Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:45])[CH:6]([N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:42])[CH:25]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH:20]([CH2:43][CH3:44])[CH2:19]1)[CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1.Cl>C1COCC1.O>[C:38]([O:37][C:35]([NH:34][CH:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:24]([N:21]1[CH2:22][CH2:23][N:18]([CH:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[C:5]([OH:45])=[O:4])[CH2:19][CH:20]1[CH2:43][CH3:44])=[O:42])=[O:36])([CH3:39])([CH3:40])[CH3:41]
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1C(=O)C(Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)O)CCN1C(=O)C(Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
LiOH (0.2 g, 7.9 mmol) is added to the cold solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-chlorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 42, (1.0 g, 1.6 mmol) in THF/H2O (2/1, 30 mL). The reaction mixture is stirred overnight. The reaction mixture is cooled in ice bath and the pH is adjusted to 3 with 1M HCl. The aqueous layer is extracted with EtOAc (3×75 mL) and dried over Na2SO4. The organic layers are concentrated in vacuo to afford 1.0 g (quantitative yield) of the desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7](Br)[CH:8]=[CH2:9]>C(OCC)C>[CH2:9]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:8]=[CH2:7]
Reactant: C1CCNCC1
Reactant: C=CCBr
Solvent: CCOCC
Product: C=CCN1CCCCC1
Temperature: 5 °C

Procedure:
213 9 of piperidine dissolved in 300 mL of diethyl ether and was added to a 1 L 3-necked round-bottomed flask. The mixture was cooled to 5° C. with an ice bath. While stirring, a solution of 151.2 g of allyl bromide in 60 mL of diethyl ether was added slowly to the piperidine solution. After addition was complete, the reaction mixture was allowed to stir at room temperature for 18 hours. The white precipitate formed was removed by filtration. Ether was removed from the filtrate at room temperature using a rotary evaporator. The residual liquid was fractionally distilled yielding 108 g of N-allylpiperidine. To a 500 mL 3-necked round-bottomed flask was added 40.1 9 of N-allylpiperidine dissolved in 50 mL of diethyl either. After cooling to 5° C. with an ice bath, a solution of 38.7 g of allyl bromide in 30 mL of diethyl ether was added slowly. After completion of addition of allyl bromide the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 24 hours. The solid residue thus formed was collected by filtration and was washed twice with 1.5 L of diethyl ether. The washed solid was dried under vacuum yielding 44 9 of N,N-diallylpiperidinium bromide as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH2:13][CH2:12][CH2:11]1)[C:5]#[N:6].[C:19]1(C)C=CC=CC=1>>[CH3:19][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH2:13][CH2:12][CH2:11]1)[C:5]#[N:6]
Reactant: N#Cc1ccc(C2CCCc3cncn32)c(Br)c1
Reactant: Cc1ccccc1
Product: Cc1cc(C#N)ccc1C1CCCc2cncn21

Procedure:
3-Bromo-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-5-yl)benzonitrile, prepared above, is converted to the corresponding toluene by the method outlined in Tet. Lett. 2000, 41, 6237. MS (ESI) m/z 238.1 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.77-1.89 (m, 2H), 1.91-2.00 (m, 1H), 2.29-2.39 (m, 1H), 2.45 (s, 3H), 2.86-2.93 (m, 2H), 5.71 (t, J=6.1 Hz, 1H), 6.77 (d, J=8.1 Hz, 1H), 6.81 (s, 1H), 7.29 (s, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.61 (s, 1H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:32](/[CH:33]=[CH:34]/[CH:35]=[O:36])=[C:31]([CH:37]([CH3:39])[CH3:38])[N:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27](=[O:40])[NH:28]3)=[CH:19][CH:18]=1>O1CCCC1.CCCCCC.O.C(O)(=O)C>[CH3:8][O:7][C:1](=[O:6])[CH2:2][C:3](=[O:4])[CH2:5][CH:35]([OH:36])/[CH:34]=[CH:33]/[C:32]1[C:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[C:24]2[C:29](=[N:30][C:31]=1[CH:37]([CH3:39])[CH3:38])[NH:28][C:27](=[O:40])[CH:26]=[CH:25]2
Reactant: CC(C)c1nc2[nH]c(=O)ccc2c(-c2ccc(F)cc2)c1/C=C/C=O
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)/C=C/c1c(C(C)C)nc2[nH]c(=O)ccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102 %

Procedure:
5.47 g (50.7 mmol) of methyl acetoacetate in 5 ml of tetrahydrofuran are added dropwise at -5° C. to 0° C. under argon to a suspension of 1.69 g (56.4 mmol) of 80% strength sodium hydride in 50 ml of anhydrous tetrahydrofuran. After 15 min, 41 ml (67.6 mmol) of 15% strength butyl lithium in hexane are added dropwise at the same temperature and, after a further 15 min, a solution of 5.68 g (16.9 mmol) of the compound from Example 5 in 150 ml of tetrahydrofuran. The mixture is stirred at room temperature for one hour, then 11.2 g of acetic acid in 120 ml of water are cautiously added dropwise and the mixture is extracted three times with ethyl acetate. The organic phases are washed with saturated sodium hydrogen carbonate and sodium chloride solution, dried over sodium sulphate and concentrated. 7.8 g of crude methyl-(E)-7[5-(4 -fluorophenyl)1,2-dihydro-7-isopropyl-2-oxo-1,8-naphthyridin-6-yl]-5-hydroxy-3-oxo-hept-6-enoate are obtained as orange oil.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:12](O)(=[O:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].B(F)(F)F.CCOCC>O>[C:12]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[OH:11])(=[O:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCC(=O)O
Reactant: Oc1cccc2ccccc12
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCC(=O)c1ccc2ccccc2c1O

Procedure:
1-Naphthol (72.1 g, 500 mmol) and pentadecanoic acid (121.2 g, 500 mmol) were mixed with boron trifluoride etherate (400 ml) and heated on a steam bath for 4 hours. Then 400 ml water was carefully added and heating was continued to remove as much of the ether as possible. The precipitated solid was filtered off, washed well with water and air dried. The crude product was recrystallized from ethanol to give the pentadecanoylnaphthol as light yellow plates. Yield: 110 g (60 percent).
Reaction SMILES: C[O:2][C:3](=[O:12])[CH2:4][CH2:5][N:6]1[CH:10]=[C:9](I)[CH:8]=[N:7]1.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[C:23]([NH2:37])=[N:24][CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1.[F-].[K+]>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.O1CCOCC1.O>[NH2:37][C:23]1[N:24]=[CH:25][C:26]([C:9]2[CH:8]=[N:7][N:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:12])[CH:10]=2)=[CH:27][C:22]=1[C:14]1[S:13][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4s3)c2)OC1(C)C
Reactant: COC(=O)CCn1cc(I)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2cnn(CCC(=O)O)c2)cc1-c1nc2ccccc2s1
Temperature: 85 °C

Procedure:
A mixture of 3-(4-iodopyrazol-1-yl)-propionic acid methyl ester (174 mg, 0.623 mmol), 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (200.0 mg, 0.5662 mmol), Pd(PPh3)4 (50 mg, 0.04 mmol), potassium fluoride (98.7 mg, 1.70 mmol), and 4:1 dioxane:water (4:1, 1,4-dioxane:H2O, 8 mL) was heated in the microwave reactor at 85° C. for 30 min. The solution was concentrated in vacuo, and dry-loaded onto silica gel for column chromatography. The material was eluted with 2% MeOH/DCM. The fractions containing the product were concentrated in vacuo. The material was dissolved in conc. HCl (4 mL) and heated to 60° C. for 30 min in a sealed tube. The solvent was removed using the corrosive pump to afford the title compound as an orange solid. MS (ES+): m/z=366.14 (100) [MH+]. HPLC: tR=2.59 min (ZQ2, polar—5 min).
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=2)[C:8]([O:19][CH2:20][O:21][CH3:22])=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[O:30])[CH:24]=2)[CH:6]=1)C.[OH-].[K+]>CO.Cl.O>[CH:17]([C:13]1[CH:12]=[C:11]([C:9]2[CH:10]=[C:5]([CH:6]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[O:30])[CH:24]=3)[C:8]=2[O:19][CH2:20][O:21][CH3:22])[C:4]([OH:31])=[O:3])[CH:16]=[CH:15][CH:14]=1)=[O:18]
Reactant: CCOC(=O)c1cc(-c2cccc(C=O)c2)c(OCOC)c(-c2cccc(C=O)c2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCOc1c(-c2cccc(C=O)c2)cc(C(=O)O)cc1-c1cccc(C=O)c1
Yield: 78.5 %

Procedure:
To a solution of 3,5-bis-(3-formylphenyl)-4-methoxymethoxybenzoic acid ethyl ester (960 mg, 2.12 mmol) in 3 mL MeOH was added 3 mL H2O and solid KOH (179 mg, 3.18 mmol). The reaction was refluxed for 5 to 6 hours then the cooled reaction mixture was diluted with 2N HCl and water. The aqueous solution was extracted with EtOAc (3×) and the combined organic layers were dried over Na2SO4. The solvent was removed in vacuo to give an oil that was flash chromatographed (10% MeOH:90% EtOAc) on silica gel. There yielded 650 mg of the desired acid along with some of the methyl ester of the desired acid. The methyl ester was resubjected to reaction conditions to give more of the desired acid for a total yield of 690 mg, 76.6%. 1H NMR (CDCl3) δ 2.63 (s, 3H); 4.19 (s, 2H); 7.65 (t, J=7.36 Hz, 2H); 7.87–7.95 (m, 4H); 8.06–8.26 (m, 4H); 10.10 (s, 2H).
Reaction SMILES: C([N:3](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:25]=[C:26]1[CH2:33][C@:32]2(C(O)=O)[C@@H:28]([C:29](=[O:45])[N:30]([C@@H:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH3:38])[CH2:31]2)[CH2:27]1>C1(C)C=CC=CC=1>[NH2:3][C@@:32]12[CH2:33][C:26](=[CH2:25])[CH2:27][C@@H:28]1[C:29](=[O:45])[N:30]([C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:38])[CH2:31]2
Reactant: CCN(CC)CC
Reactant: C=C1C[C@@H]2C(=O)N([C@H](C)c3ccccc3)C[C@]2(C(=O)O)C1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=C1C[C@@H]2C(=O)N([C@H](C)c3ccccc3)C[C@]2(N)C1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
Triethylamine (0.489 ml, 3.50 mmol) and diphenylphosphoryl azide (0.491 ml, 2.28 mmol) were added to a solution of [(1S,5S)-7-methylene-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octan-1-yl]carboxylic acid (500 mg, 1.75 mmol) in toluene (8.75 ml) in a nitrogen atmosphere with stirring under ice-cooling. The mixture was stirred at room temperature for 30 minutes and then at 100° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and triethylamine was azeotropically removed with toluene (×3). 1,4-Dioxane (4.37 ml) and 6 mol/L hydrochloric acid (4.37 ml) were added to the resulting residue, and the mixture was stirred at 50° C. for one hour. The reaction solution was diluted with water (18.0 ml) and washed with diethyl ether (60 ml×2). The aqueous layer was made alkaline with a 1 mol/l sodium hydroxide solution, followed by extraction with chloroform (80 ml×1, 70 ml×1). The organic layer was washed with water (80 ml) and brine (80 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 238 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[C:27]([C:31]3[CH:32]=[CH:33][S:29][CH:30]=3)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccc(I)cc2)cc1
Reactant: OB(O)c1ccsc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccccc2-c2ccsc2)cc1
Yield: 72.3 %

Procedure:
Followed the same procedure as that of step 1 in Example 107 with the use of (S)-2-[4-(4-iodo-benzyl)phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (2000 mg, 4 mmol), thiophene-3-boronic acid (1200 mg, 8 mmol) to afford the title product, (1300 mg, 74%); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.79-2.08 (m, 4H), 3.26-3.44 (m, 2H), 3.70-3.95 (m, 1H), 3.93 (s, 2H), 4.03-4.18 (m, 2H), 6.82-6.88 (m, 2H), 7.10 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.35-7.41 (m, 3H), 7.50 (d, J=8.0 Hz, 2H):
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:21][C:22]([C:24]1[CH:25]=[CH:26][C:27]([OH:31])=[CH:28][C:29]=1[OH:30])=[O:23]>CC(C)=O>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([O:31][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8])=[CH:28][C:29]=1[OH:30])(=[O:23])[CH3:21]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: COC(=O)C(C)(C)CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(C)(C)CCCCOc1ccc(C(C)=O)c(O)c1

Procedure:
Following the procedure of Example 44, 2.5 g. of methyl 6-bromo-2,2-dimethylhexanoate, 1.46 g. of potassium carbonate, a catalytic amount of potassium iodide, and 1.67 g. of 2,4-dihydroxyacetophenone were reacted in 125 ml. of acetone giving 2.3 g. of the title product as an oil. M+ =308; NMR.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:33]=[CH:32][C:23]([O:24][CH2:25][C:26]([OH:31])([CH2:29][CH3:30])[CH2:27][CH3:28])=[C:22]([CH3:34])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:43][C:44](OC(C)=O)=[O:45]>CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:33]=[CH:32][C:23]([O:24][CH2:25][C:26]([O:31][C:44](=[O:45])[CH3:43])([CH2:27][CH3:28])[CH2:29][CH3:30])=[C:22]([CH3:34])[CH:21]=2)([CH2:16][CH3:17])[CH2:18][CH3:19])=[CH:11][C:10]=1[CH3:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)(CC)COc1ccc(C(CC)(CC)c2ccc(OCc3ccccc3)c(C)c2)cc1C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC(CC)(COc1ccc(C(CC)(CC)c2ccc(OCc3ccccc3)c(C)c2)cc1C)OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
A reaction mixture containing 3-{4-[1-(4-benzyloxy-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxymethyl}-pentan-3-ol (3.92 g, 8.27 mmol), Et3N (11.5 mL, 82.7 mmol) and Ac2O (3.9 mL, 41.3 mmol), is stirred at rt for 3 h. It is diluted with EtOAc (100 mL), washed with 0.1 M HCl (2×60 mL) and brine (60 mL); MgSO4 dried and concentrated to give the title compound (2.82 g, 5.47 mmol, 66%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:22]#[N:23])[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1>CCOC(C)=O>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:22]#[N:23])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2Cl)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#CC1(c2ccccc2Cl)CCNCC1

Procedure:
A solution of EtOAc saturated with HCl (200 ml) was added to 4-(2-chlorophenyl)-4-cyano-N-(1,1-dimethylethoxycarbonyl)piperidine, (880 mg, 2.74 mmol). The resulting mixture was allowed to react for 1 hour at room temperature. The EtOAc was removed in vacuo affording 4-(2-Chlorophenyl)-4-cyanopiperidine hydrochloride (4j) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-(4-bromophenyl)propan-1-ol (6.17 g, 28.69 mmol) in dichloromethane (40 ml) was added triethylamine (4.80 ml, 34.42 mmol) and methanesulfonyl chloride (2.68 ml, 34.42 mmol). Reaction mixture stirred at RT under nitrogen overnight. The reaction mixture was evaporated to dryness and partitioned between EtOAc (50 mL) and water (25 mL), the aqueous portion was extracted with EtOAc (2×25 mL). Combined organics washed with 2M hydrochloric acid (2×25 mL) and saturated brine (25 mL). The organic was dried over magnesium sulfate, filtered and evaporated to afford the sub-title compound. Yield: 8.60 g
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].[NH2:17][C:18]1[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>CO.C(Cl)Cl>[NH2:17][C:18]1[C:19]([NH:1][C:2]2[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)=[O:5])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: Nc1cccnc1Nc1ccccc1C(=O)c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
A stirred mixture of 35 g (0.163 mole) of 2-amino-4'-fluorobenzophenone and 27 g (0.21 mole) of 3-amino-2-chloropyridine was heated at 175°-180° C. for 2.5 hr. The mixture was allowed to cool to 110° C., after which 100 ml of hot toluene was added. On cooling to 50° C., 50 ml of methylene chloride was added. The solvent layer was decanted, leaving a black solid mass which was dissolved in hot methanol. The solution volume was reduced by one half and allowed to stand overnight at room temperature. The mixture was filtered and the filter cake washed twice by suspending in methylene chloride. The weight of crude solid produced was 22.5 g. The solid was dissolved in methanol and basified with 50% aqueous sodium hydroxide. The mixture was extracted with methylene chloride and the extract dried and concentrated. The residue was twice crystallized from isopropyl alcohol, decolorizing by boiling with charcoal the second time, to give 14 g (28%) solid which was red-orange in color; m.p. 121.5°-122.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:6]=[C:5]2[S:26]([N:29]1[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:30]1)(=[O:28])=[O:27].[CH:43]1([NH:46][C:47](=[O:65])[C:48]2[CH:53]=[C:52](B3OC(C)(C)C(C)(C)O3)[C:51]([CH3:63])=[C:50]([F:64])[CH:49]=2)[CH2:45][CH2:44]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Si:17]([O:16][CH2:15][C:14]([CH3:24])([CH3:25])[CH2:13][N:7]1[CH:6]=[C:5]([S:26]([N:29]2[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:30]2)(=[O:28])=[O:27])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:52]3[CH:53]=[C:48]([C:47](=[O:65])[NH:46][CH:43]4[CH2:44][CH2:45]4)[CH:49]=[C:50]([F:64])[C:51]=3[CH3:63])[CH:3]=2)[C:8]1=[O:12])([C:20]([CH3:21])([CH3:23])[CH3:22])([CH3:19])[CH3:18]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cn1cc(S(=O)(=O)N2CCCN(C(=O)OC(C)(C)C)CC2)c2cc(Br)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(S(=O)(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of tert-butyl 4-{[6-bromo-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-4-yl]sulfonyl}-1,4-diazepane-1-carboxylate (Example 46c, 83 mg) in DMF (2 mL) was treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (39 mg), Pd-118 (2.4 mg) and potassium carbonate (33 mg) under nitrogen. The resulting mixture was stirred at 70° C. for 1 h. The cooled reaction mixture was partitioned between ethyl acetate and water. The aqueous was extracted with ethyl acetate (2×100 mL). The combined organics were washed with water (3×100 mL), brine (3×100 mL) dried (MgSO4), filtered, and evaporated under reduced pressure. The crude product was purified (SiO2 chromatography, elution with 50% ethyl acetate/isohexane) to afford the subtitle compound (0.055 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.OO.[ClH:15].[Na+].[Cl-]>C(O)C(N)(CO)CO.CO>[Cl:15][C:4]1[CH:3]=[CH:2][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:12]
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: Cl
Agent: NC(CO)(CO)CO
Agent: OO
Agent: [Cl-]
Solvent: CO
Product: Oc1c(Cl)ccc2ccccc12

Procedure:
Mix 1 volume of 3 mg 4-chloro-1-naphthol per ml. methanol with 5 volumes of a solution of 0.018% hydrogen peroxide in Tris buffered saline (20 mM Tris. HCl, 500 mM NaCl, pH 7.5). This mixture provides a complete chromogenic mixture for peroxidase. Filter paper can be impregnated with the mixture as above, and rehydrated prior to use as noted above.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].CO.[H][H]>[Pd].O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:12])=[O:13]
Reactant: Nc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 23 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
2-Amino-5-nitro-benzenesulfonamide (5.00 kg, 23.0 mol), methanol (65 L), tetrahydrofuran (65 L), and 10% palladium on carbon (250 g) were charged to an autoclave. The mixture was cycled with nitrogen and hydrogen purges (3×), and the mixture was then stirred under hydrogen (50 psi) at 23° C. overnight. The catalyst was removed by filtration and the filtrate was then concentrated in vacuo to give a brown solid. The solid was further dried in vacuo at 45° C. to afford the desired product, 2,5-diamino-benzenesulfonamide (4.21 kg, 22.4 mol, 98%), as a solid. 1H NMR (400 MHz, DMSO-d6) δ: 4.54 (2H, bs), 4.98 (2H, bs), 6.55-6.60 (2H, m), 6.87 (1H, d, J=2.2 Hz), 6.99 (2H, bs). LC-MS (ESI) calcd for C6H9N3O2S 187.04, found 188.3 [M+H+].
Reaction SMILES: [CH3:1][N:2]([CH3:44])[C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:43]=[CH:42][C:12]([C:13]([NH:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([O:32][C:33]4[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=4)[C:27]([O:29]CC)=[O:28])=[CH:21][CH:20]=3)=[O:14])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[OH-].[Na+]>>[CH3:44][N:2]([CH3:1])[C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([O:32][C:33]4[CH:34]=[CH:35][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:37][CH:38]=4)[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=3)=[O:14])=[CH:42][CH:43]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(N(C)C)cn3)cc2)cc1)Oc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(OC(Cc2ccc(OCCNC(=O)c3ccc(-c4ccc(N(C)C)cn4)cc3)cc2)C(=O)O)cc1
Yield: 53.6 %

Procedure:
In a similar manner to that described in Example 2, ethyl 3-[4-[2-[4-(3-dimethylaminopyridine-6-yl)benzoylamino]ethoxy]-phenyl]-2-(4-isopropylphenoxy)propionate (429 mg), which is the product of Example 112, was reacted with aqueous sodium hydroxide solution (1N, 1.44 ml) and the reaction mixture was treated to give the title compound (219 mg) as a white powder.