Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:24][CH:13]([N:14](CC4C=CC=CC=4)[CH:15]2[CH3:16])[CH2:12][CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H][H]>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:24][CH:13]([NH:14][CH:15]2[CH3:16])[CH2:12][CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1cccc(C23CCCC(C2)N(Cc2ccccc2)C3C)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cccc(C23CCCC(C2)NC3C)c1
Yield: 95.2 %

Procedure:
A mixture of 7.21 g of 1-(3-methoxyphenyl)-6-benzyl-7-methyl-6-azabicyclo[3,2,1]octane, 2.2 g of colloid palladium and 165 ml of acetic acid is shaken at room temperature for 2 hours in a hydrogen atmosphere under atmospheric pressure. After the reaction is completed, the mixture is filtered to remove the catalyst. The filtrate is then evaporated to remove solvent. Water is added to the residue, and the aqueous mixture is made alkaline with ammonia. Then, the aqueous mixture is extracted with ether. The ether extract is dried and evaporated to remove solvent. 4.94 g of 1-(3-methoxyphenyl)-7-methyl-6-azabicyclo[3,2,1]octane are obtained. Hydrochloride: M.p. 174°-176°C(recrystallized from a mixture of acetone, ethanol and ether).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29][OH:30].[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][C:21]3[CH:22]=[CH:29][O:30][CH:23]=3)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NCc1ccoc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.103 g, 0.23 mmol) in tetrahydrofuran (4 mL) and methanol (0.030 mL, 0.8 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.200 mL, 0.4 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 2% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.08 (s, 2 H) 6.59 (s, 1 H) 6.95 (s, 1 H) 7.32 (d, J=5.15 Hz, 1 H) 7.58 (m, 3 H) 7.66 (d, J=8.09 Hz, 1 H) 7.79 (t, J=8.46 Hz, 1 H) 7.93 (d, J=7.72 Hz, 1 H) 8.24 (d, J=5.52 Hz, 1 H) 14.21 (s, 1 H) 14.83 (s, 1 H). MS (ESI−) m/z 441 (M−H)−.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([CH:13]([C:15]2[C:16]([CH3:27])=[N:17][O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)[OH:14])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].N1C=CN=C1.CCOC(C)=O>CN(C=O)C>[CH2:1]([C:8]1[O:12][C:11]([CH:13]([C:15]2[C:16]([CH3:27])=[N:17][O:18][C:19]=2[C:20]2[CH:21]=[CH:22][C:23]([Br:26])=[CH:24][CH:25]=2)[O:14][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(Cc2ccccc2)o1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O[Si](C)(C)C(C)(C)C)c1nnc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(5-Benzyl-[1,3,4]oxadiazol-2-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol (0.537 g, 1.26 mmol), tert-butyldimethylsilyl chloride (0.209 g, 3.78 mmol) and imidazole (0.095 g, 3.78 mmol) were combined in DMF (8 mL) and stirred at room temperature for 72 hours. Standard aqueous workup and silica gel chromatography (0-10% EtOAc in hexanes) gave the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1>C(N(CC)CC)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: Brc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCN(c3ccc(Br)cc3)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with 1-(4-bromophenyl)piperazine dihydrochloride in the presence of triethylamine to give 1-(4-bromophenyl)-4-(p-nitrobenzyl)piperazine
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH3:24][O:25][CH2:26][CH2:27][C:28]1([NH2:31])[CH2:30][CH2:29]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][C:28]4([CH2:27][CH2:26][O:25][CH3:24])[CH2:30][CH2:29]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: COCCC1(N)CC1
Product: COCCC1(NC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 198 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(2-methoxyethyl)cyclopropanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.58-0.73 (m, 4H) 1.79 (t, J=6.9 Hz, 2H) 3.14 (s, 3H) 3.39 (t, J=6.9 Hz, 2H) 7.72 (d, J=8.6 Hz, 2H) 8.07 (d, J=7.8 Hz, 2H) 8.27-8.34 (m, 1H) 8.37 (br. s., 1H) 8.57 (br. s., 1H) 8.77 (s, 1H) 8.79-8.83 (m, 1H) 13.46 (br. s., 1H). MS m/z 404 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1.[CH:27]1([NH:30][C:31](=[O:49])[C:32]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[C:35]([CH3:47])=[C:34]([F:48])[CH:33]=2)[CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH:27]1([NH:30][C:31](=[O:49])[C:32]2[CH:33]=[C:34]([F:48])[C:35]([CH3:47])=[C:36]([C:2]3[C:3]4[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]5[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=5[F:26])[C:4]=4[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=3)[CH:37]=2)[CH2:28][CH2:29]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 100 °C
Yield: 9.8 %

Procedure:
4-Chloro-8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]-amino}pyrido[2,3-d]pyrimidin-7(8H)-one (0.056 g, 0.17 mmol), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.065 g, 0.17 mmol), K2CO3 (0.07 g, 0.51 mmol) and tetrakis triphenyl phosphine palladium (10 mg, 0.05 eq) are dissolved in dioxane/water (3:1, 10 mL) and heated to about 100° C. for about 3 h. The mixture is concentrated and purified via reverse phase HPLC to afford the title compound (9 mg, yellow powder, mp 214.2-217.5): LC-MS m/z 540 (M+H)+, 1.69 min (ret time). HPLC indicates 96% pure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH3-]C#N.[Na+]>CN(C=O)C.CC(O)=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1cccc(-c2ccncc2)c1
Reactant: Nc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: c1ccc(NCc2cccc(-c3ccncc3)c2)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-(pyridin-4-yl)benzaldehyde from Example 1 Step 1 (2 g, 10.9 mmol, 1 equiv) in DMF/AcOH (20/2 mL), aniline (1.02 g, 11.0 mmol, 1 equiv) and NaBH3CN (2.62 g, 41.6 mmol, 4 equiv). The resulting solution was stirred 2 h at 110° C. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 30 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 1:1 ethyl acetate/petroleum ether) to give N-(3-(pyridin-4-yl)benzyl)benzenamine as light yellow oil.
Reaction SMILES: [N:1]1([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([O:9][CH3:10])=[O:8].CI.[CH3:23][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:23][C:2]1([C:7]([O:9][CH3:10])=[O:8])[CH2:3][O:4][CH2:5][CH2:6][N:1]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)C1COCCN1C(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)COCCN1C(=O)OCc1ccccc1
Temperature: -70 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
4-Benzyl 3-methyl morpholine-3,4-dicarboxylate (13.98 g, 50.1 mmol) and methyl iodide (5.70 ml, 91 mmol) was dissolved in THF (100 ml). The solution was cooled to −70° C. A solution of NaHMDS in THF (1 M, 91 ml, 91 mmol) was added via syringe over 2 minutes. The reaction solution was stirred for 5 hours at −40 to −70° C. and then was quenched with MeOH (5 ml) and HOAc (3.5 g). The reaction mixture was concentrated. The residue was then partitioned between EtOAc (400 ml) and water (150 ml). The organic phase was separated. The aqueous phase (pH about 7) was extracted with EtOAc (100 ml). The combined organic phases were washed with water (100 ml). The organic solution was then concentrated to give an oil. The residue was purified by silica gel column (220 g silica gel, Hexane/EtOAc 5:1) to afford 11.6 g of 4-benzyl 3-methyl 3-methylmorpholine-3,4-dicarboxylate as an oil (79% yield). 1H NMR (400 MHz, CDCl3) δ=1.58 (s, 3H), 3.23-3.78 (m, 9H), 4.99 (m, 2H), 7.17-7.27 (m, 5H)
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3](=[O:25])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:37]1[C:38]2[C:45]([CH3:46])=[CH:44][NH:43][C:39]=2[N:40]=[CH:41][N:42]=1>C(O)(C)C>[CH3:26][N:2]([CH3:1])[C:3](=[O:25])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:19][CH2:18][N:17]([C:37]3[C:38]4[C:45]([CH3:46])=[CH:44][NH:43][C:39]=4[N:40]=[CH:41][N:42]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1
Reactant: COCCOC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COCCOC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCN(c2ncnc3[nH]cc(C)c23)CC1
Temperature: 110 °C

Procedure:
To a solution of 3-(4-(2-methoxyethoxy)piperidine-4-carboxamido)phenyl dimethylcarbamate from step D, and N,N-diisopropylethylamine (0.28 mL, 1.6 mmol) in isopropanol (1.0 mL) was added 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (55 mg, 0.322 mmol). The reaction mixture was heated to 110° C. in a sealed high-pressure vial for 17 h, during which time the mixture became homogenous. The mixture was concentrated under vacuum and purified by prep HPLC (30×100 mm C18 column, 5-100% acetonitrile:water (10 mM NH4OAc), 15 min, 45 mL/min) to afford the title compound (17.4 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[NH2:13][C:14]1[CH:18]=[C:17]([CH:19]2[CH2:21][CH2:20]2)[NH:16][N:15]=1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][C:14]2[NH:15][N:16]=[C:17]([CH:19]3[CH2:21][CH2:20]3)[CH:18]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Clc1nc(Cl)c2c(n1)CCCC2
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Clc1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCCC2
Temperature: 90 °C

Procedure:
To a solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (500 mg, 2.46 mmol) and 3-amino-5-cyclopropylpyrazole (303 mg, 2.46 mmol) in DMF (10 mL) is added triethylamine (0.357 mL, 2.56 mmol) followed by sodium iodide (368 mg, 2.46 mmol) and the reaction mixture is heated at 90° C. for 20 h. The reaction mixture is partitioned between ethyl acetate and aqueous saturated NaHCO3. The organic layer is washed with brine and evaporated in vacuo. The residue is purified by flash chromatography (SiO2, hexane/AcOEt gradient) to give (2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2N=N1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(O)=O)CCCCC1.NC1SC2C=CC=CC=2N=1.[CH:59]1([CH2:65][C@H:66]([N:75]2[CH2:83][C:82]3[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=3)[C:76]2=[O:84])[C:67]([NH:69][C:70]2[S:71]C=CN=2)=[O:68])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1>>[S:71]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:70]1[NH:69][C:67](=[O:68])[CH:66]([N:75]1[CH2:83][C:82]2[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=2)[C:76]1=[O:84])[CH2:65][CH:59]1[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]1
Reactant: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1nc2ccccc2s1
Agent: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1nc2ccccc2s1)C(CC1CCCCC1)N1Cc2ccccc2C1=O
Yield: 44 %

Procedure:
This compound was prepared via BOP coupling of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A, 144 mg; 0.5 mmol) and 2-amino-benzothiazole (81 mg; 0.55 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-( 1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) to provide crude N-Benzothiazol-2-yl-3-cyclohexyl-2-( 1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide. The crude product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, eluent: 35% ethyl acetate/hexanes) to give 185 mg (44%) of N-Benzothiazol-2-yl-3-cyclohexyl-2-( 1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide as a white solid: EI-HRMS m/e calcd for C24H25N3O2S (M+) 419.1667, found 419.1661.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:2]1.Cl[S:18]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[S:18]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=2)(=[O:20])=[O:19])=[CH:2]1
Reactant: COc1ccc(CNCc2ccoc2)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2)Cc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
110 mg of 1-(furan-3-yl)-N-(4-methoxybenzyl)methanamine (example 5-27a) was mixed with methyl 4-(chlorosulfonyl)benzoate (example 5-10c) (117 mg, 0.5 mmol) and triethyl amine (100 uL) in DCM (5 mL). The mixture was stirred overnight at ambient temperature and concentrated. The residue was re-dissolved in ethyl acetate (20 mL), washed with 1N HCl (aq., 2 mL), followed by water (5 mL) and brine (5 mL) then dried over magnesium sulfate. The crude product was purified by preparative TLC (40% Ethyl Acetate/hexanes) to give methyl 4-(N-(furan-3-ylmethyl)-N-(4-methoxybenzyl)sulfamoyl)benzoate as a white solid. Saponification as in example 5-10 gave 4-(N-(furan-3-ylmethyl)-N-(4-methoxybenzyl)sulfamoyl)benzoic acid as a white crystalline solid (68 mg, 64% yield). MS (M−H, 400.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.72 (s, 3H), 4.13 (s, 2H), 4.26 (s, 2H), 5.99 (s, 1H), 6.87 (m, 4H), 6.87 (d, 2H, J=8.8 Hz), 7.13 (d, 2H, J=8.8 Hz), 7.39 (s, 1H), 7.49 (s, 1H), 7.95 (d, 2H, J=8.4 Hz), 8.09 (d, 2H, J=8.8 Hz).
Reaction SMILES: [CH:1]([C:4]1[NH:9][C:8](=O)[C:7]([C:11]#[N:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br-:13].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>C1(C)C=CC=CC=1>[Br:13][C:8]1[N:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[C:11]#[N:12]
Reactant: CC(C)c1ccc(C#N)c(=O)[nH]1
Reactant: [Br-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(C#N)c(Br)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a solution of the product of Example 8B (4.35 g, 0.0269 mol), tertrabutylammonium bromide (10.4 g, 0.0323 mol) and phosphorous pentoxide (8.01 g, 1.05 mol) in toluene (80 mL) was heated under reflux for 5 hours. The reaction mixture was then cooled to room temperature, water (80 mL) was added, and the mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with toluene (20 mL) and the organic layer separated. The aqueous layer was washed with toluene (50 mL) and the combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title product as a yellow oil (5.64 g, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[CH:5][N:4]=1.C1(P([N:25]=[N+:26]=[N-:27])(C2C=CC=CC=2)=O)C=CC=CC=1.C12CCCCC1CCCNN=2.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:25]=[N+:26]=[N-:27])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: C1CCC2CCCNN=C2C1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ncccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.4 g of 2-methoxy-3-hydroxymethylpyridine was dissolved in 100 ml toluene, and 13.8 ml diphenyl phosphoryl azide and 9.5 ml diazabicyclo[5.4.0]undecene were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction product which was then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 9.5 g of [(2-methoxy-3-pyridyl)methyl]azide.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([O:9][C:10]3([C:23]4[C:18](=[CH:19][C:20]([OH:25])=[C:21]([Cl:24])[CH:22]=4)[O:17][C:16]4[C:11]3=[CH:12][C:13]([Cl:27])=[C:14]([OH:26])[CH:15]=4)[C:4]2=[CH:3][CH:2]=1)=[O:8].C(O)(=O)C>C1COCC1.[Zn]>[Cl:24][C:21]1[C:20]([OH:25])=[CH:19][C:18]2[O:17][C:16]3[C:11](=[CH:12][C:13]([Cl:27])=[C:14]([OH:26])[CH:15]=3)[CH:10]([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=3[C:7]([OH:9])=[O:8])[C:23]=2[CH:22]=1
Reactant: O=C1OC2(c3cc(Cl)c(O)cc3Oc3cc(O)c(Cl)cc32)c2ccccc21
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1C1c2cc(Cl)c(O)cc2Oc2cc(O)c(Cl)cc21
Reaction time: 8 h

Procedure:
2′,7′-Dichlorofluorescein (2.0 g, 5.0 mmol) was dissolved in 80 mL of THF, containing 2 mL of acetic acid. Zn (powder, 8.0 g, 122 mmol) was added portionwise (0.5 g with ˜15 min intervals) to the solution of 2′,7′-Dichlorofluorescein. After all amount of Zn was added the reaction mixture was stirred overnight. All solids have been filtered off, washed with THF and evaporated. The residue was re-dissolved in ethyl acetate (120 mL) and washed with water (2×30 mL), brine (30 mL), dried over sodium sulfate and evaporated. The crude product (˜2.0 g, oil) was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([CH2:24][CH3:25])([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=3)[CH2:14][CH3:15])=[N:10][C:9]=2[CH:26]=1)=[O:4].Br[CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[K+].[K+]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:18]([CH3:23])[CH:17]=3)([CH2:24][CH3:25])[CH2:14][CH3:15])=[N:10][C:9]=2[CH:26]=1)=[O:4]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1nc2cc(C(=O)OC)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2cc(C(=O)OC)ccc2o1
Yield: 95.1 %

Procedure:
2-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzooxazole-5-carboxylic acid methyl ester (2.10 g, 5.94 mmol) and 1-bromopinacolone (1.59 g, 8.87 mmol) and K2CO3 (2.04 g, 14.8 mmol) are reacted analogous to Example 1, step G to give the title compound as a pale yellow oil (2.55 g, 95%). H-NMR (ppm, CDCl3) δ: 8.43 (1H, d, J=1.3 Hz), 8.01 (1H, dd, J=1.8, 8.8 Hz), 7.42 (1H, d, J=8.4 Hz), 7.01 (1H, d, J=2.2 Hz), 6.96 (1H, dd, J=2.2, 8.4 Hz), 6.51 (1H, d, J=8.8 Hz), 4.84 (2H, s), 3.95 (3H, s), 2.38 (2H, q, J=7.5 Hz), 2.32 (2H, q, J=7.5 Hz), 2.25 (3H, s), 1.25 (9H, s), 0.76 (6H, t, J=7.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.[C:14](#[N:18])[CH2:15][C:16]#[N:17].C1(C)C=CC=CC=1.C([O-])(=O)C.[NH4+].C(O)(=O)C>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[C:15]([C:14]#[N:18])[C:16]#[N:17])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: N#CCC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(=C(C#N)C#N)CCC2
Yield: 73.3 %

Procedure:
To a solution of 7-methoxy-3,4-dihydronaphthalen-1(2H)-one 46.1 (10.0 g, 56.7 mmol, Aldrich) and malononitrile (4.07 mL, 64.7 mmol) in toluene (40.0 mL, 378 mmol) was added ammonium acetate (0.938 mL, 13.1 mmol) and acetic acid (3.90 mL, 68.1 mmol). The mixture was refluxed vigorously for 17 hours and water was removed using a Dean Stark trap under the reflux condenser. The resulting mixture was concentrated and purified by silica gel column chromatography to give 48.1 (9.32 g, 73.2% yield). MS ESI (pos.) M/E: 225 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:18][C:15]1[N:14]=[CH:13][N:12]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=3[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]=12
Reactant: CN1Cc2cncn2-c2cccc(Cl)c2C1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2c(Cl)ncn2-c2cccc(Cl)c2C1=O

Procedure:
1.30 g (5.25 mmol) of 7-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one are stirred at 90° for 30 minutes in 10 ml of dimethylformamide with 800 mg (6 mmol) of N-chlorosuccinimide. Subsequently, the mixture is poured into water and extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulphate and evaporated. By column chromatography on silica gel there is obtained 3,7-dichloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 211°-212°.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])[N:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=1>C(OCC)(=O)C>[NH2:6][C:7]1[N:11]([C:12]2[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:17]=2)[N:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=1
Reactant: Cc1ccc(-n2nc(C(F)(F)F)nc2N)c(C)c1
Reactant: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(S(=O)(=O)Cl)cc1-n1nc(C(F)(F)F)nc1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
In a 25-ml eggplant flask provided with a magnetic stirrer were placed 5.83 g (50 mol) of chlorosulfonic acid and then 2.49 g (9.73 mmol) of 4-(5-amino-3-trifluoromethyl-1H-1,2,4-triazol-1-yl)-1,3-dimethylbenzene. The mixture was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and then added onto ice in small portions. Thereto was added 30 ml of ethyl acetate to give rise to phase separation. The aqueous phase was extracted with 30 ml of ethyl acetate. The ethyl acetate phase was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. Then, vacuum distillation was conducted to distill off ethyl acetate to obtain a title compound as 3.3 g of a crystal. Yield: 96%