Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[C:13]([N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:25])[CH:21]=3)[N:16]=[C:15]2[CH:26]=CN(C)C)=[CH:12][CH:11]=[CH:10][N:9]=1>O1CCCC1>[Cl:7][C:8]1[C:13]([N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:25])[CH:21]=3)[N:16]=[C:15]2[CH:26]=[O:2])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN(C)C=Cc1nc2ccc(F)cc2c(=O)n1-c1cccnc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1nc2ccc(F)cc2c(=O)n1-c1cccnc1Cl
Reaction time: 1 h
Yield: 98 %

Procedure:
To a mixture of sodium periodate (1.9 g, 8.7 mmol) in tetrahydrofuran (10 mL) and aqueous pH 7 buffer (15 mL) was added 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-(2-dimethylamino-vinyl)-3,4-dihydro-quinazolin-4-one (1.0 g, 2.90 mmol) all at once. The reaction was stirred for 1 hour. The precipitate was collected, washed well with water and dried under a nitrogen stream to afford 0.863 g (92%) of 3-(2-chloro-pyridin-3-y)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde as a yellow solid which was about a 25:1 mixture of hydrate to free aldehyde. The product was characterized as follows: mp 160-164° C.; 1H NMR (DMSOd6) δ (hydrate) 8.51 (dd, J=2, 5 Hz, 1H), 8.08 (dd, J=2, 8 Hz, 1H), 7.87-7.78 (m, 3H), 7.60 (dd, J=5, 8 Hz, 1H), 6.64 [ABq, Dn1-3=18 Hz, J=7 Hz, 2H (hydrate OHs], 5.27 [br s 1H (hydrate methine CH]. Addition of D2O to the NMR sample caused the multiplet at 6.64 ppm to disappear and sharpened up the singlet at 5.27 ppm. The presence of free aldehyde was demonstrated by a minor singlet at 9.51 ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31]([NH:33][CH2:34][C:35]#[CH:36])=[O:32])([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.C(O)(C)(C)C.[N:42]([C:45]1[C:53]([F:54])=[C:52]([F:55])[C:48]([C:49]([OH:51])=[O:50])=[C:47]([F:56])[C:46]=1[F:57])=[N+:43]=[N-:44].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O>[F:55][C:52]1[C:53]([F:54])=[C:45]([N:42]2[CH:36]=[C:35]([CH2:34][NH:33][C:31]([NH:30][C@@:15]([C:4]3[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=[C:2]([F:1])[CH:3]=3)([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:32])[N:44]=[N:43]2)[C:46]([F:57])=[C:47]([F:56])[C:48]=1[C:49]([OH:51])=[O:50]
Reactant: C#CCNC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: [N-]=[N+]=Nc1c(F)c(F)c(C(=O)O)c(F)c1F
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(NCc1cn(-c2c(F)c(F)c(C(=O)O)c(F)c2F)nn1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a suspension of (R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(prop-2-ynyl)urea (5.0 mg, 0.01 mmol), prepared as described in Procedure 3, 4, 5, 6 and 12, in a 1:1 mixture of water and tert-butyl alcohol (100 μl) was added 4-azido-2,3,5,6-tetrafluorobenzoic acid (2.3 mg, 0.01 mmol), followed by sodium ascorbate (1 M solution in H2O, 100 μL) and CuSO4.5H2O (1 mg). The reaction mixture was stirred vigorously overnight in a sealed vial. The reaction mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic portions were concentrated and the residue was dissolved in MeOH and purified by preparative HPLC (Phenoma Onyx Monolithic 10×100 mm; eluting with 10%-90% MeCN/H2O with 0.1% TFA, monitoring at 220 nm) to provide (R)-2,3,5,6-tetrafluoro-4-(4-((3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)methyl)-1H-1,2,3-triazol-1-yl)benzoic acid (Example 319, 5.7 mg, 78% yield). LC/MS: RT=3.610 min [M+H] 742.3 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm). 1H NMR (500 MHz, MeOH-d4) δ 8.02 (s, 1H), 7.10-6.79 (m, 11H), 6.53 (d, J=5 Hz, 2H), 6.27-6.04 (m, 1H), 4.38-4.31 (m, 2H), 3.81 (d, J=15 Hz, 1H), 3.73 (d, J=10 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([C:14](=[O:32])[NH:15][CH2:16][CH2:17][C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:21]=[N:20][CH:19]=2)[CH2:11][C@H:10]([C:33]([O:35][CH3:36])=[O:34])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:36][O:35][C:33]([C@H:10]1[CH2:11][C@@H:12]([C:14](=[O:32])[NH:15][CH2:16][CH2:17][C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:21]=[N:20][CH:19]=2)[CH2:13][NH:8][CH2:9]1)=[O:34]
Reactant: COC(=O)[C@H]1C[C@@H](C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CNC[C@H](C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(t-Butoxycarbonyl)-cis-3-methoxycarbonyl-5-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine (1.14 g, 2.30 mmol) was dissolved in CH2Cl2 (12 mL). Trifluoroacetic acid (6 mL) was added and the solution was stirred at ambient temperature for 3 h. The solution was concentrated to dryness to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CC1C2C(=CC=CC=2)C=CC=1.[C-]#N.[Na+].[N:28]1C=CC(C)=C[CH:29]=1>[Cu]I.O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:29]#[N:28])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: Cc1ccncc1
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: Cc1cccc2ccccc12
Solvent: O
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C

Procedure:
A 100-mL, three-necked flask equipped with a mechanical stirrer, thermometer and condenser was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (5.0 g, 0.020 mol, 99.1% purity) and 1-methylnaphthalene (20 g) while maintaining a flow of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature, and powdered sodium cyanide (powdered just prior to use) (1.25 g, 0.024 mol, assuming 95% purity), copper(I) iodide (0.57 g, 0.0030 mol) and 4-picoline (1.60 g, 0.017 mol) were added. The mixture was heated at 158 to 162° C. for 6 h, and then transferred to a 200-mL flask and allowed to cool overnight. Water (20 mL) was added dropwise to the reaction mixture over 5 minutes while stirring. After stirring for an additional 2 h, the reaction mixture was filtered, and the solid collected was washed with water (3×10 mL) and xylenes (10 mL), and then dried to a constant weight in a vacuum-oven at 50° C. to give the title compound as a light brown solid (2.8 g).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10](Cl)[CH:9]=2)[C:3]=1[C:15]([NH2:17])=O.FC(F)[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][C:22]=1O>CCO.N1CCCCC1>[C:3]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:4]2[NH:5][N:6]=[C:2]([N:1]=[CH:25][C:24]3[CH:27]=[CH:28][C:21]([OH:20])=[CH:22][CH:23]=3)[C:3]=2[C:15]#[N:17])=[CH:9][CH:10]=1)([CH3:15])([CH3:4])[CH3:2]
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)c1ccc(Nc2[nH]nc(N=Cc3ccc(O)cc3)c2C#N)cc1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and 4-(difluoromethoxy)-3-hydroxybenzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([CH2:11][OH:12])[CH:9]=[CH2:10].C(N(CC)CC)C.[CH3:20][C:21](OC(C)=O)=[O:22]>CN(C1C=CN=CC=1)C.CCOCC>[C:21]([O:12][CH2:11][C:3]1([CH:9]=[CH2:10])[CH2:4][CH2:5][C:6]([CH3:8])=[CH:7][CH:2]1[CH3:1])(=[O:22])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: C=CC1(CO)CCC(C)=CC1C
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC1(COC(C)=O)CCC(C)=CC1C
Reaction time: 5 h
Yield: 86.7 %

Procedure:
To a solution of (2,4-dimethyl-1-vinylcyclohex-3-enyl)methanol (3.50 g, 21.1 mmol), triethylamine (3.83 g, 38 mmol) and a catalytic amount of DMAP in Et2O (30 ml) was added Ac2O (3.22 g, 31.6 mmol). The mixture was stirred for 5 h, poured on water and extracted with Et2O. The combined organic layers were washed with water and brine, dried and evaporated in vacuo. The residue was distilled bulb-to-bulb to yield (2,4-dimethyl-1-vinylcyclohex-3-enyl)methyl acetate (3.81 g, 86%) as a colorless oil.
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11](S(C)=O)=[N:12][CH:13]=[C:8]2[CH2:7][NH:6][C:5]1=[O:17])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.FC(F)(F)C(O)=O>C(#N)C>[CH:1]([N:4]1[C:9]2=[N:10][C:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[CH:23][CH:24]=3)=[N:12][CH:13]=[C:8]2[CH2:7][NH:6][C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CC(C)N1C(=O)NCc2cnc(S(C)=O)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)N1C(=O)NCc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Temperature: 85 °C
Yield: 78.5 %

Procedure:
Prepared from 400 mg (1.57 mmol) of 1-isopropyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, 600 mg (3.14 mmol) of 1-(4-aminophenyl)-4-methylpiperazine and 605 μL (7.85 mmol) of trifluoroacetic acid in 6.4 mL of acetonitrile. The reaction mixture is heated at 85° C. for 48 hours. After the workup, the crude residue is triturated in ethyl acetate/dichloromethane and filtered. The solids are redissolved in dichloromethane, and the solvent is evaporated under a flow of nitrogen while ethyl acetate is added to maintain a volume of 5 mL. The suspension is filtered, and the solids are washed with ethyl acetate/dichloromethane, and dried to give 470 mg (78%) of the title compound:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:10]=3[C:9]=2[C:19]([OH:21])=O)=[CH:4][CH:3]=1.C1C=[N:26][C:25]2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.CN.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:10]=3[C:9]=2[C:19]([NH:26][CH3:25])=[O:21])=[CH:4][CH:3]=1
Reactant: On1nnc2cccnc21
Reactant: COc1ccc2sc(-c3ccc(F)cc3)c(C(=O)O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(OC)cc12
Temperature: 25 °C

Procedure:
To a solution containing 2-(4-fluorophenyl)-5-methoxybenzo[b]thiophene-3-carboxylic acid (0.57 g, 1.9 mmol), HOAT (0.28 g, 2.1 mmol), diisopropylethylamine (2.3 mL, 13.2 mmol), methylamine hydrochloride (0.20 g, 2.8 mmol) and dichloromethane (20 mL) was added EDCI (0.51 g, 13.2 mmol). The solution was maintained at room temperature for 6 h, diluted with additional DCM (20 mL), washed with water (20 mL), washed with aqueous HCl (2×20 mL, 0.1 N), dried over MgSO4, filtered and concentrated to afford 2-(4-fluorophenyl)-5-methoxy-N-methylbenzo[b]thiophene-3-carboxamide which was used without further purification. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.30 (d, J=4.27 Hz, 1H), 7.90 (d, J=8.85 Hz, 1H), 7.60 (dd, J=8.70, 5.34 Hz, 2H), 7.34 (t, J=8.85 Hz, 2H), 7.16 (d, J=2.14 Hz, 1H), 7.07 (dd, J=8.85, 2.44 Hz, 1H), 3.81 (s, 3H), 2.74 (d, J=4.58 Hz, 3H). LCMS: retention time: 2.513 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 316 (MH+).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH3:5][N:6]([CH3:30])[CH:7]([CH2:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:8]=O.C([BH3-])#N.[Na+].O>CO>[NH2:3][CH2:2][CH2:1][NH:4][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([OH:17])[C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][CH:7]([N:6]([CH3:30])[CH3:5])[CH3:8]
Reactant: NCCN
Reactant: CCCCC(=O)C(CC(C=O)N(C)C)(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(CC(c1ccccc1)(c1ccccc1)C(O)CCCCNCCN)N(C)C
Temperature: 25 °C

Procedure:
Ethylenediamine was added to a solution of 2-dimethylamino-4,4-diphenyl-5-oxononanal (12 mg), as prepared in Example 1, in methanol (0.5 ml). After the mixture was stirred at room temperature, sodium cyanoborohydride (10 mg) was added. The mixture was stirred at room temperature for 18 hours, water was added, and the aqueous mixture was extracted with chloroform. The combined extracts were washed with brine and dried (MgSO4). Rotary evaporation gave a crude product which was further dried in vacuo to yield 4 mg of N-(2-aminoethyl)-8-dimethylamino-6,6-diphenyl-5-hydroxynonylamine.
Reaction SMILES: C([N:3](CC)CC)C.[F:8][C:9]1[CH:10]=[C:11]([S:16][C:17]2C=[C:19]3[C:25]([NH:26][C:27](=[O:59])[C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:38][CH2:37][C@H:36]([NH:39]C(=O)C(F)(F)F)[CH2:35]5)=[CH:30][C:29]=4[N:46]([CH:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)C(=O)C(F)(F)F)=[N:24][NH:23][C:20]3=[N:21][CH:22]=2)[CH:12]=[C:13]([F:15])[CH:14]=1.C(O)CCC.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:39][C@H:36]1[CH2:37][CH2:38][N:34]([C:31]2[CH:32]=[CH:33][C:28]([C:27]([NH:26][C:25]3[C:19]4[C:20](=[N:21][CH:22]=[C:17]([S:16][C:11]5[CH:10]=[C:9]([F:8])[CH:14]=[C:13]([F:15])[CH:12]=5)[N:3]=4)[NH:23][N:24]=3)=[O:59])=[C:29]([NH:46][CH:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[CH:30]=2)[CH2:35]1
Reactant: O=C(Nc1n[nH]c2ncc(Sc3cc(F)cc(F)c3)cc12)c1ccc(N2CC[C@H](NC(=O)C(F)(F)F)C2)cc1N(C(=O)C(F)(F)F)C1CCOCC1
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: CO
Product: N[C@H]1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(Sc5cc(F)cc(F)c5)nc34)c(NC3CCOCC3)c2)C1
Temperature: 65 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
876 μl (20 eq) of triethylamine is added to a solution of 238 mg (0.314 mmol) of (S)—N-(5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)-4-(3-(2,2,2-trifluoroacetamido)pyrrolidin-1-yl)benzamide in 6 ml of methanol. The reaction medium is stirred at 65° C. for 4 hours. After returning to room temperature, 8 ml of n-butanol and 260 mg (6 eq) of potassium carbonate are added. The reaction medium is stirred at 80° C. for 24 hours. After returning to room temperature, the solvents are evaporated, water is added and the product is extracted with dichloromethane. The organic phase is washed with saturated sodium chloride solution, dried on magnesium sulfate, filtered and evaporated. The residue is purified by silica gel chromatography (8:2 dichloromethane/methanol as eluent) to yield 87 mg (yield=49%) of (S)-4-(3-aminopyrrolidin-1-yl)-N-(5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyrazine-3-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in the form of a brown powder.
Reaction SMILES: [OH:1][P:2]([CH2:20][CH:21]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:22]([NH:24][C@H:25]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])([CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:50](O)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>O1CCCC1>[C:6]1([CH2:5][CH:4]([P:2]([CH2:20][CH:21]([CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:22]([NH:24][C@H:25]([C:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:23])([O:1][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:3])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)P(=O)(O)CC(Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)P(=O)(CC(Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
Phenylmethyl N-[2-[[hydroxy[2-phenyl-1-[[(tert-butoxy)carbonyl]amino]ethyl]phosphinyl]methyl]-1-oxo-3-phenylpropyl]-L-phenylalaninate is treated with benzyl alcohol (1.1 eq.) in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine in tetrahydrofuran. After stirring overnight at room temperature, the mixture is filtered and then evaporated to dryness. The residue is taken up in ethyl acetate. This solution is washed 3 times with water, dried over sodium sulphate and then evaporated to dryness. The product is purified by chromatography on silica gel, eluting with a 1/9 dichloromethane/methanol mixture. The product is recovered in a yield of 60%.
Reaction SMILES: [CH2:1]([Zn]CC)C.ICI.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH:20]=[C:19]([CH2:22][OH:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[Cl-].[NH4+]>ClCCl>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][C:19]2([CH2:22][OH:23])[CH:20]([CH2:1]2)[CH2:21]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC[Zn]CC
Reactant: CC(C)(C)OC(=O)N1CC=C(CO)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CO)CC2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under ice-cooling, 15.3 ml of diethylzinc and 6.7 g of diiodomethane were added to 130 ml of dichloromethane. After further adding a solution of 1.07 g of 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-methanol in dichloromethane (20 ml), the resulting mixture was stirred at room temperature overnight. Then the reaction mixture was poured into saturated ammonium chloride, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate followed by filtration. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 90 mg of the title compound as a colorless oily substance.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[O:12][CH3:13])=[O:4].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C=O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:18]2[C:17](=[O:19])[C:16]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]3[C:14]2=[O:24])=[C:6]([O:12][CH3:13])[CH:7]=1
Reactant: COc1cc(Br)ccc1C(=O)CBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1C(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.9 %

Procedure:
A solution of compound 6d (43.5 g) in anhydrous DMF (150 mL) was cooled to 5° C. To this solution was added potassium phthalimide (26.1 g, 141 mmol). After 5 min the cooling bath was removed and the reaction was allowed to stir at RT for 3 hr. The solvent was evaporated under vacuum to provide a tan solid. The solid was rinsed with 4:1 DCM/methanol and then water. The filter cake was slurried in toluene and evaporated to dryness to afford 4′-bromo-2′-methoxy-2-(phthalimido)acetophenone (compound 6e, 39 g) as a tan solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C.[Li]CCCC.[Na+].[Cl-]>C1COCC1>[CH3:24][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([B:25]([OH:30])[OH:26])[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(B(O)O)c2)n1
Reaction time: 0.75 h
Yield: 120.5 %

Procedure:
To a solution of 2-(3-bromo-phenyl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.21) (4.00 g, 10.2 mmol) and triisopropyl borate (2.23 g, 11.8 mmol) in THF (60 mL) at −78° C. was added n-BuLi (1.6 M in hexane, 6.50 mL, 10.4 mmol) keeping the internal temperature below −65° C. Stirring was continued at −78° C. for 45 min, again triisopropyl borate (1.11 g, 5.9 mmol) and n-BuLi (1.6 M in hexane, 3.25 mL, 5.2 mmol) were added and stirring was continued at −78° C. for 30 min. A 1 M aqueous solution of NaH2PO4.2H2O was added, saturated with solid NaCl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuum to give the title compound as a yellow solid (4.39 g, 96%). MS (ISP) 358.2 [(M+H)+]; mp 140° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18](S(C)(=O)=O)=[N:19][CH:20]=2)[N:15]([CH3:27])[C:14]1=[O:28].[CH3:29][C:30]1[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[C:31]=1[NH2:32].C([O-])(C)(C)C.[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([NH:32][C:31]3[C:33]([N+:37]([O-:39])=[O:38])=[CH:34][CH:35]=[CH:36][C:30]=3[CH3:29])=[N:19][CH:20]=2)[N:15]([CH3:27])[C:14]1=[O:28]
Reactant: Cc1cccc([N+](=O)[O-])c1N
Reactant: COc1cc(OC)c(Cl)c(N2Cc3cnc(S(C)(=O)=O)nc3N(C)C2=O)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c(Cl)c(N2Cc3cnc(Nc4c(C)cccc4[N+](=O)[O-])nc3N(C)C2=O)c1Cl
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a mixture of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-7-(methylsulfonyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (450 mg, 1.01 mmol) and 2-methyl-6-nitroaniline (230 mg, 1.51 mmol) in 5 mL of N,N-dimethylformamide was added potassium tert-butanolate (339 mg, 3.02 mmol) at RT and stirred for 0.5 h. LCMS showed the reaction was completed. The mixture was quenched by 80 mL of water, and the precipitate was collected via the filtration and dried to give the title compound (290 mg, 56%) as a yellow solid, which was directly used in the next step without further purification. MS (ES+) C22H20Cl2N6O5 requires: 518, 520. Found: 519, 521 [M+H]+.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Cl[CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1.O>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=1
Reactant: Ic1cn[nH]c1
Reactant: CCOC(=O)CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)Cn1cc(I)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (6 g, 250 mmol, 60 wt % in mineral oil) was added to mixture of 4-iodo-1H-pyrazole (10 g, 50 mmol) in THF (200 mL) at room temperature under N2. The mixture was stirred at room temperature for 1 hour. Ethyl 4-chloro-3-oxobutanoate (11.6 g, 75 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: EtOAc) to afford ethyl 4-(4-iodo-1H-pyrazol-1-yl)-3-oxobutanoate. MS ESI calc'd. for C9H12IN2O3 [M+H]+ 323. found 323. 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.48 (s, 1H), 5.05 (s, 2H), 4.19-4.15 (m, 2H), 3.40 (s, 2H), 1.28-1.24 (m, 3H).