Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[F:11][C:12]([F:41])([F:40])[CH2:13][NH:14][C:15]([C:17]1([CH2:30][CH2:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16]>ClCCl.C(O)C>[F:40][C:12]([F:11])([F:41])[CH2:13][NH:14][C:15]([C:17]1([CH2:30][CH2:31][CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][N:37]([C:2]3[NH:6][C:5]4[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=4[N:3]=3)[CH2:38][CH2:39]2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:16]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: O=C(NCC(F)(F)F)C1(CCCCN2CCNCC2)c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCO
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccccc4[nH]3)CC2)c2ccccc2-c2ccccc21
Temperature: 150 °C

Procedure:
A mixture of 0.05 g (0.328 mmol) of 2-chloro-1H-benzimidazole and 0.21 g (0.487 mmol) of 9-(4-piperazin-1-yl-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide is heated to 150° C. for two hours. After cooling, the reaction mixture is dissolved in dichloromethane/ethanol. The product is purified by column chromatography on silica gel (eluant: dichloromethane/ethanol=20:1).
Reaction SMILES: Cl[C:2]1[C:3]2[O:18][CH2:17][CH2:16][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[F:15])[N:7]=1.[IH:19].[Na+].[I-]>O>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([C:6]2[N:7]=[C:2]([I:19])[C:3]3[O:18][CH2:17][CH2:16][C:4]=3[N:5]=2)[CH:13]=1
Reactant: I
Reactant: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)CCO2
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc(Cl)cc1-c1nc(I)c2c(n1)CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidine (80 mg, 0.28 mmol, 1 eq) in a 57% HI solution in water (2 ml) at rt. was added NaI (206 mg, 1.41 mmol, 5 eq). The reaction mixture was stirred at rt overnight and then poured onto ice. The product was extracted with chloroform and the aqueous layer was neutralized with NaHCO3 and extracted further with more chloroform. The organic layers were combined washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude residue 2-(5-chloro-2-fluorophenyl)-4-iodo-6,7-dihydrofuro[3,2-d]pyrimidine that was not further purified.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[C:6]([CH:8]=1)[NH2:7].[CH3:15][S:16](Cl)(=[O:18])=[O:17].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[C:6]([NH:7][S:16]([CH3:15])(=[O:18])=[O:17])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)CCOc1ccc(Br)cc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)CCOc1ccc(Br)cc1NS(C)(=O)=O
Yield: 84.2 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 17, 5-bromo-2-(2-(dimethylamino)ethoxy)aniline (1.8 g, 6.94 mmol) was mesylated with methanesulfonyl chloride (875 mg, 7.63 mol), pyridine (822 mg, 10.4 mmol), DCM (20 mL) to afford 1.97 g (83.12% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 7.71-7.0 (d, 1H), 7.2-7.16 (dd, 1H), 6.92-6.89 (d, 1H), 4.07-4.04 (t, 2H), 2.92 (s, 3H), 2.56-2.53 (t, 2H), 2.35 (s, 6H).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[OH:8][C:9]1[C:26]([OH:27])=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([OH:29])=[C:21]([OH:28])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([OH:31])=[C:15]([OH:30])[CH:16]=3)[C:11]=2[CH:10]=1.C1(C)C=CC(S(O[CH2:42][CH2:43][CH2:44][CH:45]([CH3:48])[CH2:46][CH3:47])(=O)=O)=CC=1>O>[CH3:48][CH:45]([CH2:46][CH3:47])[CH2:44][CH2:43][CH2:42][O:8][C:9]1[C:26]([O:27][CH2:42][CH2:43][CH2:44][CH:45]([CH3:48])[CH2:46][CH3:47])=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([O:29][CH2:15][CH2:16][CH2:17][CH:18]([CH3:23])[CH2:19][CH3:20])=[C:21]([O:28][CH2:42][CH2:43][CH2:44][CH:45]([CH3:48])[CH2:46][CH3:47])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([O:31][CH2:42][CH2:43][CH2:44][CH:45]([CH3:48])[CH2:46][CH3:47])=[C:15]([O:30][CH2:26][CH2:9][CH2:10][CH:11]([CH3:12])[CH2:24][CH3:25])[CH:16]=3)[C:11]=2[CH:10]=1
Reactant: CCC(C)CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1cc2c3cc(O)c(O)cc3c3cc(O)c(O)cc3c2cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)CCCOc1cc2c3cc(OCCCC(C)CC)c(OCCCC(C)CC)cc3c3cc(OCCCC(C)CC)c(OCCCC(C)CC)cc3c2cc1OCCCC(C)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
At room temperature, 3 ml of N,N-dimethylformamide (DMF) was placed in a flask, and 0.27 g of NaH (60% in oil) was added thereto. Then, 0.3 g (0.925 mmol) of 2,3,6,7,10,11-hexahydroxytriphenylene was added thereto, and after 1 hour of stirring, a mixture liquid of 1.96 g (6.84 mmol) of 4-methylhexyl p-toluenesulfonate and 2 ml of DMF was added dropwise thereto, followed by 5 hours of stirring at 70° C. After the reaction, the system was cooled to room temperature, and water was added thereto to precipitate a crystal, which was recovered by filtration. The crystal was then purified by silica gel chromatography (with toluene) and re-cystallized from acetone/methanol to obtain 0.24 g of 2,3,6,7,10,11-hexa(4-methylhexyloxy)triphenylene.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)[CH:2]([CH3:4])[CH3:3].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:73]1[N:78]=[C:77]([CH:79]2[CH2:81][CH2:80]2)[CH:76]=[CH:75][N:74]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:79]1([C:77]2[CH:76]=[CH:75][N:74]=[C:73]([C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:7]5[O:6][C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[N:9][N:8]=5)[CH:11]=4)[N:15]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[CH:14]=3)[N:78]=2)[CH2:81][CH2:80]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(CC(C)C)o4)ccc32)cc1
Reactant: Brc1nccc(C2CC2)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(C4CC4)n3)c3cc(-c4nnc(CC(C)C)o4)ccc32)cc1
Temperature: 130 °C
Yield: 39.7 %

Procedure:
To a 20 mL microwave vial was added 2-isobutyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazole (233 mg, 0.530 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (15.2 mg, 0.032 mmol), Pd2(dba)3 (14.6 mg, 0.016 mmol), 2-bromo-4-cyclopropylpyrimidine (CombiPhos Catalysts Inc., 121 mg, 0.610 mmol) and potassium phosphate (338 mg, 1.59 mmol) followed by purging with argon. The solids were treated with dioxane (4.0 mL) and water (0.4 mL) and heated in the microwave at 130° C. for 20 min. The mixture was treated with H2O and extracted with EtOAc, dried over MgSO4, filtered and concentrated. Purification (eluting with 10-60% EtOAc in Hex) afforded 2-(3-(4-cyclopropylpyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-5-isobutyl-1,3,4-oxadiazole (108 mg, 40%) as a light yellow viscous oil. MS (ESI, pos. ion) m/z: 514.1 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 9.27 (1H, s), 8.50-8.58 (2H, m), 8.09-8.13 (2H, m), 7.86 (2H, d, J=8.4 Hz), 7.24 (2H, s), 7.07 (1H, d, J=5.1 Hz), 2.84 (2H, d, J=7.2 Hz), 2.35 (3H, s), 2.29 (1H, s), 1.91 (1H, br. s.), 1.34-1.40 (2H, m), 1.17 (2H, dd, J=7.8, 2.9 Hz), 1.07 (6H, d, J=6.7 Hz).
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:19](Br)/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22]>>[CH2:19]([S:1][C:2]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22]
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Reactant: CC(C)=CCC/C(C)=C/CBr
Product: CC(C)=CCC/C(C)=C/CSc1nc2ccccc2c(=O)n1-c1ccccc1
Yield: 57.6 %

Procedure:
The title compound was prepared in a yield of 57.6%, using 2-mercapto-3-phenyl-4(3H)-quinazolinone in place of 3-isobutyl-2-mercapto-4(3H)-quinazolinone and geranyl bromide in place of 2-chloromethylpyridine hydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH3:26])=[O:24])=[N:11][N:12]2[CH:17]([C:18](O)=[O:19])[CH2:16][N:15]([CH3:21])[C:14](=[O:22])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH3:26])=[O:24])=[N:11][N:12]2[CH:17]([C:18]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:19])[CH2:16][N:15]([CH3:21])[C:14](=[O:22])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)O
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)N1CCCCC1
Reaction time: 18 h

Procedure:
The title compound was prepared from 3-benzyloxy-2-methoxycarbonyl-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-7-carboxylic acid using a procedure similar to that described in Example 2, Step 5 except that piperidine was used in place of 4-fluorobenzylamine, and the reaction time totaled 18 hours. 1H NMR (400 MHz, d6-DMSO) δ 7.50-7.48 (m, 2H), 7.40-7.31 (m, 3H), 5.88 (d, J=2.4 Hz, 1H), 5.19 (dd, J=11.2, 25.6 Hz, 2H), 4.14 (dd, J=5.2, 13.6 Hz, 1H), 3.78 (s, 3H), 3.68-3.52 (m, 4H), 3.34-3.33 (m, 1H), 2.98 (s, 3H), 1.62 (br s, 4H), 1.47 (br s, 2H); ES MS (M+H)=427.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH:16]=O)=[CH:14][C:13]2[C:8](=[C:9]([O:20][CH3:21])[CH:10]=[CH:11][C:12]=2[O:18][CH3:19])[O:7]1)=[O:5])C.[CH3:22][O:23][C:24](=[O:34])[C@@H:25]([NH2:33])[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:3][C:4]([CH:6]1[C:15]([CH2:16][NH:33][C@H:25]([C:24]([O:23][CH3:22])=[O:34])[CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:14][C:13]2[C:8](=[C:9]([O:20][CH3:21])[CH:10]=[CH:11][C:12]=2[O:18][CH3:19])[O:7]1)=[O:5]
Reactant: CCOC(=O)C1Oc2c(OC)ccc(OC)c2C=C1C=O
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: COC(=O)C1Oc2c(OC)ccc(OC)c2C=C1CN[C@@H](CC1CCCCC1)C(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 41.4 %

Procedure:
To a solution of 3-formyl-5,8-dimethoxy-2H-chromene-2-carboxylic acid ethyl ester (2.0 g, 6.48 mmol) in methanol (40 mL) containing molecular sieves (0.7 g) was added commercially available (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.51 g, 6.84 mmol) and N,N′-diisopropylethylamine (1.76 mL, 13.68 mmol). The mixture was stirred at 25° C. for 10 hours. At this time, sodium cyanoborohydride (0.86 g, 13.68 mmol) and acetic acid (0.78 mL, 13.68 mmol) were added simultaneously to the reaction mixture, and the reaction mixture was stirred for additional 16 hours at 25° C. The reaction mixture was then filtered through celite and washed with methanol. The filtrate was concentrated in vacuo. Flash column chromatography (eluant-ethyl acetate:petroleum ether 1:19, Rf=0.6) over neutral alumina afforded 3-[((S)-2-cyclohexyl-1-methoxycarbonyl-ethylamino)-methyl]-5,8-dimethoxy-2H-chromene-2-carboxylic acid methyl ester (1.2 g, 37.5%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:11])=[C:7]([NH:9][CH3:10])[CH:8]=1.CO[C:14]([CH2:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:20][CH:19]=1)=O.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[C:14]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:30][CH:31]=3)[N:9]([CH3:10])[C:7]=2[CH:8]=1
Reactant: COC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CNc1cc(OC)ccc1N
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n(C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
A mixture of 21.8 g of 5-methoxy-N-methyl-1,2-phenylenediamine (prepared as described in Preparation 9), 63.4 g of 5-(4-methoxycarbonylmethoxybenzyl)thiazolidin-2,4-dione (prepared as described in Preparation 21), 250 ml of 1,4-dioxane and 750 ml of concentrated aqueous hydrochloric acid was heated under reflux for 60 hours. At the end of this time, the reaction mixture was cooled with ice, after which the solid matter was collected by filtration. 800 ml of a 5% w/v aqueous solution of sodum hydrogencarbonate was added to this matter, and the resulting mixture was stirred at room temperature for 2 hours. Insoluble materials were then collected by filtration and dissolved in a mixture of 1000 ml of dimethylformamide and 200 ml of methanol. The resulting solution was decolorized by treatment with activated charcoal, which was then removed by filtration. The filtrate was then concentrated by evaporation under reduced pressure to a volume of about 50 ml. The resulting concentrate was added to 750 ml of diethyl ether and the solution thus obtained was allowed to stand for 2 days. At the end of this time, the resulting precipitate was collected by filtration, to give 20.1 g of the title compound, melting at 267°-27120 C. and having an Rf value=0.68 (on thin layer chromatography on silica gel; using a developing solvent of methylene chloride containing 5% v/v ethanol).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[N:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[N:9]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3ccncc3)c3ccccc32)C(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)C(=O)N(c3ccncc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To 487 mg (0.83 mmol) of 2-[3-(1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-pyridin-4-yl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 76, is added 8 mL of a 4N solution of HCl in dioxane. The reaction is stirred overnight at RT. The reaction is concentrated, then purified by silica gel flash column chromatography (gradient 3:1-4:1 ethyl acetate:hexanes) to afford 245 mg of the title compound as an oil. This oil is triturated with hexane/ethyl acetate to afford a white powder: 1H NMR (CDCl3, 400 MHz) δ8.56 (s, br, 2H), 7.82 (d, 1H, J=8.0), 7.39-7.29 (m, 6H) 7.17-7.10 (m, 3H) 6.93 (dd, 2H, J=2.1,8.5) 4.93 (m, 1H), 4.39 (d, br, 1H, J=16.1) 4.25-4.19 (m, 2H) 3.82 (s, 3H) 3.77 (m, 1H) 3.58 (dd, 1H, J=5.8, 16.2) 1.02 (dd, 6H, J=3.9, 6.6); low resolution MS (FAB)m/e 589 (MH+).
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([F:24])[CH:13]=1)([O:3][CH2:4][C:5]1C=CC=CC=1)=[O:2].CC(C)([O-])C.[Li+].ClC[C@@H](O)[CH2:34][N:35]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Cl-].[NH4+]>C(OCC)(=O)C.C(#N)C>[CH2:43]([N:35]([CH2:34][C@@H:4]1[O:3][C:1](=[O:2])[N:11]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:14]([F:24])[CH:13]=2)[CH2:5]1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Nc1ccc(N2CCOCC2)c(F)c1)OCc1ccccc1
Reactant: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Temperature: -30 °C
Yield: 59.9 %

Procedure:
N-carbobenzoxy-3-fluoro-4-morpholinylaniline (0.33 g, 1 mmol) was added to 8 mL acetonitrile. The solution was cooled to −30° C. under the protection of nitrogen flow and then 50 mmol lithium tert-butoxide was added. The mixture reacted at −30° C.˜−20° C. for 2 hours. (S)-1-chloro-3-(dibenzylamino)propan-2-ol (1.45 g, 5 mmol) was added and then the solution was heated slowly to 60° C. and the reaction was maintained for 2 hours. After the solution was cooled down, saturated ammonium chloride solution and ethyl acetate were added to separate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to provide 285 mg of white solid in 60% yield. HPLC: 99.2%.
Reaction SMILES: [NH2-].[Na+].[Cl:3][C:4]1[C:9]2[C:10](=[O:23])[N:11]3[CH2:22][CH2:21][CH2:20][C@H:12]3[C:13]3[N:14]([CH:15]=[N:16][C:17]=3[CH:18]=O)[C:8]=2[CH:7]=[CH:6][CH:5]=1.N.O1CCC[CH2:26]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:3][C:4]1[C:9]2[C:10](=[O:23])[N:11]3[CH2:22][CH2:21][CH2:20][C@H:12]3[C:13]3[N:14]([CH:15]=[N:16][C:17]=3[CH:18]=[CH2:26])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N
Agent: [Br-]
Product: C=Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20.8 g of an equimolar mixture of methyltriphenylphosphonium bromide and sodium amide were stirred for 20 minutes in 80 ml of tetrahydrofuran. 15.08 g (50 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxaldehyde was then added portionwise thereto, whereby the temperature rose to 43° with the evolution of ammonia. The mixture was stirred at room temperature for 1 hour, filtered and the filtrate was evaporated. After chromatography of the residue on silica gel while eluting with cyclohexane/ether/isopropanol (3:3:1) and recrystallization from ethyl acetate there was obtained (S)-8-chloro-11,12,13,13a-tetrahydro-1-vinyl-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 213°-215°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH3:11])=[CH:5][CH:4]=1.Cl>O1CCCC1>[CH3:6][CH2:9]/[C:10](/[C:11]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[C:9](\[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)/[CH2:11][CH3:10]
Reactant: CCC(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC/C(=C(/CC)c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
Zinc dust (654 mg, 10.0 mmol) was slurried in 20 ml dry tetrahydrofuran under an inert atmosphere, and a solution of titanium tetrachloride (0.55 ml, 5.0 mmol) in 3 ml dry benzene was added. The resulting mixture was refluxed overnight to form active Ti(II) reagent, and a solution of para-methoxypropiophenone (500 mg, 3.0 mmol) in 5 ml dry tetrahydrofuran was added. After refluxing for twelve hours, the solution was cooled to room temperature, poured into 50 ml 2 N aqueous hydrochloric acid, and extracted with ether. The ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated by solvent removal at the rotary evaporator. The residue was purified by chromatography on silica gel to give 410 mg (91%) dimestrol identified by ir, nmr, and mass spectra; mp 124°.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=1[C:16](Cl)=[O:17].[N:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][N:20]=1.C(N(CC)CC)C>C(Cl)Cl.C(OC(=O)C)C>[N:19]1[CH:24]=[CH:23][C:22]([NH:25][C:16]([C:3]2[CH:4]=[N:5][N:6]([CH:7]([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9])[C:2]=2[CH3:1])=[O:17])=[CH:21][N:20]=1
Reactant: Nc1ccnnc1
Reactant: Cc1c(C(=O)Cl)cnn1C(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccnnc2)cnn1C(C(F)(F)F)C(F)(F)F
Temperature: 22.5 °C
Reaction time: 68 h
Yield: 33.5 %

Procedure:
A solution of 398 mg 5-methyl-1-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]pyrazole-4-carbonyl chloride in 10 ml CH2Cl2 was added dropwise to a solution of 185 mg pyridazin-4-amine and 750 mg triethylamine in 30 ml CH2Cl2 at 0° C. The mixture was stirred at 20-25° C. for about 68 h, diluted with 25 ml ethylacetate, washed with 3×15 ml sat. aq. NH4Cl solution, dried over MgSO4 and evaporated. Purification by flash chromatography (CH2Cl2/MeOH) gave 160 mg of the title compound (90% purity). HPLC-MS (Method 1): RT 2.278 min, m/z [MH]+ 354.1.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](O)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2].C(Cl)(C(Cl)=O)=O.[NH2:43][C@@H:44]1[CH2:47][C@H:46]([C:48]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:49])[C:45]1([CH3:57])[CH3:56]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:31])[NH:43][C@@H:44]4[CH2:47][C@H:46]([C:48]([N:50]5[CH2:55][CH2:54][O:53][CH2:52][CH2:51]5)=[O:49])[C:45]4([CH3:57])[CH3:56])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: CC1(C)[C@H](N)C[C@@H]1C(=O)N1CCOCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.270 g, 0.542 mmol) in DCM (1 ml) 2M solution of (COCl)2 in DCM (2.71 ml, 5.42 mmol) was added at about 0° C. and the reaction mixture was stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a solution of ((1S,3R)-3-amino-2,2-dimethylcyclobutyl)(morpholino)methanone (Intermediate 14, 0.172 g, 0.0813 mmol) in DCM at 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, 1N HCl, water, brine and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.310 g: Yield: 82%; 1H NMR (300 MHz, CDCl3): δ 5.83 (d, 1H, J=7.8 Hz), 4.72 (s, 1H), 4.58 (s, 1H), 4.51-4.40 (m, 1H), 4.19-4.08 (m, 1H), 3.81-3.40 (m, 8H), 3.18-3.05 (m, 1H), 2.90-2.82 (m, 1H), 2.54-2.21 (m, 3H), 2.04 (s, 3H), 1.99-1.83 (m, 2H), 1.80-1.12 (m, 27H), 1.08-1.70 (s, 18H); Mass: [M+1]+ 693 (15%), [M+Na]+ 715 (28%); JR (KBr, cm−1): 3388, 2954, 2867, 1716, 1659, 1633, 1524, 1449, 1366, 1271, 1235, 1119, 1038, 980, 892; M.R: 71.6° C.-78.9° C.
Reaction SMILES: S(Cl)(Cl)=O.[ClH:5].[N:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]O)=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[Cl:5][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][N:6]=[CH:7][CH:8]=1
Reactant: Cl
Reactant: OCCCCCCc1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: ClCCCCCCc1ccncc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (1.03 ml) is added to 4-pyridinehexanol hydrochloride (2.42 g) and the mixture is stirred at 20° C. for 30 minutes. Excess saturated aqueous NaHCOs and CHCl3 (20 ml) is added. The organic phase is washed with saturated NaHCO3, brine and water, dried (MgSO4) and the solvent evaporated to give crude material which is purified by flash chromatography on silica gel (CH3OH:CHCl3 =1:49 by vol.) to give 4-(6-chlorohexyl)-pyridine as an oil.