Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][C:37]([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:38])[CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.C(O)(=O)C>[C:17]([O:16][C:13](=[O:15])[CH2:14][C:37]([CH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)([OH:38])[CH2:36][CH2:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:30]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(CCc1cccc(OCc2ccccc2)c1)C1CCCC1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(O)(CCc1cccc(OCc2ccccc2)c1)C1CCCC1
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
Diisopropyl amine (9.56 mL, 68.2 mmol) was dissolved in freshly distilled THF (30 mL) and cooled to -15° C. with a dry ice/acetone bath. 1.6M n-BuLi (42.7 mL, 68.2 mmol) in hexanes was then added dropwise over 20 minutes. The solution was then cooled to -40° C. and allowed to stir for 20 minutes. tert-Butyl acetate (9.2 mL, 68.2 mmol) was then dissolved in freshly distilled THF (20 mL) and added dropwise over 30 minutes to the -40° C. solution. This was allowed to stir for an additional 30 minutes at -40° C. after addition was complete. 3-(3-Benzyloxy-phenyl)-1-cyclopentyl-propan-1-one (10.51 g, 34.1 mmol) from Example YYYY was dissolved in freshly distilled THF (35 mL) and added rapidly to the -40° C. solution, such that the temperature did not exceed -40° C. Monitored reaction with TLC and shown to be complete in 5 minutes. Added glacial acetic acid dropwise (20 mL) to neutralize solution and allowed to warm to room temperature. The majority of THF was removed under reduced pressure and took up remaining organics in EtOAc. The organics were washed with brine, saturated sodium bicarbonate, and again with brine. The organics were dried over MgSO4 and the solvent removed under reduced pressure. The residue was flash chromatographed (15% EtOAc/85% hexane, silica gel) to yield the title compound as a viscous oil. 1H NMR (CDCl3) δ 1.47 (s, 9 H), 1.47-1.69 (br m, 8 H), 1.83 (m, 2 H), 2.08 (m, 1 H), 2.46 (d of ABX q, 1 H), 2.49 (d of ABX q, 1 H), 2.63 (m, 2 H), 3.78 (br s, 1 H), 5.05 (s, 2 H), 6.82 (br m, 3 H), 7.26 (t, 1 H), 7.32-7.46 (br m, 5 H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:18]4[N:19]([N:34]=[CH:35][N:36]=4)[C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][O:30]C(=O)C)[CH:24]=4)=[CH:21][N:22]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[C:18]4[N:19]([N:34]=[CH:35][N:36]=4)[C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][OH:30])[CH:24]=4)=[CH:21][N:22]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(=O)OCc1cc(-c2cnc(Nc3ccc(N4CCN(C(C)C)CC4)cc3)c3ncnn23)ccn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)N1CCN(c2ccc(Nc3ncc(-c4ccnc(CO)c4)n4ncnc34)cc2)CC1
Yield: 12.5 %

Procedure:
Acetic acid 4-{8-[4-(4-isopropylpiperazin-1-yl)phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}pyridin-2-ylmethyl ester is stirred at room temperature overnight in 10 mL of a 1.5 M solution of potassium carbonate in methanol. The pH is then brought to neutral by addition of 10% aqueous citric acid and the mixture is extracted with DCM. Purification by LC using 98/2 DCM/2M NH3 in MeOH as the eluent provides the title compound as a yellow powder (40.3 mg, 12.5% over 2 steps). 1H-NMR (400 MHz, d6-DMSO) δ(ppm) 1.02 (6H, m), 2.33 (1H, m), 2.60 (4H, br m), 3.10 (4H, br m), 4.65 (2H, d), 5.51 (1H, t), 6.96 (2H, d), 7.84-7.89 (3H, m), 8.11 (1H, s), 8.17 (1H, m), 8.61 (1H, d), 8.73 (1H, m), 10.08 (1H, s). LCMS: Rt=0.78 min (100%), m/z (ESI) 445 (M+H)+.
Reaction SMILES: [C:1]([C@:3]1([OH:34])[C:8](=[CH2:9])[CH2:7][C@H:6]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:4]12[CH3:5])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH2:16][CH2:17]1)[C@H:12]([CH2:24]N(C1C=CC=CC=1)CC)[CH2:11]3)#[CH:2].Cl.O>C1COCC1>[C:1]([C@:3]1([OH:34])[C:8](=[CH2:9])[CH2:7][C@H:6]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:4]12[CH3:5])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH2:16][CH2:17]1)[C:12](=[CH2:24])[CH2:11]3)#[CH:2]
Reactant: C#C[C@]1(O)C(=C)C[C@H]2[C@@H]3C[C@@H](CN(CC)c4ccccc4)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C#C[C@]1(O)C(=C)C[C@H]2[C@@H]3CC(=C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 8 h

Procedure:
17α-Ethynyl-17β-hydroxy-6-β-(N-phenyl-N-ethylaminomethyl)-16-methyleneandrosta-4-en-3-one (Example 3) in THF (20 ml) are mixed. Degassed hydrochloric acid (6N, 55 ml plus 20 ml THF) are added. The mixture is stirred overnight at 20°-25° under nitrogen, at which time TLC shows the reaction to be complete. Water (110 ml) is added, the mixture filtered, the solids washed with 10% hydrochloric acid, twice with water, once with 5% sodium bicarbonate, and three times with water to neutrality. Solids were then dried under nitrogen overnight to give the title compound.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[H][H]>[Pd].C(O)C>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: C1=CC2CC1CC2Cn1ccnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: c1cn(CC2CC3CCC2C3)cn1

Procedure:
A mixture of 1-(bicyclo[2.2.1]hept-5-en-2-ylmethyl)imidazole (2.0 g, 11.48 mmol) and palladium on charcoal (0.2 g, 10%) in dry ethanol was shaken in an atmosphere of hydrogen for 4.5 h. The reaction mixture was then filtered through Hyflo-Supercel, and the filtrate was concentrated under reduced pressure to afford a colourless oil. Distillation of the oil afforded 1-(bicyclo[2.2.1]heptan-2-ylmethyl)imidazole as a colourless oil, b.p. 82°-84°/0.15 mm Hg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=O)[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.[NH2:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20]>CO>[OH:21][CH:18]([CH2:19][OH:20])[CH2:17][NH:16][C:12]([C:4]1[CH:3]=[C:2]([OH:1])[CH:11]=[C:6]([C:7]([NH:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[O:9])[CH:5]=1)=[O:14]
Reactant: NCC(O)CO
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Solvent: CO
Product: O=C(NCC(O)CO)c1cc(O)cc(C(=O)NCC(O)CO)c1
Temperature: 25 °C

Procedure:
Dimethyl 5-hydroxyisophthalate (12.6 g, 60 mmol) was dissolved in methanol (36 mL) containing 3-amino-1,2-dihydroxypropane (16.4 g, 180 mmol). The mixture was heated to reflux temperature for 10 days, and, after cooling to room temperature, was evaporated. Acetone (100 mL) was added to the residue and the crystalline solid was collected by filtration. The product was purified by recrystallization from acetone. Yield 9.0 g (46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH:15]([F:17])[F:16])[N:12]3[N:18]=[CH:19][C:20]([C:21]([OH:23])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31]O)=[NH:30])=[CH:27][N:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH:15]([F:16])[F:17])[N:12]3[N:18]=[CH:19][C:20]([C:21]4[O:23][N:31]=[C:29]([C:28]5[CH:33]=[CH:34][C:25]([NH2:24])=[N:26][CH:27]=5)[N:30]=4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: N=C(NO)c1ccc(N)nc1
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(Cl)c(Cl)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.7) (179 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (92 mg, 39%). MS (ISP) 473.9 [(M+H)+]; mp 279° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]4[CH2:29][CH2:28][CH2:27]4)[CH2:23][CH2:22][C:21]([C:30]([O:32]C)=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]4[CH2:27][CH2:28][CH2:29]4)[CH2:23][CH2:22][C:21]([C:30]([OH:32])=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC2CCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC2CCC2)cc1
Temperature: 50 °C
Yield: 87.8 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-cyclobutylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.47 g). To the solution was added 1N sodium hydroxide solution (10 ml), and the mixture was heated at 50° C. overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-cyclobutylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.40 g) as yellow crystals.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[NH:9][C:8](=[O:10])[NH:7][C:6](=[O:11])[CH:5]=1>C(O)(=O)C>[Br:1][C:5]1[C:6](=[O:11])[NH:7][C:8](=[O:10])[NH:9][C:4]=1[CH3:3]
Reactant: Cc1cc(=O)[nH]c(=O)[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)[nH]c(=O)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
Bromine (39.97 g, 0.25 mole) was added dropwise to a cooled mixture of 31.5 g (0.25 mole) of 6-methyl-2,4(1H,3H)pyrimidinedione in 200 ml of glacial acetic acid. The resulting mixture was stirred at ambient temperature for 16 hours and then filtered. The solid which was collected was washed with water and dried in vacuo overnight at 69° C. to give 39.9 g of the product as a white solid, mp 254° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:16]([Br:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:5].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[Br:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:3]2[C:2]=1[NH:1][C:19](=[O:21])[N:6]([CH2:7][CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:4]2=[O:5]
Reactant: CS(=O)(=O)CCNC(=O)c1cccc(Br)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)CCn1c(=O)[nH]c2c(Br)cccc2c1=O
Temperature: 100 °C
Yield: 330.4 %

Procedure:
A glass microwave reaction vessel was charged with 2-amino-3-bromo-N-(2-(methylsulfonyl)ethyl)benzamide (480 mg, 1.494 mmol) and triphosgene (0.078 mL, 0.523 mmol, Fluka) in 1,4-dioxane (6 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 45 min. The mixture was cooled to RT and the solvent was removed to give the crude product 600 mg. MS (ESI, pos. ion) m/z: 347 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]3[CH2:22][CH2:21][N:20](C#N)[CH2:19][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#CN1CCC(c2nn(-c3ccc(F)cc3)c3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Yield: 75.6 %

Procedure:
A stirred mixture of 4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 102 (30 g, 0.094 moles) and 25% H (225 ml) was refluxed for 20 hours. The mixture was cooled, poured into H2O, and basified with a 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated which yielded 21 g (76%) of 1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indazole as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C
Reactant: c1c[nH]cn1
Product: Cc1sc2nc(-n3ccnc3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6-dimethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6-dimethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([CH:14]1[N:18]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH:41](=[O:45])[CH:42]([CH3:44])[CH3:43].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:23]([O:22][C:20](=[O:21])[C@@H:19]([N:18]1[C@H:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16][O:15][CH:14]1[CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C@@H:41]([OH:45])[CH:42]([CH3:44])[CH3:43])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)CN1C(C(c2ccccc2)c2ccccc2)OC[C@H]1c1ccccc1
Reactant: CC(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[C@H](O)[C@@H](C(=O)OC(C)(C)C)N1C(C(c2ccccc2)c2ccccc2)OC[C@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl ((4R)-2-benzhydryl-4-phenyl-oxazolidin-3-yl)-acetate (3.0 g, 6.98 mmole, obtained from Reference Example 10) in anhydrous terahydrofuran (86 ml) was cooled at −78° C. under argon. A solution of lithium diisopropylamide (2M solution in heptane/tetrahydrofuran/ethylbenzene, Aldrich) was added dropwise over a period of 10 min, and the resulting orange solution was stirred at −78° C. for 1 h. A solution of isobutyraldehyde in anhydrous tetrahydrofuran (10 ml) was added to the cooled reaction mixture via syringe, and the resulting mixture was stirred at −78° C. for an additional 1 h. Saturated sodium bicarbonate aqueous solution was added, and the mixture was warmed to room temperature. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 times). The extracts were combined, washed with saturated sodium chloride aqueous solution, dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed (flash column, silica gel, methylene chloride:methanol:diethyl ether=90:2:8) to give (2S,3S)-2-((4R)-2-benzhydryl-4-phenyl-oxazolidin-3-yl)-3-hydroxy-4-methyl-pentanoic acid tert-butyl ester (1.5 g, %) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[O:23][CH3:24])[CH:10]=[CH:9][C:8]=1[NH:25][C:26](=[O:28])[CH3:27])[CH2:2]CC.[Br-].[Li+].N12CCCN=C1CCCCC2>C(O)C>[CH2:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[O:23][CH3:24])[CH:10]=[CH:9][C:8]=1[NH:25][C:26](=[O:28])[CH3:27])[CH3:2]
Reactant: CCCCOC(=O)c1cc(CCc2cc(OC)ccc2OC)ccc1NC(C)=O
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)c1cc(CCc2cc(OC)ccc2OC)ccc1NC(C)=O

Procedure:
A mixture of 93 mg of 5-[2-(2,5-dimethoxyphenyl)ethyl]-2-acetylamino-benzoic acid butylester, 100 mg of lithium bromide, 55 mg of 1,8-diazabicyclo[5.4.0]undec-7-en and 4 ml of dry ethanol is heated to reflux for 3 hours. After neutralisation with 0.1 N aqueous hydrochloric acid, the mixture is extracted with ethyl acetate. The combined organic extracts are dried over magnesium sulfate and concentrated in vacuo. The pure title compound is obtained by silica gel chromatography (hexane/ethyl acetate=6/1) as colourless crystals. mp: 93°.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[C:13]([N+:25]([O-])=O)[C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1)[CH3:4].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:25][C:13]1[C:14](=[O:24])[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:12]=1[CH2:11][CH2:10][C@@H:9]1[C@@H:19]2[CH2:20][CH2:21][C@@:22]2([CH3:23])[C@H:8]1[CH2:7][CH2:6][C@@H:5]2[CH:3]([CH2:2][OH:1])[CH3:4]
Reactant: CC(CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 70 °C

Procedure:
A solution of 20-hydroxymethyl-4-nitropregn-4-en-3-one (0.52 g, 1.38 ml) in absolute ethanol (4.8 mL) is combined with stannous chloride (2.1 g) added in one portion and then heated to 70° C. for 6 hours. The reaction vessel is then cooled to room temperature and the solution is carefully neutralized with sodium bicarbonate (9g) over a 10 minute period. The resulting slurry is then filtered, removing a brown solid which is then stirred in 10% hydrofluoric acid (25 mL) and ethyl acetate (25 mL). The HF/EtOAc treatment is repeated. The organic phases from each filtration are combined, dried over magnesium sulphate, filtered and concentrated. The resulting residue is purified by flash chromatography to give 4-amino-20-hydroxymethylpregn-4-en-3-one as a white solid identical to the material described in U.S. Pat. No. 5,218,110 to Weintraub and U.S. Pat. No. 5,120,840 to Weintraub et al., which are both herein incorporated by reference.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:13][C:14]1[C:15]([C:19]2[CH:32]=[CH:31][C:22]([CH2:23][S:24][CH2:25][CH2:26]C(OC)=O)=[CH:21][CH:20]=2)=[N:16][O:17][CH:18]=1)=[O:12])[CH3:9].SCC[S:36]([O-:39])(=[O:38])=[O:37].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:13][C:14]1[C:15]([C:19]2[CH:20]=[CH:21][C:22]([CH2:23][S:24][CH2:25][CH2:26][S:36]([OH:39])(=[O:38])=[O:37])=[CH:31][CH:32]=2)=[N:16][O:17][CH:18]=1)=[O:12])[CH3:9]
Reactant: COC(=O)CCSCc1ccc(-c2nocc2NC(=O)OC(C)c2ccccc2Cl)cc1
Reactant: O=S(=O)([O-])CCS
Agent: [Na+]
Product: CC(OC(=O)Nc1conc1-c1ccc(CSCCS(=O)(=O)O)cc1)c1ccccc1Cl
Yield: 39.3 %

Procedure:
Reaction similar to that of Step B-7 of Example 1 was carried out using Compound 1 (100 mg, 0.256 mmol) and sodium 2-mercaptoethanesulfonate (127 mg, 0.774 mmol) to give the title compound (50 mg, 39%).
Reaction SMILES: Cl.[OH:2][C@@H:3]1[C@H:7]2[N:8](C(OC(C)(C)C)=O)[CH2:9][C@H:10]([S:11][CH3:12])[C@H:6]2[O:5][CH2:4]1>O1CCOCC1>[CH3:12][S:11][C@H:10]1[CH2:9][NH:8][C@@H:7]2[C@@H:3]([OH:2])[CH2:4][O:5][C@H:6]12
Reactant: CS[C@H]1CN(C(=O)OC(C)(C)C)[C@H]2[C@@H]1OC[C@@H]2O
Agent: Cl
Solvent: C1COCCO1
Product: CS[C@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 1 h

Procedure:
A solution of HCl in 1,4-dioxane (4M, 5.5 mL) was added to thiomethylether (54) (152 mg, 0.55 mmol). The mixture stirred for 1 hour then the solvents removed in vacuo. The residue was azeotroped with CH3CN (5 mL) to obtain (3R,3aR,6S,6aS)-6-(methylthio)hexahydro-2H-furo[3,2-b]pyrrol-3-ol which was used without further purification.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)([O:3][CH2:4][CH3:5])=[O:2].[K+].[Br-].O=P(Cl)(Cl)[Cl:22]>C(Cl)(Cl)Cl.CO>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:22])=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2nc(C)ccc2c1O
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)c1cnc2nc(C)ccc2c1Cl

Procedure:
3-Carbethoxy-4-hydroxy-7-methyl-1,8-naphthyridine (3.8 g; 0.016 M) was suspended in POCl3 (46 ml; 0.45 M) and the mixture heated at 70°-80° C. for 4 hr. The solution was concentrated in vacuo and the residue poured carefully onto crushed ice. The resulting solution was basified with 10% aq. NaOH to pH 6 and extracted with Et2O. The Et2O extracts were combined, washed with saturated brine and dried over anhydrous MgSO4. The drying agent was removed by filtration and the filtrate was decolourised by refluxing with charcoal, filtered through Kieselguhr and evaporated to dryness in vacuo to yield the product, 3.7 g. (92%), m.p. 92°-93° C. (dec.). An analytical sample was obtained by chromatography over silica gel using CHCl3 /MeOH (9:1) as eluent. m.p. 90°-91° C. (dec.) (Found: N, 11.36; C, 57.80; H, 4.66; Cl, 14.13%. C12H11ClN2O2 requires: N, 11.18; C, 57.48; H, 4.39; Cl, 14.17%), νmax (KBr) 1720, 1600, 1580, 1470, 1260, 1213, 1170, 1022, 810 cm-1, δ [(CD3)2SO] 1.39 (t), 4.4 (q), (CH3CH2), 2.74 (s) (CH3), 7.69 (d), 8.6 (d), 9.21 (s) (heterocyclic protons), m/e 250 (M+ ; 100%), 222 (41%).
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[N:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[NH2:41][CH2:42][CH:43]([OH:45])[CH3:44]>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:22]([C:20]2[N:19]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])[N:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:41][CH2:42][CH:43]([OH:45])[CH3:44])=[O:40])=[CH:15][CH:14]=3)[CH:21]=2)[CH:27]=1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Reactant: CC(O)CN
Product: CC(O)CNC(=O)Nc1ccc(-c2cc(-c3cc(F)ccc3S(C)(=O)=O)nc(N3CCOC[C@@H]3C)n2)cc1

Procedure:
Method as described for example 58 using (S)-phenyl(4-(6-(5-fluoro-2-(methylsulfonyl)phenyl)-2-(3-methylmorpholino)pyrimidin-4-yl)phenyl)carbamate (intermediate 32) (100 mg, 0.18 mmol) and 1-aminopropan-2-ol (20 mg, 0.27 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound as a yellow solid. (46 mg, 48%)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH2:17][N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[CH:19]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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].O>[F:16][C:13]1[C:14]2[CH:15]=[C:7]3[C:6]4[CH:19]=[C:2]([C:37]5[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:29]6[O:28][C:27]([C:24]7[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=7)=[C:31]([C:32]([NH:34][CH3:35])=[O:33])[C:30]=6[CH:36]=5)[CH:3]=[CH:4][C:5]=4[O:18][CH2:17][N:8]3[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)cc2-1
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
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(c3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 25 °C
Yield: 37 %

Procedure:
A mixture of 2-chloro-11-fluoro-6H-benzo[5,6][1,3]oxazino[3,4-a]indole (30 mg, 0.11 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (55 mg, 0.11 mmol), K3PO4.3H2O (88 mg, 0.33 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), X-Phos (11 mg, 0.022 mmol) was stirred in dixane/H2O (5 mL, 4:1) at 110° C. for 12 hours. Then the mixture was cooled to 25° C., water was added to it. The mixture was extracted with ethyl acetate and washed with brine, dried over Na2SO4. After the combined organic layers were concentrated, the resulting residue was purified using prep-TLC (petroleum ether:EtOAc=3:1) to provide the product of Compound 43 (25 mg, yield: 40%). 1H-NMR (CDCl3, 400 MHz) δ 9.94˜7.97 (m, 2H), 7.83˜7.86 (m, 2H), 7.62 (s, 1H), 7.37˜7.40 (m, 1H), 7.09˜7.24 (m, 5H), 6.93 (s, 1H), 6.80˜6.85 (m, 1H), 5.95 (s, 2H), 5.85 (br, 1H), 3.16 (s, 3H), 3.00˜3.01 (d, J=5.2 Hz, 3H), 2.78 (s, 3H). MS (M+H)+: 614.