Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.Cl[CH2:29][CH2:30][CH2:31][OH:32].Cl>>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:26][CH2:25][CH2:24][N:23]([CH2:29][CH2:30][CH2:31][OH:32])[CH2:22][CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCNCC4)n3)ccc21
Reactant: OCCCCl
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCN(CCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS301 starting from 66 mg (0.18 mmol) of 1-[6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-pyridin-2-yl]-1,4-diazepane and 18 μl of 3-chloro-1-propanol. The product is the hydrochloride.
Reaction SMILES: [H-].[Na+].[C:3]1([N:9]2[C:17]3[N:16]=[CH:15][NH:14][C:13]=3[C:12](=[O:18])[NH:11][C:10]2=[O:19])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([N:14]1[C:13]2[C:12](=[O:18])[NH:11][C:10](=[O:19])[N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:17]=2[N:16]=[CH:15]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c(=O)n(-c2ccccc2)c2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(-c2ccccc2)c2ncn(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.2 g (0.1315 mol) of sodium hydride were added in portions to a suspension of 30 g (0.1315 mol) of 3-phenylxanthine in 600 ml of DMF, the mixture was stirred at 25° C. for 30 minutes and then heated to 80° C. 27 g (0.1578 mol) of benzyl bromide were then added and the solution was left at 80° C. for 6 hours. After cooling to 50° C., the reaction mixture was poured into 2000 ml of ice-water, and the precipitate obtained was filtered off with suction, washed well with water and dried under reduced pressure. The dry residue was crystallized from dioxane/methanol.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>>[OH:9][CH2:10][CH2:11][N:12]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:14][OH:15]
Reactant: ClCc1ccccc1
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCCN(CCO)Cc1ccccc1
Temperature: 90 °C
Yield: 55.3 %

Procedure:
S. Gump and E.J. Nikaivitz in Example 3 of U.S. Pat. No. 2,504,977 issued April 25, 1950, show the reaction of 190 g of benzyl chloride with 315 g of N,N-bis(2-hydroxyethyl)amine at 100-125° C. for nine hours followed by addition of sufficient saturated potassium carbonate to neutralize "the formed hydrochlorides" and continued stirring of the mixture for thirty minutes at 90° C. The separated oil in isopropyl ether and ethanol was dried and distilled twice to produce 162 g (54.3% yield) of pure N,N-bis(2-hydroxyethyl)benzylamine. A 97 g portion of N,N-bis(2-hydroxyethyl)benzylamine was converted into 115 g (85.7% yield) of N,N-bis(2-chloroethyl)benzylamine hydrochloride (46.5% yield based on benzyl chloride) by adding dropwise with stirring 120 g of thionyl chloride in chloroform to a cooled (ice bath) chloroform solution of N,N-bis(2-hydroxyethyl)benzylamine, and then isolating the product and converting it to its hydrochloride salt.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[Cl:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccc(Cl)nc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (62 mg, 77%), MS (ISN) m/z=323.5 [(M+H)+], mp 300.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 6-chloro-pyridin-3-ylboronic acid (51.1 mg, 0.325 mmol).
Reaction SMILES: Cl[C:2]([N:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH2:5]1)=[O:3].[CH3:16][NH2:17]>O1CCCC1.O>[Cl:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH:6]1[CH2:7][N:4]([C:2]([NH:17][CH3:16])=[O:3])[CH2:5]1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2cccc(Cl)c2)C1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2cccc(Cl)c2)C1
Reaction time: 16 h
Yield: 39.1 %

Procedure:
A solution of 1-chlorocarbonyl-3-(3-chlorophenoxy) azetidine (0.01275 mole) in 20 ml of tetrahydrofuran was treated with 4 ml (0.05 mole) of 40% aqueous methylamine and stirred for 16 hr. The reaction mixture was diluted with water until an oil began to separate, then extracted with 3×50 ml of benzene. The combined extracts were dried over magnesium sulfate and concentrated to a solid which was recrystallized from benzene/ligoin to yield 1.2 g (40.0%) of fine white crystals, m.p. 140°-141° C.
Reaction SMILES: [CH2:1]([C@H:3]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:5](=[O:17])[CH2:4]1)[CH3:2].[OH2:18].[OH-].[K+]>CO>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([NH:6][C@H:3]([CH2:1][CH3:2])[CH2:4][C:5]([OH:17])=[O:18])=[CH:8][CH:9]=1
Reactant: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Reactant: O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](CC(=O)O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 76 %

Procedure:
2.91 g (12.0 mmol) of (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone produced in Example 6 was dissolved in methanol (15 mL) and further mixed with water (10 mL) and potassium hydroxide (1.34 g, 23.9 mmol). The resulting solution was stirred at room temperature for 14 hours. On completion of the reaction, methanol was removed by distillation and toluene (10 mL) and water (5 mL) were added to separate the solution. The separated organic layer was further mixed with water (15.2 mL) and a 30 wt % aqueous solution of potassiumhydroxide (1.02 g) to separate the solution again. The separated aqueous layers were collected together and adjusted to be pH=1.5 by concentrated hydrochloric acid and extraction with toluene (20 mL) was repeated three times. The residue obtained by concentrating the organic layer was crystallized from toluene (9 mL)/hexane (35 mL) to obtain (R)-3-[4-(trifluoromethyl)phenylamino]-pentanoic acid as awhite crystal (2.38 g, isolated yield: 76%). 1H-NMR (CDCl3, 400 MHz/ppm): δ 0.90 (3H, t), 1.5-1.8 (2H, m), 2.4-2.5 (2H, m), 3.7-3.9 (1H, m), 6.65 (2H, d), 7.39 (2H, d)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1.[C:23]([O:27][C:28]([NH:30][C@H:31]([CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1)[CH2:32][C:33](O)=[O:34])=[O:29])([CH3:26])([CH3:25])[CH3:24].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:15]([C:12]1[CH:13]=[CH:14][C:9]2[N:8]=[C:7]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:33](=[O:34])[CH2:32][C@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH:38]=4)[CH2:18]3)[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:10]=2[CH:11]=1)#[N:16]
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2ccc(C#N)cc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(C#N)cc21
Reaction time: 0.08 h
Yield: 80 %

Procedure:
(R)-1-(3-Methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole-6-carbonitrile (41E) (0.20 mmol, 80 mg) in DMF (6 mL) was added (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.22 mmol, 72 mg) and N-methylmorpholine (0.80 mmol, 0.09 mL). The reaction mixture was stirred at it for 5 min and then added HATU (0.22 mmol, 84 mg) and kept stirring at it overnight. The reaction mixture was poured into H2O, extracted with EtOAc. The extract was washed with H2O, NaHCO3, brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and purified by preparative LC/MS (40-90% CH3CN in H2O) to afford tert-Butyl (R)-4-((R)-3-(6-cyano-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (41F) (0.16 mmol, 100 mg, yield: 80%). ESI-MS: m/z 610.5 (M+H)+.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:12])[NH:5][C:6]2[C:11]\1=[CH:10][CH:9]=[CH:8][CH:7]=2.[NH2:13][C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>CCO>[O:12]=[C:4]1[NH:5][C:6]2[C:11](/[C:3]/1=[CH:2]/[NH:13][C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:21])=[O:22])[CH:17]=[CH:18][CH:19]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C1Nc2ccccc2/C1=C/O
Solvent: CCO
Product: NS(=O)(=O)c1cccc(N/C=C2\C(=O)Nc3ccccc32)c1
Temperature: 80 °C
Yield: 79.3 %

Procedure:
A mixture of 0.161 g (1.0 mmol) of (3Z)-3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one 1,2 and 0.180 g (1.05 mmol) of 3-aminobenzene-1-sulfonamide in 5 ml of EtOH was heated to 80° C. for 45 min. After cooling to ambient temperature, the solid was collected by vacuum filtration and air dried to afford 3-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-methyl]amino}benzenesulfonamide as a yellow solid (0.25 g, 79%). mp>250° C.; 1H NMR (DMSO-d6): 6.82 (d, J=7.7 Hz, 1H), 6.87-6.94 (m, 1H), 6.97-7.30 (m, 1H), 7.35 (s, 2H), 7.42-7.47 (m, 1H), 7.50-7.63 (m, 3H), 7.75 (t, J=1.8 Hz, 1H), 8.59 (d, J=12.1 Hz, 1H), 10.53 (s, 1H), 10.85 (d, J=12.3 Hz, 1H); APCI-MS: m/z 316 (m+H)+. Anal. Calcd for C15H13N3O3S: C, 57.13; H, 4.16; N, 13.32; S, 10.17. Found: C, 57.01; H, 4.23; N, 13.30; S, 10.11.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:25][C:26]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1[CH3:34])=[O:27]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:25][C:26]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:27])[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Cc1ccncc1C(=O)CBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ccncc1C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
A suspension of 100 mg (0.394 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 385.42 mg (1.18 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 139.57 mg (0.473 mmol) of 2-bromo-1-(4-methylpyrid-3-yl)ethanone hydrobromide are then added. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 140 mg of (8S)-2-chloro-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to the following characteristics:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:26])[CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[NH:8]C=O.Cl>CO>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17](=[O:26])[CH2:18][C:19]([CH3:24])([CH3:25])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:16]=2)=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(NC=O)c(F)c2)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(N)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
To a solution of methyl 4-[3′-fluoro-4′-(formylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoate (1.21 g, 3.39 mmol) in methanol (10 mL) was added conc. HCl (3.5 mL), and the resulting solution was stirred at rt for 16 h. The mixture was then concentrated, diluted with water, and the acidity was adjusted to pH ˜7 by slow addition of saturated aqueous sodium bicarbonate solution. The mixture was then extracted with dichloromethane, and the combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was then triturated with ethyl acetate/hexane to afford methyl 4-(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (998 mg, 89%). LC-MS ret. time 3.11 min, m/z 329.9 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.31 (s, 6H), 3.28 (s, 2H), 3.66 (s, 3H), 6.84 (t, 1H), 7.21–7.35 (m, 2H), 7.55 (d, 2H), 7.93 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:16])(=[N:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:4][CH:3]=1.[Br:17][C:18]1[C:19]([S:25][CH3:26])=[N:20][C:21](Cl)=[N:22][CH:23]=1.Cl>O1CCOCC1.C(#N)C.O>[CH2:14]([O:13][C:11]([N:10]=[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:21]2[N:20]=[C:19]([S:25][CH3:26])[C:18]([Br:17])=[CH:23][N:22]=2)=[CH:3][CH:4]=1)([CH3:16])=[O:9])=[O:12])[CH3:15]
Reactant: CSc1nc(Cl)ncc1Br
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(Br)c(SC)n2)cc1

Procedure:
(RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-methylsulfoximide (10 g, 42 mmol), 5-bromo-2-chloro-4-methylsulfanyl-pyrimidine (10 g, 42 mmol) and 5M HCl (8 mL) in dioxane is stirred at 60° C. in 90% acetonitrile-water (250 mL) for 36 h. TLC indicates almost complete consumption of starting sulfoximine. The reaction mixture is poured into 800 mL of aq. NaHCO3, the pasty precipitate filtered, washed with 70 mL of EtOAc, then crude material (7.5 g) is recrystallized from boiling EtOH (200 mL) to yield 6 g (35%).
Reaction SMILES: [CH:1]1[C:6](O)=CC=C(C)[CH:2]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[CH2:6]([O:19][C:16]1[CH:15]=[CH:14][C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])=[CH:18][CH:17]=1)[C:1]#[CH:2]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: Cc1ccc(O)cc1
Product: C#CCOc1ccc(C(C)(C)C)cc1
Yield: 98 %

Procedure:
Example 14 is repeated except that p-cresol is replaced by 4-t-butylphenol. The product, 4-t-butylphenyl propargyl ether, is isolated as a colorless liquid in 98% yield and characterized by pmr spectroscopy. The product is represented by the following formula: ##STR24##
Reaction SMILES: C(Cl)Cl.[Cl-].[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([F:14])[CH:13]=1)[CH2:9][Zn+].Br[C:16]1[CH:17]=[C:18]2[C:24]([NH2:25])=[N:23][NH:22][C:19]2=[N:20][CH:21]=1.O>O1CCCC1>[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([F:14])[CH:13]=1)[CH2:9][C:16]1[CH:17]=[C:18]2[C:24]([NH2:25])=[N:23][NH:22][C:19]2=[N:20][CH:21]=1
Reactant: Fc1cc(F)cc(C[Zn+])c1
Reactant: Nc1n[nH]c2ncc(Br)cc12
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Nc1n[nH]c2ncc(Cc3cc(F)cc(F)c3)cc12
Temperature: 90 °C
Yield: 93 %

Procedure:
CH2Cl2 and 28 ml (14.08 mmol) of 3,5-difluorobenzyl zinc (II) chloride are added to 1.5 g (7.04 mmol) of a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridin-3-amine in 10 ml of tetrahydrofuran. The reaction medium is heated at 90° C. for 18 hours. After returning to room temperature, the reaction is hydrolyzed by slowly adding water at 0° C. After filtration of the precipitate formed, the solid is rinsed with tetrahydrofuran and the aqueous filtrate is extracted several times with ethyl acetate. The organic phases are combined, dried on magnesium sulfate and concentrated. The residue is purified by silica chromatography (95:4.5:0.5 and then 95:4:1 dichloromethane/methanol/ammonium as eluent) to yield 1.7 g (93%) of 5-(3,5-difluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-amine in the form of a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH2:19][CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:18])=[O:17])[C:4]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34].C[OH:36]>>[OH:36][CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][CH2:20][CH2:19][S:16]([NH:15][C:5]1[C:4]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])=[C:3]([O:2][CH3:1])[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=1)(=[O:17])=[O:18]
Reactant: CO
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)CCCC(C)(C)C)nc(-c2ncccn2)nc1OC
Product: COc1ccccc1Oc1c(NS(=O)(=O)CCCC(C)(C)CO)nc(-c2ncccn2)nc1OC
Reaction time: 48 h

Procedure:
Streptomyces rimosus subsp. rimosus ATCC10970 maintained on a quarter strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flask containing 50 ml of AS-7H inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron Shaker with 1″ throw. 2 mls of this inoculum medium was then transferred to twenty 300 ml Erlenmeyer flask containing 50 ml of AP-5H production medium and incubated under the same conditions for a further 24 hours. At this point 4.5 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-4,4-dimethyl-1-pentanesulfonamide (Preparation 3) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 20 hours. The flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid, 200 mg.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](F)=[C:4](F)[C:3]=1[F:14].BrC1C=C2C(=CC=1)C(F)(F)C(F)(F)C=C2.[NH4+].[OH-]>C1COCC1.[Zn]>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[F:14]
Reactant: Fc1c(F)c(F)c2ccccc2c1F
Agent: FC1(F)C=Cc2cc(Br)ccc2C1(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Fc1ccc2ccccc2c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
A solution of the tetrafluoro naphthalene, 6-bromo-1,1,2,2-tetrafluoro-1,2-dihydronaphthalene (4.74 g, 16.80 mmol) in THF (15 ml) was treated with 30% aqueous NH4OH (30 ml) and zinc (8.45 g, 130 mmol) and stirred under N2 for 24 hours at RT. The reaction was monitored by GC/MS for disappearance of the starting material and found to be complete. The solution was filtered, extracted with hexane (30 ml), and filtered through a short silica column (20 g). The hexane solution was evaporated in vacuo to afford an oil. This crystallized on cooling to room temperature to afford 2.62 g (95% yield) of product.
Reaction SMILES: [CH:1]1[C:2]2[CH:19]=[CH:18][C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[CH:10]=[CH:9][C:8]=3[C:3]=2[O:4][C:5]=1[CH2:6][OH:7].[Mn]([O-])([O-])(=O)=O.[Ba+2]>C(Cl)Cl>[CH:1]1[C:2]2[CH:19]=[CH:18][C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[CH:10]=[CH:9][C:8]=3[C:3]=2[O:4][C:5]=1[CH:6]=[O:7]
Reactant: OCc1cc2ccc3c4ccccc4ccc3c2o1
Agent: O=[Mn](=O)([O-])[O-]
Agent: [Ba+2]
Solvent: ClCCl
Product: O=Cc1cc2ccc3c4ccccc4ccc3c2o1
Yield: 89.3 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser, N2 inlet line with bubbler was added phenanthro[1,2-b]furan-2-methanol (14A, 5.84 g, 23.5 mmol), barium manganate (Aldrich, 12.06 g, 47 mmol) and dry CH2Cl2 (400 mL). The mixture was refluxed for 6 h, filtered and the resulting dark yellow solution filtered through a small plus of SiO2 to remove inorganic salts and polar baseline material. The solvent was then removed by rotary evaporation and the crude material recrystallized using CH2Cl2 /hexane to give after drying 5.17 g (91% yield) of phenanthro[1,2-b]furan-2-carbaldehyde, mp 169°, (C,H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:14]1([CH2:17][NH:18][C:19](=[O:30])[NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH:14]1([CH2:17][NH:18][C:19](=[O:30])[NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)=[O:26])=[CH:28][CH:29]=2)[CH2:16][CH2:15]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)NCC3CC3)cc2)CC1
Reaction time: 1 h

Procedure:
To a stirred mixture of tert-butyl piperazine-1-carboxylate (45.8 mmol, 8.53 g) and 4-(3-(cyclopropylmethyl)ureido)benzoic acid (45.8 mmol, 10.73 g) in dichloromethane (200 ml) was added triethylamine (103 mmol, 14.36 mL, 10.43 g) followed by 1-propane-phosphonic acid cyclic anhydride (68.7 mmol, 40.7 mL, 43.7 g; 50% solution in ethyl acetate). The reaction was stirred for 1 hour, then poured into saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic phase was dried (magnesium sulfate), filtered and evaporated to a white solid (17.13 g)
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[CH:11]=[C:10]([NH:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[C:9]([CH3:25])=[CH:8][C:7]=2[C:6]([CH3:27])([CH3:26])[CH2:5][CH:4]=1)[CH3:2].[CH:28](=O)[CH3:29]>>[CH2:28]([N:13]([C:10]1[C:9]([CH3:25])=[CH:8][C:7]2[C:6]([CH3:27])([CH3:26])[CH2:5][CH:4]=[C:3]([CH2:1][CH3:2])[C:12]=2[CH:11]=1)[C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=1)[CH3:29]
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CC=C3CC)cc1
Reactant: CC=O
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)(C)CC=C3CC)cc1
Yield: 44.4 %

Procedure:
Following General Procedure D, ethyl 4-[(8-ethyl-3,5,5-trimethyl-5,6-dihydronaphthalen-2-yl)amino]benzoate (Compound 16, 0.25 g, 0.69 mmol) was reacted with acetaldehyde (0.8 mL, 13.8 mmol) to give 0.12 g (43%) of the title compound as a clear oil.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[C:15]([F:32])[CH:14]=2)[CH2:8]1)(=O)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:33]([CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:21][CH2:20]3)=[C:15]([F:32])[CH:14]=2)[CH2:8]1)=[N+:34]=[N-:35]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Temperature: 60 °C
Yield: 99.8 %

Procedure:
A solution of the 16.8 g (35.5 mmol) of the mesylate 3 in 400 mL of dimethylformamide was treated with 11.5 g (177.5 mmol) of sodium azide followed by warming at 60° C. for 16 h. The solution was diluted with ethyl acetate and extracted with water. The organic layer was dried (Na2SO4) and concentrated in vacuo to afford 14.9 g (100%) of the azide 4 as a light yellow solid, mp 101°-104° C., sufficiently pure for further use.