Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[V:30]>C1(C)C(C)=CC=CC=1>[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[V+5:30].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[V+5:30]
Reactant: Oc1ccccc1O
Reactant: [V]
Agent: CC(=O)/C=C(/C)O
Solvent: Cc1ccccc1C
Product: [O-]c1ccccc1[O-]
Product: [V+5]
Temperature: 100 °C

Procedure:
A solution of catechol (3.30 g, 30 mmol) and xylene (45 ml) was dehydrated by distilling 5 mL of the solution. Thereafter, 6.97 g (20 mmol) of vanadium(III) acetylacetonate was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 132° C. or higher, distilled until the amount of the solution became half. After the distillation, solid content of the product was isolated by suction filtering using a membrane suction filter. The residual solid content was heated to 100° C. under vacuum using a vacuum dryer so that remaining volatile components were completely removed. The solid content (catechol-vanadium complex) was black in color. The yield amount was 4.26 g (20.0 mmol), and the yield percentage was 100%. Catechol-vanadium complex was dissolved into acetylacetone until saturated, and then filtered to be used as a coating liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[C@@H:10]([OH:27])[CH:11]=[C:12]([CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:13](OCC)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[H-].C([Al+2])C(C)C.[H-].ClCCl.C(O)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[C@@H:10]([OH:27])[CH:11]=[C:12]([CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)CCOC1CCCCO1
Agent: CC(C)C[Al+2]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C=C(CO)CCOC1CCCCO1
Temperature: -78 °C
Yield: 103.6 %

Procedure:
16 mg of ethyl (4S,5S)-5-tert-butoxycarbonylamino-4-hydroxy-2-[2-(2-tetrahydropyranyloxy)ethyl]-7-methyl-2-octenoate was dissolved in 0.5 ml of dichloromethane, and 13 μl of boron trifluoride ethyl ether complex was added thereto as -78° C. under stirring. The mixture was stirred for 30 minutes at the same temperature. Then, 75 μl of a 1.5M isobutyl aluminum hydride toluene solution was added to the mixture and further stirred for 45 minutes. 60 μl of a 5M acetic acid dichloromethane solution was added thereto at -78° C., and the reaction solution was raised to room temperature. 10 ml of 10% citric acid aqueous solution was added thereto and extracted with ethyl acetate. The extract was washed sequentially with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 15 mg of (4S,5S)-5-tert-butoxycarbonylamino-1,4-dihydroxy- 2-[2-(2-tetrahydropyranyloxy)ethyl]-7-methyl-2-octene as a colorless oily substance.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C@@H:10]1[C:15]([C:16]#[N:17])=[C:14]([CH3:18])[N:13]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:12](=[O:29])[N:11]1[CH3:30].[ClH:31].O.[N+]([O-])([O-])=O.[Na+].[S:38](=[O:40])=[O:39]>O.C(O)(=O)C.[Cu]Cl>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([C@@H:10]2[C:15]([C:16]#[N:17])=[C:14]([CH3:18])[N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[C:12](=[O:29])[N:11]2[CH3:30])=[C:2]([S:38]([Cl:31])(=[O:40])=[O:39])[CH:7]=1)#[N:9]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2N)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: Cl
Reactant: O=S=O
Agent: Cl[Cu]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Under argon, (4R)-4-(2-amino-4-cyanophenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (2.1 g, 5.1 mmol) was initially charged in a 2:1:1 mixture of acetic acid/conc. hydrochloric acid/water (50 ml in total) at −10° C. A solution of sodium nitrate (371 mg, 5.38 mmol) in water (2 ml) was then slowly added dropwise, and the mixture was stirred at from −10° C. to −5° C. for 40 min. This solution was then added to 45 ml of a sulfur dioxide-saturated suspension, cooled to −10° C., of copper(I) chloride (101.4 mg, 1.0 mmol) in glacial acetic acid (44 ml). The mixture was stirred at 0° C. for about 30 min and then at +15° C. for 1 h (reaction monitored by HPLC and LC-MS). The reaction mixture was then cooled to 0° C. and subsequently added to about 300 ml of ice-cold water using a pipette. The precipitate was filtered off and taken up in ethyl acetate (150 ml). The solution was washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound was obtained as a solid (2.13 g, 77% of theory, purity 92%) which was used without further purification in the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH2:10]([O:12][C:13](=[O:29])[CH2:14][C:15]([CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])=O)[CH3:11].[CH2:30]([O:32][C:33](=[O:38])/[CH:34]=[C:35](\[NH2:37])/[CH3:36])[CH3:31]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[C:34]([C:33]([O:32][CH2:30][CH3:31])=[O:38])=[C:35]([CH3:36])[NH:37][C:15]=1[CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])=[O:29])[CH3:11]
Reactant: CCOC(=O)CC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: O=Cc1cccc(Cl)c1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CN2C(=O)c3ccccc3C2=O)=C(C(=O)OCC)C1c1cccc(Cl)c1
Yield: 55 %

Procedure:
28 g of 3-chlorobenzaldehyde, 56 g of phthalimidoacetoacetic acid ethyl ester and 25.8 g of β-aminocrotonic acid ethyl ester in 250 ccs of ethanol are heated to the boil under reflux for 3×24 hours, the mixture is allowed to cool, whilst stirring, and, after filtering, light yellow crystals of melting point 135°-136° C. are obtained, yield: 55%.
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:10][CH:9]([CH2:11][OH:12])[CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].Cl.NC1C(CC2C=CC(Cl)=C(Cl)C=2)C2C=C(CN[S:36]([CH2:39]CC)(=[O:38])=[O:37])C=CC=2CC1>>[CH2:1]([S:4]([N:7]1[CH2:8][CH:9]([CH2:11][O:12][S:36]([CH3:39])(=[O:38])=[O:37])[CH2:10]1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)N1CC(CO)C1
Reactant: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N)CC2
Agent: Cl
Product: CCCS(=O)(=O)N1CC(COS(C)(=O)=O)C1

Procedure:
Prepared by standard procedure from [1-(propane-1-sulfonyl)-azetidin-3-yl]-methanol and methan-1-sulfonyl chloride (e.g. example 40)
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:6][CH2:5]1.[NH:27]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]([NH2:34])[CH2:28]1>>[NH2:34][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][N:27]([CH2:2][CH2:3][N:4]2[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[C:19]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:18]=[CH:17][CH:16]=4)=[O:12])[CH2:8][CH2:9]2)[CH2:28]1
Reactant: NC1CCCCNC1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCO)CC3)cc12
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCC(N)C4)CC3)cc12

Procedure:
This compound is synthesized analogously to example 150 from 4-isobutoxy-1H-indole-2-carboxylic acid [1-(2-hydroxy-ethyl)-piperidin-4-yl]-amide, 190 and azepan-3-ylamine.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2([C:32]([O:34]C(C)(C)C)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:21][CH2:20]1)=[O:16]>C(Cl)Cl.FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:10]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:15]([NH:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:25][C:26]2([C:32]([OH:34])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:23][CH2:24]1)=[O:16]
Reactant: CC(C)(C)OC(=O)C1(CN2CCC(CNC(=O)N3C(=O)C4(CCCC4)c4ccccc43)CC2)CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC1CCN(CC2(C(=O)O)CCOCC2)CC1)N1C(=O)C2(CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-{[4-({[(2′-oxospiro[cyclopentane-1,3′-indol]-1′(2′H)-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylate (2.3 g, 4.38 mmol, step 6 of Example 1) in CH2Cl2 (14 mL), trifluoroacetic acid (18 mL) was added at room temperature, and the mixture was stirred overnight at room temperature. The mixture was concentrated to give yellow oil, CH2Cl2 (200 mL) was added and washed with sat. NaHCO3 aq. (80 mL), dried over MgSO4, filtered and concentrated gave a syrup, which was chromatographed on a column of silica gel eluting with CH2Cl2/methanol (15:1) to give 2.1 g (quant.) of the title compound as white solid. Recrystallization from ethyl acetate/n-heptane gave white powder.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=C(C2C=CC=CC=2)C(C2C=CC=CC=2)=[N:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([C:50]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)=O)=O)=[CH:44][CH:43]=1>>[F:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[C:50]([C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)=[N:22][C:21]3[C:26](=[CH:27][CH:28]=[C:19]([C:8]4[N:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[C:11]5[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=5[N:9]=4)[CH:20]=3)[N:25]=2)=[CH:44][CH:43]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)c(-c4ccccc4)nc3c1)n2C1CCCCC1
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(F)cc4)c(-c4ccc(F)cc4)nc3c1)n2C1CCCCC1

Procedure:
Prepared as described for Compound 406 using 4,4′-difluorobenzil in place of benzil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH2:27]([OH:30])[CH2:28][CH3:29]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:30][CH2:27][CH2:28][CH3:29])[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: CCCO
Product: CCCOc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.19 mmol), intermediate 42.1, and propan-1-ol (60 μl; 0.789 mmol), example 43 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH2:7][S:8]([CH2:11][CH2:12]Cl)(=[O:10])=[O:9])(=[O:6])=[O:5].[N+](C1C=C(C=C([N+]([O-])=O)C=1)C(O)=O)([O-])=O.C(N(CC)CC)C>CC(C)=O>[CH:11]([S:8]([CH2:7][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])(=[O:10])=[O:9])=[CH2:12]
Reactant: O=S(=O)(CCCl)CS(=O)(=O)CCCl
Agent: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)CS(=O)(=O)C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a well stirred solution of 53.84 g of bis-(2-chloroethylsulfonyl)methane in 300 ml of acetone containing 0.9 g of 3,5-dinitrobenzoic acid, was added dropwise at 20°-25° C. a solution of 40.48 g of triethylamine in 50 ml of acetone containing 0.15 g of 3,5-dinitrobenzoic acid. The reaction was stirred for 1 hour at 25° C. then cooled to -30° C. and filtered to remove triethylamine hydrochloride. The filtrate was evaporated to dryness on a rotary evaporator at 40° C. and water aspirator pressure. The residue was recrystallized from methanol containing 0.3 percent (wt/vol) of 3,5-dinitrobenzoic acid, to give 29.3 g (75 percent) of colorless crystalline bis(vinylsulfonyl)methane of m.p. 59°-61° C. This material readily dissolved in water to give a 2 percent by weight solution with no insoluble material present.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[O:12][CH:13]=[N:14][N:15]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(O)C>[O:12]1[CH:13]=[N:14][N:15]=[C:11]1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH:2]([OH:1])[CH2:16][N:28]1[CH2:27][CH2:26][N:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH3:17])[CH2:30][CH2:29]1
Reactant: c1ccc(-c2nnco2)c(OCC2CO2)c1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(O)COc2ccccc2-c2nnco2)CC1

Procedure:
7.3 g (0.033 mole) of 2,3-epoxypropoxy-2-(1,3,4-oxadiazol-2-yl)-benzene from Example VII and 6.4 g (0.033 mole) of 2-methoxy-phenylpiperazine in 50 ml of ethanol are refluxed for 17 hours. The solvent is stripped off on a rotary evaporator and the oily residue is taken up in methylene chloride. The solution is washed with 3×50 ml of water, dried over anhydrous sodium sulfate, filtered and concentrated. 12.6 g (93% of theory) of a pale yellow oil are obtained.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11].[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1/[CH:25]=[CH:26]/[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=[O:31].[Cl-].[NH4+]>CCCCCC.O1CCCC1.CCOCC>[OH:31][CH:30]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])[C:29]1[CH:32]=[CH:33][CH:34]=[C:27](/[CH:26]=[CH:25]/[C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]=2)[CH:28]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: O=Cc1cccc(/C=C/c2ccc3ccccc3n2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1cccc(C(O)c2cccc(/C=C/c3ccc4ccccc4n3)c2)c1
Temperature: -100 °C
Reaction time: 0.08 h

Procedure:
2.5M n-Butyl lithium solution in hexane (2.6 ml) was added dropwise to a stirred solution of 3-bromobenzonitrile (1.2 g, 6.56 mmol) in tetrahydrofuran (20 ml) and ether (20 ml) at -100° to -110° C. under nitrogen. The yellow solution was stirred at -100° C. for 5 minutes, then a solution of 3-[2(E)-(quinolin-2-yl)ethenyl]benzaldehyde (1.7 g, 6.56 mmol) in tetrahydrofuran (7 ml) was added. The dark brown solution was allowed to warm to room temperature, poured onto saturated ammonium chloride solution and extracted with ethyl acetate. The extract was dried and evaporated and the residue was chromatographed on silica in ethyl acetate-hexane (1:2) to give a pale yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:34][C:35]1[CH:36]=[C:37]([CH2:41][NH2:42])[CH:38]=[CH:39][CH:40]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[C:37]([CH2:41][NH:42][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:38]=[CH:39][CH:40]=1
Reactant: NCc1cccc(Br)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(Br)c2)n1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
A mixture of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (600 mg, 1.326 mmol), 1-(3-bromophenyl)methanamine (247 mg, 1.326 mmol), HBTU (o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (603 mg, 1.591 mmol) and Et3N (0.924 mL, 6.63 mmol) in DCM was stirred at room temperature over the weekend. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give a crude residue. It was then purified with flash chromatography eluting with 0 to 100% ethyl acetate in hexane (product came out at 100% ethyl acetate in hexane). The product fractions were combined to give N-[(3-bromophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (632 mg, 49.9%). LC-MS m/z 620 (M+H)+, 0.89 min (ret time).
Reaction SMILES: [F:1][C:2]1[C:3](=[S:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C[O-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>CO>[CH2:15]([S:9][C:3]1[C:2]([F:1])=[CH:7][NH:6][C:5](=[O:8])[N:4]=1)[CH:14]=[CH2:13]
Reactant: O=c1[nH]cc(F)c(=S)[nH]1
Reactant: C=CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCSc1nc(=O)[nH]cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
This material was prepared by the procedure described in Tetrahedron 1985, 41, 5289-5293. To a solution of 5-fluoro-4-thioxo-3,4-dihydropyrimidin-2(1H)-one (12.4 g, 84.9 mmol) and sodium methoxide (4.54 g, 84.9 mmol) in MeOH (100 mL) was added dropwise allyl bromide (10.27 g, 84.9 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. After removal of solvent, the residue was purified by normal phase chromatography (gradient, 10 to 33% EtOAc/hexane), to give 4-(allylthio)-5-fluoropyrimidin-2(1H)-one (6 g, 38%) as a white solid: mp 150-152° C.; 1H NMR (301 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.00 (d, J=4.5 Hz, 1H), 5.90 (ddt, J=16.8, 10.0, 6.8 Hz, 1H), 5.34 (dd, J=16.9, 1.4 Hz, 1H), 5.15 (dd, J=10.0, 0.7 Hz, 1H), 3.83 (d, J=6.8 Hz, 2H); ESIMS m/z 187 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[O:3][C:4]2[CH:12]=[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:9][C:5]=2[C:6](=[O:8])[CH:7]=1.[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C>[OH:1][C:2]1[O:3][C:4]2[CH:12]=[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:9][C:5]=2[C:6](=[O:8])[C:7]=1[N+:25]([O-:27])=[O:26]
Reactant: CS(=O)(=O)Nc1cc2oc(O)cc(=O)c2cc1Oc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc2oc(O)c([N+](=O)[O-])c(=O)c2cc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 20.4 %

Procedure:
3.47 g of 2-hydroxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was suspended in 50 ml of acetic acid. Thereto was added 1.67 ml of concentrated nitric acid (specific gravity: 1.38). The mixture was stirred for 20 minutes at 100°-110° C. The reaction mixture was introduced into 300 ml of ice water. The resulting crystal was collected by filtration, washed with water, and recrystallized from acetonitrile to obtain 800 mg (yield: 20.4%) of 2-hydroxy-7-methylsulfonylamino-3-nitro-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 228°-230° C. (decomposed).
Reaction SMILES: C(OC([NH:11][C@:12]1([C:36]([O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])=[O:37])[CH2:21][C:20]2[C:19]([O:22][C:23]3([CH:35]=[CH:34][CH:33]=[N:32][CH2:31]3)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:14][CH2:13]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@:12]1([C:36]([O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])=[O:37])[CH2:21][C:20]2[C:19]([O:22][C:23]3([CH:35]=[CH:34][CH:33]=[N:32][CH2:31]3)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)C1(Oc2cccc3c2C[C@](NC(=O)OCc2ccccc2)(C(=O)OCC[Si](C)(C)C)CC3)C=CC=NC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(Oc2cccc3c2C[C@](N)(C(=O)OCC[Si](C)(C)C)CC3)C=CC=NC1
Yield: 81.3 %

Procedure:
A solution of 298 mg (0.48 mmol) of tert.-butyl 3-[(S)-7-benzyloxycarbonylamino-7-trimethylsilylethoxycarbonyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy]nicotinate in 5 ml of ethanol was hydrogenated under a hydrogen atmosphere with 80 mg of palladium-charcoal (10%) at room temperature for 1 hour, whereupon the mixture was filtered over Hyflo and the filtrate was concentrated. The residue was dried in a high vacuum and chromatographed on 50 g of silica gel with chloroform/methanol (95:5), whereupon 190 mg (81.7%) of tert.-butyl 3-[(S)-7-amino-7-trimethylsilylethoxycarbonyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinate were obtained. MS (ISP): 485.5 (M+. +H+, 50), 429 (15), 401.3 (100).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([OH:3])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:53][C:54](=[O:67])[C@H:55]([OH:66])[C@H:56]([NH2:65])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[Cl:64])[CH2:50][CH2:51][CH3:52]>C(Cl)Cl>[CH2:49]([O:53][C:54]([C@H:55]([OH:66])[C@H:56]([NH:65][C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:3])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[Cl:64])=[O:67])[CH2:50][CH2:51][CH3:52]
Reactant: CCCCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1Cl
Reactant: O=C(O)CCCc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCOC(=O)[C@H](O)[C@@H](Cc1ccccc1Cl)NC(=O)CCCc1ccccc1C(=O)O
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
2-(3-Carboxy-propyl)benzoic acid (335 mg, 1.6 mmol, 1.0 eq.) was combined with DIPEA (897 μL, 3.2 eq.) and HATU (0.612 g, 1.61 mmol, 1.0 eq.) in DCM (40 mL). The resulting mixture was stirred for 10 minutes and (2R,3R)-3-amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid butyl ester (HCl salt, 519 mg, 1.6 mmol, 1.0 eq.) was added. The reaction was quenched after 1 hour by adding saturated NH4Cl and the product was extracted with DCM, dried and evaporated. The product was dissolved into AcOH (5 mL) and purified using preparative HPLC. The clean fractions were combined and lyophilized to yield 2-{3-[(1R,2R)-2-butoxycarbonyl-1-(2-chloro-benzyl)-2-hydroxy-ethylcarbamoyl]-propyl}-benzoic acid (150 mg).