Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([O:22]C)[CH:3]=1.[F:24][C:25]([F:34])([F:33])[C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.Cl.CCOCC>C(O)(C)C>[F:24][C:25]([F:33])([F:34])[C:26]1[CH:27]=[CH:28][C:29]([NH:30][C:2]2[C:11]3[C:6](=[N:7][C:8]([C:12]4[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=4)=[CH:9][CH:10]=3)[N:5]=[C:4]([OH:22])[CH:3]=2)=[CH:31][CH:32]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COc1cc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: Oc1cc(Nc2ccc(C(F)(F)F)cc2)c2ccc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
Heat 4-chloro-2-methoxy-7-(3-trifluoromethyl-pyridin-2-yl)-[1,8]naphthyridine (600 mg, 1.8 mmol), 4-trifluoromethylaniline (322 mg, 2.0 mmol) and 2M hydrochloric acid in ether (1 mL, 2.0 mmol) in isopropanol (15 mL) at 80° C. for 16 hours. Cool the mixture and collect the precipitate by filtration. Partition the solid between ethyl acetate and saturated sodium bicarbonate solution. Separate the layers and extract the aqueous layer with further ethyl acetate. Wash the combined organic extracts with brine, dry (MgSO4) and evaporate to give the title compound.
Reaction SMILES: [CH2:1]([SH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:18]([O:21][CH2:22][C:23]([CH2:34][O:35][CH2:36][CH:37]=[CH2:38])([CH2:29][O:30][CH2:31][CH:32]=[CH2:33])[CH2:24][O:25][CH2:26][CH:27]=[CH2:28])[CH:19]=[CH2:20]>>[CH2:1]([S:17][CH2:38][CH2:37][CH2:36][O:35][CH2:34][C:23]([CH2:24][O:25][CH2:26][CH2:27][CH2:28][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([CH2:29][O:30][CH2:31][CH2:32][CH2:33][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:22][O:21][CH2:18][CH2:19][CH2:20][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CCOCC(COCC=C)(COCC=C)COCC=C
Reactant: CCCCCCCCCCCCCCCCS
Product: CCCCCCCCCCCCCCCCSCCCOCC(COCCCSCCCCCCCCCCCCCCCC)(COCCCSCCCCCCCCCCCCCCCC)COCCCSCCCCCCCCCCCCCCCC

Procedure:
The procedure used was identical to that set forth in Example 4, except that 107 g of hexadecyl mercaptan (0.417 moles) was reacted with 29.64 g of pure pentaerythritol tetraallyl ether (0.1 moles). The crude product was recrystallized three times in 300 ml of hexane yielding 57 g of white solid having a melting point 55°-57° C. The elemental analysis found: C-73.4%, H-11.9%, S-10.0%, calculated for C88H164S4 (theoretical C-73.12%, H-12.4%, S-9.64% and O-4.81%).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:10][C:9]3[CH:12]=[CH:13][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-n4cccn4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(1H-pyrazol-1-yl)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 402.8 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[N:7][CH:8]=1.C(N(CC)CC)C.Cl.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH:22][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[N:5][CH:4]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1cnc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cnc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a solution of 4-{4-((5-methoxypyrimidin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-amine (8-4, 0.41 g, 1.23 mmol) in CH2Cl2 (6.0 mL) was added triethylamine (1.0 mL, 7.2 mmol) followed by isonicotinoyl chloride hydrochloride (0.35 g, 1.94 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was filtered, and recrystallized in toluene to give N-(4-{4-((5-methoxypyrimidin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-yl)isonicotinamide (8, 0.37 g) as light yellow solids in 72% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.0 (s, 1 H), 8.80 (d, J=4.9 Hz, 2 H), 8.42 (s, 2 H), 7.99 (d, J=6.0 Hz, 2 H), 7.10 (s, 1 H), 6.68 (s, 2 H), 3.81 (d, J=7.0 Hz, 2 H), 2.06 (s, 6 H), 1.21 (s, 1 H), 0.57 (d, J=6.5 Hz, 2 H), 0.32 (d, J=5.7 Hz, 2 H). ESI-MS: m/z 433.8 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([NH:22][C:19](=[O:21])[CH3:20])=[CH:24][CH:25]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Product: CC(=O)Nc1ccc(-c2nc(Nc3cc(C)[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-acetylamino-phenylboronic acid to give N-{4-[3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-phenyl}-acetamide. LC-MS m/e 358(MH+).
Reaction SMILES: [CH2:1]([Li])[CH:2]=[CH2:3].[CH3:5][O:6][C:7](=[O:26])[CH:8]=[CH:9][CH2:10][CH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13](=[O:18])[N:12]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[Cl-].[NH4+]>C1COCC1.[Cu]I>[CH3:24][C:22]([CH3:23])([O:21][C:19]([N:12]1[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH2:17][CH:11]1[CH2:10][CH:9]([CH2:3][CH:2]=[CH2:1])[CH2:8][C:7]([O:6][CH3:5])=[O:26])=[O:20])[CH3:25]
Reactant: [Li]CC=C
Reactant: COC(=O)C=CCC1CCCCC(=O)N1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(CC(=O)OC)CC1CCCCC(=O)N1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Four equivalents of allyl lithium are added to a stirring suspension of 2 equivalents copper (I) iodide in THF at -50° C. under argon. After the mixtures becomes homogeneous (approx. 20 minutes.), a solution of the title ester of Example 209 (1 equivalent) in THF is added to the cold mixture and stirred below -50° C. for approx. 30 minutes. The mixture is poured into saturated ammonium chloride solution and stirred vigorously for 15 minutes. The mixture is then partitioned between ether and water and the organic layer is washed with water and brine before it is dried (Na2SO4). The mixture is then filtered and stripped of all solvent. The title material is then purified by column chromatography.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:10][CH2:9][CH2:8][N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[C:6](=[O:28])[NH:5]1.Br[C:38]1[CH:39]=[CH:40][C:41](=[O:47])[N:42]([CH:44]2[CH2:46][CH2:45]2)[CH:43]=1>>[CH:44]1([N:42]2[C:41](=[O:47])[CH:40]=[CH:39][C:38]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:8][CH2:9][CH2:10][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:36])([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[NH:5][C:6]4=[O:28])[CH3:12])=[CH:18][CH:17]=3)=[CH:43]2)[CH2:46][CH2:45]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Reactant: O=c1ccc(Br)cn1C1CC1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C3CC3)c2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)NC1=O

Procedure:
The title compound was prepared from (S)-4-(2-hydroxy-2-methylpropyl)-4-phenyl-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-diazepan-2-one and 5-bromo-1-cyclopropylpyridin-2(1H)-one following a procedure analogous to that described in Example 11 Step 2. LC-MS Method 1 tR=1.66 min; m/z=500 (M+1). 1H NMR (CD3OD) δ 7.78 (s, 1H), 7.56 (d, 3H), 7.37 (m, 5H), 7.27 (t, 1H), 7.17 (d, 2H), 6.61 (d, 1H), 5.46 (q, 1H), 3.37 (m, 1H), 2.92 (m, 1H), 2.74 (dt, 1H), 2.39 (d, 1H), 1.53 (d, 3H), 1.16 (s, 3H), 0.58 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[NH2:5].C[Al](C)C.C[O:23][C:24](=O)/[CH:25]=[C:26](\[NH:28][C:29](=O)[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)/[CH3:27]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:24](=[O:23])[CH:25]=[C:26]([CH3:27])[N:28]=[C:29]2[CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: Nc1ccc(OCCN2CCOCC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(=O)COc1cccc(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(OCCN3CCOCC3)c(F)c2)c(COc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
To a solution of 3-fluoro-4-(2-morpholinoethoxy)aniline (0.33 g, 1.37 mmol) in DCM (20 mL) was added trimethylaluminium (2.7 mL, 5.40 mmol, 2 M in toluene) and the mixture was stirred at rt for 0.5 h. A solution of (Z)-methyl-3-(2-(3-fluorophenoxy)acetamido)but-2-enoate (0.37 g, 1.38 mmol) in DCM (5 mL) was added slowly and the resulting mixture was stirred at rt for 24 h. The mixture was quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=30:1) to give the title compound as a pale yellow solid (0.19 g, 30%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([N+:19]([O-])=O)[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOCC.[Pd]>[NH2:19][C:12]1[CH:11]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)c(N)c1
Yield: 82.6 %

Procedure:
A mixture of 4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid (56.57, 190.9 mmol) in methanol (250 mL) and palladium/carbon (5.66 g, 10% weight) was hydrogenated with a Parr-shaker overnight at 51 psi. The black mixture was filtered through a pad of Celite, and the filtrate was evaporated to give a brown oil, which was stirred in ether (300 mL) overnight. The ether slurry was filtered to give 2-amino-4-(tert-butoxycarbonylamino-methyl)-benzoic acid as a brown solid (42.0 g, 84% yield). The product was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])#[CH:32]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:34][Si:33]([C:31]#[C:32][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)([CH3:36])[CH3:35]
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CCc2cc(Br)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2c(c1)CCC2=O

Procedure:
2.11 g of 5-bromoindan-1-one are suspended in 10 ml of degassed triethylamine with 67.2 mg of palladium(II) acetate and 78.6 mg of triphenylphosphine with 2.12 ml of ethynyltrimethylsilane and the mixture is stirred under reflux for 1 h. The cooled reaction mixture is concentrated, taken up with 20 ml of satd sodium hydrogencarbonate solution and 40 ml of ethyl acetate and the organic phase is washed first with water, then with satd sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo, and the residue is chromatographed on silica gel using n-heptane/ethyl acetate 3/1. 5-Trimethylsilanylethynylindan-1-one is obtained, which is dissolved in 25 ml of methanol and stirred at room temperature for 2 h with potassium carbonate. The reaction mixture is concentrated in vacuo; the residue is stirred with 25 ml of satd sodium hydrogencarbonate solution and 50 ml of ethyl acetate, and the organic phase is then separated off and filtered through a clarifying layer. The filtrate is dried over magnesium sulfate and concentrated in vacuo, and the residue is stirred with n-heptane. The precipitate is filtered off with suction and dried in vacuo. 5-Ethynylindan-1-one of melting point 157° C. is obtained.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.C1(C)C(C)=CC=CC=1>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: Brc1ccccc1I
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: Brc1ccccc1-n1c2ccccc2c2ccccc21
Temperature: 25 °C

Procedure:
1.672 g of carbazole, 1.6 mL of 1-bromo-2-iodobenzene, 2.7646 g of potassium carbonate, 95 mg of copper iodide and 25 mL of xylene were refluxed in a nitrogen atmosphere. The mixture was cooled to room temperature, extracted with ethyl acetate, and dried with anhydrous magnesium sulfate to remove moisture, and the solvent was removed under reduced pressure. Silica gel column separation using a hexane solvent was conducted, thus obtaining a compound from which the solvent was then removed under reduced pressure, followed by vacuum drying, yielding 9-(2-bromophenyl)-9H-carbazole as a desired white solid intermediate.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O(C(CC)(C)C)[K:15].C([Li])CCC>CCCCCC>[C:1]1([CH:7]([K:15])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: CCC(C)(C)O[K]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: [K]C(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 18.3 g (109 mmol) of diphenylmethane in 400 mL of hexane were added 11.99 g (109 mmol) of potassium t-amylate. To the resulting pale yellow solution were added 68.75 mL of 1.60M (110 mmol) butyl lithium. The thick, bright orange slurry was stirred overnight. The solids were collected on a filter, washed three times with 100 mL, then twice with 50 mL of hexane, then dried under reduced pressure. The yield of bright orange powder was 18.23 g, 81.2 percent.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[S:9]1(=[O:33])=[O:32].Cl>ClCCl.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[S:9]1(=[O:33])=[O:32]
Reactant: Cc1ccccc1N1c2ccccc2N(CCN2CCN(C(=O)OC(C)(C)C)CC2)S1(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccccc1N1c2ccccc2N(CCN2CCNCC2)S1(=O)=O
Yield: 91.4 %

Procedure:
In an analogous manner as general procedure II, step 2, a solution of tert-butyl 4-{2-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperazine-1-carboxylate (0.22 g, 0.47 mmol) in dichloromethane (10 mL) was treated with hydrogen chloride (3.0 mL of a 4 M solution in dioxane), resulting in a white precipitate that was evaporated and dried under vacuum to provided 1-(2-methylphenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.16 g, 92%) as a white solid:
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([CH3:26])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19].C(Cl)Cl>O>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[C:9]=1[C:18](=[O:19])[C:17]1[CH:21]=[C:22]([CH3:26])[C:23]([O:24][CH3:25])=[C:15]([CH3:14])[CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Reactant: CCCCc1cc2ccccc2o1
Solvent: O
Solvent: ClCCl
Product: CCCCc1oc2ccccc2c1C(=O)c1cc(C)c(OC)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (ice bath) mixture of 9.4 g. (0.054 mol.) of 2-n-butylbenzofuran and 11.5 g. (0.058 mol.) of 3,5-dimethyl-4-methoxybenzoic acid chloride in 100 ml. of methylene chloride was added dropwise 28.7 g. (0.11 mol.) of stannic chloride. The reaction mixture was allowed to warm to ambient temperature, then stirred for 2 hours. Water was slowly added to the mixture and it was stirred an additional 30 minutes. The layers were separated and the organic phase was washed with water until the washings were neutral, dried (MgSO4) and concentrated to give 2-n-butyl-3-(3',5'-dimethyl-4'-methoxybenzoyl)benzofuran.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH:11]=[C:10]([CH:12]=O)[N:9]=[CH:8]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[N:7]1[CH:11]=[C:10](/[CH:12]=[CH:22]/[CH:23]=[O:24])[N:9]=[CH:8]1
Reactant: O=Cc1cn(-c2ncccn2)cn1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1cn(-c2ncccn2)cn1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 1-(2-pyrimidinyl)-1H-imidazole-4-carboxaldehyde (prepared as described in Reference Example 10) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 201 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[CH:14][C:15]2[NH:20][CH:19]([CH3:21])[O:18][C:17]([CH3:23])([CH3:22])[C:16]=2[CH:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH:19]([CH3:21])[O:18][C:17]([CH3:23])([CH3:22])[C:16]=3[CH:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1Nc2ccc(Br)cc2C(C)(C)O1
Reactant: OB(O)c1cccc(F)c1
Product: CC1Nc2ccc(-c3cccc(F)c3)cc2C(C)(C)O1

Procedure:
Prepared according to the coupling procedure for Example 17 from 3-fluorophenyl boronic acid and 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine. A yellow solid: mp 139-140° C.; 1H-NMR (CDCl3) δ 7.40-7.19 (m, 6H), 7.01-6.94 (m, 1H), 6.72 (d, 1H, J=8.24 Hz), 4.90 (q, 1H, J=5.48 Hz), 1.62 (s, 3H), 1.59 (s, 3H), 1.46 (d, 3H, J=5.5 Hz); MS (ES) m/z 272 ([M+H]+).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1>C(O)C.C(O)(=O)C.C(OCC)(=O)C.[Fe]>[CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1
Reactant: CSc1ncc([N+](=O)[O-])cn1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CSc1ncc(N)cn1
Temperature: 80 °C
Yield: 50.9 %

Procedure:
A solution of 5 g (29.2 mmol) of 2-methylsulfanyl-5-nitropyrimidine in 200 mL of absolute ethanol and 120 mL of glacial acetic acid was added 16.31 g (292 mmol) of iron powder and the mixture was heated in an oil bath maintained at 80° C. for 2 hours. The reaction was diluted with 250 mL of ethyl acetate and filtered through CELITE® filter aid. The filtrate was washed with two portions of 100 mL of water, and the pH of the organic layer was adjusted by adding saturated aqueous sodium carbonate solution until the pH was 8. The organic layer washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 2.1 g (51%) of 2-methylsulfanylpyrimidin-5-ylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: CCOC(=O)CCCBr
Reactant: N#Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C#N)cc1F
Temperature: 80 °C
Yield: 97.1 %

Procedure:
3-fluoro-4-hydroxybenzonitrile (ABCR F03756F.AB, 2 g; 14.59 mmol; 1 eq.) was dissolved in DMF (40 mL). Then ethyl 4-bromobutyrate (4.27 g; 21.88 mmol; 1.50 eq.) and potassium carbonate (3.02 g; 21.88 mmol; 1.50 eq.) were added to the reaction mixture and it was heated to 80° C. for 2 hours. The reaction mixture was cooled to RT and diluted with EtOAc. The organic layer was washed with water (3×), brine, dried over MgSO4 and concentrated affording the title compound as a yellow solid (3.56 g, 97%). 1H NMR (DMSO-d6, 300 MHz) δ 7.86-7.83 (d, J=11.43 Hz, 1H), 7.68-7.66 (d, J=8.73 Hz, 1H), 7.37-7.32 (m, 1H), 4.20-4.03 (m, 4H), 2.46-2.44 (m, 2H), 2.03-1.99 (m, 2H), 1.19-1.15 (t, J=6.62 Hz, 3H). HPLC (Method A) Rt 4.47 min (Purity: 98.8%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.C(Cl)Cl.Cl>C1COCC1.O>[F:17][C:15]([F:16])([F:18])[C:12]1[N:11]=[CH:10][C:9]([CH2:8][CH2:7][C:6]([OH:19])=[O:5])=[CH:14][CH:13]=1
Reactant: COC(=O)CCc1ccc(C(F)(F)F)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Lithium hydroxide monohydrate (330 mg) is added in one portion to a solution of 3-(6-trifluoromethyl-pyridin-3-yl)-propionic acid methyl ester (610 mg) in a mixture of THF (15 mL) and water (5 mL). The mixture is stirred for 20 h at RT. DCM and aqueous HCl (1.0 M) are added, the layers are separated and the aqueous layer is extracted twice with DCM. The combined organic extracts are dried over MgSO4 and concentrated in vacuo to give the desired propionic acid as a beige solid.
Reaction SMILES: Br[C@@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[O:21][CH3:22])[CH2:4][C:3]1=[O:23].C(=O)([O-])[O-].[Li+].[Li+].[Cl-].[Li+]>CN(C=O)C>[CH3:22][O:21][C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:20])[C@H:5]([CH2:4][C:3](=[O:23])[CH:2]=[CH:19]1)[CH2:6][CH2:7]3
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)[C@H](Br)C[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 2α-bromo-17β-methoxy-5α-androstan-3-one (U.S. Pat. No. 3,301,850, Example 15, 3.0 g.), lithium carbonate (1.5 g.) and lithium chloride (0.5 g.) in DMF (30 ml.) are heated at reflux under nitrogen for 1.5 hours. The mixture is cooled, filtered and the solids washed with DMF. The filtrate and washings are combined and diluted with water (10 ml.) to give a precipitate. The precipitate is collected, washed, dried and column chromatographed over silica gel (200 g.) eluting by gradient between SSB (5 l.) and SSB:ethyl acetate (70:30, 5 l.). The appropriate fractions (TLC) are pooled and concentrated to give a solid which after recrystallization from hexane gives the title compound, m.p. 115°-117°, UV (ethanol) λ=229 nm (ε=10,350); MS (m/e) 302, 287 and 260; NMR (CDCl3) 0.79, 1.01, 3.20, 3.34, 5.84 and 7.13 δ.