Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22]O>>[CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Reactant: CCCCCO
Product: CCCCCOC(=O)C#C[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C

Procedure:
Using the procedure of Step A of Example 7, 3 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate and 2 ml of n-amyl alcohol were reacted and the residue was chromatographed over silica gel. Elution with an 8-2 hexane-isopropyl ether mixture yielded 2.7 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-[pentyloxycarbonylethynyl]-cyclopropane-carboxylate.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:46][C:47]1[S:48][CH:49]=[CH:50][N:51]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:46][C:47]2[S:48][CH:49]=[CH:50][N:51]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reaction time: 14 h
Yield: 96.5 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 2.0 g, 6.96 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (4.62 g, 10.44 mmol), and 2-aminothiazole (1.05 g, 10.44 mmol) in methylene chloride (50 mL) at 25° C. was treated with triethylamine (2.9 mL, 20.88 mmol). The reaction mixture was stirred for 14 h. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride (3×10 mL). The combined organic layers were sequentially washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230—400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-yl-propionamide (2.48 g, 96%) as a white solid: mp 143.5-145.5° C.; EI-HRMS m/e calcd for C17H18Cl2N2OS (M+) 368.0516, found 368.0516.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([CH:27]=O)=[CH:21]2)[CH3:13].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:27][C:22]1[NH:23][C:24]2[C:20]([CH:21]=1)=[CH:19][C:18]([O:17][CH2:16][CH2:15][N:14]([CH2:12][CH3:13])[CH2:29][CH3:30])=[CH:26][CH:25]=2
Reactant: CCN(CC)CCOc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCOc1ccc2[nH]c(C=C3C(=O)Nc4ccc(Br)cc43)cc2c1
Temperature: 100 °C
Yield: 66 %

Procedure:
A mixture of 5-bromo-2-oxindole (41 mg, 0.2 mmol), 5-(2-diethylamino-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 60 mg (66%) of the title compound.
Reaction SMILES: O=[C:2]([C:7](OC)=[O:8])[C:3]([O:5][CH3:6])=[O:4].[S:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:12][C:13]([O:15][CH3:16])=[O:14]>>[OH:8][C:7]1[C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:12]([C:13]([O:15][CH3:16])=[O:14])[S:11][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C(=O)C(=O)OC
Reactant: COC(=O)CSCC(=O)OC
Product: COC(=O)c1sc(C(=O)OC)c(C(=O)OC)c1O

Procedure:
The above compound was prepared as in Preparation 7 from dimethyl ketomalonate and dimethyl thiodiacetate.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:34])[CH:11]=1>>[CH:31]1([C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([C:13]4[CH:14]=[CH:15][C:10]([N:7]5[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]5=[O:8])=[CH:11][C:12]=4[F:34])=[O:17])[CH2:23][CH2:22]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Reactant: O=C1CC[C@@H](CO)N1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)CC[C@H]3CO)cc2F)CC1
Yield: 8 %

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one (127 mg) and (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (418 mg) described in Preparation Example 121 and by the reaction and treatment in the same manner as in Example 1, the title compound (36 mg) was obtained.
Reaction SMILES: [CH2:1]1[CH:13]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]2=[O:14])[C:3](=O)[CH2:2]1.Cl.[NH2:17][OH:18].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]1[CH:13]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]2=[O:14])[C:3](=[N:17][OH:18])[CH2:2]1
Reactant: NO
Reactant: O=C1c2ccccc2CN2C(=O)CCC12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1c2ccccc2CN2C(=NO)CCC12
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A mixture consisting of 2.5 g of 1,10a-dihydropyrrolo[1,2-b]isoquinoline-3,10[2H,5H]-dione in 20 ml of 95% ethanol (EtOH), 1.72 g of hydroxylamine hydrochloride in 10 ml of water and 3.7 g of sodium acetate trihydrate in 10 ml of water was refluxed for 7 hours and thereafter allowed to stand overnight at ambient temperature. The product crystallized from the reaction mixture to give 2.2 g of crystals. Recrystallization from 95% EtOH gave 1.4 g of crystals, m.p. 206°-209° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-])=O.[H][H]>N.O[V](=O)=O.[O-2].[O-2].[Ti+4].[Pd].O>[NH2:1][C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8]
Reactant: O=C1NC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[V](=O)O
Agent: [Pd]
Agent: [Ti+4]
Solvent: O
Product: Nc1cccc2c1C(=O)NC2=O
Temperature: 60 °C
Reaction time: 17 h
Yield: 74.8 %

Procedure:
0.001 g of ammonium vanadate and 0.5 g of titanium dioxide extrudate containing 1% by weight of metallic palladium and having a particle size of 3 mm (from Johnson Matthey) are added to a suspension consisting of 50 ml of water and 1.9 g of 3-nitrophthalimide. After displacing the air with nitrogen, the latter is replaced by hydrogen at atmospheric pressure and the suspension is stirred at 60° C. for 17 hours. During this time, 102% of the theoretical amount of hydrogen, based on the 3-nitrophthalimide, is adsorbed. The resulting suspension is then sieved through a sieve having a mesh width of 1 mm. The material remaining on the sieve is washed with 50 ml of water and the combined aqueous phases are then filtered through a paper filter and washed with 250 ml of water. Drying at 80° C. under reduced pressure (125 mbar) gives 1.2 g (74%) of 3-aminophthalimide.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[N:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:3]=1.O.[NH2:30][NH2:31]>C(Cl)(Cl)Cl>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:4]2[N:3]=[C:2]([NH:30][NH2:31])[N:7]([CH3:8])[C:6](=[N:9][C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[CH:5]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: NN
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(Cl)n2)cc1OC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(NN)n2)cc1OC

Procedure:
To a suspension of 2-chloro-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (10.0 g) in chloroform (100 ml) was added hydrazine hydrate (3.66 ml). The mixture was refluxed for 6 hours. The reaction mixture was evaporated in vacuo. The residue was chromatographed on silica gel using chloroform to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2-hydrazino-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (3.46 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([NH2:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18].[OH-].[Na+]>C(O)C>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([NH:13][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:12]=1)=[O:18]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1cc(-c2ccc(Cl)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1cc(-c2ccc(Cl)cc2)no1)c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
3-(4-Chlorophenyl)-5-aminoisoxazole (1 gram) and 2,6-dichlorobenzoylchloride (5 grams) were placed in a 100 ml. reaction vessel and heated to near reflux for 11/2 hours. The mixture was then cooled to room temperature and treated with 25 ml. of 2 N NaOH and 25 ml. ethanol. After refluxing for 2 hours, the ethanol was slowly removed at reduced pressure. A solid precipitate was collected by filtration. The remaining solution was treated with activated charcoal, filtered, and cooled to room temperature. The aqueous solution was extracted with chloroform. The chloroform was washed with water and dried (Na2SO4). Removal of the solvent afforded an oily product which was recrystallized from ether/hexane, m.p. 208°-209° C.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Br[C:13]1[CH:22]=[CH:21][C:16]([NH:17][C:18](=[O:20])[CH3:19])=[CH:15][CH:14]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C2C=CC=CC=2)C=CC=CC=1>[C:18]([NH:17][C:16]1[CH:21]=[CH:22][C:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:15]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-di-tert-butylphosphino)biphenyl (6.0 mg, 0.02 mmol, 2.0 mol %), phenylboronic acid (183 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0 mmol), and 4′-bromoacetanilide (214 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) was added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL), filtered through celite, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 182 mg (86%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.O[NH:48]/[C:49](=[N:56]\[H])/[C:50]1[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=1.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[C:7]1([C:6]2([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:5][CH2:4][N:3]([CH2:19][C:20]3[O:21][N:56]=[C:49]([C:50]4[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=4)[N:48]=3)[C:2]2=[O:1])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1ccncc1
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3ccncc3)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)—N-hydroxyisonicotinimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 8.78 (d, J=5.9, 2H), 7.86 (dd, J=1.6, 4.5, 2H), 7.44-7.28 (m, 10H), 4.92 (s, 2H), 3.58 (t, J=6.5, 2H), 2.90 (t, J=6.5, 2H); MS (DCI) m/z 397.1 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1>C(O)C>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:22]#[N:23])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(I)c1
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(I)c1
Yield: 56 %

Procedure:
A mixture of 6.70 g (16.1 mmol) 4-[(3-iodophenyl)amino]-6-nitro-quinoline-3-carbonitrile, 300 ml ethanol, and 18.2 g (80.5 mmol) SnCl2 dihydrate was heated to reflux under N2. Removed heat at 2 hours, added ice water. Added sodium bicarbonate until pH was basic, forming a thick yellow mixture. Stirred for 2½ hours. Extracted with chloroform, stirred organic portion with Darco and filtered through magnesium sulfate. Stripped solvent and dried in vacuo, giving 3.48 g of yellow-brown solid: mass spectrum (electrospray m/e): M+H=387.0.
Reaction SMILES: [CH2:1]([SH:19])[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][CH2:16][CH2:17][CH3:18].[H-].[Na+].Br[C:23]([CH3:33])([CH3:32])[C:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25]>C1C=CC=CC=1>[CH2:1]([S:19][C:23]([CH3:32])([CH3:33])[C:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25])[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][CH2:16][CH2:17][CH3:18]
Reactant: CCOC(=O)CC(=O)C(C)(C)Br
Reactant: CCCCCCCCCCCCCCCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCSC(C)(C)C(=O)CC(=O)OCC
Yield: 73.3 %

Procedure:
A mixture of 14.3 g of stearylmercaptan and 200 ml of anhydrous benzene was heated with stirring, to which 1.2 g of sodium hydride was gradually added. To the reaction slurry in an ice bath, a solution containing 13.2 g of ethyl (2-bromo-2-methylpropionyl)acetate and 20 ml of anhydrous benzene was gradually added with stirring. After the completion of the addition, the reaction mixture was removed from the ice bath and stirred for three hours. The reaction mixture was then poured into ice water and neutralized by addition of glacial acetic acid. The mixture was extracted with 300 ml of ethyl acetate, the extract was washed twice with a saturated aqueous sodium chloride solution. The ethyl acetate phase was dried with anhydrous sodium carbonate. After distilling off the ethyl acetate, the residue was purified using silica gel chromatography (eluting solvent: chloroform) to obtain 16.2 g (yield 62%) of the intended compound having a melting point of 34° to 37° C.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH:8]=[CH2:9])([O-:3])=[O:2].[F:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.O.C(=O)(O)[O-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C/C(/O)=C/C(C)=O.C=C.C=C.[Rh]>[F:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([C@H:5]([CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:4][N+:1]([O-:3])=[O:2])[C:11]=1[F:10]
Reactant: OB(O)c1cccc(F)c1F
Reactant: C=CCC/C=C/[N+](=O)[O-]
Agent: [Rh]
Agent: C=C
Agent: CC(=O)/C=C(/C)O
Solvent: O
Solvent: C1COCCO1
Product: C=CCC[C@H](C[N+](=O)[O-])c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
In a 1 L round-bottom flask was dissolved (E)-1-nitrohexa-1,5-diene (12.30 g, 97 mmol) and 2,3-difluorophenylboronic acid (38.2 g, 242 mmol) in dioxane (315 mL) to give a colorless suspension. Water (6.1 mL, 340 mmol) was added. The mixture was degassed with nitrogen and in a sonicator for 20 min. Sodium bicarbonate (4.06 g, 48.4 mmol) and (S)-(+2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.807 g, 2.90 mmol) and acetylacetonatobis(ethylene)rhodium (I) (0.749 g, 2.90 mmol) were added to the solution under nitrogen. The mixture was stirred at rt for 2 min, and then heated to 35° C. for 6 h under nitrogen. Reaction was continued for another 8 h at 35° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].C([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=C.[Na].FC(F)(F)C([O-])=O>C(O)C.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2[nH]c3ccccc3c2C1
Reactant: C=Cc1ccccn1
Agent: [Cu+2]
Agent: O=C([O-])C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CCN1CCc2c(c3ccccc3n2-c2ccccn2)C1
Yield: 2.9 %

Procedure:
The title compound was prepared according to General Method 3. 2-Ethyl-2,3,4,5-tetrahydro-5-(2-pyridyl)-1H-pyrido[4,3-b]indole was prepared from 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (See Example 5) (200 mg, 1 mmol), 2-vinylpyridine (0.26 mg, 2.5 mmol), sodium (15 mg, 0.65 g atom) and CuSO4 (10 mg, catalytic) in ethanol (2 mL) at 150° C. for 16 h to obtain 8 mg of 2-ethyl-2,3,4,5-tetrahydro-5-(2-pyridyl)-1H-pyrido[4,3-b]indole as a trifluoroacetate salt after purification on reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].O.O.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34]>C1C=CC=CC=1>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[N:18]1([CH2:17][CH2:16][N:12]2[CH2:13][CH2:14][CH:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:11]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C1CCN(CCOC2CCNC2)CC1
Reactant: ClCCN1CCCCC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: C1CCN(CCOC2CCN(CCN3CCCCC3)C2)CC1
Yield: 32 %

Procedure:
A solution of 10.0 g. (0.051 mole) of 3-(2-piperidinoethoxy)pyrrolidine and 10.4 g. (0.07 mole) of 1-(2-chloroethyl)piperidine in 200 ml. dry benzene was stirred with 28 g. (0.2 mole) of potassium carbonate at reflux for 15 hr. After cooling, the reaction mixture was filtered and concentrated. The residual oil was molecularly distilled to give a slightly impure product which when treated with three equivalents of oxalic acid dihydrate gave 9.3 g. of the trioxalate salt, m.p. 155°-162° C. (32% yield). The salt was recrystallized from methanol to give 5.8 g. of white crystalline salt, m.p. 177°-179° C.
Reaction SMILES: C[N:2]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@:3]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1.O.[OH-].[Li+].O1CCOCC1>O>[C:18]([NH:2][C@:3]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: CN(C(=O)OCc1ccccc1)[C@@](C)(Cc1cc2ccccc2s1)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@](Cc1cc2ccccc2s1)(NC(=O)OCc1ccccc1)C(=O)O
Yield: 82.8 %

Procedure:
A solution of methyl N-CBZ-α-methyl-3-benzothiophenylalanine (0.6 g, 1.57 mmol), lithium hydroxide hydrate (0.14 g, 3.33 mmol) in water (20 mL), and dioxan (20 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water, washed with ether, acidified with 1N hydrochloric acid, and extracted with ethyl acetate three times. The combined extracts were washed with water, dried over magnesium sulphate, filtered, and evaporated to dryness. Crystallization from ether/hexane gave colorless crystals 0.48 g (83%); mp 133°-135° C.;
Reaction SMILES: [CH3:1][N:2]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:6](=[O:7])[NH:5][C:3]1=[O:4]>CN(C)C=N.[Pd]>[CH3:1][N:2]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4]
Reactant: Cn1c(-c2ccccc2)cc(=O)[nH]c1=O
Agent: [Pd]
Agent: CN(C)C=N
Product: CN1C(=O)NC(=O)CC1c1ccccc1
Reaction time: 20 h

Procedure:
A solution of 1-methyl-6-phenyluracil (0.65 g) in dimethylformamidine (15 ml) is treated with 10 percent palladium on carbon and reduced at 40 p.s.i. for 20 hours. The catalyst is then filtered and the filtrate evaporated to a crystalline residue. The crystallization from acetonitrile provides 5,6-dihydro-1-methyl-6-phenyl-2,4-pyrimidine-dione, m.p. 155°-6° C.
Reaction SMILES: [CH:1]1(O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.C1C=CC=CC=1>O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:17])=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: OC1CCCCC1
Solvent: O
Solvent: c1ccccc1
Product: O=C(Cc1ccc(O)cc1)OC1CCCCC1
Yield: 104.6 %

Procedure:
Cyclohexyl alcohol (6 g), 4-hydroxyphenylacetic acid (7.6 g) p-toluenesulfonic acid (1 g) and benzene (300 mL) were refluxed with continuous water separation for 8 hours. The mixture was cooled and washed with a 10% Na2CO3 solution, then with water. Drying over MgSO4 and evaporation of the solvent in vacuo gave 12.24 g of cyclohexyl 4-hydroxyphenylacetate. That compound can be represented by the formula: ##STR24##
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=2)=[CH:18][CH:17]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:2]1([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:16]3[CH:31]=[CH:30][C:19]([O:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=4)=[CH:18][CH:17]=3)[CH2:12][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NC(=O)c1ccc(Oc2ccc(CN3CCC(c4ccccc4)CC3)cc2)nc1
Yield: 93.3 %

Procedure:
Using a method similar to Example 342, using 4-phenyl-piperidine hydrochloride salt (0.0823 g, 0.416 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.100 g, 0.415 mmol), sodium triacetoxyborohydride (0.136 g, 0.642 mmol), and acetic acid (0.034 mL, 0.594 mmol) in 1,2-dichloroethane (8.0 mL) provides 0.150 g (94%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C24H26N3O2 388.2025, found 388.2039; 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.6 Hz), 8.30 (dd, 1H, 2.6, 8.8 Hz), 7.49 (d, 2H, J=8.8 Hz), 7.35-7.25 (m, 4H), 7.23-7.15 (m, 3H), 7.05 (d, 1H, J=8.8 Hz), 3.65 (s, 2H), 3.12 (d, 2H, J=11.9 Hz), 2.65-2.54 (m, 1H), 2.24 (dt, 2H, J=4.0, 11.0 Hz), 1.94-1.78 (m, 4H).