3:30]>C1COCC1>[Br:13][C:14]1[CH:19]=[C:18]([Si:31]([CH2:35][CH3:36])([CH2:33][CH3:34])[CH2:29][CH3:30])[C:17]([F:20])=[CH:16][N:15]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC[Si](Cl)(CC)CC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(Br)ncc1F
Yield: 96 %

Procedure:
To a solution of diisopropylamine (25.3 g, 250 mmol) in THF (400 ml) was added n-BuLi (100 ml, 2.5 mol/L in hexanes) below −50° C. A solution of 2-bromo-5-fluoropyridine (41.9 g, 238 mmol) in THF (60 ml) was added to the LDA-solution at −78° C. in a dropwise manner below −63° C. After 60 minutes at −78° C. triethylchlorosilane (44 ml, 262 mmol) was added in a fast manner keeping the temperature below −50° C. The cooling bath was removed and the reaction mixture was allowed to reach −20° C. The reaction mixture was poured on a mixture of 1M aq. HCl (250 ml) and aq. NH4Cl (10%). Tert.-butyl methyl ether was added and the layers were separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated to give a yellow liquid. Distillation (bp. 99-101° C., 0.5 mm Hg). afforded the title compound as a slightly yellow liquid: 66.26 g (96% yield)
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][C:7](=[O:9])[CH2:6][CH2:5][NH:4]1)=[CH2:2].Cl[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([CH3:21])[CH3:20])[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:19]([O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:4]1[CH2:5][CH2:6][C:7](=[O:9])[CH2:8][CH:3]1[CH:1]=[CH2:2])([CH3:21])[CH3:20]
Reactant: CC(C)Oc1cccc(CCl)c1
Reactant: C=CC1CC(=O)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CC1CC(=O)CCN1Cc1cccc(OC(C)C)c1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
2-vinylpiperidin-4-one (4.85 g, 38.7 mmol) in acetonitrile (40 ml) was added 1-(chloromethyl)-3-isopropoxybenzene (7.16 g, 38.7 mmol) and finely ground K2CO3 (16.1 g, 116 mmol). The mixture was stirred at 60° C. for 12 hrs. The solution was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 65i, eluting with 15% ethyl acetate/hexanes.