Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:21][CH3:22])=[C:6]([CH:8]2[C:14](=[O:15])[CH:13]3[C:16]([CH3:18])([CH3:17])[C:10]([CH3:19])([CH2:11][CH2:12]3)[C:9]2=[O:20])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[OH:37]>FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O.C1(C)C=CC=CC=1>[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[O:37][C:2]1[CH:3]=[CH:4][C:5]([CH2:21][CH3:22])=[C:6]([CH:8]2[C:14](=[O:15])[CH:13]3[C:16]([CH3:18])([CH3:17])[C:10]([CH3:19])([CH2:11][CH2:12]3)[C:9]2=[O:20])[CH:7]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CCc1ccc(Br)cc1C1C(=O)C2CCC(C)(C1=O)C2(C)C
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Cc1ccccc1
Product: CCc1ccc(Oc2ccc(Cl)cc2Cl)cc1C1C(=O)C2CCC(C)(C1=O)C2(C)C
Temperature: 170 °C

Procedure:
To a mixture of rac-3-(5-bromo-2-ethylphenyl)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.175 g, 0.48 mmol), cesium carbonate (0.314 g, 0.96 mmol) and 2,4-dichlorophenol (0.393 g, 2.41 mmol) is added copper (II) trifluoromethanesulfonate (0.009 g, 0.024 mmol) and powdered 3 Å molecular sieves (0.200 g). Degassed anhydrous toluene (2 ml) is then added, followed by purging with nitrogen and heating at 170° C. for 1 hour under microwave irradiation. After cooling to room temperature the reaction mixture is quenched with 2M aqueous hydrochloric acid and extracted with dichloromethane (×2). The organic phase is separated and concentrated under reduced pressure. The crude product is then purified by preparative reverse phase HPLC to afford rac-(1S,5R)-3-[5-(2,4-dichlorophenoxy)-2-ethylphenyl]-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12](N)=[O:13]>>[Br:10][C:7]1[CH:8]=[N:9][C:2]2[N:1]=[C:12]([OH:13])[N:11]=[CH:4][C:3]=2[CH:6]=1
Reactant: Nc1ncc(Br)cc1C=O
Reactant: NC(N)=O
Product: Oc1ncc2cc(Br)cnc2n1
Temperature: 180 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
A mixture of 2-amino-5-bromonicotinaldehyde (2.0 g, 10.0 mmol) and urea (9.0 g, 150.0 mmol) was heated at 180° C. and stirred vigorously for 2 hours. The reaction mixture was cooled to room temperature, and the resulting precipitate was collected, washed with water (3×100 mL) and co-evaporated with toluene three times to completely remove the moisture trapped. The title compound (2.1 g, 93%) was obtained as a yellow solid. MS (ES+) C8H5BrN2O requires: 225, 227, found: 226, 228 [M+H]+.
Reaction SMILES: CN1CCOCC1.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[CH:18]1([C:21]2[CH:25]=[C:24]([NH2:26])[NH:23][N:22]=2)[CH2:20][CH2:19]1.C(OCC)C>ClC>[CH:18]1([C:21]2[CH:25]=[C:24]([NH:26][C:13](=[O:14])[C:12]3[CH:16]=[CH:17][C:9]([Br:8])=[CH:10][CH:11]=3)[NH:23][N:22]=2)[CH2:20][CH2:19]1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: CCl
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: O=C(Nc1cc(C2CC2)n[nH]1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.9 %

Procedure:
122 mg (loading 1.91 mmol/g, 0.233 mmol) of polystyrene supported N-methylmorpholine were suspended in 4 ml of chloromethane and then treated with 25.6 mg (0.117 mmol) of 4-bromobenzoyl chloride followed by 4.8 mg (0.039 mmol) of 3-cyclopropyl-5-amino-pyrazole. After 48 hours under stirring at room temperature the resin was separated by filtration and washed with 2 ml of dichloromethane. The filtrate was evaporated to dryness, the residue re-dissolved in 4 ml of dichloromethane and 100 mg of polystyrene supported trisamine were added. After 48 hours or stirring at room temperature the resin was filtered, washed with 2 ml of dichloromethane and concentrated to give, after triturating with diethylether, 9.3 mg (78% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([OH:17])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH:42]4[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]4)=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH3:2]
Reactant: CCCn1c(COCC)nc2cnc3cc(O)ccc3c21
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCn1c(COCC)nc2cnc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c21
Reaction time: 72 h
Yield: 105.1 %

Procedure:
2-(Ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol (3.00 g, 10.5 mmol) and triphenylphosphine (3.43 g, 13.1 mmol) were slurried in THF (105 mL) and cooled with an ice/water bath. tert-Butyl 4-hydroxypiperidine-1-carboxylate (2.64 g, 13.1 mmol) was added followed by the dropwise addition of diisopropyl azodicarboxylate (2.58 mL, 13.1 mmol). The water bath was removed and the mixture was stirred for 72 hours under nitrogen. The solvent was removed under reduced pressure and the residue was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 1-15% CMA in chloroform) to afford 5.17 g of tert-butyl 4-{[2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate as an off-white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]([C:24]3[N:25]=[CH:26][S:27][CH:28]=3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:15])=[O:14])=[CH:9][C:8]=2[C:29]#[N:30])=[C:4]([C:33]2[N:37]([CH:38]3[CH2:41][N:40](C(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:39]3)[N:36]=[CH:35][CH:34]=2)[CH:3]=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.ClC(OC(Cl)C)=O>ClCCl>[NH:40]1[CH2:39][CH:38]([N:37]2[C:33]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:32]=[CH:31][C:5]=3[O:6][C:7]3[CH:12]=[CH:11][C:10]([S:13]([N:16]([C:24]4[N:25]=[CH:26][S:27][CH:28]=4)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])(=[O:15])=[O:14])=[CH:9][C:8]=3[C:29]#[N:30])=[CH:34][CH:35]=[N:36]2)[CH2:41]1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1ccc(Oc2ccc(Cl)cc2-c2ccnn2C2CN(C(c3ccccc3)c3ccccc3)C2)c(C#N)c1
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1ccc(Oc2ccc(Cl)cc2-c2ccnn2C2CNC2)c(C#N)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
tert-butyl {[4-(4-chloro-2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}phenoxy)-3-cyanophenyl]sulfonyl}1,3-thiazol-4-ylcarbamate, (Preparation 680, 224 mg, 0.287 mmol) was dissolved in dichloromethane (10 ml) and N,N,N′,N′-tetramethylnaphthalene-1,8-diamine (150 mg, 0.70 mmol) was added, followed by 1-chloroethyl chloroformate (0.07 ml, 0.65 mmol) and the solution was stirred at room temperature for 3.5 hours. Concentrated in vacuo and the residue was dissolved in methanol (10 ml) and refluxed for 4 hours. Concentrated in vacuo to give the crude title compound as a brown gum, 200 mg. This material was used without purification in Example 815.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][CH:11]=[CH:10][C:9]=2[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4].[OH-].[Na+]>CO.O1CCCC1>[C:24]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([O:15][CH3:16])=[C:5]([C:3]([OH:4])=[O:2])[N:6]=1)#[N:25]
Reactant: COC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(=O)O)nc(C#N)c2c(Oc3ccccc3)cccc12
Yield: 92.7 %

Procedure:
To a mixture of 1-cyano-4-methoxy-8-phenoxy-isoquinoline-3-carboxylic acid methyl ester (727 mg, 2.18 mmol) and methanol/tetrahydrofuran (12.5 mL, 1:1.5) was added 2N sodium hydroxide (5.4 mL, 10.89 mmol) at room temperature. The yellow solution was stirred at that temperature for seventy minutes before it was concentrated. Water (20 mL) was added and the mixture was adjusted to pH=2 with 1N HCl (13 mL). The mixture was then extracted with dichloromethane and ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo to give the title compound as a yellow solid (647 mg): MS: (+) m/z 320.80 (M+1).
Reaction SMILES: C([N:8]1[CH2:25][CH:24]([CH2:26][OH:27])[O:23][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[OH-].[OH-].[Pd+2]>[OH:27][CH2:26][CH:24]1[O:23][C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:14][CH2:15]2)[CH2:9][NH:8][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccccc1)CC(CO)O2
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(CO)O2
Temperature: 60 °C
Yield: 99.1 %

Procedure:
A mixture of tert-butyl 8-benzyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (4.10 g, 10.9 mmol), ammonium formate (6.87 g, 109 mmol) and Pd(OH)2 (1.53 g, 10.9 mmol) was heated at 60° C. for 1 h. The reaction mixture was cooled, filtered, and concentrated in vacuo to provide tert-butyl 10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (3.10 g, 10.8 mmol, 99%). ESI-MS m/z calc. 286.2. found 287.2 (M+1)+; Retention time: 0.75 minutes (3 min run).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[O:8])=[C:5]([C:20]#[C:21][Si](C)(C)C)[N:4]=[C:3]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:20]([C:5]1[N:4]=[C:3]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:35])([F:36])[F:34])[CH:27]=2)[N:2]([CH3:1])[C:6]=1[C:7]([N:9]1[CH2:10][CH2:11][CH:12]([N:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:13][CH2:14]1)=[O:8])#[CH:21]
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(C#C[Si](C)(C)C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#Cc1nc(-c2cccc(OC(F)(F)F)c2)n(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 13, [3-methyl-2-(3-trifluoromethoxy-phenyl)-5-trimethylsilanylethynyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 23) was reacted with potassium carbonate to give the title compound as colorless foam. MS: 447.2 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C(=O)OCC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(C(=O)OCC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-ethoxycarbonyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][CH2:5]2.[NH4+:12].[OH-]>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:7]([NH2:12])=[O:11])=[C:4]([CH2:5][OH:6])[CH:3]=1
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccc(Br)cc1CO
Reaction time: 36 h
Yield: 99 %

Procedure:
To a suspension of 5-bromoisobenzofuran-1(3H)-one III-1 (6.57 g, 30.1 mmol) in MeOH (140 mL) was added NH4OH (60 mL). The reaction vessel was sealed and stirred for 36 h. The reaction was The reaction was concentrated under vacuum to afford 4-bromo-2-(hydroxymethyl)benzamide (7.10 g, 99%) as a white solid; 1H-nmr (400 MHz, CDCl3) δ 7.80 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.68 (s, 2H), 7.61 (s, 1H), 7.59-7.50 (m, 2H), 6.34 (br s, 1H), 5.72 (br s, 1H), 4.64 (s, 2H); LC (254 nM) 1.12 min (>98%); MS (ESI) m/z=231.8.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:9][C:10]([C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]2[S:26][CH:27]=[CH:28][C:14]=2[C:13]=1O)=[O:11])[CH3:8].[N:30]1([C:36]([C:38]2[S:39][CH:40]=[CH:41][CH:42]=2)=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C1N2CCN(CC2)C1.[Cl-].[NH4+]>CN(C=O)C.[Cl-].[Na+].O.O>[CH2:7]([O:9][C:10]([C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]2[S:26][CH:27]=[CH:28][C:14]=2[C:13]=1[N:33]1[CH2:34][CH2:35][N:30]([C:36]([C:38]2[S:39][CH:40]=[CH:41][CH:42]=2)=[O:37])[CH2:31][CH2:32]1)=[O:11])[CH3:8]
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: CCOC(=O)c1c(O)c2ccsc2n(Cc2ccccc2)c1=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2ccsc2n(Cc2ccccc2)c1=O
Temperature: -45 °C
Yield: 21 %

Procedure:
Oxalyl chloride (0.66 mL, 0.008 mol) was added slowly to a solution of 7-benzyl-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester (60) (1.0 g, 0.003 mol) in 25 mL anhydrous DMF stirred at −45° C. under argon. The solution was heated to 70° C. for 4 hours, and then poured into water. A small amount of brine was added, and the precipitated solid was collected by vacuum filtration. The oily solid was dissolved in dichloromethane, dried with magnesium sulfate, and then concentrated under vacuum to yield an oil. The oil was dissolved in DMF. Piperazin-1-yl-thiophen-2-yl-methanone (1.2 g, 0.004 mol) and DABCO (0.68 g, 0.006 mol) were added to the solution under argon. The solution was heated to 110° C. for 5 hours, and then poured into a 5% ammonium chloride aqueous solution. The precipitated solid was collected by vacuum filtration, and then purified by reverse phase (MeCN/water) chromatography to yield 0.320 g (21%) of 7-benzyl-6-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester. 1H-NMR (DMSO-d6) δ 1.28 (t, J=7.2 Hz, 3H), 3.40 (b, 4H), 3.81 (b, 4H), 4.26 (q, J=7.2 Hz, 2H), 5.26 (s, 2H), 7.15 (m, 1H), 7.28 (m, 5H), 7.35 (m, 2H), 7.47 (m, 1H), 7.79 (m, 1H) ppm; EIMS m/z 508 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[O:37][CH3:38])CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[O:37][CH3:38])=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(F)ccc1OC
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ncc2c(cc(-c3cc(F)ccc3OC)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 29.6 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.21 mmol), tributyl-(5-fluoro-2-methoxy-phenyl)-stannane (128 mg, 0.31 mmol), and PdCl2(PPh3)2 (29 mg, 0.041 mmol) in DMF (5 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine and EtOAc were added. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent, the crude product was first purified by silica gel chromatography (0-60% EtOAc/hexanes+1% AcOH), then by preparative TLC (20% EtOAc/CH2Cl2) to give 27 mg of the title compound. MS: (+) m/z 435.31 (M+1).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[N:12]2[N:19]=[C:18]([CH3:20])[C:17]([N+:21]([O-])=O)=[C:13]2[O:14][C:15]=1[CH3:16]>CO.B#[Ni].O.O.O.O.O.O.[Ni](Cl)Cl>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[N:12]2[N:19]=[C:18]([CH3:20])[C:17]([NH2:21])=[C:13]2[O:14][C:15]=1[CH3:16]
Reactant: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1[N+](=O)[O-]
Agent: B#[Ni]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of black nickel boride (prepared in situ from 0.50 g, 2.15 mmol nickel (II) chloride hexahydrate and (0.080 g, 2.15 mmol sodium borohydride) in MeOH (15 ml) at RT is added a solution of 3-(2,4-dichloro-phenyl)-2,6-dimethyl-7-nitro-pyrazolo[5,1-b]oxazole (1.40 g, 4.29 mmol) in MeOH (55 ml). Further sodium borohydride (0.74 g, 19.5 mmol) is added in portions and the reaction is stirred at RT for 1 hour. The reaction is quenched by the addition of water (200 ml) and reduced in vacuo to remove the MeOH. EtOAc is added and the mixture passed through a Celite® (filter material) 521 pad. The crude product is extracted with EtOAc (2×125 ml) and the combined extracts are then extracted using 0.2N HCl (2×120 ml). The aqueous portions are combined and basified with 1N NaOH to pH10 to yield the title compound as a solid, which is filtered off and dried in vacuo; MS: m/z 296.1 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:54][OH:55])[CH:52]=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:54][OH:55])[CH2:52][OH:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1.5 h
Yield: 31.5 %

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 6p (1.27 g, 1.63 mmol) was dissolved in 10 mL of mixed solution (THF and MeOH, v:v=1:1) and followed by addition of sodium borohydride (0.12 g, 3.26 mmol) in batch. The reaction mixture was stirred for 1.5 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and was partitioned after 30 mL of ethyl acetate were added. The organic extract was washed with saturated sodium chloride solution (15 mL×2), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system E to obtain the title compound [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 6q (400 mg, white solid), yield: 31.5%. 1H NMR (400 MHz, CD3OD): δ 7.58 (dd, 1H), 7.54 (d, 1H), 7.39 (d, 1H), 7.31-7.24 (m, 13H), 7.16 (d, 2H), 7.11-7.06 (m, 4H), 4.92 (d, 1H), 4.76 (d, 1H), 4.66-4.59 (m, 1H), 4.27-4.22 (m, 2H), 4.17-4.10 (m, 2H), 4.07-4.04 (m, 3H), 3.99-3.95 (m, 2H), 3.77 (d, 1H), 3.65-3.60 (m, 2H), 3.35 (s, 2H), 3.18 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].[H-].[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C@H:16]([C@@H:19]2[CH2:21][O:20]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].O>C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C@H:16]([C@@H:19]([OH:20])[CH2:21][S:4][CH:2]([CH3:3])[CH3:1])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)S
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H]2CO2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)SC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
2-Propanethiol (98.0 μL, 1.1 mmol) was dissolved in THF (250 μL), and the mixture was cooled to 0° C. NaH (12.6 mg, 527 μmol) was slowly added in four portions and the mixture was stirred at room temperature for 10 minutes. (S)—(R)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (75 mg, 350 μmol) was dissolved in THF (0.1 mL) and added to the mixture. The resulting solution was placed in a microwave reactor for 30 minutes at 100° C., then cooled to room temperature. Hexanes (3×10 mL) was added, followed by water (10 mL). The organic layer was collected, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (0-100% EtOAc in hexanes) to yield the title compound as a clear oil (60 mg).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:12]=[N:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C.O>[Br:29][C:8]1[S:9][C:10]2[N:11]=[CH:12][N:13]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:14](=[O:16])[C:15]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1c2c(-c3ccccc3)csc2ncn1CC(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(-c3ccccc3)c(Br)sc2ncn1CC(F)(F)F
Temperature: 80 °C
Yield: 91.6 %

Procedure:
A mixture of 5-phenyl-3-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4(3H)-one (0.4 g, 1.29 mmol) and NBS (0.459 g, 2.58 mmol) in DMF (5 ml) was heated at 80° C. for 2 h. The reaction mixture was diluted with water (40 ml) and extracted with DCM (3×25 ml). The combined organic phases were washed with water (3×45 ml) and brine (30 ml), dried and concentrated to give the title compound (0.46 g, 91%). LCMS RT=1.46 min, M+H+=390.9/392.9.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[N:26]=3)=[CH:21][CH:20]=2)[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[C:38]1([OH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O1CCOCC1>CN(C=O)C>[F:31][C:27]1[N:26]=[C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][N:3]3[C:2]([O:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[C:10]4[C:5]([N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7](=[O:13])[N:8]([CH3:12])[C:9]4=[O:11])=[N:4]3)=[CH:20][CH:21]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(-c4cccc(F)n4)cc3)nc21
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Oc3ccccc3)n(Cc3ccc(-c4cccc(F)n4)cc3)nc21
Temperature: 150 °C
Yield: 67.4 %

Procedure:
3-chloro-2-(4-(6-fluoropyridin-2-yl)benzyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (40 mg, 0.095 mmol), potassium carbonate (40 mg, 0.28 mmol) and phenol (26 mg, 0.28 mmol) are placed in a Biotage microwave vial, and then 0.4 mL of dioxane is added. The vial is sealed, and then heated in a Biotage microwave instrument at 150° C. for 3 h. The reaction mixture is diluted with DMF, and then filtered. The filtrate is purified with a semi-preparative HPLC to give 32 mg of pure product as pale yellow crystals (Purity: 99.9%). MS (ESI) m/z 500.2 [M+H]+.