Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:18]2[CH:17]=[C:16]3[C:8]([C:9]4[CH:10]=[C:11]5[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19]([CH3:26])([CH3:25])[C:12]5=[CH:13][C:14]=4[CH2:15]3)=[CH:7][C:6]=2[C:5]([CH3:28])([CH3:27])[CH2:4][CH2:3]1.[Li]CCCC.[CH3:35][C:36]([CH3:42])=[C:37]1[CH:41]=[CH:40][CH:39]=[CH:38]1>C1COCC1>[CH:37]1([C:36]([CH:20]2[CH2:21][C:22]([CH3:24])([CH3:23])[C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][C:12]=3[C:19]2([CH3:26])[CH3:25])[CH2:15][C:16]2[CH:17]=[C:18]3[C:2]([CH3:29])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:28])([CH3:27])[C:6]3=[CH:7][C:8]4=2)([CH3:42])[CH3:35])[CH:41]=[CH:40][CH:39]=[CH:38]1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CCC2(C)C
Reactant: CC(C)=C1C=CC=C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(C)(C)C1C=CC=C1)C2(C)C
Temperature: 0 °C
Yield: 68.1 %

Procedure:
In a 200 ml three-necked flask purged with nitrogen, 3.11 g (8.04 mmol, 1 eq) of 1,1,4,4,7,7,10,10-octamethyl-1,2,3,4,7,8,9,10-octahydrodibenzo(b,h)-fluorene was placed at room temperature. Then, 40 ml of dehydrated THF was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled to 2° C. with an ice bath (light yellow solution) To the solution, 5.2 ml (8.48 mmol, 1.05 eq) of n-BuLi (hexane solution) was dropwise added over a period of 10 minutes, and 10 ml of dehydrated THF was further added. The ice bath was removed, and the mixture was stirred at room temperature for 22 hours (dark red slurry). After the slurry was cooled to 0° C. with an ice bath, a solution of 1.05 ml (8.54 mmol, 1.06 eq) of 6,6-dimethylfulvene in 10 ml of dehydrated THF was dropwise added over a period of 15 minutes (dark red solution). The ice bath was removed, and the solution was stirred at room temperature for 23 hours. The resulting dark red brown solution was poured into 100 ml of a diluted hydrochloride acid solution to perform quenching. After the organic phase was washed with 100 ml of a saturated saline solution, the soluble component was extracted from the aqueous layer with 50 ml of diethyl ether. The soluble component and the dispensed organic phase were together dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain a yellowish orange solid. The solid was purified by silica gel column chromatography (developing solvent: hexane) to obtain a white powder (2.70 g, yield: 68%).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11]([N:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH3:12]>C1COCC1>[CH2:11]([N:13]([CH2:17][CH3:18])[C:14](=[O:15])[O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([I:3])[CH:5]=1)[CH3:12]
Reactant: CCN(CC)C(=O)Cl
Reactant: Oc1cccc(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Oc1cccc(I)c1
Reaction time: 2 h

Procedure:
To a stirred suspension of NaH (1.09 g, 45.47 mmol), in THF (23 mL), a solution of 3-iodophenol (5.00 g, 22.73 mmol), in THF (5.70 mL) was drop wise added at room temperature. After stirring the reaction mixture for 2 h. N,N-diethylcarbamoyl chloride (6.17 g, 45.47 mmol) in THF (8 mL) was added. Stirring was continued for another 8 h. Usual aqueous work up gave the crude carbamate which was purified by column chromatography (eluent: hexane/EtOAc) on silica gel to afford compound b.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([CH2:14][C:15](=O)[CH3:16])[C:11]([CH3:13])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[N:4]1[C:15]([CH3:16])=[CH:14][CH:10]=[C:11]1[CH3:13]
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc(I)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(I)cc1F
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A solution of 2-fluoro-4-iodoaniline (25.3 g, 107 mmol), acetonylacetone (14.9 g, 131 mmol) and para-toluenesulfonic acid (203 mg, 1 mmol) in dry toluene was heated under reflux for 1 h with a Dean-Stark tap. After cooling to room temperature the mixture was poured into sodium hydrogen carbonate (saturated). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and then boiled with charcoal. Filtering to remove the charcoal followed by evaporation afforded the title compound (33.2 g, 98%) as a light brown solid. MS: m/e=315.1 (M++H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28](O)=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:35]([O:37][C:38](=[O:48])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH2:40])[CH3:36].C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([NH:40][C@@H:39]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:38]([O:37][CH2:35][CH3:36])=[O:48])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a mixture of 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid (150 mg, 0.345 mmol), L-phenylalanine ethyl ester hydrochloride (103 mg, 0.448 mmol) and diisopropylethylamine (0.078 ml , 0.448 mmol) in DMF (5 ml) was added 1-hydroxybenzotrioxazole (70 mg, 0.518 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (132 mg, 0.690 mmol). After stirring the mixture at room temperature for 4 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with 1N hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water, and brine. The resultant mixture was dried over magnesium sulfate, and evaporated in vacuo. The resultant residue was purified by silica gel column chromatography (hexane:EtOAc, 3:1 elution) to give ethyl (2S)-2-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl)methyl}benzoylamino}-3-phenylpropionate (197.1 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[C:29]([CH3:36])[CH:28]=1.CCN(CC)CC>ClCCCl>[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:35])=[C:29]([CH3:36])[CH:28]=1
Reactant: COC(=O)c1ccc(N=C=O)c(C)c1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(C)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 11.1) was reacted with 3-methyl-4-isocyanato-benzoic acid methyl ester (example 14.1) in 1,2-dichloroethane in the presence of Et3N (1.4 eq.) for 2 days under reflux conditions to give the title compound as brown solid. MS: m/e=517.1 [M+H+].
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[N+:13]([O-])=O)[N:6]([CH2:16][C:17]3[C:18](=[O:24])[N:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[N:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+]>C(O)C.O.C(OCC)(=O)C.[Fe]>[NH2:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[C:4]([CH:1]1[CH2:3][CH2:2]1)=[N:5][N:6]2[CH2:16][C:17]1[C:18](=[O:24])[N:19]([CH3:23])[CH:20]=[CH:21][CH:22]=1
Reactant: Cn1cccc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cccc(Cn2nc(C3CC3)c3c(N)cccc32)c1=O
Temperature: 75 °C

Procedure:
3-((3-Cyclopropyl-4-nitro-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one (413 mg, 1.27 mmol) was dissolved in a mixture of ethanol (6.8 mL) and water (1.7 mL). Ammonium chloride (34 mg; 0.63 mmol) and iron powder (709 mg; 12.7 mmol) were added and the mixture was stirred with heating to 75° C. under a nitrogen atmosphere for 16 hours. The mixture was allowed to cool, diluted with ethyl acetate (50 mL) and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give the crude product as a colored oil. Purification using a silica gel preparative thin layer chromatography plate (20×20 cm, 2 mm) developed in a chamber with 40% ethyl acetate/dichloromethane, drying, and eluting with 80% ethyl acetate/dichloromethane gave 3-((4-amino-3-cyclopropyl-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one as a viscous oil which began to crystallize upon drying under high vacuum (175 mg).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2-].[Li+].N.[O:14]1CCC[CH2:16][CH:15]1[O:20]C1CCCCO1.[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]O>O1CCCC1>[C:15]([O:20][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][C:32]#[C:31][CH2:30][CH2:29][CH2:28][CH3:27])(=[O:14])[CH3:16]
Reactant: C1CCC(OC2CCCCO2)OC1
Reactant: C#CCCC#CCCCC
Reactant: OCCCCCCBr
Agent: N
Agent: [Li+]
Agent: [NH2-]
Solvent: C1CCOC1
Product: CCCCC#CCCC#CCCCCCCOC(C)=O
Reaction time: 3 h

Procedure:
Two hundred and thirty grams of 1,5-decadiyne (1.7 mols) in 1200 ml of tetrahydrofuran is added to a suspension of 39 g (1.6 mols) of lithium amide in approximately 5 liters of liquid ammonia. After 3 hours, 224 g (0.85 mol) of the tetrahydropyranyl ether of hexamethylene bromohydrin was added to the deep red solution, and the mixture was then stirred overnight. Most of the ammonia was allowed to evaporate and water is then cautiously added to the residue. The bottom aqueous layer is extracted once with ether and combined with the upper organic layer, which is then washed once with water, followed by saturated salt solution. Ether and THF are removed on a roto vap and the residue is refluxed for 4 hours with a mixture of 500 ml glacial acetic acid and 100 ml of acetyl chloride. Then about 400 ml of acetic acid and other low boiling products are distilled off and residue is poured into ice water. The lower aqueous layer is extracted with ether, combined with the upper layer, washed, etc., and distilled, yielding 145 g (0.52 mols) 7,11-hexadecadiynyl acetate by 130°-132°/torr, nD21 1.4706 (61% based on starting THP derivative of hexamethylene bromohydrin).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:37]=[C:36]4[C:13]([CH:14]=[CH:15][C:16]5[N:20]=[C:19]([C@@H:21]6[CH2:25][C@H:24]([O:26][CH2:27][CH3:28])[CH2:23][N:22]6C(OC(C)(C)C)=O)[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1.Cl.[CH3:39][O:40][C:41]([NH:43][C@@H:44]([CH:48]([CH3:50])[CH3:49])[C:45](O)=[O:46])=[O:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:37]=[C:36]4[C:13]([CH:14]=[CH:15][C:16]5[N:20]=[C:19]([C@@H:21]6[CH2:25][C@H:24]([O:26][CH2:27][CH3:28])[CH2:23][N:22]6[C:45](=[O:46])[C@@H:44]([NH:43][C:41](=[O:42])[O:40][CH3:39])[CH:48]([CH3:50])[CH3:49])[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(Cl)ccc2-5)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(Cl)ccc2-5)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of tert-butyl (2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate (0.46 g, 0.9 mmol) in a mixture of CH2Cl2 (9.0 mL) and MeOH (1.5 mL) was added HCl (in dioxanes, 4M, 6.5 mL, 26.0 mmol). The resulting solution was stirred at room temperature for 2 h. The solution was concentrated to dryness under reduced pressure. To the crude intermediate in CH2Cl2 (10.0 mL) was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.17 g, 0.9 mmol), HATU (0.41 g, 1.1 mmol), and DIPEA (0.5 mL, 2.9 mmol). The resulting solution was stirred at room temperature for 48 h and diluted with CH2Cl2. The solution was washed with aqueous HCl (IN) and brine. The aqueous layers were backextracted with CH2Cl2 (2×). The resulting organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100% EtOAc(w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford methyl {(2S)-1-[(2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (0.46 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]([C:12]2[C:17]([O:18][C:19]([C:21]3[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N([CH2:33][CH3:34])CC)C.[OH2:35]>C(Cl)Cl>[CH3:34][C:33]([O:27][C:26]1[C:21]([C:19]([O:18][C:17]2[C:12]([C:10]([O:9][C:8]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:11])=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20])=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:35]
Reactant: O
Reactant: COc1ccccc1OC(=O)c1ccccc1OC(=O)c1ccccc1O
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1OC(=O)c1ccccc1OC(=O)c1ccccc1OC(C)=O
Yield: 95 %

Procedure:
224 g of guaiacol salsalate (1.0 mole) and 102 g of triethylamine are dissolved in 1 liter of methylene chloride. A solution of 197 g of freshly distilled O-acetoxybenzoylchloride (1.0 mole) in 0.5 liters of methylene chloride are added to the solution, which is under agitation at a temperature of 0°-2° C., the addition being made slowly such that the mixture temperature does not exceed 5° C. After about 4 hours at this temperature, 0.5 liters of water are added, agitation is applied energetically, and the phases are allowed to stratify. The lower organic phase is separated and concentrated under reduced pressure, the residue being taken up in 0.6 liters of ethanol. The white crystalline solid which separates is filtered off, washed with cold ethanol, and then crystallised from isobuty-methyl-ketone to obtain 385 g of product with a yield of 95%. The product has a melting point of 131°-132° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].[CH:19](Br)([CH3:21])[CH3:20].O>CS(C)=O>[CH:19]([O:7][N:8]1[C:9](=[O:18])[C:10]2[C:11](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:13])([CH3:21])[CH3:20]
Reactant: CC(C)Br
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)ON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.5 %

Procedure:
Solid potassium carbonate (8.64 g, 62.5 mmol) was added to a solution of N-hydroxyphthalimide (4.08 g, 25.0 mmol) in dimethyl sulfoxide (37 mL), and the mixture was stirred at 25° C. for 5 min. To the mixture, isopropyl bromide (3.41 mL, 37.5 mmol) was added, and the mixture stirred at 80° C. for 3 h. After ice-cooling, the mixture was poured into cold water and the resulting precipitate was collected by filtration in vacuo, washed with water (25 mL) and hexanes (15 mL) and dried in vacuo to afford 2-isopropyloxy-isoindole-1,3-dione (4.44 g, 86.6%) as a white solid which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]2[C:8](=[O:11])[NH:9][N:10]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:3]=1.[Cl-].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.ClC1C=CC(C2N=C([N:52]3[CH2:55][C:54]([NH:59][CH2:60][CH3:61])(C(N)=O)[CH2:53]3)N3C(=O)N(CC)N=C3C=2C2C=CC(Cl)=CC=2)=CC=1>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:4]2[N:3]=[C:2]([N:59]3[CH2:54][CH2:55][N:52]([CH3:53])[CH2:61][CH2:60]3)[N:7]3[C:8](=[O:11])[N:9]([CH2:33][C:32]4[CH:35]=[CH:36][C:29]([C:28]([F:38])([F:37])[F:27])=[CH:30][CH:31]=4)[N:10]=[C:6]3[C:5]=2[C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(CC)c(=O)n23)C1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Agent: [Cl-]
Product: CN1CCN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(Cc4ccc(C(F)(F)F)cc4)c(=O)n23)CC1

Procedure:
The title compound was prepared in two steps from 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one by nucleophilic displacement of chloride with the requisite amine, followed by alkylation with 4-trifluoromethylbenzyl bromide, in a manner analogous to that in which 1-(7,8-bis(4-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide was prepared. HPLC/MS: retention time=3.90 min, [M+H]30 =613.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].CO.[H][H]>[C].[Pd].C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2ccccc2c(=O)n1Cc1ccc2c(c1)OCO2
Yield: 91.3 %

Procedure:
A mixture of 2-benzo[1,3]dioxol-5-ylmethyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), 10% palladium carbon (300 mg), methanol (6 ml) and THF (6 ml) was stirred at room temperature under 1 atm hydrogen pressure for 12 hrs. Palladium carbon was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized (ethyl acetate-hexane) to give the title compound (230 mg).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][S:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]O)[OH:19])[CH3:9].C(N(CC)CC)C.[Cl-].[Li+].CS([Cl:44])(=O)=O>CN(C)C=O.O>[Cl:44][CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][S:21][CH2:20][C:11]1([OH:19])[CH2:12][CH2:13][CH:14]([OH:18])[CH:15]([O:16][CH3:17])[CH:10]1[C:2]1([CH3:9])[O:1][CH:3]1[CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: COC1C(O)CCC(O)(CSCc2ccccc2CO)C1C1(C)OC1CC=C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC1C(O)CCC(O)(CSCc2ccccc2CCl)C1C1(C)OC1CC=C(C)C
Yield: 67 %

Procedure:
In dimethylformamide (0.5 ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxy-1,4cyclohexanediol (100 mg) and triethylamine (64 μl). To the solution was added, under ice-cooling, lithium chloride (21 mg). To the mixture was added dropwise methanesulfonyl chloride (20 μl), which was stirred for hours, then the reaction was suspended by the addition of water. The product was extracted with ether, and the extract solution was washed with a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent : ethyl acetate - hexane=1:2) to give 1-(2-chloromethylbenzyl)thiomethyl-2 -(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol (70 mg: yield 67%) as a colorless oily product.
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6](C(O)=O)[CH:5]=1.C([O:15][CH2:16][CH3:17])C>[Cl-].[NH4+]>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:16]([OH:15])([CH3:17])[CH3:1])[CH:5]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: [Li]C
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1.5 M solution of methyllithium in diethyl ether (6.0 ml) dissolved in diethyl ether (15 ml) was treated dropwise with a solution of 4-chloropyridine-2-carboxylic acid in diethyl ether (15 ml) under an argon atmosphere, and stirred at room temperature for 2 hours. The reaction mixture was diluted with a saturated solution of ammonium chloride and diethyl ether, and the organic phase was washed with brine, dried and concentrated. The resultant residue was purified by a column chromatography on a silica gel (ethyl acetate:methanol=20:1) to obtain the title compound (459 mg) as a tan oil.
Reaction SMILES: CO.CN1[C:8](=[O:9])CCC1.[H-].[Na+].Br[C:13]1[N:18]=[C:17]2[N:19]([C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])[C:20]([OH:22])=[N:21][C:16]2=[N:15][CH:14]=1>CCOC(C)=O>[CH3:8][O:9][C:13]1[N:18]=[C:17]2[N:19]([C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])[C:20]([OH:22])=[N:21][C:16]2=[N:15][CH:14]=1
Reactant: CN1CCCC1=O
Reactant: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cnc2nc(O)n([C@@H](C)c3ccccc3)c2n1
Temperature: 200 °C
Yield: 29 %

Procedure:
A thick-walled microwave bottle equipped with a stirbar was charged with MeOH (2.0 equiv) and NMP (20 volume equivalents). To the resulting solution was added NaH (2.0 equiv), resulting in gas evolution. (S)-6-Bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv) was then added to the reaction, and the resulting mixture was immediately fitted with a septum and cap and heated to 200° C. in a microwave for 30 min. The reaction was then diluted with EtOAc, washed twice with saturated aq. NaHCO3 and once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse-phase preparative HPLC provided the title compound (29%) as a white solid. LCMS m/z (APCI)=271.1 (M+H).
Reaction SMILES: C[Si](N[Si](C)(C)C)(C)C.[Li][CH2:11][CH2:12][CH2:13]C.[O:15]=[C:16]1[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:19]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:18][CH2:17]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].BrCC=C>C1COCC1.CCCCCC>[CH2:13]([C@H:17]1[C:16](=[O:15])[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:19]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:18]1)[CH:12]=[CH2:11]
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: [Li]CCCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CC[C@@H]1C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
To a solution of HMDS in anhydrous THF (200 mL) was added dropwise 2.5 M n-BuLi in hexane (130 mL) and the mixture was stirred at −78° C. for 1 hr. To a solution of (S)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate (80 g, 0.311 mol) in anhydrous THF (1600 mL) stirred at −78° C. was added lithium hexamethyldisilazide in THF. After the reaction mixture was stirred at −78° C. for 1 hr, 3-bromopropene (38.47 g, 0.318 mol) in THF (200 mL) was added and stirring was continued for 2 hr. The reaction mixture was quenched with saturated ammonium chloride solution (600 mL) at −78° C. and extracted with EtOAc (3×500 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The crude product was separated by column chromatography to afford (2S,4R)-1-tert-butyl 2-ethyl 4-allyl-5-oxopyrrolidine-1,2-dicarboxylate (15 g, 16%).