Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCC[C@H]1C(O)=O.Br[C:10]1[CH:25]=[CH:24][C:13]([CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:12][CH:11]=1.[C:26]1([CH:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:33][CH2:34][NH2:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.[Cu]I.CS(C)=O>[Si:17]([O:16][CH2:15][CH2:14][C:13]1[CH:24]=[CH:25][C:10]([NH:35][CH2:34][CH2:33][CH:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:11][CH:12]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(Br)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(NCCC(c2ccccc2)c2ccccc2)cc1
Temperature: 90 °C

Procedure:
To a mixture of copper(I) iodide (0.195 g, 1.02 mmol), (S)-pyrrolidine-2-carboxylic acid (0.223 g, 1.94 mmol), (4-bromophenethoxy)(tert-butyl)dimethylsilane, prepared in the previous step, and 3,3-diphenylpropan-1-amine (3.16 g, 15.0 mmol) was added potassium phosphate (4.27 g, 20.1 mmol), and DMSO (16 mL). The reaction mixture was heated to 90° C. for 1 d and diluted with EtOAc. The organic phase was washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 5% to 15% EtOAc in hexanes) gave 4-(2-(tert-butyldimethylsilyloxy)ethyl)-N-(3,3-diphenylpropyl)benzenamine 66.
Reaction SMILES: [CH3:1][SH:2].CC(C)([O-])C.[K+].Cl[C:10]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[O:13]>O1CCCC1>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12](=[O:13])[C:11]1[CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:25][C:10]=1[S:2][CH3:1]
Reactant: COc1ccccc1C(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1cc([N+](=O)[O-])ccc1SC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A solution of methanethiol (1.7 g, 35.3 mmol) in tetrahydrofuran is added to a solution of potassium tertbutoxide (4.0 g, 35.7 mmol) in tetrahydrofuran at 0° C. A solution of 2-chloro-2'-methoxy-5-nitrobenzophenone (10.0 g, 34.3 mmol) is added portionwise to the cold reaction mixture. The reaction mixture is then warmed to and stirred at room temperature overnight and diluted with ice. The resultant aqueous mixture is filtered to give the title product as a yellow solid (9.9 g, mp 119°-122° C.).
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[Li+].Br[CH:16]([CH:20](Br)[C:21]([OH:23])=[O:22])[C:17]([OH:19])=[O:18]>>[N:1]1([CH:16]([CH:20]([N:1]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:21]([OH:23])=[O:22])[C:17]([OH:19])=[O:18])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(Br)C(Br)C(=O)O
Reactant: C1CNCCNCCNCCN1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C(C(C(=O)O)N1CCNCCNCCNCC1)N1CCNCCNCCNCC1
Temperature: 60 °C
Reaction time: 72 h
Yield: 16.2 %

Procedure:
To an aqueous solution of 1,4,7,10-tetraazacyclododecane (100 g, 580 mmol) and lithium hydroxide (5.2 g, 216 mmol) was added 2,3-dibromosuccinic acid (15.0 g, 54 mmol). After stirring at 60° C. for 3 days, the solution was cooled to ambient temperature and applied on an AG1-X8 anion exchange column [500 mL (OH-form)], the column was washed with water (1 L) and the product was eluted with 1M CH3COOH. Further purification by cation exhange chromatography on a AG5OW-X8 column [100 mL (H+form)] yielded 4.0 g (16%) of the title product as a white powder. 1H NMR (D2O) δ 2.4-3.0 (m, 32H), 3.2 (2H). 13C NMR (D2O) 40.4, 40.7, 42.9, 44.7, 61.5, 174.0. MS (FAB): m/e 459.3.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH3:21])=C([CH:18]=1)C(O)=O)(=[O:9])[CH3:8]>ClCCl.CN(C)C=O>[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH3:21])=[C:1]([CH:18]=1)[C:2]([Cl:4])=[O:3])(=[O:9])[CH3:8]
Reactant: CCOc1ccc(C(C)=O)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccc(C(C)=O)cc1C(=O)Cl

Procedure:
Oxalyl chloride (3.66 g, 0.029 mol) was added dropwise to a stirred solution of 5-acetyl-2-ethoxybenzoic acid (3.0 g, 0.014 mol) in dichloromethane (15 ml) and dimethylformamide (0.1 ml) After 3 hours at room temperature, the solvent was removed by evaporation under vacuum and the residue axeotroped with hexane (3×30 ml) to give the title compound, which was used without further purification.
Reaction SMILES: [C:1]([C:3]1([NH:9][C:10]([CH:12]([NH:20]C(OC(C)(C)C)=O)[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].[ClH:28]>O1CCOCC1>[ClH:28].[C:1]([C:3]1([NH:9][C:10]([CH:12]([NH2:20])[CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:11])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1)#[N:2]
Reactant: CC(C)(C)OC(=O)NC(CC1CCCCC1)C(=O)NC1(C#N)CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(NC(=O)C(N)CC2CCCCC2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-Butoxycarboxylic acid[1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide (1000 mg, 2.62 mmol) was dissolved in 15 mL of 4 M HCl in dioxane. The solution was stirred at ambient temperature for 1 hr. The volatiles were removed in vacuo and the resulting paste was triturated with 25 mL of diethyl ether to give a fine white solid that was collected by filtration and dried in vacuo. The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:5]2=[O:20].[BH4-].[Na+].O>CO.O1CCCC1>[CH3:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:5](=[O:20])[N:6]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:7]2[OH:12]
Reactant: Cc1cc2c(cc1C)C(=O)N(c1ccc(F)cc1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C)C(O)N(c1ccc(F)cc1)C2=O
Yield: 94.6 %

Procedure:
The product of above-mentioned (1-a) (1.0 g, 3.7 mmol) was suspended in methanol (9 ml) and tetrahydrofuran (9 ml), and sodium borohydride (0.15 g, 3.9 mmol) was added by portions thereto with stirring under ice cooling, followed by stirring at the same temperature for 30 minutes. To the reaction solution was added water, and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.95 g of 5,6-dimethyl-2-(4-fluorophenyl)-3-hydroxyisoindolin-1-one.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[NH:7]/[C:6](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)/[C:5]1=[O:20])(=O)C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[CH:21](=[C:9]1/[C:8](=[O:10])[NH:7]/[C:6](=[CH:11]\[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)/[C:5](=[O:20])[NH:4]/1)\[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(/C=C2\NC(=O)CN(C(C)=O)C2=O)cc1
Reactant: O=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(/C=c2\[nH]c(=O)/c(=C/c3ccccc3)[nH]c2=O)cc1
Temperature: 130 °C

Procedure:
A mixture of (3Z)-1-acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (9) (1.0 g, 3.6 mmol), benzaldehyde (430 μl, 4.2 mmol) and triethylamine (1.14 ml), 8.2 mmol), in dry DMF (20 ml), was heated at 130° C. for 18 h. The reaction mixture was cooled to room temperature and poured into ethyl acetate (100 ml). A yellow solid precipitated which was filtered off and dried. Yield 360 mg (31%).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Cl:6][C:7]1[N:12]=[C:11]([CH:13]=[O:14])[CH:10]=[C:9]([CH2:15][O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:8]=1>C(OCC)C>[Cl:6][C:7]1[N:12]=[C:11]([CH:13]([OH:14])[CH:1]([CH3:3])[CH3:2])[CH:10]=[C:9]([CH2:15][O:16][CH2:17][C:18]([F:21])([F:19])[F:20])[N:8]=1
Reactant: O=Cc1cc(COCC(F)(F)F)nc(Cl)n1
Reactant: CC(C)[Mg]Cl
Solvent: CCOCC
Product: CC(C)C(O)c1cc(COCC(F)(F)F)nc(Cl)n1

Procedure:
Isopropyl magnesium chloride (0.601 mL, 2M solution, 1.20 mmol) was added dropwise to a solution of 2-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine-4-carbaldehyde (180 mg, 0.71 mmol) in diethyl ether (10 mL) at −30° C. The mixture was quenched with a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate (×2). The combined organic phase was dried over sodium sulfate and concentrate. The residue was purified by column chromatography on silica to yield the title compound, 25 mg (12%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26]O)=[CH2:21].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:26][CH2:25][CH2:24][CH2:23][O:22][CH:20]=[CH2:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: C=COCCCCO
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=COCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (0.94 g, 3.1 mmol) obtained in Example 5 was dissolved in toluene (30 ml). After addition of 4-vinyloxy-1-butanol (0.51 ml, 4.2 mmol) and cyanomethylenetri-n-butylphosphorane (1.0 g, 4.1 mmol), the resulting mixture was heated under reflux for 3 days under an argon atmosphere. The reaction mixture was allowed to cool down and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to yield a white solid. The resulting white solid was washed with hexane, whereby the title compound (0.97 g, 78%) was obtained as a white powder.
Reaction SMILES: [BH4-].[K+].[CH3:3][C:4]1([CH3:21])[NH:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[O:5]1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][CH:29]([Cl:33])[C:30](Cl)=[O:31]>O>[Cl:28][CH:29]([Cl:33])[C:30]([N:8]1[C@H:7]([CH2:9][OH:10])[C@@H:6]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:13][CH:12]=2)[O:5][C:4]1([CH3:21])[CH3:3])=[O:31]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC1(C)N[C@H](CO)[C@@H](c2ccc(S(C)(=O)=O)cc2)O1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: O
Product: CC1(C)O[C@H](c2ccc(S(C)(=O)=O)cc2)[C@@H](CO)N1C(=O)C(Cl)Cl
Temperature: 55 °C
Reaction time: 6 h

Procedure:
(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound IV) (100 g, 0.3480 moles) in 500 mL of methanol reacts with 2,2-dimethoxypropane (39.9 g, 0.3828 moles) and lithium carbonate at 60-70° C. to yield (4S,5R)-2,2-dimethyl-4-ethylcarboxyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound XIVa) (113.9 g, 0.3480 moles). Addition of potassium borohydride (28.2 g, 0.5220 moles) with stirring over 4-8 hours at 50-60° C. then yields (4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound VIIIa). Addition of potassium carbonate (19.0 g, 0.1914 moles) and dichloroacetyl chloride (56.4 g, 0.3828 moles) at 20-25° C. for 2-4 hours then addition of water (500 mL) precipitates the crude product. Filtration, washing with water (250 mL) then drying yields (4R,5R)-3-dichloroacetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound XIIa).
Reaction SMILES: [CH:1]1([C:4]([C@H:6]2[CH2:10][O:9]C(C)(C)[N:7]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH2:5])[CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.N1C=CN=C1.[Si:59](Cl)([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60]>CO.CN(C)C1C=CN=CC=1>[Si:59]([O:9][CH2:10][C@@H:6]([NH:7][C:13](=[O:14])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:4]([CH:1]1[CH2:2][CH2:3]1)=[CH2:5])([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C(C1CC1)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C1CC1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 64.2 %

Procedure:
To a solution of (S)-tert-butyl 4-(1-cyclopropylvinyl)-2,2-dimethyloxazolidine-3-carboxylate (Intermediate 232, 8.25 g, 30.86 mmol) in methanol (100 mL) at room temperature was added p-toluenesulfonic acid monohydrate (1.174 g, 6.17 mmol). The reaction mixture was heated to 80° C. overnight. Another 0.2 eq of p-toluenesulfonic acid monohydrate was added. Continue heating at 80° C. for 2 hours. The reaction mixture was cooled to room temperature. Triethylamine (4.29 mL, 30.86 mmol) and di-tert-butyl dicarbonate (3.37 g, 15.43 mmol) were added. The reaction mixture was stirred over the weekend then concentrated. The residue was dissolved in ethyl acetate and washed once with saturated sodium bicarbonate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The resulting oil was dissolved in DCM (100 mL). Imidazole (2.73 g, 40.11 mmol), 4-dimethylaminopyridine (0.754 g, 6.17 mmol) and tert-butyldimethylsilyl chloride (4.65 g, 30.86 mmol) were added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered to remove solids and washed with brine twice. The organic layer was dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-10% ethyl acetate/hexanes) afforded the title compound as a colorless oil (6.77 g, 64%).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:12]2[CH2:13][C:14]([F:18])([F:17])[CH2:15][CH2:16][C@H:11]2[O:10]C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[K+]>C(O)C>[CH2:1]([NH:8][C@@H:12]1[CH2:13][C:14]([F:17])([F:18])[CH2:15][CH2:16][C@H:11]1[OH:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1O[C@@H]2CCC(F)(F)C[C@H]2N1Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O[C@@H]1CCC(F)(F)C[C@H]1NCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of trans-3-benzyl-5,5-difluorohexahydro-1,3-benzoxazol-2(3H)-one (980 mg) in ethanol (60 mL)/water (6 mL) was added potassium hydroxide (411 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/dichloromethane) to give the title compound (540 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(=O)([O-])[O-].[Na+].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.ClCCl>O1CCCC1>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: COC(CN)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(CNS(=O)(=O)c1ccc(C)cc1)OC
Reaction time: 72 h

Procedure:
5.25 g (50 mmol) of aminoacetaldehyde dimethylacetal was dissolved in 400 ml of tetrahydrofuran. 106 g (1 mol) of sodium carbonate and 11.44 g (60 mmol) of p-toluenesulfonyl chloride were added to the obtained solution. They were stirred for 3 days and then treated with dichloromethane as the extracting solvent in an ordinary manner to obtain the title compound. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:33])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[N:30][CH:29]=[CH:28][N:27]=4)[CH:21]=3)[CH2:18][C:17](=[O:33])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3cnccn3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-methyl-2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M79) (0.31 g, 0.64 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (208 mg, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH:14]=O)[C:7]=2[N:16]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:18]3)[C:7]=2[N:16]=1
Reactant: O=C(NC[C@@H]1CCCNC1)OCc1ccccc1
Reactant: COc1ccc2ncc(=O)n(CC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC[C@@H](CNC(=O)OCc4ccccc4)C3)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[6-(Methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]acetaldehyde (for a preparation see Example 126(e)) (0.30 g, 1.36 mmol) was combined with phenylmethyl [(3R)-3-piperidinylmethyl]carbamate (for a preparation see Example 92(b)) (0.337 g, 1.36 mmol) in a 1:1 MeOH/DCM solution (30 mL). Excess Na2SO4 was added as a drying agent and the solution was stirred at ambient temperature for 16 h. NaBH(OAc)3 (0.86 g, 4.08 mmol) was added and the reaction was stirred an additional 2 h. The resulting solution was concentrated onto silica gel under vacuum and the crude residue was purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the desired product as an off white solid (0.37 g, 61%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1.[O:16]=[S:17]1(=[O:34])[CH2:22][CH2:21][N:20]2[CH:23]=[CH:24][CH:25]=[C:26]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[C:19]2=[N:18]1>CS(C)=O.O>[O:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[CH2:10][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]2[C:19]3=[N:18][S:17](=[O:34])(=[O:16])[CH2:22][CH2:21][N:20]3[CH:23]=[CH:24][CH:25]=2)=[CH:32][CH:31]=1
Reactant: BrCC1CCCO1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OCC4CCCO4)cc3)C2=N1
Temperature: 130 °C
Reaction time: 5 h
Yield: 84.8 %

Procedure:
A mixture of potassium carbonate (450 mg), sodium iodide (488 mg), 2-(bromomethyl)tetrahydrofuran (538 mg) and 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (300 mg) in DMSO (10 mL) was stirred at 130° C. for 5 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with IPE to give the title compound (332 mg) as a pale yellow solid. The solid was crystallized from CH3CN-IPE to give a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1>[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)[CH2:14][CH2:15]2)[OH:9])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(OCCCCl)cc1
Agent: [I-]
Agent: [K+]
Product: O=[N+]([O-])c1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 72.5 %

Procedure:
Following the procedure of Example 1 and using potassium iodide catalyst, a mixture of 9.1 g (0.03 mole) of [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and 6.7 g (0.03 mole) of 1-(3-chloropropoxy)-4-nitrobenzene were reacted to give 10.5 g of the title compound which was recrystallized from isopropyl ether, m.p. 93.5°-94.5° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4]1>C(O)C>[OH:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CO)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CO)C1
Reaction time: 16 h
Yield: 74.3 %

Procedure:
To a stirred solution of tert-butyl (1S,4R)-4-(hydroxymethyl)cyclopent-2-enylcarbamate (step 1, about 10.0 g) in ethanol (150 ml) 10% palladium on carbon (about 1.0 g) was added and kept under hydrogen atmosphere. Reaction mass was stirred for about 16 hours. Completion of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through high-flow bed and washed with ethanol. The filtrate was concentrated under reduced pressure to furnish the title compound (7.5 g) as a light yellow liquid. ES Mass: 215 [M+1] 216 (100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1.[I-].[K+].[CH2:27]([CH:29]=[CH:30][CH2:31][NH2:32])[CH3:28]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:32][CH2:31][CH2:30][CH2:29][CH:27]=[CH2:28])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1
Reactant: Fc1ccc2c(c1)C(c1ccccc1F)=NCc1nnc(CCl)n1-2
Reactant: CCC=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCCNCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1F)=NC2

Procedure:
In the manner given in Preparation 39, 8-fluoro-1-(chloromethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide and ethylallylamine in tetrahydrofuran are reacted to give 8-fluoro-1-[(allylethylamino)methyl]-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 47 9-(Trifluoromethyl)-1-[(allylmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[C:18](=[O:21])([O-])[O-].[K+].[K+].O>N1C=CC=CC=1.[Cu](I)I>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([O:21][C:18]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)s1
Reactant: O=C([O-])[O-]
Agent: I[Cu]I
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Oc2ccccc2)s1
Temperature: 125 °C
Reaction time: 65 h
Yield: 34.7 %

Procedure:
To a solution of (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) (463 mg) in pyridine (10 mL) phenol (158 mg), copper iodide (32 mg) and potassium carbonate (97 mg) were added. The mixture was stirred at 125° C. for 65 h under nitrogen. Water was added and the aqueous layer was extracted with chloroform. Following evaporation, the residue was purified by flash chromatography using 5–20% 3.5M methanolic ammonia/chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The free base was prepared by basification of the product-containing fractions and extraction into chloroform followed by evaporation to gave the title compound (80 mg); MS (ES+) 329 (MH+).