Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[H-].[Na+].B(F)(F)F.[CH3:16][CH2:17][O:18]CC.C1OC1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:16][CH2:17][OH:18])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCOCC
Reactant: CCCCOP([O-])CC
Agent: FB(F)F
Agent: [Cl-]
Agent: [H-]
Solvent: C1CO1
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(CC)CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
4.5 g (30 mmol) of butyl ethylphosphonite (prepared as in Example 2) are dissolved in 30 ml of toluene and at 0° C. admixed with 0.72 g (30 mmol) of sodium hydride. After one hour of stirring, 5.68 g (40 mmol) of boron trifluoride etherate are added and ethylene oxide is passed in and the mixture is subsequently reacted for a further two hours. Thereafter, aqueous ammonium chloride solution is added and the mixture is warmed to room temperature. That is subsequently concentrated in vacuo, the residue is taken up in diethyl ether, insoluble salts are filtered off and the mixture is again concentrated. Chromatographic purification leaves 4.5 g (78% of theory) of butyl ethyl(2-hydroxyethyl)phosphinate being obtained as oil.
Reaction SMILES: [C:1]1([C:7]2(O[CH:11]2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][NH2:20]>C(O)C>[CH3:9][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[NH:20][N:19]=1
Reactant: CC(=O)C1(c2ccccc2)OC1c1ccncc1
Reactant: NN
Solvent: CCO
Product: Cc1n[nH]c(-c2ccncc2)c1-c1ccccc1

Procedure:
A solution of 3-phenyl-4-(4-pyridyl)-3,4-epoxy-2-butanone (step 2) (350 mg, 1.46 mmol) and anhydrous hydrazine (0.7 ml, 20 mmol) in ethanol (3 ml) was heated at reflux for 4 hours. The reaction was cooled, and the solvent was evaporated to dryness. The resulting residue was purified by chromatography (silica gel, 1:1 acetone/hexane) to give the desired product as a crystalline solid, which was recrystallized from ethyl acetate and hexane to give pure 4-(3-methyl-4-phenyl-1H-pyrazol-5-yl)pyridine (145 mg, 42%): m. p. 164-165° C. Anal. Calc'd for C15H13N3 (235.29): C, 76.57; H, 5.57; N, 17.86. Found: C, 76.49; H, 5.45; N, 17.70.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:23]([O:24][C@@H:25]2[O:33][C@H:32]([CH2:34][OH:35])[C@H:30]([OH:31])[C@H:28]([OH:29])[C@H:26]2[OH:27])[C@H:22]([O:36][C@@H:37]2[O:45][C@@H:44]([CH3:46])[C@@H:42]([OH:43])[C@@H:40]([OH:41])[C@@H:38]2[OH:39])[C@@H:21]([CH2:47][OH:48])[O:20][C@H:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=O)(=[O:3])[CH3:2].O.[NH2:50][NH2:51]>C(O)C>[C:1]([NH:4][C@@H:5]1[C@@H:23]([O:24][C@@H:25]2[O:33][C@H:32]([CH2:34][OH:35])[C@H:30]([OH:31])[C@H:28]([OH:29])[C@H:26]2[OH:27])[C@H:22]([O:36][C@@H:37]2[O:45][C@@H:44]([CH3:46])[C@@H:42]([OH:43])[C@@H:40]([OH:41])[C@@H:38]2[OH:39])[C@@H:21]([CH2:47][OH:48])[O:20][C@H:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:50][NH2:51])=[O:18])(=[O:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H]1NC(C)=O
Solvent: O
Solvent: CCO
Product: CC(=O)N[C@H]1[C@H](OCCCCCCCCC(=O)NN)O[C@H](CO)[C@@H](O[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H]1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reaction time: 4 h

Procedure:
Compound 8 (1 g) was dissolved in 85% hydrazine hydrate (4 ml) and allowed to stand for 4 h at ambient temperature. The reaction mixture was diluted with 95% ethanol (20 ml) and the solvents evaporated. The residue was dissolved in 10 ml water and dialyzed against 5 changes of water in an ultrafiltration cell. Lyophilization of the water gave 8-hydrazinocarbonyloctyl 2-acetamido-2-deoxy-4-O-(α-L-fucopyranosyl)-3-O-(β-D-galactopyranosyl)-β-D-glucopyranoside (14) in quantitative yield as an amorphous solid, [α]D --72.8° (c 1.0, water). This compound and the 5-hydrazinocarbonylpentyl analog were used to prepare the following Lewis-a antigens [Lea -O(CH2)8CONH]n -BSA where n can have any of the following values 11, 22, 30, or 45; [Lea -O(CH2)8CONH]28 -HSA; [Lea -O(CH2)8CONH]15 -polylysine; [Lea -O(CH2)8CONH(CH2)2NH]10 -dextran; [Lea -O(CH2)5CONH]n -BSA where n was 10 or 30; [Lea -O(CH2)5CONH]25 -HSA by the acyl azide method (cf example XII). The abbreviation Lea as used above stands for the Lewis-a trisaccharide determinant: ##STR12## Goat antiserum prepared against the natural Lewis-a blood group substance was found to form a precipitate with the above Lea antigens.
Reaction SMILES: C1(C)C=CC=CC=1.N1CCCCC1.[S:14]1[CH2:18][C:17](=[O:19])[NH:16][C:15]1=[O:20].[CH3:21][N:22]([CH3:46])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][C:24]=1[C:31]1[C:40]([CH3:41])=[CH:39][C:38]2[C:37]([CH3:43])([CH3:42])[CH2:36][CH2:35][C:34]([CH3:45])([CH3:44])[C:33]=2[CH:32]=1>O.C(O)(=O)C>[CH3:46][N:22]([CH3:21])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[C:18]2[S:14][C:15](=[O:20])[NH:16][C:17]2=[O:19])=[CH:25][C:24]=1[C:31]1[C:40]([CH3:41])=[CH:39][C:38]2[C:37]([CH3:42])([CH3:43])[CH2:36][CH2:35][C:34]([CH3:45])([CH3:44])[C:33]=2[CH:32]=1
Reactant: Cc1cc2c(cc1-c1cc(C=O)ccc1N(C)C)C(C)(C)CCC2(C)C
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1-c1cc(C=C3SC(=O)NC3=O)ccc1N(C)C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 63.5 %

Procedure:
To a solution of toluene (30 mL) containing piperidine (0.2 mL) and acetic acid (0.2 mL) were added 2,4-thiazolidinedione (2.34 g, 20 mmol) and 4-dimethylamino-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl)benzaldehyde (7.0 g, 20 mmol). The reaction mixture was heated at reflux for 4 hours with continuous removal of water using a Dean-Stark water separator. After cooling to room temperature, a yellow solid formed that was collected and washed with ethanol, dried under vacuum to give 5.7 g of 5-[4-dimethylamino-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl)benzylidene]thiazolidine-2,4-dione. The organic layers were combined and evaporated. Trituration from ethanol afforded 1.4 g more of product (78%). 1H NMR (300 MHz; d-DMSO): 1.21 (s, 3H); 1.24 (s, 3H); 1.27 (s, 6H); 1.65 (s, 4H); 2.05 (s, 3H); 2.55 (s, 6H); 7.06 (d, J=9 Hz, 1H); 7.13 (s, 1H); 7.20 (s, 1H); 7.21 (d, J=2.4 Hz, 1H); 7.46 (dd, J1=2.1 Hz, J2=8.7 Hz, 1H); 7.73 (s, 1H), 12.43 (s, 1H).
Reaction SMILES: F[C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([CH3:18])[C:5]([C:16]#[N:17])=[C:6]2[C:10]=1[O:9][C:8]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[N:7]2.[CH3:25][N:26]([CH3:32])[C@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1.C(N(CC)CC)C>CS(C)=O>[CH3:25][N:26]([CH3:32])[C@H:27]1[CH2:31][CH2:30][N:29]([C:2]2[C:3]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:4]([CH3:18])[C:5]([C:16]#[N:17])=[C:6]3[C:10]=2[O:9][C:8]([N:11]2[CH2:14][CH:13]([OH:15])[CH2:12]2)=[N:7]3)[CH2:28]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(O)C3)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CC(O)C3)nc2c1C#N
Temperature: 150 °C
Reaction time: 5 h
Yield: 23.6 %

Procedure:
7-Fluoro-2-(3-hydroxyazetidin-1-yl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-143) (120 mg, 0.37 mmol) was dissolved in dimethyl sulfoxide (6 ml), then (3S)-3-(dimethylamino)pyrrolidine (71 μl, 0.56 mmol) and triethylamine (189 μl, 1.11 mmol) were added, followed by stirring at 150° C. under nitrogen atmosphere for 5 hours. After cooling and fractionation with water and ethyl acetate, the organic layer was washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography. Elution with a mixed solvent of chloroform/methanol (9:1, v/v/) gave the entitled compound (36.4 mg, 23%) as a white solid.
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][C:16]1[CH:45]=[CH:44][CH:43]=[CH:42][C:17]=1[O:18][CH2:19][C:20]1[C:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[O:37][CH3:38])=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([CH3:41])=[CH:23][C:24]([CH3:40])([CH3:39])[NH:25]2)=O)(C)(C)C>>[NH2:15][C:16]1[CH:45]=[CH:44][CH:43]=[CH:42][C:17]=1[O:18][CH2:19][C:20]1[C:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[O:37][CH3:38])=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([CH3:41])=[CH:23][C:24]([CH3:40])([CH3:39])[NH:25]2
Reactant: COc1cc(F)ccc1-c1ccc2c(c1COc1ccccc1NC(=O)OC(C)(C)C)C(C)=CC(C)(C)N2
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(F)ccc1-c1ccc2c(c1COc1ccccc1N)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
4N HCl/1,4-dioxane solution (1 mL) was added to 5-(2-t-Butoxycarbonylaminophenoxymethyl)-6-(4-fluoro-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 3-79, 9.6 mg, 0.019 mmol), then the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Ethyl acetate (10 mL) and saturated aqueous NaHCO3 solution (10 mL) were added to the residue and separated. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the titled compound (5.4 mg) as a yellow oil. (Yield 70%)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:19])[CH:7]=[C:8]([CH3:18])[CH2:9]P(OCC)(OCC)=O)[CH3:4].[Br:20][C:21]1[CH2:25][CH2:24][CH2:23][C:22]=1[CH:26]=O>CN(C=O)C>[CH2:3]([O:5][C:6](=[O:19])/[CH:7]=[C:8](\[CH3:18])/[CH:9]=[CH:26]/[C:22]1[CH2:23][CH2:24][CH2:25][C:21]=1[Br:20])[CH3:4]
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Reactant: O=CC1=C(Br)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C(C)/C=C/C1=C(Br)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
2.03 g of NaH (50% in mineral oil) was suspended in 120 ml of DMF. 12.9 g of 4-(diethoxy-phosphinyl)-3-methyl-but-2-enoic acid ethyl ester was added at 0°. The mixture was stirred for 15 min at 0° and for 30 min at RT. After recooling to 0°, 5.72 g of 2-bromo-cyclopent-1-enecarbaldehyde, dissolved in 11 ml of DMF, was added drop by drop and allowed to react for 10 min. at 0° and for 2 h at RT. The mixture was then poured onto crushed ice, extracted with EtOEt, washed with sat. NaCi-solution, dried over Na2SO4, and evaporated to dryness. Purification of the residue by flash chromatography (silica gel, hexane/AcOEt=97/3) and crystallization from hexane/trace amounts of AcOEt yielded finally 3.408 g of pure (2E,4E)-5-(2-bromo-cyclopent-1-enyl)-3-methyl-penta-2,4-dienoic acid ethyl ester as yellowish crystals of mp. 85°-86°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[CH3:41][C:42]1[C:51]2[C:46](=[CH:47][C:48]([C:52]([F:55])([F:54])[F:53])=[CH:49][CH:50]=2)[NH:45][C:44](=[O:56])[C:43]=1[C:57](O)=[O:58]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][NH:6][C:57]([C:43]2[C:44](=[O:56])[NH:45][C:46]3[C:51]([C:42]=2[CH3:41])=[CH:50][CH:49]=[C:48]([C:52]([F:54])([F:55])[F:53])[CH:47]=3)=[O:58])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(C(=O)O)c(=O)[nH]c2cc(C(F)(F)F)ccc12
Reactant: NCc1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)NCc2cccc(F)c2)c(=O)[nH]c2cc(C(F)(F)F)ccc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
926 mg (7.4 mmol) 3-Fluorobenzylamine, 2.55 g (6.7 mol) HATU and 2.7 ml (19.5 mmol) NEt3 were added to a solution of 1.82 g (6.7 mmol) 4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid in THF (50 ml). The RS was stirred at 50° C. for 16 h and was then diluted with EtOAc (50 ml) at RT. The resulting precipitate was filtered off and dried in vacuo to give 2.10 g (5.6 mmol, 83%) N-[(3-Fluorophenyl)-methyl]-4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide, which was used in the next step without further purification.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:18]=[CH:17][CH:16]=[C:15]([C:19]([C@@H:21]3[N:26]4[CH2:27][C@H:28]([CH:29]=[CH2:30])[C@@H:23]([CH2:24][CH2:25]4)[CH2:22]3)=[O:20])[C:13]=2[CH:14]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:18]=[CH:17][CH:16]=[C:15]([C@H:19]([OH:20])[C@@H:21]3[N:26]4[CH2:27][C@H:28]([CH:29]=[CH2:30])[CH:23]([CH2:24][CH2:25]4)[CH2:22]3)[C:13]=2[CH:14]=1
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@@H]2C(=O)c1ccnc2ccc(OC)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12

Procedure:
600 ml. anhydrous pyridine, 100 g. crystallized quinidinone, and 300 ml. 25% solution of diisobutylaluminum hydride (DIBAH) in toluene were in a reaction vessel and the reaction was allowed to proceed until the reduction was completed as indicated by thin layer chromatography. The mixture was then heated under vacuum (25 mm Hg) to remove the pyridine. The reaction mixture was then treated with 750 ml. of a 50/50 mixture of water and ethanol, and after refluxing for 2 hours and cooling, 92.7 g. of quinidine base were obtained, exhibiting a melting point of 174.5° C.
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1)[CH:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1.[OH-].[K+]>C(O)C.[Cl-].[Na+].O>[Br:10][C:6]1[CH:5]=[C:4]([C:3]#[C:2][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cccc(C(Br)C(Br)c2cccc(Br)c2)n1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C#Cc2cccc(Br)c2)n1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
1.2 g (2.8 mMol) of 2-[1,2-dibromo-2-(3-bromophenyl)-ethyl]-6-methyl-pyridine are dissolved in 10 ml of ethanol. 0.9 g (16.1 mMol) of potassium hydroxide (powder) are added, and the resulting suspension is heated under reflux for 4 hours. The suspension is then cooled to room temperature, poured into 100 ml of brine and extracted thrice with 30 ml each of t-butyl methyl ether. The combined organic phases are washed with 30 ml of brine, dried over Sodium sulfate, filtrated and evaporated in vacua. 0.720 g of the title compound are obtained as a colorless oil crystallizing on standing; melting point 60-61°.
Reaction SMILES: Cl.C([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:15][CH:14]=2)=[O:12])[CH2:6]1)(=O)C>>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]([CH:7]2[CH2:8][CH2:9][CH2:10][NH:5][CH2:6]2)=[O:12])=[CH:14][CH:15]=1
Reactant: CC(=O)N1CCCC(C(=O)c2ccc(N3C(=O)c4ccccc4C3=O)cc2)C1
Agent: Cl
Product: Nc1ccc(C(=O)C2CCCNC2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
Concentrated hydrochloric acid (53 ml) was added to 2-[4-[(1-acetyl-3-piperidinyl)carbonyl]phenyl]-1H-isoindol-1,3 (2H)-dione (4.00 g, 10.6 mmol) obtained in Reference Example 76, which was stirred at 100° C. for 16 hours, and then insoluble matters were filtered off. Potassium carbonate was added to the filtrate to make it alkaline, and extraction was conducted using ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting residue was powdered with diisopropyl ether, to give (4-aminophenyl) (3-piperidinyl)methanone (1.69 g).
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:4]=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.Cl[C:16]1C=C(N2N=NC(C(O)C)=N2)C=CC=1>>[Br:1][CH:2]([C:3]1[N:4]=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1)[CH3:16]
Reactant: Clc1cccc(-n2nnc(CBr)n2)c1
Reactant: CC(O)c1nnn(-c2cccc(Cl)c2)n1
Product: CC(Br)c1nnn(-c2cccc(Cl)c2)n1

Procedure:
The title compound is prepared according to the procedure for 5-bromomethyl-2-(3-chloro-phenyl)-2H-tetrazole (example 7a) using 1-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl-ethanol as starting material.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[Mg+2].[Cl-].[Cl-]>C(#N)C>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1cccc(Cl)c1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1cccc(Cl)c1F
Temperature: 95 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A mixture of 2-(3-chloro-2-fluorophenyl)-2-methylpropanoic acid (1.386 g, 6.40 mmol) and thionyl chloride (60.0 mL, 823 mmol) was stirred at 95° C. for 2 hours. The reaction was concentrated in vacuo, azeotroped using DCM (2×100 mL), and dried in vacuo to give the crude acid chloride. A solution of diethyl malonate (0.967 mL, 6.40 mmol) and MgCl2 (0.263 mL, 6.40 mmol) in ACN (40 mL) at 0° C., was treated dropwise with TEA (1.87 mL, 13.4 mmol), and the mixture was stirred at 25° C. for 3 hours. A solution of the acid chloride in ACN (35 mL) was added, and the mixture was stirred at 50° C. for 18 hours. The solution was concentrated in vacuo, diluted with 10% HCl(aq) (100 mL), and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (75 mL), dried over MgSO4, concentrated, and dried in vacuo. The residue was purified by flash column chromatography (silica, 0-100% DCM in hexane) to give 1.56 g of the title compound. MS m/e=325 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31]([CH3:35])=[CH:30][N:29]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31]([CH3:35])=[CH:30][N:29]=1)=[O:27]
Reactant: Cc1cnc(C(=O)CBr)cc1C
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2cc(C)c(C)cn2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4,5-dimethylpyridine*.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCCN2CCN2C(=O)c3ccccc3C2=O)c1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CCN1CCCC1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.7 %

Procedure:
To a solution of 2-{2-[2-(3-methoxyphenyl)-1-pyrrolidinyl]ethyl}-1H-isoindole-1,3(2H)dione (1.0 g), in dry chloroform (40 ml) was added boron tribromide (99%, 1.3 ml) at -10° C., under nitrogen. The reaction mixture was stirred for 10 mins in a cooling bath and 20 mins at ambient temperature. Crushed ice was added followed by 5:1-chloroform/2-propanol (10 ml). The layers were separated, and the aqueous phase was extracted with 5:1-chloroform/2-propanol (2 times). The combined organic extracts were washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 0.89 g (93%) of product, mp 172°-175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:68]([O:72][C:73]([NH:75][CH2:76][C:77]1([C:80](O)=[O:81])[CH2:79][CH2:78]1)=[O:74])([CH3:71])([CH3:70])[CH3:69].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:22])([F:21])[F:23])[N:15]=[C:14]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:80]([C:77]5([CH2:76][NH:75][C:73](=[O:74])[O:72][C:68]([CH3:70])([CH3:69])[CH3:71])[CH2:79][CH2:78]5)=[O:81])(=[O:33])=[O:32])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CC1
Reactant: NS(=O)(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1(C(=O)NS(=O)(=O)c2ccc(Nc3nc(NC4(c5ccc(Cl)cc5)CC4)nc(OCC(F)(F)F)n3)cc2)CC1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzenesulfonamide (1 g, 1.94 mmol) in DCM (10 mL) solution were added PyBOP (1.21 g, 2.33 mmol), 1-((tert-butoxycarbonylamino)methyl)cyclopropanecarboxylic acid (0.46 g, 2.14 mmol) and DIEA (1.36 mL, 7.77 mmol). The mixture was stirred at room temperature for 16 hs. All solvents were removed under vacuum and the residue was purified by silica gel column (MeOH/hexane: 5%) to give tert-butyl (1-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)phenylsulfonylcarbamoyl)cyclopropyl)methylcarbamate (1.38 g, 100%) as a brown solid. LC-MS (Condition A), MS m/z 712.0 (M++H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=[O:29].[Cl-].[NH4+]>O1CCCC1.CCCCCC.O1CCCCC1>[Cl:13][C:14]1[C:26]([CH:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[OH:29])=[C:25]([Cl:27])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: O=Cc1ccccn1
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)c1ccc(Cl)c(C(O)c2ccccn2)c1Cl
Reaction time: 1.5 h

Procedure:
At -20° C., 4.0 g (39.6 mmol) of diisopropylamine in 120 ml of tetrahydrofuran are stirred for 40 minutes with 25.0 ml (40.0 mmol) of a 1.6 M n-butyllithium solution in hexane. At -75° C., a solution of 10.0 g (40.5 mmol) of tert-butyl 2,4-dichlorobenzoate in 30 ml of tetrahydrofuran is added dropwise, and the mixture is stirred for 1.5 h. A solution of 4.3 g (40.5 mmol) of 2-formylpyridine in 20 ml of tetrahydropyran is added dropwise and the mixture is stirred at room temperature for 2.5 h. The mixture is poured into 500 ml of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extracts are washed with water, dried over sodium sulfate, filtered and freed from the solvent under reduced pressure. The crude product is purified by silica gel chromatography using cyclohexane/ethyl acetate. Yield: 7.5 g; 1H NMR, δ [ppm], (DMSO-d6): 1.5 (s), 6.5 (m), 7.2 (m); 7.5 (m), 7.9 (m), 8.4 (d)