Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[S:24][CH:25]=[C:26]([CH2:27][O:28]COC)[C:21]=4[S:20](=[O:33])(=[O:32])[N:19]=3)=[C:14]([OH:34])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:35][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[S:24][CH:25]=[C:26]([CH2:27][OH:28])[C:21]=4[S:20](=[O:32])(=[O:33])[N:19]=3)=[C:14]([OH:34])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:35][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: COCOCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Agent: Cl
Solvent: C1COCCO1
Product: O=C1C(C2=NS(=O)(=O)c3c(CO)csc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-methoxymethoxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.42 g, 0.76 mmol) in dioxane (3 mL) was added a 4.0 M solution of hydrochloric acid in dioxane (9 mL). The reaction was stirred at 25° C. for 2 h before it was concentrated in vacuo to afford the crude product, (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-hydroxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.38 g, 0.76 mmol, 100%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:8]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.[Br-].[CH3:36][CH:37]1[O:41][C:40](=[N+:42]([CH3:44])[CH3:43])[C:39]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:38]1>O>[CH3:1][O:2][C@H:3]1[C@H:8]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[CH2:7][CH2:6][N:5]([CH:37]([CH3:36])[CH2:38][C:39]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:40]([N:42]([CH3:43])[CH3:44])=[O:41])[CH2:4]1
Reactant: CC1CC(c2ccccc2)(c2ccccc2)C(=[N+](C)C)O1
Reactant: CO[C@@H]1CNCC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CO[C@@H]1CN(C(C)CC(C(=O)N(C)C)(c2ccccc2)c2ccccc2)CC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
A mixture of 3.0 parts of trans-N-(3-methoxy-4-piperidinyl)-3-(trifluoromethyl)benzamide, 2.65 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone was stirred for 30 minutes at reflux temperature, using a water separator. After cooling 3.96 parts of N-(dihydro-5-methyl-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide were added and stirring was continued for 5 hours at reflux. After cooling overnight at room temperature, the reaction mixture was washed twice with 50 parts of water, dried, filtered and evaporated in vacuo. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 8 parts of acetonitrile. The product was filtered off and dried, yielding 1.3 parts (22.5%) of trans-3-methoxy-N,N,γ-trimethyl-α,α-diphenyl-4-[[3-(trifluoromethyl)benzoyl]amino]-1-piperidinebutanamide; mp. 197.8° C. (compound 52).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.O>C1COCC1>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(CCCBr)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(CCCn2cncn2)cc1
Temperature: 50 °C
Reaction time: 60 h
Yield: 45.3 %

Procedure:
1,2,4-triazole (0.68 g) was dissolved in THF (8.0 ml), potassium carbonate (2.7 g) was added to the mixture, a solution of 1-(3-bromopropyl)-4-nitrobenzene (1.6 g) in. THF (8.0 ml) was added dropwise to the solution, and the mixture was stirred for 60 hours at 50° C. After cooling to room temperature, the reaction solution was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 1-[3-(4-nitrophenyl)propyl]-1,2,4-triazole (0.69 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])[CH3:2].C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:16])=[O:7])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOc1ccccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A solution of 2-ethoxybenzoic acid (0.75 g, 4.5 mmol) in 23 mL of methylene chloride at 0° C. was treated with oxalyl chloride (0.44 mL, 4.9 mmol) followed by 2 drops of dimethylformamide. The solution was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure to provide 0.83 g of 2-ethoxybenzoyl chloride. To a solution of 4-trifluoromethylthiazol-2-ylamine (0.50 g, 3.0 mmol) in 10 mL THF at 0° C. was added a solution of the fleshly prepared acid chloride in 5 mL of THF and 2 mL of methylene chloride, followed by triethylamine (1.0 mL, 6.6 mmol). The reaction mixture was warmed to 65° C. and stirred 8 hours. The mixture was diluted with ethyl acetate and washed twice with water, then brine. The organic extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 30-50% ethyl acetate/hexanes gradient) afforded 0.47 g (50%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.66 (t, J=6.95 Hz, 3H), 4.38 (q, J=6.89 Hz, 2H), 7.03-7.10 (m, 2H), 7.17 (d, J=7.80 Hz, 1H), 7.42 (s, 1H), 8.29 (dd, J=7.97, 1.86 Hz, 1H) MS (DCI/NH3) m/z 317 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23]C3C=CC=CC=3)=O)=[CH:16][CH:15]=2)[N:11]=[C:10]([C:30]([O:32][CH3:33])=[O:31])[CH:9]=1.C(N(CC)CC)C.[CH:41]1([NH2:44])[CH2:43][CH2:42]1>CN(C=O)C>[CH:41]1([NH:44][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]3[N:11]=[C:10]([C:30]([O:32][CH3:33])=[O:31])[CH:9]=[C:8]([N:3]4[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]4[CH3:1])[N:13]=3)=[CH:15][CH:16]=2)=[O:23])[CH2:43][CH2:42]1
Reactant: COC(=O)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Methyl 6-[(3S)-3-methylmorpholin-4-yl]-2-[4-(phenoxycarbonylamino)phenyl]pyrimidine-4-carboxylate (547 mg) was dissolved in DMF (8 mL) and triethylamine (0.59 mL) followed by cyclopropylamine (0.491 mL) added. The reaction was stirred at 40° C. for 2 hours then the mixture was vacuumed to dryness and partitioned between DCM (50 mL) and water (50 mL). The organic layer was dried over magnesium sulphate and vacuumed to dryness then chromatographed on silica, eluting with 5% methanol in DCM, to give the desired material (351 mg) as a white solid.
Reaction SMILES: Br[CH:2]=[CH:3][CH:4]([CH3:6])[CH3:5].O.O.[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([S:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.[Na+]>CN(C)C=O>[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([S:15]([CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: CC(C)C=CBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
In dimethylformamide (20 ml) was dissolved 1-bromo-3-methyl-butene(1.49 g, 10 m moles) and sodium p-toluenesulfinate dihydrate (2.5 g, 1.16 equiv.), the solution was stirred at room temperature for 3 hours. The product was isolated in the usual manner and recrystallized from n-hexane to give 1-(p-toluenesulfonyl)-3-methyl-2-butene (2.16 g, 96.4%), melting point: 71°-72° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Br:16])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Br:16])=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(=CCCCCCCBr)c2ccc(F)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Fc1ccc(C(CCCCCCCBr)c2ccc(F)cc2)cc1

Procedure:
9.7 g (25.5 mmol) 8,8-bis-(4-fluorophenyl)-oct-7-enyl bromide are dissolved in 350 ml ethanol and added to 0.5 g palladium (5%) on activated carbon. The mixture is stirred under hydrogen atmosphere (ca. one hour) until the theoretical amount of hydrogen to be taken up is consumed. Subsequently, the mixture is filtered off from a catalyst and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with petroleum ether/acetic acid ethyl ester (80/1 to 40/1)): Yield 8.6 g (89%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[S:26]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:21]=O>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:21][C:20]2[CH:23]=[CH:24][C:25]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[C:18]([F:17])[CH:19]=2)=[C:6]1[CH3:15]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1ccc(S(=O)(=O)c2ccc(F)cc2)c(F)c1
Product: COC(=O)Cn1c(C)c(Cc2ccc(S(=O)(=O)c3ccc(F)cc3)c(F)c2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and 3-fluoro-4-(4-fluorobenzenesulfonyl)benzaldehyde.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10](Cl)[C:11]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13][C:12]=2[N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27](B(O)O)[CH2:28][CH2:29][CH3:30]>>[CH2:1]([C:8]1[N:9]=[C:10]([CH2:27][CH2:28][CH2:29][CH3:30])[C:11]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13][C:12]=2[N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCB(O)O
Reactant: Clc1nc(Cc2ccccc2)nc2c1CCN(Cc1ccccc1)CC2
Product: CCCCc1nc(Cc2ccccc2)nc2c1CCN(Cc1ccccc1)CC2

Procedure:
The title compound was prepared using a similar method to that of Preparation 39, starting from 2,7-dibenzyl-4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine of Preparation 38, Step B and n-butaneboronic acid. The title compound was obtained as a colourless oil 126 mg, 79%
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O>>[CH3:8][C:7]1[S:6][C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[C:2]1[S:13][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:1]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)c1cc(C(N)=S)c(C)s1
Product: COC(=O)c1cc(-c2nc(-c3ccccc3)cs2)c(C)s1

Procedure:
A solution of 200 mg (0.93 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate was reacted with 185 mg (0.93 mmol) of 2-bromoacetophenone in a manner similar to Example 8, step (a) to give, after purification by preparative thin layer chromatography eluting with hexanes:ethyl acetate 7/3 (v:v), a mixture of methyl 5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate and methyl 4-cyano-5-methylthiophene-2-carboxylate (96 mg, 36%) as a solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1([C:26](OCC)=[O:27])[O:7][N:6]=[C:5]([C:8]2[C:9]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:10]3[CH:16]=[N:15][N:14]([CH2:17][CH3:18])[C:11]3=[N:12][CH:13]=2)[CH2:4]1.[BH4-].[Na+]>O1CCCC1>[Br:1][CH2:2][C:3]1([CH2:26][OH:27])[O:7][N:6]=[C:5]([C:8]2[C:9]([NH:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)=[C:10]3[CH:16]=[N:15][N:14]([CH2:17][CH3:18])[C:11]3=[N:12][CH:13]=2)[CH2:4]1
Reactant: CCOC(=O)C1(CBr)CC(c2cnc3c(cnn3CC)c2NC2CCCCC2)=NO1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC(CO)(CBr)C3)cnc21
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Ethyl 5-(bromomethyl)-3-[4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-4,5-dihydroisoxazole-5-carboxylate (200 mg, 0.0004 mole) (example 19) was taken in tetrahydrofuran (15 ml). Sodium borohydride (31 mg, 0.0008 mole) was added portion wise. The reaction mixture was stirred overnight. It was quenched with saturated ammonium chloride solution. The organic solvent was removed, water was added and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product obtained was purified by column chromatography.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17].[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])=[CH:23][C:22]=1[OH:28]
Reactant: COc1cccc(CCCCCCBr)c1OC
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCCCc2cccc(OC)c2OC)cc1O
Yield: 93.6 %

Procedure:
A mixture of 1.0 g (3.3 mmol) of 1-(6-bromohexyl)-2,3-dimethoxybenzene, 0.55 g (3.3 mmol) of 2,4-dihydroxybenzoic acid methyl ester, 1.2 g (9 mmol) of potassium carbonate and 0.75 g (4.5 mmol) of potassium iodide in 25 mL of acetone was stirred at reflux for 20 hours. Workup as in Example 16 gave 1.2 g of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-2-hydroxybenzoic acid methyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=1)[C:5]2=[O:53].[CH:54](=O)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.[BH3-]C#N.[Na+]>CCO.C1COCC1>[CH2:54]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[N:6]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:32]=[N:31][N:30]=3)=[CH:21][CH:22]=1)[C:5]2=[O:53])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCc1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCc1nc2ccc(NCc3ccccc3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To 100 mg (0.14 mmol) of the amine from Example 40 in 2 mL of EtOH was added 16 mg (0.15 mmol) of benzaldehyde. The reaction mixture was heated to 60° C. for 1 hour, cooled to 0° C. and treated with 0.29 mL (0.29 mmol) of a 1M solution of NaCNBH3 in THF. The reaction mixture was stirred overnight, concentrated in vacuo, and the residue partitioned between 25 mL of EtOAc and 15 mL of water. The phases were separated and the organic phase was washed with brine (1×25 mL) and dried over MgSO4. The mixture was filtered and concentrated in vacuo and the residue was purified by flash chromatography over silica gel eluting with 25% EtOAc/hexanes to give 45 mg (0.06 mmol) of a yellow foam. 1H-NMR (CDCl3 300 MHz): 0.88 (t, 3H, J=7.4 Hz), 1.31 (m, 2H), 1.66 (m, 2H), 2.61 (3 line m, 2H, J=7.8 Hz), 4.32 (bs, 1H), 4.43 (bs, 2H), 5.28 (bs, 2H), 6.88 (m, 8H), 7.08 (m, 3H), 7.20-7.53 (m, 19H), 7.91 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2ccccc2)nc2ccc(Cl)cc12
Product: Clc1ccc2nc(-c3ccccc3)cc(Cl)c2c1

Procedure:
From 25.5 g of 6-chloro-2-phenyl-4-quinolinol and 50 ml of phosphorus oxychloride treated according to the procedure of Example 4(b) there was obtained 24.86 g of 4,6-dichloro-2-phenylquinoline, mp 114°-116°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].Cl[CH2:14][CH2:15][N:16]=[C:17]=[S:18]>C(COC)OC>[S:18]1[CH2:14][CH2:15][N:16]=[C:17]1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: S=C=NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1Cc2ccccc2N1C1=NCCS1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4.0 g (0.03 mole) of oxindole in 125 ml dry glyme there is added 1.4 g (0.03 mole) of sodium hydride (50% oil dispersion) and the mixture is stirred at room temperature for 3 hours. Then 3.6 g (0.3 mole) of 2-chloroethyl isothiocyanate in 5 ml of dry glyme is added and the mixture is refluxed overnight. After evaporation of the solvent in vacuo, the residue is chromatographed on an Alumina Act. IV column. Elution with ethyl ether yields the product which is crystallized from ethyl ether to yield 0.6 g, m.p. 97°-99°.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C.[CH:22]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])OCC>O>[CH2:30]([O:29][C:22]1([O:26][CH2:27][CH3:28])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1)[CH3:31]
Reactant: CCOC(OCC)OCC
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC1(OCC)CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a round bottom flask 6 g (6.4 ml) Cyclohexanone, a pinch of p-toluene sulfonic acid and 10 ml absolute ethanol was taken. Stirred the mixture at R.T. for 5 min. Then add to it 18.12 g (20.3 ml) triethyl orthoformate and stir for 3 hr at R.T. Then distilled on rotavapour to get a thick mass. Add to it 30 ml water and extract with (25 ml×ethyl acetate, wash the organic layer with water, dried it by adding sodium sulfate and concentrate it on rotavapour to give a colorless liquid product.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([CH:16]=[O:17])[O:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.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>[C:1]1([C:11]2[CH:12]=[C:13]([CH:16]=[O:17])[O:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1cc(Br)co1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(-c2ccccc2)co1
Temperature: 110 °C
Yield: 78.8 %

Procedure:
Phenylboronic acid (1.46 g) was added to a stirred mixture of 4-bromofuran-2-carbaldehyde (2.00 g) and tetrakis(triphenylphosphine)palladium(0) (0.396 g) in N,N-dimethylformamide (57 mL) and a solution of sodium carbonate (3.03 g) in water (7 mL). The reaction was heated at 110° C. overnight. The resulting mixture was filtered and the filtrate was partitioned between water and diethyl ether. The layers were separated and the aqueous phase was extracted with diethyl ether. The organics were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane:hexane=9:1) to obtain the title compound (1.55 g) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][NH:16][CH2:17][N:18]=[N:19][N+:20]([O-:22])=[O:21])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1.C(Cl)CCl.[Cl-].[Na+]>CN(C=O)C>[S:25]1[CH:26]=[CH:27][N:28]=[C:24]1[NH:23][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][CH2:15][NH:16][CH2:17][N:18]=[N:19][N+:20]([O-:22])=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNCN=N[N+](=O)[O-])C(=O)O
Reactant: Nc1nccs1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCNCN=N[N+](=O)[O-])C(=O)Nc1nccs1
Reaction time: 4 h
Yield: 36.4 %

Procedure:
To a stirred solution of (2S)-2-tert-butoxycarbonylamino-5-(nitroimino-amino)methylaminopentanoic acid (5.00 g, 15.6 mmol) and 2-aminothiazole (1.72 g, 17.2 mmol) in DMF (16 mL) is added EDC (3.30 g, 17.2 mmol). The solution is allowed to stir for 4 h then added to half-saturated aqueous sodium chloride solution and extracted with EtOAc. The combined organic extracts are washed with 1 N sodium bisulfate, 5% aqueous sodium bicarbonate, saturated aqueous sodium chloride, and dried over magnesium sulfate. Concentration in vacuo provides (2S)-2-tert-butoxycarbonylamino-5-(nitroimino-amino)methylaminopentanoic acid 1,3-thiazol-2-ylamide as a solid (2.28 g, 36%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1C(=O)C(F)(F)F.Cl>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1
Reactant: COc1ccc(C[C@H]2CCCN2C(=O)C(F)(F)F)cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(C[C@H]2CCCN2)cc1OC
Reaction time: 24 h
Yield: 97 %

Procedure:
To a solution of (R)-2-(3,4-dimethoxybenzyl)-1-trifluoroacetylpyrrolidine (3.2 g, 0.010 mol) in 50 mL isopropyl alcohol was added 15 mL of 12.5M HCl. The mixture was then heated under reflux until all starting material had disappeared, approximately 24 hours. The solvent was removed in vacuo to give an oil which could be recrystallized from isopropyl alcohol/ether, giving 2.5 of (R)-2-(3,4-dimethoxybenzyl)pyrrolidine (97% yield), as needles, m.p. 165°-167° C.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]=1)(=O)=O.[CH:15]12[NH:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][C:17](=[O:23])[CH2:16]2>>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:7]=[N:6][C:5]([N:22]2[CH:15]3[CH2:21][CH2:20][CH:19]2[CH2:18][C:17](=[O:23])[CH2:16]3)=[N:10][CH:9]=1
Reactant: O=C1CC2CCC(C1)N2
Reactant: CS(=O)(=O)c1ncc(C(F)(F)F)cn1
Product: O=C1CC2CCC(C1)N2c1ncc(C(F)(F)F)cn1

Procedure:
The title compound was synthesized from 2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine and 8-azabicyclo[3.2.1]octan-3-one in a manner similar to that described in Example 9.