Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:30])[N:7]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21](=[O:29])[C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:35]=[N+:36]=[N-].[Na+].[OH-].[Na+]>O.C(O)(=O)C>[N:1]([C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:30])[N:7]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][CH:18]([C:21](=[O:29])[C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH2:19][CH2:20]3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1)=[N+:35]=[N-:36]
Reactant: Nc1ccc2c(=O)n(CCN3CCC(C(=O)c4ccc(F)cc4)CC3)c(=O)[nH]c2c1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1ccc2c(=O)n(CCN3CCC(C(=O)c4ccc(F)cc4)CC3)c(=O)[nH]c2c1
Reaction time: 0.33 h
Yield: 55 %

Procedure:
To a stirred and cooled (5° C.) solution of 0.205 parts of 7-amino-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione in 50 parts of an acetic acid solution 1N was added a solution of 0.1725 parts of sodium nitrite in 2 parts of water. The whole was stirred for 20 minutes at 5° C. A solution of 0.1625 parts of sodium azide in 2 parts of water was added and stirring was continued for 20 minutes at 5° C. in vacuo. 5.5 Parts of a sodium hydroxide solution 10N were added whereupon the product solidified. The product was filtered off and crystallized from acetonitrile. The product was filtered off and dried, yielding 0.120 parts (55%) of 7-azido-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)quinazolinedione; mp. 193.7° C. (28).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[C:26]([F:29])([F:28])[F:27].Cl.N1C=CC=CC=1.C(OCCO)C>>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[CH:21][C:20]=1[C:26]([F:27])([F:28])[F:29]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(Cl)c(C(F)(F)F)c3)c2cc1OC
Temperature: 139 °C
Yield: 65.2 %

Procedure:
A mixture of 0.248 g (1 mmol) of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.215 g of 4-chloro-3-trifluoromethylaniline, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 1.5 hours; progress of the reaction was monitored by TLC. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of 1M NaHCO3, approximately pH 8. The resulting precipitate was collected, washed with water and diethyl ether, and dried in vacuo at 65° C. to give 0.266 g (65.5%) of the desired product as cream crystals. MP 265-267° C.; mass spectrum (electrospray, m/e,): 408.2(M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:5]=1.[CH3:31][C@H:32]1[CH2:37][CH2:36][C@H:35](O)[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.C1COCC1>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C@H:35]4[CH2:36][CH2:37][C@@H:32]([CH3:31])[CH2:33][CH2:34]4)=[CH:20][CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:5]=1
Reactant: C[C@H]1CC[C@H](O)CC1
Reactant: COC(=O)c1cccc(CN(c2nccc(-c3ccc(O)cc3)n2)C2CCCC2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN(c2nccc(-c3ccc(O[C@H]4CC[C@@H](C)CC4)cc3)n2)C2CCCC2)c1
Temperature: 25 °C

Procedure:
To a THF (2 mL) solution of 3-({cyclopentyl-[4-(4-hydroxy-phenyl)-pyrimidin-2-yl]-amino}-methyl)-benzoic acid methyl ester (44 mg, 0.11 mmol) was added trans-4-methyl-cyclohexanol (12.5 mg, 0.11 mmol) and triphenylphosphine (27 mg, 0.11 mmol). After the mixture was cooled 5 min. in an ice bath, diisopropyl azodicarboxylate (DIAD, 21.5 μL, 0.11 mmol) was added. The solution was stirred at room temperature until complete. Water was added, and the mixture was extracted with ethyl acetate (3×2 mL). The ethyl acetate layer was dried over Na2SO4 and concentrated. Purification was carried out by silica gel chromatography eluting with hexanes/ethyl acetate 9:1 then 4:1 to give 16 mg (30%) of 3-[(cyclopentyl-{4-[4-(cis-4-methyl-cyclohexyloxy)-phenyl]-pyrimidin-2-yl}-amino)-methyl]-benzoic acid methyl ester. LCMS m/z: 501 (M+1)+.
Reaction SMILES: O[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.ClCCl>[CH3:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: O=c1c(CO)c[nH]c2c([N+](=O)[O-])cccc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c[nH]c2c([N+](=O)[O-])cccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 1,4-dihydro-3-hydroxymethyl-8-nitro-4-oxoquinoline (3.1 g) in trifluoroacetic acid (10 ml) and dichloromethane (10 ml) was added triethylsilane (6.55 g), and the mixture was stirred at ambient temperature overnight. The mixture was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give 1,4-dihydro-3-methyl-8-nitro-4-oxoquinoline (2.3 g).
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+].Br[CH:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:30]([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[O:31]>CC(OC)(C)C>[CH2:35]([N:32]([CH2:33][CH3:34])[C:30](=[O:31])[CH:29]([N:19]1[CH2:20][CH2:21][N:16]([C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=2[F:6])[CH2:17][CH2:18]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:36]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Reactant: CCN(CC)C(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 500 mL, round-bottomed flask under a positive pressure of nitrogen was equipped with a magnetic stirrer and charged with anhydrous DMF (100 mL), 1-(2-fluoro-4-nitro-phenyl)-piperazine (4.0 g, 17.8 mmol), anhydrous K2CO3 (4.9 g, 35.5 mmol) and 2-bromo-N,N-diethyl-2-phenyl-acetamide (6.2 g, 23.0 mmol). The pale yellow reaction mixture was stirred at ambient temperature for 4 h, following which the solvent was removed on the rotary evaporator to yield a yellow colored semi-solid. MTBE (250 mL) was added and the resulting suspension was stirred at ambient temperature for 0.5 h and then filtered. The filtrate was extracted with 1.5N HCl (1×200 mL, then 1×100 mL). The aqueous layers were pooled, cooled to ˜0° C. in an ice bath and then basified with 2N NaOH (to pH ca. 13). The basified reaction mixture was extracted with MTBE (4×125 mL). The organic layers were pooled, dried over anhydrous sodium sulfate, filtered and concentrated to yield a brown colored oil. The oil was purified by silica gel chromatography (solvent: EtOAc/Hexane) to yield the title compound as a reddish-brown oil.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:13][N:14]([CH3:18])[C:15]([C:12]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12)=[O:16]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)c1cc2ccccn2n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(C)c1nn2ccccc2c1C(=O)N(C)C

Procedure:
A mixture of 1.6g of 2-isopropylpyrazolo[1,5-a]pyridine and 2.1g of N,N-dimethylcarbamoyl chloride was dissolved in 20 ml of nitrobenzene. Four grams of aluminum chloride (powder) was added at room-temperature to the resulting solution and reaction mixture was refluxed for 8 hr and concentrated under reduced pressure. Water was added to the residue and the mixture was made basic with potassium hydroxide solution, extracted with chloroform. The chloroform solution was dried over sodium sulfate and concentrated. The residue was column chromatographed over alumina to give objective product. Distillation gave colorless oil, bp 175° (2 mmHg). Yield 1.1g (50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:45]COCC[Si](C)(C)C)=[CH:5][C:6]([CH2:43][OH:44])=[C:7]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:26]4[N:30](COCC[Si](C)(C)C)[C:29]5[CH:39]=[CH:40][CH:41]=[CH:42][C:28]=5[N:27]=4)=[N:14][N:15]3COCC[Si](C)(C)C)=[CH:11][CH:10]=2)[CH:8]=1.COC1C(OCOCC[Si](C)(C)C)=CC(C)=C(C2C=C3C(C(C4N(COCC[Si](C)(C)C)C5C=CC=CC=5N=4)=NN3COCC[Si](C)(C)C)=CC=2)C=1>>[NH:30]1[C:29]2[CH:39]=[CH:40][CH:41]=[CH:42][C:28]=2[N:27]=[C:26]1[C:13]1[C:12]2[C:16](=[CH:17][C:9]([C:7]3[CH:8]=[C:3]([O:2][CH3:1])[C:4]([OH:45])=[CH:5][C:6]=3[CH2:43][OH:44])=[CH:10][CH:11]=2)[NH:15][N:14]=1
Reactant: COc1cc(-c2ccc3c(-c4nc5ccccc5n4COCC[Si](C)(C)C)nn(COCC[Si](C)(C)C)c3c2)c(CO)cc1OCOCC[Si](C)(C)C
Agent: COc1cc(-c2ccc3c(-c4nc5ccccc5n4COCC[Si](C)(C)C)nn(COCC[Si](C)(C)C)c3c2)c(C)cc1OCOCC[Si](C)(C)C
Product: COc1cc(-c2ccc3c(-c4nc5ccccc5[nH]4)n[nH]c3c2)c(CO)cc1O

Procedure:
Example 24(n) was prepared in a similar manner to that described for Example 24(a), except that 6-[5-methoxy-2-hydroxymethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazole, prepared as described below, was used instead of 6-[5-methoxy-2-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazole. 1H NMR (300 MHz, DMSO-d6) δ 13.59 (s, 1H), 12.95 (s, 1H), 9.05 (s, 1H), 8.49 (d, 1H, J=8.4 Hz), 7.72 (dd, 1H, J=6.3, 2.1 Hz), 7.60 (s, 1H), 7.51 (dd, 1H, J=6.3, 2.1 Hz), 7.31 (d, 1H, J=8.4 Hz), 7.20-7.24 (m, 2H), 7.02 (s, 1H), 6.87 (s, 1H), 5.02 (t, 1H, J=5.4 Hz), 4.32 (d, 2H, J=5.4 Hz), 3.80 (s, 3H). MS (ES) [m+H]/z calc'd 387, found 387; [m−H]/z calc'd 385, found 385.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[C:14]1([C:20]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:21]2[C:25]([C:26]3[C:31]([C:32]4[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=4)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:24][N:23]=[N:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+]>>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:38][C:35]3[CH:34]=[CH:33][C:32]([C:31]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:25]4[N:21]([C:20]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[N:22]=[N:23][N:24]=4)=[CH:37][CH:36]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:13])[CH:3]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
5,7-Dimethyl-2-ethyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine was prepared according to the procedure described in Example 7, Part A from 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine (1.51 g, 8.62 mmol), N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (5.29 g, 9.48 mmol), and NaH (17.2 mmol).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:11][CH:10]([O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-BOC-3-hydroxyazetidine (1.0 g, 5.77 mmol), 4-dimethylaminopyridine (7 mg, 0.058 mmol) and triethylamine (0.880 mL, 6.35 mmol) in DCM (15 mL) cooled at 0° C. was added dropwise methanesulfonyl chloride (0.45 mL, 5.77 mmol). The RM was stirred 18 h at rt, diluted with DCM, washed with a solution of saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. 3-Methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester obtained as an oil was used directly in the next step. To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.4 g 5.57 mmol) in DMF (20 mL) stirred at 0° C. was added sodium hydride (55% in oil, 0.243 g, 5.57 mmol). After addition the mixture was stirred 1 h at rt, a solution of the above obtained 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester (1.4 g, 5.57 mmol) in DMF (3 mL) was added. The RM was stirred 30 min at rt, and then 3 h at 95° C. After cooling at rt the mixture was poured in ice water and extracted with EtOAc. The combined organic phases were washed with a solution of saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (with heptane and EtOAc as eluants) to afford the title compound as an oil (tR 4.33 min (conditions 3), MH+=350.1)
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:3].[C:12]1([CH:18]([CH2:22][CH3:23])[C:19](O)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[O:20]=[C:19]([C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=1)[CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:22][CH3:23]
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: CS(=O)(=O)Nc1ccccc1
Solvent: O
Product: CCC(C(=O)c1ccc(NS(C)(=O)=O)cc1)c1ccccc1
Temperature: 0 °C
Yield: 23 %

Procedure:
Methanesulfonanilide (40 g., 0.234 mole) is added over a 10 minute period with stirring to polyphosphoric acid (400 g.) heated to 90°-100°C. Heating and stirring are continued for additional 10 minutes, at which time 2-phenylbutanoic acid (36.0 g., 0.219 mole) is added portionwise during 20 minutes. After heating and stirring for 10 minutes, the solution is poured into water (600 ml.) and ice (400 g.) with stirring. The water is decanted and ethyl ether (200 ml.) is added to the remaining oil with stirring. After cooling in ice water, the product crystallizes and is collected: 18.4 g., m.p. 143°-147°C. Recrystallization from isopropanol yields 15.7 g. (23% yield), m.p. 148°-150°C.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[C:17]([O:28][CH3:29])[CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.C(OCC)(=O)C>[CH3:29][O:28][C:17]1[CH:16]=[C:15]([C:13]2[CH:12]=[N:11][C:6]3[NH:7][C:8]4[CH:9]=[N:10][C:2]([C:34]5[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=5)=[CH:3][C:4]=4[C:5]=3[CH:14]=2)[CH:20]=[CH:19][C:18]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(-c2cnc3[nH]c4cnc(Br)cc4c3c2)ccc1CN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]c4cnc(-c5cnn(C)c5)cc4c3c2)ccc1CN1CCCCC1
Temperature: 130 °C
Yield: 17.3 %

Procedure:
A degassed mixture of 6-bromo-3-(3-methoxy-4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (350 mg, 0.78 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (242 mg, 1.16 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (64 mg, 0.08 mmol) in 2N aqueous sodium carbonate solution (8 mL) and acetonitrile (8 mL) was heated under microwave irradiation at 130° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (75 mL) and washed with water (50 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 50 g column, Biotage, 0-25% methanol in DCM) to afford the title compound as an off-white solid (61 mg, 17%). 1H NMR (DMSO-D6, 300 MHz): 8.95-8.92 (m, 2H), 8.85 (d, J=1.0 Hz, 1H), 8.49 (d, J=1.1 Hz, 1H), 8.22 (s, 1H), 8.00 (s, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.38-7.33 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.48 (s, 2H), 2.44-2.34 (m, 4H), 1.55-1.48 (m, 4H), 1.45-1.37 (m, 2H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:32]([N:39]1[C:44]([CH3:45])=[CH:43][C:42]([OH:46])=[C:41]([Br:47])[C:40]1=[O:48])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[F:49][C:50]1[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:51]=1[CH2:52]O>CN(C=O)C>[CH2:32]([N:39]1[C:44]([CH3:45])=[CH:43][C:42]([O:46][CH2:52][C:51]2[CH:54]=[CH:55][C:56]([F:58])=[CH:57][C:50]=2[F:49])=[C:41]([Br:47])[C:40]1=[O:48])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: OCc1ccc(F)cc1F
Reactant: Cc1cc(O)c(Br)c(=O)n1Cc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
To a degassed cold solution of DMF (10 mL) and PPh3 (resin, 0.93 g, 2.75 mmol) was added DEAD (0.44 mL, 2.75 mmol). The reaction mixture stirred at −10° C. for 20 minutes under nitrogen. A solution of 1-benzyl-3-bromo-4-hydroxy-6-methylpyridin-2(1H)-one (0.62 g, 2.1 mmol) and 2,4-difluorobenzylalcohol (0.283 mL, 2.5 mmol) in DMF (10 mL) was added to the resin suspension. The reaction mixture stirred at −10° C. for 30 minutes and then allowed to stir at room temperature for 1 hour. The resin was filtered and rinsed with fresh MeOH and the filtrate was concentrated. The residue was dissolved in ethyl acetate and purified by flash column chromatography (ethyl acetate/hexane 1:1 v/v). The appropriate fractions were concentrated. 1H-NMR (CD3OD, 400 MHz) δ 7.62 (m, 1H), 7.31 (m, 3H), 7.1 (d, 2H, J=7.2 Hz), 7.02 (t, 2H, J=8.6 Hz), 6.48 (s, 1H), 5.42 (s, 2H), 5.28 (s, 2H), 2.34 (s, 3H); ES-HRMS m/z 420.0399/422.0380 (M+H calculated for C20H17NO2F2Br requires 420.0405/422.0387).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH2:10]2)=[C:5]([F:12])[C:3]=1[NH2:4].[Br:13]N1C(=O)CCC1=O>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Br:13])[C:6]([CH:9]2[CH2:10][CH2:11]2)=[C:5]([F:12])[C:3]=1[NH2:4]
Reactant: Nc1c(Cl)ccc(C2CC2)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc(Br)c(C2CC2)c1F
Reaction time: 8 h

Procedure:
2-Chloro-5-cyclopropyl-6-fluoroaniline (9.4 g, 50.6 mmol) and N-bromosuccinimide (9.4 g, 52.8 mmol) are dissolved with stirring in 100 mL of anhydrous DMF. The reaction mixture is stirred overnight and then most of the DMF is removed by rotary evaporator under high vacuum. The residue is partitioned between 1:1 Et2O/hexane (500 mL) and water (500 mL). The organic layer is washed with brine (3×250 mL), dried (MgSO4) and concentrated by rotary evaporator. The crude material is purified using flash chromatography (7% CH2Cl2/hexanes) to give 2-chloro-4-bromo-5-cyclopropyl-6-fluoroaniline as a light orange oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.CC1C=CC(S(O[CH2:23][C@@H:24]([C@@H:39]2[C@:56]3([CH3:57])[C@H:42]([C@H:43]4[C@H:53]([CH2:54][CH2:55]3)[C@:51]3([CH3:52])[C:46]([CH2:47][C@@H:48]([O:65][CH:66]5[CH2:71][CH2:70][CH2:69][CH2:68][O:67]5)[CH2:49][C@@H:50]3[O:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][O:60]3)=[CH:45][CH2:44]4)[CH2:41][CH2:40]2)[CH2:25][CH2:26][C:27]([F:38])([F:37])[C:28]([O:31][CH:32]([O:34][CH2:35][CH3:36])[CH3:33])([CH3:30])[CH3:29])(=O)=O)=CC=1>CCOCC>[O:60]1[CH2:61][CH2:62][CH2:63][CH2:64][CH:59]1[O:58][C@@H:50]1[C@@:51]2([CH3:52])[C:46](=[CH:45][CH2:44][C@@H:43]3[C@@H:53]2[CH2:54][CH2:55][C@@:56]2([CH3:57])[C@H:42]3[CH2:41][CH2:40][C@@H:39]2[C@H:24]([CH3:23])[CH2:25][CH2:26][C:27]([F:37])([F:38])[C:28]([O:31][CH:32]([O:34][CH2:35][CH3:36])[CH3:33])([CH3:30])[CH3:29])[CH2:47][C@@H:48]([O:65][CH:66]2[CH2:71][CH2:70][CH2:69][CH2:68][O:67]2)[CH2:49]1
Reactant: CCOC(C)OC(C)(C)C(F)(F)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(C)OC(C)(C)C(F)(F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 0.410 g (0.0108 mol) of lithium aluminum hydride, 50 mL of tetrahydrofuran and 2.98 g (0.0033 mol) of [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-en-21-ol 21-(4-methylbenzenesulfonate) was heated at reflux (60°) for 1 hr and cooled to 0° C. The mixture was diluted with 120 mL of ether and quenched with the dropwise addition of 0.82 mL of water and 0.65 mL of 10% aqueous sodium hydroxide solution. The mixture was then stirred for 1 hr and filtered. The solids were triturated with ether and filtered. The combined filtrates were evaporated to dryness and chromatographed on 0.06-0.20 mm silica gel to yield [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-ene, [α]D16 +2° (c 1, CHCl3).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.C(N(CC)CC)C.[C:17](Cl)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>ClCCl>[C:17]([O:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CC1(CO)COC(=O)N1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)OCC1(C)COC(=O)N1
Yield: 69.1 %

Procedure:
A solution of 10.5 g of 2-amino-2-methyl-1,3-propanediol and 12.3 g of diethyl carbonate, 0.5 g of sodium ethoxide in 100 ml of toluene was refluxed for 20 hours, cooled and concentrated at reduced pressure to give 13.6 g of crude product. Recrystallization from ethanol gave 9.23 g (67%) of4-hydroxymethyl-4-methyloxazolidin-2-one, m.p. 115 C. To a solution of 2.62 g of 4-hydroxymethyl-4-methyloxazolidin-2-one and 5 ml of triethylamine in 100 ml of dichloromethane was added dropwise 4.6 g of dodecanoyl chloride in 10 ml of dichloromethane. After 3 hours at room temperature the reaction mixture was concentrated, the residue was taken up in ether and washed with aqueous sodium bicarbonate. The ether layer was dried and concentrated to give 4.33 g (69%) of a thick yellow oil. Recrystallization from dichloromethane/hexane (1:10) gave 2.73 g (45%) of white crystals, m.p. 53-55 C.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].CCO.Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1>O>[Br:15][C:12]1[CH:11]=[N:10][C:9]([O:3][CH2:2][CH3:1])=[CH:14][CH:13]=1
Reactant: CC[O-]
Reactant: Brc1ccc(Br)nc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ccc(Br)cn1
Temperature: 80 °C

Procedure:
A solution of NaOEt in EtOH (21%; 157 mL, 422 mmol) was added to 2,5-dibromopyridine (4-1) (20 g; 84.4 mmol) and the mixture heated to 80° C. for 16 hours. After cooling, the mixture was poured into water, extracted twice with EtOAc, washed with water then brine, dried (MgSO4) and concentrated under reduced pressure to give crude product 4-2 as a solid.