Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@@H:2]([CH2:18][N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29]C)[N:27]=2)[CH2:22][CH2:21][C:20]1=[O:31])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.CS(OS(C)(=O)=O)(=O)=O.[I-].[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[O:29]=[C:26]1[CH:25]=[CH:24][C:23]2[CH2:22][CH2:21][C:20](=[O:31])[N:19]3[CH2:18][CH:2]([CH2:3][N:4]4[CH2:5][CH2:6][CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:8][CH2:9]4)[N:27]1[C:28]=23
Reactant: COc1ccc2c(n1)N(C[C@H](O)CN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CC2
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(CC2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Temperature: 80 °C
Yield: 50.7 %

Procedure:
A solution of 1,1-dimethylethyl (1-{(2R)-2-hydroxy-3-[7-(methyloxy)-2-oxo-3,4-dihydro-1,8-naphthyridin-1(2H)-yl]propyl}-4-piperidinyl)carbamate (3.9 g, 8.97 mmol) in chloroform (150 ml) and triethylamine (3.1 ml) under argon was treated with methanesulfonic anhydride (3.1 g, 17.94 mmol) at room temperature and then heated at reflux for 2.5 h. The solvents were evaporated and the residue dissolved in acetonitrile (150 ml) and treated with sodium iodide (6.7 g, 44.85 mmol) and heated at 80° C. After 45 minutes acetonitrile was evaporated and the residue was partitioned between water (250 ml) and 20% methanol/dichloromethane (250 ml); the layers were separated and the aqueous layer was extracted with 20% methanol/dichloromethane (4×250 ml). The combined organic extracts were dried on magnesium sulphate, filtered and evaporated. The crude was purified by silica chromatography using a 0-10% methanol/dichloromethane gradient to provide the desired compound as a bright orange foam (1.83 g; 57%, impure with triethylamine residues). The aqueous layer was evaporated and then treated with chloroform; the solid was filtered off and the chloroform was evaporated to give 2.77 g of a yellow solid. The solid was dissolved in methanol and loaded onto a SCX cartridge which was pre-wet with methanol. The cartridge was washed with methanol (50 ml) and then with 2M ammonia in methanol (50 ml). The 2M ammonia in methanol was evaporated to afford the pure product as a white solid (220 mg), presumed 2:1 mixture of R:S).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][O:23][N:22](C(OCC)=O)[CH2:21][CH2:20]3)[S:17][CH:18]=2)[CH2:10]1.[OH-].[K+].Cl.[OH-].[Na+]>C(O)C.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][O:23][NH:22][CH2:21][CH2:20]3)[S:17][CH:18]=2)[CH2:10]1
Reactant: CCOC(=O)N1CCC(c2nc(C3=NOC(c4c(F)cccc4F)C3)cs2)CO1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Fc1cccc(F)c1C1CC(c2csc(C3CCNOC3)n2)=NO1
Temperature: 25 °C

Procedure:
A solution of ethyl 5-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]tetrahydro-2H-1,2-oxazine-2-carboxylate (i.e. the product of Step J) (0.30 g, 0.71 mmol) and potassium hydroxide (0.20 g, 3.50 mmol) in ethanol (10 mL) and water (1 mL) was heated at reflux for 20 h, and then cooled to room temperature. The reaction mixture was acidified by the addition of concentrated hydrochloric acid, heated at 70° C. for about 20 minutes, cooled to room temperature, and then basified by the addition of sodium hydroxide (1%). The reaction mixture was extracted with ethyl acetate (20 mL) and combined organic extracts were concentrated under reduced pressure to provide the title compound as a yellow oil (0.235 g) which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[Br:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[N:16][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14]([O:10][C:4]2[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:13]=1
Reactant: OB(O)c1cncc(Br)c1
Reactant: COc1cc(O)cc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Cl)cc(Oc2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 372 mg (2.346 mmol) of 3-chloro-5-methoxyphenol (B-1), 947 mg (4.692 mmol) of 5-bromopyridine-3-boronic acid (13-1), 426 mg (2.346 mmol) of copper (II) acetate and 4.0 g of freshly activated powdered 4A molecular sieves was stirred in 20 mL of DCM in a screw top glass sealed tube. The reaction was then treated with 1.635 mL (11.73 mmol) of triethylamine and the vessel was loosely capped. The mixture was vigorously stirred at room temperature for 48 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to a black residue. The residue was purified on a CombiFlash silica column eluted with an ethyl acetate:hexanes gradient to give the desired product 13-2 as an oil (Rf=0.7, EtOAc:hexanes 1:4). MS: M+1=314. 1H NMR(CDCl3): 3.79 (s, 3H), 6.47 (m, 1H), 6.61 (m, 1H), 6.74 (m, 1H), 7.46 (m, 1H), 8.33 (d, 1H), 8.46 (d, 1H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:15][CH2:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].Cl>C(OCC)(=O)C>[C:8]([NH:15][CH2:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([O:22][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:21])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COC(=O)CCC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 89 %

Procedure:
Triethylamine (2.22 g; 22.0 mmol) was added dropwise to a stirred solution of 5-(Boc-amino)-4-oxopentanoic acid (4.62 g; 20.0 mmol) and t-butyl bromoacetate (4.30 g; 22.0 mmol) in ethyl acetate (60 mL) under argon at ambient temperature. The mixture (slurry) was refluxed for 17 h, then cooled to ambient temperature, poured into 0.5 M HCl (100 mL) and shaken thoroughly. The aqueous portion was extracted with ethyl acetate (2×20 mL). The combined organic solutions were washed with saturated NaHCO3 solution (1×20 mL) and saturated NaCl solution (1×20 mL) then dried (MgSO4), filtered and evaporated. Evaporation resulted in an amber oil that was purified by flash chromatography on a 40×55-mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (600 mL), collecting 5×100 mL fractions. Evaporation of fractions 1 and 2 resulted in 6.15 g (89%) product (yellow oil).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.Br>CN(C)C=O.C1(C)C=CC=CC=1.O>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:4][CH2:3][CH2:2][OH:1])=[O:18])=[CH:15][CH:14]=1
Reactant: NCCO
Reactant: O=C(Cl)c1ccc(OCCCCCCBr)cc1
Agent: Br
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(NCCO)c1ccc(OCCCCCCBr)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 300 of 2-hydroxyethylamine in 1.2 liter of dimethylformamide at 0° C. was added dropwise 450 ml of 4-(6-bromohexyloxy)benzoyl chloride in 50 ml of toluene over a 30 minute period. After an additional 30 minutes of stirring, 48% hydrobromic acid (about 200 ml) was added until the pH reached 5-5.5, and the mixture was diluted with 1200 ml of water and extracted with isopropyl acetate (total of 2500 ml). The extracts were washed with water and saturated sodium chloride solution, filtered, and concentrated to a volume of about 1 liter. The mixture was cooled and the solid which separated was collected by filtration and dried at 40° C. to give 332.7 g of 4-(6-bromohexyloxy)-N-(2-hydroxyethyl)benzamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH2:11])([O-:3])=[O:2].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.O>C1(C)C(C)=CC=CC=1>[NH2:11][C:5]1[CH:6]=[CH:7][C:8]([N:10]=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=Cc1ccc(F)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: Nc1ccc(N=Cc2ccc(F)cc2)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A solution of 15.3 g (100 mmol) 2-nitro-p-phenylenediamine and 13.6 g (110 mmol) 4-fluorobenzaldehyde in 400 ml xylene is heated under reflux in the presence of 0.5 g of an acid ion exchanger (for example Nafion) for 3 hours in a water separator. Insoluble constituents are filtered out hot and the mixture is allowed to stand overnight at room temperature. An orange-yellow solid crystallizes out. This solid is suction filtered, washed with a little toluene and dried in a vacuum. 22.0 g (85% of theory) 2-amino-5-(4-fluorobenzylideneamino)-nitrobenzene is obtained as orange-yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][N:3]=1.[C:9](=[O:16])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[NH2:10].[OH-].[Na+].O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[F:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:10][C:9](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: Fc1ccnc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(F)ccn1
Temperature: 100 °C
Yield: 128.9 %

Procedure:
Palladium (II) acetate (1.69 g, 7.53 mmol) and Xantphos (8.71 g, 15.05 mmol) were dissolved/suspended in degassed 1,4-dioxane (1200 mL) in a nitrogen atmosphere. 2-Chloro-4-fluoropyridine (99 g, 753 mmol) and tert-butyl carbamate (97 g, 828 mmol) in 1,4-dioxane (550 mL) were added, followed by sodium hydroxide (45.2 g, 1.12 mol) and water (20 mL). The resulting mixture was heated at 100° C. for 2 h. The mixture was cooled to ambient temperature and filtered over celite. The residue was washed with 1,4-dioxane and the filtrate was concentrated to afford a yellow solid (206 g). The crude material was recrystallized from 2-propanol (400 mL) and dried to afford the title compound (120.8 g) as a white solid. LCMS 213 [M+H], RT 1.96 minutes, purity 94%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([O:26][CH2:27][CH2:28][CH:29]=[C:30]([F:32])[F:31])[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1>CO>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C@@:4]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([O:26][CH2:27][CH2:28][CH:29]=[C:30]([F:31])[F:32])[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2ccc(F)c(OCCC=C(F)F)c2)N=C1N
Solvent: CO
Product: CN1C(=O)[C@](c2ccc(OC(F)F)cc2)(c2ccc(F)c(OCCC=C(F)F)c2)N=C1N

Procedure:
A racemic mixture of 2-amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxy]-4-fluorophenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one was separated by chiral HPLC using column type Chiralcel AD, 5×50 cm; the mobile phase was 15% ethanol in hexane with 0.1% diethylamine at 100 mL/min to obtain the title S-isomer as a glass, identified by NMR and mass spectral analyses [mp glass; [α]D25=16° (c=1%, MeOH); MS (ES) m/z 454.0].
Reaction SMILES: [CH3:1][C:2]1([C:5](Cl)=[O:6])[CH2:4][CH2:3]1.[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][C:2]1([C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[O:6])[CH2:4][CH2:3]1
Reactant: c1c[nH]cn1
Reactant: CC1(C(=O)Cl)CC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C(=O)n2ccnc2)CC1
Reaction time: 3 h
Yield: 91 %

Procedure:
A solution of 1-methylcyclopropylcarbonyl chloride (11.8 g) in toluene (15 ml) was added dropwise to a solution of imidazole (13.6 g) in tetrahydrofuran (100 ml) whilst maintaining the temperature below 25° C. The mixture was stirred for 3 hours and filtered. The filtrate was evaporated to dryness to give 1-(1-methylcyclopropylcarbonyl)-imidazole (13.6 g) as a white solid, mp 34°-35° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:35]1([C:41]#[CH:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:42]#[C:41][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C#Cc5ccccc5)n4)cc3)cc2)CC1
Temperature: 40 °C

Procedure:
1-{4′-[4-(6-Bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.200 g, 0.386 mmol) was dissolved in toluene along with phenylacetylene (0.051 mL, 0.46 mmol), copper(I) iodide (0.367 g, 1.93 mmol), triethylamine (0.269 mL, 1.93 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.032 g, 0.039 mmol). The reaction was heated to 40° C. for 3 days then cooled, diluted with EtOAc and filtered through a plug of silica gel. The crude material was purified on silica gel to yield the title compound.
Reaction SMILES: [Br:1]Br.Cl.[C:4]([C:7]1[CH:8]=[CH:9][C:10]([NH2:17])=[C:11]([CH:16]=1)[CH2:12][N:13]([CH3:15])[CH3:14])(=[O:6])[CH3:5].N>C(O)(=O)C>[C:4]([C:7]1[CH:8]=[C:9]([Br:1])[C:10]([NH2:17])=[C:11]([CH:16]=1)[CH2:12][N:13]([CH3:14])[CH3:15])(=[O:6])[CH3:5]
Reactant: BrBr
Reactant: CC(=O)c1ccc(N)c(CN(C)C)c1
Agent: Cl
Agent: N
Solvent: CC(=O)O
Product: CC(=O)c1cc(Br)c(N)c(CN(C)C)c1

Procedure:
9.0 gm of bromine were added dropwise to a solution of 12.8 gm of 5-acetyl-2-amino-N,N-dimethyl-benzylamine hydrochloride in 100 ml of 80% acetic acid. Subsequently, the reaction mixture was made alkaline with 2 N ammonia, extracted twice with chloroform, and the organic extract was evaporated. By recrystallization of the residue from ethanol/water, 5-acetyl-2-amino-3-bromo-N,N-dimethyl-benzylamine, m.p. 92-95° C, was obtained.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[CH:9][CH:8]=2)[C:5]([S:19][CH2:20][C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])=[N:4][CH:3]=1.C([O:30][C:31](=[O:34])[CH2:32][NH2:33])C.BrC1N(C2C3C(=CC=CC=3)C(C#N)=CC=2)C(SCC(O)=O)=NC=1.NCC(NCC(OCC)=O)=O>>[Br:1][C:2]1[N:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[CH:9][CH:8]=2)[C:5]([S:19][CH2:20][C:21]([NH:23][CH2:24][C:25]([NH:33][CH2:32][C:31]([OH:34])=[O:30])=[O:27])=[O:22])=[N:4][CH:3]=1
Reactant: N#Cc1ccc(-n2c(Br)cnc2SCC(=O)NCC(=O)O)c2ccccc12
Reactant: CCOC(=O)CN
Agent: CCOC(=O)CNC(=O)CN
Agent: N#Cc1ccc(-n2c(Br)cnc2SCC(=O)O)c2ccccc12
Product: N#Cc1ccc(-n2c(Br)cnc2SCC(=O)NCC(=O)NCC(=O)O)c2ccccc12

Procedure:
2-(2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)acetamido)acetic acid is prepared via either of the two routes shown below. In the first, 2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)acetic acid (see eg 3) is coupled with glycine ethyl ester and then hydrolyzed to the acid. In the second, 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid (see eg 1) is coupled with NH2-Gly-Gly-OEt, which is then hydrolyzed to the acid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][C:8](=O)[CH3:9].[NH2:12][NH2:13]>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH3:9])[NH:13][N:12]=1
Reactant: NN
Reactant: CC(=O)CC(=O)c1ccco1
Solvent: CO
Product: Cc1cc(-c2ccco2)n[nH]1
Reaction time: 24 h
Yield: 97.9 %

Procedure:
To a solution of 1.07 g (7.03 mmol) of 1-(2-furyl)-1,3-butanedione in 26 mL of MeOH at 25° C. was added 0.442 mL (14.07 mmol) of hydrazine. The reaction was stirred for 24 h then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexanes/EtOAc (1:1) as eluent to give 1.02 g (98%) of title compound: low resolution MS (Cl) m/e 149 (MH+).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:13]=[CH:12][C:11]([CH:14](Cl)[CH2:15][NH:16][CH:17]([CH3:19])[CH3:18])=[CH:10][C:4]=1[NH:5][S:6]([CH3:9])(=[O:8])=[O:7].[CH3:21][SH:22]>C(Cl)CCl>[OH:2][C:3]1[CH:13]=[CH:12][C:11]([CH:14]([S:22][CH3:21])[CH2:15][NH:16][CH:17]([CH3:19])[CH3:18])=[CH:10][C:4]=1[NH:5][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CS
Reactant: CC(C)NCC(Cl)c1ccc(O)c(NS(C)(=O)=O)c1
Agent: Cl
Solvent: ClCCCl
Product: CSC(CNC(C)C)c1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 1 g sample of 2'-hydroxy-5'-[1-chloro-2-(isopropylamino)ethyl]methanesulfonanilide hydrochloride is slowly added to 5 ml of methylmercaptan in 25 ml of ethylene dichloride at 0° to -10° C. under N2 atmosphere. This mixture is first stirred several hours at ice-bath temperature and then stirred at ambient temperature for 24 hours. The mixture is filtered. The filter cake is washed with ethylene dichloride, added to water, and basified with 10% NaOH solution to pH 10 in an ice bath. The aqueous mixture is extracted several times with methylene chloride. The combined extracts are dried over MgSO4 and evaporated to dryness thus yielding the crude product compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38]Br>CN(C)C=O.O>[Br:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:3]2[CH:4]=[C:5]([C@H:8]3[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]3)[CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:25][CH:24]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOCCBr)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
To a stirred suspension of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (100 mg, 0.26 mmol) in N,N-dimethylformamide (3 mL) and cesium carbonate (162 mg, 0.52 mmol) was added 1-bromo-2-(2-bromoethoxy)ethane (182 mg, 0.79 mmol). The mixture was stirred overnight at room temperature. The solution was diluted with water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC to give 30 mg of yellow oil (21% yield), which was used in the next step without purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][CH3:11])=[CH:4][CH:3]=1.[BH3-]C#[N:15].[Na+]>CC(O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH2:15])[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: CCC(=O)Cc1ccc(I)cc1
Agent: [Na+]
Solvent: CC(C)O
Product: CCC(N)Cc1ccc(I)cc1
Temperature: 90 °C

Procedure:
5.95 g (21.7 mmol) 1-(4-iodophenyl)-butane-2-one (I39) are added to 150 mL 2-propanol and transferred into an autoclav. 25.1 g (326 mmol) NH4OAc and 4.09 g (65.1 mmol) NaCNBH3 are added and the mixture is stirred at 90° C. over night. The reaction is quenched by the addition of sat. aq. NaHCO3 solution and extracted with EtOAc (3×). The combined organic layers are washed with brine, dried with Na2SO4 and the solvent is removed in vacuo. The compound is used without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])[CH:6]=1.[CH3:16][C:17]([CH3:21])([CH3:20])[C:18]#[CH:19].O>N1CCCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][C:17]([CH3:21])([CH3:20])[C:18]#[C:19][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])[CH:6]=1
Reactant: C#CC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1-n1cc(I)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: C1CCNCC1
Product: CC(C)(C)C#Cc1cnn(-c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-iodo-1-(2-nitro-phenyl)-1H-pyrazole (24 g, 76 mmol) in piperidine (215 ml) were added successively copper(I) iodide (0.7 g, 3.8 mmol), bis(triphenylphosphine)palladium(II) chloride (2.7 g, 3.8 mmol) and 3,3-dimethyl-1-butyne (12.5 g, 0.15 mol). This mixture was stirred for 16 hours at room temperature. Subsequently, it was poured into 1 litre of water, stirred for 15 minutes and extracted with tert-butyl methyl ether. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated. The remaining oil was purified by silica gel chromatography using ethyl acetate and hexane as eluents, giving Compound No. 6.030.r (20 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][C@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:15]2[CH2:16][CH2:17][CH2:18][C@@H:14]2[CH3:13])[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1
Reactant: C[C@H]1CCCN1
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(N2CCC[C@@H]2C)cc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
A mixture of 1-bromo-3-methoxy-5-nitrobenzene (500 mg, 2.16 mmol), (S)-2-methylpyrrolidine (200 mg, 2.37 mmol), Pd2(dba)3 (248 mg, 0.43 mmol), BINAP (538 mg, 0.86 mmol), Cs2CO3 (2.11 g, 6.48 mmol) and dioxane (20 mL) was heated to 100° C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to afford (S)-1-(3-methoxy-5-nitrophenyl)-2-methylpyrrolidine (430 mg, 85%) as yellow oil. LC-MS: 237 [M+H]+, tR=1.77 min.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH:6]([C:8]1[NH:9][C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:13]=[C:12]([Cl:23])[N:11]=2)[CH3:7])=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:15]2[N:16]=[C:8]3[N:9]([C:10]=2[N:11]=1)[CH2:2][C:3](=[O:4])[NH:5][CH:6]3[CH3:7]
Reactant: CC(NC(=O)CBr)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1NC(=O)Cn2c1nc1c(N3CCOCC3)nc(Cl)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
A mixture of 2-bromo-N-[1-(2-chloro-6-morpholin-4-yl-9H-purin-8-yl)-ethyl]-acetamide (275 mg, 0.68 mmol) and cesium carbonate (0.48 g, 1.36 mmol) in anhydrous DMF (10 mL) was stirred at RT for 2 h, then diluted with water and extracted five times with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2) gradient 0-5% methanol in DCM) to give 3-Chloro-8-methyl-1-morpholin-4-yl-7,8-dihydro-2,4,4b,7,9-pentaaza-fluoren-6-one (93 mg, 42%). LCMS RT=2.41 min, [M+H]+=323/325